The prevalence of obesity is growing among reproductive-age women. This is concerning because obesity has significant health-related consequences. Aside from the long-term risks of diabetes, heart disease, and some types of cancer, obesity poses immediate threats for young women including subfertility and adverse early and late pregnancy outcomes. Epidemiologic and experimental studies demonstrate associations between prepregnancy obesity and poor reproductive outcomes; however, the mechanisms involved are poorly understood. We discuss current knowledge of the pathophysiology of obesity in early reproductive events and how these events may affect reproductive outcomes including fertility and miscarriage risk. We also discuss avenues for future research and interventions to improve reproductive outcomes for obese women.
Almost a quarter of reproductive-age women in the United States are obese, with a body mass index (BMI) of 30 kg/m 2 or greater. This figure is worrisome because obesity may jeopardize long-term health with increased risks of type 2 diabetes, cardiovascular disease, and some types of cancer.
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Of more immediate concern for reproductive-age women, obesity is associated with increased risks of subfertility. For those who do conceive, obesity has been associated with increased risks of miscarriage, preeclampsia, and congenital anomalies in the offspring. Of further concern, emerging evidence suggests that children born to obese mothers are at increased risk for obesity, type 2 diabetes, and cardiovascular disease later in life, perhaps the result of epigenetic modification of the embryonic genome in response to the alterations of the in utero environment in the setting of maternal obesity ( Table 1 ).
| Outcome | Odds ratio (95% CI) | Reference | Type of study | Patients, n |
|---|---|---|---|---|
| Subfertility | 2.2 (1.8–2.6) | Nohr et al | Prospective cohort | 4901 |
| Miscarriage | 1.67 (1.25–2.25) | Metwally et al | Metaanalysis | 2257 |
| Various fetal anomalies | 1.2 (1.03–1.4, cleft lip and palate); 2.24 (1.86–2.69, spina bifida) | Stothard et al | Metaanalysis | 863; 1188 |
| Large for gestational age | 2.3 (1.9–2.7) | Nohr et al | Prospective cohort | 4901 |
| Preeclamspia | 1.6 (1.1–2.25, obese vs nonobese); 3.3 (2.4–4.5, morbidly obese vs nonobese) | Weiss et al | Prospective cohort | 15,225; 14,629 |
| Obesity in the offspring at age 1 y (BMI ≥95th percentile) | 1.9 (1.3–2.6) | Nohr et al | Prospective cohort | 4901 |
Interventions aimed at improving reproductive outcomes for obese pregnant women often focus on limiting weight gain during pregnancy ; however, many of the risks of obesity in pregnancy may be linked to abnormalities in reproductive events occurring preconceptionally and early in pregnancy including abnormalities in events of oocyte recruitment and development, ovulation, preimplantation embryonic development, and implantation,
Although managing weight gain during pregnancy may be helpful in preventing some adverse outcomes in obese pregnancy, such intervention does not address abnormalities in events that have already occurred. Accordingly, increased intervention for weight loss and increased efforts in counseling of the risks of obesity to reproductive potential and outcome should also be undertaken by clinicians working with reproductive-age women. For obese women who do conceive, research elucidating the pathophysiology of obesity in early reproductive events may help shed light on effective interventions for preventing the adverse pregnancy outcomes that weight management in pregnancy has not been able to address.
Obesity and ovulation
Increased incidence of subfertility among obese women may be attributed in part to the frequent cooccurrence of obesity with polycystic ovary syndrome (PCOS), a relatively common condition characterized by hyperandrogenism and anovulation and associated with insulin resistance. PCOS is not uncommon in women of normal weight; however, in obese women insulin resistance may lead to clinical features consistent with PCOS.
Insulin resistance and hyperinsulinemia consequent of obesity hamper hepatic production of steroid hormone-binding globulin (SHBG) with subsequent hyperandrogenemia. Lower SHBG levels and increased peripheral aromatization of androgens to estrogens in obese women also result in higher free circulating estrogen levels, which may lead to increased negative feedback on the hypothalamic-pituitary axis.
This increased negative feedback adversely affects the gonadotropin secretion that is needed for adequate ovarian follicular recruitment and subsequent ovulation. Weight loss among obese women with PCOS often helps in restoring ovulation and improving chances of conception.
Independent of PCOS, obesity is associated with abnormalities of the hypothalamic-pituitary-ovarian (HPO) axis that may affect the quality of follicular development and ovulation. As a consequence, fertility is decreased, even among obese women with regular menses. In a large study of women participating in the Study of Women’s Health Across the Nation (SWAN), a BMI increasing greater than 25 kg/m 2 was associated with a longer follicular phase and a shortened luteal phase. A further detailed study conducted by some of the same researchers demonstrated decreased luteinizing hormone (LH) amplitude and mean serum LH levels in cycling obese women compared with women of normal weight, possibly leading to a shortened luteal phase.
Whereas the concept and definition of the luteal phase deficiency and its role in fertility have long been debated, shorter luteal phases theoretically could affect endometrial development and subsequent embryo implantation. If this problem did exist in obese women, it could explain in part findings demonstrating that obesity may be associated with increased risk of miscarriage in spontaneous conceptions and decreased embryonic implantation rates in obese women receiving donor oocytes after in vitro fertilization (IVF).
The mechanism responsible for the observed decreased LH pulse amplitude in obese women is unknown. Several theories exist including interference of adipokine hormones or hormones made by adipose tissue, including leptin, tumor necrosis factor (TNF)-alpha, or interleukin-1beta, with the pituitary response to gonadotropin-releasing hormone. Although some work has been done to investigate the effects of obesity on the HPO axis and infertility in animal models, further work examining these relationships in women is needed.
Obesity and the oocyte
Insight into the importance of maternal physiology on oocyte quality can be demonstrated in experimental animal models of maternal diabetes in which there is an increase in granulosa cell apoptosis of the ovarian follicle and impaired oocyte maturation. Similar to diabetes, obesity is a condition marked by aberrations in circulating levels of substrates for energy production, and it too appears to have effects on oocyte quality. Visually, these effects appear to be primarily on oocyte maturation, although there are data suggesting that even subjectively normal oocytes are altered at the molecular level by conditions like PCOS.
These alterations are in genes associated with chromosome alignment and segregation during mitosis and/or meiosis and in genes associated with peroxisome proliferator-activated receptors, receptors important to cellular growth and development in the fetus and known to be activated by thiazolidinedione drugs. Thiazolidinedione drugs have been shown to improve oocyte competence as measured by embryonic development in mouse models of maternal obesity and to induce ovulation in women with PCOS.
There are a variety of factors that may impair oocyte maturation in obese women including abnormalities in ovarian follicular recruitment and development due to blunted LH amplitude as discussed earlier. On the other hand, there is evidence that the follicular environment in which the oocyte develops and matures is altered in obese women compared with nonobese women.
Because these differences are noted in women undergoing IVF during which exogenous gonadotropins are used to achieve follicular recruitment and development, it is unlikely that the abnormalities are the result of obesity-related HPO axis dysfunction. Instead, it may be that some component of obesity alters composition of the follicular fluid directly, which could influence oocyte metabolism or metabolism of the cells that support the developing oocyte and follicle including granulosa cells, cumulus cells, and theca cells.
Changes in the metabolism of these cells could further alter the composition of follicular fluid. Alterations noted in follicular fluid from obese women include increased insulin, glucose and lactate, increased androgen activity, increased C-reactive protein, and decreased human chorionic gonadotropin levels. There is also evidence that follicular leptin levels correlate with BMI. In vitro studies have shown that leptin impairs steroidogenesis in granulosa cells, and such an impairment could also have an impact on follicular development, oocyte quality, and ovulation in obese women.
Further work is needed to determine how oocyte quality specifically influences pregnancy outcome for obese women; however, as mentioned in previous text, data from animal models of obesity and type 1 diabetes mellitus demonstrate that poor maternal physiology affects oocyte quality. In the case of type 1 diabetes, these affected oocytes predispose to an increased risk of fetal abnormalities including congenital anomalies and fetal growth restriction, perhaps via adverse effects on the meiotic spindle of the oocyte or on mitochondrial structure and function.
Similar to diabetes, obesity is also a condition of abnormal maternal physiology. Although laboratory evidence supports a role for poor oocyte quality as a factor in adverse reproductive outcomes in the setting of obesity, clinical evidence is lacking.
One avenue to consider exploring for additional information regarding relationships between oocytes and pregnancy outcome is data from donor oocyte cycles in clinical IVF practice. One published abstract suggests donor oocytes taken from obese women do not affect live birth rates in recipient women of normal weight; however, the numbers of patients included in the study were too small (64 IVF cycles using oocytes from normal-weight women vs 8 IVF cycles using oocytes from donors who were obese) to adequately control for potential confounding factors.
On the other hand, some IVF centers may restrict oocyte donation to women of normal weight because overweight and obese women are known to require additional gonadotropin stimulation in their IVF cycles, and they often produce fewer oocytes, which can increase the cost of an IVF cycle. Because of this exclusion, it may be difficult to find existing data to explore this question further. National IVF databases such as those compiled by the Society for Assisted Reproductive Technology may provide adequate numbers for future study and are worth pursuing.
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