Almost half of reproductive aged women in the United States are overweight or obese (1Practice Committee of the American Society for Reproductive Medicine
Obesity and reproduction: a committee opinion.). Given this prevalence, along with the fact that obesity has been demonstrated to impair reproduction in men and women, it is imperative to understand comprehensively the relationship between obesity and reproductive outcomes (1Practice Committee of the American Society for Reproductive Medicine
Obesity and reproduction: a committee opinion.). It has been established that female obesity can cause changes in the hypothalamic-pituitary-ovarian axis leading to menstrual irregularities and ovulatory dysfunction (2Broughton D.E. Moley K.H. Obesity and female infertility: potential mediators of obesity’s impact.). Additionally, women with obesity have a longer time to conception, decreased fecundity ratios, increased rates of miscarriage, and decreased live birth rates (1Practice Committee of the American Society for Reproductive Medicine
Obesity and reproduction: a committee opinion., 2Broughton D.E. Moley K.H. Obesity and female infertility: potential mediators of obesity’s impact.). Obesity also has been associated with reduced live birth rates after in vitro fertilization (IVF), suggesting that factors beyond ovulatory dysfunction affect reproductive success (2Broughton D.E. Moley K.H. Obesity and female infertility: potential mediators of obesity’s impact.). Despite this knowledge, it remains unclear why obesity is associated with impaired reproductive outcomes. Proposed etiologies fall into three main categories: effects on the oocyte, the embryo, and the endometrium (1Practice Committee of the American Society for Reproductive Medicine
Obesity and reproduction: a committee opinion., 2Broughton D.E. Moley K.H. Obesity and female infertility: potential mediators of obesity’s impact.).In this month’s issue of Fertility and Sterility, Stovezky et al. (3

Stovezky Y, Romanski PA, Bortoletto P, Spandorfer SD. Body mass index is not associated with embryo ploidy in patients undergoing in vitro fertilization with preimplantation genetic testing. Fertil Steril. In press.

) evaluated whether increases in aneuploidy may be the cause of impaired reproductive outcomes in women with obesity. They examined whether there was an association between body mass index (BMI) and embryonic aneuploidy and mosaicism in women undergoing IVF with trophectoderm biopsy for preimplantation genetic testing for aneuploidy (PGT-A). In this retrospective cohort study of 1,750 women undergoing their first cycle of IVF with PGT-A, no relationship between BMI and number or proportion of aneuploid, mosaic, or euploid embryos was found in an age-adjusted model. These results were supported further when the investigators did a subgroup analysis, stratifying women by age (40 years), and found no association between BMI and ploidy status of embryos.The findings presented by Stovezky et al. (3

Stovezky Y, Romanski PA, Bortoletto P, Spandorfer SD. Body mass index is not associated with embryo ploidy in patients undergoing in vitro fertilization with preimplantation genetic testing. Fertil Steril. In press.

) are concordant with other studies suggesting that aneuploidy rates are not higher in women with obesity who undergo IVF with PGT-A and that women with obesity have higher miscarriage rates after euploid embryo transfer (4Goldman K.N. Hodes-Wertz B. McCulloh D.H. Flom J.D. Grifo J.A. Association of body mass index with embryonic aneuploidy., 5Cozzolino M. García-Velasco J.A. Meseguer M. Pellicer A. Bellver J. Female obesity increases the risk of miscarriage of euploid embryos.). Additionally, in studies that have examined products of conception after miscarriage, lower or similar rates of aneuploidy have been reported in women who are overweight or obese (5Cozzolino M. García-Velasco J.A. Meseguer M. Pellicer A. Bellver J. Female obesity increases the risk of miscarriage of euploid embryos.). Together, these findings suggest that a mechanism other than embryonic aneuploidy may underlie inferior reproductive outcomes in women with obesity. However, it is possible that the technology of PGT-A and cytogenetics, while able to capture ploidy status, is unable to identify other markers of impaired chromosomal or cellular function, such as epigenetic methylation or dysfunctional mitochondria, that may influence reproductive outcomes in ways yet unknown.If embryonic aneuploidy is not increased and, therefore, cannot be deemed responsible for increased miscarriage rates in women with obesity, altered endometrial receptivity may offer an alternative explanation (2Broughton D.E. Moley K.H. Obesity and female infertility: potential mediators of obesity’s impact.). Mouse models have shown impaired decidualization associated with obesity, a necessary component in the process of endometrial receptivity. Interestingly, data regarding the effect of obesity in women undergoing donor-oocyte embryo transfers are mixed (3

Stovezky Y, Romanski PA, Bortoletto P, Spandorfer SD. Body mass index is not associated with embryo ploidy in patients undergoing in vitro fertilization with preimplantation genetic testing. Fertil Steril. In press.

). While some studies have found maternal BMI to be associated with clinical pregnancy and miscarriage rates, other data have not supported an association (2Broughton D.E. Moley K.H. Obesity and female infertility: potential mediators of obesity’s impact.). Conflicting results make it challenging to draw clear conclusions on whether obesity negatively impacts the endometrium.This well-designed study by Stovezky et al. (3

Stovezky Y, Romanski PA, Bortoletto P, Spandorfer SD. Body mass index is not associated with embryo ploidy in patients undergoing in vitro fertilization with preimplantation genetic testing. Fertil Steril. In press.

) has a number of strengths. The large size of the cohort allows for meaningful comparisons between groups with different BMIs. Further, the investigators only studied women undergoing their first IVF attempt, which should have limited selection bias toward patients with a history of reproductive failure. However, it also is important to consider the limitations of this study. We would argue that the biggest limitation of examining the relationship between obesity and aneuploidy is the use of BMI as a measure of health. Although it is the most used objective measure of weight available, BMI is actually a symptom of many other factors and not a disease in and of itself. BMI can be altered by insulin resistance, thyroid dysfunction, obstructive sleep apnea, dysfunctional eating, poor nutrition, and limited activity, among others. By focusing on BMI and not assessing the variables that lead to increased BMI, a very complex metabolic situation is simplified. This is important to recognize given that not all women who have the same BMI are identical in terms of how reproductive outcomes are influenced. While BMI is a useful marker in clinical studies, it does not explain the many metabolic complexities that impact overall health and reproduction of individual patients. Simply stated, not all women who have a BMI that classifies them as overweight or obese should be viewed as identical.The findings presented by Stovezky et al. (3

Stovezky Y, Romanski PA, Bortoletto P, Spandorfer SD. Body mass index is not associated with embryo ploidy in patients undergoing in vitro fertilization with preimplantation genetic testing. Fertil Steril. In press.

) raise important clinical questions regarding how to best counsel and manage patients with obesity who desire to conceive. If BMI does not appear to be associated with ploidy status, is the cause of impaired reproductive outcomes treatable with lifestyle modifications? Although there is some evidence that individuals who are able to achieve and sustain weight loss have improved rates of conception, require fewer treatment cycles, and have increased live birth rates, the data are not conclusive (2Broughton D.E. Moley K.H. Obesity and female infertility: potential mediators of obesity’s impact.). Studies on the effect of weight loss on fertility are limited by poor adherence to protocols and high study discontinuation rates (2Broughton D.E. Moley K.H. Obesity and female infertility: potential mediators of obesity’s impact.). There also is limited evidence regarding the impact of bariatric surgery on fertility outcomes (1Practice Committee of the American Society for Reproductive Medicine
Obesity and reproduction: a committee opinion., 2Broughton D.E. Moley K.H. Obesity and female infertility: potential mediators of obesity’s impact.). Given the absence of clear evidence, it is not possible to simply counsel patients that “weight loss” will reverse the impact of obesity on reproductive success. Going a step further, instead of focusing on “weight loss,” we believe that there should instead be a promotion of “well-being.” Women should be encouraged to address their “well-being” by improving nutrition, increasing physical activity and working to treat their medical comorbidities that contribute to higher BMIs. With these measures, weight loss is likely to occur, but even if weight loss is not profound, it seems inevitable that a healthier maternal state will lead to improved outcomes.

Another clinically relevant question to ponder is if women with obesity have decreased success with IVF but produce equivalent numbers of euploid embryos, how do we prioritize IVF while optimizing maternal health before conception to improve live birth rates and decrease pregnancy complications? The data on euploidy rates among women with obesity suggest maternal age remain the strongest predictor of embryo ploidy status. Given this, perhaps there should be a focus on cryopreserving oocytes or embryos at younger ages despite elevated BMIs and then working to optimize health before pregnancy. Many practices require patients to achieve a certain BMI before starting the IVF process. However, knowing that healthy weight loss can require significant time and that aneuploidy rates increase with maternal age but not with increasing BMI, then perhaps the aim instead should be to retrieve oocytes in women with obesity at as young an age as possible. There may not be a reason for women with obesity to wait to conceive at all, but certainly these data suggest that holding to retrieve oocytes until an optimal BMI is achieved will lead to increased aneuploidy rates from increasing maternal age. Ultimately, is it worth the “weight” to delay IVF in women with obesity? Perhaps as a field we should reconsider this and prioritize oocyte or embryo cryopreservation as an initial step while focusing on improvement of “well-being” before embryo transfer is performed.

ReferencesPractice Committee of the American Society for Reproductive Medicine

Obesity and reproduction: a committee opinion.

Fertil Steril. 104: 1116-1126Broughton D.E. Moley K.H.

Obesity and female infertility: potential mediators of obesity’s impact.

Fertil Steril. 107: 840-847

Stovezky Y, Romanski PA, Bortoletto P, Spandorfer SD. Body mass index is not associated with embryo ploidy in patients undergoing in vitro fertilization with preimplantation genetic testing. Fertil Steril. In press.

Goldman K.N. Hodes-Wertz B. McCulloh D.H. Flom J.D. Grifo J.A.

Association of body mass index with embryonic aneuploidy.

Fertil Steril. 103: 744-748Cozzolino M. García-Velasco J.A. Meseguer M. Pellicer A. Bellver J.

Female obesity increases the risk of miscarriage of euploid embryos.

Fertil Steril. 115: 1495-1502Article InfoPublication History

Published online: July 04, 2021

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DOI: https://doi.org/10.1016/j.fertnstert.2021.06.004

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©2021 American Society for Reproductive Medicine, Published by Elsevier Inc.

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