9.1
Introduction
The World Health Organization defines obesity as abnormal or excessive fat accumulation that impairs health. Obesity is most commonly defined using body mass index (BMI). The percentage of obese women (BMI ≥30) in the United Kingdom has increased from 16.4% in 1993 to 23.8% in 2004. In the reproductive age group, a third of the women are overweight (BMI 25–30) and one in five are obese.
Overweight women are known to be at a higher risk of menstrual dysfunction and ovulatory problems. This is due to altered secretion of pulsatile GnRH, resulting in altered SHBG, ovarian/adrenal androgens, and luteinising hormone (LH). Obese women are more likely to experience reproductive problems and therefore seek assisted conception treatment.
In women undergoing assisted reproduction techniques (ART), obesity has been associated with the need for higher doses of gonadotrophins, increased cycle cancellation rates, and fewer oocytes retrieved. Lower rates of embryo transfer (ET), pregnancy and live birth have also been reported, as have higher miscarriage rates. However, other studies have been unable to find any negative impact of obesity on ART outcome. A recent survey of assisted reproduction clinics in the United Kingdom demonstrates a wide variation in their approach towards obese infertile women. Obstetrics data suggest that maternal and foetal risks increase in the obese individuals.
The main cause of infertility in the obese relates to disturbances in ovulation. These, for the most part, can be resolved with a combined approach involving weight reduction strategies together with pharmacologically induced ovulation induction. Refractory dysovulation occurs with greater frequency in the obese, and for them, the use of ART has to be considered. ART, specifically IVF, will address the issues of egg and sperm availability, as well as tubal infertility for the obese, just as it does for the general infertile population. There is no definitive evidence that unexplained infertility occurs with greater frequency in the obese; though given the abovementioned remarks with respect to oocyte, embryo, and endometrial factors, one might have expected this to be the case. The practical issues that arise through the use of these techniques in overweight women need to be considered carefully.
9.1.1
Cycle effects
The impact of obesity on reproductive function is complex. The association between obesity and anovulation is well established. Obesity induces a series of hormonal changes of insulin resistance, hyperinsulinemia, low sex hormone- binding globulin, elevated androgens, increased peripheral conversion of androgens to oestrogens, increased free insulin- like growth factor 1, and high leptin. The combined effect of these changes causes hypothalamic dysfunction, aberrant gonadotropin secretion, reduced folliculogenesis, and lower luteal progesterone levels resulting in anovulation.
Increased levels of serum and follicular fluid leptin are described with increasing BMI. High levels of leptin impair follicular development and reduce ovarian steroidogenesis through direct effects on theca and granulose cells. There is also an inverse relationship of increasing BMI with reduced serum adiponectin levels. The low adiponectin levels are associated with elevated serum insulin levels, which increase circulating androgen levels in part linked to a reduction in the production of sex hormone binding globulin by the liver.
The trend to hyperandrogenism in the obese is also contributed by IGF-1-mediated effects on LH-induced steroidogenesis by theca cells. Enhanced androgen production causes granulosa cell apoptosis with direct consequences for follicle function. The increased availability of androgens for peripheral conversion to oestrogens in adipose tissue has pituitary effects with impaired FSH production affecting the ovarian follicular development. The clinical manifestations of the biochemical disturbances described include anovulatory cycles and subfertility. Ovarian dysregulation associated with hyperandrogenism, insulin resistance, menstrual irregularity, and infertility is commonly found in women with polycystic ovarian syndrome, many of whom are obese.
However, even in ovulatory women, obesity appears to inhibit natural fecundity and prolong the time to conception. A Dutch study showed women with a BMI of 35 had a 26% lower likelihood of spontaneous pregnancy, and women with a BMI of 40 had a 43% lower likelihood of spontaneous pregnancy than women with a BMI between 21 and 29.
9.1.2
Effects on the oocyte
A number of studies have suggested that oocyte yield after stimulation for IVF may be affected in the obese. Quantitative effects have been described where increased doses of gonadotrophins are required to elicit an ovarian response, and the ultimate yield of cumulus–oocyte complexes may be less than in normal weight controls. This may be linked to disturbances in leptin production or sensitivity as described earlier. Some studies have suggested that fertilisation rates of oocytes retrieved may be impaired in the obese, but this observation has not been consistent. Prospective studies are needed to clarify this issue. The observation of increased risks of miscarriage in the obese after IVF has been attributed by some to qualitative effects on oocytes leading to aberrant embryo development.
9.1.2.1
Effects on embryos
As with oocytes, the literature is not consistent with respect to the effects of obesity on embryonic development. Some studies have suggested that markers of embryo quality differ in the obese. Furthermore, there may be less available surplus embryos for cryostorage potentially having an impact on cumulative pregnancy rates per episode of ovarian stimulation. Some have suggested that these observed effects are unreliable since studies may not have taken into account potential confounders such as age, parity, and duration of infertility. Further work is required to inform this controversial debate.
9.1.2.2
Effects on the endometrium
Obesity may also alter the endometrium. There is evidence of altered endometrial gene expression during the implantation window of natural cycles in obese women. Similarly, there is evidence of lower implantation and clinical pregnancy rates in obese donor egg recipients.
There is an increase in miscarriage rate in the obese both in natural conception and that associated with infertility treatment. Specific to IVF, a 50% increased risk of miscarriage in women with a BMI of 30 kg/m 2 has been described. While embryo quality will be an important determinant of implantation potential, studies using an egg donation model suggest that endometrial factors are likely to be involved in this phenomenon as well. The precise mechanism is not understood but ovarian steroid regulation of endometrial development, perturbations in inflammatory and coagulation pathways, perhaps linked to insulin resistance, have been suggested to be involved.
9.1.3
Patient selection
The selection of which patients to treat, and in whom treatment should be deferred until weight loss is achieved, should ideally depend on age, tests of ovarian reserve, and the presence of comorbidities. If tests of ovarian reserve, which might include age, serum anti-Müllerian hormone (AMH), and/or antral follicle count, suggest that there is good ovarian reserve with no other comorbidities, then it is appropriate to defer treatment up until the desired BMI is obtained. However, if there is evidence of ovarian aging, there is a limited time for weight loss. In these circumstances, it might be wiser to proceed with the treatment. Despite this, healthcare professionals have a duty of care not just to the patient but also to the potential child, and treatment should arguably not be provided if there are significant obstetric and perinatal risks such as in cases of extreme morbid obesity. There are data showing that levels of AMH are reduced and hence the egg number in obese women.
9.1.4
Stimulation regime
Obesity has been associated with a reduced response to gonadotropins. In a large retrospective cohort study gonadotropin/intrauterine insemination (IUI) cycles, BMI over 30 was associated with significantly higher gonadotropin requirements, prolonged gonadotropin stimulation, lower peak oestradiol levels, and fewer large and medium size follicles. The reduced responsiveness of obese women to gonadotropins is likely due to the increased volume of distribution.
In IVF patients, female obesity is associated with increased gonadotropin requirements (both increases starting dose and duration of gonadotropins), higher cycle cancellation rates, decreased peak oestradiol levels, and decreased oocyte yield. However, there has been little consensus regarding the impact of female obesity on IVF success rates. Some studies have reported reductions of clinical pregnancy and live birth rates on the order of 15%–30% in obese women undergoing IVF compared to nonobese controls. Other studies have reported reductions in clinical pregnancy and live birth rates of more than 50%. In contrast, at least nine studies have reported no discernible impact of female obesity on IVF pregnancy.
As alluded to the abovementioned fact, there are observational data suggesting that the requirement of gonadotrophins is increased by at least 20% if BMI is >30 kg/m 2 . Chong et al. demonstrated that patients who have normal or <10% ideal body weight (IBW) are more likely to respond to lower doses of hMG than patients whose weight is 10% above IBW and, in particular, those who are 25% above their IBW. A high BMI was associated with a higher FSH threshold dose. This observation is supported by findings that the total dose of gonadotrophins needed to induce ovulation is increased in parallel with body weight. Why heavier women may need more hormones to induce ovulation or for controlled ovarian hyperstimulation is not clear. It may be related to the greater amount of body surface, inadequate oestradiol metabolism, and decreased sex hormone binding globulin. Also, the intramuscular absorption of the drug may be slower and incomplete in obese patients because of increased subcutaneous fat or fat infiltration of the muscle.
The effect of FSH at the ovarian level is dependent on plasma concentrations of the hormone. This, in turn, is influenced not just by the dose administered but also by endogenous FSH secretion, metabolic clearance rate, and the volume of distribution, which are individual and differ from woman to woman and are influenced by BMI. Elimination of FSH is carried out largely by the kidneys and the liver. The clearance rate is dependent on filtration, secretion, and reabsorption. The extent to which a drug is bound to plasma proteins also determines the fraction of drug extracted by the eliminating organs, which, in turn, is dependent on BMI and weight.
However, there is no randomised controlled trial in the literature testing the hypothesis that increasing the dose of gonadotrophins in obese women improves the live birth rates.
There is no evidence to suggest that one regime of pituitary suppression (agonist or antagonist) is better in obese women compared to those with normal BMI.
9.1.5
Monitoring of stimulation
While there are no data in the literature quantifying differences of monitoring in those with higher BMI, it is accepted generally that the performance and interpretation of ultrasound scans can be difficult in the obese. Theoretically, were oestradiol to be used in monitoring response to stimulation, the levels might be expected to differ in the obese from those with a normal BMI. However, there is no evidence to suggest that with overweight patients, it is advantageous to use both ultrasound and oestradiol in monitoring stimulated cycles
9.1.6
Egg collection
Clinical staff will be sensitive to the challenges which the care of women with high BMI undergoing surgical procedures present. While there is no evidence from the literature that there are more problems in caring for those who are obese, this is probably because most units are not treating morbidly obese women. That said, obese women will require a higher dose of sedation, due to increased surface area, which potentially may lead to a higher risk of exposure to the side effects of the drugs utilised, but in the absence of any published data in the literature, the perceived increase in risk remains theoretical.
Obesity complicates the delivery of assisted reproductive technologies. In obese women undergoing controlled ovarian hyperstimulation, the ovaries may shift to a higher position in the pelvis, making them more difficult to visualise with transvaginal scanning and increasing the risk of complications with oocyte retrieval such as bleeding, infection, and injury to surrounding tissue. In addition, the risks of providing anaesthesia to obese patients is well described, and makes management of these patients through nonhospital centres a challenge. In a recent survey of obesity policies at IVF facilities in the United States, 62% of respondents cited anaesthesia concerns as the primary reason for their BMI cut-off.
9.1.7
Embryo transfer
For the most part the procedure of ET is simple. However, with moves toward ultrasound-guided (USG) ET that may involve the use of abdominal ultrasound, USG-guided ET will be difficult in obese women due to poor views. Whether this would lead to lower pregnancy rate remains unknown as there are no data in the literature to explore either difficulties with the procedure or lower pregnancy rates.
9.1.8
hCG trigger
Theoretically, bioactive levels of hCG used for the ovulatory trigger will be less in obese women. However, as long as more than equivalent of 1000 IU of recombinant hCG is given as the ovulatory trigger, oocyte fertilisation rates and luteal function are unlikely to be influenced by differences in bioavailable gonadotrophin. Most ovulatory triggered preparations now contain at least 6500 IU of hCG.
9.1.9
Luteal support
Luteal support for obese women should be the same as that for women with normal BMI. This is because the vaginal pessaries are locally absorbed and bypass first-pass metabolism. There are no data comparing luteal support and outcomes in various BMI groups.
9.1.10
Pregnancy rate
All systematic reviews of observational studies have repeatedly demonstrated a detrimental impact of obesity on pregnancy rates. The largest single series comes from the Society of Assisted Reproduction (SART) in the United States. This analysis showed that failure to achieve a clinical intrauterine gestation was significantly more likely among obese women.
9.1.11
Clinical pregnancy rates
Clinical pregnancy rates in women with obesity undergoing gonadotropin IUI study findings are mixed. Some studies report no difference in the clinical pregnancy rates in obese patients compared to nonobese controls, while several others report a paradoxical increase. Possible reasons for an increased effectiveness of gonadotropin/ IUI in women with obesity include correction of anovulation, and compensation for erectile dysfunction and decreased frequency of intercourse.
The SART registry shows that there is a slight decline in the number of oocytes retrieved and the number of high-quality embryos as the BMI rises over 40. Implantation, clinical pregnancy, and live birth rates all decline gradually with increasing severity of obesity. However, the absolute decline in pregnancy rates is small. The overall likelihood of a live birth per cycle start declined from 31.4% in women with a normal BMI, to 28% in women with a BMI of 30–34.9, to 24.3% in women with a BMI of 40–44.5, and down to 21.2% in women with a BMI of >50.
The exact mechanism by which obesity lowers IVF success rates is unclear. Some studies have demonstrated alterations in embryo development and day-3 spent culture media metabolomics, while others have not detected any changes of indicators of embryo quality between obese women and nonobese controls. Alternatively, obesity may alter endometrial receptivity. Perhaps the best model to help elucidate the impact of obesity on reproduction is oocyte donation. Several studies have suggested that obesity does not impact donor egg recipient implantation or live birth rates, while other studies have found a negative association.
9.1.12
Miscarriage rate
As discussed earlier, it is uncertain whether the cause of increased miscarriages is linked to oocyte quality or other factors within the endometrium involved in implantation. The pregnancy loss rate (8.6% with normal BMI to 13.5% with BMI over 40) in oocyte recipients is comparable to the change in pregnancy loss reported by SART in women using their own eggs: 11.3% with normal BMI to 14.8% with BMI of 40–45, 17.6% with BMI of 45–50, and 20.3% with BMI over 50, suggesting that changes in embryo quality are probably not the primary driver for the BMI-related increase in pregnancy loss rates after IVF. Obesity clearly increases miscarriage risk. However, the absolute risk of pregnancy loss in women with obesity undergoing IVF is still lower than the reported risk of spontaneous pregnancy loss in women with two or more prior pregnancy losses (25%) or women aged over 40 (≥ 35%).
9.1.13
Live birth rate
The SART data demonstrated that the live birth was 1.27 times lower in obese women as compared to those with normal BMI. However, the results also indicate that there are significant differences in pregnancy and live birth rates after ART when analysed by race and ethnicity, even within the same BMI categories. Analyses done by the subgroups demonstrated that prognosis was poorer when obesity was associated with polycystic ovary syndrome, while the oocyte origin (donor or nondonor) did not modify the overall interpretation.
Many adverse maternal, foetal, and neonatal outcomes are known to be associated with obesity. Management of the infertile thus poses complex questions linked to the welfare of potential mothers and their offspring. Many pregnancy-associated complications occur with greater frequency in the obese, for example, pregnancy-induced hypertension and gestational diabetes. Need for intervention carries with the specifics of the difficulty of surgery in those who are morbidly obese, together with the potential for complications such as infection, venous thromboembolism, and anaesthetic hazards. Maternal mortality, while a rare occurrence, has associations with obesity, and a recent report highlighted the fact that many maternal deaths occurred in women with preexisting medical conditions, including obesity, which seriously affected the outcome of their pregnancies. Foetal risks in pregnancy are a concern with observed increased occurrence of foetal abnormality, macrosomia, low birth weight, neonatal mortality, and stillbirth. An influential report suggested that obesity is the principal modifiable risk factor for stillbirth in the developed world, greater than increased maternal age and smoking. Recent evidence suggests that maternal BMI was a significant risk factor for preterm delivery, even in pregnancies as a result of frozen ETs, following freeze all cycles.
Beyond these short-term outcomes, the long-term health of individuals born to obese mothers is a public health issue of concern. Children of the obese will grow up with greater risks of coronary heart disease, hypertension, glucose intolerance, and diabetes as well as themselves being obese, thereby perpetuating the problem for the subsequent generation.
The management of the obese infertile raises economic issues of note given increased costs not only associated with treatment but also those associated with the management of complicated pregnancies, particularly the need for increased surveillance, higher rates of operative delivery, and the management of women with gestational diabetes and hypertension.
Debate within the last few years has taken place as to whether these morbidities and adverse outcomes, together with higher costs, should play a part in whether the obese should be permitted the same access to infertility services as those who are not overweight. It could be argued with the prevalence of obesity being at the level it is that in fact the boundaries of what can be considered normal in the population have changed. Adverse outcomes however would suggest this is not the case. It has been argued that a restrictive policy would lead to stigmatisation of the obese, but genuine health hazards are being increasingly identified, which carry significant implications for the individuals concerned. It has even been suggested that the autonomy of the individual to determine their own health would be being infringed by policies to deny access to care. On the other hand, the identification of long-term health risks could be considered as an opportunity for the empowerment of the individual to make lifestyle adjustments that may have real health benefits for themselves. Bearing in mind the issues described earlier, it is clear that patients have responsibilities beyond themselves, and healthcare professionals similarly have responsibilities to offspring and to society at large. Scarce resources, particularly at the present time, should be used to maximum effect. Interventions to assist individuals to achieve and sustain weight loss are not always effective. However, it would be anomalous for the reproductive health sector not to share with other areas of medical practice the public health responsibility for health promotion messages relevant to weight. Losing weight may of course delay the initiation of treatment and this is important particularly in those who seek assistance in later reproductive years. However, in the younger patient the amount of weight loss to make a difference may not be substantial and the time taken to achieve a target may not adversely affect the chance of treatment being successful. That said, there is no randomised trial evidence at present that weight loss programs prior to IVF treatment have an appreciable effect on outcomes or pregnancy-associated complications.
9.2
Conclusion
There is irrefutable evidence that fertility potential is adversely affected in the obese. The proportion of patients accessing infertility services who are obese is increasing. Natural fecundity, responses to treatment, and pregnancy outcomes are suboptimal in this group of patients. The mechanisms whereby these effects are manifested are not fully understood, but it is likely that the causes are multifactorial, including endocrine, inflammatory pathways, as well as effects on oocyte quality. Interventions to address subfertility while offering increased potential for conception raise important questions relevant to the safety of mothers and offspring. While adverse outcomes are increased in this group of patients, the absolute risk to the individual of complications remains relatively small. Most conceptions will result in healthy live-born, but offspring will have increased lifetime health risks. Ethical issues in this sphere of reproductive medicine challenge principles of helping the individual while taking account of consequences for others, not least the potential child but, bearing in mind the costs of treatment, pregnancy care, and, beyond, the views of society at large.
More research in this area is needed with clearly defined patient populations, using standardised BMI criteria and uniform outcome measures. Access to individual patient data may allow more refined methods of analysis including the ability to adjust for confounders in generating combined OR. Further research is needed in determining the best measure of obesity for reproductive outcome.
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