Overview of Gestational Diabetes

**3**

**Chapter 1**

*Amita Ray*

**1. The condition**

Diabetes Mellitus

under the stress giving rise to a disease state [1].

diabetes, and GDM during a previous pregnancy [2].

metabolism or even a gross metabolic dysregulation [2].

**2. The magnitude of the problem**

Introductory Chapter: Gestational

Pregnancy, though a physiological condition, involves increased stress on a mother's biological processes. Advanced age, frequent pregnancies with shortened intervals, and several other risk factors may cause one of these processes to buckle

Gestational diabetes is a typical example which occurs as a temporary condition during pregnancy and is characterized by hyperglycemia and its varied manifestations. The word "gestational" implies exaggerated physiological response in pregnancy. Pregnancy is a state of insulin resistance, which has been designed by nature with the aim to supply the fetus with adequate nutrition at all times, irrespective of the mother's feeding cycles or habits. When this resistance, which is a physiological response to pregnancy, becomes aggravated and overcomes the pancreas capacity to secrete extra insulin, the result is a constant state of hyperglycemia. Risk factors and risk markers for GDM are age (the older a woman the higher her risk of GDM), overweight or obesity, excessive weight gain during pregnancy, a family history of

Human placental lactogen and prolactin, the levels of which steadily increase during pregnancy, also contribute to the phenomena of increased insulin resistance by preventing the intake of insulin into peripheral tissue. A lesser explored hormone adiponectin exerts a protective effect by inhibiting hepatic glucose production. In GDM pregnancies, there is a significant decrease in placental adiponectin from an early stage of pregnancy, which now appears to be another independent risk factor for GDM. Adiponectin levels are also affected by pro-inflammatory cytokines, thus indicating a relationship between inflammation and carbohydrate

According to the International Diabetes Federation (2017), 21.3 million or 16.2% of live births had some form of hyperglycemia in pregnancy, and a majority of these (85.1%) were due to gestational diabetes and one out of seven births is affected by gestational diabetes. The WHO Global Report on diabetes (2016) also gives similar figures: 75–90% of cases of hyperglycemia in pregnancy are due to gestational diabetes and 10–25% of pregnancies are affected by gestational diabetes. To complicate matters, a maximum number of these cases are from the low- and middle-income countries emphasizing the fact that diabetes per se as well as gestational diabetes are not the diseases of the affluent society who have access to quality health care [3]. A large number of these cases are from those sections of the population who do have

#### **Chapter 1**

## Introductory Chapter: Gestational Diabetes Mellitus

*Amita Ray*

#### **1. The condition**

Pregnancy, though a physiological condition, involves increased stress on a mother's biological processes. Advanced age, frequent pregnancies with shortened intervals, and several other risk factors may cause one of these processes to buckle under the stress giving rise to a disease state [1].

Gestational diabetes is a typical example which occurs as a temporary condition during pregnancy and is characterized by hyperglycemia and its varied manifestations. The word "gestational" implies exaggerated physiological response in pregnancy. Pregnancy is a state of insulin resistance, which has been designed by nature with the aim to supply the fetus with adequate nutrition at all times, irrespective of the mother's feeding cycles or habits. When this resistance, which is a physiological response to pregnancy, becomes aggravated and overcomes the pancreas capacity to secrete extra insulin, the result is a constant state of hyperglycemia. Risk factors and risk markers for GDM are age (the older a woman the higher her risk of GDM), overweight or obesity, excessive weight gain during pregnancy, a family history of diabetes, and GDM during a previous pregnancy [2].

Human placental lactogen and prolactin, the levels of which steadily increase during pregnancy, also contribute to the phenomena of increased insulin resistance by preventing the intake of insulin into peripheral tissue. A lesser explored hormone adiponectin exerts a protective effect by inhibiting hepatic glucose production. In GDM pregnancies, there is a significant decrease in placental adiponectin from an early stage of pregnancy, which now appears to be another independent risk factor for GDM. Adiponectin levels are also affected by pro-inflammatory cytokines, thus indicating a relationship between inflammation and carbohydrate metabolism or even a gross metabolic dysregulation [2].

#### **2. The magnitude of the problem**

According to the International Diabetes Federation (2017), 21.3 million or 16.2% of live births had some form of hyperglycemia in pregnancy, and a majority of these (85.1%) were due to gestational diabetes and one out of seven births is affected by gestational diabetes. The WHO Global Report on diabetes (2016) also gives similar figures: 75–90% of cases of hyperglycemia in pregnancy are due to gestational diabetes and 10–25% of pregnancies are affected by gestational diabetes. To complicate matters, a maximum number of these cases are from the low- and middle-income countries emphasizing the fact that diabetes per se as well as gestational diabetes are not the diseases of the affluent society who have access to quality health care [3]. A large number of these cases are from those sections of the population who do have access to basic antenatal care, where missing gestational diabetes is common and associated with grim outcomes for the mother and baby.

#### **3. Maternal and fetal complications**

Undetected, unmonitored, and uncontrolled gestational diabetes leads to severe maternal and fetal morbidity and mortality. GDM has a spectrum of both shortand long-term complications for both the mother and the fetus [4].

Among the short-term complications, are those that happen in the index pregnancy, hypertension is often associated with type 2 diabetes and so is true for GDM. Women who have GDM often develop hypertension during pregnancy and when compared to women who are euglycemic during pregnancy the difference is significant. Pregnancy-induced hypertension leads to several other problems in terms of preeclampsia and even eclampsia.

Several reasons for short-term morbidity in the mother are related to the increased size of the fetus. Nonprogress of labor and cephalopelvic disproportion due to a large-sized baby may lead to instrumental deliveries, perineal injuries, and C-sections.

For the fetus, the hallmark complication of GDM is macrosomia and the problems resulting from it. These could be sudden fetal demise, shoulder dystocia, obstructed labor, hydramnios, malpresentations, and cord prolapse. Macrosomia also leads to earlier onset of labor, giving rise to a preterm baby with all the associated risks of prematurity. The chief among these is the respiratory distress syndrome (RDS) due to lack of surfactant: this is a combined effect of prematurity as well as the fact that hyperglycemia per se also delays lung maturity.

The baby of a GDM mother has more chances of admission to intensive care due to RDS and also because it is more prone to metabolic derangements which are typical of this condition. Hypoglycemia, hyperbilirubinemia, and hypomagnesemia are significantly more in babies of GDM mothers.

When considering long-term complications of GDM recurrence of GDM in subsequent pregnancies and the development of type 2 diabetes in later life are the ones of major concern. A GDM mother has about 30–60% chance of recurrence in subsequent pregnancies. A systematic review of 28 studies covering the same number of years showed that a GDM mother has a cumulative incidence ranging from 2.6 to 70% of type 2 diabetes. Recurrence of GDM in subsequent pregnancies and the development of type 2 diabetes in later life are linked to risk factors like obesity, interval between pregnancies, and the amount of insulin needed during the index pregnancy.

Long-term complications in the neonate of a GDM mother are obesity and type 2 diabetes in adult life. The girl child also runs the risk of GDM in her pregnancy.

#### **4. The controversies**

Screening and diagnosis of gestational diabetes is varied and till date a single universal guideline has been elusive. This is compounded by the fact that both gestational diabetes and type 2 diabetes are very dependent on ethnicity. This often leads to the question as to whether a single mathematical figure would actually reflect hyperglycemia and its complications in different ethnic groups.

International and national bodies advise various ways to screen gestational diabetes. Large numbers of such guidelines confuse the primary health provider and the practicing obstetrician. In this era of evidence-based medicine, there is need

**5**

*Introductory Chapter: Gestational Diabetes Mellitus DOI: http://dx.doi.org/10.5772/intechopen.86855*

different countries and ethnic groups.

the condition are also in the process.

**5. Recent advances**

**6. The way ahead**

society about this epidemic.

should make allowance for both [5, 6].

ered as the disease of the elite society.

for a single robust, evidence, practical guideline, the use of which would ensure the early detection and adequate management of gestational diabetes at the earliest in

Although screening for GDM remains the mainstay for early detection, biomarkers for predicting, and monitoring the condition have also been identified. These biomarkers are altered as a result of the underlying pathology of GDM and thus help in predicting the condition before it actually becomes manifest clinically. These biomarkers may be related to insulin resistance, chronic inflammation, and altered placental function all of which are related to the patho-physiology of GDM. Micro-RNAs, one such group of biomarkers are a class of RNAs which are not involved in coding but can modulate gene expression. Thus, particular levels of

Efforts are also being made to combine several biomarkers to form a risk score for prediction of GDM. Combining clinical risk factors and biomarkers to predict

Gestational diabetes mellitus has a well-documented link with maternal age, family history, diet, obesity, and lack of exercise. Both ethnicity and deprivation are major contributors to an increased risk of GDM. Research has confirmed that a better diet, increased physical activity, an appropriate pre-pregnancy Body Mass Index could reduce the development of gestational diabetes mellitus. The challenge now is to find ways of delivering these benefits in real life rather than in purely research settings. Keeping these things in mind, the first aim should be primary prevention. It plays the most significant role in creating awareness as regards gestational diabetes among public. Awareness should particularly target the groups which are at high risk for developing diabetes. Primary steps in preventing gestational diabetes can delay or halt further developments which in turn reduce both the need for gestational diabetes care and other required treatments. Prevention of gestational diabetes and diabetes per se should be considered a public health priority. The biggest task faced by the medical fraternity is lack of awareness across all segments of

A uniform consensus on how to screen for and diagnose gestational diabetes is another focus area for national and international bodies. As both ethnicity and deprivation are major contributors to this disease condition, the guidelines framed

Another area that needs looking into is the identification of markers which could predict the condition with reasonable accuracy. It is also essential that such markers be cost-effective as both diabetes and gestational diabetes can no longer be consid-

circulating micro-RNAs can be used as biomarkers to predict GDM.

for a single robust, evidence, practical guideline, the use of which would ensure the early detection and adequate management of gestational diabetes at the earliest in different countries and ethnic groups.

#### **5. Recent advances**

*Gestational Diabetes Mellitus - An Overview with Some Recent Advances*

and long-term complications for both the mother and the fetus [4].

well as the fact that hyperglycemia per se also delays lung maturity.

are significantly more in babies of GDM mothers.

associated with grim outcomes for the mother and baby.

**3. Maternal and fetal complications**

terms of preeclampsia and even eclampsia.

C-sections.

index pregnancy.

**4. The controversies**

access to basic antenatal care, where missing gestational diabetes is common and

Undetected, unmonitored, and uncontrolled gestational diabetes leads to severe maternal and fetal morbidity and mortality. GDM has a spectrum of both short-

Among the short-term complications, are those that happen in the index pregnancy, hypertension is often associated with type 2 diabetes and so is true for GDM. Women who have GDM often develop hypertension during pregnancy and when compared to women who are euglycemic during pregnancy the difference is significant. Pregnancy-induced hypertension leads to several other problems in

Several reasons for short-term morbidity in the mother are related to the increased size of the fetus. Nonprogress of labor and cephalopelvic disproportion due to a large-sized baby may lead to instrumental deliveries, perineal injuries, and

For the fetus, the hallmark complication of GDM is macrosomia and the problems resulting from it. These could be sudden fetal demise, shoulder dystocia, obstructed labor, hydramnios, malpresentations, and cord prolapse. Macrosomia also leads to earlier onset of labor, giving rise to a preterm baby with all the associated risks of prematurity. The chief among these is the respiratory distress syndrome (RDS) due to lack of surfactant: this is a combined effect of prematurity as

The baby of a GDM mother has more chances of admission to intensive care due to RDS and also because it is more prone to metabolic derangements which are typical of this condition. Hypoglycemia, hyperbilirubinemia, and hypomagnesemia

When considering long-term complications of GDM recurrence of GDM in subsequent pregnancies and the development of type 2 diabetes in later life are the ones of major concern. A GDM mother has about 30–60% chance of recurrence in subsequent pregnancies. A systematic review of 28 studies covering the same number of years showed that a GDM mother has a cumulative incidence ranging from 2.6 to 70% of type 2 diabetes. Recurrence of GDM in subsequent pregnancies and the development of type 2 diabetes in later life are linked to risk factors like obesity, interval between pregnancies, and the amount of insulin needed during the

Long-term complications in the neonate of a GDM mother are obesity and type 2

diabetes in adult life. The girl child also runs the risk of GDM in her pregnancy.

Screening and diagnosis of gestational diabetes is varied and till date a single universal guideline has been elusive. This is compounded by the fact that both gestational diabetes and type 2 diabetes are very dependent on ethnicity. This often leads to the question as to whether a single mathematical figure would actually

International and national bodies advise various ways to screen gestational diabetes. Large numbers of such guidelines confuse the primary health provider and the practicing obstetrician. In this era of evidence-based medicine, there is need

reflect hyperglycemia and its complications in different ethnic groups.

**4**

Although screening for GDM remains the mainstay for early detection, biomarkers for predicting, and monitoring the condition have also been identified. These biomarkers are altered as a result of the underlying pathology of GDM and thus help in predicting the condition before it actually becomes manifest clinically. These biomarkers may be related to insulin resistance, chronic inflammation, and altered placental function all of which are related to the patho-physiology of GDM. Micro-RNAs, one such group of biomarkers are a class of RNAs which are not involved in coding but can modulate gene expression. Thus, particular levels of circulating micro-RNAs can be used as biomarkers to predict GDM.

Efforts are also being made to combine several biomarkers to form a risk score for prediction of GDM. Combining clinical risk factors and biomarkers to predict the condition are also in the process.

#### **6. The way ahead**

Gestational diabetes mellitus has a well-documented link with maternal age, family history, diet, obesity, and lack of exercise. Both ethnicity and deprivation are major contributors to an increased risk of GDM. Research has confirmed that a better diet, increased physical activity, an appropriate pre-pregnancy Body Mass Index could reduce the development of gestational diabetes mellitus. The challenge now is to find ways of delivering these benefits in real life rather than in purely research settings. Keeping these things in mind, the first aim should be primary prevention. It plays the most significant role in creating awareness as regards gestational diabetes among public. Awareness should particularly target the groups which are at high risk for developing diabetes. Primary steps in preventing gestational diabetes can delay or halt further developments which in turn reduce both the need for gestational diabetes care and other required treatments. Prevention of gestational diabetes and diabetes per se should be considered a public health priority. The biggest task faced by the medical fraternity is lack of awareness across all segments of society about this epidemic.

A uniform consensus on how to screen for and diagnose gestational diabetes is another focus area for national and international bodies. As both ethnicity and deprivation are major contributors to this disease condition, the guidelines framed should make allowance for both [5, 6].

Another area that needs looking into is the identification of markers which could predict the condition with reasonable accuracy. It is also essential that such markers be cost-effective as both diabetes and gestational diabetes can no longer be considered as the disease of the elite society.

*Gestational Diabetes Mellitus - An Overview with Some Recent Advances*

#### **Author details**

Amita Ray Department of Obstetrics and Gynecology, IQ City Medical College, Durgapur, West Bengal, India

\*Address all correspondence to: amitarays@gmail.com

© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

**7**

59-62

*Introductory Chapter: Gestational Diabetes Mellitus DOI: http://dx.doi.org/10.5772/intechopen.86855*

[1] Kampmann U, Madsen LR, Skajaa GO, Iversen DS, Moeller N, Ovesen P. Gestational diabetes: A clinical update. World Journal of Diabetes. 2015;**6**(8):1065-1072

**References**

2006;**49**(7):1677-1685

[2] Catalano PM, Hoegh M, Minium J, Huston-Presley L, Bernard S, Kalhan S, et al. Adiponectin in human pregnancy: Implications for regulation of glucose and lipid metabolism. Diabetologia.

[3] Ferrara A. Increasing prevalence of gestational diabetes mellitus: A public health perspective. Diabetes Care. 2007;**30**(Suppl 2):S141-S146

MEstablishing diagnosis of gestational diabetes mellitus: Impact of the hyperglycemia and adverse pregnancy outcome study. Seminars in Fetal and Neonatal Medicine. 2009;**14**(2):94-100

[5] Jensen DM, Korsholm L, Ovesen P, Beck-Nielsen H, Mølsted-Pedersen L, Damm P. Adverse pregnancy outcome in women with mild glucose intolerance: Is there a clinically meaningful threshold value for glucose? Acta Obstetricia et Gynecologica Scandinavica. 2008;**87**:

[6] Metzger BE, Gabbe SG, Persson B, Buchanan TA, Catalano PA, Damm P, et al. International Association of Diabetes and Pregnancy Study Groups recommendations on the diagnosis and classification of hyperglycemia in pregnancy. Diabetes Care. 2010;**33**:676

[4] Yogev Y, Metzger BE. Hod

*Introductory Chapter: Gestational Diabetes Mellitus DOI: http://dx.doi.org/10.5772/intechopen.86855*

#### **References**

*Gestational Diabetes Mellitus - An Overview with Some Recent Advances*

**6**

**Author details**

Durgapur, West Bengal, India

Department of Obstetrics and Gynecology, IQ City Medical College,

© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

\*Address all correspondence to: amitarays@gmail.com

provided the original work is properly cited.

Amita Ray

[1] Kampmann U, Madsen LR, Skajaa GO, Iversen DS, Moeller N, Ovesen P. Gestational diabetes: A clinical update. World Journal of Diabetes. 2015;**6**(8):1065-1072

[2] Catalano PM, Hoegh M, Minium J, Huston-Presley L, Bernard S, Kalhan S, et al. Adiponectin in human pregnancy: Implications for regulation of glucose and lipid metabolism. Diabetologia. 2006;**49**(7):1677-1685

[3] Ferrara A. Increasing prevalence of gestational diabetes mellitus: A public health perspective. Diabetes Care. 2007;**30**(Suppl 2):S141-S146

[4] Yogev Y, Metzger BE. Hod MEstablishing diagnosis of gestational diabetes mellitus: Impact of the hyperglycemia and adverse pregnancy outcome study. Seminars in Fetal and Neonatal Medicine. 2009;**14**(2):94-100

[5] Jensen DM, Korsholm L, Ovesen P, Beck-Nielsen H, Mølsted-Pedersen L, Damm P. Adverse pregnancy outcome in women with mild glucose intolerance: Is there a clinically meaningful threshold value for glucose? Acta Obstetricia et Gynecologica Scandinavica. 2008;**87**: 59-62

[6] Metzger BE, Gabbe SG, Persson B, Buchanan TA, Catalano PA, Damm P, et al. International Association of Diabetes and Pregnancy Study Groups recommendations on the diagnosis and classification of hyperglycemia in pregnancy. Diabetes Care. 2010;**33**:676

**9**

**Chapter 2**

**Abstract**

**1. Introduction**

Diabetes

A Clinical Insight into Gestational

Pregnancy is a diabetogenic state manifested by insulin resistance and hyperglycaemia. The age group at risk of getting gestational diabetes is between 20 and 39 years in 96.8% of cases. Gestational diabetes is the development of symptoms and signs of diabetes mellitus during pregnancy and the glucose level reverting to normal during puerperium. Depending on the type of population and the diagnostic criteria used, gestational diabetes is said to complicate 1–16% of all pregnancies. Many researchers in American, European and Asian surveys have reported 3–6% of prevalence. Compared with white European women, the prevalence rate for GD is increased approximately elevenfold in women from the Indian subcontinent, eightfold in South East Asia, sixfold and threefold in Arab and black Afro-Caribbean women, respectively. Such figures draw a potent clinical interest towards gestational diabetes (GD), and this chapter attempts to highlight some major aspects of GD in respect to both the mother and the foetus or the newborn specially emphasizing on its management as per the World Health Organization (WHO)

*HH Siddiqui, Tarique Mahmood, Mohd. Haris Siddiqui,* 

*Paramdeep Bagga, Farogh Ahsan and Arshiya Shamim*

and International Federation of Gynaecology and Obstetrics (FIGO).

**Keywords:** antenatal care, hyperinsulinaemia, impaired glucose tolerance, International Federation of gynaecology and obstetrics, medical nutrition therapy

comparatively at higher risk of developing type 2 diabetes later [1–10].

Gestational diabetes (GD) is characterised with impaired glucose tolerance (IGT) whose first recognition or onset is during pregnancy. International statistics claim that out of 10 pregnancies, at least 1 is associated with diabetes, most of which are GD. Lack 0f diagnosis or treatment of GD can lead to significant maternal and foetal complications. Moreover, women with GD and their offsprings are

The incidence of GD is expected to increase at an expedited rate in the near future, amounting to one in every five pregnant women suffering from GD. According to a field study conducted in one of the Indian states under the 'Diabetes in Pregnancy'— Awareness and Prevention project, in most of the pregnant women screened in urban, semiurban and rural areas, respectively, the prevalence of GD was reported to be 17.8% in the urban, 13.8% in the semiurban and 9.9% in the rural areas [11–16]. GD may result in development of many pregnancy-associated disorders like polyhydramnios, pre-eclampsia, prolonged labour, obstructed labour, caesarean section, uterine atony, postpartum haemorrhage, infection and progression of retinopathy which are the leading global causes of maternal morbidity and mortality.

**Chapter 2**

## A Clinical Insight into Gestational Diabetes

*HH Siddiqui, Tarique Mahmood, Mohd. Haris Siddiqui, Paramdeep Bagga, Farogh Ahsan and Arshiya Shamim*

#### **Abstract**

Pregnancy is a diabetogenic state manifested by insulin resistance and hyperglycaemia. The age group at risk of getting gestational diabetes is between 20 and 39 years in 96.8% of cases. Gestational diabetes is the development of symptoms and signs of diabetes mellitus during pregnancy and the glucose level reverting to normal during puerperium. Depending on the type of population and the diagnostic criteria used, gestational diabetes is said to complicate 1–16% of all pregnancies. Many researchers in American, European and Asian surveys have reported 3–6% of prevalence. Compared with white European women, the prevalence rate for GD is increased approximately elevenfold in women from the Indian subcontinent, eightfold in South East Asia, sixfold and threefold in Arab and black Afro-Caribbean women, respectively. Such figures draw a potent clinical interest towards gestational diabetes (GD), and this chapter attempts to highlight some major aspects of GD in respect to both the mother and the foetus or the newborn specially emphasizing on its management as per the World Health Organization (WHO) and International Federation of Gynaecology and Obstetrics (FIGO).

**Keywords:** antenatal care, hyperinsulinaemia, impaired glucose tolerance, International Federation of gynaecology and obstetrics, medical nutrition therapy

#### **1. Introduction**

Gestational diabetes (GD) is characterised with impaired glucose tolerance (IGT) whose first recognition or onset is during pregnancy. International statistics claim that out of 10 pregnancies, at least 1 is associated with diabetes, most of which are GD. Lack 0f diagnosis or treatment of GD can lead to significant maternal and foetal complications. Moreover, women with GD and their offsprings are comparatively at higher risk of developing type 2 diabetes later [1–10].

The incidence of GD is expected to increase at an expedited rate in the near future, amounting to one in every five pregnant women suffering from GD. According to a field study conducted in one of the Indian states under the 'Diabetes in Pregnancy'— Awareness and Prevention project, in most of the pregnant women screened in urban, semiurban and rural areas, respectively, the prevalence of GD was reported to be 17.8% in the urban, 13.8% in the semiurban and 9.9% in the rural areas [11–16].

GD may result in development of many pregnancy-associated disorders like polyhydramnios, pre-eclampsia, prolonged labour, obstructed labour, caesarean section, uterine atony, postpartum haemorrhage, infection and progression of retinopathy which are the leading global causes of maternal morbidity and mortality.

Moreover, GD could also pose foetal risks including spontaneous abortion, intrauterine death, stillbirth, congenital malformation, birth injuries, neonatal hypoglycaemia and infant respiratory distress syndrome.

Long-term clinical effects of GD are important contributors to the burden of non-communicable diseases in many countries [17, 18].

#### **2. Aetiology and pathophysiology of GD**

During normal pregnancy, resistance to insulin action increases. In most pregnancies, the pancreas is able to meet the increased insulin demands, and normal blood glucose level is maintained. On the contrary, women who develop GD have impaired beta-cell response resulting in insufficient insulin secretion to meet the increased insulin demands. The following factors tend to enhance the chances of developing GD:


Products of the placenta, including tumour necrosis factor-alpha (TNF-α) and human chorionic somatomammotropin, are considered to play pathological roles in inducing maternal insulin resistance. Insulin resistance is observed at peak levels in the third trimester of pregnancy. Women who develop GD have pathologically impaired beta-cell function that leaves them with inability of adapting to pregnancy. In GD, as in type 2 diabetes, the deficit in beta-cell function is usually multifactorial and polygenetic. However, unmasked by the increased insulin needs of pregnancy, autoimmune diabetes and maturity-onset diabetes of youth (MODY) may occasionally be first recognised as GD. Hyperglycaemia in late pregnancy is associated with macrosomia and neonatal hypoglycaemia, hyperbilirubinemia and hypocalcaemia, as well as adverse maternal outcomes, including gestational hypertension, pre-eclampsia and caesarean delivery [19–35].

#### **3. Strategical diagnosis of GD**

Profound international evidences and standard protocols suggest definite guidelines for screening pregnant women for GD.

**11**

*A Clinical Insight into Gestational Diabetes DOI: http://dx.doi.org/10.5772/intechopen.85892*

GD [36, 37].

alone by MNT [38–42].

**3.1 Testing and management of GD**

conducted if it is her first visit for ANC [45–51].

**3.2 Methodology for diagnosis**

of pregnant women:

The American and Canadian guidelines recommend universal screening by two-step approach. This includes a screening with 50-g 1-hour blood glucose test (>140 mg/dL taken as screen positive). Women who screen positive are subjected to 100-g oral glucose tolerance test (OGTT), and those with 2 or more abnormal

Similarly, the National Institute for Health and Care Excellence (NICE), UK, and Australian guidelines recommend a slightly different risk-based screening. It recommends a 75-g 2-hour OGTT. Women with fasting blood glucose ≥126 mg/dL

The WHO and International Federation of Gynaecology and Obstetrics (FIGO)

Almost all guidelines agree to the management of GD using medical nutrition therapy (MNT) which is a standard diet plan for GD-diagnosed mothers and insulin therapy if required. Recently, global evidences have also concluded that the traditional biguanide—metformin—is safe and effective for GD management after 20 weeks of gestation if blood glucose level is not controlled

GD pregnant women should be managed by medical nutrition therapy (MNT) and metformin or insulin therapy as required. In the postpartum period, OGTT must be repeated at 6 weeks post delivery; if blood glucose is <140 mg/dL, then women should be referred for postprandial blood glucose (PPBS) testing annually [43, 44].

Ideally, all pregnant women should be screened for gestational diabetes, espe-

Trained human resources are required to manage the cases after diagnosis.

The first testing should be done during the first antenatal contact as early as possible in pregnancy. If the first test result is negative, the test must be repeated between the second and third trimester of pregnancy. It is important to conduct a second test as most pregnant women develop blood glucose intolerance during this period (24–28 weeks). Mostly, one third of all GD-positive women are diagnosed during the first trimester. Hence, the test is repeated after the second trimester. There should be at least a gap of 4 weeks between the two tests. The test should

be conducted for all pregnant women even if she comes late in pregnancy for ANC. However, if the woman is over 28 weeks of pregnancy, only one test should be

The following stepwise protocol complies with the WHO guidelines for screening

• The test is conducted with intake of 75 g of oral glucose dissolved in approximately 300 mL of water, irrespective of whether the pregnant woman comes in fasting or non-fasting state, followed by measuring the blood glucose level by a plasmastandardised glucometer after 2 hours of ingestion (postprandial blood glucose).

• If within 30 minutes of oral glucose intake the mother vomits, the test has to be repeated the next day. If vomiting occurs after 30 minutes, the test continues.

endorse universal screening for GD at 24–28 weeks of gestation using the 75-g

values of blood glucose are diagnosed with gestational diabetes.

2-hour blood sugar (fasting ≥126 mg/dL and PP ≥140 mg/dL).

cially those who have one or more risk factors discussed above.

Testing for GD is recommended twice during ante natal care (ANC).

and postprandial (PP) blood glucose ≥140 mg/dL are diagnosed with

#### *A Clinical Insight into Gestational Diabetes DOI: http://dx.doi.org/10.5772/intechopen.85892*

*Gestational Diabetes Mellitus - An Overview with Some Recent Advances*

caemia and infant respiratory distress syndrome.

**2. Aetiology and pathophysiology of GD**

pregnancy.

• Nonwhite ancestry.

• Weight gain.

• Family history of type 2 diabetes.

non-communicable diseases in many countries [17, 18].

Moreover, GD could also pose foetal risks including spontaneous abortion, intrauterine death, stillbirth, congenital malformation, birth injuries, neonatal hypogly-

Long-term clinical effects of GD are important contributors to the burden of

During normal pregnancy, resistance to insulin action increases. In most pregnancies, the pancreas is able to meet the increased insulin demands, and normal blood glucose level is maintained. On the contrary, women who develop GD have impaired beta-cell response resulting in insufficient insulin secretion to meet the increased insulin demands. The following factors tend to enhance the chances of developing GD:

• Obesity: Leads to increased insulin resistance, which is further compounded by

• Polycystic ovarian syndrome: Associated with insulin resistance and obesity.

• Age: Due to age-related decreased pancreatic beta-cell reserve.

• Intake of diet with low-fibre and high-glycaemic index.

tension, pre-eclampsia and caesarean delivery [19–35].

**3. Strategical diagnosis of GD**

for screening pregnant women for GD.

• Lack of physical activity: Exercise increases insulin sensitivity.

• Prior GD: GD recurs in as many as 80% of subsequent pregnancies.

Products of the placenta, including tumour necrosis factor-alpha (TNF-α) and human chorionic somatomammotropin, are considered to play pathological roles in inducing maternal insulin resistance. Insulin resistance is observed at peak levels in the third trimester of pregnancy. Women who develop GD have pathologically impaired beta-cell function that leaves them with inability of adapting to pregnancy. In GD, as in type 2 diabetes, the deficit in beta-cell function is usually multifactorial and polygenetic. However, unmasked by the increased insulin needs of pregnancy, autoimmune diabetes and maturity-onset diabetes of youth (MODY) may occasionally be first recognised as GD. Hyperglycaemia in late pregnancy is associated with macrosomia and neonatal hypoglycaemia, hyperbilirubinemia and hypocalcaemia, as well as adverse maternal outcomes, including gestational hyper-

Profound international evidences and standard protocols suggest definite guidelines

• Smoking: Increases insulin resistance and decreases insulin secretion.

**10**

The American and Canadian guidelines recommend universal screening by two-step approach. This includes a screening with 50-g 1-hour blood glucose test (>140 mg/dL taken as screen positive). Women who screen positive are subjected to 100-g oral glucose tolerance test (OGTT), and those with 2 or more abnormal values of blood glucose are diagnosed with gestational diabetes.

Similarly, the National Institute for Health and Care Excellence (NICE), UK, and Australian guidelines recommend a slightly different risk-based screening. It recommends a 75-g 2-hour OGTT. Women with fasting blood glucose ≥126 mg/dL and postprandial (PP) blood glucose ≥140 mg/dL are diagnosed with GD [36, 37].

The WHO and International Federation of Gynaecology and Obstetrics (FIGO) endorse universal screening for GD at 24–28 weeks of gestation using the 75-g 2-hour blood sugar (fasting ≥126 mg/dL and PP ≥140 mg/dL).

Almost all guidelines agree to the management of GD using medical nutrition therapy (MNT) which is a standard diet plan for GD-diagnosed mothers and insulin therapy if required. Recently, global evidences have also concluded that the traditional biguanide—metformin—is safe and effective for GD management after 20 weeks of gestation if blood glucose level is not controlled alone by MNT [38–42].

GD pregnant women should be managed by medical nutrition therapy (MNT) and metformin or insulin therapy as required. In the postpartum period, OGTT must be repeated at 6 weeks post delivery; if blood glucose is <140 mg/dL, then women should be referred for postprandial blood glucose (PPBS) testing annually [43, 44].

#### **3.1 Testing and management of GD**

Ideally, all pregnant women should be screened for gestational diabetes, especially those who have one or more risk factors discussed above.

Trained human resources are required to manage the cases after diagnosis. Testing for GD is recommended twice during ante natal care (ANC).

The first testing should be done during the first antenatal contact as early as possible in pregnancy. If the first test result is negative, the test must be repeated between the second and third trimester of pregnancy. It is important to conduct a second test as most pregnant women develop blood glucose intolerance during this period (24–28 weeks). Mostly, one third of all GD-positive women are diagnosed during the first trimester. Hence, the test is repeated after the second trimester.

There should be at least a gap of 4 weeks between the two tests. The test should be conducted for all pregnant women even if she comes late in pregnancy for ANC. However, if the woman is over 28 weeks of pregnancy, only one test should be conducted if it is her first visit for ANC [45–51].

#### **3.2 Methodology for diagnosis**

The following stepwise protocol complies with the WHO guidelines for screening of pregnant women:


• The threshold blood glucose level of ≥140 mg/dL is considered as limit for diagnosis of GD [52–61].

#### **4. Internationally acceptable guidelines for management of GD**

#### **4.1 Guiding principles**

All pregnant women who screen positive for GD in the first test are subjected to medical nutrition therapy (MNT) and physical exercise for 2 weeks. The woman is advised to walk or exercise for at least 30 minutes a day.

After 2 weeks on MNT and physical exercise, a 2-hour PPBS (post meal) should be done. All standardised protocols for management of GD suggest initial management with MNT and physical exercise strictly. If diabetes is not controlled with MNT (lifestyle changes) alone, metformin or insulin therapy is recommended.

If 2-hour PPBS is <120 mg/dL, the test is to be repeated as per high-risk pregnancy protocol, i.e. to undertake eight tests (four regular tests and four additional). It is recommended to conduct at least one test every month during the second and third trimester. More follow-up tests can be done as recommended by the gynaecologist. If 2-hour PPBS is ≥120 mg/dL, medical management (metformin or insulin therapy) has to be started as per guidelines (**Figure 1**) [62–66].

**13**

*A Clinical Insight into Gestational Diabetes DOI: http://dx.doi.org/10.5772/intechopen.85892*

**4.2 Medical nutrition therapy (MNT)**

controlled balanced meal plan which promotes:

• Optimal nutrition for maternal and foetal health

• Adequate energy for appropriate gestational weight gain

• Achievement and maintenance of normoglycaemia [67, 68]

the optimal weight gain during the entire tenure of pregnancy [24, 69].

**4.3 The significance of the individualised nutrition plan assessment in GD**

Assessment of diet or nutrition plan in GD is an important criterion for diagnosis and subsequent follow-up on mother's and foetus' development. The nutrition plan must be individualised from patient to patient so that accurate appraisal of the woman's nutritional status could be assessed. This assessment includes defining her body mass index (BMI) or percentage of desirable weight during pre-pregnancy to

The energy demand of the body during pregnancy increases many times than that in a nonpregnant state. Individualization of nutritional requirement proves to be very helpful in determining the energy requirement and making amendments in

Normally calorie monitoring is not a point of concern in the first trimester unless a woman is underweight. It becomes more significant during the second and third trimester to monitor the energy requirements. Calorie intake should suffice

Ideally, for an average woman, weight gain of 10–12 kg is considered normal during pregnancy; an additional 350 kcal/day intake to the adult requirement is

Severe caloric restriction is strictly prohibited as it may cause ketonaemia and ketonuria in the mother as well as impair physical and mental growth in the off-

Energy requirement (kcal/day) = BMR × PAL (1)

where the basal metabolic rate (BMR) for an adult female in the age group of 18–30 years is calculated as 14 × BW (kg) + 471 and similarly BMR for adult females

Carbohydrates are essential for both the mother and the baby. They are the ultimate source of glucose in the blood. Hence, the nature, quantity and frequency

All pregnant women with GD should get medical nutrition therapy (MNT) as soon as diagnosis is made. MNT for GD primarily involves a carbohydrate-

*4.2.1 Healthy eating during pregnancy*

**4.4 Monitoring calorie intake in GD**

the diet plan based on weight change patterns.

the appropriate weight gain during gestation.

spring (**Tables 1** and **2**)[70–72].

*4.4.1 Daily intake of carbohydrates*

recommended during the second and third trimester.

Energy requirement can be calculated as follows:

\*BMR = basal metabolic rate; \*PAL = physical activity level.

of carbohydrate intake influence greatly the blood glucose level.

of age group 30–60 years as 8.3 × BW (kg) + 788 (*\*BW = body weight)*.

**Figure 1.** *Standard health management protocol for pregnant women with GD.*

#### **4.2 Medical nutrition therapy (MNT)**

#### *4.2.1 Healthy eating during pregnancy*

*Gestational Diabetes Mellitus - An Overview with Some Recent Advances*

advised to walk or exercise for at least 30 minutes a day.

therapy) has to be started as per guidelines (**Figure 1**) [62–66].

diagnosis of GD [52–61].

**4.1 Guiding principles**

• The threshold blood glucose level of ≥140 mg/dL is considered as limit for

All pregnant women who screen positive for GD in the first test are subjected to medical nutrition therapy (MNT) and physical exercise for 2 weeks. The woman is

After 2 weeks on MNT and physical exercise, a 2-hour PPBS (post meal) should be done. All standardised protocols for management of GD suggest initial management with MNT and physical exercise strictly. If diabetes is not controlled with MNT (lifestyle changes) alone, metformin or insulin therapy is recommended. If 2-hour PPBS is <120 mg/dL, the test is to be repeated as per high-risk pregnancy protocol, i.e. to undertake eight tests (four regular tests and four additional). It is recommended to conduct at least one test every month during the second and third trimester. More follow-up tests can be done as recommended by the gynaecologist. If 2-hour PPBS is ≥120 mg/dL, medical management (metformin or insulin

**4. Internationally acceptable guidelines for management of GD**

**12**

**Figure 1.**

*Standard health management protocol for pregnant women with GD.*

All pregnant women with GD should get medical nutrition therapy (MNT) as soon as diagnosis is made. MNT for GD primarily involves a carbohydratecontrolled balanced meal plan which promotes:


#### **4.3 The significance of the individualised nutrition plan assessment in GD**

Assessment of diet or nutrition plan in GD is an important criterion for diagnosis and subsequent follow-up on mother's and foetus' development. The nutrition plan must be individualised from patient to patient so that accurate appraisal of the woman's nutritional status could be assessed. This assessment includes defining her body mass index (BMI) or percentage of desirable weight during pre-pregnancy to the optimal weight gain during the entire tenure of pregnancy [24, 69].

#### **4.4 Monitoring calorie intake in GD**

The energy demand of the body during pregnancy increases many times than that in a nonpregnant state. Individualization of nutritional requirement proves to be very helpful in determining the energy requirement and making amendments in the diet plan based on weight change patterns.

Normally calorie monitoring is not a point of concern in the first trimester unless a woman is underweight. It becomes more significant during the second and third trimester to monitor the energy requirements. Calorie intake should suffice the appropriate weight gain during gestation.

Ideally, for an average woman, weight gain of 10–12 kg is considered normal during pregnancy; an additional 350 kcal/day intake to the adult requirement is recommended during the second and third trimester.

Severe caloric restriction is strictly prohibited as it may cause ketonaemia and ketonuria in the mother as well as impair physical and mental growth in the offspring (**Tables 1** and **2**)[70–72].

Energy requirement can be calculated as follows:

$$\text{Energy requirement (kcal/day)} = \text{BMR} \times \text{PAL} \tag{1}$$

\*BMR = basal metabolic rate; \*PAL = physical activity level.

where the basal metabolic rate (BMR) for an adult female in the age group of 18–30 years is calculated as 14 × BW (kg) + 471 and similarly BMR for adult females of age group 30–60 years as 8.3 × BW (kg) + 788 (*\*BW = body weight)*.

#### *4.4.1 Daily intake of carbohydrates*

Carbohydrates are essential for both the mother and the baby. They are the ultimate source of glucose in the blood. Hence, the nature, quantity and frequency of carbohydrate intake influence greatly the blood glucose level.


#### **Table 1.**

*Energy requirement in relation to nature of lifestyle.*


#### **Table 2.**

*Calorie requirement according to body mass index (BMI).*

The carbohydrates must be evenly distributed through the daily food chart foods in order to avoid high blood glucose level. It is better to spread carbohydrate foods over three small meals and two to three snacks each day than taking three large meals [8, 73–78].

Complex carbohydrates (like whole-grain cereals like oats, vegetables and fruits) should be preferred over simple carbohydrates like food with lots of added sugar or honey. Also keeping a record of the number of carbohydrate serves that a mother eats during the day helps her to eat the right amount of carbohydrates [79].

#### *4.4.2 Daily intake of fats*

Overall fat intake by a pregnant woman should be planned in a manner that saturated fat such as butter, coconut oil, palm oil, red meat, organ meat and full cream milk amounts to less than 10% of total calories. The dietary cholesterol must be less than 300 mg/dL. In obese and overweight patients, a lower-fat diet overall can help slow the rate of weight gain [80].

#### *4.4.3 Daily intake of proteins*

Proteins are a very important dietary element for the growth and health of the foetus.

At least three servings of protein foods are recommended every day to meet the increased demand. Milk and milk products, egg, fish, chicken, pulses, nuts, etc. are all rich sources of protein that a mother can take during her pregnancy [80].

#### **5. Pharmacotherapy of GD with metformin and insulin**

The widely accepted treatment protocol for gestational diabetes advocates metformin or insulin therapy for clinical management of pregnant women diagnosed with GD that is not well controlled with MNT alone. Insulin is the first drug of choice for GD mothers.

The advantage of insulin therapy over metformin is that it can be started any time during pregnancy for GD management. If the gestation is less than 20 weeks,

**15**

*A Clinical Insight into Gestational Diabetes DOI: http://dx.doi.org/10.5772/intechopen.85892*

20 weeks of gestation for clinical management of GD.

orally up to a maximum dose up to 2 g/day.

**5.1 Common side effects with metformin**

• Diarrhoea

• Stomach pain

• Lactic acidosis

**5.2 Types of insulins**

• Low blood glucose

*5.2.1.1 Regular (U-100) insulin*

*5.2.1.2 Regular (U-500) insulin*

• Heartburn

• Nausea

and medical nutrition therapy (MNT) is not effective in controlling blood glucose levels, insulin should be started, but metformin can be considered only after

Metformin therapy can be started at 20 weeks of pregnancy, if MNT has not been able to control blood glucose alone. In the cases where the woman's blood glucose is not controlled even with the maximum dose of metformin and MNT, the therapy must be switched to insulin therapy. The dose of metformin is 500 mg BID

The incidence of hypoglycaemia and weight gain with metformin is less than insulin. If insulin is required in high doses, metformin may be added to the treatment. Any pregnant women on insulin therapy should be instructed to keep sugar/

Unlike the nonpregnant patients with diabetes who have a plethora of choices to achieve glucose control, the pregnant cases with GD offer a big challenge to the clinicians when it comes to the choice of drugs for its management. In the recent years, we have come across a variety in new insulins, novel delivery systems and additional concentrations of existing insulins. With an alarming increase in the gestational diabetic population, the demands of the newer insulins will be ever increasing; hence, understanding these insulins becomes crucial. Additional pharmacokinetic and pharmacodynamic studies of these insulins in pregnancy are also required [85].

It is identical to human insulin and is synthesised in *Escherichia coli* bacteria. It is used before meal to compensate for heavy carbohydrates. The onset of action is around 30 minutes but can range from 10 to 75 minutes. The peak action is achieved at 3 hours (range 20 minutes to 7 hours), and the overall duration of action is

It is identical to human insulin but more concentrated than the U-100 formulation; its pharmacokinetic profile differs from U-100 as well. The onset is ~30 minutes, but the duration of action can last up to 24 hours. Severe hypoglycaemia may occur 24 hours

*5.2.1 Short-acting insulin and rapid-acting insulin analogues*

~8 hours. U-100 vials can stay at room temperature for 31 days [86].

glucose powder handy at home to treat hypoglycaemia if it occurs [81–84].

#### *A Clinical Insight into Gestational Diabetes DOI: http://dx.doi.org/10.5772/intechopen.85892*

and medical nutrition therapy (MNT) is not effective in controlling blood glucose levels, insulin should be started, but metformin can be considered only after 20 weeks of gestation for clinical management of GD.

Metformin therapy can be started at 20 weeks of pregnancy, if MNT has not been able to control blood glucose alone. In the cases where the woman's blood glucose is not controlled even with the maximum dose of metformin and MNT, the therapy must be switched to insulin therapy. The dose of metformin is 500 mg BID orally up to a maximum dose up to 2 g/day.

The incidence of hypoglycaemia and weight gain with metformin is less than insulin. If insulin is required in high doses, metformin may be added to the treatment. Any pregnant women on insulin therapy should be instructed to keep sugar/ glucose powder handy at home to treat hypoglycaemia if it occurs [81–84].

#### **5.1 Common side effects with metformin**


*Gestational Diabetes Mellitus - An Overview with Some Recent Advances*

**S. no. Body mass index Calorie requirement**

*Calorie requirement according to body mass index (BMI).*

*Energy requirement in relation to nature of lifestyle.*

2. 18.5–22.9 (normal) Calorie requirement as per activity 3. 23–24.9 (overweight) Calorie requirement as per activity

The carbohydrates must be evenly distributed through the daily food chart foods in order to avoid high blood glucose level. It is better to spread carbohydrate foods over three small meals and two to three snacks each day than taking three large

1. <18.5 (underweight) Calorie requirement as per activity + 500 kcal/day

1. Sedentary 1900 + 350 2250 2. Moderately active 2230 + 350 2580 3. Highly active 2850 + 350 3200

**S. no. Nature of lifestyle Energy requirement during pregnancy Total energy requirement (kcal/day)**

4. >25 (obese) Calorie requirement as per activity—500 kcal/day

Complex carbohydrates (like whole-grain cereals like oats, vegetables and fruits) should be preferred over simple carbohydrates like food with lots of added sugar or honey. Also keeping a record of the number of carbohydrate serves that a mother eats during the day helps her to eat the right amount of carbohydrates [79].

Overall fat intake by a pregnant woman should be planned in a manner that saturated fat such as butter, coconut oil, palm oil, red meat, organ meat and full cream milk amounts to less than 10% of total calories. The dietary cholesterol must be less than 300 mg/dL. In obese and overweight patients, a lower-fat diet overall

Proteins are a very important dietary element for the growth and health of the

At least three servings of protein foods are recommended every day to meet the increased demand. Milk and milk products, egg, fish, chicken, pulses, nuts, etc. are

all rich sources of protein that a mother can take during her pregnancy [80].

The widely accepted treatment protocol for gestational diabetes advocates metformin or insulin therapy for clinical management of pregnant women diagnosed with GD that is not well controlled with MNT alone. Insulin is the first drug

The advantage of insulin therapy over metformin is that it can be started any time during pregnancy for GD management. If the gestation is less than 20 weeks,

**5. Pharmacotherapy of GD with metformin and insulin**

**14**

foetus.

meals [8, 73–78].

**Table 2.**

**Table 1.**

*4.4.2 Daily intake of fats*

*4.4.3 Daily intake of proteins*

of choice for GD mothers.

can help slow the rate of weight gain [80].


#### **5.2 Types of insulins**

Unlike the nonpregnant patients with diabetes who have a plethora of choices to achieve glucose control, the pregnant cases with GD offer a big challenge to the clinicians when it comes to the choice of drugs for its management. In the recent years, we have come across a variety in new insulins, novel delivery systems and additional concentrations of existing insulins. With an alarming increase in the gestational diabetic population, the demands of the newer insulins will be ever increasing; hence, understanding these insulins becomes crucial. Additional pharmacokinetic and pharmacodynamic studies of these insulins in pregnancy are also required [85].

#### *5.2.1 Short-acting insulin and rapid-acting insulin analogues*

#### *5.2.1.1 Regular (U-100) insulin*

It is identical to human insulin and is synthesised in *Escherichia coli* bacteria. It is used before meal to compensate for heavy carbohydrates. The onset of action is around 30 minutes but can range from 10 to 75 minutes. The peak action is achieved at 3 hours (range 20 minutes to 7 hours), and the overall duration of action is ~8 hours. U-100 vials can stay at room temperature for 31 days [86].

#### *5.2.1.2 Regular (U-500) insulin*

It is identical to human insulin but more concentrated than the U-100 formulation; its pharmacokinetic profile differs from U-100 as well. The onset is ~30 minutes, but the duration of action can last up to 24 hours. Severe hypoglycaemia may occur 24 hours after the initial dose, although there are clinical reports suggesting that in pregnancy, severe hypoglycaemia is rare with U-500 insulin. Two to three injections daily are required, and a U-500 vial is good for 40 days at room temperature while in use [87–89].

#### *5.2.1.3 Insulin aspartate*

It is produced in a type of yeast, *Saccharomyces cerevisiae*, and is homologous to human insulin. It should be taken 5–10 minutes prior to meals. It can be administered as injections or in an insulin pump. The time of peak concentration ranges between 40 and 50 minutes, and the duration of action is 3–5 hours. It is also available in the forms of pens, penfills and vials that retain their pharmacological potency for at least 28 days at room temperature while in use. The risk of developing hypoglycaemia with insulin aspartate is less than regular insulin, although patients allergic to yeast must avoid it as this could potentially cause a site reaction [90].

#### *5.2.1.4 Insulin lispro (U-100 and U-200)*

It is an analogue produced in *Escherichia coli*. Its onset of action is 10–15 minutes, peak action is attained in 30–90 minutes and the duration of action is 3–4 hours. Intraperitoneal injections are preferred for the maximum absorption and shortest duration of action. It can be used in the form of insulin pumps or as multiple daily injections. The U-100 and U-200 formulations are bioequivalent, having the same pharmacokinetics. Insulin lispro U-200 is only available in pens to avoid administration errors. Pens, penfills and vials can be stored for 28 days at room temperature while in use [91].

#### *5.2.2 Intermediate insulin and long-acting insulin analogues*

#### *5.2.2.1 Insulin isophane (NPH)*

It is a U-100, intermediate-acting insulin. It is produced in *Escherichia coli* and is identical to human insulin available as a suspension. The onset of action is 1–2 hours, with an average peak action of 4 hours (range, 4–8 hours). Duration of action lasts for 10–20 hours. Vials remain usable for 31 days at room temperature, whereas pens can be used for 14 days [92].

#### *5.2.2.2 Insulin detemir (U-100)*

This is a long-acting analogue of insulin produced in *S. cerevisiae*. One of the setbacks with this formulation is that it can potentially cause a reaction in patients who are allergic to yeast. Detemir lacks a defined peak of action, but the pharmacological action lasts for up to 20 hours. The time to onset of action ranges between 1 and 2 hours. The pen and vial can be used up to 42 days at room temperature while in use. The chances of developing hypoglycaemia with detemir are less than NPH in pregnant women [93].

#### *5.2.2.3 Insulin glargine (U-100)*

It is a long-acting analogue produced in *Escherichia coli.* It differs from other contemporaries in terms of its distribution in plasma; the acidic solution is neutralised in subcutaneous tissue to form microprecipitates. These microprecipitates slowly release glargine over a duration of 24 hours, resulting in no well-defined peak. Its onset of action is 1–2 hours. Vials and pens are reusable for 28 days at room temperature.

**17**

*5.4.1 Indication*

not be controlled by diet alone.

*A Clinical Insight into Gestational Diabetes DOI: http://dx.doi.org/10.5772/intechopen.85892*

*5.2.2.4 Insulin degludec U-100 and U-200*

They are long-acting analogues approved by the US Food and Drug Administration (FDA) in September 2015. The U-100 and the U-200 are considered bioequivalent. Insulin degludec is extracted by means of recombinant DNA technology implemented in *S. cerevisiae*, to avoid potential reaction to the yeast, if allergic. Insulin degludec's slow absorption into blood and prolonged action are attributed to the formation of soluble multi-hexamers. Its onset of action is ~1 hour and takes 8 days to reach steady state, and, once achieved, its duration of action lasts for 42 hours. It is usually administered once daily at any time of the day due to its long duration of action. Noncompliant patients may inject their dose at intervals of 8–40 hours without significant decreases in glycosylated haemoglobin (HbA1C) compared to taking it at the same time every day. U-100 degludec and U-200 degludec are only dispensed in pens to decrease administration errors. Pens are

Insulin in the form of inhalational powder is a newer form of insulin introduced in recent years. Human insulin inhalation powder was approved by the FDA in 2014. Inhaled human insulin is produced in *Escherichia coli* and is adsorbed onto fumaryl diketopiperazine and polysorbate 80 carrier particles. Inhalation powder is equivalent unit for unit to insulin lispro. Its onset is 12–15 minutes, and it takes ~57 minutes to reach peak levels in plasma. The duration of action is ~2 hours. Inhaled human insulin is contraindicated in patients with chronic pulmonary obstructive disease as it may precipitate chronic bronchospasm. Sealed blister cards at room temperature must be discarded after 10 days. If kept in the refrigerator, they are

A new advent in the field of glucose-lowering agents is glyburides. It is an oral hypoglycaemic class of drugs used for the management of type-II diabetes mellitus. Pharmacologically it belongs to sulphonylurea class of insulin secretagogues. These agents stimulate β cells of the pancreas to release insulin. The members of this class have different binding sites on their target pancreatic β-cell receptor. Their dose, rate of absorption, duration of action and route of elimination also differ from the conventional hypoglycaemic agents. Apart from lowering the blood glucose level directly, glyburide also increases peripheral glucose utilisation, decreases hepatic gluconeogenesis and may increase the number and sensitivity of insulin receptors. Glyburides proved to be advantageous over insulin because weight gain associated with it is less than in the case of insulin. However, one of its fallacies is that it may cause hypoglycaemia and require consistent food intake to decrease this risk. The risk of hypoglycaemia is increased in elderly, debilitated and malnourished individuals. Glyburide has been shown to decrease fasting plasma glucose, postprandial blood glucose and glycosylated haemoglobin (HbA1c) levels. It is metabolised in the liver. Its metabolites are excreted in urine and faeces in approximately equal proportions [96].

It is prescribed to be taken at meal time to lower the blood glucose level in patients with non-insulin-dependent diabetes mellitus where hyperglycaemia can-

good for up to 56 days at room temperature while in use [93].

**5.3 Novel drug delivery system for insulin**

good for use up to 1 month (**Figure 2**)[94, 95].

**5.4 Glyburides-new hypoglycaemic drugs**

*Gestational Diabetes Mellitus - An Overview with Some Recent Advances*

*5.2.1.3 Insulin aspartate*

site reaction [90].

while in use [91].

*5.2.2.1 Insulin isophane (NPH)*

*5.2.2.2 Insulin detemir (U-100)*

*5.2.2.3 Insulin glargine (U-100)*

whereas pens can be used for 14 days [92].

*5.2.1.4 Insulin lispro (U-100 and U-200)*

*5.2.2 Intermediate insulin and long-acting insulin analogues*

after the initial dose, although there are clinical reports suggesting that in pregnancy, severe hypoglycaemia is rare with U-500 insulin. Two to three injections daily are required, and a U-500 vial is good for 40 days at room temperature while in use [87–89].

It is produced in a type of yeast, *Saccharomyces cerevisiae*, and is homologous

It is an analogue produced in *Escherichia coli*. Its onset of action is 10–15 minutes, peak action is attained in 30–90 minutes and the duration of action is 3–4 hours. Intraperitoneal injections are preferred for the maximum absorption and shortest duration of action. It can be used in the form of insulin pumps or as multiple daily injections. The U-100 and U-200 formulations are bioequivalent, having the same pharmacokinetics. Insulin lispro U-200 is only available in pens to avoid administration errors. Pens, penfills and vials can be stored for 28 days at room temperature

It is a U-100, intermediate-acting insulin. It is produced in *Escherichia coli* and is identical to human insulin available as a suspension. The onset of action is 1–2 hours, with an average peak action of 4 hours (range, 4–8 hours). Duration of action lasts for 10–20 hours. Vials remain usable for 31 days at room temperature,

This is a long-acting analogue of insulin produced in *S. cerevisiae*. One of the setbacks with this formulation is that it can potentially cause a reaction in patients who are allergic to yeast. Detemir lacks a defined peak of action, but the pharmacological action lasts for up to 20 hours. The time to onset of action ranges between 1 and 2 hours. The pen and vial can be used up to 42 days at room temperature while in use. The chances of developing hypoglycaemia with detemir are less than NPH in pregnant women [93].

It is a long-acting analogue produced in *Escherichia coli.* It differs from other contemporaries in terms of its distribution in plasma; the acidic solution is neutralised in subcutaneous tissue to form microprecipitates. These microprecipitates slowly release glargine over a duration of 24 hours, resulting in no well-defined peak. Its onset of action is 1–2 hours. Vials and pens are reusable for 28 days at room temperature.

to human insulin. It should be taken 5–10 minutes prior to meals. It can be administered as injections or in an insulin pump. The time of peak concentration ranges between 40 and 50 minutes, and the duration of action is 3–5 hours. It is also available in the forms of pens, penfills and vials that retain their pharmacological potency for at least 28 days at room temperature while in use. The risk of developing hypoglycaemia with insulin aspartate is less than regular insulin, although patients allergic to yeast must avoid it as this could potentially cause a

**16**

#### *5.2.2.4 Insulin degludec U-100 and U-200*

They are long-acting analogues approved by the US Food and Drug Administration (FDA) in September 2015. The U-100 and the U-200 are considered bioequivalent. Insulin degludec is extracted by means of recombinant DNA technology implemented in *S. cerevisiae*, to avoid potential reaction to the yeast, if allergic. Insulin degludec's slow absorption into blood and prolonged action are attributed to the formation of soluble multi-hexamers. Its onset of action is ~1 hour and takes 8 days to reach steady state, and, once achieved, its duration of action lasts for 42 hours. It is usually administered once daily at any time of the day due to its long duration of action. Noncompliant patients may inject their dose at intervals of 8–40 hours without significant decreases in glycosylated haemoglobin (HbA1C) compared to taking it at the same time every day. U-100 degludec and U-200 degludec are only dispensed in pens to decrease administration errors. Pens are good for up to 56 days at room temperature while in use [93].

#### **5.3 Novel drug delivery system for insulin**

Insulin in the form of inhalational powder is a newer form of insulin introduced in recent years. Human insulin inhalation powder was approved by the FDA in 2014. Inhaled human insulin is produced in *Escherichia coli* and is adsorbed onto fumaryl diketopiperazine and polysorbate 80 carrier particles. Inhalation powder is equivalent unit for unit to insulin lispro. Its onset is 12–15 minutes, and it takes ~57 minutes to reach peak levels in plasma. The duration of action is ~2 hours. Inhaled human insulin is contraindicated in patients with chronic pulmonary obstructive disease as it may precipitate chronic bronchospasm. Sealed blister cards at room temperature must be discarded after 10 days. If kept in the refrigerator, they are good for use up to 1 month (**Figure 2**)[94, 95].

#### **5.4 Glyburides-new hypoglycaemic drugs**

A new advent in the field of glucose-lowering agents is glyburides. It is an oral hypoglycaemic class of drugs used for the management of type-II diabetes mellitus. Pharmacologically it belongs to sulphonylurea class of insulin secretagogues. These agents stimulate β cells of the pancreas to release insulin. The members of this class have different binding sites on their target pancreatic β-cell receptor. Their dose, rate of absorption, duration of action and route of elimination also differ from the conventional hypoglycaemic agents. Apart from lowering the blood glucose level directly, glyburide also increases peripheral glucose utilisation, decreases hepatic gluconeogenesis and may increase the number and sensitivity of insulin receptors. Glyburides proved to be advantageous over insulin because weight gain associated with it is less than in the case of insulin. However, one of its fallacies is that it may cause hypoglycaemia and require consistent food intake to decrease this risk. The risk of hypoglycaemia is increased in elderly, debilitated and malnourished individuals. Glyburide has been shown to decrease fasting plasma glucose, postprandial blood glucose and glycosylated haemoglobin (HbA1c) levels. It is metabolised in the liver. Its metabolites are excreted in urine and faeces in approximately equal proportions [96].

#### *5.4.1 Indication*

It is prescribed to be taken at meal time to lower the blood glucose level in patients with non-insulin-dependent diabetes mellitus where hyperglycaemia cannot be controlled by diet alone.

#### **Figure 2.** *Insulin therapy for GD*\**.*

#### *5.4.2 Half-life (t 1/2) and duration of action*

The half-life of unchanged drug lies between 1 and 2 hours and its metabolites have an extended half-life of 10 hours. Duration of action is 12–24 hours.

#### *5.4.3 Side effects*

Nausea, heartburn, stomach fullness and weight gain may occur.

#### *5.4.4 Precautions*


**19**

**Table 3.**

*A Clinical Insight into Gestational Diabetes DOI: http://dx.doi.org/10.5772/intechopen.85892*

**Hypoglycaemia Considerations**

Symptoms • Hunger

Causes • Extensive physical activity

• Insulin overdose

• Irritability • Blurred vision

• 5–7 glucose candies

hyperglycaemia

future

present

• Glass of soft drink rich in calories

serve of fast-acting carbohydrates

Lifestyle management • Plan to eat regular meals with adequate carbohydrate serves

*Aspects surrounding hypoglycaemia in women under oral hypoglycaemic drugs or insulin.*

• Light headedness/headache • Sweating/shaking/weakness • Tingling around the lips

blood sugar.

caemia and may cause disulfiram-like reaction.

Pregnancy may cause or worsen diabetes.

• Alcohol intake must be avoided under its medication as it aggravates hypogly-

• Older adults may be more sensitive to the side effects of this drug, especially low

• During pregnancy, this medication should be used only when clearly needed.

Criteria • *Mild hypoglycaemia:* Blood glucose level is <4.0 mmol/L and may or may not be associated with symptoms of a low blood glucose level

requires third-party assistance to manage the episode

of consciousness and requires urgent medical treatment

• Three-heaped teaspoons of sugar or honey dissolved in water

Treatment • Consume one 15-g serve of fast-acting carbohydrates (one of the following)

• Lack or inadequate carbohydrate in meal • Alcohol consumption (decreases blood glucose)

• *Severe hypoglycaemia:* Blood glucose level is very low, generally <3.0 mmol/L, and is associated with confusion and potential loss of consciousness. The woman

• Severe hypoglycaemia (when unable to self-treat) can lead to confusion and loss

• If after 15 minutes symptoms persist or BGL is less than 4.0 mmol/L, repeat one

• Do not overtreat with fast-acting carbohydrates as this may lead to rebound

• Eat a snack (e.g. sandwich or glass of milk) or usual meal if within 30 minutes

• Be prepared and carry a food snack at all times (including while exercising) • Aim to take long- or intermediate-acting insulin at the same time each day • Identify causal factors of the hypoglycaemic episode and avoid/mitigate for the

• Carry blood glucose metre at all times so BGL can be checked if symptoms

• When BGL is 4.0 mmol/L or above, eat longer-lasting carbohydrate

• Avoid overtreatment of hypoglycaemia resulting in hyperglycaemia

• Document BGL and time of hypoglycaemic episode

*Gestational Diabetes Mellitus - An Overview with Some Recent Advances*

**18**

*5.4.3 Side effects*

*Insulin therapy for GD*\**.*

**Figure 2.**

*5.4.4 Precautions*

*5.4.2 Half-life (t 1/2) and duration of action*

• Contraindicated in hypersensitive patients.

The half-life of unchanged drug lies between 1 and 2 hours and its metabolites

• Given the high risk of hypoglycaemia associated with it. Patients must be counselled to avoid driving, the use of machinery or any activity that requires alertness or clear vision as low blood glucose levels may cause drowsiness, fatigue and blurred vision.

have an extended half-life of 10 hours. Duration of action is 12–24 hours.

Nausea, heartburn, stomach fullness and weight gain may occur.



**Table 3.**

*Aspects surrounding hypoglycaemia in women under oral hypoglycaemic drugs or insulin.*


#### **5.5 Monitoring blood glucose levels in GD mothers**

The blood glucose monitoring in gestational diabetic cases remains a bone of contention amongst clinicians worldwide. There have been various cohort studies propounding different procedures for blood glucose level monitoring. Some suggest the evaluation of HbA1C levels as accurate parameter; others suggest ultrasonography and laboratory testing of postprandial blood glucose levels every 2 weeks. For women whose fasting blood glucose levels remain <105 md/dL are well managed alone with medical nutrition therapy, whereas for those whose blood glucose levels are >105 mg/dL require additional medical assistance including insulin therapy. The foetal abdominal circumference (AC) is also considered a pivotal parameter for monitoring the GD mothers. If the foetal AC is <70th percentile at 30 weeks, perinatal outcomes will be free from any complications with continued management on diet therapy and without glucose self-monitoring. The excess risk of macrosomia is attributed to women with a foetal AC >70th percentile at 30 weeks. Such pregnancies will benefit only from aggressive glucose lowering by insulin therapy. The fasting or preprandial glucose targets of 60–80 mg/dL have to be met in such cases to eliminate the excess risk of stillbirth [98–101].

#### **5.6 Hypoglycaemia**

Hypoglycaemia is uncommon in women with GD who are only on MNT; the risk of developing hypoglycaemia is however increased in women on pharmacotherapy, i.e. insulin or metformin. Hypoglycaemia incurs potent hazards to the health of the foetus. Hence, management of hypoglycaemia is also a crucial aspect in GD. If hypoglycaemia is asymptomatic, BGL results must be confirmed prior to starting the treatment (**Table 3**)[102].

#### **6. Special obstetric care for pregnant women with GD**

#### **6.1 Antenatal care (ANC)**

Antenatal care is defined as the procedure of regular check-ups that allow clinicians to treat and prevent potential health problems throughout the course of the pregnancy and to promote healthy lifestyles that benefit both the mother and child. In the case of pregnant women with GD, they must be closely monitored. GD women who are diagnosed before 20 weeks of pregnancy undergo foetal anatomical survey by means of ultrasonography within 18–20 weeks of pregnancy.

At 28–30 weeks of gestation, a foetal growth scan should be performed and repeated at 34–36 weeks of gestation. There should be at least 3-week gap between the two ultrasounds, and it should include foetal biometry and amniotic fluid estimation.

In GD women having uncontrolled blood glucose level or any other complication of pregnancy, the antenatal visits should be programmed at least once monthly as per the protocol for high-risk pregnancy.

**21**

*A Clinical Insight into Gestational Diabetes DOI: http://dx.doi.org/10.5772/intechopen.85892*

Monitoring of abnormal foetal growth and amniotic fluid volume for growth restriction and polyhydramnios, respectively, at each ANC visit is clinically important. Pregnant women with GD should be diligently monitored for gestational

Antenatal steroids in pregnant women with GD between 24 and 34 weeks of gestation requiring early delivery should be administered as per standardised guidelines. Most guidelines like FIGO suggest dexamethasone injection. More vigilant monitoring of blood glucose levels should be done for the next 72 hours following injection. In the case of raised blood glucose levels during this period, adjustment of

The rate of foetal morbidity in pregnant women with GD is more than the normal ones. This risk is further accelerated in pregnant women under drug management. Hence vigilant foetal surveillance is required that includes foetal heart rate

Pregnant women with GD but well controlled of blood glucose (2-hour PPBS <120 mg/dL) levels may be delivered at their respective health facility just like any normal pregnant woman. However, pregnant women with GD on insulin therapy with uncontrolled blood glucose levels (2-hour PPBS ≥120 mg/dL) on MNT and physical exercise and metformin or insulin requirement >20 U/day should be referred at 34–36 weeks for delivery planning at Comprehensive Emergency Obstetric Care (CEmOC) centres under supervi-

Most GD pregnancies are associated with delayed lung maturity of the foetus; hence routine delivery prior to 39 weeks is not recommended. Such referred cases must get assured indoor admission or can be kept in a birth waiting home with

If pregnant women with GD present poor blood glucose levels, accompanied with risk factors like gestational hypertension, previous stillbirth and other complications, then the timing of delivery has to be individualised by the obstetrician

Vaginal delivery is preferred, and lower segment caesarean section (LSCS) is done for obstetric indications only such as in the case of foetal macrosomia, a condition where the estimated foetal weight is >4 kg where vaginal delivery may cause

Regular blood glucose monitoring of the pregnant women with GD on metformin or insulin is required during labour. The morning dose of insulin/metformin is withheld on the day of induction of labour, and pregnant women are subjected to 2

IV infusion with normal saline (NS) is to be started and regular insulin to be

added according to blood glucose levels as per **Table 4** [105–108].

Managing the delivery timing in GD mother is very crucial if pregnant women with GD and well-controlled blood glucose have not undergone parturition spontaneously; induction of labour should be scheduled at or after 39 weeks

hypertension, proteinuria and other obstetric complications.

**6.2 Monitoring foetal health in pregnant women with GD**

monitoring by auscultation on each antenatal care visit [105, 106].

round-the-clock availability of gynaecologist for monitoring.

insulin dose should be made as required [103–105].

**6.3 Management of parturition in the case of GD**

sion of a gynaecologist [107].

shoulder dystocia in the newborn.

hourly monitoring of blood glucose.

**6.4 Timing of delivery**

of pregnancy.

accordingly.

#### *A Clinical Insight into Gestational Diabetes DOI: http://dx.doi.org/10.5772/intechopen.85892*

*Gestational Diabetes Mellitus - An Overview with Some Recent Advances*

your newborn.

drugs pass into breast milk [97].

**5.5 Monitoring blood glucose levels in GD mothers**

to eliminate the excess risk of stillbirth [98–101].

**6. Special obstetric care for pregnant women with GD**

**5.6 Hypoglycaemia**

the treatment (**Table 3**)[102].

**6.1 Antenatal care (ANC)**

per the protocol for high-risk pregnancy.

• If glyburide is used, it may be switched to insulin at least 2 weeks before the expected delivery date because of glyburide's risk of causing low blood sugar in

• It is unknown if this medication passes into breast milk. However, similar

The blood glucose monitoring in gestational diabetic cases remains a bone of contention amongst clinicians worldwide. There have been various cohort studies propounding different procedures for blood glucose level monitoring. Some suggest the evaluation of HbA1C levels as accurate parameter; others suggest ultrasonography and laboratory testing of postprandial blood glucose levels every 2 weeks. For women whose fasting blood glucose levels remain <105 md/dL are well managed alone with medical nutrition therapy, whereas for those whose blood glucose levels are >105 mg/dL require additional medical assistance including insulin therapy. The foetal abdominal circumference (AC) is also considered a pivotal parameter for monitoring the GD mothers. If the foetal AC is <70th percentile at 30 weeks, perinatal outcomes will be free from any complications with continued management on diet therapy and without glucose self-monitoring. The excess risk of macrosomia is attributed to women with a foetal AC >70th percentile at 30 weeks. Such pregnancies will benefit only from aggressive glucose lowering by insulin therapy. The fasting or preprandial glucose targets of 60–80 mg/dL have to be met in such cases

Hypoglycaemia is uncommon in women with GD who are only on MNT; the risk of developing hypoglycaemia is however increased in women on pharmacotherapy, i.e. insulin or metformin. Hypoglycaemia incurs potent hazards to the health of the foetus. Hence, management of hypoglycaemia is also a crucial aspect in GD. If hypoglycaemia is asymptomatic, BGL results must be confirmed prior to starting

Antenatal care is defined as the procedure of regular check-ups that allow clinicians to treat and prevent potential health problems throughout the course of the pregnancy and to promote healthy lifestyles that benefit both the mother and child. In the case of pregnant women with GD, they must be closely monitored. GD women who are diagnosed before 20 weeks of pregnancy undergo foetal anatomical

At 28–30 weeks of gestation, a foetal growth scan should be performed and repeated at 34–36 weeks of gestation. There should be at least 3-week gap between the two ultrasounds, and it should include foetal biometry and amniotic fluid

In GD women having uncontrolled blood glucose level or any other complication of pregnancy, the antenatal visits should be programmed at least once monthly as

survey by means of ultrasonography within 18–20 weeks of pregnancy.

**20**

estimation.

Monitoring of abnormal foetal growth and amniotic fluid volume for growth restriction and polyhydramnios, respectively, at each ANC visit is clinically important. Pregnant women with GD should be diligently monitored for gestational hypertension, proteinuria and other obstetric complications.

Antenatal steroids in pregnant women with GD between 24 and 34 weeks of gestation requiring early delivery should be administered as per standardised guidelines. Most guidelines like FIGO suggest dexamethasone injection. More vigilant monitoring of blood glucose levels should be done for the next 72 hours following injection. In the case of raised blood glucose levels during this period, adjustment of insulin dose should be made as required [103–105].

#### **6.2 Monitoring foetal health in pregnant women with GD**

The rate of foetal morbidity in pregnant women with GD is more than the normal ones. This risk is further accelerated in pregnant women under drug management. Hence vigilant foetal surveillance is required that includes foetal heart rate monitoring by auscultation on each antenatal care visit [105, 106].

#### **6.3 Management of parturition in the case of GD**

Pregnant women with GD but well controlled of blood glucose (2-hour PPBS <120 mg/dL) levels may be delivered at their respective health facility just like any normal pregnant woman. However, pregnant women with GD on insulin therapy with uncontrolled blood glucose levels (2-hour PPBS ≥120 mg/dL) on MNT and physical exercise and metformin or insulin requirement >20 U/day should be referred at 34–36 weeks for delivery planning at Comprehensive Emergency Obstetric Care (CEmOC) centres under supervision of a gynaecologist [107].

#### **6.4 Timing of delivery**

Most GD pregnancies are associated with delayed lung maturity of the foetus; hence routine delivery prior to 39 weeks is not recommended. Such referred cases must get assured indoor admission or can be kept in a birth waiting home with round-the-clock availability of gynaecologist for monitoring.

Managing the delivery timing in GD mother is very crucial if pregnant women with GD and well-controlled blood glucose have not undergone parturition spontaneously; induction of labour should be scheduled at or after 39 weeks of pregnancy.

If pregnant women with GD present poor blood glucose levels, accompanied with risk factors like gestational hypertension, previous stillbirth and other complications, then the timing of delivery has to be individualised by the obstetrician accordingly.

Vaginal delivery is preferred, and lower segment caesarean section (LSCS) is done for obstetric indications only such as in the case of foetal macrosomia, a condition where the estimated foetal weight is >4 kg where vaginal delivery may cause shoulder dystocia in the newborn.

Regular blood glucose monitoring of the pregnant women with GD on metformin or insulin is required during labour. The morning dose of insulin/metformin is withheld on the day of induction of labour, and pregnant women are subjected to 2 hourly monitoring of blood glucose.

IV infusion with normal saline (NS) is to be started and regular insulin to be added according to blood glucose levels as per **Table 4** [105–108].


**Table 4.**

*Rate and amount of insulin-normal saline infusion in relation to blood glucose level.*

#### *6.4.1 Neonatal care for baby of a GD mother*

Immediate and timely management of all neonates in a proper NICU facility emphasising on early breastfeeding is done on a priority basis to prevent hypoglycaemia. Under any emergency situations, the sick neonates must be immediately resuscitated as per standard guidelines.

Hypoglycaemia monitoring of the newborn is started within an hour of delivery and repeated every 4 hours (prior to next feed) until four stable glucose values are obtained.

The newborn with the normal birth weight and blood glucose level of <45 mg/dL is considered hypoglycaemic and requires immediate medical management. In the case of intrauterine growth restriction (IUGR), newborns' Blood Glucose level limit is <54 mg/dL [108].

#### *6.4.2 Diagnosis of hypoglycaemia*

The glucometers' testing method is not very reliable for diagnosis of hypoglycaemia as their precision decreases at lower blood glucose level. The most definite diagnosis of hypoglycaemia is by measurement of blood glucose using established laboratory methods such as glucose oxidase method by calorimeter. However, if laboratory facility is unavailable at the place of childbirth, then the treating physician can take a decision to send a blood glucose sample to the laboratory at the nearest location without delaying the next management step. However, under adverse circumstances, blood glucose values obtained by glucometers may be considered for all operational steps if it's the question of newborn's wellbeing.

#### *6.4.3 Symptoms of hypoglycaemia*

Symptoms of hypoglycaemia are difficult to observe as in most cases it is asymptomatic, variable and observed only in a smaller proportion of patients or newborns:

**23**

*A Clinical Insight into Gestational Diabetes DOI: http://dx.doi.org/10.5772/intechopen.85892*

*6.4.4 Management of hypoglycaemia in newborn*

• Any unexplained clinical feature in baby of diabetic mother

available at the facility, then it can also be involved in feeding the baby.

All cases of newborn with hypoglycaemia should be managed in the following

Whether there are any symptoms of hypoglycaemia or not, if a baby is born to a GD mother, its blood glucose level must be checked immediately between 1 and 2 hours after birth. If blood glucose values are <45 mg/dL, this should be considered as 'hypoglycaemia'. The primary management in such cases is that the newborn should be given breastfeed without any delay. Direct breastfeeding is the best management step for neonatal hypoglycaemia. If the infant is unable to suck, expressed breast milk from the mother should be given. If the mother is not in a position to give breastfeed or in the case of no breast milk secretion, the baby should be given any formula feed. If the lactation management centres (human milk banks) are

After an hour of breastfeeding the newborn, blood glucose level must be monitored again. If it is found to be more than 45 mg/dL, 2 hourly feeding (breastfeeding if not available, formula feed can be given) should be ensured by explaining to the

If at any point of time the blood glucose level drops below 20 mg/dL, immediate intravenous bolus injection of 10% dextrose at 2 mL/kg body weight of baby should be given. This should be followed by intravenous infusion of 10% of dextrose at a rate of 100 mL/kg/day. Blood glucose should be checked 30 minutes after starting the infusion. If it is still less than 20 mg/dL, the infant should be referred to a higher

Immediate postpartum care required for women with GD is a lot similar to that for women without GD, but these women are at high risk to develop type 2 diabetes mellitus in the future, although in 80% of cases, the glucose level usually returns to

Subsequently, ANC must be performed 75-g OGTT (fasting and 2-hour PP) at 6 weeks postpartum to evaluate glycaemic status of a woman. Cut-off for normal plasma and abnormal blood glucose levels in the fasting and 75-g OGTT values are

• Difficulty in feeding

• Episodes of sweating

mother/relatives and supervised.

centre where a paediatrician is available [109, 110].

• Fasting blood glucose (≥126 mg/dL)

• 75-g OGTT (2-hour blood glucose)

*6.4.5 Postdelivery follow-up of pregnant women with GD*

• Eye rolling

manner:

*6.4.4.1 Step 1*

*6.4.4.2 Step 2*

normal postdelivery.

[111–113]:


*A Clinical Insight into Gestational Diabetes DOI: http://dx.doi.org/10.5772/intechopen.85892*


*Gestational Diabetes Mellitus - An Overview with Some Recent Advances*

*Rate and amount of insulin-normal saline infusion in relation to blood glucose level.*

**Blood glucose level Amount of insulin to be added in** 

Immediate and timely management of all neonates in a proper NICU facility emphasising on early breastfeeding is done on a priority basis to prevent hypoglycaemia. Under any emergency situations, the sick neonates must be immediately

**500 mL of NS**

90–120 mg/dL 0 100 ml/hour (16 drops/min) 120–140 mg/dL 4 U 100 ml/hour (16 drops/min) 140–180 mg/dL 6 U 100 ml/hour (16 drops/min) >180 mg/dL 8 U 100 ml/hour (16 drops/min)

**Rate of NS infusion**

Hypoglycaemia monitoring of the newborn is started within an hour of delivery and repeated every 4 hours (prior to next feed) until four stable glucose values are obtained. The newborn with the normal birth weight and blood glucose level of <45 mg/dL is considered hypoglycaemic and requires immediate medical management. In the case of intrauterine growth restriction (IUGR), newborns' Blood Glucose level limit

The glucometers' testing method is not very reliable for diagnosis of hypoglycaemia as their precision decreases at lower blood glucose level. The most definite diagnosis of hypoglycaemia is by measurement of blood glucose using established laboratory methods such as glucose oxidase method by calorimeter. However, if laboratory facility is unavailable at the place of childbirth, then the treating physician can take a decision to send a blood glucose sample to the laboratory at the nearest location without delaying the next management step. However, under adverse circumstances, blood glucose values obtained by glucometers may be considered for

Symptoms of hypoglycaemia are difficult to observe as in most cases it is asymptomatic, variable and observed only in a smaller proportion of patients or

all operational steps if it's the question of newborn's wellbeing.

*6.4.1 Neonatal care for baby of a GD mother*

resuscitated as per standard guidelines.

is <54 mg/dL [108].

**Table 4.**

*6.4.2 Diagnosis of hypoglycaemia*

*6.4.3 Symptoms of hypoglycaemia*

• Stupor or apathy

• Jitteriness or tremors

• Episodes of cyanosis

• Intermittent apnoeic spells or tachypnoea

• Weak and high-pitched cry, limpness and lethargy

• Convulsions

**22**

newborns:


#### *6.4.4 Management of hypoglycaemia in newborn*

All cases of newborn with hypoglycaemia should be managed in the following manner:

#### *6.4.4.1 Step 1*

Whether there are any symptoms of hypoglycaemia or not, if a baby is born to a GD mother, its blood glucose level must be checked immediately between 1 and 2 hours after birth. If blood glucose values are <45 mg/dL, this should be considered as 'hypoglycaemia'. The primary management in such cases is that the newborn should be given breastfeed without any delay. Direct breastfeeding is the best management step for neonatal hypoglycaemia. If the infant is unable to suck, expressed breast milk from the mother should be given. If the mother is not in a position to give breastfeed or in the case of no breast milk secretion, the baby should be given any formula feed. If the lactation management centres (human milk banks) are available at the facility, then it can also be involved in feeding the baby.

After an hour of breastfeeding the newborn, blood glucose level must be monitored again. If it is found to be more than 45 mg/dL, 2 hourly feeding (breastfeeding if not available, formula feed can be given) should be ensured by explaining to the mother/relatives and supervised.

#### *6.4.4.2 Step 2*

If at any point of time the blood glucose level drops below 20 mg/dL, immediate intravenous bolus injection of 10% dextrose at 2 mL/kg body weight of baby should be given. This should be followed by intravenous infusion of 10% of dextrose at a rate of 100 mL/kg/day. Blood glucose should be checked 30 minutes after starting the infusion. If it is still less than 20 mg/dL, the infant should be referred to a higher centre where a paediatrician is available [109, 110].

#### *6.4.5 Postdelivery follow-up of pregnant women with GD*

Immediate postpartum care required for women with GD is a lot similar to that for women without GD, but these women are at high risk to develop type 2 diabetes mellitus in the future, although in 80% of cases, the glucose level usually returns to normal postdelivery.

Subsequently, ANC must be performed 75-g OGTT (fasting and 2-hour PP) at 6 weeks postpartum to evaluate glycaemic status of a woman. Cut-off for normal plasma and abnormal blood glucose levels in the fasting and 75-g OGTT values are [111–113]:


#### **7. Conclusion**

This chapter summarises all the clinical aspects surrounding gestational diabetes, ranging from its pathophysiology, aetiology right to its proper clinical management, for both the mother and the newborn, to a GD mother. Pregnancy affects both the maternal and foetal metabolisms, and even the nondiabetic woman exerts a diabetogenic effect. Amongst pregnant women, 2–17.8% develop GD. Metabolic changes in the normal pregnant women also have a degree of insulin resistance that shunts glucose preferentially to the foetus. To maintain blood glucose levels within a tight range, the normal pregnant woman must increase her insulin secretion up to fourfold. When the pancreas is not able to compensate for the increased insulin needs of pregnancy, GD occurs resulting in hyperglycaemia and hyperinsulinemia.

#### **Acknowledgements**

The authors are highly thankful to Prof. S.W. Akhtar, Hon'ble Chancellor Integral University, and Prof. Syed Misbahul Hasan, Dean of the Faculty of Pharmacy, Integral University, Lucknow, India, for providing an academically rich environment in the university's infrastructure to explore and study extensively into clinically relevant fields.

#### **Conflict of interest**

The authors declare that there are no 'conflicts of interest' in regard to this chapter's contents.

**25**

**Author details**

HH Siddiqui1

Farogh Ahsan2

provided the original work is properly cited.

, Tarique Mahmood2†

and Arshiya Shamim2

\*Address all correspondence to: arshiyas@iul.ac.in

1 Faculty of Pharmacy, Integral University, Lucknow, India

*A Clinical Insight into Gestational Diabetes DOI: http://dx.doi.org/10.5772/intechopen.85892*

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

, Mohd. Haris Siddiqui1

\* †

2 Department of Bioengineering, Integral University, Lucknow, India

† These authors have equally contributed in structuring the chapter.

, Paramdeep Bagga2

,

#### **Notes/thanks/other declarations**

None.

#### **List of abbreviations**


*A Clinical Insight into Gestational Diabetes DOI: http://dx.doi.org/10.5772/intechopen.85892*

*Gestational Diabetes Mellitus - An Overview with Some Recent Advances*

This chapter summarises all the clinical aspects surrounding gestational diabetes, ranging from its pathophysiology, aetiology right to its proper clinical management, for both the mother and the newborn, to a GD mother. Pregnancy affects both the maternal and foetal metabolisms, and even the nondiabetic woman exerts a diabetogenic effect. Amongst pregnant women, 2–17.8% develop GD. Metabolic changes in the normal pregnant women also have a degree of insulin resistance that shunts glucose preferentially to the foetus. To maintain blood glucose levels within a tight range, the normal pregnant woman must increase her insulin secretion up to fourfold. When the pancreas is not able to compensate for the increased insulin needs of pregnancy, GD occurs resulting in hyperglycaemia and hyperinsulinemia.

The authors are highly thankful to Prof. S.W. Akhtar, Hon'ble Chancellor Integral University, and Prof. Syed Misbahul Hasan, Dean of the Faculty of Pharmacy, Integral University, Lucknow, India, for providing an academically rich environment in the university's infrastructure to explore and study extensively into

The authors declare that there are no 'conflicts of interest' in regard to this

• Normal (<140 mg/dL)

• IGT (140–199 mg/dL)

• Diabetes (≥200 mg/dL)

**7. Conclusion**

**Acknowledgements**

clinically relevant fields.

**Conflict of interest**

**List of abbreviations**

ANC antenatal care BMI body mass index BMR basal metabolic rate

GD gestational diabetes IGT impaired glucose tolerance IUGR intrauterine growth restriction LSCS lower segment caesarean section MNT medical nutrition therapy NCD non-communicable diseases OGTT oral glucose tolerance test PPBS postprandial blood sugar

CEmOC comprehensive emergency obstetric care

**Notes/thanks/other declarations**

chapter's contents.

None.

**24**

### **Author details**

HH Siddiqui1 , Tarique Mahmood2† , Mohd. Haris Siddiqui1 , Paramdeep Bagga2 , Farogh Ahsan2 and Arshiya Shamim2 \* †

1 Faculty of Pharmacy, Integral University, Lucknow, India

2 Department of Bioengineering, Integral University, Lucknow, India

\*Address all correspondence to: arshiyas@iul.ac.in

† These authors have equally contributed in structuring the chapter.

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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[82] Russo LM, Nobles C, Ertel KA, Chasan-Taber L, Whitcomb BW. Physical activity interventions in pregnancy and risk of gestational diabetes. Obstetrics and Gynecology.

[83] Thangaratinam S, Rogozinska E, Jolly K, Glinkowski S, Duda W, Borowiack E, et al. Interventions to reduce or prevent obesity in

pregnant women: A systematic review. Health Technology Assessment.

2015;**125**(3):576-582

2012;**16**(31):1-191

Australia. 2013;**198**(3):1-8

[70] Han S, Crowther C, Middleton P. Interventions for pregnant women with hyperglycaemia not meeting gestational diabetes and type 2 diabetes diagnostic

Systematic Reviews. 2012;**1**:CD009037. DOI: 10.1002/14651858.CD009037.

[72] Schmidt MI, Duncan BB, Reichelt AJ, Branchtein L, Matos MC, Costa e Forti A, et al. Gestational diabetes diagnosed with a 2-h 75-g oral glucose tolerance test and adverse pregnancy outcomes. Diabetes Care. 2001;**24**(7):1151-1155

[73] MacNeill S, Dodds L, Hamilton DC, Armson BA, VandenHof M. Rates and risk factors for recurrence of gestational diabetes. Diabetes Care.

[74] Metzger BE, Buchanan TA, Coustan DR, de Leiva A, Dunger DB, Hadden DR, et al. Summary and recommendations of the fifth international workshop-conference on gestational diabetes. Diabetes Care.

2007;**30**(Suppl 2):S251-S260

Publication No.09-EHC014-3. Queensland Clinical Guideline: Gestational Diabetes Refer to Online Version, Destroy Printed Copies After

Use Page 33 of 38; 2009

[75] Agency for Healthcare Research and Quality. Gestational diabetes: Caring for women during and after pregnancy.

[76] Malcolm JC, Lawson ML, Gaboury I, Lough G, Keely E. Glucose tolerance of offspring of mother with gestational

criteria. Cochrane Database of

[71] Wendland EM, Torloni MR, Falavigna M, Trujillo J, Dode MA, Campos MA, et al. Gestational diabetes and pregnancy outcomes-a systematic review of the World Health Organization (WHO) and the International Association of Diabetes in pregnancy study groups (IADPSG) diagnostic criteria. BMC Pregnancy and

Childbirth. 2012;**12**:23

2001;**24**(4):659-662

pub2.2012

**30**

[84] Tobias D, Zhang C, van Dam R, Bower K, Hu F. Physical activity before and during pregnancy and risk of gestational diabetes. Diabetes Care. 2011;**34**:223-229

[85] Humulin R. U-100 Package Insert. Indianapolis, Indiana: Eli Lilly and Company; 2015

[86] Zuckerwise LC, Werner EF, Pettker CM, McMahon-Brown EK, Thung SS, Han C. Pregestational diabetes with extreme insulin resistance: Use of U-500 insulin in pregnancy. Obstetrics and Gynecology. 2012;**120**:439-442

[87] Humulin R. U-500 Package Insert. Indianapolis, Indiana: Eli Lilly and Company; 2014

[88] NovoLog. Package Insert. Bagsvaerd, Denmark: Novo Nordisk; 2015

[89] Mathiesen ER, Kinsley B, Amiel SA, et al. Maternal glycemic control and hypoglycemia in type 1 diabetic pregnancy: A randomized trial of insulin aspart versus human insulin in 322 pregnant women. Diabetes Care. 2007;**30**:771-776

[90] Humalog. Package Insert. Indianapolis, Indiana: Eli Lilly and Company; 2015

[91] Apidra. Package Insert. Bridgewater, NJ: Sanofi-Aventis; 2015

[92] Humulin N. Package Insert. Indianapolis, Indiana: Eli Lilly and Company; 2015

[93] Levemir. Package Insert. Bagsvaerd, Denmark: Novo Nordisk; 2015

[94] Herrera KM, Rosenn BM, Foroutan J, et al. Randomized controlled trial of insulin detemir versus NPH for the treatment of pregnant women with diabetes. American Journal of Obstetrics and Gynecology. 2015;**213**:426. e1-4426e7

[95] Schnedl WJ, Krause R, Halwachs-Baumann G, Trinker M, Lipp RW, Krejs GJ. Evaluation of HbA1c determination methods in patients with hemoglobinopathies. Diabetes Care. 2000;**23**(3):339-344

[96] Monami M, Luzzi C, Lamanna C, Chiasserini V, Addante F, Desideri CM, et al. Three-year mortality in diabetic patients treated with different combinations of insulin secretagogues and metformin. Diabetes/ Metabolism Research and Reviews. 2006;**22**(6):477-482

[97] Gidwani S. Solid Oral Dosage Form of Metformin and Glyburide and the Method of Preparation Thereof. U.S. Patent US20040175421, 2004

[98] de Veciana M, Major CA, Morgan MA, Asrat T, Toohey JS, Lien JM, et al. Postprandial versus preprandial blood glucose monitoring in women with gestational diabetes mellitus requiring insulin therapy. The New England Journal of Medicine. 1995;**333**:1237-1241

[99] Buchanan TA, Kjos SL, Montoro MN, Wu PYK, Madrilejo NG, Gonzalez M, et al. Use of fetal ultrasound to select metabolic therapy for pregnancies complicated by mild gestational diabetes. Diabetes Care. 1994;**17**:275-283

[100] Kjos SL, Schaefer-Graf U, Sardesi S, Peters RK, Buley A, Xiang AH, et al. A randomized controlled trial utilizing glycemic plus fetal ultrasound parameters versus glycemic parameters to determine insulin therapy in gestational diabetes with fasting hyperglycemia. Diabetes Care. 2001;**24**:1904-1910

[101] Zhu WW, Yang HX, Wei YM, Yan J, Wang ZL, Li XL, et al. Evaluation of the value of fasting plasma glucose

in the first prenatal visit to diagnose gestational diabetes in China. Diabetes Care. 2013;**36**(3):586-590

[102] Hughes RC, Moore MP, Gullam JE, Mohamed K, Rowan J. An early pregnancy HbA1c >/=5.9% (41 mmol/ Mol) is optimal for detecting diabetes and identifies women at increased risk of adverse pregnancy outcomes. Diabetes Care. 2014;**37**(11):2953-2959

[103] Balaji V, Madhuri BS, Ashalatha S, Sheela S, Suresh S, Seshiah V. A1C in gestational diabetes in Asian Indian women. Diabetes Care. 2007;**30**(7):1865-1867

[104] Fong A, Serra AE, Gabby L, Wing DA, Berkowitz KM. Use of hemoglobin A1c as an early predictor of gestational diabetes. American Journal of Obstetrics and Gynecology. 2014;**21**(641):e1-e7

[105] Jones GR, Barker G, Goodall I, Schneider HG, Shephard MD, Twigg SM. Change of HbA1c reporting to the new SI units. The Medical Journal of Australia. 2011;**195**(1):45-46

[106] Crowther CA, Hiller JE, Moss JR, McPhee AJ, Jeffries WS, Robinson JS. Effect of treatment of gestational diabetes on pregnancy outcomes. The New England Journal of Medicine. 2005;**352**(24):2477-2486

[107] East C, Dolan W, Forster D. Antenatal breast milk expression by women with diabetes for improving infant outcomes. Cochrane Database of Systematic Reviews. 2014;**7**:CD010408. DOI: 10.1002/14651858.CD010408. pub2.2014

[108] Forster DA, Jacobs S, Amir LH, Davis P, Walker SP, McEgan K, et al. Safety and efficacy of antenatal milk expressing for women with diabetes in pregnancy: Protocol for a randomised controlled trial. BMJ Open. 2014;**4**(10):e006571

[109] Soltani H, Scott AM. Antenatal breast expression in women with diabetes: Outcomes from a retrospective cohort study. International Breastfeeding Journal. 2012;**7**(1):18

[110] Ismail NAM, Raji HO, Wahab AN, Mustafa N, Kamaruddin NA, Jamil MA. Glycemic control among pregnant diabetic women on insulin who fasted during ramadan. Iranian Journal of Medical Sciences. 2011;**36**(4):254-259

[111] Black MH, Sacks DA, Xiang AH, Lawrence JM. The relative contribution of prepregnancy overweight and obesity, gestational weight gain, and IADPSG-defined gestational diabetes to fetal overgrowth. Diabetes Care. 2013;**36**(1):56-62 Available from: mdc

[112] Institute of Medicine. Weight Gain During Pregnancy. Reexamining the Guidelines. 2009. Available from: www. iom.edu [Accessed: December 05, 2014]

[113] Queensland Clinical Guidelines. Obesity in Pregnancy. Guideline No. MN15.14-V5-R20. Queensland Health. 2015. Available from: http://www. health.qld.gov.au/qcg/

**33**

Section 2

Management

Section 2

## Management

*Gestational Diabetes Mellitus - An Overview with Some Recent Advances*

[109] Soltani H, Scott AM. Antenatal

retrospective cohort study. International Breastfeeding Journal. 2012;**7**(1):18

[110] Ismail NAM, Raji HO, Wahab AN, Mustafa N, Kamaruddin NA, Jamil MA. Glycemic control among pregnant diabetic women on insulin who fasted during ramadan. Iranian Journal of Medical Sciences. 2011;**36**(4):254-259

[111] Black MH, Sacks DA, Xiang AH, Lawrence JM. The relative contribution of prepregnancy overweight and obesity, gestational weight gain, and IADPSG-defined gestational diabetes to fetal overgrowth. Diabetes Care. 2013;**36**(1):56-62 Available from: mdc

[112] Institute of Medicine. Weight Gain During Pregnancy. Reexamining the Guidelines. 2009. Available from: www. iom.edu [Accessed: December 05, 2014]

[113] Queensland Clinical Guidelines. Obesity in Pregnancy. Guideline No. MN15.14-V5-R20. Queensland Health. 2015. Available from: http://www.

health.qld.gov.au/qcg/

breast expression in women with diabetes: Outcomes from a

in the first prenatal visit to diagnose gestational diabetes in China. Diabetes

[102] Hughes RC, Moore MP, Gullam JE,

[103] Balaji V, Madhuri BS, Ashalatha S, Sheela S, Suresh S, Seshiah V. A1C in gestational diabetes in Asian Indian women. Diabetes Care.

[104] Fong A, Serra AE, Gabby L, Wing DA, Berkowitz KM. Use of hemoglobin A1c as an early predictor of gestational diabetes. American Journal of Obstetrics and Gynecology.

[105] Jones GR, Barker G, Goodall I, Schneider HG, Shephard MD, Twigg SM. Change of HbA1c reporting to the new SI units. The Medical Journal of

[106] Crowther CA, Hiller JE, Moss JR, McPhee AJ, Jeffries WS, Robinson JS. Effect of treatment of gestational diabetes on pregnancy outcomes. The New England Journal of Medicine.

Australia. 2011;**195**(1):45-46

2005;**352**(24):2477-2486

[107] East C, Dolan W, Forster D. Antenatal breast milk expression by women with diabetes for improving infant outcomes. Cochrane Database of Systematic Reviews. 2014;**7**:CD010408. DOI: 10.1002/14651858.CD010408.

[108] Forster DA, Jacobs S, Amir LH, Davis P, Walker SP, McEgan K, et al. Safety and efficacy of antenatal milk expressing for women with diabetes in pregnancy: Protocol for a randomised controlled trial. BMJ Open.

Mohamed K, Rowan J. An early pregnancy HbA1c >/=5.9% (41 mmol/ Mol) is optimal for detecting diabetes and identifies women at increased risk of adverse pregnancy outcomes. Diabetes Care. 2014;**37**(11):2953-2959

Care. 2013;**36**(3):586-590

2007;**30**(7):1865-1867

2014;**21**(641):e1-e7

**32**

pub2.2014

2014;**4**(10):e006571

**35**

**Chapter 3**

**Abstract**

oral hypoglycemic

**1. Introduction**

*Ahmed Mohamed Maged*

Treatment of Gestational Diabetes

Management of gestational diabetes mellitus (GDM) should consider both the maternal, fetal, and neonatal effects of the disease, line of treatment, and physiological changes during pregnancy. Women with GDM are classified into two categories according to their fasting blood glucose levels. Dietary control is mandatory in both classes, and the addition of pharmacological agents in those with fasting and 2-h postprandial plasma glucose levels <95 and 120 mg/dL is controversial (American College of Obstetricians and Gynecologists, 2013). Individualization of the diet in GDM according to women weight and height is recommended by the American Diabetes Association (ADA), and restriction of carbohydrate to a level that maintains normal glucose level is mandatory with individualization of the caloric intake according to women BMI and weight gain during pregnancy.

**Keywords:** gestational diabetes, management, diabetic diet, insulin, exercise,

and Gynecologists (ACOG) and American Diabetes Association [4].

fetal condition, and blood sugar levels.

height [10] through a registered dietitian [11].

**1.1 Dietary modifications**

The main aim of treatment of gestational diabetes is to prevent fetal, maternal, and neonatal complications. A randomized controlled trial which involved 1000 women with GDM showed that treatment of GDM is associated with the reduction of all neonatal complications, namely, birth injuries, shoulder dystocia, and perinatal morbidity and mortality. Treatment also reduced the rate of development of preeclampsia from 18 to 12% and the rate of large for gestational age (LGA) from 22 to 13% [1]. Even in women with mild GDM, treatment reduced the rate of LGA, the mass of neonatal fat, shoulder dystocia, cesarean section, and hypertensive disorders associating pregnancy [2, 3]. Improving the pregnancy outcome in women with GDM can be achieved through maintenance of fasting blood sugar levels <95 mg/dl (5.3 mmol/L), 1-h postprandial blood sugar <140 mg/dl (7.8 mmol/L), and 2-h postprandial blood sugar <120 mg/dl as recommended by both the American College of Obstetricians

The treatment of GDM starts with dietary modifications along with particular nutritional approaches [5–7] combined with exercise [8, 9]. If this combination failed to maintain the needed glucose levels, pharmacological treatment starts, regardless of the lines used for treatment, proper monitoring of maternal health,

Dietary counseling should be individualized according to women weight and

#### **Chapter 3**

### Treatment of Gestational Diabetes

*Ahmed Mohamed Maged*

#### **Abstract**

Management of gestational diabetes mellitus (GDM) should consider both the maternal, fetal, and neonatal effects of the disease, line of treatment, and physiological changes during pregnancy. Women with GDM are classified into two categories according to their fasting blood glucose levels. Dietary control is mandatory in both classes, and the addition of pharmacological agents in those with fasting and 2-h postprandial plasma glucose levels <95 and 120 mg/dL is controversial (American College of Obstetricians and Gynecologists, 2013). Individualization of the diet in GDM according to women weight and height is recommended by the American Diabetes Association (ADA), and restriction of carbohydrate to a level that maintains normal glucose level is mandatory with individualization of the caloric intake according to women BMI and weight gain during pregnancy.

**Keywords:** gestational diabetes, management, diabetic diet, insulin, exercise, oral hypoglycemic

#### **1. Introduction**

The main aim of treatment of gestational diabetes is to prevent fetal, maternal, and neonatal complications. A randomized controlled trial which involved 1000 women with GDM showed that treatment of GDM is associated with the reduction of all neonatal complications, namely, birth injuries, shoulder dystocia, and perinatal morbidity and mortality. Treatment also reduced the rate of development of preeclampsia from 18 to 12% and the rate of large for gestational age (LGA) from 22 to 13% [1]. Even in women with mild GDM, treatment reduced the rate of LGA, the mass of neonatal fat, shoulder dystocia, cesarean section, and hypertensive disorders associating pregnancy [2, 3].

Improving the pregnancy outcome in women with GDM can be achieved through maintenance of fasting blood sugar levels <95 mg/dl (5.3 mmol/L), 1-h postprandial blood sugar <140 mg/dl (7.8 mmol/L), and 2-h postprandial blood sugar <120 mg/dl as recommended by both the American College of Obstetricians and Gynecologists (ACOG) and American Diabetes Association [4].

The treatment of GDM starts with dietary modifications along with particular nutritional approaches [5–7] combined with exercise [8, 9]. If this combination failed to maintain the needed glucose levels, pharmacological treatment starts, regardless of the lines used for treatment, proper monitoring of maternal health, fetal condition, and blood sugar levels.

#### **1.1 Dietary modifications**

Dietary counseling should be individualized according to women weight and height [10] through a registered dietitian [11].

JSOG committee on nutrient and metabolism problems described a caloric intake of 25–30 kcal/kg (+150 Kcal for the first half and + 350 kcal for the second half of pregnancy) [12].

The Ministry of Health and Welfare recommended a caloric intake of 25–30 kcal/kg (+ 50,250 and 450 kcal for the first, second, and third trimester, respectively) [13].

The ideal diet components are not yet determined. However excessive weight gain with postprandial hyperglycemia is commonly associated with diet that included 50–60% of carbohydrate. ACOG recommended the limitation of carbohydrate to 33–40% of the required calories and the remaining 60% to be gained from proteins (20%) and fats (40%) [4].

The complex form of carbohydrates is preferable over simple ones as they are absorbed slower without producing significant hyperglycemia. Complex carbohydrates also decrease insulin resistance [6].

If the routine three meals daily failed to achieve the target blood sugar, each meal should be divided in 2:1 or 1:1 ratio to eat 4–6 meals per day [14].

The ADA recommended "MyPlate" as a healthy guide for each meal which consists of 25% protein, 25% starch, and 50% non-starchy foods as vegetables especially steamed ones. Creating MyPlate is a simple and effective method allowing proper control of the blood glucose levels and losing weight (http://www.diabetes. org/food-and-fitness/food/planning-meals/create-your-plate/).

Some foods to be avoided include highly processed foods as white bread, fast foods, alcohol, baked products as muffins and cakes, sugary drinks, candy, and high starch foods as white rice and white potatoes.

#### **2. Exercise**

Although there are many randomized studies done to evaluate the effects of physical exercise and lifestyle modifications in adults with diabetes, only few ones evaluated these effects in pregnant women with GDM. These studies proved that exercise improves the blood glucose [8, 15–18]. These beneficial effects may occur as a result of the increase of lean muscle mass with subsequent increase in insulin sensitivity. So a moderate exercise program is highly recommended for women with GDM [11]. A moderate intensity aerobic exercise for at least 150 minutes weekly [19] or simple exercise as walking after each meal for 10–15 minutes [20] is recommended.

The Finnish GDM prevention trial (RADIEL)—a multicenter randomized controlled study—evaluated the efficacy of combined dietary and physical activity modifications in prevention of GDM and obesity-related perinatal complications [21]. Counseling was achieved through three visits to the study nurse at 13, 23, and 35 weeks of pregnancy. Dietary modification was done according to Nordic Nutrition Recommendations encouraging the intake of vegetables, fruits and berries, high-fiber whole-grain products, low-fat dairy products, vegetable fats high in unsaturated fatty acids, and fish and low-fat meat products with lower intake of sugar- and saturated fatty acid-rich foods. [22]. Physical moderate exercise for 150 minutes at least per week is recommended [23]. They found that these modifications had no effects on either the incidence of GDM or perinatal complications [24].

#### **2.1 Pharmacologic treatment**

Pharmacologic treatment is indicated when dietary management and exercise failed to achieve the target glucose levels.

**37**

**Table 1.**

*Treatment of Gestational Diabetes*

monitored blood glucose [4].

*2.1.1 Oral antidiabetic medications*

gum, and thiazolidinedione.

improve pregnancy outcome [32].

*Modified from Gabbe and Graves [30].*

tablet intake, ease of storage, and safe needle disposal.

**Type Onset** 

*Describes the onset, peak, and duration of action of the commonly used insulins.*

(**Table 1**) [27–29].

*DOI: http://dx.doi.org/10.5772/intechopen.86988*

Basically, insulin is the standard treatment for GDM [11]. Insulin has the advantage of non-crossing of the placenta. It is given according to the timing of the occurrence of hyperglycemia. If hyperglycemia is present throughout the day both in the fasting and postprandial state, a divided dose of combination of either long or intermediate acting insulin with the short acting one is recommended. The typical total starting dose is 0.7–1 unit/ kg of body weight. If hyperglycemia is detected only at a specific times, focusing the insulin dose at that specific time of hyperglycemia is done, e.g., high fasting blood sugar is treated using a nighttime intermediateacting insulin, while elevated post-breakfast blood sugar is treated by short-acting insulin before breakfast. The maintenance dose is then adjusted according to the

The insulin analogs as insulin aspart and lispro are preferred over the regular insulin as a short-acting type. They do not cross the placenta, and their main advantage is their faster onset of action allowing the women to receive their injection at the time of the meal not 10–15 minutes before it as needed in the regular type. This advantage provides better control of the glucose level, and less attacks of hypoglycemia resulted from timing error [25, 26]. Intermediate- and long-acting insulin include the basic isophane insulin (NPH) and recent insulin glargine and detemir

Historically oral hypoglycemics should be avoided as early agents cross the placenta, resulting in fetal hyperinsulinemia with subsequent macrosomia and congenital malformations (most commonly in the ear) and severe neonatal hypoglycemia. Now their use in GDM is increasing despite them not approved by the US Food and Drug Administration [31] and the recommendation of ADA that insulin is the first-line therapy for GDM [11] as these products have advantages as ease of

Oral antidiabetic medications include biguanides, sulfonylurea, acarbose, Guar

**(min)**

Insulin lispro 1–15 1–2 4–5 Insulin aspart 1–15 1–2 4–5 Regular insulin 30–60 2–4 6–8 Isophane insulin suspension (NPH) 60–180 5–7 13–18 Insulin glargine 60–120 No peak 24 Insulin detemir 60–180 Minimal at 8–10 18–26

**Peak (h)**

**Duration (h)**

Metformin is a biguanide that decreases intestinal glucose absorption and hepatic gluconeogenesis and increases peripheral glucose uptake. Historically, it was given to women used in pregestational diabetic women and women with polycystic ovary syndrome who suffer from infertility. In the latter group, it was continued until completion of the first trimester, despite the limited evidence of its ability to

#### *Treatment of Gestational Diabetes DOI: http://dx.doi.org/10.5772/intechopen.86988*

*Gestational Diabetes Mellitus - An Overview with Some Recent Advances*

half of pregnancy) [12].

proteins (20%) and fats (40%) [4].

drates also decrease insulin resistance [6].

starch foods as white rice and white potatoes.

respectively) [13].

**2. Exercise**

recommended.

**2.1 Pharmacologic treatment**

failed to achieve the target glucose levels.

JSOG committee on nutrient and metabolism problems described a caloric intake of 25–30 kcal/kg (+150 Kcal for the first half and + 350 kcal for the second

The ideal diet components are not yet determined. However excessive weight gain with postprandial hyperglycemia is commonly associated with diet that included 50–60% of carbohydrate. ACOG recommended the limitation of carbohydrate to 33–40% of the required calories and the remaining 60% to be gained from

The complex form of carbohydrates is preferable over simple ones as they are absorbed slower without producing significant hyperglycemia. Complex carbohy-

If the routine three meals daily failed to achieve the target blood sugar, each

The ADA recommended "MyPlate" as a healthy guide for each meal which consists of 25% protein, 25% starch, and 50% non-starchy foods as vegetables especially steamed ones. Creating MyPlate is a simple and effective method allowing proper control of the blood glucose levels and losing weight (http://www.diabetes.

Some foods to be avoided include highly processed foods as white bread, fast foods, alcohol, baked products as muffins and cakes, sugary drinks, candy, and high

Although there are many randomized studies done to evaluate the effects of physical exercise and lifestyle modifications in adults with diabetes, only few ones evaluated these effects in pregnant women with GDM. These studies proved that exercise improves the blood glucose [8, 15–18]. These beneficial effects may occur as a result of the increase of lean muscle mass with subsequent increase in insulin sensitivity. So a moderate exercise program is highly recommended for women with GDM [11]. A moderate intensity aerobic exercise for at least 150 minutes weekly [19] or simple exercise as walking after each meal for 10–15 minutes [20] is

The Finnish GDM prevention trial (RADIEL)—a multicenter randomized controlled study—evaluated the efficacy of combined dietary and physical activity modifications in prevention of GDM and obesity-related perinatal complications [21]. Counseling was achieved through three visits to the study nurse at 13, 23, and 35 weeks of pregnancy. Dietary modification was done according to Nordic Nutrition Recommendations encouraging the intake of vegetables, fruits and berries, high-fiber whole-grain products, low-fat dairy products, vegetable fats high in unsaturated fatty acids, and fish and low-fat meat products with lower intake of sugar- and saturated fatty acid-rich foods. [22]. Physical moderate exercise for 150 minutes at least per week is recommended [23]. They found that these modifications had no effects on either the incidence of GDM or perinatal complications [24].

Pharmacologic treatment is indicated when dietary management and exercise

meal should be divided in 2:1 or 1:1 ratio to eat 4–6 meals per day [14].

org/food-and-fitness/food/planning-meals/create-your-plate/).

The Ministry of Health and Welfare recommended a caloric intake of 25–30 kcal/kg (+ 50,250 and 450 kcal for the first, second, and third trimester,

**36**

Basically, insulin is the standard treatment for GDM [11]. Insulin has the advantage of non-crossing of the placenta. It is given according to the timing of the occurrence of hyperglycemia. If hyperglycemia is present throughout the day both in the fasting and postprandial state, a divided dose of combination of either long or intermediate acting insulin with the short acting one is recommended. The typical total starting dose is 0.7–1 unit/ kg of body weight. If hyperglycemia is detected only at a specific times, focusing the insulin dose at that specific time of hyperglycemia is done, e.g., high fasting blood sugar is treated using a nighttime intermediateacting insulin, while elevated post-breakfast blood sugar is treated by short-acting insulin before breakfast. The maintenance dose is then adjusted according to the monitored blood glucose [4].

The insulin analogs as insulin aspart and lispro are preferred over the regular insulin as a short-acting type. They do not cross the placenta, and their main advantage is their faster onset of action allowing the women to receive their injection at the time of the meal not 10–15 minutes before it as needed in the regular type. This advantage provides better control of the glucose level, and less attacks of hypoglycemia resulted from timing error [25, 26]. Intermediate- and long-acting insulin include the basic isophane insulin (NPH) and recent insulin glargine and detemir (**Table 1**) [27–29].

#### *2.1.1 Oral antidiabetic medications*

Historically oral hypoglycemics should be avoided as early agents cross the placenta, resulting in fetal hyperinsulinemia with subsequent macrosomia and congenital malformations (most commonly in the ear) and severe neonatal hypoglycemia. Now their use in GDM is increasing despite them not approved by the US Food and Drug Administration [31] and the recommendation of ADA that insulin is the first-line therapy for GDM [11] as these products have advantages as ease of tablet intake, ease of storage, and safe needle disposal.

Oral antidiabetic medications include biguanides, sulfonylurea, acarbose, Guar gum, and thiazolidinedione.

Metformin is a biguanide that decreases intestinal glucose absorption and hepatic gluconeogenesis and increases peripheral glucose uptake. Historically, it was given to women used in pregestational diabetic women and women with polycystic ovary syndrome who suffer from infertility. In the latter group, it was continued until completion of the first trimester, despite the limited evidence of its ability to improve pregnancy outcome [32].


#### **Table 1.**

*Describes the onset, peak, and duration of action of the commonly used insulins.*

Although metformin can cross the placenta, its long-term metabolic effects on the growing fetus are not known [33]. One study showed the absence of any developmental effects till the age of 2 years of life [34].

In a randomized controlled trial, 751 pregnant women having GDM were assigned to treatment with insulin or metformin ± insulin. The perinatal outcome was similar among the two groups [35].

Another smaller trial showed that women assigned to metformin had lower blood glucose, lower maternal weight gain during pregnancy, and lower incidence of neonatal hypoglycemia [36].

In a network meta-analysis that included unpublished trials, there was a difference between insulin and metformin treatments regarding neonatal birth weight, hypoglycemia, or mode of delivery [37].

Therefore, women with GDM are carefully counseled about the use of metformin. They should know that it is not superior to insulin, there are no definitive data about its long-term effects of the growing fetus, and 26–46% of women on metformin will need to add insulin to replace it or to potentiate its effects for better glucose control [35, 36].

Metformin starting dose is usually 500 mg once daily at nighttime for 1 week, and then the dose is increased according to the response. The maximum daily dose is 2500–3000 mg daily in two–three divided doses.

Contraindications to metformin include impaired kidney function, and serum creatinine should be evaluated before the start of treatment.

Side effects of metformin occur in 2.5–45.7% of cases [38], and the commonest is GIT upset in the form of abdominal pain and diarrhea. Its use may be associated with higher rate of lactic acidosis, preeclampsia, and neonatal jaundice. So the drug is instructed to be administered with meals and to increase the needed dose gradually.

A systematic review stated that metformin use during pregnancy is safe and effective regarding the short-term pregnancy outcomes. There are no solid guidelines about the duration of metformin use during pregnancy, so it is based on clinical experience on a case-by-case basis [39].

Sulfonylurea used in GDM includes glyburide, tolbutamide, glibenclamide, and gliclazide. Chlorpropamide crosses, while glibenclamide does not cross the placenta.

Glyburide augments insulin secretion by pancreas (through binding adenosine triphosphate potassium channel receptors of the beta cells) and extrapancreatic tissues. It also increases insulin sensitivity of peripheral tissues. It should not be used as a first-line treatment as most studies showed inferior results when compared to insulin or metformin [31].

The dose of glyburide is 2.5–20 mg per day in divided doses. The maximum dose is 30 mg daily [40]. Even with these high doses, 4–16% of patients will need the addition of insulin for adequate glycemic control [41–44].

Contraindications include allergy to sulfa, and side effects include mild infrequent GIT side effects as nausea, vomiting, and diarrhea.

Although some individual trials showed no difference regarding blood glucose control between glyburide and insulin [41–46], meta-analyses reported higher incidence of macrosomia, maternal, and neonatal hypoglycemia [35, 36, 47]. Other trials found that women used glyburide and had higher incidence of hypertension, hyperbilirubinemia, and still birth than those on insulin therapy [31, 42, 48–52].

Other sulfonylurea include Thiazolidinedione as Pioglitazone & Rosiglitazone which decrease insulin resistance by reducing RESISTIN hormone released from adipose tissue. Their use during pregnancy cannot be recommended as no enough reports to support their use.

**39**

*Treatment of Gestational Diabetes*

after proper consultation.

*DOI: http://dx.doi.org/10.5772/intechopen.86988*

together against insulin weakens that meta-analysis.

need for adding insulin before describing it.

**3. Other medications used in GDM**

ment of neonatal outcome [59].

and ketone bodies and glycosylated hemoglobin.

minimum is two measurements per day [4].

**4. Glucose monitoring**

each meal) [4].

A Cochrane meta-analysis evaluated 7381 women with GDM and reported similar pregnancy outcomes when insulin therapy is compared with oral antidiabetic agents (metformin, glyburide, both, and acarbose) [53]. However these oral antidiabetic agents have different safety and efficacy, so pooling all of them

To sum up, the current available data show the absence of short-term hazards, but the long-term effects are still unknown. So, the women should be counseled about the unknown proven safety of the oral antidiabetic agents and the high rate of

ACOG considers insulin as the first-line treatment for GDM and describes oral agents (mainly metformin and rarely glyburide) as an alternative in women who decline insulin use (for financial issues or non-availability of safe administration)

As there are many evidences that link oxidative stress and development of complications of diabetes with pregnancy, the use of antioxidants was suggested to improve pregnancy outcome [54]. Oxygen free radicals released during aerobic metabolism cause cellular damage [55, 56]. Many authors reported the participation

An interesting randomized controlled trial was conducted that involved 200 women with GDM who were assigned to receive antioxidant (1 gram L-ascorbic acid daily) or placebo. Maged and colleagues found that antioxidants significantly decreased the required insulin dose to control blood sugar and oxidative markers (glutathione, malondialdehyde, superoxide dismutase). In placental tissue homogenate, maternal blood and neonatal blood were significantly different between the two groups. In the antioxidant group, the neonatal blood sugar was more stable within 2 h of delivery, and the neonatal ICU admission was lower than other women. They concluded that the use of antioxidant administration during pregnancy in women with GDM reverses the oxidative stresses resulting in the improve-

Monitoring of glucose control is through blood testing urine analysis for glucose

The optimal frequency of blood glucose testing in women with GDM is not known. However, four evaluations daily seem to be satisfactory (fasting and after

Fasting blood sugar is predictive of neonatal fat mass and subsequent development of childhood obesity and diabetes [60], and 1-h postprandial level was predictive of better blood sugar control and subsequent development of LGA and cesarean delivery [61], so both should be measured. The postprandial measurement can be after 1 or 2 h as the peak glucose level occurs almost 90 min after meals [62].

After stabilization of the blood sugar, individualization of the frequency of glucose measurement according to the gestational age, adherence of the patient to treatment and the needs of further adjustment is recommended. However the

Measurement neither at 1 h nor at 2 h is superior to the other [63–65].

of reactive oxygen species in diabetes associated with pregnancy [57, 58].

#### *Treatment of Gestational Diabetes DOI: http://dx.doi.org/10.5772/intechopen.86988*

*Gestational Diabetes Mellitus - An Overview with Some Recent Advances*

developmental effects till the age of 2 years of life [34].

was similar among the two groups [35].

hypoglycemia, or mode of delivery [37].

is 2500–3000 mg daily in two–three divided doses.

clinical experience on a case-by-case basis [39].

addition of insulin for adequate glycemic control [41–44].

quent GIT side effects as nausea, vomiting, and diarrhea.

creatinine should be evaluated before the start of treatment.

of neonatal hypoglycemia [36].

control [35, 36].

gradually.

insulin or metformin [31].

reports to support their use.

Although metformin can cross the placenta, its long-term metabolic effects on the growing fetus are not known [33]. One study showed the absence of any

In a randomized controlled trial, 751 pregnant women having GDM were assigned to treatment with insulin or metformin ± insulin. The perinatal outcome

Another smaller trial showed that women assigned to metformin had lower blood glucose, lower maternal weight gain during pregnancy, and lower incidence

In a network meta-analysis that included unpublished trials, there was a difference between insulin and metformin treatments regarding neonatal birth weight,

Therefore, women with GDM are carefully counseled about the use of metformin. They should know that it is not superior to insulin, there are no definitive data about its long-term effects of the growing fetus, and 26–46% of women on metformin will need to add insulin to replace it or to potentiate its effects for better glucose

Metformin starting dose is usually 500 mg once daily at nighttime for 1 week, and then the dose is increased according to the response. The maximum daily dose

Contraindications to metformin include impaired kidney function, and serum

Side effects of metformin occur in 2.5–45.7% of cases [38], and the commonest is GIT upset in the form of abdominal pain and diarrhea. Its use may be associated with higher rate of lactic acidosis, preeclampsia, and neonatal jaundice. So the drug is instructed to be administered with meals and to increase the needed dose

A systematic review stated that metformin use during pregnancy is safe and effective regarding the short-term pregnancy outcomes. There are no solid guidelines about the duration of metformin use during pregnancy, so it is based on

Sulfonylurea used in GDM includes glyburide, tolbutamide, glibenclamide, and gliclazide. Chlorpropamide crosses, while glibenclamide does not cross the placenta. Glyburide augments insulin secretion by pancreas (through binding adenosine triphosphate potassium channel receptors of the beta cells) and extrapancreatic tissues. It also increases insulin sensitivity of peripheral tissues. It should not be used as a first-line treatment as most studies showed inferior results when compared to

The dose of glyburide is 2.5–20 mg per day in divided doses. The maximum dose is 30 mg daily [40]. Even with these high doses, 4–16% of patients will need the

Contraindications include allergy to sulfa, and side effects include mild infre-

Although some individual trials showed no difference regarding blood glucose control between glyburide and insulin [41–46], meta-analyses reported higher incidence of macrosomia, maternal, and neonatal hypoglycemia [35, 36, 47]. Other trials found that women used glyburide and had higher incidence of hypertension, hyperbilirubinemia, and still birth than those on insulin therapy [31, 42, 48–52]. Other sulfonylurea include Thiazolidinedione as Pioglitazone & Rosiglitazone which decrease insulin resistance by reducing RESISTIN hormone released from adipose tissue. Their use during pregnancy cannot be recommended as no enough

**38**

A Cochrane meta-analysis evaluated 7381 women with GDM and reported similar pregnancy outcomes when insulin therapy is compared with oral antidiabetic agents (metformin, glyburide, both, and acarbose) [53]. However these oral antidiabetic agents have different safety and efficacy, so pooling all of them together against insulin weakens that meta-analysis.

To sum up, the current available data show the absence of short-term hazards, but the long-term effects are still unknown. So, the women should be counseled about the unknown proven safety of the oral antidiabetic agents and the high rate of need for adding insulin before describing it.

ACOG considers insulin as the first-line treatment for GDM and describes oral agents (mainly metformin and rarely glyburide) as an alternative in women who decline insulin use (for financial issues or non-availability of safe administration) after proper consultation.

#### **3. Other medications used in GDM**

As there are many evidences that link oxidative stress and development of complications of diabetes with pregnancy, the use of antioxidants was suggested to improve pregnancy outcome [54]. Oxygen free radicals released during aerobic metabolism cause cellular damage [55, 56]. Many authors reported the participation of reactive oxygen species in diabetes associated with pregnancy [57, 58].

An interesting randomized controlled trial was conducted that involved 200 women with GDM who were assigned to receive antioxidant (1 gram L-ascorbic acid daily) or placebo. Maged and colleagues found that antioxidants significantly decreased the required insulin dose to control blood sugar and oxidative markers (glutathione, malondialdehyde, superoxide dismutase). In placental tissue homogenate, maternal blood and neonatal blood were significantly different between the two groups. In the antioxidant group, the neonatal blood sugar was more stable within 2 h of delivery, and the neonatal ICU admission was lower than other women. They concluded that the use of antioxidant administration during pregnancy in women with GDM reverses the oxidative stresses resulting in the improvement of neonatal outcome [59].

#### **4. Glucose monitoring**

Monitoring of glucose control is through blood testing urine analysis for glucose and ketone bodies and glycosylated hemoglobin.

The optimal frequency of blood glucose testing in women with GDM is not known. However, four evaluations daily seem to be satisfactory (fasting and after each meal) [4].

Fasting blood sugar is predictive of neonatal fat mass and subsequent development of childhood obesity and diabetes [60], and 1-h postprandial level was predictive of better blood sugar control and subsequent development of LGA and cesarean delivery [61], so both should be measured. The postprandial measurement can be after 1 or 2 h as the peak glucose level occurs almost 90 min after meals [62]. Measurement neither at 1 h nor at 2 h is superior to the other [63–65].

After stabilization of the blood sugar, individualization of the frequency of glucose measurement according to the gestational age, adherence of the patient to treatment and the needs of further adjustment is recommended. However the minimum is two measurements per day [4].

Women under self-monitoring of blood glucose daily had significantly lower incidence of fetal macrosomia and less weight gain than those under intermittent measurement of fasting glucose during semi-weekly antenatal visits [66].

de Veciana and colleagues randomly assigned 66 women with GDM for preprandial or 1-h postprandial measurement of blood sugar. They found that postprandial group had better blood glucose control with less macrosomia, cesarean delivery for cephalopelvic disproportion, and neonatal hypoglycemia [61].

A review included 10 trials of 538 women (468 and 70 women with type 1 and type 2 diabetes). Different glucose monitoring methods were compared without clear advantage of one method over the others. Two trials (43 women) comparing **self-monitoring versus standard care** proved no difference for cesarean section or glycemic control. One study (100 women) compared **self-monitoring versus hospitalization** and found no clear difference for hypertensive disorders, cesarean section, or preterm birth. Another study (61 women) which compared **preprandial versus postprandial glucose monitoring** proved no clear difference regarding cesarean section, macrosomia, or glycemic control. Three studies (84 women) which compared **automated telemedicine monitoring versus conventional system** found no clear difference for cesarean section and mortality or morbidity. **CGM was compared to intermittent monitoring** in two studies (225 women), and there was no difference for preeclampsia and cesarean section and large for gestational age. One trial (25 women) compared **constant CGM versus intermittent CGM** and found no clear difference between groups for cesarean section, glycemic control, or preterm birth [67].

#### **4.1 Glycosylated hemoglobin**

Hemoglobin (Hb) A forms about 90% of hemoglobin in adults, and its glycosylation occurs due to irreversible nonenzymatic binding of glucose to N-terminal of β chain. Hb A1 is divided into Hb A1 a1, Hb A1 a2, Hb A1 b, and Hb A1 C (the most important). The mean plasma glucose over the erythrocyte life span is correlated with the degree of glycosylation. Its advantages include that it is a single, nonfluctuating blood test that reflects the glucose levels over the last 4–8 weeks. So, HbA1c is an attractive test that can be added to routine investigations done in the first antenatal evaluation as it serves as a diagnostic tool for women with undiagnosed diabetes or at risk of its development [68]. If measured during the first trimester, it gives an idea about blood glucose control in the periconceptional period and during organogenesis. Its main disadvantage is its affection by red blood cell turnover [6] which results in the absence of clear recommendations for its use to diagnose GDM [69–71]. HbA1C increases also in cases of non-hemolytic anemias and chronic renal failure [72]. Women with A1c of 10–12% have up to a 25% risk of major malformations.

#### **4.2 Fetal assessment**

Like women with pregestational diabetes, women with GDM should follow antenatal fetal assessment especially those with poor glycemic control and women under medical treatment with insulin or oral antidiabetic agents [73]. It should start at 32 weeks of gestational age and earlier in women with GDM associated with other factors that may adversely affect fetal outcome as hypertensive disorders [74].

There is no consensus about antepartum fetal monitoring in properly controlled women without medical treatment, and if done it usually starts to alter at 32 weeks. The specific test used and its frequency are dependent on the regional practice, but

**41**

*syndrome* [74].

*Treatment of Gestational Diabetes*

**5. Obstetrical management**

**6. Postpartum evaluation**

*DOI: http://dx.doi.org/10.5772/intechopen.86988*

associated with fetal hyperglycemia [4].

amniotic fluid measurement is probably included as polyhydramnios is commonly

kick especially during the third trimester, and women on insulin treatment are offered for hospital admission and CTG monitoring three times weekly [74].

Timing and management of delivery of women with GDM are dependent on glycemic control, fetal condition, and associated complications. Women with proper glycemic control without associated medical problems are followed up till term [75, 76]. A comparison was done between women with GDM who were subjected to labor induction at 38 weeks and those who were followed up till 41 weeks of gestation, which revealed similar CS rate and all other outcomes except the higher occurrence of neonatal hyperbilirubinemia in one study [77], lower incidence of LGA in another study [78], and lower incidence of shoulder dystocia in a third one [79] in the induction group. A more recent study found a lower rate of CS in the induction group [80]. So women with GDM using medications with proper control of blood

In women with poor control of their blood sugar, timing of delivery is determined by balancing the risk of prematurity and the ongoing risk of intrauterine fetal death. In general earlier delivery in women with good glycemic control is recommended [75, 76], but the clear guides for glycemic control and timing of delivery are absent [81]. In general delivery between the start of 37 weeks and the completion of 38 weeks appears appropriate, while delivery at 34 weeks till the completed 36 weeks should be attempted only in women with abnormal fetal well-

being assessment and those with failed hospital control of blood sugar [4]. Ultrasound assessment of fetal size should be done in all women with GDM. However only 22% of fetuses diagnosed as LGA by ultrasound had macrosomia after birth [82]. To prevent one case of permanent brachial plexus injury, 588 and 962 CS should be performed for ultrasonographic estimated fetal weight of 4500 and 4000 gm, respectively [83, 84]. So women with GDM and macrosomic

fetus should be counseled about the elective CS risks and benefits [85].

fasting glucose levels, or impaired glucose tolerance [11] (**Figure 1**). ACOG practice bulletin No. 190: Gestational diabetes mellitus [4].

to be hospitalized for cardiovascular morbidity [93].

Women with GDM should be evaluated postpartum as 15–70% will develop diabetes later in life [86–90]. These women were estimated to have sevenfold increased risk of developing type 2 DM when compared to controls [91]. So, screening after 4–12 weeks of delivery is recommended to identify those with diabetes, impaired

The Fifth International Workshop-Conference on Gestational Diabetes recommended that women with GDM undergo evaluation with a 75-g oral glucose tolerance test at 6–12 weeks postpartum [92]. These recommendations are shown in **Table 2**. Women with GDM are at an increased risk for cardiovascular complications associated with dyslipidemia, hypertension, and abdominal obesity—the *metabolic* 

Kessous and colleagues found that women with GDM were 2.6 times more likely

sugar delivered better during the 39 weeks of gestation [4].

At Parkland Hospital, women with GDM are routinely asked to count daily fetal

#### *Treatment of Gestational Diabetes DOI: http://dx.doi.org/10.5772/intechopen.86988*

*Gestational Diabetes Mellitus - An Overview with Some Recent Advances*

cephalopelvic disproportion, and neonatal hypoglycemia [61].

control, or preterm birth [67].

**4.1 Glycosylated hemoglobin**

major malformations.

**4.2 Fetal assessment**

Women under self-monitoring of blood glucose daily had significantly lower incidence of fetal macrosomia and less weight gain than those under intermittent

de Veciana and colleagues randomly assigned 66 women with GDM for preprandial or 1-h postprandial measurement of blood sugar. They found that postprandial group had better blood glucose control with less macrosomia, cesarean delivery for

A review included 10 trials of 538 women (468 and 70 women with type 1 and type 2 diabetes). Different glucose monitoring methods were compared without clear advantage of one method over the others. Two trials (43 women) comparing **self-monitoring versus standard care** proved no difference for cesarean section or glycemic control. One study (100 women) compared **self-monitoring versus hospitalization** and found no clear difference for hypertensive disorders, cesarean section, or preterm birth. Another study (61 women) which compared **preprandial versus postprandial glucose monitoring** proved no clear difference regarding cesarean section, macrosomia, or glycemic control. Three studies (84 women) which compared **automated telemedicine monitoring versus conventional system** found no clear difference for cesarean section and mortality or morbidity. **CGM was compared to intermittent monitoring** in two studies (225 women), and there was no difference for preeclampsia and cesarean section and large for gestational age. One trial (25 women) compared **constant CGM versus intermittent CGM** and found no clear difference between groups for cesarean section, glycemic

Hemoglobin (Hb) A forms about 90% of hemoglobin in adults, and its glycosylation occurs due to irreversible nonenzymatic binding of glucose to N-terminal of β chain. Hb A1 is divided into Hb A1 a1, Hb A1 a2, Hb A1 b, and Hb A1 C (the most important). The mean plasma glucose over the erythrocyte life span is correlated with the degree of glycosylation. Its advantages include that it is a single, nonfluctuating blood test that reflects the glucose levels over the last 4–8 weeks. So, HbA1c is an attractive test that can be added to routine investigations done in the first antenatal evaluation as it serves as a diagnostic tool for women with undiagnosed diabetes or at risk of its development [68]. If measured during the first trimester, it gives an idea about blood glucose control in the periconceptional period and during organogenesis. Its main disadvantage is its affection by red blood cell turnover [6] which results in the absence of clear recommendations for its use to diagnose GDM [69–71]. HbA1C increases also in cases of non-hemolytic anemias and chronic renal failure [72]. Women with A1c of 10–12% have up to a 25% risk of

Like women with pregestational diabetes, women with GDM should follow antenatal fetal assessment especially those with poor glycemic control and women under medical treatment with insulin or oral antidiabetic agents [73]. It should start at 32 weeks of gestational age and earlier in women with GDM associated with other factors that may adversely affect fetal outcome as hypertensive disorders [74].

There is no consensus about antepartum fetal monitoring in properly controlled women without medical treatment, and if done it usually starts to alter at 32 weeks. The specific test used and its frequency are dependent on the regional practice, but

measurement of fasting glucose during semi-weekly antenatal visits [66].

**40**

amniotic fluid measurement is probably included as polyhydramnios is commonly associated with fetal hyperglycemia [4].

At Parkland Hospital, women with GDM are routinely asked to count daily fetal kick especially during the third trimester, and women on insulin treatment are offered for hospital admission and CTG monitoring three times weekly [74].

#### **5. Obstetrical management**

Timing and management of delivery of women with GDM are dependent on glycemic control, fetal condition, and associated complications. Women with proper glycemic control without associated medical problems are followed up till term [75, 76].

A comparison was done between women with GDM who were subjected to labor induction at 38 weeks and those who were followed up till 41 weeks of gestation, which revealed similar CS rate and all other outcomes except the higher occurrence of neonatal hyperbilirubinemia in one study [77], lower incidence of LGA in another study [78], and lower incidence of shoulder dystocia in a third one [79] in the induction group. A more recent study found a lower rate of CS in the induction group [80]. So women with GDM using medications with proper control of blood sugar delivered better during the 39 weeks of gestation [4].

In women with poor control of their blood sugar, timing of delivery is determined by balancing the risk of prematurity and the ongoing risk of intrauterine fetal death. In general earlier delivery in women with good glycemic control is recommended [75, 76], but the clear guides for glycemic control and timing of delivery are absent [81]. In general delivery between the start of 37 weeks and the completion of 38 weeks appears appropriate, while delivery at 34 weeks till the completed 36 weeks should be attempted only in women with abnormal fetal wellbeing assessment and those with failed hospital control of blood sugar [4].

Ultrasound assessment of fetal size should be done in all women with GDM. However only 22% of fetuses diagnosed as LGA by ultrasound had macrosomia after birth [82]. To prevent one case of permanent brachial plexus injury, 588 and 962 CS should be performed for ultrasonographic estimated fetal weight of 4500 and 4000 gm, respectively [83, 84]. So women with GDM and macrosomic fetus should be counseled about the elective CS risks and benefits [85].

#### **6. Postpartum evaluation**

Women with GDM should be evaluated postpartum as 15–70% will develop diabetes later in life [86–90]. These women were estimated to have sevenfold increased risk of developing type 2 DM when compared to controls [91]. So, screening after 4–12 weeks of delivery is recommended to identify those with diabetes, impaired fasting glucose levels, or impaired glucose tolerance [11] (**Figure 1**).

ACOG practice bulletin No. 190: Gestational diabetes mellitus [4].

The Fifth International Workshop-Conference on Gestational Diabetes recommended that women with GDM undergo evaluation with a 75-g oral glucose tolerance test at 6–12 weeks postpartum [92]. These recommendations are shown in **Table 2**.

Women with GDM are at an increased risk for cardiovascular complications associated with dyslipidemia, hypertension, and abdominal obesity—the *metabolic syndrome* [74].

Kessous and colleagues found that women with GDM were 2.6 times more likely to be hospitalized for cardiovascular morbidity [93].

#### *Gestational Diabetes Mellitus - An Overview with Some Recent Advances*

#### **Figure 1.**

*Management of postpartum screening results. Abbreviations: FPG, fasting plasma glucose, OGTT, oral glucose tolerance test; IGT, impaired glucose tolerance.*


#### **Table 2.**

*Fifth international workshop-conference: Metabolic assessments recommended after pregnancy with gestational diabetes.*

Shah and coworkers also reported excessive cardiovascular disease by 10 years in women with GDM [94].

#### **7. Recurrent gestational diabetes**

The risk of recurrence of GDM is estimated to be 40% in primiparous women [95]. Women with higher body mass index are more likely to have impaired glucose tolerance in subsequent pregnancies. Therefore, lifestyle modifications, including weight control and exercise between pregnancies, may prevent the recurrence of GDM [96]. Overweight and obese women in their first pregnancy will lower the risk of GDM, if they lose 2 or more units of their body mass index [97]. The risk of GDM in second pregnancy was 4.2% in women without GDM in their first pregnancy against 41.3 percent in those with a history of gestational diabetes in their first pregnancy [98].

#### **8. Contraception**

Women with recent GDM can use low-dose hormonal contraceptives safely as the rate of developing of diabetes is similar in oral contraceptive users and nonusers

**43**

*Treatment of Gestational Diabetes*

trial.

randomization.

type of evidence.

**Author details**

Ahmed Mohamed Maged

Kasr Alainy Hospital, Cairo University, Egypt

provided the original work is properly cited.

\*Address all correspondence to: dr\_ahmedmaged08@kasralainy.edu.eg

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

*DOI: http://dx.doi.org/10.5772/intechopen.86988*

consequences as intrauterine device.

studies, or reports of expert committees.

outlined by the US Preventive Services Task Force:

ies, preferably from more than one center or research group.

of any hormonal contraception [99]. Care should be taken in women at risk of cardiovascular diseases as obese, hypertensive, and dyslipidemic women with direction of the contraceptive choice toward a method without potential cardiovascular

Studies were reviewed and evaluated for quality according to the method

II-1 Evidence obtained from well-designed controlled trials without

I Evidence obtained from at least one properly designed randomized controlled

II-2 Evidence obtained from well-designed cohort or case–control analytic stud-

II-3 Evidence obtained from multiple time series with or without the intervention. Dramatic results in uncontrolled experiments also could be regarded as this

III Opinions of respected authorities, based on clinical experience, descriptive

#### *Treatment of Gestational Diabetes DOI: http://dx.doi.org/10.5772/intechopen.86988*

*Gestational Diabetes Mellitus - An Overview with Some Recent Advances*

**Time Test Purpose**

glucose

1-year postpartum 75 g, 2-h OGTT Assess glucose metabolism Annually Fasting plasma glucose Assess glucose metabolism Triannually 75 g, 2-h OGTT Assess glucose metabolism Prepregnancy 75 g, 2-h OGTT Classify glucose metabolism

Post-delivery 1–3 days Fasting or random plasma

Shah and coworkers also reported excessive cardiovascular disease by 10 years in

*Fifth international workshop-conference: Metabolic assessments recommended after pregnancy with gestational* 

*Management of postpartum screening results. Abbreviations: FPG, fasting plasma glucose, OGTT, oral glucose* 

Detect persistent, overt diabetes

75 g, 2-h OGTT Postpartum classification of glucose metabolism

The risk of recurrence of GDM is estimated to be 40% in primiparous women [95]. Women with higher body mass index are more likely to have impaired glucose tolerance in subsequent pregnancies. Therefore, lifestyle modifications, including weight control and exercise between pregnancies, may prevent the recurrence of GDM [96]. Overweight and obese women in their first pregnancy will lower the risk of GDM, if they lose 2 or more units of their body mass index [97]. The risk of GDM in second pregnancy was 4.2% in women without GDM in their first pregnancy against 41.3 percent in those with a history of gestational diabetes in their first pregnancy [98].

Women with recent GDM can use low-dose hormonal contraceptives safely as the rate of developing of diabetes is similar in oral contraceptive users and nonusers

**42**

women with GDM [94].

Early postpartum (6–12 week)

*Metzger et al. [92].*

**Table 2.**

*diabetes.*

**Figure 1.**

**8. Contraception**

**7. Recurrent gestational diabetes**

*tolerance test; IGT, impaired glucose tolerance.*

of any hormonal contraception [99]. Care should be taken in women at risk of cardiovascular diseases as obese, hypertensive, and dyslipidemic women with direction of the contraceptive choice toward a method without potential cardiovascular consequences as intrauterine device.

Studies were reviewed and evaluated for quality according to the method outlined by the US Preventive Services Task Force:

I Evidence obtained from at least one properly designed randomized controlled trial.

II-1 Evidence obtained from well-designed controlled trials without randomization.

II-2 Evidence obtained from well-designed cohort or case–control analytic studies, preferably from more than one center or research group.

II-3 Evidence obtained from multiple time series with or without the intervention. Dramatic results in uncontrolled experiments also could be regarded as this type of evidence.

III Opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert committees.

#### **Author details**

Ahmed Mohamed Maged Kasr Alainy Hospital, Cairo University, Egypt

\*Address all correspondence to: dr\_ahmedmaged08@kasralainy.edu.eg

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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[67] Moy FM, Ray A, Buckley BS, West HM. Techniques of monitoring blood glucose during pregnancy for women with pre-existing diabetes. Cochrane Database of Systematic Reviews 11 Jun 2017;(6):CD009613. DOI: 10.1002/14651858.CD009613.pub3.

[68] Malkani S, Mordes JP. Implications

of using hemoglobin A1C for diagnosing diabetes mellitus. The American Journal of Medicine.

[69] Seino Y, Nanjo K, Tajima N, Kadowaki T, Kashiwagi A, Araki E, et al. Report of the committee on the classification and diagnostic criteria of diabetes mellitus. Journal of Diabetes

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[70] Mosca A, Paleari R, Dalfra MG, Di Cianni G, Cuccuru I, Pellegrini G, et al. Reference intervals for hemoglobin A1c in pregnant women: Data from an Italian multicenter study. Clinical Chemistry. 2006;**52**:1138-1143

[71] Lowe LP, Metzger BE, Dyer AR, Lowe J, McCance DR, Lappin TR, et al. Hyperglycemia and adverse pregnancy outcome (HAPO) study: Associations of maternal A1C and glucose with pregnancy outcomes. Diabetes Care.

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2008;**198**:287

[58] Brownlee M. The pathobiology of diabetic complications: A unifying mechanism. Diabetes.

[59] Maged AM, Torky H, Fouad MA, GadAllah SH, Waked NM, Gayed AS, et al. Role of antioxidants in gestational diabetes mellitus and relation to fetal outcome: A randomized controlled trial. The Journal of Maternal-Fetal & Neonatal Medicine. 2016;**29**(24):4049-4054. DOI:

10.3109/14767058.2016.1154526

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[61] de Veciana M, Major CA, Morgan MA, Asrat T, Toohey JS, Lien JM, et al. Postprandial versus preprandial blood glucose monitoring in women with gestational diabetes mellitus requiring insulin therapy. The New England Journal of Medicine.

[62] Ben-Haroush A, Yogev Y, Chen R, Rosenn B, Hod M, Langer O. The postprandial glucose profile in the diabetic pregnancy. American Journal

of Obstetrics and Gynecology.

Perinatology. 2005;**25**:241-244

[64] Moses RG, Lucas EM, Knights S. Gestational diabetes mellitus. At what time should the postprandial glucose level be monitored? The Australian &

[63] Weisz B, Shrim A, Homko CJ, Schiff E, Epstein GS, Sivan E. One hour versus two hours postprandial glucose measurement in gestational diabetes: A prospective study. Journal of

[60] Durnwald CP, Mele L, Spong CY, Ramin SM, Varner MW, Rouse DJ, et al. Glycemic characteristics and neonatal outcomes of women treated for mild gestational diabetes. Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) maternal-Fetal medicine units network (MFMU). Obstetrics and

2005;**54**:1615-1625

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[72] Benaiges D, Flores-Le Roux JA, Marcelo I, Mane L, Rodriguez M, Navarro X, et al. Is first-trimester HbA1c useful in the diagnosis of gestational diabetes? Diabetes Research and Clinical Practice. 2017;**133**:85-91

[73] Wu K, Cheng Y, Li T, Ma Z, Liu J, Zhang Q, et al. The utility of HbA1c combined with haematocrit for early screening of gestational diabetes mellitus. Diabetology and Metabolic Syndrome. *2018*;*10*:14 https://doi. org/10.1186/s13098-018-0314-9

[74] American College of Obstetricians and Gynecologists. Antepartum fetal surveillance. Practice bulletin No. 145. Obstetrics and Gynecology. 2014;**124**:182-192

[75] Cunningham FG, Leveno KJ, Bloom SL, et al. Diabetes mellitus. In: Cunningham FG, Williams JW, editors. William's Obstetrics. 24th ed. New York (NY): McGraw-Hill; 2014. pp. 1125-1146 [Chapter 57]

[76] Spong CY, Mercer BM, D'alton M, Kilpatrick S, Blackwell S, Saade G. Timing of indicated late-preterm and early-term birth. Obstetrics and Gynecology. 2011;**118**:323-333

[77] American College of Obstetricians and Gynecologists. Medically indicated late-preterm and earlyterm deliveries. Committee opinion No. 560. Obstetrics and Gynecology. 2013;**121**:908-910

[78] Alberico S, Erenbourg A, Hod M, Yogev Y, Hadar E, Neri F, et al. Immediate delivery or expectant management in gestational diabetes at term: The GINEXMAL randomised controlled trial. GINEXMAL group. BJOG. 2017;**124**:669-677

[79] Lurie S, Insler V, Hagay ZJ. Induction of labor at 38 to 39 weeks of gestation reduces the incidence of shoulder dystocia in gestational diabetic patients class A2. American Journal of Perinatology. 1996;**13**:293-296

[80] Witkop CT, Neale D, Wilson LM, Bass EB, Nicholson WK. Active compared with expectant delivery management in women with gestational diabetes: A systematic review. Obstetrics and Gynecology. 2009;**113**:206-217. (Systematic Review)

[81] Melamed N, Ray JG, Geary M, Bedard D, Yang C, Sprague A, et al. Induction of labor before 40 weeks is associated with lower rate of cesarean delivery in women with gestational diabetes mellitus. American Journal of Obstetrics and Gynecology. 2016;**214**:364.e1-8

[82] Caughey AB, Valent AM. When to deliver women with diabetes in pregnancy? American Journal of Perinatology. 2016;**33**:1250-1254

[83] Scifres CM, Feghali M, Dumont T, Althouse AD, Speer P, Caritis SN, et al. Large-for-gestational-age ultrasound diagnosis and risk for cesarean delivery in women with gestational diabetes mellitus. Obstetrics and Gynecology. 2015;**126**:978-986

[84] Rouse DJ, Owen J, Goldenberg RL, Cliver SP. The effectiveness and costs of elective cesarean delivery for fetal macrosomia diagnosed by ultrasound. JAMA. 1996;**276**:1480-1486

[85] Garabedian C, Deruelle P. Delivery (timing, route, peripartum glycemic control) in women with gestational diabetes mellitus. Diabetes & Metabolism. 2010;**36**:515-521

[86] American College of Obstetricians and Gynecologists. Fetal macrosomia. Practice bulletin No. 173. Obstetrics and Gynecology. 2016;**128**:e195-e209

[87] Kim C, Newton KM, Knopp RH. Gestational diabetes and the incidence of type 2 diabetes: A systematic review. Diabetes Care. 2002;**25**:1862-1868. (Systematic Review)

[88] Kaaja RJ, Greer IA. Manifestations of chronic disease during pregnancy. JAMA. 2005;**294**:2751-2757

[89] Buchanan TA, Xiang AH. Gestational diabetes mellitus. The Journal of Clinical Investigation. 2005;**115**:485-491

[90] Russell MA, Phipps MG, Olson CL, Welch HG, Carpenter MW. Rates of postpartum glucose testing after gestational diabetes mellitus. Obstetrics and Gynecology. 2006;**108**:1456-1462

[91] Chodick G, Elchalal U, Sella T, Heymann AD, Porath A, Kokia E, et al. The risk of overt diabetes mellitus among women with gestational diabetes: A population-based study. Diabetic Medicine. 2010;**27**:779-785

[92] Bellamy L, Casas JP, Hingorani AD, Williams D. Type 2 diabetes mellitus after gestational diabetes: A systematic review and meta-analysis. Lancet. 2009;**373**:1773-1779. (Meta-analysis)

[93] Metzger BE, Buchanan TA, Coustan DR, et al. Summary and recommendations of the fifth international workshop-conference on gestational diabetes. Diabetes Care. 2007;**30**(Suppl 2):S251

[94] Kessous R, Shoham-Vardi I, Pariente G, et al. An association between gestational diabetes mellitus and longterm maternal cardiovascular morbidity. Heart. 2013;**99**:1118

[95] Shah BR, Retnakaran R, Booth GL. Increased risk of cardiovascular disease in young women following gestational diabetes. Diabetes Care. 2008;**31**(8):1668

[96] Holmes HJ, Casey BM, Lo JY, et al. Likelihood of diabetes recurrence in women with mild gestational diabetes

(GDM). American Journal of Obstetrics and Gynecology. 2003;**189**(6):161

[97] Kim C, Cheng YJ, Beckles GL. Cardiovascular disease risk profiles in women with histories of gestational diabetes but without current diabetes. Obstetrics and Gynecology. 2008;**112**(4):875

[98] Ehrlich SF, Hedderson MM, Feng J, et al. Change in body mass index between pregnancies and the risk of gestational diabetes in a second pregnancy. Obstetrics and Gynecology. 2011;**117**(6):1323

[99] Getahun D, Fassett MJ, Jacobsen SJ. Gestational diabetes: Risk of recurrence in subsequent pregnancies. American Journal of Obstetrics and Gynecology. 2010;**203**:467

**51**

**Chapter 4**

**Abstract**

**1. Introduction**

needs, and insulin must be injected.

'gestational diabetes mellitus' (GDM) [2].

direct and indirect healthcare costs [5].

Diabetes

*and Simona Diana Stefan*

Insulin Therapy in Gestational

The prevalence of gestational diabetes risen in several populations during the past 20 years, and increased direct and indirect healthcare costs, including those for insulin treatment. Establishing the optimal treatment and initiation momentum are critical to achieve glycemic control and minimize the impact on fetal development and perinatal complications. Insulin is the only therapy that does not cross the placenta, and some of its types were proved to be safe in pregnancy. Intrapartum management is based on intravenous insulin administration, and standard protocols should be implemented in every center. Postpartum management requires special attention, as insulin necessary has a fast decline exposing mothers to hypoglycemia.

**Keywords:** gestational diabetes, insulin therapy, macrosomia, neonatal hypoglycemia

Gestational diabetes (GD) is one of the most common pathologies in pregnancy.

Gestational diabetes has been defined as any degree of glucose intolerance with onset or first recognition during pregnancy [1]. In pregnancy, there are multiple hormonal changes, including hyperinsulinemia and an insulin-resistant state; thus the pancreatic beta cell function becomes insufficient to meet the body's reasonable

There is also the possibility that hyperglycemia was present before the pregnancy; therefore International Association of Diabetes and Pregnancy Study

Groups (IADPSG) defined the pregnancy hyperglycemia as either 'overt diabetes' or

Considering the ascending trend of type 2 diabetes mellitus and obesity from the last decades, GD has intuitively the same tendency [3, 4]. The prevalence of GD is estimated at approximately 135,000 cases per year in the US [5], representing on average 3–8% of all pregnancies [6]. It is estimated that the prevalence of GD has increased by 10–100% in several racial groups during the past 20 years, increasing

The goal of treatment for women with GD (recommended by both American

Gynecologists-ACOG) is a fasting plasma glucose level <95 mg/dl, a 1-hour post-prandial glucose level of less than 140 mg/dl and a 2-hour post-prandial glucose level of less than 120 mg/dl, whereas for the HbA1c the target is <6–6.5% (42–48 mmol/mol); lower HbA1c—6% (42 mmol/mol) is optimal if it can be achieved without significant

Diabetes Association-ADA, and the American College of Obstetricians and

*Anca Pantea-Stoian, Roxana Adriana Stoica*

#### **Chapter 4**

*Gestational Diabetes Mellitus - An Overview with Some Recent Advances*

(GDM). American Journal of Obstetrics and Gynecology. 2003;**189**(6):161

[97] Kim C, Cheng YJ, Beckles GL. Cardiovascular disease risk profiles in women with histories of gestational diabetes but without current

diabetes. Obstetrics and Gynecology.

[98] Ehrlich SF, Hedderson MM, Feng J, et al. Change in body mass index between pregnancies and the risk of gestational diabetes in a second pregnancy. Obstetrics and Gynecology.

[99] Getahun D, Fassett MJ, Jacobsen SJ. Gestational diabetes: Risk of recurrence in subsequent pregnancies. American Journal of Obstetrics and Gynecology.

2008;**112**(4):875

2011;**117**(6):1323

2010;**203**:467

Diabetes Care. 2002;**25**:1862-1868.

[88] Kaaja RJ, Greer IA. Manifestations of chronic disease during pregnancy.

[90] Russell MA, Phipps MG, Olson CL, Welch HG, Carpenter MW. Rates of postpartum glucose testing after gestational diabetes mellitus. Obstetrics and Gynecology. 2006;**108**:1456-1462

[91] Chodick G, Elchalal U, Sella T, Heymann AD, Porath A, Kokia E, et al. The risk of overt diabetes mellitus among women with gestational diabetes: A population-based study. Diabetic Medicine. 2010;**27**:779-785

[92] Bellamy L, Casas JP, Hingorani AD, Williams D. Type 2 diabetes mellitus after gestational diabetes: A systematic review and meta-analysis. Lancet. 2009;**373**:1773-1779. (Meta-analysis)

[94] Kessous R, Shoham-Vardi I, Pariente

G, et al. An association between gestational diabetes mellitus and longterm maternal cardiovascular morbidity.

[95] Shah BR, Retnakaran R, Booth GL. Increased risk of cardiovascular disease in young women following gestational diabetes. Diabetes Care.

[96] Holmes HJ, Casey BM, Lo JY, et al. Likelihood of diabetes recurrence in women with mild gestational diabetes

[93] Metzger BE, Buchanan TA, Coustan DR, et al. Summary and recommendations of the fifth international workshop-conference on gestational diabetes. Diabetes Care.

2007;**30**(Suppl 2):S251

Heart. 2013;**99**:1118

2008;**31**(8):1668

(Systematic Review)

2005;**115**:485-491

JAMA. 2005;**294**:2751-2757

[89] Buchanan TA, Xiang AH. Gestational diabetes mellitus. The Journal of Clinical Investigation.

**50**

## Insulin Therapy in Gestational Diabetes

*Anca Pantea-Stoian, Roxana Adriana Stoica and Simona Diana Stefan*

#### **Abstract**

The prevalence of gestational diabetes risen in several populations during the past 20 years, and increased direct and indirect healthcare costs, including those for insulin treatment. Establishing the optimal treatment and initiation momentum are critical to achieve glycemic control and minimize the impact on fetal development and perinatal complications. Insulin is the only therapy that does not cross the placenta, and some of its types were proved to be safe in pregnancy. Intrapartum management is based on intravenous insulin administration, and standard protocols should be implemented in every center. Postpartum management requires special attention, as insulin necessary has a fast decline exposing mothers to hypoglycemia.

**Keywords:** gestational diabetes, insulin therapy, macrosomia, neonatal hypoglycemia

#### **1. Introduction**

Gestational diabetes (GD) is one of the most common pathologies in pregnancy. Gestational diabetes has been defined as any degree of glucose intolerance with onset or first recognition during pregnancy [1]. In pregnancy, there are multiple hormonal changes, including hyperinsulinemia and an insulin-resistant state; thus the pancreatic beta cell function becomes insufficient to meet the body's reasonable needs, and insulin must be injected.

There is also the possibility that hyperglycemia was present before the pregnancy; therefore International Association of Diabetes and Pregnancy Study Groups (IADPSG) defined the pregnancy hyperglycemia as either 'overt diabetes' or 'gestational diabetes mellitus' (GDM) [2].

Considering the ascending trend of type 2 diabetes mellitus and obesity from the last decades, GD has intuitively the same tendency [3, 4]. The prevalence of GD is estimated at approximately 135,000 cases per year in the US [5], representing on average 3–8% of all pregnancies [6]. It is estimated that the prevalence of GD has increased by 10–100% in several racial groups during the past 20 years, increasing direct and indirect healthcare costs [5].

The goal of treatment for women with GD (recommended by both American Diabetes Association-ADA, and the American College of Obstetricians and Gynecologists-ACOG) is a fasting plasma glucose level <95 mg/dl, a 1-hour post-prandial glucose level of less than 140 mg/dl and a 2-hour post-prandial glucose level of less than 120 mg/dl, whereas for the HbA1c the target is <6–6.5% (42–48 mmol/mol); lower HbA1c—6% (42 mmol/mol) is optimal if it can be achieved without significant

hypoglycemia; also, the target may be relaxed to 7% (53 mmol/mol) in order to prevent hypoglycemia [7, 8].

#### **2. Lifestyle intervention**

After diagnosis GD, to reach the goals for plasma glucose levels, the first step is the initiation of a lifestyle intervention program (including medical nutrition therapy—MNT and physical activity—PA).

MNT is the cornerstone of the GDM treatment. MNT alone can assure glycemic targets in 80–90% of GDM patients [9]. Maternal height and weight are key factors for the medical nutrition therapy, providing adequate calories and nutrients for both maternal and fetal nutrition, maintaining glycemic targets and the absence of ketones with appropriate weight gain [10–12]. For a GDM mother with a normal body mass index (BMI) of 18.5–24.9 kg/m2 , the number of adequate calories is about 30 kcal/kg [9]. Nevertheless, since more than 60% of women diagnosed with GDM are overweight or obese, a caloric restriction is needed. The ADA states that no research identifies a specific optimal calorie intake for women with GDM and that the calorie needs are no different from those of pregnant women without GDM [7]. Therefore, ADA issued only general recommendations (following the dietary reference intakes) for 175 g of carbohydrate, 71 g of protein, 28 g of fiber, emphasizing the importance of the amount and type of carbohydrate with significant impact concerning the glucose levels, especially postprandial glucose peak [7]. ADA recommends individualized nutrition plan developed by a registered dietitian familiar with the management of GDM [7]. The National Institute for Health and Care Excellence (NICE) guidelines recommend a healthy diet, emphasizing the importance of low glycemic index foods (that should replace those with a high glycemic index) for GDM women; also there is the recommendation for a dietitian when GDM is present [13].

The carbohydrate intake should be reduced to 33–45% of the total calories, and distributed over 3 meals, and 2–4 snacks/day, thus reducing postprandial glucose peak [8, 14], while as the rest of the calories should be divided between protein (20%) and lipids (40%) [15].

Excessive weight gain during pregnancy should be avoided for GDM women [16]. The weight gain during pregnancy depends on pre-pregnancy BMI:


Physical activity improves glycemic control in GDM women. The generally accepted recommendation is daily moderate-intensity regular exercise (walking 30 minutes/day or more—if no medical contraindications) improves blood glucose control [13, 14].

#### **3. Pharmacological treatment**

Pharmacological treatment is recommended when lifestyle intervention does not reduce hyperglycemia to reach the glycemic target. There is no international

**53**

[28, 29].

*Insulin Therapy in Gestational Diabetes DOI: http://dx.doi.org/10.5772/intechopen.84569*

lifestyle intervention [13, 19].

sons with insulin treatment.

unable to administer insulin safely.

reach targeted glycemic control [19].

**3.1 Metformin**

**3.2 Glyburide**

are lacking [7].

**3.3 Insulin therapy**

consensus on when to start pharmacological treatment of GDM [18]. The Canadian Diabetes Association (CDA) and NICE guidelines, both recommend beginning pharmacological treatment if glycemic control is not achieved after 1–2 weeks of

Oral antidiabetic medication has been described in a previous chapter. The authors want to resume the most important clinical implications and the compari-

The use of metformin in GDM after the glycemic target is not reached with lifestyle intervention is recommended by the NICE guidelines [13]. Metformin is classified as a category B drug, which implies that there is no evidence of animal, or fetal toxicity or teratogenicity. In general, metformin appears to be a safe alternative to insulin for the GDM treatment, but it crosses the placenta, and it may be present in a higher concentration in the fetal circulation than in the maternal circulation [19]. Studies were performed for the assessment of metformin exposure in-utero. There is no evidence that the metformin is affecting the fetus with regards to an early motor, linguistic, social, [20], metabolic [20, 21], and neurodevelopmental [22, 23] outcomes, but long-term follow up studies are needed. The metformin was associated with a lower risk of neonatal hypoglycemia and less maternal weight gain than insulin in two systematic reviews [24, 25]. Almost half of the patients with GDM who were initially treated with metformin needed insulin to achieve acceptable glucose control [26]. Metformin remains an option as a second line treatment in GDM women who refuse insulin treatment or who are

Glyburide (glibenclamide) was associated with increased birth weight, macrosomia and neonatal hypoglycemia compared with insulin [20, 25], and similar to metformin, crosses the placenta [27]. Glyburide therapy during pregnancy is not recommended as first- or second-line treatment, but it may be used as third-line treatment if insulin is refused, and metformin is either refused or insufficient to

There is no human data for the use of any other antihyperglycemic medication in the treatment of GDM (DPP-4 inhibitors, GLP-1 receptor agonists or SGLT2 inhibitors) [19]. Patients treated with oral therapy should be informed that they cross the placenta. No adverse effects on the fetus have been demonstrated; long-term studies

Insulin is the first-line antihyperglycemic medication recommended for treatment of GDM [7, 19]. None of the currently available insulin preparations has been demonstrated to cross the placenta [7]. If glycemic control is not achieved after 1–2 weeks of lifestyle intervention, insulin treatment should be initiated [19]. Insulin remains the gold standard treatment for GDM women that do not reach glycemic targets with lifestyle intervention, as recommended by several guidelines (see **Table 1** below). Insulin use reduces fetal and maternal morbidity

consensus on when to start pharmacological treatment of GDM [18]. The Canadian Diabetes Association (CDA) and NICE guidelines, both recommend beginning pharmacological treatment if glycemic control is not achieved after 1–2 weeks of lifestyle intervention [13, 19].

Oral antidiabetic medication has been described in a previous chapter. The authors want to resume the most important clinical implications and the comparisons with insulin treatment.

#### **3.1 Metformin**

*Gestational Diabetes Mellitus - An Overview with Some Recent Advances*

hypoglycemia [7, 8].

and lipids (40%) [15].

**2. Lifestyle intervention**

therapy—MNT and physical activity—PA).

body mass index (BMI) of 18.5–24.9 kg/m2

hypoglycemia; also, the target may be relaxed to 7% (53 mmol/mol) in order to prevent

After diagnosis GD, to reach the goals for plasma glucose levels, the first step is the initiation of a lifestyle intervention program (including medical nutrition

MNT is the cornerstone of the GDM treatment. MNT alone can assure glycemic targets in 80–90% of GDM patients [9]. Maternal height and weight are key factors for the medical nutrition therapy, providing adequate calories and nutrients for both maternal and fetal nutrition, maintaining glycemic targets and the absence of ketones with appropriate weight gain [10–12]. For a GDM mother with a normal

about 30 kcal/kg [9]. Nevertheless, since more than 60% of women diagnosed with GDM are overweight or obese, a caloric restriction is needed. The ADA states that no research identifies a specific optimal calorie intake for women with GDM and that the calorie needs are no different from those of pregnant women without GDM [7]. Therefore, ADA issued only general recommendations (following the dietary reference intakes) for 175 g of carbohydrate, 71 g of protein, 28 g of fiber, emphasizing the importance of the amount and type of carbohydrate with significant impact concerning the glucose levels, especially postprandial glucose peak [7]. ADA recommends individualized nutrition plan developed by a registered dietitian familiar with the management of GDM [7]. The National Institute for Health and Care Excellence (NICE) guidelines recommend a healthy diet, emphasizing the importance of low glycemic index foods (that should replace those with a high glycemic index) for GDM women; also there is the recommendation for a dietitian when GDM is present [13]. The carbohydrate intake should be reduced to 33–45% of the total calories, and distributed over 3 meals, and 2–4 snacks/day, thus reducing postprandial glucose peak [8, 14], while as the rest of the calories should be divided between protein (20%)

Excessive weight gain during pregnancy should be avoided for GDM women

) [17]

Physical activity improves glycemic control in GDM women. The generally accepted recommendation is daily moderate-intensity regular exercise (walking 30 minutes/day or more—if no medical contraindications) improves blood glucose control [13, 14].

Pharmacological treatment is recommended when lifestyle intervention does not reduce hyperglycemia to reach the glycemic target. There is no international

[16]. The weight gain during pregnancy depends on pre-pregnancy BMI:

• 11.5–16 kg for normal weight (BMI 18.5–24.9 kg/m2

• 7–11.5 kg for overweight (BMI 25–29.9 kg/m2

• 5–9 kg for obese (BMI ≥30.0 kg/m2

**3. Pharmacological treatment**

• 12.5–18 kg of weight gain for underweight women (BMI <18.5 kg/m<sup>2</sup>

, the number of adequate calories is

);

)

);

**52**

The use of metformin in GDM after the glycemic target is not reached with lifestyle intervention is recommended by the NICE guidelines [13]. Metformin is classified as a category B drug, which implies that there is no evidence of animal, or fetal toxicity or teratogenicity. In general, metformin appears to be a safe alternative to insulin for the GDM treatment, but it crosses the placenta, and it may be present in a higher concentration in the fetal circulation than in the maternal circulation [19]. Studies were performed for the assessment of metformin exposure in-utero. There is no evidence that the metformin is affecting the fetus with regards to an early motor, linguistic, social, [20], metabolic [20, 21], and neurodevelopmental [22, 23] outcomes, but long-term follow up studies are needed. The metformin was associated with a lower risk of neonatal hypoglycemia and less maternal weight gain than insulin in two systematic reviews [24, 25]. Almost half of the patients with GDM who were initially treated with metformin needed insulin to achieve acceptable glucose control [26]. Metformin remains an option as a second line treatment in GDM women who refuse insulin treatment or who are unable to administer insulin safely.

#### **3.2 Glyburide**

Glyburide (glibenclamide) was associated with increased birth weight, macrosomia and neonatal hypoglycemia compared with insulin [20, 25], and similar to metformin, crosses the placenta [27]. Glyburide therapy during pregnancy is not recommended as first- or second-line treatment, but it may be used as third-line treatment if insulin is refused, and metformin is either refused or insufficient to reach targeted glycemic control [19].

There is no human data for the use of any other antihyperglycemic medication in the treatment of GDM (DPP-4 inhibitors, GLP-1 receptor agonists or SGLT2 inhibitors) [19]. Patients treated with oral therapy should be informed that they cross the placenta. No adverse effects on the fetus have been demonstrated; long-term studies are lacking [7].

#### **3.3 Insulin therapy**

Insulin is the first-line antihyperglycemic medication recommended for treatment of GDM [7, 19]. None of the currently available insulin preparations has been demonstrated to cross the placenta [7]. If glycemic control is not achieved after 1–2 weeks of lifestyle intervention, insulin treatment should be initiated [19]. Insulin remains the gold standard treatment for GDM women that do not reach glycemic targets with lifestyle intervention, as recommended by several guidelines (see **Table 1** below). Insulin use reduces fetal and maternal morbidity [28, 29].


#### **Table 1.**

*Insulin initiation recommendations.*

#### *3.3.1 Types of insulin*

#### *3.3.1.1 Human insulin*

#### *3.3.1.1.1 Regular insulin*

Regular insulin (U-100, U-500) is identical to human insulin, and it is used as mealtime insulin to cover postprandial hyperglycemia. Its time to onset is about 30 minutes (10–75 minutes), the peak effect is in 3 hours (2.5–5 hours), and the effect ends at about 8 hours (up to 24 hours for U500). The FDA pregnancy category is B [30].

#### *3.3.1.1.2 Human insulin inhalation (nasal insulin)*

Human insulin inhalation (nasal insulin) is equivalent unit-for-unit to insulin lispro. Its onset is 15 minutes, and its peak action time is ∼50 minutes. Duration of action is about 2 hours. Inhaled human insulin carries a boxed warning for bronchospasms in patients with chronic lung disease. It is a pregnancy category C drug [30].

#### *3.3.1.2 Rapid-acting insulin analogs*

Another analog of human insulin is insulin aspart produced from *Saccharomyces cerevisiae*, a type of yeast. Aspart should be taken 5–10 minutes before a meal. It can be used like for multiple subcutaneous injections or in insulin pumps. Its peak action time is 40–50 minutes, and its duration of action is 3–5 hours. Insulin aspart produce less hypoglycemia than the regular insulin [31]. The FDA pregnancy category is B and can be used in pregnancy. Data from two clinical trials (349 exposed pregnancies) do not indicate any adverse effect on pregnancy or fetal/neonatal health compared with human insulin [30].

#### *3.3.1.2.1 Insulin aspart*

Insulin aspart was introduced on the market with nicotinamide and L-arginine hydrochloride as excipients to enhance its absorption. Although the active molecule is identical, there are no available data for its use in pregnancy and its excretion in human milk [30].

**55**

*Insulin Therapy in Gestational Diabetes DOI: http://dx.doi.org/10.5772/intechopen.84569*

nancy or fetal/neonatal health [30].

glulisine in pregnant women [30].

*3.3.1.3 Intermediate insulin*

*3.3.1.3.1 Insulin isophane*

*3.3.1.4 Basal analogs*

toxicity [30].

*3.3.1.4.2 Insulin glargine*

*3.3.1.4.1 Insulin detemir*

Insulin lispro (U-100 and U-200) is an analog produced in *Escherichia coli* cultures. Its onset of action is 10–15 minutes. The peak is at 30–90 minutes, and its duration of action is 3–4 hours. Also, it can be used in insulin pumps or pens. The U-100 and U-200 formulations have the same bioequivalence and pharmacokinetics. The FDA pregnancy category is B and can be used in pregnancy. The data from a large number of exposed pregnancies do not indicate any adverse effect on preg-

Insulin glulisine is a recombinant insulin. It is obtained using *Escherichia coli*. It works fast nearly in 10–15 minutes. Its peak installs in 55 minutes, and its full duration is 4–5 hours. Although it can be used in some insulin pumps, it is not approved for all pump brands. The FDA pregnancy category is C. In this case, the vigilance should be given when prescribing glulisine to pregnant women, and the drug should only be used if the potential benefit justifies the potential risk to the fetus. There are limited data (less than 300 pregnancy outcomes) from the use of insulin

Insulin isophane (NPH) is an intermediate-acting insulin. It is also produced in *Escherichia coli*. It is similar to human insulin and is presented in a liquid suspension. Its onset of action is maximum 2 hours, with an average peak of 4 hours. NPH full duration of action is 10–20 hours. No restrictions on use in gestational diabetes or pregnancy; do not cross the placental barrier. The FDA pregnancy category is B [30].

Insulin detemir (U-100) is a long-acting analog produced in *Saccharomyces cerevisiae*. Detemir insulin lacks a defined peak and lasts for up to 24 hours, and time to onset of action can be 1–2 hours. The detemir insulin has less incidence of hypoglycemia compared to NPH regimen in pregnant women [32]. The FDA pregnancy category is B; considered during pregnancy. The potential benefit must be considered against the possible increased risk of adverse pregnancy outcomes. One clinical trial suggests a possible increased risk of serious adverse maternal outcomes compared with isophane insulin and data from an additional 250 outcomes from pregnant women exposed to insulin detemir suggest no maternal or fetal/neonatal

Insulin glargine (U-100) is a long-acting analog produced in *Escherichia coli.* The acidic solution is neutralized in subcutaneous tissue, and micro precipitates are formed. These micro precipitates slowly release glargine over 24 hours. Its onset of action is 1–2 hours, its duration of action are 24 hours and has no peak. The FDA

*3.3.1.2.2 Insulin lispro*

*3.3.1.2.3 Insulin glulisine*

#### *3.3.1.2.2 Insulin lispro*

*Gestational Diabetes Mellitus - An Overview with Some Recent Advances*

International Federation of Gynecology and

American College of Obstetricians and Gynecologists (ACOG), 2018

Obstetrics (FIGO), 2015

Regular insulin (U-100, U-500) is identical to human insulin, and it is used as mealtime insulin to cover postprandial hyperglycemia. Its time to onset is about 30 minutes (10–75 minutes), the peak effect is in 3 hours (2.5–5 hours), and the effect ends at about 8 hours (up to 24 hours for U500). The FDA pregnancy category is B [30].

Canadian Diabetes Association (CDA), 2018 If glycemic control is not achieved in 2 weeks after the

American Diabetes Association (ADA), 2018 First line therapy if glycemic control is not achieved after

diet intervention

diet intervention


• Diagnosing diabetes before 20 weeks of gestation

• Fasting plasma blood glucose above 110 mg/dl • 1-hour postprandial glycemia above 140 mg/dl • Weight gain over 12 kilograms during pregnancy

First line therapy if glycemic control is not achieved after

• Oral therapy for more than 30 weeks

initiation of medical, nutritional intervention

Human insulin inhalation (nasal insulin) is equivalent unit-for-unit to insulin lispro. Its onset is 15 minutes, and its peak action time is ∼50 minutes. Duration of action is about 2 hours. Inhaled human insulin carries a boxed warning for bronchospasms in patients with chronic lung disease. It is a pregnancy category C drug [30].

Another analog of human insulin is insulin aspart produced from *Saccharomyces cerevisiae*, a type of yeast. Aspart should be taken 5–10 minutes before a meal. It can be used like for multiple subcutaneous injections or in insulin pumps. Its peak action time is 40–50 minutes, and its duration of action is 3–5 hours. Insulin aspart produce less hypoglycemia than the regular insulin [31]. The FDA pregnancy category is B and can be used in pregnancy. Data from two clinical trials (349 exposed pregnancies) do not indicate any adverse effect on pregnancy or fetal/neonatal

Insulin aspart was introduced on the market with nicotinamide and L-arginine hydrochloride as excipients to enhance its absorption. Although the active molecule is identical, there are no available data for its use in pregnancy and its excretion in

**54**

*3.3.1 Types of insulin*

*Insulin initiation recommendations.*

**Table 1.**

*3.3.1.1 Human insulin*

*3.3.1.1.1 Regular insulin*

*3.3.1.1.2 Human insulin inhalation (nasal insulin)*

*3.3.1.2 Rapid-acting insulin analogs*

health compared with human insulin [30].

*3.3.1.2.1 Insulin aspart*

human milk [30].

Insulin lispro (U-100 and U-200) is an analog produced in *Escherichia coli* cultures. Its onset of action is 10–15 minutes. The peak is at 30–90 minutes, and its duration of action is 3–4 hours. Also, it can be used in insulin pumps or pens. The U-100 and U-200 formulations have the same bioequivalence and pharmacokinetics. The FDA pregnancy category is B and can be used in pregnancy. The data from a large number of exposed pregnancies do not indicate any adverse effect on pregnancy or fetal/neonatal health [30].

#### *3.3.1.2.3 Insulin glulisine*

Insulin glulisine is a recombinant insulin. It is obtained using *Escherichia coli*. It works fast nearly in 10–15 minutes. Its peak installs in 55 minutes, and its full duration is 4–5 hours. Although it can be used in some insulin pumps, it is not approved for all pump brands. The FDA pregnancy category is C. In this case, the vigilance should be given when prescribing glulisine to pregnant women, and the drug should only be used if the potential benefit justifies the potential risk to the fetus. There are limited data (less than 300 pregnancy outcomes) from the use of insulin glulisine in pregnant women [30].

#### *3.3.1.3 Intermediate insulin*

#### *3.3.1.3.1 Insulin isophane*

Insulin isophane (NPH) is an intermediate-acting insulin. It is also produced in *Escherichia coli*. It is similar to human insulin and is presented in a liquid suspension. Its onset of action is maximum 2 hours, with an average peak of 4 hours. NPH full duration of action is 10–20 hours. No restrictions on use in gestational diabetes or pregnancy; do not cross the placental barrier. The FDA pregnancy category is B [30].

#### *3.3.1.4 Basal analogs*

#### *3.3.1.4.1 Insulin detemir*

Insulin detemir (U-100) is a long-acting analog produced in *Saccharomyces cerevisiae*. Detemir insulin lacks a defined peak and lasts for up to 24 hours, and time to onset of action can be 1–2 hours. The detemir insulin has less incidence of hypoglycemia compared to NPH regimen in pregnant women [32]. The FDA pregnancy category is B; considered during pregnancy. The potential benefit must be considered against the possible increased risk of adverse pregnancy outcomes. One clinical trial suggests a possible increased risk of serious adverse maternal outcomes compared with isophane insulin and data from an additional 250 outcomes from pregnant women exposed to insulin detemir suggest no maternal or fetal/neonatal toxicity [30].

#### *3.3.1.4.2 Insulin glargine*

Insulin glargine (U-100) is a long-acting analog produced in *Escherichia coli.* The acidic solution is neutralized in subcutaneous tissue, and micro precipitates are formed. These micro precipitates slowly release glargine over 24 hours. Its onset of action is 1–2 hours, its duration of action are 24 hours and has no peak. The FDA

pregnancy category was previously C, no human pregnancy data. May be considered during pregnancy, if necessary, but we do not have clinical data on exposed pregnancies from controlled clinical studies available. The data from pregnant women (between 300 and 1000 pregnancy outcomes) indicate no adverse effects on pregnancy, nor malformations or feto-neonatal toxicity [30].

#### *3.3.1.4.3 Insulin glargine*

Insulin glargine (U-300) is a long-acting insulin. It is not bioequivalent to glargine U-100, but it had the same structure and was approved in February 2015. Glargine U-300 is produced in *Escherichia coli*. Its peak action develops over 6 hours and continues for an entire 24 hours. The serum concentrations decline after 16–36 hours. It is dosed once daily. There is no clinical experience until now with the use of insulin glargine (U-300) in pregnant women [30].

#### *3.3.1.4.4 Insulin degludec*

Insulin degludec U-100 and U-200 are considered bioequivalent. The insulin degludec's mode of slow absorption and prolonged action is based on the formation of soluble multi-hexamers. Insulin degludec onset of action is nearly 1 hour and has no peak. It is dosed once daily. It can be dosed at any time of the day because of its long duration of action. There is no clinical experience in pregnant women [30].

#### *3.3.2 Insulin regimens*

There are many insulin regimens proposed for treating hyperglycemia, but the multiple daily injections (MDI) is by far the most efficient and the most flexible [33].

The insulin regimen should be chosen based on the blood glucose profile. Therefore, if fasting glycaemia is higher than 90–95 mg/dl, basal insulin should be initiated. It can be a long-acting insulin analog or neutral protamine Hagedorn. The basal insulin dose can be calculated according to the weight: 0.2 units/kg/day.

If the hyperglycemia follows a meal, than rapid-acting insulin or regular insulin should be initiated before that m74eal (begin with 1 u of insulin for 10–15 g of carbohydrates).

Sometimes both fasting and postprandial glycaemia are elevated, thereby needing MDI: 3 mealtime insulin and basal insulin. The total daily insulin requirement during the first trimester, is 0.7 units/kg/day, while in the second trimester it is 0.8 units/kg/day, and in the third trimester, it is 0.9–1.0 units/kg/day. This does not necessarily fit all pregnancies. Usually, in pregestational diabetes, the total insulin dose is up to twice higher than in GDM.

In the case of morbid obesity, the initial doses of insulin can be increased to 1.5–2.0 units/kg to overcome the combined IR of pregnancy and obesity [9].

Usually, the calculated total daily dose of insulin should be divided in two as for type 1 and type 2 diabetes: 50% as basal insulin at bedtime, and 50% divided between 3 meals and given as rapid-acting, or regular insulin before meals.

The doses of insulin have to be continuously optimized, so the self-monitoring blood glucose is essential.

Rapid-acting insulin analogs are preferred over regular insulin in pregnancy because there is a lower risk of hypoglycemia, and because they provide a better postprandial blood glucose control [29, 33].

**57**

**Table 2.**

*Glycemic targets during pregnancy.*

*Insulin Therapy in Gestational Diabetes DOI: http://dx.doi.org/10.5772/intechopen.84569*

**3.4 Glycemic targets and control**

Insulin initiation is synthesized in **Table 1**.

Blood glucose control in important in gestational diabetes because it confers the future mother a sense of disease control and validation that diet and treatment are doing their effect as the glycemic control improves, the risk of maternal and fetal complications decreases, a principle that was demonstrated by HAPO study results [34]. The results of this landmark study and other seven randomized trials have been included in a Cochrane analysis that compared the treatment of gestational diabetes mellitus (GDM) with standard care. It demonstrated a lower risk of a composite endpoint (death, shoulder dystocia, humerus, clavicle fracture or nerve palsy), and also a lower risk of pre-eclampsia and macrosomia (birth weight over 4000 g or 90th

Thereby, gestational auto monitoring and surveillance by an obstetrician in collaboration with the diabetologist, nutritionist and midwife is essential for achieving glycemic targets during pregnancy, labor and after birth. These targets are synthe-

Although glycated hemoglobin values must be interpreted with caution in patients with dilution anemia, iron deficiency anemia or other hematological

FIGO, 2015 Capillary pre-prandial glucose <95 mg/dl

CDA, 2018 Capillary pre-prandial glucose <95 mg/dl

ADA, 2018 Capillary pre-prandial glucose <95 mg/dl

Capillary pre-prandial glucose <95 mg/dl

Capillary 1 hour post-prandial glucose

Capillary 2 hour post-prandial glucose

Capillary 1 hour post-prandial glucose

Capillary 2 hour post-prandial glucose

Capillary 1 hour post-prandial glucose

Capillary 2 hour post-prandial glucose

Capillary 1 hour post-prandial glucose

Capillary 2 hour post-prandial glucose

(5.3 mmol/l)

(5.3 mmol/l)

(5.3 mmol/l)

(5.3 mmol/l)

<140 mg/dl (7.8 mmol/l)

<120 mg/dl (6.7 mmol/l)

<140 mg/dl (7.8 mmol/l)

<120 mg/dl (6.7 mmol/l)

<140 mg/dl (7.8 mmol/l)

<120 mg/dl (6.7 mmol/l)

<140 mg/dl (7.8 mmol/l)

<120 mg/dl (6.7 mmol/l)

percentile), with no differences between oral and injectable treatment [35].

*3.3.3 Insulin initiation*

sized in **Tables 2** and **3**.

**3.5 Methods for glucose monitoring**

5th International Workshop Conference Gestational Diabetes and International Association of Diabetes and

*3.5.1 Glycated hemoglobin (HbA1c)*

Pregnancy Study Group, 2007

#### *3.3.3 Insulin initiation*

*Gestational Diabetes Mellitus - An Overview with Some Recent Advances*

on pregnancy, nor malformations or feto-neonatal toxicity [30].

the use of insulin glargine (U-300) in pregnant women [30].

*3.3.1.4.3 Insulin glargine*

*3.3.1.4.4 Insulin degludec*

women [30].

flexible [33].

0.2 units/kg/day.

carbohydrates).

dose is up to twice higher than in GDM.

postprandial blood glucose control [29, 33].

blood glucose is essential.

*3.3.2 Insulin regimens*

pregnancy category was previously C, no human pregnancy data. May be considered during pregnancy, if necessary, but we do not have clinical data on exposed pregnancies from controlled clinical studies available. The data from pregnant women (between 300 and 1000 pregnancy outcomes) indicate no adverse effects

Insulin glargine (U-300) is a long-acting insulin. It is not bioequivalent to glargine U-100, but it had the same structure and was approved in February 2015. Glargine U-300 is produced in *Escherichia coli*. Its peak action develops over 6 hours and continues for an entire 24 hours. The serum concentrations decline after 16–36 hours. It is dosed once daily. There is no clinical experience until now with

Insulin degludec U-100 and U-200 are considered bioequivalent. The insulin degludec's mode of slow absorption and prolonged action is based on the formation of soluble multi-hexamers. Insulin degludec onset of action is nearly 1 hour and has no peak. It is dosed once daily. It can be dosed at any time of the day because of its long duration of action. There is no clinical experience in pregnant

There are many insulin regimens proposed for treating hyperglycemia, but the multiple daily injections (MDI) is by far the most efficient and the most

The insulin regimen should be chosen based on the blood glucose profile.

If the hyperglycemia follows a meal, than rapid-acting insulin or regular insulin

Sometimes both fasting and postprandial glycaemia are elevated, thereby needing MDI: 3 mealtime insulin and basal insulin. The total daily insulin requirement during the first trimester, is 0.7 units/kg/day, while in the second trimester it is 0.8 units/kg/day, and in the third trimester, it is 0.9–1.0 units/kg/day. This does not necessarily fit all pregnancies. Usually, in pregestational diabetes, the total insulin

In the case of morbid obesity, the initial doses of insulin can be increased to 1.5–2.0 units/kg to overcome the combined IR of pregnancy and obesity [9]. Usually, the calculated total daily dose of insulin should be divided in two as for type 1 and type 2 diabetes: 50% as basal insulin at bedtime, and 50% divided between 3 meals and given as rapid-acting, or regular insulin before meals.

The doses of insulin have to be continuously optimized, so the self-monitoring

Rapid-acting insulin analogs are preferred over regular insulin in pregnancy because there is a lower risk of hypoglycemia, and because they provide a better

Therefore, if fasting glycaemia is higher than 90–95 mg/dl, basal insulin should be initiated. It can be a long-acting insulin analog or neutral protamine Hagedorn. The basal insulin dose can be calculated according to the weight:

should be initiated before that m74eal (begin with 1 u of insulin for 10–15 g of

**56**

Insulin initiation is synthesized in **Table 1**.

#### **3.4 Glycemic targets and control**

Blood glucose control in important in gestational diabetes because it confers the future mother a sense of disease control and validation that diet and treatment are doing their effect as the glycemic control improves, the risk of maternal and fetal complications decreases, a principle that was demonstrated by HAPO study results [34]. The results of this landmark study and other seven randomized trials have been included in a Cochrane analysis that compared the treatment of gestational diabetes mellitus (GDM) with standard care. It demonstrated a lower risk of a composite endpoint (death, shoulder dystocia, humerus, clavicle fracture or nerve palsy), and also a lower risk of pre-eclampsia and macrosomia (birth weight over 4000 g or 90th percentile), with no differences between oral and injectable treatment [35].

Thereby, gestational auto monitoring and surveillance by an obstetrician in collaboration with the diabetologist, nutritionist and midwife is essential for achieving glycemic targets during pregnancy, labor and after birth. These targets are synthesized in **Tables 2** and **3**.

#### **3.5 Methods for glucose monitoring**

#### *3.5.1 Glycated hemoglobin (HbA1c)*

Although glycated hemoglobin values must be interpreted with caution in patients with dilution anemia, iron deficiency anemia or other hematological


#### **Table 2.** *Glycemic targets during pregnancy.*


#### **Table 3.**

*Glycemic targets during labor.*

pathologies like minor thalassemia [36, 37], it proves to be useful in checking the self-reported date by the pregnant, especially if she is treated with insulin.

Other parameters that could be used for short-term (2–3 weeks) evaluation of blood glucose control is glycated albumin. It is not influenced by iron deficiency, but the values are low in nephrotic syndrome or thyroid disorders that sometimes are present in pregnancy. This marker was studied in GDM, but the cutoff limits are not precisely known with consideration of some population differences [38]. Molecules like fructosamine or 1,5-anhydroglucitol have not proven their utility [39–41].

#### *3.5.2 Self-monitoring of capillary blood glucose (SMBG)*

The efficiency of capillary blood testing (8 determinations per day) in pregnant diabetes patients has been demonstrated since the 1980s [42]. Current guidelines [7, 8, 12, 18] mention in general terms the frequency and optimal period (fasting, 1 or 2 hours postprandial) when a test should be done without customizing for treatment, previous glycemic control.

In healthy adult pregnant women, 1-hour glycemia during a glucose challenge test was a better marker for insulin sensibility, being correlated with a fetal abdominal circumference in echography [43]. In Jovanovic and collab study [42], glycemia at 1 hour after food intake in the third trimester was the best predictor for birth weight. Combs et al. used the same 1-hour glycemia to establish the best threshold (130 mg/dl) for which the risk for macrosomia and small for gestational age (SGA) is reduced [44]. Metzger was the one that proposed that 2-hours postprandial glycemia should be used in GDM with the limit of 120 mg/dl [34]. Two clinical studies compared the blood glucose determination concluding that 1-hour glycemia is superior, but with two important biases—lack of randomization and low statistical power [45, 46].

A randomized clinical trial demonstrated that patients who adjusted insulin doses based on 1-hour postprandial glycemia had a lower risk of giving birth to a macrosomia, or to have a cesarean procedure; also, the risk for neonatal hypoglycemia was smaller [47]. Not only the glycemic values *per se* is important, but also the pregnant women with GDM should be taught to estimate their carbohydrate intake and physical activity and adjust the insulin doses. Other factors that cannot be influenced are a hormonal secretion from the placenta, daily cortisol secretion variability that contributes to glucose excursions. Sivan et al. observed in their study a pattern in which 1-hour postprandial glycemia is abnormally raised in the morning, and 2 hours postprandial glycemia is abnormally raised in the evening [48].

The frequency of determination is as much as necessary. Based on a randomized control trial (RCT) the initial recommendation for SMBG is 4 tests per day, with the possibility to lessen the number of determinations according to if the patient has good control and the fetal morphology is normal [49]. In basal-bolus insulin-treated GDM 7 tests per day are recommended, but patient adherence is weak (a mean of 4.2 in an observational study) [50].

The limit for SMBG consists in the accuracy bias: lowering hematocrit by dilution makes the capillary glucose to be overestimated. Some glucometers have included in their software functions to correct the hematocrit values, but the majority uses colorimetric and amperometric methods that depend on it. Considering the tight glycemic control required during pregnancy and the fact that insulin doses are

**59**

**Table 4.**

*Insulin Therapy in Gestational Diabetes DOI: http://dx.doi.org/10.5772/intechopen.84569*

quality criteria [51].

complications.

*3.6.1 Neonatal hypoglycemia*

newborns [56–59].

adjusted based on SMBG, some researchers recommend that the bias and imprecision should be set at below 2% and the meters be verified according to international

Systems for interstitial glucose monitoring have been used together with insulin pumps in type 1 diabetes pregnancies in RCTs and observational studies [52, 53]. In GDM pregnancies data come from small observational studies where they showed benefit for disclosing high and low glycemic excursions missed by SMBG [54].

Glycemic sensors can be used as a guide for therapy initiation, as demonstrated

by Kestilä et al. [55]. The anti-diabetes medication was introduced in a higher proportion of GDM women with CGMS versus SMBG. Nevertheless, there were not any significant differences for the perinatal endpoints. The long-term impact of glycemic control during pregnancy is not known; therefore, the benefit of this intervention must be balanced with unnecessary treatment. The techniques for

All these efforts in using the best method for monitoring insulin therapy in GDM are to maintain glycemic control for preventing fetal and maternal

Glucose is a nutrient that freely crosses the placenta from maternal to fetal circulation, to assure the energy required for growth. Immediately after birth, the glucose source disappears with a physiologic "hypoglycemia" in the blood of the newborn that triggers the secretion of counterregulatory hormones (glucagon, steroids, catecholamines, growth hormone). In GDM pregnancies, the glycemia is continuously raised and determines a consecutive higher secretion of insulin that makes hypoglycemia more severe and prolonged than in normal

1 hour postprandial

1 hour postprandial

1 hour postprandial Dinner preprandial 1 hour postprandial

*Insulin glucose monitoring techniques [adapted from American Association of Clinical Endocrinologist and* 

Preprandial (lunch, dinner) 1 hour postprandial

Bedtime


*3.5.3 Continuous interstitial glucose monitoring (glucose sensors, CGMS)*

monitoring blood glucose are summarized in **Table 4**.

**3.6 Fetal complications associated with insulin therapy**

**Regimen SBGM CGMS**

GDM with diet or oral antidiabetics Fasting

GDM with basal insulin Fasting

GDM with premixed insulin Fasting

GDM with basal bolus Fasting

*American College of Endocrinology].*

#### *Insulin Therapy in Gestational Diabetes DOI: http://dx.doi.org/10.5772/intechopen.84569*

*Gestational Diabetes Mellitus - An Overview with Some Recent Advances*

FIGO, 2015 Capillary glucose 72–126 mg/dl (4–7 mmol/l) ACOG, 2018 Capillary glucose 70–110 mg/dl (3.9–3.1 mmol/l)

*3.5.2 Self-monitoring of capillary blood glucose (SMBG)*

biases—lack of randomization and low statistical power [45, 46].

treatment, previous glycemic control.

**Table 3.**

*Glycemic targets during labor.*

4.2 in an observational study) [50].

pathologies like minor thalassemia [36, 37], it proves to be useful in checking the self-reported date by the pregnant, especially if she is treated with insulin.

Other parameters that could be used for short-term (2–3 weeks) evaluation of blood glucose control is glycated albumin. It is not influenced by iron deficiency, but the values are low in nephrotic syndrome or thyroid disorders that sometimes are present in pregnancy. This marker was studied in GDM, but the cutoff limits are not precisely known with consideration of some population differences [38]. Molecules like fructosamine or 1,5-anhydroglucitol have not proven their utility [39–41].

The efficiency of capillary blood testing (8 determinations per day) in pregnant diabetes patients has been demonstrated since the 1980s [42]. Current guidelines [7, 8, 12, 18] mention in general terms the frequency and optimal period (fasting, 1 or 2 hours postprandial) when a test should be done without customizing for

In healthy adult pregnant women, 1-hour glycemia during a glucose challenge test was a better marker for insulin sensibility, being correlated with a fetal abdominal circumference in echography [43]. In Jovanovic and collab study [42], glycemia at 1 hour after food intake in the third trimester was the best predictor for birth weight. Combs et al. used the same 1-hour glycemia to establish the best threshold (130 mg/dl) for which the risk for macrosomia and small for gestational age (SGA) is reduced [44]. Metzger was the one that proposed that 2-hours postprandial glycemia should be used in GDM with the limit of 120 mg/dl [34]. Two clinical studies compared the blood glucose determination concluding that 1-hour glycemia is superior, but with two important

A randomized clinical trial demonstrated that patients who adjusted insulin doses based on 1-hour postprandial glycemia had a lower risk of giving birth to a macrosomia, or to have a cesarean procedure; also, the risk for neonatal hypoglycemia was smaller [47]. Not only the glycemic values *per se* is important, but also the pregnant women with GDM should be taught to estimate their carbohydrate intake and physical activity and adjust the insulin doses. Other factors that cannot be influenced are a hormonal secretion from the placenta, daily cortisol secretion variability that contributes to glucose excursions. Sivan et al. observed in their study a pattern in which 1-hour postprandial glycemia is abnormally raised in the morning,

and 2 hours postprandial glycemia is abnormally raised in the evening [48].

The limit for SMBG consists in the accuracy bias: lowering hematocrit by dilution makes the capillary glucose to be overestimated. Some glucometers have included in their software functions to correct the hematocrit values, but the majority uses colorimetric and amperometric methods that depend on it. Considering the tight glycemic control required during pregnancy and the fact that insulin doses are

The frequency of determination is as much as necessary. Based on a randomized control trial (RCT) the initial recommendation for SMBG is 4 tests per day, with the possibility to lessen the number of determinations according to if the patient has good control and the fetal morphology is normal [49]. In basal-bolus insulin-treated GDM 7 tests per day are recommended, but patient adherence is weak (a mean of

**58**

adjusted based on SMBG, some researchers recommend that the bias and imprecision should be set at below 2% and the meters be verified according to international quality criteria [51].

#### *3.5.3 Continuous interstitial glucose monitoring (glucose sensors, CGMS)*

Systems for interstitial glucose monitoring have been used together with insulin pumps in type 1 diabetes pregnancies in RCTs and observational studies [52, 53]. In GDM pregnancies data come from small observational studies where they showed benefit for disclosing high and low glycemic excursions missed by SMBG [54].

Glycemic sensors can be used as a guide for therapy initiation, as demonstrated by Kestilä et al. [55]. The anti-diabetes medication was introduced in a higher proportion of GDM women with CGMS versus SMBG. Nevertheless, there were not any significant differences for the perinatal endpoints. The long-term impact of glycemic control during pregnancy is not known; therefore, the benefit of this intervention must be balanced with unnecessary treatment. The techniques for monitoring blood glucose are summarized in **Table 4**.

All these efforts in using the best method for monitoring insulin therapy in GDM are to maintain glycemic control for preventing fetal and maternal complications.

#### **3.6 Fetal complications associated with insulin therapy**

#### *3.6.1 Neonatal hypoglycemia*

Glucose is a nutrient that freely crosses the placenta from maternal to fetal circulation, to assure the energy required for growth. Immediately after birth, the glucose source disappears with a physiologic "hypoglycemia" in the blood of the newborn that triggers the secretion of counterregulatory hormones (glucagon, steroids, catecholamines, growth hormone). In GDM pregnancies, the glycemia is continuously raised and determines a consecutive higher secretion of insulin that makes hypoglycemia more severe and prolonged than in normal newborns [56–59].


#### **Table 4.**

*Insulin glucose monitoring techniques [adapted from American Association of Clinical Endocrinologist and American College of Endocrinology].*

Neonatal transient hypoglycemia could have implications in the neurocognitive development as was shown by magnetic resonance imaging [60]. Also, it has psychological implications on the mother-child relationship because they are separated after birth for treatment. Hence, based on their study results, Voormolen et al. recommend screening all newborns from GDM women in the first 12 hours after birth because the majority of the events occur in this interval, with a higher incidence being in the insulin-treated group [58].

A series of studies demonstrated that newborns of GDM patients that were treated with metformin had fewer hypoglycemic events than those of women treated with insulin [21, 61]. Insulin analogs have a lower rise in postprandial glycemic values without elevating hypoglycemic risk and should be preferred to human insulins [29, 33].

Regarding sulfonylureas, a meta-analysis demonstrated that glyburide treatment GDM had a higher risk of neonatal hypoglycemia and also macrosomia that the metformin-treated GDM [62].

#### *3.6.2 Congenital anomalies*

The relationship between insulin therapy and congenital anomalies was studied, especially in type 1 diabetes. The most important confounding factor is glycemic control. Although some case reports indicate an association between the use of insulin lispro and the risk of teratogenesis [63], another meta-analysis supports the fact that it is safe for use [64]. This risk could be explained by mitogenesis stimulation by binding with a higher affinity for IGF-1 receptors. Lispro insulin has a 1.5 and insulin glargine a 6.5 fold increase of receptor binding [65]. There are only retrospective studies that indicate glargine as safe insulin in pregnancy [66].

#### **3.7 Birth complications associated with insulin therapy**

#### *3.7.1 Cesarean section (CS)*

A Cochrane analysis of 1481 women with GDM showed that in the treatment group there was a higher number of induced labors versus the group with standard antenatal care, but with no difference regarding the number of births by CS [35]. Another meta-analysis did not demonstrate a correlation between the use of different types of insulin-like aspart, lispro and the birth by CS [67, 68]. Although the risk is not influenced by insulin treatment, it can be reduced by induction of labor (IOL) in 38th–39th week of gestation with better outcomes for the fetus [69].

#### *3.7.2 Vacuum-assisted birth*

Although pre-gestational diabetes raises the risk for vacuum assisted birth (shoulder dystocia, humerus, clavicle, skull fracture, Erb's palsy, subarachnoidian or subdural hemorrhages, asphyxia, convulsion), in GDM the risk was similar to that in the general population and could not be related to insulin therapy [68, 70]. A particular situation is with GDM that appeared in pregnancies obtained by assisted reproductive technology where the risk for perinatal and obstetrical complications is probably increased by the adverse effect of hyperglycemia, not by insulin treatment [71].

#### *3.7.3 Fetal morbidity*

Evidence that indicates a higher risk for fetal morbidity and mortality in GDM a scarce and less pronounced as in pre-gestational diabetes. Current decisions of IOL

**61**

*Insulin Therapy in Gestational Diabetes DOI: http://dx.doi.org/10.5772/intechopen.84569*

ence the morbidity [73].

*3.8.1 Maternal hypoglycemia*

diabetes than in GDM [74].

*3.8.2 Hypertension*

pre-eclampsia [68].

insulin drip [78].

**3.9 Intrapartum management**

intravenous glucose is perfused.

adjustments in insulin perfusion rates.

as compared to expectant management should be individualized because the studies lack in this area. An RCT that showed that there is no difference between the two strategies regarding morbidity, but the IOL reduces the risk for shoulder dystocia in the macrosomic fetus [72]. The use of insulin analogs like detemir does not influ-

Hypoglycemia threshold is specific for every individual. In pregnancy, there is a reduction of this threshold by 20% [74]. Patients with GDM that are treated with insulin must maintain a glycemia above 3.7 mmol/l (66 mg/dl) according to CDA, or

Insulin analogs are superior to human insulin because the hypoglycemic events are less frequent in type 1 diabetic pregnancies [75]. The use of multiple daily injec-

Maternal hypoglycemia affects the fetus just in severe cases when is associated with loss of consciousness or secondary to trauma. Also, it was observed that repeated episodes could lead to growth over the 90th percentile [77]. These episodes are more likely to be present in the first trimester in women who had pregestational

There is moderate quality evidence that indicates higher hypertension associated hypertension without giving details in insulin-treated GDM. This fact should be further researched because it is in contradiction with a non-modified risk for

During the latent phase of labor hepatic gluconeogenesis is sufficient for providing the caloric requirements, but becomes exiguous during the active phase when

Lowering maternal glycemia is necessary for preventing neonatal hypoglycemia, balancing this risk with that for ketosis. Capillary blood glucose should be tested every hour and urinary ketone bodies every time is possible [77]. ACOG agreed to the protocol proposed by Coustan [79] for maintaining a mean intrapartum glycemic value of 100 mg/dl. For this, blood glucose should be tested every 2 hours with

Women with GDM or type 2 diabetes, which were treated with oral therapy have a low insulin requirement and in most cases do not need treatment during labor. Thus, CDA recommends a "watchful waiting" and insulin initiation just in cases where glycemia is above 146 mg/dl (7.0 mmol/l) [19]. Ryan mentions the same principle in a review published before—if GDM pregnant had a necessary below 0.5 u/kg/day, they

The study of Rosenberg and collab. demonstrated there is no significant difference in neonatal hypoglycemia, neonatal injury, Apgar score at 1–5 minutes in patients with insulin therapy that were managed with two approaches: dextrose 5% 125 ml/h with a simultaneous insulin drip (adjustable rate 0.5–2.5 u/h) or dextrose 5% alternating with ringer lactate (125 ml/h) and insulin introduction when the targets are exceeded [77]. Other researchers recommend dextrose 10% with an

**3.8 Maternal complications associated with insulin therapy**

tions is as effective as continuous subcutaneous insulin infusion [76].

above 3.9 mmol/l (70 mg/dl) according to ADA [7].

as compared to expectant management should be individualized because the studies lack in this area. An RCT that showed that there is no difference between the two strategies regarding morbidity, but the IOL reduces the risk for shoulder dystocia in the macrosomic fetus [72]. The use of insulin analogs like detemir does not influence the morbidity [73].

#### **3.8 Maternal complications associated with insulin therapy**

#### *3.8.1 Maternal hypoglycemia*

*Gestational Diabetes Mellitus - An Overview with Some Recent Advances*

incidence being in the insulin-treated group [58].

**3.7 Birth complications associated with insulin therapy**

insulins [29, 33].

metformin-treated GDM [62].

*3.6.2 Congenital anomalies*

*3.7.1 Cesarean section (CS)*

*3.7.2 Vacuum-assisted birth*

*3.7.3 Fetal morbidity*

Neonatal transient hypoglycemia could have implications in the neurocognitive development as was shown by magnetic resonance imaging [60]. Also, it has psychological implications on the mother-child relationship because they are separated after birth for treatment. Hence, based on their study results, Voormolen et al. recommend screening all newborns from GDM women in the first 12 hours after birth because the majority of the events occur in this interval, with a higher

A series of studies demonstrated that newborns of GDM patients that were treated with metformin had fewer hypoglycemic events than those of women treated with insulin [21, 61]. Insulin analogs have a lower rise in postprandial glycemic values without elevating hypoglycemic risk and should be preferred to human

GDM had a higher risk of neonatal hypoglycemia and also macrosomia that the

Regarding sulfonylureas, a meta-analysis demonstrated that glyburide treatment

The relationship between insulin therapy and congenital anomalies was studied, especially in type 1 diabetes. The most important confounding factor is glycemic control. Although some case reports indicate an association between the use of insulin lispro and the risk of teratogenesis [63], another meta-analysis supports the fact that it is safe for use [64]. This risk could be explained by mitogenesis stimulation by binding with a higher affinity for IGF-1 receptors. Lispro insulin has a 1.5 and insulin glargine a 6.5 fold increase of receptor binding [65]. There are only retrospective studies that indicate glargine as safe insulin in pregnancy [66].

A Cochrane analysis of 1481 women with GDM showed that in the treatment group there was a higher number of induced labors versus the group with standard antenatal care, but with no difference regarding the number of births by CS [35]. Another meta-analysis did not demonstrate a correlation between the use of different types of insulin-like aspart, lispro and the birth by CS [67, 68]. Although the risk is not influenced by insulin treatment, it can be reduced by induction of labor (IOL) in 38th–39th week of gestation with better outcomes for the fetus [69].

Although pre-gestational diabetes raises the risk for vacuum assisted birth (shoulder dystocia, humerus, clavicle, skull fracture, Erb's palsy, subarachnoidian or subdural hemorrhages, asphyxia, convulsion), in GDM the risk was similar to that in the general population and could not be related to insulin therapy [68, 70]. A particular situation is with GDM that appeared in pregnancies obtained by assisted reproductive technology where the risk for perinatal and obstetrical complications is probably increased by the adverse effect of hyperglycemia, not by insulin treatment [71].

Evidence that indicates a higher risk for fetal morbidity and mortality in GDM a scarce and less pronounced as in pre-gestational diabetes. Current decisions of IOL

**60**

Hypoglycemia threshold is specific for every individual. In pregnancy, there is a reduction of this threshold by 20% [74]. Patients with GDM that are treated with insulin must maintain a glycemia above 3.7 mmol/l (66 mg/dl) according to CDA, or above 3.9 mmol/l (70 mg/dl) according to ADA [7].

Insulin analogs are superior to human insulin because the hypoglycemic events are less frequent in type 1 diabetic pregnancies [75]. The use of multiple daily injections is as effective as continuous subcutaneous insulin infusion [76].

Maternal hypoglycemia affects the fetus just in severe cases when is associated with loss of consciousness or secondary to trauma. Also, it was observed that repeated episodes could lead to growth over the 90th percentile [77]. These episodes are more likely to be present in the first trimester in women who had pregestational diabetes than in GDM [74].

#### *3.8.2 Hypertension*

There is moderate quality evidence that indicates higher hypertension associated hypertension without giving details in insulin-treated GDM. This fact should be further researched because it is in contradiction with a non-modified risk for pre-eclampsia [68].

#### **3.9 Intrapartum management**

During the latent phase of labor hepatic gluconeogenesis is sufficient for providing the caloric requirements, but becomes exiguous during the active phase when intravenous glucose is perfused.

The study of Rosenberg and collab. demonstrated there is no significant difference in neonatal hypoglycemia, neonatal injury, Apgar score at 1–5 minutes in patients with insulin therapy that were managed with two approaches: dextrose 5% 125 ml/h with a simultaneous insulin drip (adjustable rate 0.5–2.5 u/h) or dextrose 5% alternating with ringer lactate (125 ml/h) and insulin introduction when the targets are exceeded [77]. Other researchers recommend dextrose 10% with an insulin drip [78].

Lowering maternal glycemia is necessary for preventing neonatal hypoglycemia, balancing this risk with that for ketosis. Capillary blood glucose should be tested every hour and urinary ketone bodies every time is possible [77]. ACOG agreed to the protocol proposed by Coustan [79] for maintaining a mean intrapartum glycemic value of 100 mg/dl. For this, blood glucose should be tested every 2 hours with adjustments in insulin perfusion rates.

Women with GDM or type 2 diabetes, which were treated with oral therapy have a low insulin requirement and in most cases do not need treatment during labor. Thus, CDA recommends a "watchful waiting" and insulin initiation just in cases where glycemia is above 146 mg/dl (7.0 mmol/l) [19]. Ryan mentions the same principle in a review published before—if GDM pregnant had a necessary below 0.5 u/kg/day, they

could be initially monitored. Otherwise, patients with type 1 diabetes or type 2, GDM with a necessary above this limit will need insulin perfusions [78]. Insulin perfusion rates could be adjusted using sliding scales as proposed by Dude [80].

Although most of the studies use protocols for intravenous insulin administration, patients with insulin pumps can choose to keep their device during labor [81, 82]. This is recommended in centers with experience because during labor they can become unable to handle the pump given the pain, or some incidents like catheter avulsion could appear. In these cases, the patient is informed that a switch to an insulin drip is needed [19].

Another problem comes out when betamethasone is administered for premature birth. In patients with type 1 diabetes, an increase up to 40% of all doses during the next 5 days assures an adequate glycemic control [83]. A retrospective analysis of insulin drips in pregnant with GDM injected by a standard anticipatory protocol and with higher doses was associated with improving glycemic variability and decreasing by 25% the absolute risk for neonatal hypoglycemia [84].

#### **3.10 Postpartum management**

Insulin requirements drop quickly after giving birth and women are exposed to hypoglycemia. Patients with GDM usually do not need insulin, and women with type 1 and type 2 diabetes return to the previous regimen, but at doses that are at 60% of the antepartum necessary [85]. In the case where the doses are not remembered, half of the third-trimester dose could be injected. Another alternative is calculating dose per kilogram. With an insulin pump, the doctor will titrate downward the basal rate and boluses on a similar algorithm or adjust based on the information from glucose sensors for newer models.

Breastfeeding influences insulin sensibility: as the frequency of lactation increases, the HOMA and ISI (0, 120) have better values [86], so during breastfeeding the insulin requirement falls by 10% [87].

#### **3.11 Future research directions**

There is a lot of missing evidence in optimal treatment for GDM. Insulin treatment could be improved by developing automatic algorithms for calculating the appropriate doses like that proposed by Dinglas [88]. Moreover, fetal morbidity can be influenced by better monitoring like using glucose sensors that are more accurate in the hypoglycemic range [89–91].

Micro-RNAs are now extensively studied in different domains and might apply to diagnosing and selecting GDM patients that require insulin treatment [92].

Not eventually, the whole perspective of insulin therapy will change if the oral bioavailability of this peptide hormone will be enhanced. Polymeric nanocarriers and mucoadhesive discs were studied in diabetic rats and are the future expectation for mothers with diabetes [93].

**63**

**Author details**

provided the original work is properly cited.

*Insulin Therapy in Gestational Diabetes DOI: http://dx.doi.org/10.5772/intechopen.84569*

**Notes/thanks/other declarations**

This chapter was financed by Novo Nordisk.

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

Anca Pantea-Stoian\*, Roxana Adriana Stoica and Simona Diana Stefan Nutrition and Metabolic Diseases Department, "Carol Davila" University of

Medicine and Pharmacy Diabetes, Bucharest, Romania

\*Address all correspondence to: ancastoian@yahoo.com

#### **Acknowledgements**

All authors had an equal contribution and shared the first authorship.

#### **Conflict of interest**

None.

### **Notes/thanks/other declarations**

*Gestational Diabetes Mellitus - An Overview with Some Recent Advances*

needed [19].

**3.10 Postpartum management**

rates could be adjusted using sliding scales as proposed by Dude [80].

decreasing by 25% the absolute risk for neonatal hypoglycemia [84].

information from glucose sensors for newer models.

ing the insulin requirement falls by 10% [87].

**3.11 Future research directions**

in the hypoglycemic range [89–91].

for mothers with diabetes [93].

**Acknowledgements**

**Conflict of interest**

None.

could be initially monitored. Otherwise, patients with type 1 diabetes or type 2, GDM with a necessary above this limit will need insulin perfusions [78]. Insulin perfusion

Although most of the studies use protocols for intravenous insulin administration, patients with insulin pumps can choose to keep their device during labor [81, 82]. This is recommended in centers with experience because during labor they can become unable to handle the pump given the pain, or some incidents like catheter avulsion could appear. In these cases, the patient is informed that a switch to an insulin drip is

Another problem comes out when betamethasone is administered for premature birth. In patients with type 1 diabetes, an increase up to 40% of all doses during the next 5 days assures an adequate glycemic control [83]. A retrospective analysis of insulin drips in pregnant with GDM injected by a standard anticipatory protocol and with higher doses was associated with improving glycemic variability and

Insulin requirements drop quickly after giving birth and women are exposed to hypoglycemia. Patients with GDM usually do not need insulin, and women with type 1 and type 2 diabetes return to the previous regimen, but at doses that are at 60% of the antepartum necessary [85]. In the case where the doses are not remembered, half of the third-trimester dose could be injected. Another alternative is calculating dose per kilogram. With an insulin pump, the doctor will titrate downward the basal rate and boluses on a similar algorithm or adjust based on the

Breastfeeding influences insulin sensibility: as the frequency of lactation increases, the HOMA and ISI (0, 120) have better values [86], so during breastfeed-

There is a lot of missing evidence in optimal treatment for GDM. Insulin treatment could be improved by developing automatic algorithms for calculating the appropriate doses like that proposed by Dinglas [88]. Moreover, fetal morbidity can be influenced by better monitoring like using glucose sensors that are more accurate

Micro-RNAs are now extensively studied in different domains and might apply

Not eventually, the whole perspective of insulin therapy will change if the oral bioavailability of this peptide hormone will be enhanced. Polymeric nanocarriers and mucoadhesive discs were studied in diabetic rats and are the future expectation

to diagnosing and selecting GDM patients that require insulin treatment [92].

All authors had an equal contribution and shared the first authorship.

**62**

This chapter was financed by Novo Nordisk.

### **Author details**

Anca Pantea-Stoian\*, Roxana Adriana Stoica and Simona Diana Stefan Nutrition and Metabolic Diseases Department, "Carol Davila" University of Medicine and Pharmacy Diabetes, Bucharest, Romania

\*Address all correspondence to: ancastoian@yahoo.com

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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[17] Rasmussen KM, Catalano PM, Yaktine AL. New guidelines for weight gain during pregnancy: What obstetrician/gynecologists should know. Current Opinion in Obstetrics & Gynecology. 2009;**21**:521-526

[18] Diagnostic Criteria and Classification of Hyperglycaemia First Detected in Pregnancy. World Health Organization; 2013. PMID: 24199271

[19] Diabetes Canada Clinical Practice Guidelines Expert Committee. Diabetes Canada: Clinical practice guidelines for the prevention and management of diabetes in Canada. Canadian Journal of Diabetes. 2018;**42**(Suppl 1):S1-S325

[20] Ijäs H, Vääräsmäki M, Saarela T, et al. A follow-up of a randomised study of metformin and insulin in gestational diabetes mellitus: Growth and development of the children at the age of 18 months. BJOG. 2015;**122**:994-1000

[21] Rowan JA, Rush EC, Obolonkin V, et al. Metformin in gestational diabetes: The offspring follow-up (MiG TOFU): Body composition at 2 years of age. Diabetes Care. 2011;**34**:2279-2284

[22] Tertti K, Eskola E, Ronnemaa T, et al. Neurodevelopment of two-yearold children exposed to metformin and insulin in gestational diabetes mellitus. Journal of Developmental and Behavioral Pediatrics. 2015;**36**:752-757

[23] Wouldes TA, Battin M, Coat S, et al. Neurodevelopmental outcome at 2 years in offspring of women randomised to metformin or insulin treatment for gestational diabetes. Archives of Disease in Childhood. Fetal and Neonatal Edition. 2016;**101**:F488-F493

[24] Balsells M, García-Patterson A, Sola I, Roqué M, Gich I, Corcoy R. Glibenclamide, metformin, and insulin for the treatment of gestational diabetes: A systematic review and meta-analysis. BMJ. 2015;**350**:h102

[25] Jiang Y-F, Chen X-Y, Ding T, Wang X-F, Zhu Z-N, Su S-W. Comparative efficacy and safety of OADs in management of GDM: Network metaanalysis of randomized controlled trials. The Journal of Clinical Endocrinology and Metabolism. 2015;**100**:2071-2080

[26] Rowan JA, Hague WM, Gao W, Battin MR, Moore MP, MiG Trial Investigators. Metformin versus insulin for the treatment of gestational diabetes. The New England Journal of Medicine. 2008;**358**:2003-2015

[27] Hebert MF, Ma X, Naraharisetti SB, et al. Obstetric-fetal pharmacology research unit network. Are we optimizing gestational diabetes treatment with glyburide? The pharmacologic basis for better clinical practice. Clinical Pharmacology and Therapeutics. 2009;**85**:607-614

[28] Hadden DR. When and how to start insulin treatment in gestational diabetes: A UK perspective. Diabetic Medicine. 2001;**18**:960-964

[29] Mecacci F, Carignani L, Cioni R, et al. Maternal metabolic control and perinatal outcome in women with gestational diabetes treated with regular or lispro insulin: Comparison with nondiabetic pregnant women. European Journal of Obstetrics, Gynecology, and Reproductive Biology. 2003;**111**:19-24

[30] European Medicines Agency. European Medicines Agency. Available from: http://www.ema.europa.eu/ema/ [Accessed: November 2, 2018]

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**64**

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[8] American College of Obstetricians and Gynecologists. Committee on practice bulletins—Obstetrics. ACOG practice bulletin No. 190: Gestational diabetes mellitus. Obstetrics and Gynecology. 2018;**131**(2):e49-e64. DOI: 10.1097/AOG.0000000000002501

[9] Jovanovic L. Role of diet and insulin treatment of diabetes in pregnancy. Clinical Obstetrics and Gynecology.

[10] Beaser RS et al. Joslin's Diabetes Deskbook, A Guide for Primary Care Providers. 2nd ed. Lippincott: Wiliams

[11] American Diabetes Association, Bantle JP, Wylie-Rosett J, Albright AL, Apovian CM, Clark NG, et al. Nutrition recommendations and interventions for diabetes: A position statement of the American Diabetes Association. Diabetes Care. 2008;**31**:S61-S78

[12] The International Federation of Gynecology and Obstetrics (FIGO) Initiative on gestational diabetes mellitus: A pragmatic guide for diagnosis, management, and care. International Journal of Gynecology & Obstetrics. 2015;**13**(1):S173-S211. DOI: 10.1016/S0020-7292(15)30007-2

[13] Diabetes in Pregnancy: Management from Preconception to the Postnatal Period NICE Guideline. 2015. Available from: www.nice.org.uk/guidance/ng3

[14] Blumer I, Hadar E, Hadden DR, Jovanovič L, Mestman JH, Murad MH, et al. Diabetes and pregnancy: An endocrine society clinical practice guideline. The Journal of Clinical Endocrinology and Metabolism.

[15] Mulford MI, Jovanovic-Peterson L, Peterson CM. Alternative therapies for the management of gestational diabetes. Clinics in Perinatology. 1993;**20**:619-634

2013;**98**:4227-4249

& Wilkins; 2010. pp. 595-601

2000;**43**:46-55

[1] World Health Organisation and Department of Non-Communicable Disease Surveillance. Definition, Diagnosis and Classification of Diabetes Mellitus and its Complications. Part 1.

[2] International Association of Diabetes and Pregnancy Study Groups Consensus Panel, Metzger BE, Gabbe SG, Persson B, Buchanan TA, Catalano PA, et al. International association of diabetes and pregnancy study groups recommendations on the diagnosis and classification of hyperglycemia in pregnancy. Diabetes Care. 2010;**33**:

676-682. PMID: 20190296

[3] Caprio S. Development of type 2 diabetes mellitus in the obese adolescent: A growing challenge. Endocrine Practice. 2012;**18**:791-795

[4] Ferrara A. Increasing prevalence of gestational diabetes mellitus: A public health perspective. Diabetes Care. 2007;**30**(Suppl 2):S141-S146

[5] American College of Obstetricians and Gynecologists. ACOG practice bulletin: Assessment of risk factors for preterm birth: Clinical management

gynecologists: Number 31. Obstetrics and Gynecology. 2001;**98**:709-716

guidelines for obstetrician-

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[7] American Diabetes Association.

Management of diabetes in pregnancy: Standards of medical care in diabetes. Diabetes Care. 2018;**41**(Suppl.1):S137-S143. DOI:

10.2337/dc07-s225

10.2337/dc18-S013

Geneva: WHO; 1999

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DOI: 10.1038/sj.jp.7211243

NEJM199511093331901

10.1067/mob.2001.117184

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[53] Feig DS, Corcoy R, Donovan LE, et al. Pumps or multiple daily injections

diabetes: A prespecified analysis of the CONCEPTT randomized trial. Diabetes Care. 2018;**41**(12):2471-2479. DOI:

[54] Chen R, Yogev Y, Ben-Haroush A, Jovanovic L, Hod M, Phillip M. Continuous glucose monitoring for the evaluation and improved control of gestational diabetes mellitus. The Journal of Maternal-Fetal & Neonatal

[55] Kestilä KK, Ekblad UU, Rönnemaa T. Continuous glucose monitoring versus self-monitoring of blood glucose in the treatment of gestational diabetes mellitus. Diabetes Research and Clinical

DOI: 10.1530/EJE-17-0804

in pregnancy involving type 1

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[57] Nicholson W, Bolen S, Witkop CT, Neale D, Wilson L, Bass E. Benefits and risks of oral diabetes agents compared with insulin in women with gestational diabetes: A systematic review. Obstetrics and Gynecology. 2009;**113**:193-205. DOI: 10.1097/AOG.0b013e318190a459

[58] Voormolen DN, de Wit L, van Rijn BP, et al. Neonatal hypoglycemia following diet-controlled and insulintreated gestational diabetes mellitus. Diabetes Care. 2018:1-7. DOI: 10.2337/

[59] Hawdon JM. Definition of neonatal hypoglycemia: Time for a rethink? Archives of Disease in Childhood. Fetal and Neonatal Edition. 2013;**98**:F382-F383. DOI: 10.1136/

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[48] Sivan E, Weisz B, Homko C, et al. One or two hours postprandial glucose measurements: Are they the same? American Journal of Obstetrics and Gynecology. 2001;**185**:604-607. DOI:

[49] Crowther CA, Hiller JE, Moss JR, et al. Effect of treatment of gestational

[50] Langer O, Levy J, Brustaman L, et al. Glycemic control in gestational diabetes mellitus-how tight is tight enough: Small for gestational age versus large for gestational age? American Journal of Obstetrics and Gynecology. 1989;**161**(3):646-653.

diabetes mellitus on pregnancy outcomes. The New England Journal of Medicine. 2005;**352**(24):2477-2486.

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[51] Immanuel J, Simmons D. A perspective on the accuracy of blood glucose meters during pregnancy. Diabetes Care. 2018;**41**(10):2053-2058.

[52] Rys PM, Ludwig-Slomczynska AH, Cyganek K, Malecki MT. Continuous subcutaneous insulin infusion vs multiple daily injections in pregnant women with type 1 diabetes mellitus: A systematic review and meta-analysis of randomised controlled trials and observational studies. European Journal

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PMID: 2782347

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[38] Shimizu I, Hiramatsu Y, Omori Y, Nakabayashi M. Glycated albumin reflects maternal and perinatal outcome in a multicenter study of Japan. Diabetes

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[35] Alwan N, Tuffnell DJ, West J. Treatments for gestational diabetes. Cochrane Database of Systematic Reviews. 2009;**8**(3):CD003395. DOI: 10.1002/14651858.CD003395.pub2

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[47] de Veciana M, Major CA, Morgan MA, et al. Postprandial versus preprandial blood glucose monitoring in women with gestational diabetes mellitus requiring insulin therapy. The New England Journal of Medicine. 1995;**333**(19):1237-1241. DOI: 10.1056/ NEJM199511093331901

[48] Sivan E, Weisz B, Homko C, et al. One or two hours postprandial glucose measurements: Are they the same? American Journal of Obstetrics and Gynecology. 2001;**185**:604-607. DOI: 10.1067/mob.2001.117184

[49] Crowther CA, Hiller JE, Moss JR, et al. Effect of treatment of gestational diabetes mellitus on pregnancy outcomes. The New England Journal of Medicine. 2005;**352**(24):2477-2486. DOI: 10.1056/NEJMoa042973

[50] Langer O, Levy J, Brustaman L, et al. Glycemic control in gestational diabetes mellitus-how tight is tight enough: Small for gestational age versus large for gestational age? American Journal of Obstetrics and Gynecology. 1989;**161**(3):646-653. PMID: 2782347

[51] Immanuel J, Simmons D. A perspective on the accuracy of blood glucose meters during pregnancy. Diabetes Care. 2018;**41**(10):2053-2058. DOI: 10.2337/dc18-0833

[52] Rys PM, Ludwig-Slomczynska AH, Cyganek K, Malecki MT. Continuous subcutaneous insulin infusion vs multiple daily injections in pregnant women with type 1 diabetes mellitus: A systematic review and meta-analysis of randomised controlled trials and observational studies. European Journal of Endocrinology. 2018;**178**(5):545-563. DOI: 10.1530/EJE-17-0804

[53] Feig DS, Corcoy R, Donovan LE, et al. Pumps or multiple daily injections in pregnancy involving type 1 diabetes: A prespecified analysis of the CONCEPTT randomized trial. Diabetes Care. 2018;**41**(12):2471-2479. DOI: 10.2337/dc18-1437

[54] Chen R, Yogev Y, Ben-Haroush A, Jovanovic L, Hod M, Phillip M. Continuous glucose monitoring for the evaluation and improved control of gestational diabetes mellitus. The Journal of Maternal-Fetal & Neonatal Medicine. 2003;**14**:256-260

[55] Kestilä KK, Ekblad UU, Rönnemaa T. Continuous glucose monitoring versus self-monitoring of blood glucose in the treatment of gestational diabetes mellitus. Diabetes Research and Clinical Practice. 2007;**77**(2):174-179

[56] Rowan JA, Gao W, Hague WM, McIntyre HD. Glycemia and its relationship to outcomes in the metformin in gestational diabetes trial. Diabetes Care. 2010;**33**:9-16. DOI: 10.2337/ dc09-1407

[57] Nicholson W, Bolen S, Witkop CT, Neale D, Wilson L, Bass E. Benefits and risks of oral diabetes agents compared with insulin in women with gestational diabetes: A systematic review. Obstetrics and Gynecology. 2009;**113**:193-205. DOI: 10.1097/AOG.0b013e318190a459

[58] Voormolen DN, de Wit L, van Rijn BP, et al. Neonatal hypoglycemia following diet-controlled and insulintreated gestational diabetes mellitus. Diabetes Care. 2018:1-7. DOI: 10.2337/ dc18-0048

[59] Hawdon JM. Definition of neonatal hypoglycemia: Time for a rethink? Archives of Disease in Childhood. Fetal and Neonatal Edition. 2013;**98**:F382-F383. DOI: 10.1136/ archdischild-2012-303422

[60] McKinlay CJD, Alsweiler JM, Ansell JM, et al. Neonatal hypoglycemia and neurodevelopmental outcomes at 2 years. The New England Journal of Medicine. 2015;**373**:1507-1518. DOI: 10.1056/NEJMoa1504909

[61] Simeonova-Krstevska S, Bogoev M, et al. Maternal and neonatal outcomes in pregnant women with gestational diabetes mellitus treated with diet, metformin or insulin. Open Access Macedonian Journal of Medical Sciences. 2018;**6**(5):803-807. DOI: 10.3889/oamjms.2018.200

[62] Zeng YC, Li MJ, Chen Y, Jiang L, Wang SM, Mo XL, et al. The use of glyburide in the management of gestational diabetes mellitus: A metaanalysis. Advances in Medical Sciences. 2014;**59**:95-101. DOI: 10.1016/j. advms.2014.03.001

[63] Diamond T, Kormas N. Possible adverse fetal effect of insulin lispro. The New England Journal of Medicine. 1997;**337**(14):1009-1010

[64] Nørgaard K, Sukumar N, Rafnsson SB, Saravanan P. Efficacy and safety of rapid-acting insulin analogs in special populations with type 1 diabetes or gestational diabetes: Systematic review and meta-analysis. Diabetes Therapy. 2018;**9**(3):891-917. DOI: 10.1007/ s13300-018-0411-7

[65] Kurtzhals P, Schaffer L, Sorensen A, et al. Correlations of receptor binding and metabolic and mitogenic potencies of insulin analogs designed for clinical use. Diabetes. 2000;**49**:999-1005

[66] Callesen NF, Damm J, Mathiesen JM, et al. Treatment with the longacting insulin analogues detemir or glargine during pregnancy in women with type 1 diabetes: Comparison of glycaemic control and pregnancy outcome. Journal of Maternal-Fetal and Neonatal Medicine. 2013;**26**:588-592

[67] Martis R, Crowther CA, Shepherd E, Alsweiler J, Downie MR, Brown J. Treatments for women with gestational diabetes mellitus: An overview of Cochrane systematic reviews. Cochrane Database of Systematic Reviews. 2018;**14**(8):CD012327. DOI: 10.1002/14651858.CD012327.pub2

[68] Brown J, Grzeskowiak L, Williamson K, Downie MR, Crowther CA. Insulin for the treatment of women with gestational diabetes. Cochrane Database of Systematic Reviews. 2017;**5**(11):CD012037. DOI: 10.1002/14651858.CD012037.pub2

[69] Melamed N, Ray JG, Geary M, et al. Induction of labor before 40 weeks is associated with lower rate of cesarean delivery in women with gestational diabetes mellitus. American Journal of Obstetrics and Gynecology. 2016;**214**(364):e1-e8

[70] Vitner D, Hiersch L, Ashwal E, Nassie D, Yogev Y, Aviram A. Outcomes of vacuum-assisted vaginal deliveries of mothers with gestational diabetes mellitus. The Journal of Maternal-Fetal & Neonatal Medicine. 2018;**2**:1-5. DOI: 10.1080/14767058.2018.1468880

[71] Kouhkan A, Khamseh ME, Pirjani R, et al. Obstetric and perinatal outcomes of singleton pregnancies conceived via assisted reproductive technology complicated by gestational diabetes mellitus: A prospective cohort study. BMC Pregnancy and Childbirth. 2018;**18**(1):495. DOI: 10.1186/ s12884-018-2115-4

[72] Hod M, Mathiesen ER, Jovanovic L, et al. Perinatal outcomes in a randomized trial comparing insulin detemir with NPH in pregnant women with type 1 diabetes. The Journal of Maternal-Fetal & Neonatal Medicine. 2014;**27**(1):7-13. DOI: 10.3109/14767058.2013.799650

**69**

*Insulin Therapy in Gestational Diabetes DOI: http://dx.doi.org/10.5772/intechopen.84569*

[74] Toledano Y, Hadar E, Hod M. Safety of insulin analogues as compared with human insulin in pregnancy. Expert Opinion on Drug Safety. 2016;**15**(7):963-973. DOI: 10.1080/14740338.2016.1182153

[75] Farrar D, Tuffnell DJ, West J, West HM. Continuous subcutaneous insulin infusion versus multiple daily injections of insulin for pregnant women with diabetes. Cochrane Database of Systematic Reviews. 2016;**6**:CD005542

[76] Seaquist ER, Anderson J, Childs B, et al. Hypoglycemia and diabetes: A report of a workgroup of the American Diabetes Association and the Endocrine Society. Diabetes Care 2013;**36**:1384-95

[77] Rosenberg VA, Eglinton GS, Rauch ER, Skupski DW. Intrapartum maternal glycemic control in women with insulin requiring diabetes: A randomized clinical trial of rotating fluids versus insulin drip. American Journal of Obstetrics and Gynecology.

[78] Ryan EA, Al-Agha R. Glucose control during labor and delivery.

[79] Coustan DR, Carpenter MW. The diagnosis of gestational diabetes. Diabetes Care. 1998;**21**(Suppl 2):B5-B8.

[80] Dude A, Niznik CM, Szmuilowicz

ED, Peaceman AM, Yee LM. Management of diabetes in the intrapartum and postpartum patient. American Journal of Perinatology.

Current Diabetes Reports. 2014;**14**(1):450. DOI: 10.1007/

2006;**195**:1095-1099

s11892-013-0450-4

PMID: 9704220

2013;**36**:1384-1395

[73] Seaquist ER, Anderson J, Childs B, et al. Hypoglycemia and diabetes: A report of a workgroup of the American Diabetes Association and the Endocrine Society. Diabetes Care.

2018;**35**(11):1119-1126. DOI: 10.1055/s-0038-1629903

2016;**33**:1253-1259

[81] Drever E, Tomlinson G, Bai AD, et al. Insulin pump use compared with intra-venous insulin during labour and delivery: The INSPIRED observational cohort study. Diabetic Medicine.

[82] Fresa R, Visalli N, Di Blasi V, et al. Experiences of continuous subcutaneous insulin infusion in pregnant women with type 1 diabetes during delivery from four Italian centers: A retrospective observational

study. Diabetes Technology & Therapeutics. 2013;**15**:328-334

[83] Mathiesen ER, Christensen AB, Hellmuth E, Hornnes P, Stage E, Damm P. Insulin dose during glucocorticoid treatment for fetal lung maturation in diabetic pregnancy: Test of an algorithm [correction of analgoritm]. Acta Obstetricia et Gynecologica Scandinavica. 2002;**81**(9):835-839

[84] Rowe CW, Putt E, Brentnall O, Gebuehr A, Allabyrne J, Woods A, et al. An intravenous insulin protocol designed for pregnancy reduces neonatal hypoglycaemia following betamethasone

administration in women with

2018. DOI: 10.1111/dme.13864

[85] Ringholm L, Mathiesen ER, Kelstrup L, Damm P. Managing type 1 diabetes mellitus in pregnancyfrom planning to breastfeeding. Nature Reviews. Endocrinology. 2012;**8**(11):659-667. DOI: 10.1038/

[86] Gunderson EP, Hedderson MM, Chiang V, Crites Y, Walton D, Azevedo RA, et al. Lactation intensity and postpartum maternal glucose tolerance and insulin resistance in women with recent GDM: The SWIFT cohort. Diabetes Care. 2012;**35**:50-56

nrendo.2012.154

gestational diabetes. Diabetic Medicine.

*Insulin Therapy in Gestational Diabetes DOI: http://dx.doi.org/10.5772/intechopen.84569*

*Gestational Diabetes Mellitus - An Overview with Some Recent Advances*

[67] Martis R, Crowther CA, Shepherd

E, Alsweiler J, Downie MR, Brown J. Treatments for women with gestational diabetes mellitus:

An overview of Cochrane systematic reviews. Cochrane Database of Systematic Reviews. 2018;**14**(8):CD012327. DOI: 10.1002/14651858.CD012327.pub2

[68] Brown J, Grzeskowiak L,

Williamson K, Downie MR, Crowther CA. Insulin for the treatment of women with gestational diabetes. Cochrane Database of Systematic Reviews. 2017;**5**(11):CD012037. DOI: 10.1002/14651858.CD012037.pub2

[69] Melamed N, Ray JG, Geary M, et al. Induction of labor before 40 weeks is associated with lower rate of cesarean delivery in women with gestational diabetes mellitus. American Journal of Obstetrics and Gynecology.

[70] Vitner D, Hiersch L, Ashwal E, Nassie D, Yogev Y, Aviram A. Outcomes of vacuum-assisted vaginal deliveries of mothers with gestational diabetes mellitus. The Journal of Maternal-Fetal & Neonatal Medicine. 2018;**2**:1-5. DOI: 10.1080/14767058.2018.1468880

[71] Kouhkan A, Khamseh ME, Pirjani R, et al. Obstetric and perinatal outcomes of singleton pregnancies conceived via assisted reproductive technology complicated by gestational diabetes mellitus: A prospective cohort study. BMC Pregnancy and Childbirth.

[72] Hod M, Mathiesen ER, Jovanovic L,

2018;**18**(1):495. DOI: 10.1186/

et al. Perinatal outcomes in a randomized trial comparing insulin detemir with NPH in pregnant women with type 1 diabetes. The Journal of Maternal-Fetal & Neonatal Medicine. 2014;**27**(1):7-13. DOI: 10.3109/14767058.2013.799650

s12884-018-2115-4

2016;**214**(364):e1-e8

[60] McKinlay CJD, Alsweiler JM, Ansell JM, et al. Neonatal hypoglycemia and neurodevelopmental outcomes at 2 years. The New England Journal of Medicine. 2015;**373**:1507-1518. DOI:

[61] Simeonova-Krstevska S, Bogoev M, et al. Maternal and neonatal outcomes in pregnant women with gestational diabetes mellitus treated with diet, metformin or insulin. Open Access Macedonian Journal of Medical Sciences. 2018;**6**(5):803-807. DOI:

[62] Zeng YC, Li MJ, Chen Y, Jiang L, Wang SM, Mo XL, et al. The use of glyburide in the management of gestational diabetes mellitus: A metaanalysis. Advances in Medical Sciences.

2014;**59**:95-101. DOI: 10.1016/j.

[63] Diamond T, Kormas N. Possible adverse fetal effect of insulin lispro. The New England Journal of Medicine.

[64] Nørgaard K, Sukumar N, Rafnsson SB, Saravanan P. Efficacy and safety of rapid-acting insulin analogs in special populations with type 1 diabetes or gestational diabetes: Systematic review and meta-analysis. Diabetes Therapy. 2018;**9**(3):891-917. DOI: 10.1007/

[65] Kurtzhals P, Schaffer L, Sorensen A, et al. Correlations of receptor binding and metabolic and mitogenic potencies of insulin analogs designed for clinical use. Diabetes. 2000;**49**:999-1005

[66] Callesen NF, Damm J, Mathiesen JM, et al. Treatment with the longacting insulin analogues detemir or glargine during pregnancy in women with type 1 diabetes: Comparison of glycaemic control and pregnancy outcome. Journal of Maternal-Fetal and Neonatal Medicine. 2013;**26**:588-592

advms.2014.03.001

1997;**337**(14):1009-1010

s13300-018-0411-7

10.1056/NEJMoa1504909

10.3889/oamjms.2018.200

**68**

[73] Seaquist ER, Anderson J, Childs B, et al. Hypoglycemia and diabetes: A report of a workgroup of the American Diabetes Association and the Endocrine Society. Diabetes Care. 2013;**36**:1384-1395

[74] Toledano Y, Hadar E, Hod M. Safety of insulin analogues as compared with human insulin in pregnancy. Expert Opinion on Drug Safety. 2016;**15**(7):963-973. DOI: 10.1080/14740338.2016.1182153

[75] Farrar D, Tuffnell DJ, West J, West HM. Continuous subcutaneous insulin infusion versus multiple daily injections of insulin for pregnant women with diabetes. Cochrane Database of Systematic Reviews. 2016;**6**:CD005542

[76] Seaquist ER, Anderson J, Childs B, et al. Hypoglycemia and diabetes: A report of a workgroup of the American Diabetes Association and the Endocrine Society. Diabetes Care 2013;**36**:1384-95

[77] Rosenberg VA, Eglinton GS, Rauch ER, Skupski DW. Intrapartum maternal glycemic control in women with insulin requiring diabetes: A randomized clinical trial of rotating fluids versus insulin drip. American Journal of Obstetrics and Gynecology. 2006;**195**:1095-1099

[78] Ryan EA, Al-Agha R. Glucose control during labor and delivery. Current Diabetes Reports. 2014;**14**(1):450. DOI: 10.1007/ s11892-013-0450-4

[79] Coustan DR, Carpenter MW. The diagnosis of gestational diabetes. Diabetes Care. 1998;**21**(Suppl 2):B5-B8. PMID: 9704220

[80] Dude A, Niznik CM, Szmuilowicz ED, Peaceman AM, Yee LM. Management of diabetes in the intrapartum and postpartum patient. American Journal of Perinatology.

2018;**35**(11):1119-1126. DOI: 10.1055/s-0038-1629903

[81] Drever E, Tomlinson G, Bai AD, et al. Insulin pump use compared with intra-venous insulin during labour and delivery: The INSPIRED observational cohort study. Diabetic Medicine. 2016;**33**:1253-1259

[82] Fresa R, Visalli N, Di Blasi V, et al. Experiences of continuous subcutaneous insulin infusion in pregnant women with type 1 diabetes during delivery from four Italian centers: A retrospective observational study. Diabetes Technology & Therapeutics. 2013;**15**:328-334

[83] Mathiesen ER, Christensen AB, Hellmuth E, Hornnes P, Stage E, Damm P. Insulin dose during glucocorticoid treatment for fetal lung maturation in diabetic pregnancy: Test of an algorithm [correction of analgoritm]. Acta Obstetricia et Gynecologica Scandinavica. 2002;**81**(9):835-839

[84] Rowe CW, Putt E, Brentnall O, Gebuehr A, Allabyrne J, Woods A, et al. An intravenous insulin protocol designed for pregnancy reduces neonatal hypoglycaemia following betamethasone administration in women with gestational diabetes. Diabetic Medicine. 2018. DOI: 10.1111/dme.13864

[85] Ringholm L, Mathiesen ER, Kelstrup L, Damm P. Managing type 1 diabetes mellitus in pregnancyfrom planning to breastfeeding. Nature Reviews. Endocrinology. 2012;**8**(11):659-667. DOI: 10.1038/ nrendo.2012.154

[86] Gunderson EP, Hedderson MM, Chiang V, Crites Y, Walton D, Azevedo RA, et al. Lactation intensity and postpartum maternal glucose tolerance and insulin resistance in women with recent GDM: The SWIFT cohort. Diabetes Care. 2012;**35**:50-56

Chapter 5

Abstract

resistance.

71

type 2 diabetes mellitus

1. Introduction

Diabetes

Breastfeeding and Gestational

Enrique Morales-Avila and Arturo Zárate

Renata Saucedo, Jorge Valencia, María Isabel Peña-Cano,

Breastfeeding is recommended as the preferred method of feeding for infants for at least 1 year, because of its multiple immediate and long-term benefits for both the mother and child. Among women with a history of gestational diabetes mellitus (GDM), breastfeeding is associated with increased insulin sensitivity, improved insulin secretion, improved glucose tolerance, and a reduced incidence of type 2 diabetes mellitus (T2DM). Lactation has also been associated with postpartum weight loss, reduced long-term obesity risk, a lower prevalence of the metabolic syndrome, hypertension, and cardiovascular disease. The mechanisms underlying the benefits of breastfeeding for the mother are unclear. However, a role of adipose tissue-produced cytokines (adipokines) has been suggested. Lactation appears to mobilize adipose tissue accrued during pregnancy, and some changes in adipokine levels have been reported. Higher lactation intensity has been associated with lower plasma leptin, a peptide mainly associated with appetite regulation and insulin

Keywords: gestational diabetes, breastfeeding, leptin, insulin resistance,

Breastmilk is the physiologic norm for infant nutrition, offering multiple health

benefits and protection for babies and mothers [1–4]. WHO recommends that breastfeeding be initiated within 1 hour of birth, that it continue with no other foods or liquids for the first 6 months of life, and that it be continued with complementary feeding (breastfeeding with other age-appropriate foods) until at least 24 months of age. However, global breastfeeding rates remain far below international targets. In most high-income countries, the prevalence of breastfeeding at 12 months is lower than 20%, and it is highest in sub-Saharan Africa, south Asia, and parts of Latin America [5]. In Mexico, rates of breastfeeding are particularly low, 38.3% of Mexican women initiate breastfeeding soon after giving birth, only 14.4% of these women report exclusively breastfeeding at 6 months postpartum, 35.5% report any breastfeeding at 12 months postpartum, and 14.1% report any breastfeeding at 2 years postpartum. Importantly, breastfeeding rates vary by

demographic area and are highest in rural over urban area [6].

[87] Riviello C, Mello G, Jovanovic LG. Breastfeeding and the basal insulin requirement in type 1 diabetic women. Endocrine Practice. 2009;**15**:187-193

[88] Dinglas C, Muscat J, Adams T, Peragallo-Dittko V, Vintzileos A, Heo HJ. Software-guided insulin dosing improves intrapartum glycemic management in women with diabetes mellitus. American Journal of Obstetrics and Gynecology. 2018;**219**(2):191. e1-191.e6. DOI: 10.1016/j. ajog.2018.05.003

[89] Harris DL, Bartin MR, Weston PJ, Harding JE. Continuous glucose monitoring in newborn babies at risk of hypoglycemia. The Journal of Pediatrics. 2010;**157**:198-202.e1

[90] Perri A, Giordano L, Corsello M, et al. Continuous glucose monitoring (CGM) in very low birth weight newborns needing parenteral nutrition: Validation and glycemic percentiles. Italian Journal of Pediatrics. 2018;**44**(1):99. DOI: 10.1186/ s13052-018-0542-5

[91] McKinlay CJD, Chase JG, Dickson J, et al. Continuous glucose monitoring in neonates: A review. Maternal Health, Neonatology and Perinatology. 2017;**3**:18. DOI: 10.1186/ s40748-017-0055-z

[92] Ibarra A, Vega-Guedes B, Brito-Casillas Y, Wägner AM. Diabetes in pregnancy and microRNAs: Promises and limitations in their clinical application. Non-Coding RNA. 2018;**4**(4):pii: E32. DOI: 10.3390/ ncrna4040032

[93] Gedawy A, Martinez J, Al-Salami H, Dass CR. Oral insulin delivery: Existing barriers and current counterstrategies. The Journal of Pharmacy and Pharmacology. 2018;**70**(2):197-213. DOI: 10.1111/jphp.12852

#### Chapter 5

*Gestational Diabetes Mellitus - An Overview with Some Recent Advances*

[87] Riviello C, Mello G, Jovanovic LG. Breastfeeding and the basal insulin requirement in type 1 diabetic women. Endocrine Practice. 2009;**15**:187-193

[88] Dinglas C, Muscat J, Adams T, Peragallo-Dittko V, Vintzileos A, Heo HJ. Software-guided insulin dosing improves intrapartum glycemic management in women with diabetes mellitus. American Journal of Obstetrics and Gynecology. 2018;**219**(2):191.

[89] Harris DL, Bartin MR, Weston PJ, Harding JE. Continuous glucose

monitoring in newborn babies at risk of hypoglycemia. The Journal of Pediatrics.

[90] Perri A, Giordano L, Corsello M, et al. Continuous glucose monitoring (CGM) in very low birth weight newborns needing parenteral nutrition: Validation and glycemic percentiles. Italian Journal of

Pediatrics. 2018;**44**(1):99. DOI: 10.1186/

e1-191.e6. DOI: 10.1016/j.

ajog.2018.05.003

2010;**157**:198-202.e1

s13052-018-0542-5

s40748-017-0055-z

ncrna4040032

10.1111/jphp.12852

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**70**

## Breastfeeding and Gestational Diabetes

Renata Saucedo, Jorge Valencia, María Isabel Peña-Cano, Enrique Morales-Avila and Arturo Zárate

#### Abstract

Breastfeeding is recommended as the preferred method of feeding for infants for at least 1 year, because of its multiple immediate and long-term benefits for both the mother and child. Among women with a history of gestational diabetes mellitus (GDM), breastfeeding is associated with increased insulin sensitivity, improved insulin secretion, improved glucose tolerance, and a reduced incidence of type 2 diabetes mellitus (T2DM). Lactation has also been associated with postpartum weight loss, reduced long-term obesity risk, a lower prevalence of the metabolic syndrome, hypertension, and cardiovascular disease. The mechanisms underlying the benefits of breastfeeding for the mother are unclear. However, a role of adipose tissue-produced cytokines (adipokines) has been suggested. Lactation appears to mobilize adipose tissue accrued during pregnancy, and some changes in adipokine levels have been reported. Higher lactation intensity has been associated with lower plasma leptin, a peptide mainly associated with appetite regulation and insulin resistance.

Keywords: gestational diabetes, breastfeeding, leptin, insulin resistance, type 2 diabetes mellitus

#### 1. Introduction

Breastmilk is the physiologic norm for infant nutrition, offering multiple health benefits and protection for babies and mothers [1–4]. WHO recommends that breastfeeding be initiated within 1 hour of birth, that it continue with no other foods or liquids for the first 6 months of life, and that it be continued with complementary feeding (breastfeeding with other age-appropriate foods) until at least 24 months of age. However, global breastfeeding rates remain far below international targets. In most high-income countries, the prevalence of breastfeeding at 12 months is lower than 20%, and it is highest in sub-Saharan Africa, south Asia, and parts of Latin America [5]. In Mexico, rates of breastfeeding are particularly low, 38.3% of Mexican women initiate breastfeeding soon after giving birth, only 14.4% of these women report exclusively breastfeeding at 6 months postpartum, 35.5% report any breastfeeding at 12 months postpartum, and 14.1% report any breastfeeding at 2 years postpartum. Importantly, breastfeeding rates vary by demographic area and are highest in rural over urban area [6].

Breastfeeding has protective effects on maternal health, including a reduced risk of breast cancer and ovarian cancer, obesity, hypertension, stroke, hyperlipidemia, metabolic syndrome, and type 2 diabetes mellitus (T2DM) [7–11].

In a recent study of women with previous GDM diagnosed according to the new "International Association of Diabetes and Pregnancy Study Groups" (IADPSG)

criteria, that included women with a milder metabolic impairment,

and triglycerides [28].

Breastfeeding and Gestational Diabetes DOI: http://dx.doi.org/10.5772/intechopen.82000

3. Long-term benefits of breastfeeding

for <10 months at 4 years postpartum [29].

OGTT (69.5 vs. 84.2%, p = 0.041) [33].

delivery [29].

14 years [31].

73

breastfeeding for almost 3 months improved the metabolic outcomes, such as fasting and 2 h glycemia at OGTT, an index of insulin resistance (HOMA-IR)

It has been demonstrated that the favorable effects of lactation on glucose metabolism persist after weaning. Chouinard-Castonguay et al., in a cross-sectional study, showed that lactation duration was an independent predictor of fasting insulin concentrations and insulin sensitivity indices up to a mean of 4 years after

It has been suggested that a longer duration of breastfeeding is associated with a

In a longitudinal analysis, Buchanan found no difference in the prevalence of diabetes at 11–26 months postpartum [30]. Similarly, Kjos, in a retrospective study, reported that breastfeeding was not associated with the progression to T2DM within a follow-up of 7.5 years after delivery [27], and in a retrospective cohort study, the Nurses' Health Study, breastfeeding did not affect the risk of diabetes at

However, of interest, one prospective study that assessed the development of

Also, the positive metabolic impact of breastfeeding has been reported in women with mild forms of GDM. A recent study showed that women with glucose intolerance in early postpartum breastfed less often than women with a normal

The discrepancy among the different studies could be a result of the differences in the design of the study, the severity of GDM, diagnosis of T2DM, breastfeeding assessment, follow-up time postpartum sample size, lifestyle behaviors, ethnic characteristics, and, finally, the use of oral contraceptives. Birth control with progestin-only oral contraceptive pills has been associated with an increased risk of T2DM during the first 2 years of use. Kjos reported a threefold increase in the risk of T2DM at 7.5 years postpartum in breastfeeding women with recent GDM. By contrast, use of low dose progestin/estrogen combination oral contraceptive pills

The potential mechanisms involved in the protective effects of breastfeeding on glucose metabolism include breastfeeding-related hormones such as prolactin and estrogen [34]. Prolactin levels are elevated and estradiol is lower in breastfeeding

T2DM in women with GDM for up to 20 years after delivery found that breastfeeding reduced the risk of diabetes by 46%; median time to postpartum diabetes was 12.3 years for women who breastfed versus 2.3 years for women who did not breastfeed, independently of maternal BMI and insulin use during pregnancy [32]. Moreover, women who breastfed for >3 months had lower risk of

diabetes than women who breastfed for ≤3 months (P = 0.029).

during breastfeeding does not increase the risk of T2DM [27].

4. Mechanisms in the protective effects of breastfeeding

lower risk of T2DM. However, results in some studies have been inconsistent. Chouinard-Castonguay found that women who reported lactating for >10 months had impaired glucose tolerance less frequently compared with women who lactated

One of the strongest risk factors for T2DM is a history of gestational diabetes mellitus (GDM). Among women with a history of GDM, the cumulative risk of developing T2DM at 10 years postpartum ranges from 20 to 50% [12]. Infant feeding method is a modifiable risk factor for the development of diabetes; breastfeeding confers short- and long-term benefits on metabolism reducing the risk of developing T2DM.

Despite the important benefits of breastfeeding, there is evidence to suggest that lower rates of breastfeeding occur in women with GDM and that the duration of breastfeeding is shorter compared with that of healthy mothers [13, 14]. The explanations to account for these rates are higher rates of cesarean sections and neonatal intensive care unit admissions, which include increased recovery time for the mother, prolonged separation of mother and baby, and decreased or delayed bonding [15]. Other factors influencing the lower rates of breastfeeding in GDM are insulin therapy during pregnancy and obesity; women with insulin-treated diabetes have less intention to breastfeed and women with high BMI may have different hormonal patterns, delaying onset of milk production [16, 17].

Insulin treatment is related to severity of GDM, and this marked gestational disturbance in insulin and glucose metabolism may interfere with the hormonal pathways for initiation of lactogenesis. Results from a study of gene expression profiles at different stages of lactation suggested that decreased insulin sensitivity may delay milk production as a result of protein tyrosine phosphatase, receptor type F overexpression in the mammary gland [18].

On the other hand, the GDM treatment with oral hypoglycemic agents has not been related to milk production by the mothers [16]. Glyburide and metformin are the two oral hypoglycemic agents most commonly used during pregnancy, and both are safe with breastfeeding [19].

#### 2. Short-term benefits of breastfeeding

Lactation confers favorable metabolic changes, including lower fasting and postprandial blood glucose, as well as insulin, and triglycerides, and greater insulin sensitivity, and plasma HDL-C [20]. Glucose is diverted for milk production via noninsulin-mediated pathways of uptake by the mammary gland and, thus, lactating women exhibit lower blood glucose [21].

On the other hand, lactation promotes postpartum weight loss [22]; lactogenesis increases maternal total energy expenditure by 15–25% [23]. Prospective studies have reported more rapid weight loss within 6 months postpartum, and lower weight retention at 1 year postpartum [24].

Studies in women with recent GDM report more favorable glucose tolerance and lipid metabolism during 4 months postpartum for lactating compared with non-lactating women [25]. At 6–9 weeks postpartum, the SWIFT cohort in a racially and ethnically diverse group found a dose-response relationship between increasing intensity of lactation and decreasing fasting plasma glucose and both fasting and 2-h insulin, as well as improved insulin sensitivity [26].

In a retrospective cohort among Latinas with recent GDM, Kjos et al. reported 5 mg/dL lower fasting blood glucose for any intensity of lactation versus no lactation, and an improved glucose tolerance determined by the glucose area under the curve from the oral glucose tolerance test (OGTT) [27].

Breastfeeding and Gestational Diabetes DOI: http://dx.doi.org/10.5772/intechopen.82000

Breastfeeding has protective effects on maternal health, including a reduced risk of breast cancer and ovarian cancer, obesity, hypertension, stroke, hyperlipidemia,

One of the strongest risk factors for T2DM is a history of gestational diabetes mellitus (GDM). Among women with a history of GDM, the cumulative risk of developing T2DM at 10 years postpartum ranges from 20 to 50% [12]. Infant feeding method is a modifiable risk factor for the development of diabetes; breastfeeding confers short- and long-term benefits on metabolism reducing the

Despite the important benefits of breastfeeding, there is evidence to suggest that lower rates of breastfeeding occur in women with GDM and that the duration of breastfeeding is shorter compared with that of healthy mothers [13, 14]. The explanations to account for these rates are higher rates of cesarean sections and neonatal intensive care unit admissions, which include increased recovery time for the mother, prolonged separation of mother and baby, and decreased or delayed bonding [15]. Other factors influencing the lower rates of breastfeeding in GDM are insulin therapy during pregnancy and obesity; women with insulin-treated diabetes have less intention to breastfeed and women with high BMI may have different

Insulin treatment is related to severity of GDM, and this marked gestational disturbance in insulin and glucose metabolism may interfere with the hormonal pathways for initiation of lactogenesis. Results from a study of gene expression profiles at different stages of lactation suggested that decreased insulin sensitivity may delay milk production as a result of protein tyrosine phosphatase, receptor type

On the other hand, the GDM treatment with oral hypoglycemic agents has not been related to milk production by the mothers [16]. Glyburide and metformin are the two oral hypoglycemic agents most commonly used during pregnancy, and both

Lactation confers favorable metabolic changes, including lower fasting and postprandial blood glucose, as well as insulin, and triglycerides, and greater insulin sensitivity, and plasma HDL-C [20]. Glucose is diverted for milk production via noninsulin-mediated pathways of uptake by the mammary gland and, thus, lactat-

On the other hand, lactation promotes postpartum weight loss [22]; lactogenesis increases maternal total energy expenditure by 15–25% [23]. Prospective studies have reported more rapid weight loss within 6 months postpartum, and lower

Studies in women with recent GDM report more favorable glucose tolerance and lipid metabolism during 4 months postpartum for lactating compared with non-lactating women [25]. At 6–9 weeks postpartum, the SWIFT cohort in a racially

In a retrospective cohort among Latinas with recent GDM, Kjos et al. reported 5 mg/dL lower fasting blood glucose for any intensity of lactation versus no lactation, and an improved glucose tolerance determined by the glucose area under the

and ethnically diverse group found a dose-response relationship between increasing intensity of lactation and decreasing fasting plasma glucose and both

fasting and 2-h insulin, as well as improved insulin sensitivity [26].

curve from the oral glucose tolerance test (OGTT) [27].

metabolic syndrome, and type 2 diabetes mellitus (T2DM) [7–11].

Gestational Diabetes Mellitus - An Overview with Some Recent Advances

hormonal patterns, delaying onset of milk production [16, 17].

F overexpression in the mammary gland [18].

2. Short-term benefits of breastfeeding

ing women exhibit lower blood glucose [21].

weight retention at 1 year postpartum [24].

72

are safe with breastfeeding [19].

risk of developing T2DM.

In a recent study of women with previous GDM diagnosed according to the new "International Association of Diabetes and Pregnancy Study Groups" (IADPSG) criteria, that included women with a milder metabolic impairment, breastfeeding for almost 3 months improved the metabolic outcomes, such as fasting and 2 h glycemia at OGTT, an index of insulin resistance (HOMA-IR) and triglycerides [28].

It has been demonstrated that the favorable effects of lactation on glucose metabolism persist after weaning. Chouinard-Castonguay et al., in a cross-sectional study, showed that lactation duration was an independent predictor of fasting insulin concentrations and insulin sensitivity indices up to a mean of 4 years after delivery [29].

#### 3. Long-term benefits of breastfeeding

It has been suggested that a longer duration of breastfeeding is associated with a lower risk of T2DM. However, results in some studies have been inconsistent. Chouinard-Castonguay found that women who reported lactating for >10 months had impaired glucose tolerance less frequently compared with women who lactated for <10 months at 4 years postpartum [29].

In a longitudinal analysis, Buchanan found no difference in the prevalence of diabetes at 11–26 months postpartum [30]. Similarly, Kjos, in a retrospective study, reported that breastfeeding was not associated with the progression to T2DM within a follow-up of 7.5 years after delivery [27], and in a retrospective cohort study, the Nurses' Health Study, breastfeeding did not affect the risk of diabetes at 14 years [31].

However, of interest, one prospective study that assessed the development of T2DM in women with GDM for up to 20 years after delivery found that breastfeeding reduced the risk of diabetes by 46%; median time to postpartum diabetes was 12.3 years for women who breastfed versus 2.3 years for women who did not breastfeed, independently of maternal BMI and insulin use during pregnancy [32]. Moreover, women who breastfed for >3 months had lower risk of diabetes than women who breastfed for ≤3 months (P = 0.029).

Also, the positive metabolic impact of breastfeeding has been reported in women with mild forms of GDM. A recent study showed that women with glucose intolerance in early postpartum breastfed less often than women with a normal OGTT (69.5 vs. 84.2%, p = 0.041) [33].

The discrepancy among the different studies could be a result of the differences in the design of the study, the severity of GDM, diagnosis of T2DM, breastfeeding assessment, follow-up time postpartum sample size, lifestyle behaviors, ethnic characteristics, and, finally, the use of oral contraceptives. Birth control with progestin-only oral contraceptive pills has been associated with an increased risk of T2DM during the first 2 years of use. Kjos reported a threefold increase in the risk of T2DM at 7.5 years postpartum in breastfeeding women with recent GDM. By contrast, use of low dose progestin/estrogen combination oral contraceptive pills during breastfeeding does not increase the risk of T2DM [27].

#### 4. Mechanisms in the protective effects of breastfeeding

The potential mechanisms involved in the protective effects of breastfeeding on glucose metabolism include breastfeeding-related hormones such as prolactin and estrogen [34]. Prolactin levels are elevated and estradiol is lower in breastfeeding

women than in non-lactating women. In vitro experiments of rat pancreatic islets cultured with prolactin have shown enhanced stimulated insulin secretion through stimulation of b-cell proliferation by downregulating the expression of menin [35, 36]. Also, prolactin modulates the transcription factors STAT5 and PPARg, and the expression of lipoprotein lipase, which are co-expressed in breast, adipose tissue, and skeletal muscle [37].

GDM, showing that women with longer duration of lactation had greater weight loss at postpartum and lower leptin levels compared with women who lactated for a short period. This difference remained statistically significant after adjustment for weight [58]. Similarly, a previous study with a large cohort of women with recent GDM that utilized a quantitative measure of lactation intensity found that mean leptin concentrations were inversely associated with lactation intensity (lower by 15–21%) independent of maternal pre-pregnancy obesity, race, weight loss, sociodemographics, and postpartum insulin resistance [41]. It has been suggested

On the other hand, leptin is a long-term regulator of appetite that serves as an anorexigenic signal when adipose stores are high [60]. It has been detected in breast milk at concentrations of 0.35–4.6 μg/L [61], and the concentration of leptin in breast milk is correlated to indices of maternal adiposity, including body mass index (r = 0.65, P < 0.02), and fat mass (r = 0.65, P < 0.02) [62]. This evidence provides an attractive explanation for the ability of breast milk to regulate infant body weight. Bouret has recently suggested that the presence of appetite hormones may permanently affect the appetite-regulating system of the infant by affecting the development of the hypothalamus. These differences in appetite hormone exposure may create permanent changes in the way the brain reacts to appetite hormones and

Another adipokine related to abnormal glucose metabolism during pregnancy is

adiponectin. It has been suggested that low levels of adiponectin may induce severe insulin resistance prior to the onset of GDM [64]. Gunderson evaluated the relationship between lactation intensity and plasma adiponectin among postpartum women with previous GDM and found that higher lactation intensity was associated with 6% lower adiponectin. This inverse association remained after adjustment for insulin resistance [41]. This observation is consistent with the action of prolactin in suppressing the production and secretion of adiponectin from human adipo-

5. Implications of breastfeeding in the offspring of the GDM mother

Infants of mothers with GDM are at increased risk of prematurity, macrosomia, hypoglycemia, respiratory distress, hypocalcemia, polycythemia, and hyperbilirubinemia. Breastfeeding has many established benefits for child health; it prevents child morbidity due to diarrhea, respiratory infections, and otitis media [5]. In particular, in the offspring of the GDM mother, lactation has been associated with

On the other hand, exposure to maternal gestational diabetes has been shown to increase the risk of obesity, childhood-onset type 2 diabetes in offspring, as well as the risk of adult-onset type 2 diabetes and gestational diabetes in those offspring [66]. Breastfeeding confers protection against these medical complications; exclusive breastfeeding decreases the risk of the development of childhood-onset type 2

Benefits of breastfeeding on children's health are likely due to the unique composition of breast milk. Human milk is a source of immunoglobulins, hormones and growth factors including leptin, adiponectin, ghrelin, peptide YY, glucagon-like peptide-1, resistin, and obestatin, which are involved in food intake regulation and energy balance, and may have a role in the regulation of growth and development in the neonatal period and infancy, as well as long-term effects on metabolic

that during lactation, prolactin suppresses leptin secretion [59].

satiety cues [63].

Breastfeeding and Gestational Diabetes DOI: http://dx.doi.org/10.5772/intechopen.82000

cytes [13].

lower episodes of hypoglycemia [65].

diabetes and obesity [67].

programming [68].

75

On the other hand, it has been suggested that lactation improves insulin sensitivity by mobilizing lipids derived from liver and muscle for lactogenesis rather than by redirecting lipids into adipocytes [34].

Another mechanism is the influence of lactation on regional fat tissue metabolism; some studies have reported enhanced fat mass mobilization from the trunk and thighs for lactating women [38, 39]. In keeping with this, another study reported that lactation history is associated with a smaller visceral fat area in women who reported they lactated for at least 3 months [40].

There is also evidence that leptin, which is an adipokine positively associated with body adiposity and insulin resistance, is modified in breastfeeding women with previous GDM [41]. Leptin directly affects whole-body insulin sensitivity by regulating the efficiency of insulin-mediated glucose metabolism by skeletal muscle and by hepatic regulation of gluconeogenesis through its action on gene expression of phosphoenolpyruvate carboxykinase [42, 43]. Moreover, it exerts an acute inhibitory effect on insulin secretion, and upregulates inflammatory mediators like TNFα and interleukin-6, which contribute to excessive insulin resistance both at the level of the whole body and in specific organs, including in the liver, muscle, and brain [44].

Leptin is predominantly produced by adipocytes, but is also produced by non-adipose tissues such as stomach, intestine, ovaries, and in particular, the placenta [45]. Maternal leptin levels increase two- to threefold in pregnancy, with a peak occurring around 28 weeks of gestation and decreasing to pre-pregnancy concentrations after delivery [46]. It has been suggested that the rise in maternal leptin concentration during pregnancy may result from an upregulation of adipocyte leptin synthesis in the presence of increasing insulin resistance and hyperinsulinemia in the second half of pregnancy [47]. However, there is strong evidence that the placenta, rather than maternal adipose tissue, contributes to the increase of maternal leptin concentrations during pregnancy [48]. Leptin induces human chorionic gonadotropin production, regulates placental growth, angiogenesis, trophoblast invasion, and nutrient transfer [49]. Leptin enhances the mobilization of maternal fat stores to increase availability and to support transplacental transfer of lipid substrates [50]. Moreover, leptin upregulates placental System A amino acid transport, to increase fetal nutrient availability [51]. Leptin serves as a mitogen for a growing number of cell types, including endothelial cells, hemopoietic cells, lung epithelial cells, and pancreatic b-cells in vitro [52]. Leptin could therefore be stimulating growth of tissues in the developing fetus.

Leptin contributes to the pathophysiologic relationship between GDM and subsequent T2DM. In our previous study, we found that women with previous GDM persisted with insulin resistance in the postpartum period, in association with higher leptin levels compared with the control group [53]. It is possible that postpartum insulin resistance may be contributing to these elevated levels. A positive association between leptinemia and insulinemia has been reported in numerous studies of obese and non-obese humans [54, 55]. Experimentally, increased insulin levels may stimulate leptin production in adipocytes, and vice versa, an increase in leptin levels may lead to insulin resistance and alter b-cell secretory capacity [56, 57]. Interestingly, we recently reported that breastfeeding was associated with better metabolic profile in the early postpartum period in women with previous

#### Breastfeeding and Gestational Diabetes DOI: http://dx.doi.org/10.5772/intechopen.82000

women than in non-lactating women. In vitro experiments of rat pancreatic islets cultured with prolactin have shown enhanced stimulated insulin secretion through stimulation of b-cell proliferation by downregulating the expression of menin [35, 36]. Also, prolactin modulates the transcription factors STAT5 and PPARg, and the expression of lipoprotein lipase, which are co-expressed in breast, adipose

Gestational Diabetes Mellitus - An Overview with Some Recent Advances

On the other hand, it has been suggested that lactation improves insulin sensitivity by mobilizing lipids derived from liver and muscle for lactogenesis rather

Another mechanism is the influence of lactation on regional fat tissue metabolism; some studies have reported enhanced fat mass mobilization from the trunk and thighs for lactating women [38, 39]. In keeping with this, another study reported that lactation history is associated with a smaller visceral fat area in women

There is also evidence that leptin, which is an adipokine positively associated with body adiposity and insulin resistance, is modified in breastfeeding women with previous GDM [41]. Leptin directly affects whole-body insulin sensitivity by regulating the efficiency of insulin-mediated glucose metabolism by skeletal muscle and by hepatic regulation of gluconeogenesis through its action on gene expression of phosphoenolpyruvate carboxykinase [42, 43]. Moreover, it exerts an acute inhibitory effect on insulin secretion, and upregulates inflammatory mediators like TNFα and interleukin-6, which contribute to excessive insulin resistance both at the level of the whole body and in specific organs, including in the liver, muscle, and

Leptin is predominantly produced by adipocytes, but is also produced by non-adipose tissues such as stomach, intestine, ovaries, and in particular, the placenta [45]. Maternal leptin levels increase two- to threefold in pregnancy, with a peak occurring around 28 weeks of gestation and decreasing to pre-pregnancy concentrations after delivery [46]. It has been suggested that the rise in maternal leptin concentration during pregnancy may result from an upregulation of adipo-

hyperinsulinemia in the second half of pregnancy [47]. However, there is strong evidence that the placenta, rather than maternal adipose tissue, contributes to the increase of maternal leptin concentrations during pregnancy [48]. Leptin induces

angiogenesis, trophoblast invasion, and nutrient transfer [49]. Leptin enhances the mobilization of maternal fat stores to increase availability and to support transplacental transfer of lipid substrates [50]. Moreover, leptin upregulates placental System A amino acid transport, to increase fetal nutrient availability [51]. Leptin serves as a mitogen for a growing number of cell types, including endothelial cells, hemopoietic cells, lung epithelial cells, and pancreatic b-cells in vitro [52]. Leptin could therefore be stimulating growth of tissues in the developing fetus. Leptin contributes to the pathophysiologic relationship between GDM and subsequent T2DM. In our previous study, we found that women with previous GDM persisted with insulin resistance in the postpartum period, in association with

higher leptin levels compared with the control group [53]. It is possible that postpartum insulin resistance may be contributing to these elevated levels. A positive association between leptinemia and insulinemia has been reported in numerous studies of obese and non-obese humans [54, 55]. Experimentally, increased insulin levels may stimulate leptin production in adipocytes, and vice versa, an increase in leptin levels may lead to insulin resistance and alter b-cell secretory capacity [56, 57]. Interestingly, we recently reported that breastfeeding was associated with better metabolic profile in the early postpartum period in women with previous

cyte leptin synthesis in the presence of increasing insulin resistance and

human chorionic gonadotropin production, regulates placental growth,

tissue, and skeletal muscle [37].

brain [44].

74

than by redirecting lipids into adipocytes [34].

who reported they lactated for at least 3 months [40].

GDM, showing that women with longer duration of lactation had greater weight loss at postpartum and lower leptin levels compared with women who lactated for a short period. This difference remained statistically significant after adjustment for weight [58]. Similarly, a previous study with a large cohort of women with recent GDM that utilized a quantitative measure of lactation intensity found that mean leptin concentrations were inversely associated with lactation intensity (lower by 15–21%) independent of maternal pre-pregnancy obesity, race, weight loss, sociodemographics, and postpartum insulin resistance [41]. It has been suggested that during lactation, prolactin suppresses leptin secretion [59].

On the other hand, leptin is a long-term regulator of appetite that serves as an anorexigenic signal when adipose stores are high [60]. It has been detected in breast milk at concentrations of 0.35–4.6 μg/L [61], and the concentration of leptin in breast milk is correlated to indices of maternal adiposity, including body mass index (r = 0.65, P < 0.02), and fat mass (r = 0.65, P < 0.02) [62]. This evidence provides an attractive explanation for the ability of breast milk to regulate infant body weight. Bouret has recently suggested that the presence of appetite hormones may permanently affect the appetite-regulating system of the infant by affecting the development of the hypothalamus. These differences in appetite hormone exposure may create permanent changes in the way the brain reacts to appetite hormones and satiety cues [63].

Another adipokine related to abnormal glucose metabolism during pregnancy is adiponectin. It has been suggested that low levels of adiponectin may induce severe insulin resistance prior to the onset of GDM [64]. Gunderson evaluated the relationship between lactation intensity and plasma adiponectin among postpartum women with previous GDM and found that higher lactation intensity was associated with 6% lower adiponectin. This inverse association remained after adjustment for insulin resistance [41]. This observation is consistent with the action of prolactin in suppressing the production and secretion of adiponectin from human adipocytes [13].

#### 5. Implications of breastfeeding in the offspring of the GDM mother

Infants of mothers with GDM are at increased risk of prematurity, macrosomia, hypoglycemia, respiratory distress, hypocalcemia, polycythemia, and hyperbilirubinemia. Breastfeeding has many established benefits for child health; it prevents child morbidity due to diarrhea, respiratory infections, and otitis media [5]. In particular, in the offspring of the GDM mother, lactation has been associated with lower episodes of hypoglycemia [65].

On the other hand, exposure to maternal gestational diabetes has been shown to increase the risk of obesity, childhood-onset type 2 diabetes in offspring, as well as the risk of adult-onset type 2 diabetes and gestational diabetes in those offspring [66]. Breastfeeding confers protection against these medical complications; exclusive breastfeeding decreases the risk of the development of childhood-onset type 2 diabetes and obesity [67].

Benefits of breastfeeding on children's health are likely due to the unique composition of breast milk. Human milk is a source of immunoglobulins, hormones and growth factors including leptin, adiponectin, ghrelin, peptide YY, glucagon-like peptide-1, resistin, and obestatin, which are involved in food intake regulation and energy balance, and may have a role in the regulation of growth and development in the neonatal period and infancy, as well as long-term effects on metabolic programming [68].

#### 6. Suggestions for mothers with GDM regarding breastfeeding

Women whose pregnancy is affected by GDM should be educated early as to the benefits of breastfeeding their offspring. An increase in breastfeeding duration among women with GDM has been demonstrated with prenatal education. Breastfeeding support in the hospital immediately after delivery and during the postpartum period as well as community support that encourages breastfeeding are also essential. Electronic alerts via text message or email, automated letters, and nurse phone contact may increase uptake. This targeted breastfeeding support for women with GDM is feasible and efficacious, and could be integrated into GDM management [69].

Likewise, insulin treatment during pregnancy should be considered a targeting indicator for providing extra skilled breastfeeding support to GDM women who decide to breastfeed [16].

#### 7. Conclusions

Breastfeeding is recommended and encouraged for mothers, as it has multiple benefits for both women and children. Mothers who breastfeed have been shown to have reduced risk of developing subsequent breast cancer and ovarian cancer, obesity, hypertension, stroke, hyperlipidemia, metabolic syndrome, and T2DM. In women with GDM, several studies suggest that breastfeeding is associated with reduced risk of T2DM. Despite this important benefit, there is evidence to suggest that lower rates of breastfeeding occur in women with GDM. Evidence has shown that healthcare provider support of breastfeeding along with patient education has a significant impact on breastfeeding rates. The medical and behavioral communities should be better able to design, implement, and administer public health programs that may promote healthy lifestyle behaviors including breastfeeding among GDM women, and mitigating T2DM risk.

#### Acknowledgements

RS holds a fellowship from the National System of Investigators. We thank the Hospital of Gynecology and Obstetrics, Medical Center La Raza, Instituto Mexicano del Seguro Social, for providing patient care services.

Author details

Renata Saucedo<sup>1</sup>

Social, Mexico City, Mexico

Breastfeeding and Gestational Diabetes DOI: http://dx.doi.org/10.5772/intechopen.82000

State of Mexico, Mexico

77

\*, Jorge Valencia<sup>1</sup>

\*Address all correspondence to: sgrenata@yahoo.com

Enrique Morales-Avila<sup>2</sup> and Arturo Zárate<sup>1</sup>

provided the original work is properly cited.

, María Isabel Peña-Cano<sup>2</sup>

1 Endocrine Research Unit, National Medical Center, Instituto Mexicano del Seguro

© 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

2 Faculty of Chemistry, Universidad Autonoma del Estado de Mexico,

,

This work was supported by scientific grants from IMSS.

#### Conflict of interest

The authors declare that there is no conflict of interests regarding the publication of this chapter.

#### Thanks

This chapter is dedicated to the memory of Dr. Arturo Zárate (1936–2018), pioneer in the field of Gynecological Endocrinology in Mexico.

Breastfeeding and Gestational Diabetes DOI: http://dx.doi.org/10.5772/intechopen.82000

6. Suggestions for mothers with GDM regarding breastfeeding

Gestational Diabetes Mellitus - An Overview with Some Recent Advances

among women with GDM has been demonstrated with prenatal education. Breastfeeding support in the hospital immediately after delivery and during the postpartum period as well as community support that encourages breastfeeding are also essential. Electronic alerts via text message or email, automated letters, and nurse phone contact may increase uptake. This targeted breastfeeding support for women with GDM is feasible and efficacious, and could be integrated into GDM

management [69].

7. Conclusions

decide to breastfeed [16].

GDM women, and mitigating T2DM risk.

del Seguro Social, for providing patient care services.

This work was supported by scientific grants from IMSS.

pioneer in the field of Gynecological Endocrinology in Mexico.

The authors declare that there is no conflict of interests regarding the

This chapter is dedicated to the memory of Dr. Arturo Zárate (1936–2018),

Acknowledgements

Conflict of interest

Thanks

76

publication of this chapter.

Women whose pregnancy is affected by GDM should be educated early as to the benefits of breastfeeding their offspring. An increase in breastfeeding duration

Likewise, insulin treatment during pregnancy should be considered a targeting indicator for providing extra skilled breastfeeding support to GDM women who

Breastfeeding is recommended and encouraged for mothers, as it has multiple benefits for both women and children. Mothers who breastfeed have been shown to have reduced risk of developing subsequent breast cancer and ovarian cancer, obesity, hypertension, stroke, hyperlipidemia, metabolic syndrome, and T2DM. In women with GDM, several studies suggest that breastfeeding is associated with reduced risk of T2DM. Despite this important benefit, there is evidence to suggest that lower rates of breastfeeding occur in women with GDM. Evidence has shown that healthcare provider support of breastfeeding along with patient education has a significant impact on breastfeeding rates. The medical and behavioral communities should be better able to design, implement, and administer public health programs that may promote healthy lifestyle behaviors including breastfeeding among

RS holds a fellowship from the National System of Investigators. We thank the Hospital of Gynecology and Obstetrics, Medical Center La Raza, Instituto Mexicano

#### Author details

Renata Saucedo<sup>1</sup> \*, Jorge Valencia<sup>1</sup> , María Isabel Peña-Cano<sup>2</sup> , Enrique Morales-Avila<sup>2</sup> and Arturo Zárate<sup>1</sup>

1 Endocrine Research Unit, National Medical Center, Instituto Mexicano del Seguro Social, Mexico City, Mexico

2 Faculty of Chemistry, Universidad Autonoma del Estado de Mexico, State of Mexico, Mexico

\*Address all correspondence to: sgrenata@yahoo.com

© 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

### References

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breastfeeding on maternal metabolism: Implications for women with gestational diabetes. Current Diabetes Reports. 2014;14:460. DOI: 10.1007/s11892-013-

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0460-2

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[18] Lemay DG, Ballard OA, Hughes MA, Morrow AL, Horseman ND, Nommsen-Rivers LA. RNA sequencing

transcriptome reveals distinct gene expression profiles at three stages of lactation. PLoS One. 2013;8:e67531. DOI:

[19] Refuerzo JS. Oral hypoglycemic agents in pregnancy. Obstetrics and Gynecology Clinics of North America. 2011;38:227-234. DOI: 10.1016/j.

[20] Stuebe A. Associations among lactation, maternal carbohydrate metabolism, and cardiovascular health. Clinical Obstetrics and Gynecology. 2015;58:827-839. DOI: 10.1097/ GRF.0000000000000155

[21] Bell AW, Bauman DE. Adaptations

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2009;38:586-594

ajcn.113.073049

[9] Stuebe AM, Schwarz EB, Grewen K, Rich-Edwards JW, Michels KB, Foster EM, et al. Duration of lactation and incidence of maternal hypertension: A longitudinal cohort study. American Journal of Epidemiology. 2011;174: 1147-1158. DOI: 10.1093/aje/kwr227

[10] Schwarz EB, Ray RM, Stuebe AM, Allison MA, Ness RB, Freiberg MS, et al. Duration of lactation and risk factors for maternal cardiovascular disease. Obstetrics and Gynecology. 2009;113: 974-982. DOI: 10.1097/01. AOG.0000346884.67796.ca

[11] Jacobson LT, Hade EM, Collins TC, Margolis KL, Waring ME, Van Horn LV, et al. Breastfeeding history and risk of stroke among parous postmenopausal women in the Women's Health Initiative. Journal of the American Heart Association. 2018;7:e008739. DOI: 10.1161/JAHA.118.008739

[12] Bellamy L, Casas JP, Hingorani AD, Williams D. Type 2 diabetes mellitus after gestational diabetes: A systematic review and meta-analysis. Lancet. 2009; 373:1773-1779. DOI: 10.1016/ S0140-6736(09)60731-5

[13] Asai-Sato M, Okamoto M, Endo M, Yoshida H, Murase M, Ikeda M, et al. Hypoadiponectinemia in lean lactating women: Prolactin inhibits adiponectin secretion from human adipocytes. Endocrine Journal. 2006;53:555-562

[14] Hummel S, Hummel M, Knopff A, Bonifacio E, Ziegler AG. Breastfeeding in women with gestational diabetes. Deutsche Medizinische Wochenschrift. 2008;133:180-184. DOI: 10.1055/s-2008-1017493

#### Breastfeeding and Gestational Diabetes DOI: http://dx.doi.org/10.5772/intechopen.82000

[15] Soltani H, Arden M. Factors associated with breastfeeding up to 6 months postpartum in mothers with diabetes. Journal of Obstetric, Gynecologic, and Neonatal Nursing. 2009;38:586-594

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Gestational Diabetes Mellitus - An Overview with Some Recent Advances

SE. Breastfeeding and risk of ovarian cancer in two prospective cohorts. Cancer Causes & Control. 2007;18:

[9] Stuebe AM, Schwarz EB, Grewen K, Rich-Edwards JW, Michels KB, Foster EM, et al. Duration of lactation and incidence of maternal hypertension: A longitudinal cohort study. American Journal of Epidemiology. 2011;174: 1147-1158. DOI: 10.1093/aje/kwr227

[10] Schwarz EB, Ray RM, Stuebe AM, Allison MA, Ness RB, Freiberg MS, et al. Duration of lactation and risk factors for

[11] Jacobson LT, Hade EM, Collins TC, Margolis KL, Waring ME, Van Horn LV, et al. Breastfeeding history and risk of stroke among parous postmenopausal women in the Women's Health

Initiative. Journal of the American Heart Association. 2018;7:e008739. DOI:

[12] Bellamy L, Casas JP, Hingorani AD, Williams D. Type 2 diabetes mellitus after gestational diabetes: A systematic review and meta-analysis. Lancet. 2009;

[13] Asai-Sato M, Okamoto M, Endo M, Yoshida H, Murase M, Ikeda M, et al. Hypoadiponectinemia in lean lactating women: Prolactin inhibits adiponectin secretion from human adipocytes. Endocrine Journal. 2006;53:555-562

[14] Hummel S, Hummel M, Knopff A, Bonifacio E, Ziegler AG. Breastfeeding in women with gestational diabetes. Deutsche Medizinische Wochenschrift. 2008;133:180-184. DOI: 10.1055/s-

2008-1017493

maternal cardiovascular disease. Obstetrics and Gynecology. 2009;113:

974-982. DOI: 10.1097/01. AOG.0000346884.67796.ca

10.1161/JAHA.118.008739

373:1773-1779. DOI: 10.1016/ S0140-6736(09)60731-5

517-523

[2] Gunderson EP, Lewis CE, Wei GS, Whitmer RA, Quesenberry CP, Sidney S. Lactation and changes in maternal metabolic risk factors. Obstetrics and Gynecology. 2007;109:729-738

[3] Hanson LA. Human milk and host defence: Immediate and long-term effects. Acta Paediatrica Supplement.

Breastfeeding and the risk of obesity and related metabolic diseases in the child. Metabolic Syndrome and Related

[5] Victora CG, Bahl R, Barros AJ, França

Disorders. 2005;3:222-232. DOI:

GV, Horton S, Krasevec J, et al. Breastfeeding in the 21st century: Epidemiology, mechanisms, and lifelong effect. Lancet. 2016;387: 475-490. DOI: 10.1016/S0140-6736(15)

[6] Gutiérrez JP, Rivera-Domarco J, Shamah-Levy T, Villalpando-

de Salud Pública (MX); 2012

of published studies. Human

Hernández S, Franco A, Cuevas-Nasu L, et al. Encuesta Nacional de Salud y Nutrición 2012. Resultados Nacionales. Cuernavaca, México: Instituto Nacional

[7] Bernier MO, Plu-Bureau G, Bossard N, Ayzac L, Thalabard JC. Breastfeeding and risk of breast cancer: A metaanalysis

Reproduction Update. 2000;6:374-386

[8] Danforth KN, Tworoger SS, Hecht JL, Rosner BA, Colditz GA, Hankinson

10.1089/met.2005.3.222

[4] Plagemann A, Harder T.

[16] Matias SL, Dewey KG, Quesenberry CP Jr, Gunderson EP. Maternal prepregnancy obesity and insulin treatment during pregnancy are independently associated with delayed lactogenesis in women with recent gestational diabetes mellitus. The American Journal of Clinical Nutrition. 2014;99:115-121. DOI: 10.3945/ ajcn.113.073049

[17] Finkelstein SA, Keely E, Feig DS, Tu X, Yasseen AS III, Walker M. Breastfeeding in women with diabetes: Lower rates despite greater rewards. A population-based study. Diabetic Medicine. 2013;30:1094-1101

[18] Lemay DG, Ballard OA, Hughes MA, Morrow AL, Horseman ND, Nommsen-Rivers LA. RNA sequencing of the human milk fat layer transcriptome reveals distinct gene expression profiles at three stages of lactation. PLoS One. 2013;8:e67531. DOI: 10.1371/journal.pone.0067531

[19] Refuerzo JS. Oral hypoglycemic agents in pregnancy. Obstetrics and Gynecology Clinics of North America. 2011;38:227-234. DOI: 10.1016/j. ogc.2011.02.013

[20] Stuebe A. Associations among lactation, maternal carbohydrate metabolism, and cardiovascular health. Clinical Obstetrics and Gynecology. 2015;58:827-839. DOI: 10.1097/ GRF.0000000000000155

[21] Bell AW, Bauman DE. Adaptations of glucose metabolism during pregnancy and lactation. Journal of Mammary Gland Biology and Neoplasia. 1997;2:265-278

[22] Baker JL, Gamborg M, Heitmann BL, Lissner L, Sørensen TI, Rasmussen KM. Breastfeeding reduces postpartum weight retention. The American Journal of Clinical Nutrition. 2008;88:1543-1551. DOI: 10.3945/ajcn.2008.26379

[23] Butte NF, Hopkinson JM, Mehta N, Moon JK, Smith EO. Adjustments in energy expenditure and substrate utilization during late pregnancy and lactation. The American Journal of Clinical Nutrition. 1999;69:299-307

[24] Janney CA, Zhang D, Sowers M. Lactation and weight retention. The American Journal of Clinical Nutrition. 1997;66:1116-1124

[25] Gunderson EP. Impact of breastfeeding on maternal metabolism: Implications for women with gestational diabetes. Current Diabetes Reports. 2014;14:460. DOI: 10.1007/s11892-013- 0460-2

[26] Gunderson EP, Hedderson MM, Chiang V, Crites Y, Walton D, Azevedo RA, et al. Lactation intensity and postpartum maternal glucose tolerance and insulin resistance in women with recent GDM: The SWIFT cohort. Diabetes Care. 2012;35:50-56. DOI: 10.2337/dc11-1409

[27] Kjos SL, Peters RK, Xiang A, Thomas D, Schaefer U, Buchanan TA. Contraception and the risk of type 2 diabetes mellitus in Latina women with prior gestational diabetes mellitus. Journal of the American Medical Association. 1998;280:533-538

[28] Corrado F, Giunta L, Granese R, Corrado S, Micali M, Santamaria A, et al. Metabolic effects of breastfeeding in women with previous gestational diabetes diagnosed according to the IADPSG criteria. The Journal of Maternal-Fetal & Neonatal Medicine. 2017;19:1-4. DOI: 10.1080/ 14767058.2017.1377175

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Hormone and Metabolic Research. 1997; 29:220-224

New York: Nova Science Publishers,

Breastfeeding and Gestational Diabetes DOI: http://dx.doi.org/10.5772/intechopen.82000

> pregnancy: Marker for fat accumulation and mobilization? Acta Obstetricia et Gynecologica Scandinavica. 1998;77:

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12-0939

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[54] Saad MF, Khan A, Sharma A. Physiological insulinemia acutely modulates plasma leptin. Diabetes. 1998;47:544-549

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Section 3

Current Concepts

Section 3
