Fig. 6.1
Changes in weight and ovulation rates during the study period for those subjects who completed 6 months of trial. The number of spontaneous pregnancies is shown in the bottom panel. From Clark AM, Ledger W, Galletly C, Tomlinson L, Blaney F, Wang X, et al. Weight loss results in significant improvement in pregnancy and ovulation rates in anovulatory obese women. Human Reproduction. 1995 Oct;10(10):2705–12. PubMed PMID: 8567797. With permission from Oxford University Press, UK
Sustained weight loss is also among the more economical fertility treatments, as it is considerably less expensive than most other medical or surgical management strategies. The entire 6-month program in the aforementioned study cost considerably less than a single cycle of IVF at the same institution. While weight loss should be encouraged in all obese patients seeking fertility, it may be of particular interest to those with limited resources and/or a longstanding history of infertility.
Ovulation Induction and Superovulation
When ovulation is irregular or absent, women can undergo ovulation induction with oral or injectable medications; the response to these is generally attenuated in obese women compared to those of normal weight. Compared with women of normal weight, overweight and obese women often require higher doses of clomiphene, the first-line agent commonly used to induce ovulation. Previous work by Lobo and colleagues [13] has demonstrated a positive correlation between weight and ovulatory dose of clomiphene, with only 20 % of women over 200 lb ovulating in response to 50 mg clomiphene, and an additional 20 % ovulating at a dose of 100 mg. Elevated BMI, and more specifically central body fat distribution, can predict increased resistance to clomiphene; such women often require higher doses to achieve ovulation [14].
When clomiphene is ineffective at effecting ovulation, letrozole is a common second-line agent. This aromatase inhibitor has been found to induce ovulation in more than 25 % of patients with clomiphene resistance [15]. No published studies have examined the optimal dosing of letrozole for ovulation induction in obese women, possibly reflecting its off-label use for this indication. However, in a small study examining pregnancy outcomes in 90 obese and nonobese women undergoing treatment with letrozole and intrauterine insemination (IUI), there was no difference in pregnancy rates between obese and nonobese women [16].
If oral ovulation induction fails, the next treatment is typically gonadotropin injections, with or without the concurrent use of oral agents, in an attempt to stimulate multifollicular development. This treatment is often paired with intrauterine insemination (IUI) to maximize chances of conception. Obese women require greater quantities of medications to effect ovulation, not only with oral agents, but also with injectable gonadotropins. In a retrospective study of more than 300 women undergoing more than 800 cycles of superovulation and IUI, the mean total gonadotropin dosages per cycle were higher for obese women as compared to those of normal weight, even when analyzing only first cycles [17]. Peak estradiol levels during gonadotropin stimulation have been found to be inversely proportional to BMI, with lower estradiol levels per follicle in obese women [18]. However, once medication regimens have been optimized for peak estradiol and follicular development, obese women undergoing gonadotropin-IUI are generally able to achieve pregnancy rates comparable to those seen in normal weight women [18].
In Vitro Fertilization
When ovulation induction has failed to achieve pregnancy, many patients may proceed with the more intensive treatment of in vitro fertilization (IVF)—a process involving superovulation, oocyte retrieval, ex vivo fertilization and embryo culture, and embryo transfer. A common misconception among many patients is that any detrimental impact of obesity on fertility outcomes can be overcome using assisted reproductive technologies (ART), but obesity appears to impact each step of the IVF process, even at the microscopic level.
Ovarian Stimulation
Similar to superovulation with IUI, gonadotropin requirements are typically higher in obese as compared to nonobese women undergoing IVF. Obese women undergoing gonadotropin stimulation for IVF have lower peak [19–21] and per follicle estradiol levels [21]. Obese women require a greater total amount of gonadotropins to achieve a similar degree of follicular growth as compared to overweight or normal-weight women [22, 23], resulting in an increased length of gonadotropin stimulation prior to oocyte retrieval [20]. Given this gonadotropin “resistance,” obese women are more likely to have a cycle cancellation, often related to poor ovarian response to follicular stimulation [24, 25].
The higher risks of cycle cancellation and increased gonadotropin requirement in obese women may lead to higher-than-average costs for IVF in obese women. In a retrospective analysis of more than 1,700 first IVF cycles, there were no differences in cost per IVF cycle across all ranges of BMI [26]. However, considering that multiple cycle starts might be required to ultimately lead to an oocyte retrieval, and the decreased chances of pregnancy in obese women undergoing ART (reviewed later in this chapter), the cumulative financial cost to achieve a “take-home baby” may be greater for obese women.
Special consideration should be given when considering ovulation induction outcomes in obese women with PCOS; this unique group is characterized by high antral follicle counts that should offer good chances for follicular recruitment in response to gonadotropin stimulation. However, obese women with PCOS also require higher doses of gonadotropins to achieve a comparable degree of follicular development to their nonobese counterparts. In one study of 72 patients with PCOS, women with a BMI ≥ 40 kg/m2 required higher doses of gonadotropin to achieve the same number of mature follicles than those with a BMI < 40 kg/m2 (2,606.8 IU versus 1924.6 IU, p = 0.03) [27]. This difference was noted even though there was no difference in the total number of follicles between the two groups (follicles >12 mm: p = 0.5, follicles >16 mm: p = 0.87).
Oocyte Retrieval, Maturity, and Fertilization
Oocyte retrieval for IVF can be particularly challenging in obese women. Visceral adipose and redundant inguinal tissue can make manipulation of a transvaginal ultrasound probe technically difficult, thereby compromising visualization of the ovaries. As discussed above, obesity is associated with lower peak estradiol levels and fewer follicles for a given level of estradiol. Thus, the total number of follicles available for oocyte retrieval may be lower than in nonobese women of a similar age. Jungheim and colleagues [27] described fewer oocytes retrieved in women with a BMI ≥ 40 kg/m2 than those with a BMI < 40 kg/m2 (8.9 versus 13.6, p = 0.0006), which is consistent with the findings of other studies [24, 28]. Several of the cases were noted to be technically difficult in the medical record, and when these cases were removed from the analysis, there was no longer a difference in numbers of oocytes retrieved (10.42 versus 13.63, p = 0.06).
Transabdominal oocyte retrieval is an alternative approach when patient obesity compromises transvaginal access to the ovaries. In a retrospective case-control study of 69 patients undergoing transabdominal oocyte retrieval owing to one or both ovaries being inaccessible through the vagina, comparable numbers of mature oocytes were retrieved transabdominally as compared to transvaginal (9.2 versus 7.3, p = 0.14), though the total number of oocytes retrieved was less in the transabdominal group (11.9 versus 14.1, p = 0.008) [29].
It is unclear whether obesity affects oocyte development, and some investigators have examined follicular fluid to identify correlations between serum and follicular metabolites that may be detrimental to the development of quality oocytes. Compared with nonobese women, obese women have higher serum concentrations of free fatty acids, and in a study of 102 women undergoing IVF, elevated follicular free fatty acids were associated with poor cumulus oocyte complex morphology [30]. Though this study did not find a strong correlation between follicular and serum free fatty acid concentrations (r < 0.31 for each free fatty acid studied), another follicular fluid study found that elevated follicular total protein and lipoprotein A1 were correlated with serum values and were associated with poor chances for embryo development [28]. Clinical utility of these markers will depend on the ability of studies to depict a consistent correlation with BMI and treatment outcomes.
The total number of mature oocytes retrieved may also be lower in obese women. In a retrospective review of 1,293 patients undergoing their first IVF stimulation cycle, women with a BMI ≥ 40 kg/m2 had significantly fewer mature oocytes retrieved compared to women with a BMI < 40 kg/m2 (11.69 ± 0.90 for a BMI ≥ 40, compared to 14.1 ± 0.32 for a BMI < 25 kg/m2, 14.16 ± 0.54 for a BMI 25–30 kg/m2, 13.45 ± 0.49 for a BMI 30–40 kg/m2, p < 0.02) [20]. There are data to suggest, however, that changes in BMI might improve the mature oocyte yield. In a prospective cohort study, Chavarro and colleagues [31] noted that obese (BMI ≥ 30 kg/m2) and overweight women (BMI 25–30 kg/m2) had a higher yield of metaphase II oocytes after a short-term weight loss of >1 kg from initial baseline appointment to the time of retrieval as compared to similarly obese and overweight women whose weight did not change (10.1 [95 % CI 8.5–11.6] compared to 7.8 [95 % CI 6.9–8.8], p = 0.03). This study hints at a biological plausibility for the observed association between BMI and oocyte maturity and quality. Unfortunately, the authors were not able to correlate this change in BMI with pregnancy or live birth rates; future studies might investigate this relationship further.
Some clinicians would suggest that insemination and fertilization rates, rather than subjective assessment performed by heterogeneously trained embryologists, provide a more objective assessment of oocyte maturity in obese women. Several published studies found no difference in fertilization rates between obese and nonobese women [20, 32, 33] but this is not a uniform finding [21].
Taken together, these data suggest that oocyte quality is impaired in obese women but is possibly reversible with a reduction in body weight.
Embryo Quality and Transfer
Data regarding the quality of embryos created from the oocytes of obese women are inconsistent. Several large retrospective studies show no correlation of embryo quality with obesity, specifically no differences in grade [24], number of cells [24, 33], or degree of fragmentation [33]. However, a smaller retrospective study of 426 cycles demonstrated that, compared to normal-weight women under 35 years old, obese women under 35 years old had lower embryo grades (2.3 ± 1.4 versus 2.0 ± 0.6, p = 0.02), fewer cryopreserved embryos (0.2 ± 1.2 versus 1.1 ± 2.2, p = 0.04), and higher numbers of discarded embryos (6.4 ± 0.7 versus 4.5 ± 0.3, p = 0.007) [32].
Transabdominal ultrasound, fast becoming a near universal tool in facilitating optimal placement of the transfer catheter during embryo transfer, is more difficult in obese women. It is plausible that the greater difficulty in optimal visualization during transabdominal ultrasound of obese women may lead to adverse IVF outcomes, but few researchers have investigated this hypothesis. A single retrospective review of 417 first IVF cycles revealed a nonsignificant increase in the inability to visualize the air bubbles during embryo transfer on women with a BMI > 25 kg/m2 (p = 0.06); this was accompanied by a non-significant decrease in implantation rate, and no change in ongoing pregnancy rate [34]. Given the paucity of published studies examining embryo transfer protocol in obese patients, no summary statements can be made as to whether the known technical challenges in transfer in obese women result in adverse pregnancy outcomes.
Implantation and Clinical Pregnancy
Whether the endometria of obese women have poorer receptivity for implanting embryos is unclear. Assessment of the preconception endometrium, either by hysteroscopy or endometrial biopsy, is not compulsory in the infertility workup unless the patient has risk factors or symptoms suggesting abnormal pathology. However, in a retrospective study of over 200 women with infertility, asymptomatic obese women had a higher number of precycle endometrial polyps compared with nonobese women (52 % versus 15 %, p = 0.04); the authors suggest that hysteroscopy should be routinely performed in obese women prior to cycle start to optimize the endometrium prior to stimulation [35]. The effect of endometrial polyps on fertility is poorly understood and understudied; it is possible that obesity may be a common link between endometrial polyps and infertility.
In addition to macroscopic changes such as uterine polyps, obese women may have unidentified microscopic or biochemical alterations in the endometrium that alter uterine receptivity. Some studies have revealed lower implantation rates in obese women [33, 34, 36] but others have shown no difference [25, 37]. In a retrospective analysis of 4,609 patients undergoing their first IVF cycle, the odds of implantation were as low as 0.52 among obese women as compared to nonobese women [38]. In a meta-analysis from 2007, Maheshwari summarized the findings of 21 studies and confirmed nearly a 30 % lower odds of pregnancy in overweight or obese women undergoing IVF [23]. The odds for implantation are also decreased in obese women with PCOS [34].
Many authors have tried to linearize implantation and clinical pregnancy rate data to mathematically predict patient outcomes with increasing BMI, with some limited success. A retrospective study of 171 women correlated a one unit increase in BMI with a 0.84 diminished odds of pregnancy; this was comparable to the diminishment in the odds of pregnancy with a one-unit elevation in baseline FSH. Conversely, a one-unit decrease in BMI increased the odds of pregnancy by 1.19 [36]. However, given the relatively low median BMI (20.5) of participants, with no patients above a BMI of 28, the applicability of this data to clinical practice is limited. In a larger retrospective study of over 6,000 women, nearly 25 % of overweight or obese women (BMI > 25 kg/m2) had decreased odds of pregnancy; for each unit of BMI increase above 25 kg/m2, there was a decrease in odds of pregnancy by 0.98. There was also a decrease in cumulative pregnancy rate with increasing BMI, from 93.7 % pregnancy within four cycles for women with a BMI < 20 kg/m2, to 87.1 % for women with a BMI ≥ 30 kg/m2 [33].
Obesity does not appear to impact the risk of multiple gestation after fertility treatment. In a retrospective cohort of 90 patients, there were no differences in rates of multiple gestations between obese and nonobese women undergoing letrozole/IUI cycles [16]. Similarly, there were no differences in multiple births in 4,609 fresh cycles of IVF across all ranges of BMI from <18.5 kg/m2 to ≥40 kg/m2 [38].
Endometrial Receptivity Versus Poor Embryo Quality: Which Is Responsible for the Decreased Pregnancy Rates in Obese Women?
While data suggest that the implantation rate for obese women is poorer than normal-weight women, the majority of studies are unable to differentiate the impact of embryo quality from that of endometrial receptivity. Are implantation rates low because of poor embryo quality or because of a hostile intrauterine environment? This is currently a heavily debated topic and there are data available to support both possibilities.
An ideal study would eliminate one of the variables in question—for example, examining implantation and pregnancy rates in obese women who undergo IVF using oocytes from nonobese donors. In a study of 10,000 first IVF cycles using oocytes from healthy normal-weight donors, rates of implantation were significantly lower when recipient BMI increased beyond 25 kg/m2 (38.5 % in women with a BMI 25–29.9 kg/m2 versus 39.9 % in recipients with a BMI 20–24.9 kg/m2, p < 0.001), and dramatically so after recipient BMI increased beyond 30 kg/m2 (30.5 % p < 0.001) [39]. Clinical pregnancy rates were similarly diminished with increasing BMI (55.9 % in recipients with a BMI 20–24.9 kg/m2 compared to 54.3 % for a BMI 25–29.9 kg/m2, and 45.4 for women with a BMI ≥ 30, p < 0.001). Clinical miscarriage rate and ectopic pregnancy rates were similar for all BMI groups. In the setting of unchanged laboratory and embryo parameters, these data suggest that uterine receptivity may be compromised in obese women.
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