**4. Transgenerational effects of parental obesity**

There is good evidence to show that maternal obesity during pregnancy is a risk factor for obesity in the offspring [55]. There is also an increasing body of evidence that obesity in males and females periconceptionally can impact on the metabolic health and even fertility of future generations. By using animal models, the impact of maternal and paternal obesity on offspring and future generations has been examined. Studies have demonstrated that obesity and other health conditions can be transmitted across multiple generations via epigenetic mechanisms down either the maternal or the paternal line.

An elegant murine study by Huypens and others [56] induced obesity in both male and female parents for 6 weeks with a high-fat diet (HFD) and then performed IVF. Embryos created from all combinations of parents were transferred into a lean dam, to negate the impact of obesity during pregnancy (**Figure 2**).

Female offspring born from both maternal and paternal obese parents gained more weight than the male offspring. The risk of female offspring obesity was reduced if only the female parent was obese, suggesting an additive effect.

Females from obese parents also had significant metabolic derangements. They demonstrated a delay in blood glucose clearance leading to hyperinsulinemia and increased fat mass. Male offspring demonstrated severe insulin resistance before

**Figure 2.**

*Embryos created from different combinations of obese and lean parents were transferred into a lean surrogate dam, to determine the impact of overweight and obesity in male and female parents on the next generation [55].*

any change in body weight. This insulin resistance was acquired in the offspring via the maternal line.

Another study by Fullston and others [57] demonstrated that paternal obesity initiated changes to metabolic health and obesity in multiple subsequent generations. Insulin resistance and obesity were transmitted to both the female and male first-generation offspring and then through both parental lineages to the second generation with amplified obesity in the female offspring in the first generation and in their sons in the second generation.

Epigenetics is the hypothesized mechanism for transgenerational disease patterns. It was thought that this was in utero exposure to epigenetic modification of offspring DNA or histone modification during developmental stages without alteration to the DNA itself. However, this has been broadened to include transgenerational (meiotic) alterations and occurs through several possible processes including DNA methylation, histone modification, DNA-binding proteins, and noncoding RNA [6] (**Figure 1**).

In the study by Fullston and others [57], they demonstrated that diet-induced paternal obesity leads to an alteration in mRNAs and microRNAs within the rodent testes, with alteration in the sperm microRNA content as well. They also detected

**63**

*Reproductive Consequences of Obesity*

*DOI: http://dx.doi.org/10.5772/intechopen.80897*

**5. Effectiveness of weight loss strategies**

**5.1 Lifestyle intervention and behavior modification**

25% reduction in global methylation of germ cell DNA. These modifications are potential signals to program obesity and impaired metabolic health in offspring. These effects have also been demonstrated in humans with hypomethylation of sperm being associated with subfertility [58]. Another study [59] demonstrated, in a mouse model of diet-induced obesity, sperm tRNA-derived small RNAs impaired offspring glucose tolerance and induced insulin resistance. Other studies have also demonstrated that both maternal and paternal obesity can cause epigenetic changes

that predispose offspring to obesity or metabolic disease later in life [60].

There is no doubt that obesity contributes to significant periconceptional and perinatal morbidity and has been clearly associated with prolonged time to conception, increased pregnancy loss, and higher rates of adverse pregnancy outcomes such as preeclampsia and gestational diabetes along with preterm birth and in turn increased fetal morbidity and mortality. As mentioned previously, there is increasing information that it affects fertility and miscarriage rates so it is not unexpected that national and international guidelines focus on weight loss prior to either spontaneous conception or assisted reproduction [4, 32, 61] and that first-line management is ideally with lifestyle intervention and behavior modification.

It is controversial as to whether weight loss through dietary intervention, exercise programs, or behavior modification will impact significantly on spontaneous conception rates or success with assisted reproduction. There are a group of studies that suggest improved ovulatory frequency, pregnancy rates, and cost per pregnancy achieved in assisted reproduction [32, 62]. One randomized controlled trial demonstrated that a 12-week diet and exercise program resulted in a mean weight loss of 5.4 kg in the intervention group, a trend toward a higher clinical pregnancy rate and a significant difference in live birth rates [63]. A secondary analysis of two parallel randomized controlled trials in obese PCOS women also demonstrated that deferred ovulation induction treatment preceded by lifestyle modification resulted in significantly improved ovulation rates and live birth rates when compared with immediate treatment [62]. Weight reduction in an obese anovulatory population has been shown to improve pregnancy rates. A 6-month lifestyle intervention induced an average weight loss of 10 kg, which resulted in return of ovulation in 90% of participants and 78% conceiving. The miscarriage rate was 18% [64]. However, other studies suggest surprisingly little impact on conception and fertility outcomes. One large multicenter randomized controlled trial involving a 12-week intensive dietary intervention followed by IVF demonstrated a significant weight reduction in the intervention group, but this was not reflected in reproductive outcomes [65]. Live birth rates through IVF and miscarriage rates were not significantly different. The authors did note that the spontaneous pregnancy rates in the intervention group compared to the immediate treatment group were significantly higher. This may, however, have been due to having a longer time to achieve a

spontaneous pregnancy, albeit they were then older at the time of IVF [65]. Firstly, lifestyle modification often results in only a modest weight loss. In a general population large-scale disease prevention programs including intensive counseling, support, and changes in diet and exercise, a 4–6 kg weight loss could be achieved but was sufficient to reduce the incidence of diabetes and metabolic syndrome [66]. Unfortunately, achieved weight loss is often regained relatively

*Reproductive Consequences of Obesity DOI: http://dx.doi.org/10.5772/intechopen.80897*

*Obesity*

**62**

the maternal line.

**Figure 2.**

RNA [6] (**Figure 1**).

in their sons in the second generation.

any change in body weight. This insulin resistance was acquired in the offspring via

*Embryos created from different combinations of obese and lean parents were transferred into a lean surrogate dam, to determine the impact of overweight and obesity in male and female parents on the next generation [55].*

Another study by Fullston and others [57] demonstrated that paternal obesity initiated changes to metabolic health and obesity in multiple subsequent generations. Insulin resistance and obesity were transmitted to both the female and male first-generation offspring and then through both parental lineages to the second generation with amplified obesity in the female offspring in the first generation and

Epigenetics is the hypothesized mechanism for transgenerational disease patterns. It was thought that this was in utero exposure to epigenetic modification of offspring DNA or histone modification during developmental stages without alteration to the DNA itself. However, this has been broadened to include transgenerational (meiotic) alterations and occurs through several possible processes including DNA methylation, histone modification, DNA-binding proteins, and noncoding

In the study by Fullston and others [57], they demonstrated that diet-induced paternal obesity leads to an alteration in mRNAs and microRNAs within the rodent testes, with alteration in the sperm microRNA content as well. They also detected

25% reduction in global methylation of germ cell DNA. These modifications are potential signals to program obesity and impaired metabolic health in offspring. These effects have also been demonstrated in humans with hypomethylation of sperm being associated with subfertility [58]. Another study [59] demonstrated, in a mouse model of diet-induced obesity, sperm tRNA-derived small RNAs impaired offspring glucose tolerance and induced insulin resistance. Other studies have also demonstrated that both maternal and paternal obesity can cause epigenetic changes that predispose offspring to obesity or metabolic disease later in life [60].

### **5. Effectiveness of weight loss strategies**

There is no doubt that obesity contributes to significant periconceptional and perinatal morbidity and has been clearly associated with prolonged time to conception, increased pregnancy loss, and higher rates of adverse pregnancy outcomes such as preeclampsia and gestational diabetes along with preterm birth and in turn increased fetal morbidity and mortality. As mentioned previously, there is increasing information that it affects fertility and miscarriage rates so it is not unexpected that national and international guidelines focus on weight loss prior to either spontaneous conception or assisted reproduction [4, 32, 61] and that first-line management is ideally with lifestyle intervention and behavior modification.

#### **5.1 Lifestyle intervention and behavior modification**

It is controversial as to whether weight loss through dietary intervention, exercise programs, or behavior modification will impact significantly on spontaneous conception rates or success with assisted reproduction. There are a group of studies that suggest improved ovulatory frequency, pregnancy rates, and cost per pregnancy achieved in assisted reproduction [32, 62]. One randomized controlled trial demonstrated that a 12-week diet and exercise program resulted in a mean weight loss of 5.4 kg in the intervention group, a trend toward a higher clinical pregnancy rate and a significant difference in live birth rates [63]. A secondary analysis of two parallel randomized controlled trials in obese PCOS women also demonstrated that deferred ovulation induction treatment preceded by lifestyle modification resulted in significantly improved ovulation rates and live birth rates when compared with immediate treatment [62]. Weight reduction in an obese anovulatory population has been shown to improve pregnancy rates. A 6-month lifestyle intervention induced an average weight loss of 10 kg, which resulted in return of ovulation in 90% of participants and 78% conceiving. The miscarriage rate was 18% [64].

However, other studies suggest surprisingly little impact on conception and fertility outcomes. One large multicenter randomized controlled trial involving a 12-week intensive dietary intervention followed by IVF demonstrated a significant weight reduction in the intervention group, but this was not reflected in reproductive outcomes [65]. Live birth rates through IVF and miscarriage rates were not significantly different. The authors did note that the spontaneous pregnancy rates in the intervention group compared to the immediate treatment group were significantly higher. This may, however, have been due to having a longer time to achieve a spontaneous pregnancy, albeit they were then older at the time of IVF [65].

Firstly, lifestyle modification often results in only a modest weight loss. In a general population large-scale disease prevention programs including intensive counseling, support, and changes in diet and exercise, a 4–6 kg weight loss could be achieved but was sufficient to reduce the incidence of diabetes and metabolic syndrome [66]. Unfortunately, achieved weight loss is often regained relatively

quickly [61]. It is reported that weight loss through behavior modification and lifestyle change of greater than 10% and sustained for longer than 12 months occurs in only 20% of individuals who start a program [67].

Additionally, lifestyle modification has been attributed to positive effects on the endocrine and metabolic profile of an individual and that this, and not the weight loss, is the cause of the reported improved reproductive outcomes [68]. As such, there is a call for caution on delaying fertility treatment to allow lifestyle modification and weight loss to occur [69].

#### **5.2 Pharmacological agents**

Due to the modest weight loss from lifestyle intervention, pharmacotherapy is required as an adjunct to deliver better outcomes. There is good evidence to show that it can be used to help manage hypertension, diabetes, and cardiovascular disease in the obese population when used in addition to not replacing lifestyle intervention.

National and international bodies concur that these pharmacological agents can be used to help with weight loss prior to conceiving in those who are obese or those who are overweight with associated weight-related coexisting conditions [4, 32, 61]. It is important to note, however, that none of these drugs have been studied in men or women before conception and their effects on menstrual cycles, ovulation, or even pregnancy rates are unknown.

Phentermine is a sympathomimetic agent that suppresses appetite. Studies have indicated significant weight loss at 6 months compared to placebo [70]. There are side effects of dry mouth, agitation, insomnia, and tachycardia, and it is not recommended in patients with a history of cardiovascular disease. It is the most commonly used weight loss drug in Australia and the USA.

Orlistat inhibits pancreatic and gastric lipases and so reduces the absorption of dietary fats. It is found to be effective for weight loss [71] but has the side effects of fat malabsorption including steatorrhea, fecal incontinence, and fat-soluble vitamin deficiency [72].

Liraglutide is a glucagon-like peptide-1 agonist and controls hyperglycemia without causing hypoglycemia or weight gain. This drug was initially used to treat type 2 diabetes mellitus but its side effect profile of decreased appetite and subsequent weight loss led to its use as a weight loss agent. Studies demonstrate significant weight loss over placebo and improvement on cardiometabolic parameters [73]. Common side effects are nausea, vomiting, and diarrhea, which are dose related and diminish over time.

Topiramate, an anticonvulsant, has also been used to treat obesity due to the side effect of weight loss and is used as either monotherapy or in combination with phentermine. A naltrexone/bupropion combination has also been demonstrated to provide average weight loss over 12 months [74], and Lorcaserin, a selective 5-hydroxytryptamine 2c receptor agonist, also suppresses appetite with a 3.6% weight loss over a year [75].

All of these agents are contraindicated in pregnancy.

One agent not contraindicated in pregnancy is metformin. Metformin is a biguanide that inhibits hepatic glucose production and increases peripheral tissue sensitivity to insulin, resulting in a reduced circulating insulin and accompanying decreased body weight. Although not intended as a weight loss agent, it is known to reduce weight by 1–2 kg alongside a low-calorie diet and its safety in pregnancy is well studied [61].

Many obese men and women also self-medicate with herbal supplements although their safety and effectiveness have not been demonstrated.

Unfortunately, much like with lifestyle intervention and behavior modification strategies, weight loss is modest at best, and dropout rates with these medications due to time and also side effects typically exceed 30% [76].

**65**

*Reproductive Consequences of Obesity*

**5.3 Bariatric surgery**

BMI > 35 kg/m2

*DOI: http://dx.doi.org/10.5772/intechopen.80897*

tion along with pregnancy rates [81–83].

different bariatric surgery procedures [93].

fertility due to age [4, 61].

impact on male fertility.

There is an increasing number of bariatric surgical procedures being performed worldwide with nearly 200,000 cases being reported recently [77]. The surgeries vary between restrictive, such as the sleeve gastrectomy or the laparoscopic adjustable gastric banding and the malabsorptive procedures such as biliopancreatic diversion or a mixed restrictive/malabsorptive procedure such as the Roux en Y gastric bypass.

The benefits of bariatric surgery include significant and long-term weight loss. The latest IFSO report demonstrated mean weight loss of 30% at 1 year postsurgery [77], and the Swedish Obese Study [61] showed significant weight reduction was maintained even after 10 years of follow-up [78]. Additionally, bariatric surgery has

In women, bariatric surgery has been shown to improve menstrual regularity [79], correct ovulation [80], improve clinical and biochemical hyperandrogenism along with hyperinsulinemia and glycemic control, and improve both sexual func-

In men, bariatric surgery improves hormone profiles by increasing testosterone and decreasing SHBG and estradiol [84]. Studies have not demonstrated an improvement in sperm quality, and in fact there have been case reports that have shown a deterioration on sperm parameters following surgery, likely due to nutritional deficiencies [48, 85]. This is in opposition to findings of longer-term stable sperm parameters following significant weight loss postbariatric surgery [86]. There is no doubt that more research needs to be done in this area to clarify this

The obstetric impact of bariatric surgery is profound with the risks of complications such as gestational diabetes, preeclampsia, and fetal macrosomia significantly reduced following surgery when compared to morbidly obese women [61]. Rare surgical complications (bowel obstruction, herniation, band events, and surgical line strictures) have been reported in pregnancy due to intra-abdominal pressure, displacement from the gravid uterus, and even hyperemesis [87, 88]. However, nutritional deficiencies due to malabsorptive-type surgery or noncompliance with long-term supplementation can have a significant effect on fertility and pregnancy outcomes. Deficiencies in iron, vitamin A, vitamin D, vitamin B12, vitamin K, and calcium can lead to maternal complications (e.g., anemia, osteopenia) and fetal complications (e.g., congenital abnormalities) [87]. Although there are no randomized prospective trials addressing time to conception after bariatric surgery, it is suggested to delay pregnancy 1–2 years postsurgery to avoid fetal exposure to nutritional deficiencies from rapid maternal weight loss [87, 89–91]. A large age and BMI-matched cohort study has demonstrated that the chance of preterm birth and small-for-gestational age (SGA) singletons were greater in women with a history of bariatric surgery than in women without such surgery and that the risk of still birth or neonatal death was slightly higher in the bariatric surgery group as well [92]. The median time from surgery to conception was 1.1 years. There does not appear to be any significant differences in obstetric or perinatal outcomes when comparing the

There are, however, studies comparing pregnancies conceived less than 1 year after bariatric surgery to those conceived greater than 1 year after surgery and found no difference in bariatric complications, pregnancy related, or perinatal outcomes [93, 94]. Therefore, when considering advanced age of the woman, the benefits of postponing pregnancy must be balanced against the risk of declining

with concomitant medical conditions exacerbated by obesity [61].

) or with

Bariatric surgery is considered with morbid obesity (BMI > 40 kg/m2

been shown to improve endocrine and metabolic profiles [61].

#### **5.3 Bariatric surgery**

*Obesity*

quickly [61]. It is reported that weight loss through behavior modification and lifestyle change of greater than 10% and sustained for longer than 12 months occurs

Additionally, lifestyle modification has been attributed to positive effects on the endocrine and metabolic profile of an individual and that this, and not the weight loss, is the cause of the reported improved reproductive outcomes [68]. As such, there is a call for caution on delaying fertility treatment to allow lifestyle modifica-

Due to the modest weight loss from lifestyle intervention, pharmacotherapy is required as an adjunct to deliver better outcomes. There is good evidence to show that it can be used to help manage hypertension, diabetes, and cardiovascular disease in the obese population when used in addition to not replacing lifestyle intervention. National and international bodies concur that these pharmacological agents can be used to help with weight loss prior to conceiving in those who are obese or those who are overweight with associated weight-related coexisting conditions [4, 32, 61]. It is important to note, however, that none of these drugs have been studied in men or women before conception and their effects on menstrual cycles, ovulation, or

Phentermine is a sympathomimetic agent that suppresses appetite. Studies have indicated significant weight loss at 6 months compared to placebo [70]. There are side effects of dry mouth, agitation, insomnia, and tachycardia, and it is not recommended in patients with a history of cardiovascular disease. It is the most

Orlistat inhibits pancreatic and gastric lipases and so reduces the absorption of dietary fats. It is found to be effective for weight loss [71] but has the side effects of fat malabsorption including steatorrhea, fecal incontinence, and fat-soluble vitamin

Liraglutide is a glucagon-like peptide-1 agonist and controls hyperglycemia without causing hypoglycemia or weight gain. This drug was initially used to treat type 2 diabetes mellitus but its side effect profile of decreased appetite and subsequent weight loss led to its use as a weight loss agent. Studies demonstrate significant weight loss over placebo and improvement on cardiometabolic parameters [73]. Common side effects are nausea, vomiting, and diarrhea, which are dose

Topiramate, an anticonvulsant, has also been used to treat obesity due to the side effect of weight loss and is used as either monotherapy or in combination with phentermine. A naltrexone/bupropion combination has also been demonstrated to provide average weight loss over 12 months [74], and Lorcaserin, a selective 5-hydroxytryptamine 2c receptor agonist, also suppresses appetite with a 3.6% weight loss over a year [75].

One agent not contraindicated in pregnancy is metformin. Metformin is a biguanide that inhibits hepatic glucose production and increases peripheral tissue sensitivity to insulin, resulting in a reduced circulating insulin and accompanying decreased body weight. Although not intended as a weight loss agent, it is known to reduce weight by 1–2 kg alongside a low-calorie diet and its safety in pregnancy is well studied [61]. Many obese men and women also self-medicate with herbal supplements

Unfortunately, much like with lifestyle intervention and behavior modification strategies, weight loss is modest at best, and dropout rates with these medications

commonly used weight loss drug in Australia and the USA.

All of these agents are contraindicated in pregnancy.

due to time and also side effects typically exceed 30% [76].

although their safety and effectiveness have not been demonstrated.

in only 20% of individuals who start a program [67].

tion and weight loss to occur [69].

even pregnancy rates are unknown.

related and diminish over time.

deficiency [72].

**5.2 Pharmacological agents**

**64**

There is an increasing number of bariatric surgical procedures being performed worldwide with nearly 200,000 cases being reported recently [77]. The surgeries vary between restrictive, such as the sleeve gastrectomy or the laparoscopic adjustable gastric banding and the malabsorptive procedures such as biliopancreatic diversion or a mixed restrictive/malabsorptive procedure such as the Roux en Y gastric bypass. Bariatric surgery is considered with morbid obesity (BMI > 40 kg/m2 ) or with BMI > 35 kg/m2 with concomitant medical conditions exacerbated by obesity [61].

The benefits of bariatric surgery include significant and long-term weight loss. The latest IFSO report demonstrated mean weight loss of 30% at 1 year postsurgery [77], and the Swedish Obese Study [61] showed significant weight reduction was maintained even after 10 years of follow-up [78]. Additionally, bariatric surgery has been shown to improve endocrine and metabolic profiles [61].

In women, bariatric surgery has been shown to improve menstrual regularity [79], correct ovulation [80], improve clinical and biochemical hyperandrogenism along with hyperinsulinemia and glycemic control, and improve both sexual function along with pregnancy rates [81–83].

In men, bariatric surgery improves hormone profiles by increasing testosterone and decreasing SHBG and estradiol [84]. Studies have not demonstrated an improvement in sperm quality, and in fact there have been case reports that have shown a deterioration on sperm parameters following surgery, likely due to nutritional deficiencies [48, 85]. This is in opposition to findings of longer-term stable sperm parameters following significant weight loss postbariatric surgery [86]. There is no doubt that more research needs to be done in this area to clarify this impact on male fertility.

The obstetric impact of bariatric surgery is profound with the risks of complications such as gestational diabetes, preeclampsia, and fetal macrosomia significantly reduced following surgery when compared to morbidly obese women [61]. Rare surgical complications (bowel obstruction, herniation, band events, and surgical line strictures) have been reported in pregnancy due to intra-abdominal pressure, displacement from the gravid uterus, and even hyperemesis [87, 88]. However, nutritional deficiencies due to malabsorptive-type surgery or noncompliance with long-term supplementation can have a significant effect on fertility and pregnancy outcomes. Deficiencies in iron, vitamin A, vitamin D, vitamin B12, vitamin K, and calcium can lead to maternal complications (e.g., anemia, osteopenia) and fetal complications (e.g., congenital abnormalities) [87]. Although there are no randomized prospective trials addressing time to conception after bariatric surgery, it is suggested to delay pregnancy 1–2 years postsurgery to avoid fetal exposure to nutritional deficiencies from rapid maternal weight loss [87, 89–91]. A large age and BMI-matched cohort study has demonstrated that the chance of preterm birth and small-for-gestational age (SGA) singletons were greater in women with a history of bariatric surgery than in women without such surgery and that the risk of still birth or neonatal death was slightly higher in the bariatric surgery group as well [92]. The median time from surgery to conception was 1.1 years. There does not appear to be any significant differences in obstetric or perinatal outcomes when comparing the different bariatric surgery procedures [93].

There are, however, studies comparing pregnancies conceived less than 1 year after bariatric surgery to those conceived greater than 1 year after surgery and found no difference in bariatric complications, pregnancy related, or perinatal outcomes [93, 94]. Therefore, when considering advanced age of the woman, the benefits of postponing pregnancy must be balanced against the risk of declining fertility due to age [4, 61].
