Abstract
“…meta-analyses indicate that female overweight or obesity result in poorer assisted reproductive technology outcomes.”
Consequences of obesity
The global overweight and obesity epidemic has caused increased health risks, including declining fertility rates in developed countries. Data from 2007 to 2008 estimate that 64% of American women fell within either the obese or the overweight category with BMI >25 kg/m2 and 36% were obese (BMI >30 kg/m2) [1]. Similarly, more than half of women are either overweight or obese in many European countries [2,3]. Obesity is associated with an increased risk of hypertension, Type 2 diabetes, coronary heart disease, gall bladder disease and osteoarthritis. Additionally higher rates of preconceptional obesity have been associated with increasing rates of pregnancy complications, labor induction and Cesarean section [4,5].
Moreover, obesity is related to a decrease in natural fecundity caused by effects on secretion of hypothalamic gonadotrophins and steroid production, decreased ovulation rate, increased time to pregnancy and increased rates of miscarriage, pregnancy complications and congenital anomalies [6]. Mild-to-moderate weight loss in anovulatory women is associated with the return of spontaneous ovulation and a reduction in the need for ovulation induction [7].
Female overweight & assisted reproductive technology outcomes
Three recent meta-analyses (MA) have explored the influence of female BMI on the chance of obtaining pregnancy or live birth following assisted reproductive technology (ART) treatment [8–10]. Rittenberg et al. included 33 studies covering 47,967 treatment cycles [9]. Their results indicated that women who were overweight or obese had significantly lower clinical pregnancy (relative risk [RR]: 0.90; p < 0.0001) and live birth rates (RR: 0.84; p = 0.0002) and significantly higher miscarriage rates (RR: 1.31; p < 0.0001) compared with women with a BMI <25 kg/m2 following treatment [9]. Similarly, Maheshwari et al. analyzed 37 studies and found lower pregnancy (odds ratio [OR]: 0.71; 95% CI: 0.62–0.81) and higher miscarriage rates (OR: 1.33; 95% CI: 1.06–1.68) and a requirement for higher doses of gonadotrophins after IVF in women with BMI >25 kg/m2, but insufficient evidence regarding the effect of raised BMI on live birth rate [8]. Rittenberg et al. found that the probability of live birth after ART was reduced by 9% (95% CI: 2–15%) in overweight women compared with a reduction of 20% (95% CI: 12–29%) in the obese group [9]. Koning et al. analyzed 27 studies that reported on BMI and success of ART, the pooled ORs for overweight versus normal weight on live birth, and ongoing and clinical pregnancy following ART were 0.90 (95% CI: 0.82–1.0), 1.01 (95% CI: 0.75–1.4) and 0.94 (95% CI: 0.69–1.3), respectively [10]. A dose-response relationship between increasing BMI and lower chance of success rates after ART has been suggested [9,11]. In accordance with this, a recent retrospective cohort study on 4609 first ART cycles demonstrated that patients with a BMI 30–35 kg/m2 have a 37% lower chance of having a live birth than women with a normal BMI, while women with a BMI 35–39 and >40 kg/m2 had a 61–68% lower chance of live birth [12].
“…higher rates of preconceptional obesity have been associated with increasing rates of pregnancy complications, labor induction and Cesarean section.”
All three MA encountered considerable methodological and clinical heterogeneity among the included studies, with Rittenberg et al. and Maheshwari et al. both finding significantly lower pregnancy rates among overweight and obese women, while Rittenberg et al. and Koning et al. found significantly lower live birth rates in overweight and obese women compared with normal-weight controls. Overall, the MA indicate that female overweight or obesity result in poorer ART outcomes.
Possible explanations of the association between BMI and outcome of ART have been discussed. Luke et al. found maternal obesity to cause lower live birth rates among treatments with the use of autologous, as well as donor, oocytes, but the effect was most severe among treatments using autologous oocytes [13]. This suggests a detrimental effect of obesity on the fetal environment, which cannot be ascribed to the quality of the embryo, as detected in a previous study [14]. Increased rate of miscarriage has also been found to be associated with overweight and obesity, and this will consequently cause the live birth rate to decrease [8,9]. A MA on the risk of miscarriage in women with a BMI >25 kg/m2 without polycystic ovary syndrome revealed an OR of 1.67 (95% CI: 1.25–2.25), regardless of the method of conception [15]. However, this study found no increased chance of miscarriage after IVF/intracytoplasmic sperm injection in overweight and obese women.
“Underweight … also has a negative influence on female reproductive health due to disturbances in the hypothalamic–pituitary axis, causing ovulatory disturbances.”
Costs and outcomes of fertility care in overweight and obese women were evaluated in a hypothetical cohort of 1000 women separated into anovulatory and ovulatory groups [3]. The study demonstrated that there is an increased cost per live birth owing to infertility treatment for overweight and obese women when compared with normal BMI women. The costs were the highest in the anovulatory group, with a cost per live birth of €4653 and €6045, and a corresponding reduction in live birth rates of 22 and 24%, in overweight and obese women, respectively. This is in comparison with normal weight women whose cost per live birth was €3016. In ovulatory women, on the other hand, live birth rates were reduced, at 14 and 15% in overweight and obese women, respectively, and thus cost per live birth was lower than in anovulatory women [3]. Maheshwari argued that these findings should be taken cautiously, as despite the model's robust methodology, it was based on data from various observational studies with inherent biases [16]. In agreement, the authors of both papers stated that reduced effectiveness of treatment is not a reason to withhold treatment; however, a certain BMI upper threshold prior to ART treatment should be discussed, knowing that specific cut-off values are always questionable [3,16].
Female underweight & ART outcomes
Underweight (BMI <18.5kg/m2) also has anegative influence on female reproductive health due to disturbances in the hypothalamic–pituitary axis, causing ovulatory disturbances. However, the literature on the influence of underweight on ART outcomes is scarce. Two studies did not find any significant impact of underweight on clinical pregnancy or live birth rates after IVF, but the latter found a significantly higher proportion of cancelled ART cycles in Danish underweight women [11,17]. A very recent study on 4609 patients undergoing their first ART cycle confirmed that no decreased risk of achieving pregnancy or live birth is seen in underweight women [12]. Two studies reported low BMI to be associated with poorer IVF outcome [18,19]. The conclusions regarding the influence on underweight on IVF outcomes appear less stringent than those of overweight or obese women due to the scarcity of studies.
Future perspective
It should be implicit in all preconceptional counseling to emphasize that women who are trying to conceive should follow a healthy lifestyle and try to achieve a normal BMI. Weight loss should be the gold standard in anovulatory overweight and obese women [7].
The advantage of weight loss prior to fertility treatment in overweight and obese women with regular menstrual cycles is still controversial. It is well established that overweight women undergoing IVF treatment require higher doses of gonadotrophins, and MA show that ART outcomes in overweight and obese women are poorer.
Many questions remain: will weight loss prior to IVF treatment increase success rates? To whom should we offer a weight loss treatment program? Is there a certain threshold of female age and weight class? What should the weight loss program include – food restriction, diet, training, motivational interview and counseling or cognitive therapy, or an integration of all of these interventions? Furthermore, how long should the time period be between weight loss treatment and the initiation of ART treatment in order to avoid ART treatment during the catabolic phase?
A recent prospective cohort pilot study among infertile couples showed that motivational interviewing techniques and support were effective in promoting healthy lifestyle changes [20]. Overweight and obese women frequently have a partner that is also overweight or obese, and male overweight has been shown to be an independent risk factor for prolonged time to pregnancy [21]. Furthermore, a recent pilot study of weight loss in men with a BMI >33 kg/m2 showed that those with the largest weight loss had statistically significant increases in total sperm count and normal sperm morphology [22]. Therefore, it seems to be of importance to develop interventions that target the couple if both are overweight/obese, not only the female partner. Many fertility clinics have an upper treatment threshold of BMI for initiating ART treatment, but there are no evidence-based guidelines regarding fertility treatment in overweight and obese infertile women [23].
“Many questions remain: will weight loss prior to IVF treatment increase success rates? To whom should we offer a weight loss treatment program?”
Reproductive healthcare providers should be cautious about underweight women, particularly if anovulation is the cause of the infertility, and be sure that no eating disturbance or overtraining is the cause of the lower weight. IVF treatment for overweight and obese women is a challenge, and these women are at a disadvantage compared with their normal weight counterparts. Women referred for IVF treatment should be counseled of the negative implications of increased BMI on reproductive outcomes and their general health. Weight loss and a healthy lifestyle should be encouraged in all couples undergoing fertility treatment. To our knowledge, there are two ongoing European multicenter intervention studies on the effect of weight loss prior to ART treatment on pregnancy and live birth rates: a Dutch randomized controlled trial [23] and a Swedish randomized controlled trial (NCT01566929). The results of these reports will show the effects of weight reduction intervention strategies on couples seeking ART treatment in order to elucidate whether there is an effect of weight loss on ART outcomes and, furthermore, who will most benefit from it and the optimal time interval between weight loss and beginning ART treatment.
Financial & competing interests disclosure
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.