Abstract
The prevalence of obesity is continuing to increase among women. Women who are in their reproductive years are disproportionately affected by obesity. The link between obesity and increased morbidity from various conditions, including cardiovascular disease, Type 2 diabetes, osteoarthritis and malignancies, is well established. This article discusses the current state of obesity among reproductive age women in the USA and reviews the impact of maternal obesity on reproduction. The genetic contribution to human obesity is also discussed, as is reproduction following weight reduction surgery.
Defining obesity & the problem in the USA
Several definitions for obesity exist but the most widely accepted definition is that from the WHO, which defines obesity as abnormal or excessive fat accumulation that presents a risk to health, using BMI as a crude estimate of obesity. Grade 1 (overweight) is defined as a BMI score of25–29.9, Grade 2 (obesity) is defined as a BMI score of 30–39.9 and Grade 3 (severe or morbid obesity) is defined as a BMI score greater than or equal to 40. Numerous organizations including the WHO have recognized obesity as an epidemic in both developed and developing nations worldwide. In the USA alone, over 72 million adults are obese and, since the 1980s, the rates of obesity have doubled for adults and more than tripled for children [101]. According to the 2007 Behavioral Risk Factor Surveillance System, which is a self-reported health survey system, Colorado was the only US state to have a prevalence of less than 20% for obesity. The data are even more worrisome for women of reproductive age, with a 19.1 and 24.8% prevalence of obesity in those aged 18–29 and 30–39 years, respectively. In 2007, the prevalence of obesity among African–American and Hispanic women was reported as 39.9 and 28.8%, respectively [102]. Since this is a self-reported survey, the rates probably exceed these reported values. The obesity condition is also costly, with an estimated US$117 billion spent annually on obesity-related health conditions [101]. These health conditions affect patient morbidity/mortality as well as quality of life and the consequences of long-standing obesity include profound cardiovascular disease, Type 2 diabetes, osteoarthritis, malignancies and death.
Obesity is a complex, multifactorial chronic disease influenced by genetic, endocrine, metabolic, environmental, cultural, behavioral and psychological factors; however, the basic mechanism occurs when long-term energy intake exceeds energy output, leading to the storage of excess energy as adipose tissue. Obesity-related pathologies are thought to be a result of the nature of the adipocyte cell, which was once regarded only as a storage depot for fat. It is now known that the adipocyte is also an endocrine cell that is capable of releasing substances including interleukins, TNF, leptin, complement factors and prothrombotic factors, such as plasminogen activator inhibitor-1 [1]. Metabolic syndrome, a constellation of factors that are associated with an increased risk for cardiovascular disease and Type 2 diabetes, is associated with increased abdominal and visceral adipocyte accumulation, as well as insulin resistance. Certainly, obesity will remain an important issue for healthcare providers, but will be especially important for those involved in women's health since cardiovascular disease, which is strongly associated with obesity, remains the leading cause of death for women. According to the American Heart Association (AHA), more women than men die each year of cardiovascular disease [2].
Genetic contribution to human obesity
Increased body fat mass is associated with increased consumption of calories and fats, as well as with changes in physical activity involving adopting a more sedentary lifestyle. However, there is compelling evidence for genetic influences on body fat mass. Studies performed on twins and adopted patients support the notion that adiposity is a highly heritable trait, with the estimated genetic contribution ranging between 40 and 70% [3]. Although most genes that influence human obesity are unknown, studies of single gene disorders leading to extreme obesity have provided insight into the regulation of body weight [4]. Spontaneous monogenic mutations in rats have led to human investigation for monogenic obesity syndromes. Approximately 20 different genes have been implicated in human monogenic causes of obesity but they only account for less than 5% of all severe obesity cases [4]. Mutations in the leptin–melanocortin pathway have been linked to alterations in energy balance in humans with a resultant increase in hyperphagia, commonly observed in obese individuals. The leptin–melanocortin pathway is the regulatory mechanism of energy homeostasis. Leptin is a protein produced predominantly in the fat cells of tissues and is secreted in response to increased energy stores, which correlates with fat mass and BMI. Leptin crosses the blood–brain barrier, activating a series of reactions in the arcuate nucleus of the hypothalamus. Disruptions in this pathway lead to alterations in the satiety signal and energy homeostasis. Gene mutations involving leptin and the leptin receptor, α-melanocyte-stimulating hormone and its receptor, melanocortin 4 receptor and proopiomelanocortin, have been described in several cases of morbidly obese patients [5]. Individuals may be homozygous or heterozygous for these conditions with varying phenotypic expressions. Congenital leptin deficiency is a rare autosomal recessive disorder resulting from a homozygous mutation in the leptin gene. The extremely low levels of leptin usually results in severe, early-onset childhood obesity, hyperphagia and lack of pubertal development. Thyroid and growth hormone dysfunction are also seen in these individuals owing to the fact that leptin regulates prohormone convertase, which is necessary for the synthesis of thyrotropin-releasing hormone and growth hormone-releasing hormone [4]. Congenital leptin deficiency is unique because it can be treated with exogenous leptin, which results in profound weight loss, reduction in body fat mass and resumption of normal pubertal development in treated children. Other mutations in genes that affect neuro-development resulting in obesity include single minded-1, brain-derived neurotrophic factor and tropomyosin-related kinase B. These genes regulate differentiation and proliferation of neurons during development, with mutations resulting in impaired cognition, memory loss, hyperphagia and obesity. The exact roles of these genes in the development of adult obesity remain unclear [4].
Gestational weight gain, reproductive health & adverse pregnancy outcomes Gestational weight gain
One way to potentially decrease obesity in women of reproductive age is to curtail the amount of weight gained during and retained after pregnancy. In 1990, the Institute of Medicine (IOM) issued guidelines for weight gain during pregnancy, which were recently revised in May 2009 in order to address the issues of gestational weight retention and obesity in reproductive age women. The IOM now recommends that women who have a BMI score of less than 18.5 should gain 28–40 pounds during pregnancy; women with a BMI score of 18.5-24.9 should gain 25–35 pounds during pregnancy; women with a BMI score of25-29.9 should gain 15–25 pounds during pregnancy; and women with a BMI score over 30 should gain 11–20 pounds during pregnancy. Using the 1990 IOM guidelines as a reference point, in 1998, Schieve et al. reported that only 36% of non-Hispanic white women, 33% of non-Hispanic black women and 36% of Hispanic women included in the sample gained weight within the IOM recommended range [6]. Additional data from the Nutrition Surveillance System in the USA demonstrated that approximately 37% of women gained more that the IOM recommendations in 1993 and, in 2004, the number increased to 46%. Retaining a significant amount of weight after pregnancy leads to obesity and other health risks later in life. In 2002, Rooney and Schauberger examined a cohort of women over a 10-year period and reported that the most significant predictors of weight change at long-term follow-up (~8.5 years) were weight gained during pregnancy and weight retention at 6-months postpartum [7]. In 2003, Linne and colleagues conducted a longitudinal study of participant weight gain during pregnancy and at 1 and 15-years postpartum using questionnaires [8]. Women who were of normal weight before pregnancy and of normal weight at 15-years postpartum were compared with those who were of normal weight before pregnancy and had become overweight at 15 years postpartum. The authors concluded that the participants who had become overweight at 15-years postpartum had gained more weight during the index pregnancy and had retained more weight at 1-year postpartum. It will be interesting to see what percentage of women gain above the new IOM guidelines and if any long-term difference in postpartum weight retention will be seen, now that practitioners are paying more attention to this subject matter.
Reproductive health
Obesity has a negative impact on reproductive health. Menstrual irregularities are common in both overweight and obese women, starting in the adolescent years and extending into adulthood. Spontaneous abortion after natural conception and after using assisted reproductive technology is increased in obese and morbidly obese women compared with women who have a normal BMI [9,10]. In 2004, Lashen and colleagues conducted a matched case–control study and reported a significantly higher risk of early miscarriage and repetitive early miscarriage in spontaneous conceptions among obese patients compared with normal-weight controls [11]. In 2007, Masheshweri et al. documented similar results among overweight and obese women after assisted reproduction [12]. Assisted reproductive technologies, including IVF, intracytoplasmic sperm injection and gamete intrafallopian tube transfer, are associated with a longer duration of gonadotrophin stimulation, more frequent cycle cancellations, lower numbers of oocytes retrieved and lower pregnancy rates in obese women [9]. Speculation regarding the reduced pregnancy rates in obese women following spontaneous conception, as well as following IVF and intracytoplasmic sperm injection, is focused on the changes in endocrine hormones associated with obesity. Leptin is thought to inhibit ovarian follicular development. Furthermore, circulating insulin, which is increased in obese women secondary to peripheral tissue resistance, results in increased ovarian androgen production, which can lead to menstrual irregularities and difficulty with conception. Obesity is a common feature of polycystic ovarian syndrome (PCOS), the most frequently encountered endocrine disorder in women of reproductive age and one of the most common causes of secondary amenorrhea. Although obesity is not required to diagnose PCOS, it is estimated that as many as 50% of patients with PCOS are obese, depending on the race of the population studied [13].
Maternal & fetal outcomes
Obesity increases morbidity for both mother and infant and is associated with a variety of adverse pregnancy outcomes. Multiple studies have attempted to link obesity with an increased risk for congenital anomalies, including neural tube, abdominal wall and cardiac defects, but the reported results are conflicting. In 2008, Rasmussen et al. conducted a meta-analysis with regard to the association of obesity and neural tube defects [14]. Data from 12 studies were included. Data were presented for obese and severely obese pregnant women in 11 and five studies, respectively, and were compared with normal-weight pregnant women. The authors concluded that maternal obesity is associated with a 1.7-fold increased risk and that severe obesity is associated with a greater than threefold increased risk for neural tube defects. Another meta-analysis on this subject was conducted by Stothard et al. in 2009 [15]. Of the studies that were analyzed, 39 met the criteria for inclusion, and various congenital malformations were reviewed. In women who were obese at the start of pregnancy, the metaanalysis demonstrated a significantly increased risk for neural tube defects, including spina bifida, cardiovascular anomaly, cleft lip and palate, anorectal atresia, hydrocephaly and a limb reduction anomaly. The mechanism of action for the observed associations between obesity and birth defects is unknown. Possible explanations include increased serum glucose from undiagnosed pregestational diabetes, increased serum insulin, triglycerides and uric acid, chronic hypoxia and failed detection of the fetus with a sonogram leading to delivery of infants that some patients may have elected to terminate. Obese women may have lower serum folic acid levels when compared with their normal-weight counterparts, which could potentially explain the increased neural tube defects. Furthermore, suboptimal ultrasound visualization of both fetal cardiac and craniospinal structures is more likely in obese compared with nonobese women [16].
Additional obstetrical complications associated with maternal obesity include hypertensive disorders, gestational diabetes and stillbirth. Gestational diabetes mellitus (GDM) is well-established as a consequence of obesity in pregnancy, with one study reporting the odds ratio (OR) of developing GDM to be 2.6 for obese women and 4.0 for morbidly obese women, respectively [17]. Other studies have demonstrated similar findings, with a two- to threefold increase in the rate of GDM in obese compared with nonobese women [18,19]. In an overview of 13 cohort studies, O'Brien et al. observed a consistent and linear rise in the risk for pre-eclampsia with increasing prepregnancy BMI [20]. In a prospective, population-based cohort study in 2004, Cedergren compared 3480 women with morbid obesity (BMI: >40) and 12,698 women with obesity (BMI: between 35.1 and 40) with women of normal weight (BMI: 19.8–26) [21]. A threefold increased risk of antepartum stillbirth (after 28 weeks) in the group of morbidly obese women was observed. Morbid obesity (BMI: >35) increases the risk of birthweights greater than 4000 g (OR: 2.1; 95% CI: 1.3-3.2) [17]. Reports regarding the risk for urinary tract infections, intrauterine growth restriction, spontaneous preterm labor and postpartum hemorrhage are conflicting and more research in obese patients is needed in these areas.
A meta-analysis performed by Chu et al. in 2007 estimated that the risk of having a cesarean delivery was approximately two- and three-times higher among obese and severely obese women, respectively, compared with women of normal weight. In addition, the majority of these deliveries were performed during the first stage of labor and based on indications of dystocia and fetal distress [22]. The reason for this increased rate of cesarean delivery in obese women is unknown but could be related to maternal pelvic soft tissue dystocia, fetal macrosomia (inability to accurately perform Leopolds maneuver, which is a systematic way to determine the position, presentation and size of a fetus), inadequate pelvimetry and intrapartum complications (e.g., inability to adequately monitor the fetus and contractions). In a retrospective chart review, Durnwald et al. demonstrated that successful vaginal birth after one previous cesarean section significantly decreased with increasing pregravid BMI [23]. Indeed, macrosomia is common among the offspring of obese mothers. Weiss and colleagues reported that the OR of delivering an infant greater than 4000 g were 1.7 and 2.0 for obese and morbidly obese women, respectively, compared with women of normal weight [17]. Observational studies have also found that infants of overweight and obese mothers are 60–100 g heavier than those of normal-weight women, thus increasing the risk of birth trauma. Anesthetic complications, including difficult epidural and spinal anesthesia, difficult maternal intubation and increased risks for aspiration pneumonia and death, have been observed in population-based studies. In 1988, Endler et al. reported that, out of 15 obstetrical deaths related to anesthesia, 12 patients were obese [24]. In 1989, Sachs et al. reported similar findings [25]. Poor surface land-marks, patient positioning and deeper depths make the induction of regional anesthesia more difficult in obese gravidas. Clinkscales and colleagues found a significant positive correlation between BMI and depth to lumbar epidural space in pregnant obese women undergoing epidural anesthesia [26]. In addition, smaller airways secondary to increased soft tissue may make rescue intubations more difficult in this patient population. Obesity also increases the risk of venous thromboembolism. Using a large, nationwide database, James et al. determined the incidence of venous thromboembolism during pregnancy and the postpartum period for their population. The authors demonstrated a fourfold increased risk for thromboembolic events in obese patients [27].
Reproduction following bariatric surgery
Surgery as a treatment for morbid obesity was first performed in the 1960s. In 1991, the NIH issued guidelines for the surgical therapy of morbid obesity, collectively referred to as bariatric surgery. The NIH recommended that patients with a BMI score greater than or equal to 40 are potential candidates for bariatric surgery and that patients with a BMI score greater than or equal to 35 with comorbidities such as cardiopulmonary issues, diabetes, difficult ambulation and joint disorders as a result of their weight, may also be considered for these procedures. The NIH did not make any recommendations regarding bariatric surgeries for adolescents and children [28].
Bariatric surgery procedures are on the rise. A recent meta-analysis revealed that the incidence of inpatient bariatric procedures increased by 800% between 1995 and 2005, with women accounting for 83% of procedures carried out in those aged between 18 and 45 years [29]. According to recent estimates, bariatric surgeries among adolescents increased more than fivefold between 1997 and 2003, from 51 to 282 procedures, with girls comprising over 70% of these patients [30]. The laparoscopic approach has increased the popularity of bariatric surgery, as well as decreasing the length of hospital stay and some morbidity associated with these procedures. Bariatric surgery has been demonstrated to be an effective weight loss tool, and patients who have undergone these procedures have experienced complete resolution or improvement in chronic comorbid conditions, such as chronic hypertension, Type 2 diabetes, obstructive sleep apnea and hyperlipidemia [31]. Nevertheless, these procedures are not without risk, and these risks will depend on the patient's age, comorbid conditions and degree of obesity.
After bariatric surgery, many women improve for conditions such as irregular menses and anovulation. In 2006, Teitelman et al. conducted a survey of women who underwent bariatric surgery. Of 98 patients who were anovulatory before the procedure, 71.4% (70 patients) regained normal menstrual cycles after surgery [32]. The authors concluded that menstrual disorders may completely resolve after bariatric surgery, although infertility and menstrual disorders are not indications for carrying out this procedure. Other studies have also documented an improvement in PCOS following weight reduction surgery [33]. Many women remain obese during conception even after the procedure since they have not fully accomplished their maximum weight loss, and the timing from weight reduction surgery to conception has been the subject of numerous case–control studies and case reports. In 2006, Dao et al. conducted a retrospective review over a 3-year period and compared pregnancy within 1 year of bariatric surgery (early group) with pregnancy after 1 year (late group) [34]. The study was limited to a small number of subjects, but the authors reported a trend towards more miscarriages in the early compared with the late group. Other pregnancy complications, including fetal weight, did not differ between the two groups. Others have documented contradictory findings. In 2008, Patel et al. conducted a retrospective chart review to investigate the safety of laparoscopic Roux-en-Y gastric bypass (LRYGB) and its potential effect on obesity-related perinatal complications [35]. In the review, 26 patients who delivered after LRYGB and 254 controls were included. The perinatal complications in the LRYGB patients were similar to those experienced by the nonobese controls and lower than in the obese and severely obese controls, although statistical significance was not noted for all complications. No spontaneous abortions or stillbirths occurred in the LRYGB patients and no LRYGB patients required intravenous nutrition or hydration. When the early group (<12 months after LRYGB) was compared with the late group (>18 months after LRYGB), the pregnancy complication rates were similar. The study was also limited by a small sample size.
The review articles of Maggard et al. and Guelinckx et al. acknowledge that reproductive outcomes after bariatric surgery is a pertinent topic, but large studies on this topic are lacking [29,36]. After conducting an intensive review of available articles on this subject matter, Guelinckx noted that most studies are too underpowered to detect possible significant differences in certain perinatal outcomes [36]. In addition, no homogeneity exists in the control groups of the case–control studies and, in some studies, subjects served as their own controls. One set of authors concluded that the danger of the methodological weaknesses of these studies is that they lead to under-reporting of perinatal complications after bariatric surgery. Although review studies have demonstrated a decrease in pregnancy complications, such as pregestational diabetes, gestational diabetes, gestational hypertension and preeclampsia after bariatric surgery, others have documented an increase in failed induction of labor, preterm premature rupture of membranes and cesarean deliveries [29]. Owing to the potential for numerous perinatal complications, both obstetricians and surgeons should consider pregnancy after bariatric surgery as high risk, requiring attention to weight gain/loss, presence of nutritional deficiencies and serial fetal ultrasound to detect fetal growth restriction [36]. Gastrointestinal complaints such as nausea, vomiting and vague abdominal pain, which are common during pregnancy, may indicate a more serious diagnosis in patients who have had bariatric surgery. Case reports have documented bowel strangulation, small bowel volvulus and intestinal obstruction following weight loss surgery. Although these complications are probably rare, complications from bariatric surgery may manifest in pregnancy and should be considered in patients with persistent gastrointestinal complaints.
Future perspective
The rate of obesity may continue to increase among women, especially women of reproductive age. This increase in obesity will also be accompanied by increases in Type 2 diabetes and earlier-onset cardiovascular disease. The recently revised IOM guidelines regarding the recommended weight gain in pregnancy is an attempt to address this epidemic among women of reproductive age; however, future studies are needed in order to determine if this will be effective in decreasing excessive weight retention postpartum. Future research is also needed in the areas of diet, nutrition and exercise during pregnancy for the obese gravida and her offspring.
Research is currently underway to further clarify the roles of monogenic mutations in adult obesity syndromes. The leptin–melanocortin pathway continues to be the target of research, and promising results are on the horizon, including the utilization of leptin-sensitizing agents, which could represent a treatment option for obese patients who have leptin resistance. The leptin–melanocortin pathway is just a small piece of a very complex puzzle. Further investigation into the specific roles of melanocortin receptor 4 and other hypothalamic receptors may aid in the development of therapeutic modalities for this heterogeneous disorder. Practitioners who take care of women will prove to be the primary contenders in the medical efforts against obesity and should use every encounter with an obese woman as an opportunity for dietary and exercise counseling.
Executive summary
Obesity is defined as a BMI score greater than or equal to 30.
In the USA, over 72 million adults are obese, with an estimated US$117 billion spent annually on obesity-related health conditions.
Obesity is a complex, multifactorial chronic disease that is influenced by genetic, endocrine, metabolic, environmental, cultural, behavioral and psychological factors.
Approximately 20 different genes have been implicated in human monogenic obesity but they only account for less than 5% of all severe obesity cases.
Mutations in the leptin–melanocortin pathway have been linked to alterations in energy balance in humans.
Congenital leptin deficiency is unique because it can be treated with exogenous leptin, which results in profound weight loss and resumption of normal pubertal development in treated children.
The Institute of Medicine made revisions to its previous guidlines regarding the recommended amount of weight gain during pregnancy in May 2009.
In 2004, approximately 46% of women gained more weight during pregnancy than the Institute of Medicine recommends.
Spontaneous abortion after natural conception and utilization of assisted reproductive technology is increased in obese and morbidly obese women compared with women who have a normal BMI score.
Obesity is associated with an increased risk of congenital malformations including neural tube defects, cardiac malformations and cleft lip/palate.
Pregnancy in the obese gravida is associated with a variety of adverse outcomes, including hypertensive disorders, gestational diabetes, difficulty with anesthesia and abnormal labor.
The incidence of bariatric surgery is increasing in women of reproductive age, as well as in adolescent girls.
Bariatric surgery is an effective weight loss tool but is associated with adverse complications in the immediate postoperative period and beyond.
Common pregnancy-related complaints, such as nausea, vomiting and vague abdominal pain, may indicate a more serious diagnosis in pregnant women who have previously undergone bariatric surgery.
Footnotes
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
No writing assistance was utilized in the production of this manuscript.