Pregnancy and Preterm Labour

#### **Chapter 3**

## Challenges Facing during Pregnancy and Measures to Overcome

*Gayatri Devi Ramalingam, Saravana Kumar Sampath and Jothi Priya Amirtham*

#### **Abstract**

Pregnancy is a time of transformation for both the mother and the baby, with significant physical and emotional changes. There are many discomforts that occur during pregnancy. Morning sickness, headache and backache, bladder and bowel changes, changes in hair and skin colour, indigestion and heartburn, leg cramps and swelling, vaginal thrush and discharge are the few common complications facing during pregnancy. As a result, the aim of this study was to describe the difficulties in obtaining health information and the measures to overcome the discomfort during pregnancy. Research articles for this review were searched by using the keywords "pregnancy", health issues", "measures to overcome", "challenges". There were studies that looked at the health problems that women face during pregnancy were included in this review article. Pregnancy issues such as gestational diabetes mellitus, hypertension, preeclampsia, caesarean birth, and postpartum weight retention are all more likely in overweight and obese women. More research into the link between nutritional advancements and the rising prevalence of GDM in the developing world is needed. Iron supplementation has been linked to glucose dysregulation and hypertension in mid-pregnancy; its effectiveness and potential risks should be carefully considered. As a result, legislators and health planners should remove barriers, promote self-care, and improve the quality of life for pregnant women, ultimately improving their health.

**Keywords:** Pregnancy, management, gestational diabetes, Preeclampsia, Anaemia

#### **1. Introduction**

Pregnancy is a time of transformation for both the mother and the baby, with significant physical and emotional changes. Even in uncomplicated pregnancies, these improvements can impact pregnant women's quality of life as well as maternal and child health. Women's wellbeing, as well as their current level of understanding and knowledge, would undoubtedly have a significant impact on society [1]. Pregnant women need health information to improve their self-care skills and increase their empowerment when following preventive health habits. The cardiovascular system undergoes various changes as a result of pregnancy. A normal, healthy pregnant woman's blood volume rises by nearly 50% over that of a non-pregnant woman. In addition, due to the vascular permeability associated

with extreme preeclampsia, efforts to increase blood volume in these patients have been unsuccessful [1, 2]. Pregnancy (critical care scenario) is the reduction in venous return to the heart and decrease in cardiac output associated with the supine position. This effect is obviously more pronounced in the third trimester, when the uterus is largest. The so-called supine hypotensive syndrome.

When treating a critically ill pregnant woman, various hematologic changes must be taken into account. During pregnancy, the thrombocyte count remains largely constant, it leads to thrombocytosis. These improvements, when combined with a decrease in fibrinolysis, lead to the hypercoagulable state of pregnancy. Deep vein thrombosis and pulmonary embolism are five times more common during and immediately after pregnancy [3]. Both the residual volume and the expiratory reserve volume decrease, resulting in an obligate reduction in functional residual capacity. During pregnancy, the vital ability remains the same. Because of the reduction in residual volume, total lung capacity is only slightly reduced. The reduction in residual volume has a minor impact on total lung capacity. The tidal volume is raised, resulting in an increase in minute volume [4]. Early in pregnancy, both renal plasma flow and glomerular filtration rate rise. The increase in glomerular filtration rate reaches 50%, lowering serum creatinine to 0.8 mg/dL, the upper limit of average. Only a few changes in the gastrointestinal tract during pregnancy are essential in terms of critical care. The time it takes for the stomach to clear and the chance of aspiration that comes with general anaesthesia are both increased during labour. Placental development may cause a significant increase in alkaline phosphatase, but this does not mean hepatic obstruction. Gallbladder stasis can lead to increased stone formation.

The liver is the primary source of net endogenous glucose development while not pregnant. Fasting glucose levels in pregnant women decline as the pregnancy progresses [5]. GDM is characterised as the presence of glucose concentrations in pregnant women that are at the upper end of the population range for glucose and are first observed during pregnancy [6]. Insulin sensitivity decreases overall during pregnancy. Maternal insulin sensitivity, characterised as a decrease in the glucose infusion rate during the euglycemic hyperinsulinemic clamp to maintain 90 mg/dL, decreases in lean women during early pregnancy [7]. Since lean women are more likely to begin their pregnancies with greater insulin sensitivity than obese women, the increases in insulin concentration are more pronounced in lean women [8]. During pregnancy, healthy pregnant women's adipose tissue stores increase significantly. The mother and foetus can easily obtain calories from the subcutaneous stores, particularly during late pregnancy and lactation. Increases in visceral fat can be linked to decreased insulin sensitivity during late pregnancy [9].

In their research, Das and Sarka found that pregnant women faced a variety of difficulties when seeking health information, including inadequate hospital treatment, long wait times, anxiety and shame about discussing pregnancy with a physician, and a lack of time [10]. There are many discomforts that occur during pregnancy. Morning sickness, headache and backache, bladder and bowel changes, changes in hair and skin colour, indigestion and heartburn, leg cramps and swelling, vaginal thrush and discharge are the few common complications facing during pregnancy. As a result, the aim of this study was to describe the difficulties in obtaining health information and the measures to overcome the discomfort during pregnancy.

#### **2. Materials and methods**

Research articles for this review were searched by using the keywords "pregnancy", health issues", "measures to overcome", "challenges". The following were used as exclusion criteria: 1) the subject was unrelated to the study's goal; 2) there was no abstract available; 3) The research was limited to a single medical issue involving pregnancy in older women. 4) The report dealt with postpartum and maternity issues; and 5) the full research paper was not easily accessible. We looked for original research papers that were written in English and reported on studies that were performed using qualitative or quantitative methods. The current research did not include any other review papers. There were studies that looked at the health problems that women face during pregnancy were included in this review article.

#### **3. Dental problems**

According to previous literature, pregnant women's dental health care demands differ dramatically from those of the general population. The most frequent oral health concerns during pregnancy include periodontal disease, Xerostomia, halitosis, and tooth movement. During pregnancy, the hormonal balance of pregnant women alters. Because the placenta produces increased levels of oestrogen and progesterone during pregnancy, several tissues endure modifications. Increased sensitivity to irritations arises in the gingiva during this time [11]. Low vitamin C levels are thought to be another cause of this condition. When compared to mothers with healthy periodontium, mothers with attachment loss have an increased risk of giving birth to babies with low birth weight [12]. Tooth decay is more common among pregnant women for a variety of reasons, including increased acidity in the mouth, sweet food demands, and a lack of attention to oral health. Vomiting can have a severe impact on oral hygiene and induce degradation of the mother enamel layer [13]. Due to the effect of pregnancy hormones, pregnant women bleed more easily and may postpone brushing their teeth and it leads to an increase in bacterial plaque [14]. Due to diminished flow of saliva, caries are more likely to develop at this time. Pregnancy oral tumour is indistinguishable from pyogenic granuloma and occurs in up to 5% of pregnancies. Increased progesterone, in combination with local irritants and microorganisms, causes this vascular lesion [15]. With a prevalence of 60 to 75 percent, gingivitis is the most frequent dental illness among pregnant women. A severe aggravation of preexisting gingivitis occurs in around half of all pregnant women [16]. Researchers discovered very few oral bacteria in the amniotic fluid and placenta of women who had preterm labour with periodontitis in one investigation [17]. PGE2 production reduces placental blood flow, resulting in placental necrosis and intrauterine growth restriction [18]. Salivary oestrogen levels are greater in women who are expecting preterm babies than in women who are expecting full-term babies. Salivary oestrogen promotes oral mucosa proliferation and desquamation, as well as a rise in subgingival crevicular fluid levels. Desquamating cells offer a favourable environment for bacterial growth by supplying nutrients, hence preventing infection [19].

#### **3.1 Management**

Oral acid exposure is reduced through dietary and lifestyle changes, as well as the use of antiemetics, antacids, or both. Acid can be neutralised by rinsing the mouth with a teaspoon of baking soda in a cup of water after vomiting [20]. To lessen the risk of enamel damage, pregnant women should be encouraged to avoid brushing their teeth shortly after vomiting and to brush with a toothbrush with soft bristles when they do. Fluoride mouthwash can protect teeth that have been eroded or are sensitive. Proper dental hygiene can help women with previous periodontal

disease lower the risk of recurrence or worsening disease during pregnancy. Education, clear communication, and the creation of continuing collaborative relationships can help physicians and dentists solve this dilemma. Physicians and dental colleagues can communicate information about the safety of dental treatment during pregnancy [21]. There is a link between plaque accumulation and caries prevalence during pregnancy and preventive maintenance methods. Mouthwashes or warm salty water should be gargled. Gums are relaxed and gum sensitivity is reduced by drinking warm salty water [22]. During this time, women can maintain their oral health by taking the required precautions, preventing potentially irreversible tooth disorders.

#### **4. Hypertension**

The mother's cardiovascular physiology adapts significantly as a result of the hormonal changes that occur during pregnancy [23]. Oestrogen, progesterone, and relaxin levels rise early in the first trimester, resulting in systemic vasodilation [24]. The RAAS is activated to promote salt and water retention, resulting in an increase in plasma volume. When this is paired with an increase in ventricular wall mass, it results in greater stroke volume. During pregnancy, the combination of increased stroke volume and tachycardia causes an increase in cardiac output, which compensates for the decrease in vascular resistance in order to keep blood pressure high enough for mother and placental perfusion [25]. The increased volume load in the heart causes left ventricular hypertrophy, which is proportional to the increased cardiac labour necessary to accomplish the increased cardiac output [26]. Some changes in the systemic hemodynamics of pregnant women who are predisposed to hypertension may occur before the condition manifests itself clinically. A systolic blood pressure of 160 mmHg or a diastolic blood pressure of 110 mmHg, or both, indicates severe preeclampsia in pregnancy. Eclampsia is a severe form of pregnancy-induced hypertension that affects one in every 1,600 pregnancies and appears at the end of the pregnancy [27]. When compared to singleton pregnancies, twin pregnancies had more than three times the risk of developing hypertension during pregnancy [28]. Preeclamptic patients have lower renin levels than nonpregnant women, although they are still significantly higher than non-pregnant women. Because most preeclamptic individuals have a somewhat reduced plasma volume, maintaining relatively high levels of these hormones may be necessary [29].

Preeclampsia is the pathophysiology of de novo hypertension and proteinuria in pregnancy. The delivery of the placenta frequently triggers the remission of preeclampsia's acute clinical symptoms, implying that the placenta plays a key role in the disease's pathophysiology. The placenta undergoes substantial blood supply throughout normal pregnancy to allow circulation between the foetus and the mother [30]. The pathogenesis of preeclampsia has long been focused on altered uteroplacental blood flow. Relaxin is a hormone secreted more during pregnancy which acts as vasodilation. According to Jeyabalan et al., low first trimester relaxin concentrations were linked to an increased risk of preeclampsia [31].

#### **4.1 Management**

For non-severe hypertension in pregnancy, oral labetalol is a first-line treatment [32]. Other beta-blockers, such as oxprenolol, are less thoroughly studied than labetalol, and it is used as a first-line treatment for non-severe hypertension in pregnancy [33]. In contrast, when oxprenolol was compared to methyldopa, the results and safety were found to be equal [34]. When mothers are exposed to

calcium channel blockers during the first trimester, there is low teratogenicity [35]. Elsewhere in pregnancy, ACE inhibitors are still the first-line treatment for hypertension [36]. For non-severe hypertension, thiazide diuretics are considered second-line therapy.

### **5. Gestational diabetes (GDM)**

The prevalence of gestational diabetes mellitus (GDM) is rising in lockstep with the rise in overweight and obesity among women of childbearing age. GDMaffected pregnancies increase the risk of caesarean and surgical vaginal delivery, macrosomia, neonatal hypoglycemia, and hyperbilirubinemia for both mother and child [37]. The onset of GDM is linked to a number of risk factors. Obesity, advanced maternal age, a significant family history of diabetes and belonging to an ethnic group are with a high prevalence of T2DM, polycystic ovarian syndrome, and chronic glucosuria. Because GDM usually starts in the late second trimester, when development is complete, congenital abnormalities do not occur at a higher rate in people with gestational diabetes. Because of the physiological, endocrine, and metabolic changes that occur throughout pregnancy in order to meet the fetus's constant nutritional and oxygen needs, a diabetogenic condition comparable to type 2 diabetes (T2D) develops, increasing insulin resistance, lowering insulin sensitivity, and thus increasing the demand for insulin [38]. As a result of the increased placental glucose transport, maternal hyperglycemia causes foetal hyperinsulinemia. Foetal macrosomia is caused by a high insulin level in the foetus, which accelerates growth [39]. Although glucose metabolism changes during pregnancy, tolerance occurs and there is no effect on the mother or the foetus when insulin production rises. There is a higher risk of foetal when there is an inappropriate response. When the output of the pancreatic b-cells does not match the insulin requirement of the tissues as a result of alterations in insulin resistance, abnormal glucose tolerance ensues [40]. Early in pregnancy, fasting blood glucose levels drop, and this trend continues throughout the pregnancy. Insulin sensitivity decreases as pregnancy progresses, reaching pregravid levels about 34–36 weeks of pregnancy [40, 41]. Increases in hepatic glucose production during pregnancy show that the insulin action deficiency also affects the liver. Placental loss of anti-insulin hormones such as human placental lactogen, cortisol, oestrogen, and progesterone causes insulin resistance after mid-pregnancy. Low FBS, a low kidney glucose threshold, and enhanced insulin production are all effects of these hormones [42]. Maternal tissues become increasingly insulin resistant during pregnancy. This is thought to be produced in part by placental hormones and in part by unknown obesity and pregnancy-related variables. The main locations for glucose disposal throughout the body are skeletal muscle and adipose tissue. Insulin-mediated whole-body glucose elimination declines by 50% during pregnancy, and the woman must raise her insulin output by 200–250 percent to maintain a euglycemic condition [43]. Even while most women revert to a euglycaemic state immediately after delivery, women who have had GDM have a significantly higher chance of developing T2DM [44]. The biochemical relationship between GDM and T2DM is still unknown. Insulin resistance and/or aberrant insulin production define both illnesses [45]. Multiple potential protein indicators for later GDM have been discovered through proteomic screening in early pregnancy, including a cluster linked with insulin production, binding, resistance, and signalling [46]. An oral glucose tolerance test (OGTT) is usually used to identify GDM during 24–28 weeks of pregnancy. Because most of the physiologic insulin resistance of pregnancy will be firmly established, this timeframe has traditionally been favoured for routine GDM diagnosis. Another important difference in GDM testing techniques around

the world is the ongoing debate over whether testing should be universal (for all pregnant women) or targeted solely for women with risk factors linked to a higher probability of a positive result.

#### **5.1 Management**

Preventive interventions are needed to avoid the undesired consequences of obesity and hyperglycemia during pregnancy, given the global rise in obesity and the resulting increase in GDM [38, 47]. In roughly 70 to 85 percent of women with diagnosed GDM, lifestyle changes are enough to meet glycemic objectives [48]. Dietary counselling, in combination with physical activity and blood glucose self-monitoring, is the major intervention indicated for GDM [49]. A lower-carbohydrate diet with more animal protein and fat enhanced the risk of type 2 diabetes. As a result, it's possible that the diet that's best for treating GDM in women is not the best long-term diet [50]. Other nutritional treatments, such as probiotics and vitamin supplements, have gained popularity, but there is not enough data to suggest their widespread usage [51]. Insulin therapy is the preferred treatment because it does not cross the placenta and is thus deemed safe for the foetus. Metformin therapy was deemed safe and effective, and the women preferred it for insulin treatment [52]. Another study states that Metformin and sulfonylurea have been increasingly and safely used in the treatment of GDM [53]. In diabetic pregnant women with vitamin D deficiency/insufficiency, vitamin D administration can lower the chance of developing GDM and/or improve glycemic control [54]. Vitamin D regulates intracellular calcium to promote insulin production and attenuates insulin resistance by acting directly on pancreatic beta cells via the development of vitamin D receptors and the enzyme 25(OH)D-1-alfa-hydroxylase [55]. Furthermore, recent evidence from a large prospective trial suggests that increased physical activity may help reduce the risk of T2DM progression [56]. Exercise activities did not have a significant influence on the overall incidence of GDM in obese or overweight pregnant women, but when the effect measure was taken into account, the incidence of GDM was 24 percent lower in that group [57]. The following five components of guideline content were examined: GDM diagnosis, prenatal care, intrapartum care, neonatal care, and postpartum care. The majority of the suggestions in the guidelines were on prenatal care, particularly all types of therapy that could lower the risk of bad pregnancy outcomes due to uncontrolled blood sugar prior to conception [58]. The usage of information technology and digital platforms by diabetic pregnant women is fast rising around the world [59]. Telemedicine has been linked to high patient satisfaction since it allows for quick management of care across distances with fewer face-to-face physician appointments [60]. As a result, the use of e-platforms in the management of gestational diabetes shows encouraging results in terms of patient satisfaction and has no negative impact on pregnancy outcomes. Adequately powered RCTs are needed to assess whether such healthcare technologies are costeffective or can help enhance care in urban or distant settings [61].

#### **6. Gestational thrombocytopenia and anaemia**

During pregnancy, several biological markers, particularly haematological, are physiologically altered. Biologists and doctors who are aware of these changes in the maternal body can screen for potential abnormalities. The haematological parameters must adjust in several ways, including providing vitamins and minerals for foetal haematopoiesis (iron, vitamin B12, folic acid), which can increase maternal anaemia, and preparing for birth bleeding, which is necessary to improve homeostasis [62]. The total blood volume increases by roughly 1.5 litres during pregnancy, primarily to meet the demands of the new vascular bed and to compensate for blood loss that occurs during birth [63]. At 6–12 weeks of pregnancy, the plasma volume expands by 10–15 percent. When maternal erythropoietin production rises, RBC mass rises as well, albeit at a slower rate than plasma volume, resulting in a drop in haemoglobin concentration. Dilutional anaemia is the result [64]. Haemodilution also contributes to a decrease in the rate of haematocrit (HCT) and haemoglobin (HGB), resulting in a false anaemia. Such a change is natural for pregnant women and demonstrates the adoption of a different threshold for the definition of pregnancy anaemia. The WHO defines anaemia in pregnancy as having a total circulating HGB concentration of less than 11 g/dl or an HCT of less than 33% at any point during the pregnancy. During pregnancy, RBC indices do not vary much. However, in an iron-replete woman, there is a slight rise in mean corpuscular volume (MCV) of around 4 fl, which peaks around 30–35 weeks gestation and does not indicate a vitamin B12 or folate shortage. The increased MCV can be explained by increased RBC production to fulfil the demands of pregnancy [65]. The haemoglobin concentration does not change until the 16th week of pregnancy, after which it falls steadily to the second trimester due to the expansion of plasma volume [66]. Haemodilution, or an increase in plasma volume greater than an increase in red cell mass, is the underlying cause of anaemia during pregnancy. This condition is also known as 'physiological anaemia of pregnancy' [67]. Because length is more stable than weight, haemoglobin demonstrated a positive connection with infant length but not with weight [68]. Haemoglobin and haematocrit increased on the first day after birth, decreased on the third and fifth days, and then began to rise again by day 42, achieving normal haemoglobin in non-pregnant women [69]. Because of the greater metabolic oxygen requirement, erythropoietin levels are 50 percent greater, which explains the mild bone marrow erythroid hyperplasia and enhanced reticulocyte count. A combination of a lowered maternal RBCs oxygen affinity from an enhanced 2,3 Diphosphoglycerate and a low maternal pCO2 results in enhanced oxygen transfer throughout the placenta [70].

Pregnancy causes an increase in white blood cell count, with the lowest limit of the reference range typically being 6,000/cumm. Leucocytosis occurs during pregnancy as a result of the physiologic stress that comes with being pregnant [71]. Throughout the first and second trimesters of pregnancy, lymphocyte count drops, then rises during the third trimester. Total leukocyte count levels rise significantly in the II and III trimesters, but there is no difference between pregnant and non-pregnant women in the I trimester. In the first trimester of pregnancy, non-anaemic women have a higher TLC count than anaemic women, but in the second and third trimesters, anaemic women have a higher TLC count than non-anaemic women [62]. During normal pregnancy, leukocytosis is caused by an enhanced inflammatory response, which can be caused by selective immunological tolerance, immunosuppression, and immunomodulation of the foetus [72]. During pregnancy, the ratio of monocytes to lymphocytes rises dramatically. During pregnancy, however, eosinophil and basophil numbers do not alter appreciably [73]. The neutrophil count starts to rise in the second month of pregnancy and reaches a plateau in the second or third trimester, when total white blood cell counts range from 9,000 to 15,000 cells per microliter.

In 7–8 percent of all pregnancies, gestational thrombocytopenia occurs. Due to rapid degradation, platelet counts are slightly lower which results in younger, bigger platelets present in pregnancy. The majority of thrombocytopenia in pregnancy is caused by increased blood loss [74]. Although the average platelet count falls monotonically during pregnancy, platelet aggregation increases, notably during the last 8 weeks of pregnancy [75]. The decline in the quantity of circulating platelets during pregnancy has been attributed to increased platelet consumption as well as a

shorter life span in the uteroplacental circulation [76]. As the pregnancy progresses, the platelet volume distribution width widens dramatically and continually. As a result, as pregnancy progresses, the mean platelet volume becomes an insensitive indicator of platelet size.

Primary immune thrombocytopenia (ITP) affects about 3% of women who are thrombocytopenic at delivery. It occurs in 1/1000–1/10 000 pregnancies [77]. Twothirds of women with ITP have pre-existing disease, according to most studies, and one-third are diagnosed for the first time during pregnancy [78]. The pathophysiological mechanism of thrombotic thrombocytopenic purpura (TTP) is thrombotic microangiopathy. Microangiopathic hemolytic anaemia, thrombocytopenia, fever, neurological signs, and renal impairment are all symptoms of TTP. Pregnancy is thought to be the trigger event in between 5 to 25% of TTP cases [79]. TTP occurs in the second trimester of pregnancy and occasionally in the postpartum period, although it is uncommon in the first trimester [80]. If TTP appears during the first trimester, regular plasma exchange may be able to maintain pregnancy.

#### **6.1 Management**

Preventing anaemia in pregnancy requires effective communication about diet and nutrition to all pregnant women. Most experts recommend regular iron supplementation during pregnancy since the extra demand for iron is typically unmet by a typical diet. Although iron supplementation recommendations vary by location, the CDC recommends that all pregnant women begin a 30 mg/day iron supplementation [81]. he average iron density in a typical Indian diet is 8.5 mg/1000 Kcal, with 13.3 and 5.3 percent iron absorption in pregnancy from a rice-based and wheat-based Indian diet, respectively [82]. Women can use smartphone applications to learn about their daily iron needs, the iron content of various foods, and how to track their dietary iron intake. We support the creation and use of such applications. For improved absorption, all pregnant women should be told to take oral iron on an empty stomach or 1 hour after meals, preferably with a vitamin C-rich product like orange juice or guava. Supplement 2 outlines the oral iron treatments that can be used during pregnancy [82, 83].

The choice of therapy is based on the urgency of the platelet increase, the duration of the increase, and any potential side effects, and should be determined on an individual basis for each patient. Platelets should be available on standby if the mother's platelet count remains low (50 109/l) around the time of delivery, but they are likely to be destroyed rapidly after infusion if due to an immune reaction, so they should be given in well-established rather than early labour if there are increased bleeding complications [84]. Given that there is no evidence that Caesarean delivery is safer for the foetus with thrombocytopenia than a simple vaginal delivery, which is usually safer than caesarean for the mother, the mode of delivery should be decided on obstetric concerns. Treatment may be required just during the later part of the third trimester to boost the platelet level before epidural anaesthesia or C section section if the individual is asymptomatic and the platelet count is more than 20\*109 /L [85]. Depending on the platelet level and stability, general measures such as avoiding aspirin, nonsteroidal anti-inflammatory medications, and intramuscular injections might be explored. Because low-dose aspirin is now commonly administered in pregnancy for a variety of reasons, it should not be avoided unless the risk of bleeding is significant. Prednisone at a low dose or intravenous immunoglobulin, or both, are viable alternatives in these circumstances. In symptomatic pregnant ITP patients or if the platelet count is less than standard level, other therapeutic options are available. When combined with intravenous immunoglobulin, a large dose of steroids can be employed [86]. Corticosteroids and intravenous IVIG are the most common treatments for maternal ITP [87].

### **7. Conclusion**

When it came to getting health information, pregnant women faced personal, societal, and structural challenges. As a result, legislators and health planners should remove barriers, promote self-care, and improve the quality of life for pregnant women, ultimately improving their health. Pregnancy issues such as gestational diabetes mellitus, hypertension, preeclampsia, caesarean birth, and postpartum weight retention are all more likely in overweight and obese women. More research into the link between nutritional advancements and the rising prevalence of GDM in the developing world is needed. Iron supplementation has been linked to glucose dysregulation and hypertension in mid-pregnancy; its effectiveness and potential risks should be carefully considered.

### **Acknowledgements**

I would like to thank Saveetha Institute of Medical and Technical Sciences for giving me this opportunity to carry out the research work.

### **Funding Support**

This study received no specific support from public, private, or non-profit funding bodies.

### **Conflict of interest**

No potential conflict of interest relevant to this article was reported.

### **Author details**

Gayatri Devi Ramalingam1 \*, Saravana Kumar Sampath2 and Jothi Priya Amirtham1

1 Department of Physiology, Saveetha Dental College, SIMATS, Chennai, Tamil Nadu, India

2 Department of Anatomy, SEGI University, Malaysia

\*Address all correspondence to: gayatri.physio88@gmail.com; dr.sharan\_anatomist@yahoo.com

© 2021 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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#### **Chapter 4**

## Premature Birth, Management, Complications

*Panagiotis Tsikouras, Anastasia Bothou, Aggeliki Gerede, Ifigenia Apostolou, Fotini Gaitatzi, Dorelia Deuteraiou, Anna Chalkidou, Xanthoula Anthoulaki, Spyridon Michalopoulos, Georgios Dragoutsos, Ioannis Tsirkas, Irini Babageorgaka, Theopi Nalbanti, Natalia Sachnova, Alexios Alexiou, Constantinos Nikolettos, Apostolos Lazarou, Stefanos Zervoudis, Panagiotis Peitsidis and Nikolaos Nikolettos*

#### **Abstract**

In recent years an increase in premature births (PB) rate has been noticed, as this pregnancy complication that still remain an important cause of perinatal morbidity and mortality, is multifactorial and prediction is not easy in many cases. There are many bibliographic data supporting the view that PB have also genetic predisposition. The trend of "recurrence" of PB in women as well as its increased frequency in ethnic groups suggests its association with genetic factors, either as such or as an interaction of genes and environment. Immunomodulatory molecules and receptors as well as polymorphisms of various genes and/or single nucleotides (single nucleotide polymorphisms, SNPs) now allow with advanced methods of Molecular Biology the identification of genes and proteins involved in the pathophysiology of PB. From the history of a pregnant woman, the main prognostic factor is a previous history of prematurity, while an ultrasound assessment of the cervix between 18 and 24 weeks is suggested, both in the developed and the developing world. According to the latest data, an effective method of successful prevention of premature birth has not been found. The main interventions suggested for the prevention of premature birth are the cervical cerclage, the use of cervical pessary, the use of progesterone orally, subcutaneously or transvaginally, and for treatment administration of tocolytic medication as an attempt to inhibit childbirth for at least 48 hours to make corticosteroids more effective. Despite the positive results in reducing mortality and morbidity of premature infants, the need for more research in the field of prevention, investigation of the genital code and the mechanism of initiation of preterm birth is important.

**Keywords:** preterm birth, predisponding factors, complications

#### **1. Introduction**

Premature birth defined as the onset of labor before the 37th week of pregnancy and is a clinical symptom that is accompanied by multiple pathogenetic causes. The etiology is multifactorial and complex. It is not a normal premature birth, but a distinct syndrome with specific characteristics [1–5]. Sometimes, the mother, the placenta and the fetus altogether are involved to a different degree. The exact mechanism is not known. Uterine cramps that cause premature birth are coordinated uterine contractions that cause progressive change (elimination and/or dilation) of the cervix before the 37th week of pregnancy. In contrast, premature contractions are rhythmic contractions of the uterus that do not cause a change in the cervix [1–5]. Specifically, in 1948, the World Health Organization (WHO) defined with the term "prematurity" the delivery of a newborn weighing <2500 g. The primary problem that arose was that it characterized a multitude of newborns with heterogeneous fetal development as premature. Therefore, in 1960 Battaglia and Lubchenco used measurements from a large population of newborns to establish the rules of fetal development.

Prematurity based on Birth Weight is divided into "low birth weight" infants <2500 g, "very low birth weight" infants <1500 g (approximately 1–1.5% of live births) and "extremely low birth weight" infants <1000 g (this category includes 0.7% of all live births).

Premature is the newborn that will be born at a gestational age less than the 37th week of pregnancy. Very premature is the newborn which will be born at a gestational age less than 32 weeks of gestation.

Premature birth is subdivided into automatic preterm birth as a consequence of premature contractions with an incidence of 35% of unknown etiology, a corresponding incidence of 25% resulting from premature rupture of membranes and in 25% of cases iatrogenic, as a consequence of medical or obstetric such as maternal hypertension, fetal development pathology and gestational bleeding, while in cases of multiple pregnancy the incidence rate is 15% [6–11].

#### **2. Epidemiology**

It contributes a large 75% to the formation of perinatal morbidity and mortality and it is estimated that about 50% of long-term neurological problems are related to prematurity. The incidence is between 10 and 12% over a period of about 15 years (1981–1996) and includes about 467,000 births in United States of America, compared to European developed countries in which the rates of prematurity are lower at 5–6%. Prematurity has gradually increased from 6–13% of all births and it is estimated that 13,000,000 premature babies are born per year worldwide [1–5].

The highest rate of 60% is observed in countries of South Asia and Central Africa while in African Americans it occurs with twice the frequency of 18% compared to Caucasians. It is generally and worldwide accepted that an embryo is viable for more than 20 weeks and in Greece for more than 22 weeks of gestation. Moreover, the implementation of treatment programs for pregnant women with symptoms of threatened preterm delivery, failed to reduce the incidence of preterm birth [12–14]. The lack of progress may be partly related to the increase in the frequency of multiple pregnancies as a result of the widespread use of assisted reproduction methods, but the main cause remains largely unclear. The incidence of prematurity (23rd-24th weeks to <37 weeks) in the US, for single pregnancies is 9.43%, for twins 50.74% and for triplets 91.03%.

It has also been observed that opposed to the Caucasian race, the black race is associated with an increased rate of low birth weight neonates and preterm delivery. There is great heterogeneity within the same racial group, however members of the same race may have different frequency of precocities in different geographical areas. The differences remain even after the control for the social order. The racial difference has not decreased over time. The mother's race is a stronger indicator of precocity than the father's race, although the father's race is also important. The probability that the racial difference is genetically determined is based on data showing different distribution of gestational age in the black and white population. The gestational age distributions for black and non-black women appear to deviate by 1 week, resulting in a mean gestational age of 39 weeks for blacks 37 and 40 weeks for whites [15–20].

Approximately 1/3 of health expenditures in infancy and childhood are due to complications of preterm delivery as 10% of surviving infants have long-term disabilities such as developmental or behavioral problems [12–14]. The Financial Cost in US for health care amounts to 9 billion \$/year and the 35% of the expenses is for newborns and 10% for children. Also, the high cost of hospitalization of newborns <1500 g should be emphasized in intensive care units [12–14]. In Germany, out of a total of 50,000 preterm births (BP) and the annual cost are as follows: PB <32 weeks 300 million €, PB ≥ 32 weeks 400 million € and cost for tocolysis 112 million €.

It is estimated that about 85% of neonatal deaths in Western countries are attributed to prematurity and 10% of these neonates will suffer from some form of long-term disability. Of the reported rate of prematurity, 10% of the neonates delivered before the 37th week of pregnancy, about 1.5% before the end of the 32nd week and approximately 0.5% of premature births will take place in the period before the 28th week [12–14]. Premature birth is a potentially very serious problem for newborns and the morbidity and mortality rates are inversely proportional to the maturity of the organic systems, especially the lungs [6, 21].

In particular, in the 22nd week of pregnancy, the temporary survival rate is 40%, respiratory distress syndrome 70%, intra-abdominal bleeding 25%, sepsis 25% and necrotic enterocolitis 8% with a final survival rate of 5% [6, 21]. Some of the following changes are observed between 22nd and 34th week of pregnancy: sepsis 4%, increase of temporary survival to 97% reduction of respiratory distress syndrome to 14%, intra-abdominal bleeding 0%, necrotic 3% with intestinal necrosis final survival 97% [6–11]. The prognosis of newborns improves when the gestation period is prolonged. Recent literature reports indicate the following neonatal survival rates: at 23 weeks 6–9%, at 24 weeks 17–58%, at 25 weeks 35–85%, at 27–28 weeks 90% and at 33 weeks 95%.

#### **3. Risk factors of preterm birth stimulation**

Primary risk factors:


Secondary risk factors:


#### **4. Maternal causes and conditions in pregnancy related to preterm birth**

#### **4.1 Socio-economic and racial factors**

The low socio-economic status of pregnant women related to education, employment or family income and racial, demographic, environmental factors is one of the most common factors associated with the occurrence of preterm birth. Statistically, a causal relationship has been found between the economic situation and the low level of education.

Mothers with a low level of education are more likely to give birth to low birth weight babies and less likely to give birth to large babies. The average birth weight increases with the greater education of the mother. White mothers with 12 years of education, on average, had 82 g heavier babies than mothers with less education, while the corresponding difference for newborns born to black women was 66 g. Mothers with ≥12 years of education had even heavier neonates. The risk of having a very low birth weight neonate has been shown to vary depending on the level of education among white, but not among black women [11, 22–26].

Newborns born from low-educated mothers are less likely to survive. Loweducated mothers have characteristics that are blamed for the birth of low birth weight babies. They are more likely to be young, have less prenatal care, smoke during pregnancy, have a poor diet and have more difficult access to medical care. Also, women in lower social classes have higher levels of stress with elevated catecholamine levels that can lead to increased uterine contractions. Better education of the mother could improve her diet, reduce smoking during pregnancy but also reduce other harmful factors [11, 22–26].

#### **4.2 Maternal age**

Maternal age (under 19 or over 35) is associated with an increased incidence of preterm birth [27–30]. However, the risk may not come from age itself but from the factors associated with it. For the young women, it is more usual to suffering of vaginitis than the older women, which may have other health problems, such as fibroids, hypertension and metabolic diseases [15–20]. Also, women with body weight before pregnancy under 50 kg and height below 150 cm, have higher rates of preterm birth. Therefore, chronological age is not an independent factor of gestational age but the increased risks reflect characteristics of the mother's advanced age.

Great importance was given to the premature birth of women over 35 years old due to the growing population of pregnant women with first pregnancies at an older age. However, there are views on the increased risk in those over the age of 30, compared to women aged 20–29. Maybe due to the improvement of perinatal care, the relative risk of preterm delivery in women aged >35 years old, decreased from 1.7% in 1976 to 1% in 1981. Adolescent white women give birth to newborns that are lighter by 149gr, while black women by 99gr, compared to those of mothers aged 20–34 years. Mothers aged 35 years and older give birth to children which are 50gr heavier than those of women 20–34 years [15–20].

Neonatal mortality is also slightly higher in younger and older women.

#### **4.3 Burdened obstetric history**

The existence of a burdened obstetric history seems to be directly related to the frequency of preterm birth. Miscarriages, especially in the second trimester, previous preterm births and stillbirths, increase the risk of premature births in subsequent pregnancies. A previous history of low birth weight or preterm birth is one of the most important factors for the next preterm birth. The literature states that the relative risk with a history of preterm birth is 34%, while it is even higher for the third childbirth, although both previous ones were premature. Racial differences have been observed in the relationship between first and second preterm birth, while the previous history of preterm birth is a significant risk factor for premature rupture of membranes.

The number of pregnancies does not seem to affect the likelihood of preterm birth as the results of several studies are contradictory. It is generally accepted that first-born infants weigh less on average compared to their offspring at each gestational age. The explanation for the reported data is not known. It is possible that fetal development is more limited in primiparous pregnant women, due to the anatomy of the muscular walls of the uterus, compared to those with multiple pregnancies [15–20].

There is an increased risk of preterm birth compared to the short interval between two pregnancies, but the results are not statistically significant. It is therefore not clear whether there is any relationship between short interval between births and prematurity.

#### **4.4 Previous stillbirths or neonatal deaths**

#### *4.4.1 Previous induced abortions*

The contribution of abortions to the increased risk of premature birth depends on the type of abortion, the degree of dilation of the cervix, the gestational age and the number of abortions [15–20].

#### *4.4.2 History of infertility*

Women who have undergone assisted reproduction therapy in single pregnancies show a prematurity rate of 10–20%. The increase is due to pre-existing reproductive abnormalities, an increased rate of multiple pregnancies, and an increasing number of cesarean sections before the 37th week of pregnancy.

#### **4.5 Various diseases of the mother**

Maternal diseases related to pregnancy (e.g. preeclampsia and eclampsia) or unrelated to pregnancy (chronic kidney disease, anemia, chronic hypertension, respiratory failure, etc.) are common causes of premature birth or low birth weight babies. Most of these diseases cause pathology in the placental circulation resulting in problematic fetal development and low body weight. Also the most well-known of the endocrine diseases associated with increased prematurity are diabetes mellitus and hyperthyroidism [20, 31–35].

#### *4.5.1 Smoking and alcohol*

Smoking seems to be responsible for an increased rate of prematurity, is associated with placental abruption and perinatal mortality. This effect of smoking is attributed to the increase in anthracylamoglobin and the action of nicotine. Also various toxins also known as Cyanide reduce the levels of vitamin B12 resulting in metabolic disorders. Anthracycline hemoglobin increases from 1.2% to 4.1% and reduces the oxygen available for fetal oxygenation while nicotine increases epinephrine secretion and causes vasoconstriction, further aggravating fetal oxygenation [20, 31–35].

Alcohol abuse, in addition to its association with prematurity, has also been linked to an increased risk of brain damage in premature infants.

#### *4.5.2 Illegal drug use*

Marijuana and cocaine have been studied more for their potential effects on preterm birth. There is no serious evidence that marijuana is associated with prematurity. In contrast, cocaine has been studied much more with a wealth of literature linking its use to preterm birth [20, 31–35].

#### *4.5.3 Medical monitoring*

Inadequate medical follow-up, as expressed by the late first visit of the pregnant woman and the limited number of visits, has a direct impact on the increase of prematurity. This is confirmed by the increased rate of prematurity in pregnant women, especially in adolescent pregnant women who are not monitored by their personal doctor or midwife, where the system of free medical care applies [20, 31–35].

#### *4.5.4 Surgical diseases during pregnancy*

Acute surgical diseases of the abdomen, such as acute appendicitis, are associated with an increased incidence of preterm birth due to the effect of bacterial endotoxins [20, 31–35].

#### *4.5.5 Uterine congenital abnormalities and diseases*

Uterine congenital abnormalities characterized as anatomical are responsible for a small percentage of preterm births. The most common occurrences are in the

#### *Premature Birth, Management, Complications DOI: http://dx.doi.org/10.5772/intechopen.98324*

double uterus, unicorn, duodenum and hypoplastic uterus where the incidence of miscarriage is close to 30% and the risk of premature birth reaches 20% if the pregnancy continues beyond the 20th week of pregnancy. There is also an association with prematurity and fibroids, endometrial adhesions idiopathic myometrial activity [20, 31–35].

#### *4.5.6 Insufficiency of internal cervical os*

The uterus and cervix come from the union of M*ü*ller ducts. The cervix is made up of extracellular connective tissue and type I, III and IV collagen fibers. The percentage of smooth muscle fibers is 10–15%. The percentage of muscle and fibrous components ranges from 29% in the inner cervix to 6% in the outer cervix. Other components of the cervix are glycosaminoglycans, proteoglycans, fibronectin and elastin. Before and during labour, the number of ligaments between the collagen fibers decreases, the concentration of hyaluronic acid increases and this leads to elimination and dilation of the cervix and uterine contractions.

Internal cervical insufficiency is a fairly common cause of prematurity. Also a history with conical resection of the cervix is responsible for an increased rate of premature birth which is observed with a frequency of 14% for the first pregnancy and quadruples in subsequent ones [35–40].

#### *4.5.7 Maternal infections*

Inflammations of the vagina and cervix caused by anaerobic microbes, Trichomonas, Chlamydia, gonococci and streptococci of group B, usually lead to premature birth, premature rupture of membranes and low birth weight infants. With preventive examinations at the beginning of pregnancy such as vaginal fluid culture and the application of treatment in case of positive results, we achieve the reduction of the possibility for premature birth [35–40].

Subclinical chorioamnionitis can predispose to preterm birth. However, the infection is associated with less than 20% of cases of premature birth without complications. The most common link between infection and premature birth is bacterial vaginosis. Disruption of the nitric acid and prostaglandin balance of the myometrium can cause premature contractions and consequent labor.

The vagina is normally colonized by a variety of microorganisms, many of which are flora, while others are potentially pathogenic. It is not fully known whether the bacterial flora itself acts as a trigger for preterm birth or secondarily becomes active only when the cervix is unable to fulfill its protection against incurable infections. Ascending infection is one of the most important mechanisms that progress to premature birth. The infection can act as a trigger, either in the sense that it is more likely to lead to premature birth when the cervix is open at the end of pregnancy, or when the cervix opens prematurely. The degree of cervical dilation affects the risk of ascending infection.

Infection that occurs with intact embryonic membranes reduces infection by the flora of the vagina and cervix. The incidence of amniotic fluid infection varies depending on gestational age at birth. It is particularly high in very premature fetuses and gradually decreases at 30–34 weeks and remains stable until the end of pregnancy [35–40].

#### *4.5.8 Infection of the lower urinary tract*

The essential role of the infection in preterm birth was confirmed by the finding in the amniotic fluid or the dermis and the amniotic fluid of women with

pathogenic microorganisms (Ureoplasma urealiticun, Mycoplasma hominis, *Streptococcus agalactiae*). In particular, the detection rate of the above infectious microorganisms during pregnancy according to the literature is Ureoplasma urealiticun 60%, Trichomonas vaginalis 34%, Mycoplasma hominis20%, Streptococcus agalacticae 5–18% and Gardanerella vaginallis 12% anerobe. Chorioamniosis colonization was twice as much as amniotic fluid. This colonization was more common and inversely proportional to the gestational age and birth weight of the newborn, in women with intact membranes whose labor was spontaneous, compared with women of the same gestational age who gave birth due to medical or obstetric indications other than automatic childbirth. The inverse relationship between positive choriamnia cultures and gestational age was not observed in women giving birth due to medical indications [35–40].

Among women who gave birth up to 30 weeks by spontaneous delivery, choriamnius culture was positive in 73%, compared with 21% of births due to indications. Horiamnius cultures were positive in 83% of mothers with spontaneous onset of labor and in 16% of mothers who gave birth due to indications, in newborns weighing less than 1000 g. An equal number of newborns are born at gestational ages who have proinflammatory cytokines in the amniotic fluid, with negative fluid culture, so that the majority of newborns born under 26 weeks and a significant proportion of those born under 30 weeks have inflammation or inflammation amniotic fluid These findings are mirrored in histological studies of the dermis and amniotic fluid, infiltrated by polymorphonuclear neutrophils in almost all pregnancies of 20–23 weeks, in the majority of those under 26 weeks, and in a significant proportion of those born before 30 weeks [35–40].

The reason for the high frequency of infections - inflammations in the amniotic fluid and chorioamnion is inexplicable in very premature pregnancies under 26 weeks, even under 30 weeks. The flora studies are incomplete from the beginning to the 23rd week of pregnancy, while from the 23rd to the end they show a rather stable vaginal flora [35–40].

The cervix begins to change composition and have maturation elements between 20 and 26 weeks, under the influence of biochemical changes (prostaglandins and interleukin) and uterine contractions. Changes in the cervix increase the exposure to vaginal cervical bacteria of the upper cervix, lower uterus and chorioamnion, resulting in increased amniotic fluid and chorioamnion infection, the most vulnerable barrier between the fetus and the environment.

Most amniotic infections are subclinical, with no maternal fever, uterine tenderness, tachycardia, or foul-smelling amniotic fluid. Very often, however, the mother's infection is not obvious until the infection of the fetus begins. The only fetal sign indicative of amniotic infection is fetal tachycardia, an unstable symptom of systemic neonatal infection. But what makes an amniotic infection fetal and not maternal? The fetus first responds to the infection by responding to the fetal part of the chorioamnion. Proinflammatory cytokines and prostaglandins accumulate in the amniotic fluid. A systemic fetal immune response occurs and produces proinflammatory cytokines and other evidence in the fetal blood [35–40].

Periodontitis has also been studied in women who have low birth weight neonates, resulting from either spontaneous preterm delivery or premature rupture of membranes. It has been found that these mothers have more severe periodontal disease than those who give birth to normal weight babies. It is possible that oral infection with Gram (−) anaerobic microbes fusobacterium nucleutatum, to act periodically, as a chronic factor of hematogenous dispersion of bacteria or bacterial agents (lipopolysaccharides and endotoxins), in the placental unit [35–40].

#### **5. Causes and conditions of embryoplacutic unit related to preterm birth**

#### **5.1 Multiple pregnancies**

A multiple pregnancy is at greater risk for preterm birth due to the continuous dilation of the uterus and the onset of premature contractions. If the average pregnancy is 280.5 days, in twin pregnancies it is 261 days and in triplets is 247 days [41–44].

#### **5.2 Congenital fetal abnormalities**

Increased rate of prematurity due to uterine overstretching is due to polyamine and especially hydramnios. The 1/3 of pregnancies with polyamnios leads to premature birth. The main causes of polyamniosis are congenital abnormalities of the fetus's nervous and digestive systems, intestinal obstruction, septal hernia, Potter's like Syndrome, Skeletal Deformities (Amniotic bands <24 weeks), chromosomal abnormalities, infections. In particular, hydramnios is associated with congenital abnormalities of the fetal nervous system such as aneurysm (due to polydramnios), renal agenesis (due to oligamnius) in combination with pulmonary hypoplasia and endogenous metabolic disorders and some of them are causative factors of preterm birth [45–50].

#### **5.3 Abnormalities of the placenta and umbilicus**

Abnormalities in the morphology, implantation and function of the placenta can often lead to premature birth. Placentas with membranous umbilical cord protrusion are at greater risk for premature onset of labor. Also the precursor placenta is an important factor in causing premature birth. It is characteristic that it is more common in premature births than in normal ones. Premature placental abruption has an even higher incidence in preterm birth than in normal.

#### **5.4 Breech fetal presentation**

Breech presentation of the fetus in the first trimester of pregnancy has an incidence of 20% compared to all pregnancies and only 2% of this percentage leads to premature birth. However, sciatic projection is associated with increased perinatal mortality as well as placental abnormalities thus increasing the likelihood of preterm delivery.

#### **5.5 Premature rupture of membranes**

Spontaneous rupture of fetal membranes (s-PROM) before the end of 37 weeks and 1 hour before the onset of labor covers 14.3% in all preterm births. It is distinguished in term Premature Rupture of membranes (t-PROM) which is defined as rupture of membranes after the 37th week of pregnancy and constitutes the majority of cases and in preterm Premature rupture of membranes (p-PROM) which is defined as rupture of membranes before the 37th week of pregnancy has an incidence of 3% and is responsible for 40% of preterm births. Its incidence is 10–15% of pregnancies.

Findings observed are contractions (4 per 20 min or 8 per 60 min) and cervical dilation >2 cm and/or cervical effacement >80%. It is associated with complications related to the outcome of pregnancy and perinatal outcome, increases the chance of premature birth and neonatal morbidity and mortality to 1–2% [45–50].

The incidence rates are 6% - 10% <37 weeks, 1.5% <32 weeks, 0.5% <28 weeks. Often there is no obvious predisposing factor. The main causes of PROM are malnutrition, vaginitis, cervical insufficiency, abnormalities of the uterus. Pregnancy usually precedes the same episode. The diagnosis of PROM is based on the history of the pregnant woman where discharge from the vagina is reported. The differential diagnosis from other conditions (alkaline urine, inflammation) is usually made by direct examination of the cervical spine and by testing the sunflower map.

The complications of PROM, in addition to those of prematurity, include inflammation of the mother and the fetal placenta, as well as umbilical cord prolapse, which implies significant perinatal morbidity and mortality [45–50]. Babies born with symptoms of sepsis are 4 times more likely to have neonatal mortality than those who do not. In addition, there are risks for the mother from the complications of possible chorioamnionitis [45–50].

Diagnosis is not always easy. It seems that taking a good medical history and then examining the woman using a vaginal dilator helps a lot. Moreover, obstetric ultrasound is helpful in diagnosis. Specifically, the presence of amniotic fluid in the posterior vaginal dome is very helpful in the diagnosis. The nitrazine test and the microscopic examination of the amniotic fluid for the typical image of the fern, have a sensitivity of 90% with false positives of 17% and 6%, respectively due to the mixture of urine and blood or cervical mucus, respectively.

#### **6. PROM monitoring**

Criteria for diagnosing chorioamnionitis include: fever, tachycardia, fetal tachycardia, odorous vaginal fluids, leukocytosis and uterine tenderness. Vitals are taken every 4–8 hours and the existence of one or a combination of the above findings raises the suspicion of fetal infection. Doppler ultrasound, biophysical profile and fetal heart rate have been used from time to time in various studies to distinguish infected fetuses from non-infected ones and therefore pregnancy can be prolonged without success in distinguishing which fetuses are in risk and which not.

Women should be monitored clinically for signs of chorioamnionitis. Apart from vaginal fluid culture at the time of introduction no other need to be taken on a weekly basis. According to the American College of Obstetricians and Gynecologists, CRP and white blood cell count should be checked twice a week. No daily blood draws are needed for leukocytosis and CRP, due to the low sensitivity. Biophysical and Doppler can be done but have no significant prognostic value [45–50].

#### **6.1 Role of antibiotics**

Although different regimens have been used in various studies (penicillins, erythromycin, clindamycin, from 2 doses - 10 days) it seems that the prolongation of pregnancy is stable and the morbidity for mother and newborn is reduced. It is recommended 5–7 days administration of macrolides (erythromycin, azithromycin). Clindamycin is preferred when there is allergy in the first option.

Administration of ceftriaxone, clarithromycin metronidazole β-lactam, appears to significantly extend the time to delivery and the frequency of chorioamnionitis (23 vs. 12 days, p: 0.01, and 50% vs. 67%, p: 0.05, respectively). Finally, there are insufficient data to prove the direct favorable contribution of antibiotics in reducing neonatal morbidity and mortality. Nevertheless the combination of the mentioned antibiotics used as empirical therapy against the

#### *Premature Birth, Management, Complications DOI: http://dx.doi.org/10.5772/intechopen.98324*

aforementioned germs ureaplasma, mycoplasma, anaerobes and gram negative bacteria according to bibliographic data offered satisfactory results in the early and early rupture of fetal membranes for both the mother and the fetus. Strategy for treating a subclinical possible infection. The administration of clavulanic acid should be avoided due to the possible cause of necrotic enterocolitis in the fetus and in cases of group B streptococci additional antibiotics should be given during delivery. Antibiotics are effective in treating infection without being able to prevent a premature birth.

#### **6.2 Role of steroids**

According to the instructions of the American College of Obstetricians and Gynecologists, it is recommended to administer a single dose of steroids in pregnancies <32 weeks with PPROM that do not show signs of infection. Two meta-analyzes conclude that steroids in PPROM significantly reduce Respiratory Difficulty Syndrome, encephalopathy and intra-abdominal bleeding. It does not appear to increase the rate of infection from their administration. A single dose should be given to pregnant women from 24 to 34 weeks. The manifolds are associated with a smaller head size and smaller birth weight [45–50].

#### **6.3 Role of tocolysis**

Tocolysis in women with CPR is not recommended because this treatment does not statistically significantly improve perinatal outcome. The administration of tocolysis to women with CPR and contractions to act on steroids and antibiotics remains unclear. Attempting to suppress preterm uterine-related contractions using first-line tocolytic therapy can achieve prolongation of gestational age. Among the administered tocolytics, β-sympathomimetics do not excel in the other categories in terms of their effectiveness and in addition are associated with a negligible rate of side effects. Conservative treatment with β-sympathomimetics or magnesium offers almost nothing in the whole treatment effort. Careful selection of cases is recommended. Hospitalization for 48–72 hours may be needed, but other than that, informing pregnant woman about possible symptoms of chorioamnionitis is necessary (e.g. temperature measurement).

#### **6.4 PROM and cerclage**

There are no randomized studies on what should be done in such cases. Some studies show a tendency for chorioamnionitis to start earlier, while others show a prolongation of pregnancy. The risks and benefits of suturing for a short time until steroids work have not been adequately studied [45–50].

#### **6.5 PROM and childbirth**

Childbirth should be scheduled between 34th and 40th weeks. If extended beyond this time limit the pregnant woman should be explained the increased chance of choriamnionitis and the reduced chance of respiratory problems from the newborn. In Premature Childbirth the hypoxia is greater compared to that of a full term. Vaginal delivery is recommended at a young gestational age (≤ 25th week). In fetal difficulty many suggest cesarean section. Between 26th and 34th week is no different from the way after 34th week. Vaginal childbirth is the appropriate route of completion of childbirth when there are no abnormal shapes and projections, elements of fetal difficulty, e.g. IUGR [45–50].

Iatrogenic PROM occurs after deliberate medical intervention, when it is estimated that continued pregnancy is at greater risk for the mother and fetus than prematurity.

*Complications of the placenta*: placental abruption, placenta previa.

*Amniotic fluid complications*: oligamnium, polyamnion, chorioamnionitis, premature rupture of membranes.

*Fetal causes*: congenital anomalies, multiple pregnancy, residual development, fetal discomfort.

#### **7. Pathophysiology of preterm labor**

Activation of the maternal/fetal hypothalamic–pituitary–adrenal axis (HPA) due to maternal or fetal stress: connection between maternal psychosocial stress and preterm birth - mechanism similar to normal childbirth.

The following factors such as: Stress, Autoimmune mechanisms, PROM, Inflammation, Bleeding, Uterine overdistension, Multiple pregnancies, disorders of axis (pituitary axis), Inflammation, Environmental factors, Social factors, Activation of mechanisms, induction of contractions leading to effacement and dilation of cervix and finally labor [51–56].

Chorioamnionitis or systemic inflammation from systemic or ascending infection: cervical, decidual and fetal membrane's cytokines activation (macrophage activation, production of interleukins IL 1, IL 6, IL 8, cachectin, 5-hydroxytryptheptamine, release of fibronectin in cervical and vaginal secretions).

Bleeding from decidual: three or seven fold risk of prematurity, especially as a result of premature rupture of membranes.

Uterine oversdistension: myometrial stimulation, increased cytokine expression [50–60].

#### **7.1 Preterm labor: the mechanism includes**

Activation of the maternal and/or fetal HPA axis (psychological or physical stress).

Inflammatory reaction - local or systemic.

Bleeding from decidual.

Increased uterine stretching (multiple pregnancies, hydramnion).

Cervical insufficiency.

Activation of HPA axis.

An increase of CRH levels (corticosteroids) can cause a raise of PG (Prostaglandin) levels and consequently an increase of the MMPs (metalloproteinases) activity, Activation of metals of protein (MMPs) of the parent substance (MMP-1, −3, −8, −9) leads to degradation of the fibrous tissue, and premature rupture of membranes. Bacterial products and/or profibrous cytokines acting on cervical cells of the uterus may cause a change of MMPs expression. High concentrations MMP-8 of amniotic fluid are associated with PB (before the 32nd week of pregnancy) so induction of uterine contractions (directly or by functional "withdrawal" of progesterone) [50–60].

The angiogenic factor VEGF, expressed in embryonic membranes and perishable, is essentially involved in normal angiogenesis and placentalization - thus ensuring way to normal fetal growth and development - while at the same time modifying its permeability in placenta and amniotic membranes. Daneshmand et al. and Kramer et al. suggest that both the VEGF factor and (VEGF-R1 and VEGF-R2) receptors have reduced expression in hypoxic

#### *Premature Birth, Management, Complications DOI: http://dx.doi.org/10.5772/intechopen.98324*

conditions and chorioamnionitis, disrupt the smooth functioning of placental abruption and lead to PB. Similarly, Parazoglou et al. proved the correlation among two common VEGF functional gene polymorphisms (−634G/C and 936C/T) with PB [50–60].

In case of preterm labor, CRH levels are ≥ 2 MoM.

Elevated levels of ACTH (Cortical Adrenal Hormone) and CRH can result in raised levels of DHEA (dehydroepiandrosterone) and 16-OH-DHEA-S (dehydroepiandrosterone sulfate) as increased E1 (estrone) – E3 (estradiole). As a result uterine contractions are induced. (Activation through binding in oxytocin receptors, involvement of MLCK (myosin light chain kinase) and calmodulin. Increased E3 in saline is observed in premature labor, 3–4 weeks before delivery.

Inflammatory reaction is mediated through the following cytokine agents:

Cytokines, TNF-α, Il-1, Il-1β, Il-6, Il-8, Il-10, GM-CSF and finally prostagladines increase.

Fetal membranes, trophoblast and the chorionic villi react, in response to inflammation and ischemic lesions of placental unit and cause an increase in cytokines levels in maternal plasma, in the amniotic fluid of women with preterm labor and in cultures of amniotic fluid.

TNF-α is also found in decidual macrophages as well as in chorion villi and trophoblast. The TNF-α factor is found in maperishable cells of perishables, villi and trophoblast, in both the 1st and 3rd trimester of pregnancy. Its allele gene A region −308 of the TNF-α promoter leads to an increase production of it. Roberts et al. reported positive correlation between polymorphism of the TNF-α promoter region (−308 A allele) and the PB and/or premature rupture among African American women [50–60].

On the contrary, Amory et al. found that homozygotes for the TNF-α allele-863 A gene is significantly increased frequency of PB, chorionicamniotnitis and perinatal morbidity, but this is not associated with an adverse outcome. Il-1 is detected in amniotic fluid, in decidua and trophoblast. The receptor antagonist of IL-1 inhibits the biological effects of IL-1, blocking its receptors. Consequently reduction of IL-1 production and induced from that of prostaglandin production by them endometrial tissue can prevent PB associated with infection Il-1β is found in chorionic villi, decidua, amniotic fluid and placental cultures [50–60]. Elevated levels of Il-6 are usually found in the amniotic fluid, with inflammation. Interleukin-6 (IL-6) is the cytokine expressed more than any other in pregnancy. The finding of extremelly high levels of the specific cytokine in the amniotic fluid pregnant women who presented with some kind of inflammation and its very low concentration in cases of PB "idiopathic" etiology, make it one of the most sensitive and specific PB indicators On the contrary, they were found to be reduced in cases of premature birth. Il-10 is also elevated in amniotic fluid after amniocentesis during the second trimester in pregnancies with IUGR and chorioamnionitis [50–60]. Interleukin-10 (IL-10) is known to be major inhibitory cytokine in the process synthesis of cytokines by both T cells (interferon-γ and IL-2), as well as by monocytes macrophages (TNF-α, IL-6, IL-8, and IL-12) and as therefore plays an important role in achieving the outcome of the pregnancy by securing the maternity tolerance to the allogeneic fetus. In most pregnancies IL-10 is detected in amniotic fluid Its high levels in amniotic fluid of pregnancies complicated with residual embryonic development as well as in cases of pregnant women with clinical symptoms chorioamnionitis associated with dysfunctional for immune activity in pregnancy and in PB [50–60].

Increased levels of interleukin-8 (IL-8) are found in monocytes, in inflammation, in chorioamnionitis and may be used in the future as a prognostic marker of preterm birth. Interleukin-8 (IL-8), a derivative of monocytes; caused by

inflammation, may be used in the future as a PB predictor marker as it has been detected in pregnant women.

Inter twined with chorioamnionitis, and the antigen compatibility (also a derivative of macrocells, which is considered necessary in cellular immune response) is associated with inflammation of the elements of pregnancy.

Bacteria, specially their wall lipoproteins and/or endotoxins can stimulate an increase of IL-1β, TNF-α, IL-8, IL-6, proteases, collagenase, elastase as well as raise of Phospholipase A2 led to PGF2a endothelins and finally increase the myometrial sensitivity to oxytocin [51–56].

#### **7.2 Chorioamnionitis**

It is observed in 12% of premature labors with intact membranes. Histological diagnosis of chorioamnionitis is 40% confirmed in the placenta.

It is also known that frequency of choriomnionitis is inversely proportional with gestational age.

#### **8. Preterm labor and genetic background**

#### **8.1 Modern molecular biology certifies a premature gene**

Quickly developing fields studying human genome (genomic) and protein products (proteomic) may allow the identification of genes and proteins respectively involved in the pathology of PT, making in this way it is possible to develop concrete diagnostic and therapeutic approaches against that. The use of DNA arrays helps to identify the different gene expression and their involvement in childbirth, early or full term.

Reduced expression insulin-dependent factor II (IGF-II), of galgranulin A and B (calgranulin A and B) and of the G-protein-binding receptor (G-protein-coupled receptor) was observed in the myometrium during childbirth - in contrast increased expression of the binding genes protein storage of insulin-dependent IGFs (IGFbinding protein), the binding of the Ca2+/CaM ion protein (Ca2+/CaM binding protein), the C-kinase substrate (kinase C substrate) and the converting enzyme of angiotensin-converting enzyme is noticed. Also, the use of DNA arrays in expression of their cytokine genes fetal membranes of women with endometrial inflammation and who gave birth prematurely, showed hyper-expression in 22 genes and subexpression in 4 on a total of 90 of genes studied. The IL-1β genes of oncostatin M and the enhancer pre-B-cell enhancing factor factor) were those with the greatest difference expression.

These studies demonstrate the potential for genomic research in the identification of genes involved in the pathophysiology of complex diseases, as in the case of PB.

Although the results of studies with the use DNA arrays may show significant over- or under-expression in a set of genes, that not necessarily related to level changes of their protein expression [50–60].

DNA analysis is based on molecular biology methods, such as:

1.The investigation of the functional variability of the candidate gene.


*Premature Birth, Management, Complications DOI: http://dx.doi.org/10.5772/intechopen.98324*

Mutations and polymorphisms in the cytokine genes seem to be involved in pathogenesis of preterm labor. There is an association between preterm labor and the functional change of a cytokine gene. So, mother's carriers of this mutations, may be can be intensively followed up in the future [51–56].

Proteolytic action of MMPs on fetal membranes and cervical mucus leads to progressive cervical effacement and therefore to PROM.

Bleeding observed in more than 2 trimesters increases the relative risk of PROM 7 times.

According to Salafia et al. [61], in 38% of preterm labors hematoma and/or hemosiderin deposition was detected, instead 0.8% in full-term pregnancies.

According to Gargano et al. [62], in cases of preterm labor, Factor V Leyden & angiotensinogen -6G mutations are associated with an increased relative risk (OR: 4.8) of placental abruption in Caucasians but not in African-American pregnant women.

It is also found increased frequency of PROM in women with increased TF (tissue factor - major cellular mediator of hemostasis).

Uterine overdistension due to multiple pregnancy or polydydramnios are the most common risk factors for preterm labor. Uterine distension leads to oxytocin receptors activation and increase of PG and MLCK.

According to Nemeth et al. [63] fetal membranes rupture stimulate the cytokines, PGs and collagenase production. Warren et al. [64] suggest that cervical incompetence may have a genetic background alleles that control anti-inflammatory mediators, that were found in women with high risk for cervical incompetence. Sanbhag et al. [65] women diagnosed with CIN III are in high risk for preterm labor even have not been cured by cone-biopsy. Congenital cervical incompetence is basically rare [51–56].

In conclusion, preterm labor seems to be a result of the following mechanisms:

1.Factors stimulated the HPA axon activation.

2.Inflammatory response.

3.Decidual bleeding.

4.Uterine overdistension.

Common mechanism– Contraction associated proteins (CAPs) and proteases production.

#### **9. Preterm labor prediction**

To predict preterm labor are suggested:

1.Cervical ultrasound evaluation (18–24 Weeks).

Combination of cervical length and funneling significantly increases the possibility of preterm labor. Combination of cervical length and dilatation of internal os, increases the sensitivity, but only 29%.

2.Fetal fibronectin (FFN).

#### **10. Recommendation as routine method in high risk pregnancies**

Nowadays, diagnostic view is focused on score systems that combine ultrasound, biochemical and endocrinologic parameters with molecular methods, such as fetal DNA measurement in maternal circulation. Not rarely, among asymptomatic or low risk pregnancies may be can be found high risk pregnancies for preterm labor.

There is a significant statistical correlation between preterm labor and cervical length <20 mm−25 mm [56, 66–69].

#### **11. Controversial aspects for the efficacy of ultrasound examination**

Transvaginal cervical length measurement between 18 and 24 weeks is commonly suggested as a reliable index of preterm labor. On the other hand, some studies support that generalized preventive cervical measurement has no sufficient evidence.

The timing of cervical measurement in asymptomatic pregnancies with increased risk for preterm labor (history of preterm labor and history of PROM) seems to significantly affect the estimated risk of preterm labor.

Some other studies propose the combination of cervical length measurement and the detection of fetal fibronectin.

Transvaginal ultrasound confirm the preterm labor diagnosis in high risk pregnancies, especially when was applied in the first trimester.

Regarding the cervical cerclage as a method of preventing preterm labor, we clearly suggest that it should be performed only in women with previous history of preterm labor and if ultrasound examinations indicate cervical incompetence.

#### **12. Biochemical markers of preterm labor**


#### **12.1 Vaginocervical fetal fibronectin (fFN)**

Vaginocervical fetal fibronectin (fFN) is a glycoprotein of the extracellular matrix that affects the maintenance of placental adherence to the maternal decidua. Generally, fFN can be found in cervicovaginal fluid early in gestation until 20th week. The detection of fFN after the 20 week may indicate a disruption of the decidual-chorionic interface of the amniotic membrane and is linked with a significant increased risk of preterm labor. Diagnostic tests based on fFN have sensitivity 81.7% and specificity 82.5%.

The absence of FFN is a strong marker that preterm labor is unlikely to occur within the next 7–14 days. So, negative prognostic value in some studies exceeding 99%. The prognostic value of FFN is higher in pregnancies 24–28 weeks, in

comparison with older gestational ages and much stronger for short-term predictions (7–14 days), than in using for the overall outcome [56, 66–69].

#### **13. Preterm labor diagnosis**

Painful contractions are observed at regular intervals combined with progressive effacement and dilation of the cervix. However in 50% of cases contractions may not induce premature labor.

#### **14. Pre-symptomatic control for preterm labor**

Cervical assessment is necessary to evaluate the risk for preterm labor. Cervical length <15 mm observed in 2% of women in 23th w, in 90% of cases happens labor before 28 weeks.

Cervical length >15 mm implies 4% risk for preterm labor.

Cervical length < 5 mm implies 78% risk for preterm labor.

High Bishop's score increases the risk of preterm labor.

Using the ultrasound cervical length measurement we have to remember that normal average is about 34–40 mm, without bulging of the fetal membranes into the internal os. The major risk factor coming from obstetric history that can be used for the evaluation of preterm risk in the current pregnancy is the previous preterm labor. Avoiding factors as urinary tract infections, vaginal infections, smoking, drug abuse and physically demanding work is also important [56, 66–73].

#### **14.1 Fetal fibronectin measurement**

Fetal fibronectin helps to maintain the integrity of the extracellular matrix between chorion villi and basal decidua. It is usually not detected after 20 weeks and until the membranes rupture happens.

If fibronectin was detected, the risk of preterm labor significantly increases.

The presence of fibronectin at 23 weeks implies 60% possibility for labor before 28th week.

#### **15. Preterm neonates and prematurity complications**

The prematurity importance is related to the complications that brings both for the newborn survival as well as for the later development. These complications are often unknown and maybe have unclear long-term effects. Medical decisions are normally defined by the possible effects in combination with the available information depending on the gestational age.

Complications of preterm labor arise from immature systems and organs that are not able to normally function in a ecto-uterine environment. The risk of acute neonatal disease decreases with advancing gestational age demonstrating the fragility of the brain, lungs, immune system, kidneys, skin, eyes and gastrointestinal tract.

#### **15.1 Disorders of preterm neonates**

The following are the most important acute and chronic problems faced by premature infants admitted to the Intensive Care Unit. More specifically, these refer the developmental and mental retardation, cerebral palsy, deafness, blindness, transient dystonia, feeding difficulties and speech delay [70–83].

#### *15.1.1 Disorders of thermoregulation*

Premature infants usually present difficulties in thermoregulation due to the immaturity of the homeostatic mechanism of production and elimination. Contributing factors include the large ratio of body surface area/weight, thin and immature skin, immaturity of the autonomic nervous system and incomplete development of sweat glands that can allow increased heat and fluid loss.

#### *15.1.2 Newborn respiratory distress syndrome*

Newborn Respiratory Distress Syndrome (NRBS) or hyaline membrane disease is caused due to the deficiency of surfactant factor and is clinically manifested with respiratory distress of varying severity. Its frequency is inversely proportional to gestational age, reaching 80% for premature infants born before 28 weeks. Surfactant factor is produced by pneumocytes type II and reduces cell surface tension by preventing the development of atelectasis at the end of expiration.

In premature infants, in which the surfactant is deficient, cell atelectasis develops and gas exchange is disrupted. Newborns with RDS show respiratory distress immediately after birth or within the first 4 hours, clinically presented by tachypnea, intercostal or subcostal retraction, wheezing, tachycardia and cyanosis.

Diagnosis based on x-ray chest as there are characteristic findings, consisting of an air bronchogram and a reticular appearance that can reach to complete opacity. Treatment is etiological by intratracheally administration of exogenous surfactant factor.

Symptomatic treatment of NRDS is based on oxygen administration and continuous positive airway pressure (CPAP) can be applied with a nasopharyngeal catheter or mechanical ventilation through a tracheal tube [70–83] (**Figures 1-3**)**.**

**Figure 1.** *Intubated neonate.*

*Premature Birth, Management, Complications DOI: http://dx.doi.org/10.5772/intechopen.98324*

**Figure 2.** *CPAP in preterm neonate.*

#### *15.1.3 Apnea prematurity and bradycardia*

In preterm neonates born < 32 weeks of gestation, apnea episodes are common, characterized by periods of stop breathing lasting more than 10–15 seconds, accompanied by cyanosis and bradycardia.

#### *15.1.4 Bronchopulmonary dysplasia*

Bronchopulmonary dysplasia or chronic lung disease is the most common lung disease affecting premature neonates. It is characterized by rapid and shallow breathing, dyspnea, shortness of breath, cough, and need for more oxygen. Bronchopulmonary dysplasia may be a temporary condition, but in some children, symptoms persist into adulthood, increasing the risk of developing chronic respiratory disease, such as chronic obstructive pulmonary disease (COPD) [70–83].

#### *15.1.5 Cardiovascular disorders*

These symptoms include prolonged capillary refill (>3 seconds), paleness, decreased muscle tone, lethargy, tachycardia followed by bradycardia and persistent

**Figure 3.** *Preterm neonate,weight 490 gr, 23 W.*

respiratory distress, despite oxygen administration and mechanical respiratory support. In some neonates, hypotension appears from the beginning or as a late sign of shock [70–83].

#### *15.1.6 Patent ductus arteriosus (PDA)*

The major cardiovascular disorder of premature neonates is the patent ductus arteriosus stay. Its frequency reaches 25% of the total in all preterm infants and exceeds 50% in those born less than 1000 grams.

PDA may be asymptomatic or clinically presented by intense heartbeat, Corrigan pulse, and systolic or continuous murmur. If there is severe left–right escape, it causes pulmonary congestion with difficulty breathing and increased need for oxygen and mechanical respiratory support. Other manifestations include tachycardia, hepatomegaly, heart failure, and recurrent episodes of apnea. The diagnosis is based on chest X-ray which shows pulmonary edema or an increase heart shadow and on clinical examination. Finally, it is confirmed by echocardiogram, heart and large vessels Doppler. Treatment includes fluid restriction and administration of indomethacin or ibuprofen. If conservative treatment does not work then duct surgical ligation is performed [70–83].

#### *15.1.7 Neurological disorders*

Central nervous system of preterm neonates is really susceptible specifically in damages caused by labor injuries that can affect the immature intracranial structures, by the capillary bleeding, by coagulation disorders and recurrent hypoxia. It's also worth to mention the perseverance for hypoglycemia and blood pressure fluctuations that reflect in cerebral flow and pressure [70–83].

#### *15.1.8 Neonatal brain hemorrhage*

Cerebral bleed is one of the most serious problems of prematurity, as it is the commonest cause of death and disability. Its frequency is inversely proportional to

#### *Premature Birth, Management, Complications DOI: http://dx.doi.org/10.5772/intechopen.98324*

gestational age and occurs in 50–60% of newborns born less than 1000 grams and in 10–20% of newborns with a birth weight of 1000 to 1500 grams [3].

The frequency has actually decreased in recent years, however, cerebral hemorrhage remain a major complication, as the survival of very preterm infants increases. 90% of brain bleeding occur in the first 3 days of life and starts in the germinal matrix, a group of immature thin-walled capillaries which is located on the head of the caudate nucleus and underneath ventricular ependyma, behind the Monroe foramen.

Size of this area is gradually decreasing, starting from 2.5 mm at 23–24 weeks to 1.4 mm at 32 weeks, and is completely regressed at 34 weeks. The diagnosis of cerebral hemorrhage and its complications based on brain ultrasound [70–83].

#### *15.1.9 Gastrointestinal disorders*

Nutrition improvement is particularly essential in the treatment of low birth weight full-term infants as well as in preterm neonates. All preterm infants are at risk due to limited nutrient stores and specific physical and developmental characteristics [70–83].

#### *15.1.10 Necrotizing enterocolitis*

The incidence of the disease in extremely preterm infants can reached 10% and the mortality in these children is about 30%. Prematurity is the most important risk factor.

The onset of the disease initiates usually within the first 10 days of life (in 90% of cases), but can range from the 1st day of life until to the 3rd month.

Symptoms in newborns vary and in mild cases recess without important sequel. Abdominal distention and lethargy are early signs of a more serious form of the disease, followed by bilious vomiting, gastrointestinal bleeding and, in severe cases, erythema of the anterior abdominal wall (especially in periumbical region).

The prognosis is actually bad and mortality rate can reach up to 20%. Bowel stenosis and malabsorption syndrome in cases of surgical resection of a large part of the intestine are some long-term complications [70–83].

#### *15.1.11 Hematological disorders*

The premature neonate is usually predisposed to hematological disorders due to increased capillary fragility, increased bleeding mood, slow red blood cell production, increased fetal hemoglobin, blood loss due to frequent peripheral blood draws and decreased albumin levels in peripheral blood. These newborns are checked for signs of bleeding at the puncture site, in the gastrointestinal tract and in the respiratory system.

#### *15.1.12 Metabolic disorders*


Hypoglycaemia is defined as a fall in serum glucose below 40mg/dl for preterm and full-term infants.

• Hyperglycemia

Hyperglycemia is defined as an increase in the plasma glucose value> 130 mg/dl.

#### Retinopathy of prematurity

It is observed in very premature infants, who have been given oxygen in large concentrations and for a long time. After the recognition of the administered oxygen as a causative factor, the retinopathy of prematurity is now a rare disease. Newborns who are more likely to develop retinopathy are those weighing less than 1,500 grams and those who have been given oxygen in high doses for a prolonged therapy.

• Neonatal jaundice

Jaundice is probably the most common neonatal disorder especially in premature neonates.

#### **15.2 Preterm labor management**

Maternal well-being control (infection; bleeding; WB; CRP; Urine and vaginal culture).

Fetal Well-being control (NST, US, Blood pressure, Doppler).

Corticosteroids administration if preterm labor <34 weeks is possible (betamethazone, dexamethazone) result to decrease newborn respiratory distress syndrome (50%), necrotizing enterocolitis and intraventricular hemorrhage.

Corticosteroids are contraindicated in cases of maternal sepsis.

Antibiotics: are not routinely recommended, if maternal infection is absent. Tocolysis is recommended at least until steroids administration is completed [70–83].

#### *15.2.1 Contraindications of tocolysis*

A. Relatives

Severe Vaginal bleeding Preclamspia Severe fetal growth restriction

B. Absolute

Fetal death Fetal anomalies incompatible with life Chorioamnionitis Severe fetal distress Maternal indication for delivery

#### **16. Conclusion**

Despite the great progress of neonatology and prenatal medicine, prematurity is a serious factor in neonatal morbidity and mortality. Causative factors leading to prematurity have not yet been completely identified and are a really multifactorial condition. Preterm labor can be caused by a number of many different factors, such as in the case of various infections or diseases of the mother, in the absence of prenatal control, the low socio-economic level. Preterm labor is a traumatic experience and extremely stressful not only for the newborn but for the whole family.

#### *Premature Birth, Management, Complications DOI: http://dx.doi.org/10.5772/intechopen.98324*

Parents are possessed by feelings of frustration, failure as well as anxiety about the survival and future development of their baby.

The severity of a preterm birth lies in the fact that premature neonates are at greater risk for short-term and long-term complications including normal physical and mental development, disability and congenital disorders.

This is because the newborn is fully developed in the last weeks of pregnancy. That's the reason that medical and obstetric staff should contribute from the beginning of a pregnancy, in the investigation of all the causes of preterm labor in order to apply in clinical routine the appropriate treatment protocols.

### **Author details**

Panagiotis Tsikouras1 \*, Anastasia Bothou<sup>2</sup> , Aggeliki Gerede1 , Ifigenia Apostolou3 , Fotini Gaitatzi1 , Dorelia Deuteraiou1 , Anna Chalkidou1 , Xanthoula Anthoulaki1 , Spyridon Michalopoulos1 , Georgios Dragoutsos1 , Ioannis Tsirkas1 , Irini Babageorgaka1 , Theopi Nalbanti1 , Natalia Sachnova1 , Alexios Alexiou1 , Constantinos Nikolettos1 , Apostolos Lazarou1 , Stefanos Zervoudis4 , Panagiotis Peitsidis1 and Nikolaos Nikolettos1

1 Department of Obstetrics and Gynecology Democritus, University of Thrace Medical School, Alexandroupolis, Greece

2 Second Department of Surgery, Democritus University of Thrace Medical School, Alexandroupolis, Greece

3 Neonatal Intensive Unit Care, University Hospital of Thrace Medical School, Alexandroupolis, Greece

4 Technological Educational Institute of Athens and Rea Maternity Hospital, Athens, Greece

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

© 2021 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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Section 3

## Papillary Neoplasm and Melanoma

#### **Chapter 5**

## Papillary Neoplasm of Breast-Changing Trends in Diagnosis and Management

*Amrit Pal Singh Rana and Manjit Kaur Rana*

#### **Abstract**

Papillary neoplasm of breast comprises of seven separate heterogeneous entities ranging from benign, atypical and malignancy including non-invasive and invasive carcinoma. Papillary carcinoma (PC) is seen more commonly in older postmenopausal women with favorable prognosis. PC breast typically presents with bloody nipple discharge and an abnormal mass with radiologic features of intraductal mass. Encapsulated PC and solid PC is to be treated as in situ carcinoma, but distinction of invasive PC from non invasive carcinoma is critical both at microscopic and molecular level. So, surgical excision should be the choice of definitive diagnostic technique in papillary neoplasm instead of core needle biopsy. Furthermore, treatment guidelines for invasive PC also have been framed, but incidence of recurrence and death attributable to various subtypes of carcinoma remained same. So, this is important topic to be addressed to understand the need for further management and outcome of the disease.

**Keywords:** papilloma, invasive carcinoma, intraductal, carcinoma in situ, solid papillary carcinoma

#### **1. Introduction**

Papillary neoplasm of the breast is a broad range of heterogeneous group of lesions that are characterized by presence of papillae supported by fibrovascular cores lined by epithelial cells with or without myoepithelial cell layer. These neoplasms may be benign, atypical or malignant and are difficult to diagnose. The main diagnostic concern is differentiating benign and malignant lesions, which can be challenging both on imaging as well as on histopathological examination [1].

#### **2. Definition of papillary neoplasm breast**

World health organization (WHO) in 2021 classified breast intraductal papillary neoplasm as intraductal papillomas (intraductal papilloma with atypical hyperplasia, intraductal papilloma with ductual carcinoma in situ (DCIS), intraductal papilloma with lobular carcinoma in situ), intraductal papillary carcinoma (solid papillary carcinoma, encapsulated carcinoma) and invasive carcinoma [1, 2].

#### **3. Epidemiology**

#### **3.1 Age and sex**

The benign conditions are commonly seen in between 30 and 50 years of age and PC commonly affects postmenopausal age group. Papillary neoplasms have sex predilection for females though intracystic papillary carcinoma (IPC) is rarely seen in males too. The clinical presentation in males and females is similar except for a higher median age in males [3, 4].

#### **3.2 Incidence**

Papillary neoplasms are less commonly seen and account for less than 3% of breast tumors and PC of the breast accounts for 0.5–1% of breast cancer [5]. The frequency of lymph node involvement in invasive papillary carcinoma, its local recurrence and distant recurrence may be 0–11%, 3–70% and 0–4%, respectively. Solid papillary carcinoma (SPC) constitutes only 1% of all the breast carcinomas, presenting as localized mass in approximately 90% of the cases, lymph node metastases in 8%, and distant metastases in less than 0.8% only. Intracystic papillary carcinoma also has localized involvement in approximately 89.6% of the cases with 0.4% distant metastases [6, 7].

#### **4. Pathophysiology**

Many researchers have analyzed the risk factors for malignant transformation in benign papilloma of breast, however the results remain inconsistent. Some investigators considered same attributable factors for carcinoma arising in papillary neoplasm as that of other carcinomas. The contributing predisposing risk factors are age, family history, genetic predilection, diet and weight gain, alcoholism, and endocrine factors [8, 9].

#### **5. Clinical features**

Papillary neoplasms may be central and peripheral in location and solitary or multiple in number. And most papillomas are centrally located with a wide age distribution and originate in the large ducts, and are typically solitary. The most common clinical presentation is serous or serosanguineous nipple discharge. The benign solitary papilloma has 1.5 to 2.0 times high risk of breast carcinoma whereas four times increased risk of malignant transformation is noted in atypical papillomas. The peripheral papillomas arise in the terminal duct lobular units and are often discovered incidentally on imaging studies and risk of carcinoma is even higher than solitary papilloma. And very rarely, benign papillomas of breast presenting with local or distant metastases have been reported [10–18]. However, behavior and management of papillary carcinoma whether in situ or invasive remain a matter of debate. The lymph node involvement, local recurrence and distant recurrence may be seen. Solid papillary carcinoma are localized lesions and may involve lymph node however distant metastasis is rare [6, 7]. Common clinical features include nipple discharge and palpable masses in some cases, however papillary lesions may be diagnosed in asymptomatic women or on screening [19].

*Papillary Neoplasm of Breast-Changing Trends in Diagnosis and Management DOI: http://dx.doi.org/10.5772/intechopen.100115*

#### **6. Diagnosis**

Treatment of benign papillary neoplasms require careful evaluation as the presence of papillary architecture is known to be associated with a higher risk of carcinoma breast [20]. The precise diagnosis of papillary neoplasm of the breast is difficult on cytomorphological charaterstics alone. A benign diagnosis on fine needle aspiration or core needle biopsy may not completely exclude malignancy especially if it manifests as focal carcinoma in-situ or abruption of the myoepithelial layer. Microcalcification is an important factor in the management of breast intraductal papillomas diagnosed on core biopsy [21–24]. The benign papillary lesions can be diagnosed with sonographically guided 14-gauge core needle biopsy. The sensitivity for detecting papillary lesions is greater by ultrasound than mammography. The USG findings of papillary neoplasm are found to be correlated with pathologic findings [13, 25]. Recently, automated breast ultrasound scanners have been developed, and the ultrasound volume data set of the whole breast can be acquired in a standard manner [26]. MRI features including a mass size exceeding 10mm may indicate a papilloma with high-risk or malignant lesions [27].

However, histopathological examination is the gold standard tool for the diagnosis. Nevertheless, the morphology is more important than the immunostaining pattern, and diagnosis of neoplastic proliferation should not be made on the immunostaining pattern alone. For intraductal papillary neoplasm CK5/6 is good marker to differentiate between intraductal hyperplasia (CK5/6 positive) and intraductal proliferation resembling DCIS or ADH (CK5/6 negative). Immunohistochemical examination with CK5/6 and a panel of two myoepithelial markers (p63, SMA, CD10, calponin) acts as useful tool in assessing papillary neoplasms of the breast [28, 29].

#### **7. Treatment and prognosis**

The treatment of benign and atypical papilloma is being evolved. The surgical excision of all papillary lesions is recommended for definitive diagnosis and standard management for malignant papillary lesions [24, 30]. Li X et al. suggested the vacuum assisted excision is applicable for complete excision of small papillomas, even papillomas with atypical hyperplasia [31]. Bianchi et al. also emphasized that, in addition to surgery, vacuum assisted excision of beingn intraductal papilloma may be done [32]. However, some authors have recommended that benign papillary lesions diagnosed by core needle biopsy (CNB) might not require immediate excision, but may be safely managed with imaging follow-up for at least 5 years rather than with surgical excision [33, 34]. Accurate results and coordination between a trained radiologist and pathology are of utmost importance in the decision making between follow-up or surgery [35]. However, Fatima K et al. have observed no reliable clinical or imaging features that can pre-surgically predict atypical upgradation or malignant potential [30]. Tokiniwa H and fellows detected surgical excision advantageous for papillary lesions especially for the lesions located far from the nipple [36]. The atypical papillary lesions should be excised surgically (**Figure 1**) [37].

Intraductal carcinomas like encapsulated papillary carcinoma (EPC) with presence of myoepithelial cells at the periphery should be treated as DCIS and with lack of myoepithelial cells may behave in an indolent invasive pattern with reported lymphnode metastasis and lymphovascular invasion. The present harmony is to manage EPC as in situ disease, though recurrence may be seen associated with aggressive behavior (**Figure 2**).

**Figure 1.** *Surgically excised specimen of papillary neoplasm.*

**Figure 2.** *Surgically excised specimen of EPC.*

Due to lack of evidence of behavior and criterion of diagnosis, SPC is difficult to categorize as benign or malignant and current consensus is to consider it as an insitu disease. Consensus is to treat these types of neoplasms for local control without axillary node sampling or systemic therapy. Inspite of very low risk of metastatic potential, evidence does not support use of conventional forms of adjuvant systemic therapy. IPC is known to have benign behavior with 100% disease-specific survival rate so to be treated with similar way to other types of carcinoma breast except in cases with moderate nuclear atypia [7, 38].

#### **8. Conclusion**

Papillary neoplasm is difficult to detect and diagnose, if diagnosed, surgical excision is the treatment of choice. Encysted and solid papillary carcinoma should *Papillary Neoplasm of Breast-Changing Trends in Diagnosis and Management DOI: http://dx.doi.org/10.5772/intechopen.100115*

be treated as DCIS, irrespective of nuclear grading. Amongst imaging studies ultrasoography is better than mammography. In difficult cases immunohistochemical markers (CK 5/6 and minimum two myeloepithelial markers provide the support. Invasive papillary carcinoma may be treated as per guidelines of invasive carcinoma breast and shows good prognosis.

### **Author details**

Amrit Pal Singh Rana1 \* and Manjit Kaur Rana2

1 Department of Surgery, Baba Farid University of Health Sciences, Faridkot, Punjab, India

2 Department of Pathology/Lab Medicine, All India Institute of Medical Sciences, Bathinda, Punjab, India

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

© 2021 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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#### **Chapter 6**

## A Review of Progesterone Effects on Human Melanoma Cell Growth In-Vitro

*Pandurangan Ramaraj*

#### **Abstract**

Progesterone, a female sex hormone not only has a role in reproduction, but also in protecting females in melanoma. A survey of steroid hormones actions steroid hormones actions survey on melanoma cells and literature survey showed that progesterone inhibited mouse and human melanoma cell growth significantly in-vitro. Progesterone not only inhibited cell growth, but also affected adhesion and migration functions (essential for metastasis) in-vitro. This observation correlated with the clinical studies where they had shown showed an increased survival and delayed metastasis in menstruating females in melanoma. Further, progesterone level in menstruating females (1000–1500 ng/dL) compared to post-menopausal females (20–100 ng/dL) also correlated with previous clinical studies. Progesterone action on melanoma cells, as reported by other researchers also supported the findings from this lab. Hence, progesterone could be the steroid hormone protecting menstruating females in melanoma. Moreover, our recent studies showed that progesterone suppressed pro-inflammatory cytokine IL-8 secretion by the melanoma cells, which decreased melanoma cell growth in-vitro. Hence, progesterone apart from reproductive function may also be involved in protecting menstruating females in melanoma.

**Keywords:** progesterone, menstruating females, protection in melanoma, IL-8 secretion

#### **1. Introduction**

Skin is not only a largest organ in the body, but also an endocrine organ and a target site for other hormones [1–3]. Skin has all the elements of a functional hypothalamo-pituitary-adrenal axis [4]. So, it has CRH (corticotropic releasing hormone), POMC (pre-opiomelano cortin) and associated peptides ACTH (adreno corticotropic hormone), α-MSH (α-melanocyte stimulating hormone), β-endorphin [5]. Expression of these peptides is environmentally regulated and their dysfunction can lead to skin and systemic diseases [6]. Skin neuroendocrine system acts by preserving and maintaining the skin structural and functional integrity [7]. This network allow skin to maintain local and global homeostasis that is vital for survival [6, 7]. Skin and hair follicles not only have functional melatonin receptor, but to a larger extent serve as an extra-pineal organ to synthesize melatonin [8]. Skin has the ability to synthesize glucocorticoid from cholesterol or from

steroid intermediates of systemic origin [6]. By interacting with glucocorticoid receptor, immune functions and physiological functions of epidermal, dermal and subcutaneous structures are regulated [9]. Since, synthesis and site of actions of hormones are nearby, it suggests auto, para and intracrine mode of actions. Levels of local production changes in response to environmental stress. This local glucosteroidogenesis is essential for skin homeostasis and prevent skin pathology. Sex steroids such as androgens, estrogens and progestins are essential for a healthy skin [1, 2]. Melanocyte, which is transformed to melanoma is also under the influence of melanocyte stimulating hormone (MSH) from pituitary. Generally, melanoma is not labeled as a hormone dependent cancer because of the fact that ultraviolet (UV) rays from the Sun is the major cause for melanoma [10]. UV rays cause deoxy ribonucleic acid (DNA) damages and other inflammatory changes in the skin, which result in skin cancer [11]. About 90% of melanoma is caused by environmental factors such as UV rays, radiations and only 10% is inherited in the family. So, melanoma is never considered as a hormone dependent cancer. However, existing evidences point to a hormone relatedness to survival or a hormone responsive nature of melanoma [12, 13].

### **2. In-vitro studies from our lab**

In-vitro studies from our lab showed the involvement of progesterone in the regulation of mouse and human melanoma cell growth.

#### **2.1 Effect of Steroids on mouse melanoma (B16F10) cell growth**

Initially four sex steroids viz., dehydroepiandsterone (DHEA), androstenedione (AD), testosterone (T) and progesterone (P4) were used to find out their effect on mouse melanoma (B16F10) cell growth. Though all four steroids showed a dosedependent decrease in cell growth, yet progesterone alone showed a significant inhibition of the mouse melanoma cell growth [14].

#### **2.2 Dose-response curves with mouse (B16F10) and human (BLM) melanoma cells**

As the initial study was carried out at high concentrations (100, 150 and 200 μM). dose-response study was carried out to rule out toxic effect of steroids on melanoma cell growth inhibition. Mouse (B16F10) and human melanoma (BLM) cells showed a dose-dependent cell growth inhibition, suggesting the inhibition was a biological action and not a toxic inhibition of cell growth at high concentrations [14, 15].

#### **2.3 Effect of related steroids on mouse melanoma cell growth**

A weak androgen DHEA also inhibited mouse melanoma cell growth, but it was not as significant as the inhibition of progesterone on mouse melanoma cells. But, RU-486 a progesterone receptor antagonist and also a glucocorticoid receptor antagonist showed significant inhibition of mouse melanoma cell growth [14, 15].

#### **2.4 Mechanism of progesterone and RU-486 actions**

Since progesterone and its receptor antagonist (RU-486) showed significant inhibition on melanoma cell growth, it raised the question whether progesterone *A Review of Progesterone Effects on Human Melanoma Cell Growth In-Vitro DOI: http://dx.doi.org/10.5772/intechopen.101239*

receptor was involved in this action. However, a co-incubation experiment of progesterone and RU-486 showed an additive effect on melanoma cell growth inhibition, suggesting that the action was not mediated through progesterone receptor and that each hormone acted through different mechanisms resulting in an additive effect on the inhibition of melanoma cell growth. Similarly human melanoma cell growth showed an additive effect on cell growth inhibition, when progesterone at fixed concentration (10 μM) was co-incubated with varying concentrations of RU-486 (10, 50 and 100 μM).

#### **2.5 Dose-curve with cholesterol to check non-specific action of steroids**

Since inhibition was seen with DHEA, progesterone and RU-486, it raised the question whether it was a specific effect on melanoma cell lines or common effect on all cancer cell lines? So, cells were incubated with cholesterol the parent compound of all steroids. Though, cholesterol showed initial decrease in cell growth, it failed to show a dose-dependent inhibition of cell growth. It was almost flat line from 10 μM to 200 μM, suggesting that the inhibition by progesterone and RU-486 was specific to melanoma cells.

#### **2.6 Effect of progesterone and RU-486 on human gastric cancer cell (NUGC3) line**

The effect of progesterone and RU-486 seen on mouse and human melanoma cells raised the question whether it was a non-specific effect on melanoma cell lines. So, progesterone and RU-486 were incubated separately with human gastric cancer (NUGC3) cell line. Progesterone and RU-486 did not show a significant inhibition as seen that of on melanoma cells, suggesting the inhibition was specific to melanoma cells.

#### **2.7 Effect of progesterone and RU-486 on normal rat vascular smooth muscle cells**

So far experiments were carried out on transformed cells and hence the effect on normal cells was not known. So, normal rat vascular smooth muscle cells were used. Progesterone and RU-486 were incubated with smooth muscle cells, which did not show a significant inhibition, suggesting progesterone and RU-486 inhibition were specific to melanoma cells.

#### **2.8 Mechanism of inhibition of human melanoma cell growth**

As progesterone showed a dose-dependent inhibition of human melanoma (BLM) cell growth, the mechanism of inhibition was determined. After ruling out necrosis and apoptosis, autophagy [12] as the mechanism was detected by co-incubation with 3-MA (methyl adenine) and progesterone. Results showed a partial increase in cell growth (rescue of cell growth) with 3-MA and progesterone co-incubation compared to cells incubated with progesterone alone, suggesting the mechanism of inhibition of cell growth was due to autophagy.

#### **2.9 Other in-vitro functions inhibited by progesterone**

Progesterone not only inhibited cell growth, but also other in-vitro functions such as adhesion and migration. Both adhesion and migration functions were essential for metastasis. Clinical study showed that menstruating females were

better protected in melanoma in terms of increased survival and delayed metastasis than post-menopausal women and men of any age. Literature survey also revealed that progesterone level in menstruating females was 100–150 ng/ml in the follicular phase and 1000–1500 ng/dL in the luteal phase [16]. Whereas, post-menopausal females' progesterone level was 20–100 ng/dL and males' levels were between 27 and 90 ng/dL. The last two groups were not protected in melanoma, as per the clinical studies. In fact, progesterone in-vitro action also suggested the same. Study of progesterone effect on melanoma cells by other researchers also showed the effect of progesterone on other human melanoma cell lines. Fang et al. from China showed inhibition of A375 and A875 cell line growth by progesterone and RU-486 and that their actions were not mediated through progesterone receptor [17]. Moroni et al. [18] repeated the study with the same lines using progesterone concentrations up to 1000 μM. Kanda and Watanbe [19] already showed the inhibition of human melanoma cell growth by progesterone along with dihydrotestosterone (DHT) and estradiol (E2). However, these studies did not correlate progesterone with the protective function as reported by the clinical studies.

#### **3. Summary**

Progesterone, a female sex steroid significantly inhibited mouse and human melanoma cell growth significantly in-vitro. RU-486, a progesterone receptor antagonist also significantly inhibited melanoma cell growth significantly. But the action was not mediated through progesterone receptor. In addition, effect of progesterone and RU-486 were found to be not a spurious or a toxic action. In-vitro studies also showed that progesterone inhibited human melanoma cells and the mechanism of inhibition was due to autophagy. Progesterone also inhibited adhesion and migration functions (essential for metastasis) of human melanoma cells in-vitro. This observation correlated well with the previous clinical studies which reported that menstruating females were better protected (increased survival and delayed metastasis) in melanoma than post-menopausal women and men of any age. Research works around the globe also showed inhibition of human melanoma cells by progesterone. Progesterone action was mediated by the suppression of IL-8 secretion by melanoma cells.

#### **4. Conclusion**

As shown by the in-vitro studies, progesterone could be protecting menstruating females in melanoma. In fact progesterone could be the appropriate steroid because progesterone is anti-inflammatory in nature. Further studies from our lab showed that progesterone suppressed pro-inflammatory cytokine IL-8 [20]. In fact, progesterone could be the appropriate steroid because progesterone is antiinflammatory in nature. So, progesterone action could be mediated by the suppression of pro-inflammatory cytokine IL-8, which decreased melanoma cell growth in-vitro. Hence, survival of menstruating females in melanoma may be dependent on progesterone. So, progesterone apart from its effect on reproduction has also a role in protecting females from melanoma.

*A Review of Progesterone Effects on Human Melanoma Cell Growth In-Vitro DOI: http://dx.doi.org/10.5772/intechopen.101239*

#### **Author details**

Pandurangan Ramaraj Department of Biochemistry, Kirksville College of Osteopathic Medicine, A.T. Still University, Kirksville, MO, United States

\*Address all correspondence to: pramaraj@atsu.edu

© 2021 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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Section 4
