Keywords
obesity - in vitro fertilization - assisted reproductive technology - infertility
Obesity is a highly prevalent chronic disease that affects over 600 million adults worldwide. Within developed nations, the United States experiences significantly higher obesity rates, with over 40% of American adults meeting criteria for obesity based on 2018 data.[1] Since 1960, the number of individuals with obesity in the United States has doubled. This trend also extends to women of reproductive age, with nearly 30% of U.S. women found to have obesity immediately prior to pregnancy. Additionally, the prevalence in this group increased by 11% over just a 3-year time period.[2]
The impact of obesity on reproductive-aged women is profound and is correlated with numerous reproductive risks and complications both prior to and during pregnancy. Obesity is associated with anovulation, longer-time to pregnancy, infertility, increased rates of miscarriage, and several obstetrical risks, both maternal and fetal.[3]
[4] While the clinical impact of obesity on female reproduction is well reported, the effect of weight loss on improving fertility outcomes beyond improvements in ovulation is less clear.[3]
[4]
Reproductive care specialists are faced with the challenge of treating infertility in the setting of steadily increasing rates of obesity. There are several fertility treatments available to women with infertility ranging from oral and injectable medications, intrauterine insemination, and in vitro fertilization (IVF). This review will focus on the impact of obesity on IVF including clinical outcomes, limitations to care, and data regarding how various weight-loss strategies may or may not impact IVF outcomes.
Pathophysiology
It is estimated by the World Health Organization that approximately one in every six people of reproductive age worldwide experiences infertility in their lifetime.[5] Many women with obesity can achieve pregnancy naturally despite their weight. However, women with overweight and obesity often have a longer time to pregnancy, and increased rates of infertility.[6]
The relationship between excess adipose accumulation and infertility is complex and multifactorial. The most comprehensively understood link between obesity and reduced fertility lies in the distinction between regular ovulation and irregular or absence of ovulation. Hormonal imbalances, along with a combination of disorders related to insulin, low levels of sex hormone binding proteins, and elevated androgen levels, contribute to this phenomenon. Collectively, these factors disrupt the secretion of hypothalamic gonadotropin hormones, leading to a decrease in both the quantity of mature ovarian follicles and progesterone levels during the menstrual cycle.[7]
Adipose tissue serves as a multifunctional endocrine organ responsible for storage and secretion of several factors.[8] Adipose-derived cytokines, called adipokines, have an important function in metabolism and are increasingly being studied for their roles in adiposity-induced subfertility. These adipokines, including leptin, ghrelin, resistin, visfatin, chemerin, omentin, and adiponectin, play a significant role in the regulation of reproductive hormones from the brain as well as ovarian function.[9]
[10] Disruptions or abnormalities in these adipokines can impact reproductive health, such as the exacerbation of polycystic ovary syndrome (PCOS) often seen in women with high adipose tissue levels. Adiponectin receptors, which are ubiquitously expressed in reproductive tissues like the ovaries, endometrium, and placenta, have been associated with recurrent implantation failure when their expression is reduced.[11] Reduced adiponectin may also contribute to decreased endometrial receptivity and an increased risk of diabetes, as adiponectin is involved in glucose uptake in the liver. This impairment affects insulin sensitivity, further linking obesity to insulin resistance and risk of type 2 diabetes mellitus.[12]
Obesity affects ovarian follicles in various ways, often resulting in an altered composition of the follicular fluid in which the oocyte develops. These changes to the follicle environment have been associated with poor follicular development, as well as inhibition of normal ovulation and alterations of follicular function.[13]
[14] Lipolysis, the breakdown of fat, influences the composition of non-esterified fatty acids in follicular fluid. Follicular fluid in individuals with a high body mass index (BMI) contains elevated levels of oleic acid, which is associated with increased embryo fragmentation.[13] At the blastomere stage, elevated levels of stearic acid, also found in the follicular fluid of women with a high BMI, are associated with poor blastomere scores. Leptin, a hormone found in high concentrations in individuals with obesity, has been shown to impair folliculogenesis and reduce ovulation rates. In vitro models also demonstrate direct inhibition of estriol production by granulosa cells.[15] Leptin-rich mice models have also demonstrated impaired folliculogenesis, decreased ovulation rates, and increased apoptosis in granulosa cells.[15]
Impact of Obesity on Assisted Reproduction
Impact of Obesity on Assisted Reproduction
Given the steady increase in obesity rates among reproductive-aged women, reproductive care providers are encountering an increasing number of women with obesity and infertility who require assisted reproductive technology (ART) to build their families. Early studies suggest that women with infertility and obesity may experience overall poorer outcomes when undergoing IVF, ultimately resulting in decreased live birth rates (LBRs).[16] These findings have recently been challenged in some studies as outlined below.
Ovarian Response
Notable ovarian response differences have been reported for women with higher BMIs undergoing IVF. Specifically, women with obesity often require higher starting and overall gonadotropin doses, as well as longer duration of injections for adequate follicular development.[17] Early studies further found that despite higher gonadotropin doses, ovarian stimulation resulted in fewer mature follicles leading to either more frequent cycle cancelations or a decrease in the number of oocytes obtained during egg retrieval.[18]
[19]
[20] There are different proposed mechanisms for the observed decreased response in the setting of obesity. These include a distributional effect given the increased body mass, versus a decrease in ovarian reserve as noted by anti-mullerian hormone (AMH) levels. Indeed, several studies demonstrate that obesity is associated with lower AMH levels.[21]
[22]
Oocyte Quality
In addition to oocyte number, obesity has also been shown to impact oocyte quality. Several studies show that with increasing BMI, graded oocyte quality is reduced, resulting in lower fertilization rates.[18]
[23] Recent research aimed at evaluating the etiology of altered oocyte quality have shown that obesity is associated with dysregulation at the level of the follicle, including altered proteins related to inflammation and metabolism.[24]
[25]
[26] This is a suggested contributor to the finding that women with obesity are also less likely to achieve clinical pregnancy even after IVF embryo transfer.[27]
Donor oocyte models have also suggested intrinsic oocyte quality alterations in the setting of obesity.[28]
[29] For example, Coyne et al found no difference in pregnancy outcomes when oocytes from normal weight donors were transferred to women with obesity. Specially, there were no statistically significant differences in the implantation rates, clinical pregnancy rates, or LBRs per embryo transfer among patients in the three BMI groups.[28]
Embryo Quality
Once fertilized, it has been suggested that resultant embryos may also be of poorer quality, which may ultimately result in an increased risk of miscarriage.[29]
[30] Metwally et al conducted a retrospective analysis of 426 IVF cycles undergoing intracytoplasmic sperm injection (ICSI) with patients stratified by age.[31] They found that while oocyte grade/quality was not compromised in the setting of obesity, embryo quality was significantly decreased in women younger than 35 years with obesity compared with overweight and normal BMI groups of the same age. It is important to note that studies do not appear to show a difference in euploidy/aneuploidy rates in women with obesity.[21]
[32] However, some research suggest that women with obesity do experience an increased risk of miscarriage, even in the setting of chromosomally normal pregnancies.[33]
[34]
Endometrial Receptivity
It is well established that the hyperestrogenic environment associated with obesity leads to a significantly increased risk of complex hyperplasia and endometrial cancer.[35] With obesity having such a pronounced impact on the endometrium, additional studies have investigated the impact of obesity on the endometrium as it relates to implantation. It has been reported that an elevated BMI alters gene expression in the endometrium during the window of implantation. This altered expression was even more evident in women with obesity who also have infertility or PCOS.[36] Bellver et al also assessed whether the use of donor oocytes from women with normal weight would change the observed differences in fertility outcomes between women with and without obesity. They found that implantation, pregnancy, clinical pregnancy, twin pregnancy, and live-birth rates were all significantly reduced as BMI increased.[37] However, similar to the Coyne's study discussed above, a systematic review and meta-analysis found no difference in implantation, clinical pregnancy rates, miscarriage, or live birth according to BMI status when donor oocytes from women with normal weight were used.[28]
[29]
Pregnancy and Live Birth
There is conflicting evidence regarding clinical pregnancy and LBRs in women with obesity undergoing IVF. Some studies report reduced pregnancy and LBRs between 15 and 30% in women with obesity, while others report no difference compared with patients with normal BMIs.[38]
[39]
[40]
[41]
A 2011 meta-analysis of 33 studies was performed to analyze the effect of elevated BMI on clinical pregnancy, miscarriage, and live-birth rates following IVF and ICSI ART cycles. The authors found that women with overweight, defined as BMI > 25, had lower pregnancy outcomes, decreased LBRs, and higher miscarriage rates.[30] One of the largest studies conducted by Provost et al included 239,127 fresh IVF cycles analyzed between 2008 and 2010 from the Society for Assisted Reproductive Technology (SART) registry data, and found progressively worsening rates of implantation, clinical pregnancy live birth with increasing BMI.[42]
More recent data contradict these previous findings and highlights the complexity and heterogeneity of obesity. Akpinar et al found that while patients with obesity required higher doses of gonadotropins and had fewer oocytes, there was no difference in implantation and clinical pregnancy rates.[43] Similarly, the recent Appraisal of Body Content study found no difference in IVF outcomes based on obesity status.[21] This prospective cohort study analyzed nearly 1,900 couples with infertility undergoing IVF and performed bioelectric impedance analysis for body fat percentage and BMI calculations at the time of egg retrieval. Their findings suggest nearly equivalent outcomes between women with obesity and normal weight with the exception of a small increased risk for very low birth weight infants in the maternal obesity category.[21] Specifically, there was no difference in number of oocytes retrieved, mature oocytes, fertilization rates, euploidy rates, implantation rates, and LBRs. Additionally, Kim et al found higher blastocyst formation rates in patients with obesity compared with overweight and normal weight patients. It is important to note that all oocytes in this study were fertilized via ICSI and all patients underwent a frozen embryo transfer; thus, the authors hypothesized that ICSI may have overcome intrinsic oocyte quality issues and that the use of frozen embryos may also have improved outcomes due to improved uterine synchrony and increased progesterone levels.[21] These findings suggest that through further research, ART has the potential to overcome many of the biological limitations associated with obesity and infertility. In conclusion, elevated BMI is associated with adverse reproductive outcomes in women undergoing IVF treatment, including higher miscarriage rates and lower birth rates in some, but not all studies. More research with larger and diverse cohorts are needed to further clarify these observations and identify the intrinsic factors affected by obesity.
Limited Access to Care
Aside from altered responses to medications, an elevated BMI can pose technical challenges to performing IVF including difficult ultrasound monitoring, challenging oocyte retrievals, and anesthetic risks.[44] In response to these as well as maternal–fetal risks, BMI cutoffs have been imposed at many fertility clinics worldwide. However, most national professional organizations around the world remain ambiguous in their recommendations, spurring controversies and a range of individualized practices between clinics. In New Zealand and Australia, a BMI over 35 kg/m2 is considered an absolute contraindication to IVF and publicly funded IVF is limited to those with a BMI less than 32 kg/m2.[45] The UK National Institute for Health and Care Excellence (NICE) guidelines do not explicitly advise against providing IVF to women with obesity but point out that obesity may impact fertility and recommend providing weight loss advice to those women. The British Fertility Society published guidelines in 2007, stating that severely obese women should have their fertility treatment deferred until they have lost weight.[46] Furthermore, in the United Kingdom publicly funded IVF is limited to those with a BMI below 30 to 35 kg/m2.
In the United States, no such formal restrictions exist. However, a 2014 study surveying U.S. fertility clinics found that 35% reported using a BMI or body weight cutoff points to determine eligibility for IVF treatment. The mean BMI cutoff point was ∼38.5 kg/m2. Importantly, 46% of these clinics implemented a BMI limit yet did not offer weight loss treatment recommendations.[47] A more recent study found that now 65% of surveyed clinics enforce BMI cutoffs.[48]
Major arguments for imposing BMI cutoff include the technical difficulty of the retrieval and anesthesia safety concerns among women with obesity. However, a study specifically investigating the safety of transvaginal oocyte retrieval in women with obesity undergoing ART found that overall, serious complications were in fact uncommon. None of the patients with BMI >40 kg/m2 required converting to endotracheal intubation during the procedure or hospital admission following. 6.25% of the patients with obesity required an oral or nasal airway for improved oxygen saturation compared with only 1% of those with BMI < 40 kg/m2. They concluded that transvaginal oocyte retrievals can be performed safely on individuals with obesity in the outpatient setting.[49] Notably, the American Society of Reproductive Medicine recently stated that “on the basis of available evidence, there is no medical or ethical directive for adopting a society-wide BMI threshold for offering fertility treatment; rather, there is considerable evidence arguing against such a policy.”[3]
As obesity rates are highest among Black and Hispanic populations, it is important to highlight that BMI cutoffs disproportionally limit access to ART among minority populations.[50] Furthermore, in the United States where IVF is not publicly funded, much of the fertility care provided in the country is paid out-of-pocket by patients, further compounding the barriers to care among those with lower socioeconomic status who also have higher rates of obesity.[51]
Treatment Strategies
Given concern for poorer reproductive outcomes as well as lower BMI requirements enforced to access care, women are commonly counseled toward weight loss prior to fertility treatment. The evidence, however, is mixed as to how weight loss may or may not improve outcomes. The studies discussed below are outlined in [Table 1].
Table 1
IVF outcomes after weight loss interventions
|
Author (year)
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Study type
|
Population and intervention
|
Major findings
|
|
Moran et al[56] (2011)
|
Lifestyle modification
Randomized controlled trial
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46 women with infertility and BMI ≥28 but <45 kg/m2 undergoing IVF.
Randomized to:
Diet and exercise for 5–9 wk before IVF (n = 21)
Control group (n = 25)
|
No difference in live birth rate (38.8% in the lifestyle intervention vs. 25% in the control group; p = 0.48)
|
|
Chavarro et al[52] (2012)
|
Lifestyle modification
Cohort study
|
170 women with infertility followed up for change in body weight between baseline and the last clinical appointment prior to an IVF cycle
|
Short-term weight loss was associated with a higher proportion of metaphase II (MII) oocytes retrieved: 91% for women who lost 3 kg or more and 86% for women whose weight remained stable (p = 0.002)
No difference in clinical pregnancy (p = 0.09) or live birth rates (p = 0.12)
|
|
Sim et al[53] (2014)
|
Lifestyle modification
Randomized controlled trial
|
49 women with infertility and obesity undergoing IVF.
Randomized to:
12-wk of very-low-energy diet for the initial 6 wk followed by a hypocaloric diet, plus a weekly group program (n = 26)
Control group received recommendations for weight loss and the same printed material (n = 22)
|
Clinical pregnancy rate was higher in the intervention group (48 vs. 14%, p = 0.007) and higher live births (44 vs. 14%; p = 0.02)
|
|
Espinós et al[54] (2017)
|
Lifestyle modification
Randomized controlled trial
|
41 women with infertility and BMI ≥30 but <40 kg/m2 undergoing IVF.
Randomized to:
Intervention (n = 21) with 12-wk diet and exercise pre-IVF
Control group (n = 20)
|
No difference in clinical pregnancy rate after fresh embryo transfer (66.7 vs. 41.2%) (OR with 95% CI = 2.85 [0.7–11.3]).
Significantly higher cumulative live birth rate in intervention group (61.9 vs. 30%: p = 0.045)
|
|
Einarsson et al[57] (2017)
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Lifestyle modifications
Randomized controlled trial
|
317 women with infertility and BMI ≥30 but <35 kg/m2 undergoing IVF.
Randomized to:
16-wk weight reduction program with strict diet and dietitian counseling before IVF (n = 152)
Immediate IVF (n = 153)
|
No difference in overall live birth rate (difference: 2.2%, 95% CI: 12.9 to −8.6, p = 0.77)
Significantly greater weight reduction for intervention group (−9.44 kg vs. +1.95 kg; p < 0.0001)
Increased spontaneous pregnancy in weight loss group (10.5 vs. 2.6%; p = 0.009)
|
|
Wu et al[55] (2022)
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Lifestyle modification
Case–control study
|
352 patients with PCOS infertility and overweight/obesity, defined by BMI >25 kg/m2, undergoing IVF.
Cases: 6-mo pretreatment of weight loss prior to IVF. Further divided into 4 groups based on amount of weight lost (0, 1–5, 5–10, and >10 kg).
Controls: 75 tubal factor infertility patients
|
PCOS patients with less weight loss required more gonadotropins and days of stimulation (p < 0.05), fewer oocytes retrieved (11.76 ± 7.12 vs. 16.64 ± 7.28; p < 0.05) and fewer high-quality embryos (36.32 vs. 43.11%; p < 0.05) than patients with more weight loss.
Patients in groups with 5–10 kg weight loss and >10 kg weight loss had significantly increased implantation rates (64.37 and 62.9% vs. 42.82%; p < 0.05), clinical pregnancy rate (63.22 and 61.29% vs. 40.95%; p < 0.05) and live birth rates (56.32 and 54.83% vs. 29.5%; p < 0.05) compared with the group without weight loss.
Significantly decreased miscarriage rates for patients with weight loss over 5 kg compared with 0 kg weight loss (12.73 and 13.16% vs. 32.56%; p < 0.05)
|
|
Salamun et al[68] (2018)
|
Pharmacologic treatment
Randomized open-label study
|
28 women with infertility, PCOS and obesity (BMI ≥ 30 kg/m2) undergoing IVF.
Randomized to:
Metformin for 12 wk (n = 14)
Metformin and low-dose liraglutide for 12 wk (n = 14)
|
Significantly increased pregnancy rates per embryo transfer (85.7 vs. 28.6%; p = 0.03) and cumulative pregnancy rates over 12 mo (69.2 vs. 35.7%) in the intervention group with addition of low-dose liraglutide
|
|
Wang et al[60] (2021)
|
Pharmacologic treatment
Randomized controlled trial
|
877 infertile women with overweight/obesity, defined by BMI >25 kg/m2, undergoing IVF
Randomized to:
Orlistat (n = 439) for 4–12 wk
Placebo (n = 438) for 4–12 wk
|
No significant difference in rates of conception (36.9 vs. 36.3%; p = 0.854), clinical pregnancy (31.7 vs. 30.4%; p = 0.678), pregnancy loss (19.4 vs. 15%; p = 0.339), or live birth rate (25.5 vs. 25.6%; p = 0.984)
Orlistat was beneficial for weight reduction (−2.49 kg vs. −1.22 kg; p = 0.005)
|
|
Tong et al[61] (2022)
|
Pharmacologic treatment
Retrospective case–control study
|
29 women with overweight/obesity, defined by BMI > 25 kg/m2, undergoing IVF/ICSI
Cases: Orlistat intervention (29 patients underwent 37 embryo transfers)
Controls: age and BMI matched (29 patients underwent 38 embryo transfers)
|
Significantly higher clinical pregnancy rate of the orlistat group (59.46 vs. 39.47%; p = 0.004)
No significant difference in the live birth rate between the two groups (54.05 vs. 36.84%; p > 0.05)
|
|
Tsur et al[72] (2014)
|
Bariatric surgery
Retrospective case series
|
7 women with infertility who underwent IVF treatment before and after bariatric surgery
|
Surgery reduced treatment costs through reduced number of gonadotropins required during stimulation (p = 0.043)
No between-cycle differences in number of oocytes retrieved (10.1 ± 6.3 vs. 8.7 ± 6.5; p = 0.6), percentage of mature oocytes (79 vs. 90.9%; p = 0.1), or percent of high-quality embryos (28.2 vs. 37.2%; p = 0.78)
|
|
Milone et al[73] (2017)
|
Bariatric surgery
Retrospective case series
|
40 women with infertility who underwent IVF before and after bariatric surgery
|
Significantly lower gonadotropin units and length of stimulation after surgery (p = 0.001)
Significantly increased follicles (p = 0.005), mature oocytes retrieved (p = 0.008), and high-quality embryos (0.5 ± 0.6 vs. 1.1 ± 0.9; p = 0.003) after surgery.
Significantly increased pregnancy rate (37.5 vs. 0%; p < 0.001) and live birth rate (35 vs. 0%; p < 0.001) after surgery
|
|
Grzegorczyk-Martin et al[74] (2020)
|
Bariatric surgery
Retrospective cohort study
|
332 patients divided into 3 age-matched groups undergoing IVF
Groups:
Bariatric surgery patients (83 patients, mean BMI 28.9 kg/m2)
BMI-matched nonoperated patients (166 patients, mean BMI 28.8 kg/m2)
Nonoperated patients with obesity (83 patients, mean BMI 37.7 kg/m2)
|
No significant difference in cumulative birth rates between the surgery patients and the two nonoperated groups (22.9, 25.9, and 12.0%)
Live birth rate per transfer in obesity group was significantly lower compared with the other two groups (9.3 vs. 20% and 18%; p = 0.0167)
No difference in miscarriage rates between the three groups (38.7, 35.8, 56.5%; p = 0.256)
No significant difference in average number of mature oocytes and embryos obtained among the three groups
|
|
Nilsson-Condori et al[75] (2022)
|
Bariatric surgery
Case–control study
|
153 patients undergoing IVF after bariatric surgery
Cases: 153 patients underwent bariatric surgery before IVF
Controls: up to 5 nonoperated control patients selected for each surgery case matched by age, parity, and BMI at treatment
|
No significant difference in the cumulative pregnancy rate (40.5 vs. 49.1%; p = 0.062) or cumulative live birth rates (29.4 vs. 33.1%; p = 0.395) between the surgery group and the matched controls
Significantly fewer number of retrieved oocytes (7.6 vs. 8.9; p = 0.005) and frozen embryos (1.0 vs. 1.5; p = 0.041) in the surgery group
Significantly lower birth weight in children born to bariatric surgery patients (p = 0.037)
|
Abbreviations: BMI, body mass index; ICSI, intracytoplasmic sperm injection; IVF, in vitro fertilization; PCOS, polycystic ovary syndrome.
Lifestyle Modifications
In women with obesity, a reduced-calorie diet and exercise interventions are often the first recommended treatment strategy. As previously discussed, obesity affects ovulation and menstrual cycles, response to fertility treatment, pregnancy rates, and outcome. Weight reduction is an effective strategy for resumption of ovulation among women with irregular menses. Regarding IVF specifically, outcomes are varied.
A 2012 cohort study of 170 women undergoing IVF observed patient-driven weight changes prior to treatment and found short-term weight loss was associated with an improved number of mature oocytes retrieved but no difference in clinical pregnancy or LBRs.[52] Conversely, higher LBRs have been observed in randomized control trials with patients undergoing lifestyle intervention for weight loss before IVF treatments.[53]
[54] A more recent 2022 study out of China found that weight loss of more than 5 kg in patients with obesity and PCOS resulted in improved implantation, clinical pregnancy, and LBRs.[55] However, the presence of PCOS diagnosis offers a confounding pathophysiology compared with patients with obesity alone.
Several studies have not shown clinical improvements with lifestyle modifications prior to IVF. Moran et al randomized patients to a 5- to 9-week diet and exercise intervention before IVF or a control group without lifestyle interventions. They found no difference in LBRs between the groups despite more weight loss observed in the intervention arm.[56] Another randomized trial out of Sweden divided 317 women with infertility to either 16 weeks of weight reduction followed by IVF or immediate IVF treatment. The weight reduction group followed a strict low-calorie diet with counseling by a dietitian. While weight reduction in the intervention group was significantly higher, they did not find a statistically significant difference in overall LBR. They did, however, find increased spontaneous pregnancy in the weight loss group.[57]
Pharmacological Treatments
There are currently four anti-obesity medications approved in the United States for chronic weight management. Anti-obesity medications can facilitate weight loss by decreasing nutrient absorption or altering gut–brain regulation, ultimately resulting in decreased appetite and/or increased satiety.
Orlistat
Orlistat is an oral medication that works by decreasing nutrient absorption and is typically associated with ∼3 to 6% weight loss.[58]
[59] Orlistat treatment is beneficial for weight loss; however, it has not been shown to significantly improve reproductive outcomes in women with obesity prior to IVF. Wang et al conducted a randomized controlled trial across 19 reproductive medical centers in China from 2017 to 2019. Approximately 900 women with infertility and a BMI > 25 scheduled for IVF were enrolled and randomly allocated to receive orlistat or placebo treatment for 4 to 12 weeks. Live birth rates were not found to be significantly different between the two groups. It was concluded that no significant differences existed between the groups in terms of rates of conception, clinical pregnancy, or pregnancy loss.[60] A smaller scale study, also out of China, found increased clinical pregnancy rates with the use of Orlistat compared with age and BMI-matched controls, but no difference in LBRs between groups.[61]
Phentermine/Topamax
Phentermine is a stimulant medication approved for short-term (3 months) treatment which has been shown to induce over 7% weight loss at 6 months.[62] The combination of phentermine plus topiramate, a traditionally anticonvulsant medication, has been approved by the FDA for chronic management of obesity and has shown improved weight loss when used in combination, with an average expected weight loss of 5 to 11% over 1 year.[63] There are no trials that have assessed phentermine or phentermine/Topamax use prior to IVF.
Bupropion/Naltrexone
Bupropion reduces appetite through stimulation of proopiomelanocortin (POMC) neurons for melanocyte stimulating hormone release responsible for regulation of food intake and energy expenditure. It is used in combination with an opioid antagonist, naltrexone, that blocks inhibitory feedback on POMC cells.[64] There are no trials that have assessed the combination of bupropion/naltrexone use prior to IVF.
Glucagon-Like Peptide-1 Receptor Agonists
The glucagon-like peptide-1 (GLP-1) agonists, Semaglutide and Liraglutide, are injectable medications administered either once weekly or once daily and are FDA approved for chronic weight management. GLP-1 receptor agonists improve glycemic control by stimulating insulin secretion from the β-pancreatic cells and suppressing glucagon release from the α-pancreatic cells.[65] GLP-1 is a gut-derived incretin hormone that inhibits gastric emptying, increases feelings of satiety, and reduces appetite ultimately resulting in significant weight loss. O'Neil et al conducted a comparison study between the degree of weight reduction in adults with a BMI > 30 kg/m2 using liraglutide and those using Semaglutide. They reported that liraglutide 3.0 mg daily showed an estimated mean weight loss of 7.8% after a year.[66] In more recent studies, Semaglutide is notable for even further reduction in body weight by 15% or more after 1 year of use.[67] Weight loss observed with Semaglutide is greater than that reported for other approved anti-obesity medications: orlistat (6%), phentermine–topiramate (8–10%), and naltrexone–bupropion (5%).[59]
In a prospective study by Salamun et al, 28 women with infertility and PCOS received a 12-week preconception intervention of metformin alone or liraglutide plus metformin before undergoing IVF treatment. The authors found that those who received liraglutide had a significantly higher pregnancy rate after IVF compared with metformin.[68] It is important to note that few studies have been performed with these medications in the setting of fertility treatments given contraindications in pregnancy.
Bariatric Surgery
Bariatric surgery remains the most effective strategy for weight loss in patients with severe obesity.[69] Today, laparoscopic sleeve gastrectomy and Roux-en-Y gastric bypass are most commonly performed.[70] Observational studies show that surgical intervention for obesity is associated with increased rates of spontaneous conception,[71] but improvements in LBR associated with IVF treatments have yet to be clearly established.
There have been a handful of studies investigating IVF outcomes after bariatric surgery. Two studies assess outcomes in patients who had IVF treatments both before and after bariatric surgery. One of these studies assessed seven patients and found that, while patients required less gonadotropins after surgery, there was no difference in oocytes retrieved or maturity rates.[72] Milone et al also noted reduced gonadotropin dosing when comparing IVF cycles before and after bariatric surgery in their study of 40 women with idiopathic infertility. Additionally, they reported a significantly increased number of oocytes retrieved, higher oocyte maturity, increased embryo quality, as well as increased pregnancy and LBR after surgery.[73]
Grzegorczyk-Martin et al assessed first-time IVF cycle outcomes in three groups: bariatric surgery patients, BMI-matched nonoperated patients, and nonoperated patients with obesity.[74] They noted no significant difference in cumulative LBRs comparing the bariatric surgery group to the nonoperated groups. However, the LBR per transfer in the obesity group was significantly lower. There was also a significantly smaller weight for gestational age observed in newborns of the bariatric surgery group.[74]
A recent case–control study out of Sweden utilized data from a national registry to analyze 153 women undergoing IVF after bariatric surgery with up to 5 nonoperated control patients matched by age, parity, and BMI at treatment. They found no significant difference in the cumulative LBR between the bariatric surgery group and the matched controls group.[75] Similar to the study of Grzegorczyk-Martin et al, birth weight was significantly lower in the children born to patients having undergone bariatric surgery suggesting a potential nutritional impact on pregnancy for this population.
Conclusions
From this review of the literature, it is evident that studies of IVF and obesity are limited. Obesity has a significant impact on reproduction as demonstrated by reduced fertility, increased miscarriages, and poorer outcomes with assisted reproductive treatments. However, recent large-scale studies question several prior findings regarding the specific impact of obesity on IVF. Furthermore, access to fertility treatments is often restricted in this population, reducing trials and assessments among women with severe obesity. Women with obesity are often counseled to utilize weight loss therapies including lifestyle modifications, pharmacotherapies, or surgical approaches prior to ART treatments with little evidence basis. This review found limited and mixed data for the various treatment strategies for obesity prior to IVF. In summary, while obesity may impact IVF outcomes, further research is still needed to determine the optimal approach for women with infertility and obesity planning IVF.
