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Box 1.  

Deleterious Effects Described in Obese Women Undergoing IVF

Impact of Bodyweight and Lifestyle on IVF Outcome: Bodyweight

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Bodyweight

Underweight

There are fewer studies of fertility in underweight women than in overweight women. It has been suggested that the association of bodyweight and IVF outcome is of an 'inverted U-shape', implying that being both under- and overweight has a deleterious effect on assisted reproduction outcome, reducing the probability of achieving pregnancy.[7,18-20] The medical literature has long suggested a link between low bodyweight, excessive exercise and infertility in women, with improvement in fertility rates associated with a reduction in exercise and modest weight gain.[8,21,22] From a biological point of view, since reproduction involves energy expenditure, it is logical that the physiological control mechanisms are linked to those involved with appetite and nutrition. Energy balance regulates reproductive function, and undernutrition has been related to anovulation, amenorrhoea and pregnancy complications.[23] However, data on underweight women are not as consistent as those on their obese counterparts. In fact, some authors have failed to find any impact of being underweight on reproduction, including IVF procedures. This lack of evidence could be due to differences among patient populations or statistical phenomena due to the infrequency of underweight.[24-26]

Underweight could affect both ovarian and endometrial function, leading to a poorer reproductive outcome. However, in a recent study performed using the oocyte donation model,[27] the ongoing pregnancy rate per cycle initiated fell significantly when the BMI of recipients surpassed 25 kg/m2, while no differences were detected between normal weight (20-24.9 kg/m2) and underweight (<20 kg/m2) patients, suggesting that there was no deleterious effect on the endometrium. Therefore, the inverted U-shape of bodyweight in fertility described so often in natural and assisted conceptions could not exist in cycles with donated ova, thereby pointing to the negative effect of undernutrition on the ovary. In fact, some authors have suggested that undernutrition would have an impact on ovarian function by disturbing the hypothalamic control of gonadotrophin secretion and the dopaminergic and opioid systems.[23,28] More studies are necessary in order to determine the real effect of undernutrition on assisted reproduction. In women with eating disorders, the main risk seems to be associated with maternal and fetal outcomes once pregnancy is achieved.[23]

Overweight

The interactions between genetic predisposition,[28] prenatal overnutrition (programming of appetite),[29] and postnatal lifestyle and environmental factors,[23] lead to obesity, but contribute differently in each subject. The high prevalence of obesity in developed countries seems to be the result of a combination of reduced exercise, changes in dietary composition and increased caloric intake.[30] In the USA and most European countries, 60% of women are overweight (≥25 kg/m2), 30% are obese (≥30 kg/m2) and 6% are morbidly obese (≥35 kg/m2), according to the WHO criteria.[30,31,192]

Obesity affects the general and older population, but also young women who become or try to become pregnant. In a recent study performed in the UK with 36,821 women, the trend in maternal obesity between January 1990 and December 2004 was calculated in young women with a mean age of 24-28 years.[32] The prevalence of obesity was 9.9% in 1990 and 16% in 2004, and has been estimated to reach 22% in 2010. This report and others provide evidence that obesity is increasing among women of childbearing age who may be potential candidates for ART.

Obesity increases morbidity and mortality as a result of a variety of associated pathologies, such as cardiovascular and cerebrovascular diseases, Type 2 diabetes, sleep apnea, gastrointestinal diseases, osteoarthritis and cancer.[33] In the field of gynecology and reproduction, obesity has been associated with menstrual disorders, hirsutism, infertility, miscarriage and obstetric complications.[34] In addition, over a third to 50% of polycystic ovary syndrome (PCOS) subjects are overweig or obese.[35]

Infertility in natural cycles is almost three-times higher among obese women.[36] Similarly, obese women are more prone to fail to become pregnant in assisted conception cycles.[37,38] Central obesity connotes a worse prognosis.[18,37,39,40] Impairment of ovarian function and reproductive outcome as a result of excess weight is thought to be caused by endocrine and metabolic alterations; namely an excessive estrogen production, dysregulation of steroid metabolism, reduced availability of gonadotrophinreleasing hormone, increased opioid activity, and changes in the secretion and action of insulin and other adipose hormones (e.g., leptin, adiponectin, resistin and ghrelin) (Figure 1).[25,41-44] This endocrine profile leads to the three main pathophysiological features through which obesity affects reproduction: hyperinsulinism, functional hyperandrogenism and anovulation.[25,41,43] Obviously, the complete clinical picture (Figure 1) appears when morbid obesity is present, especially with associated central distribution or PCOS. Such alterations can affect follicle growth, embryo development and implantation in both natural and assisted conception cycles.[41,45,46] Ferlitsch et al. reported that, by raising BMI by one unit, the odds for pregnancy decreased by 0.84 in IVF.[47] Similarly, each reduction of BMI by one unit, increased the chance of pregnancy by 1.19.

Figure 1. (click image to zoom) Endocrine and metabolic disturbances in obese women. The interactions between genetic predisposition, prenatal overnutrition ('programming of appetite'), postnatal lifestyle and environmental factors lead to obesity, but contribute differently in each subject. Obesity has been related to several metabolic and endocrine disturbances, which are more frequent when morbid obesity exists, especially with central distribution or associated with PCOS. In fact, between a third and half of PCOS patients are obese. The three main pathophysiological features associated with obesity are hyperinsulinism, functional hyperandrogenism and anovulation. Hyperinsulinism is a consequence of the insulin resistance related to the weight excess, more common in cases of central obesity. Increased β-endorphin serum levels described in obese people, frequently associated with PCOS, have been also related to hyperinsulinisim. Hyperinsulinism leads to long-term health consequences, such as glucose intolerance, Type 2 diabetes and dyslipemia. In addition, hyperinsulinism inhibits the liver synthesis of SHBG, increasing the free and biological active levels of androgens (testosterone, dihydrotestosterone and androstenediol), and induces an increased androgen production by the adrenals, leading to a state of 'functional hyperandrogenism'. The reduced serum ghrelin levels present in obese women have also been related to this type of hyperandrogenism because ghrelin and androgen levels are counterbalanced; this mechanism being another possible pathway of hyperinsulinemic-induced hyperandrogenism. The increased local androgen concentration in the ovary generated through the direct stimulation of techa cells by the insulin excess, leads to follicular atresia and, thus, to anovulation. Leptin serum levels are related to the amount of fat tissue in the body. In obese women, there is a state of leptin resistance that induces hyperleptinemia. High levels of leptin appear to act directly on the ovary also inducing anovulation. The clinical consequences of this picture are hirsutism, menstrual disturbances and infertility. A4 = Androstenedione; DHT = Dihydrotestosterone; DM = Diabetes mellitus; GI = Glucose intolerance; GnRH = Gonadotrophin-releasing hormone; PCOS = Polycystic ovary syndrome ; SHBG = Sex hormone-binding globulin; T = Testosterone.

 

In this review, which focuses on IVF treatments, the current evidence regarding four important questions will be addressed:

  • Does obesity impair the chances of becoming pregnant through IVF?sOnce the pregnancy is achieved, does obesity increase the risk of a poor obstetric outcome?
  • How does obesity affect reproductive outcome? Is the endometrium or the oocyte-embryo complex affected, or both?
  • How can the reproductive performance be improved in obese patients?

Obesity & Chances of Pregnancy Following IVF. A delayed spontaneous conception has been reported in obese women, mainly due to a higher risk of ovulatory infertility, but also in women with regular ovarian cycles in whom the probability of pregnancy is reduced by 5% for every additional unit of BMI that exceeds 29 kg/m2.[48] These findings may suggest the presence of anovulation despite regular menses, the release of ova with reduced fertilization potential or endometrial abnormalities.[44] In addition, the ovarian response to gonadotrophins or clomiphene citrate has been shown to be lower in obese women undergoing ovulation induction for programmed coitus or intrauterine inseminations, with or without PCOS,[49-53] while the effect on pregnancy rates remains controversial. That said, some papers have suggested a lower possibility of conception than in the normal-weight population.[37,51,54]

Both IVF and intracytoplasmic sperm injection (ICSI) procedures in obese women undergoing controlled ovarian hyperstimulation (COH) require higher doses of gonadotrophins due to the 'gonadotrophin resistance' that characterizes these patients,[25,55,56] also observed when associated with PCOS.[54] Doses of gonadotrophins need to be raised as BMI increases in both long- and short-stimulation protocols.[57] Crosignani et al. reported a negative response to COH on day 7 and at the end of the treatment in non-PCOS patients undergoing IVF, and found that overall failure rates rose with each tertile of body mass or surface areas, which suggested that the response to ovarian stimulation was inversely related to BMI.[38] Indeed, obese patients undergoing COH have been shown to require longer periods of ovarian stimulation and exhibit higher cancelation rates in both ovulation induction[50] and IVF/ICSI,[25,28-60] which may be the result of an insufficient response. A higher incidence of follicular asynchrony in obese women undergoing COH was also reported by Kably-Ambe et al.[61]

Fertilization rates have been shown to be negatively affected by low concentrations of periovulatory human chorionic gonadotrophin (hCG). Carrell et al. reported an inverse correlation between BMI and intrafollicular hCG concentration, which was significantly lower among patients with a BMI of over 30 kg/m2 than among those with a BMI of 20-30 or under 20 kg/m2.[62] This finding was related to the inferior embryo quality and lower pregnancy rates observed among the overweight and obese patients assessed. Estradiol concentrations (hCG/day) have been seen to peak at lower levels in obese women undergoing COH for IVF, both with[63] and without[55,64] an association with an impaired cycle outcome. In the same way, one report related a thicker endometrium at oocyte retrieval to obesity, although it was not found to have a negative effect on final outcome.[63]

Higher doses of gonadotrophins, a longer period of ovarian stimulation and higher cycle cancelation rates due to insufficient response are frequent among obese patients, and all three characteristics have been attributed to what is known as gonadotrophin resistance. Similar findings have been observed in obese egg donors. It would represent an attenuated response caused by a reduced absorption of the drug[65] or the way in which it is distributed throughout the body. In this way, the altered pharmacokinetics of gonadotrophins in obese women would seem to result in lower effective concentrations of exogenous follicle-stimulating hormone (FSH).[66] The selection of multiple growing follicles during ovarian stimulation with FSH requires the serum FSH concentration to exceed a certain threshold.[67] The threshold effect of exogenous FSH is lower among obese women,[68] leading to a lower number of selected follicles, fewer collected oocytes and the need for higher doses of FSH for stimulation.[25] Leptin serum concentration is also thought to induce gonadotrophin resistance. Leptin levels are related to the amount of adipose tissue in the body.[42] The stimulatory effect of FSH on steroid synthesis by granulosa cells in vitro is inhibited by leptin,[69,70] and high concentrations of intrafollicular leptin have been related to relative gonadotrophin resistance during ovarian stimulation for IVF in PCOS women.[71] In these women, the higher incidence of android obesity has also been associated with a poorer IVF outcome.[39]

In summary, however, it must be said that the conclusions of reports addressing the aforementioned aspects are varied and contradictory; indeed, some have found obesity to have no negative effect on ovarian response in IVF.[63,64,72]

Obese patients are generally reported to experience lower live birth rates, particularly when this parameter is calculated per IVF/ICSI cycle initiated. A healthy liveborn is less probable among these subjects due to a combination of lower implantation and pregnancy rates, higher preclinical and clinical miscarriage rates and more frequent complications during pregnancy for both mother and fetus.[34] Obesity and the endocrine alterations associated are thought to affect corpus luteum function,[73] early embryo development,[74,75] trophoblast function[76] and endometrial receptivity.[77,78]

Obesity is also considered to have a deleterious effect on embryo implantation.[56,63] The roles of the ovary and endometrium in this effect are unclear, although recent studies using the oocyte donation model have provided interesting data (see later). Nevertheless, some reports have found no relationship between BMI and implantation rates.[25,79,80]

Lower pregnancy rates have been described in obese women following ovulation induction or ART.[56,63,81] Nichols et al. observed an odds ratio (OR) for conception of 0.53 (95% confidence interval [CI]: 0.32-0.86) in overweight women undergoing IVF.[63] Similarly, Wang et al. described a progressive reduction of the OR for fecundity - defined as the probability of achieving at least one pregnancy throughout the ART treatment: IVF, ICSI or gamete intrafallopian transfer (GIFT) - in IVF patients from 25 kg/m2 (OR: 0.81; 95% CI: 0.68-0.97) to 35 kg/m2 or higher (OR: 0.50; 95% CI: 0.32-0.77) of BMI.[82] This represented a reduction of almost a third in obese women (30.34.9 kg/m2) and 50% in very obese women (.35 kg/m2). This effect seems to be more acute in cases of central obesity, in which the waist-to-hip ratio is over 0.80.[39]

However, other authors have not found any significant association between high BMI and chance of pregnancy after IVF.[25,57,59,64] These conflicting results are related to aspects of the methodology of the studies, such as their retrospective nature, the small sample sizes employed and their subsequent low statistical power, the incompletely characterized or unstratified patient heterogeneity, inconsistent definitions of obesity and normal weight, combination of overweight and obesity in the same study group, disregard for the influence of the obese spouse on pregnancy rates, mixture of central and noncentral obesity, and lack of homogeneity in the type of treatment employed.

In an attempt to provide clarification, a recent systematic review of the effect of overweight and obesity on ART has concluded that pregnancy rates in nonoverweight women (20-25 kg/m2) are significantly higher (OR: 1.40; 95% CI: 1.22-1.60) than those in overweight women (>25 kg/m2). Similarly, nonobese women (20-30 kg/m2) presented significantly higher pregnancy rates (OR: 1.47; 95% CI: 1.20-1.80) than obese patients (>30 kg/m2).[83] Therefore, considering current evidence, it can be concluded that obesity negatively affects IVF pregnancy rates.

Obesity & Poor Obstetric Outcome. Miscarriage rates are higher among obese women who have conceived naturally[18,84,85] or through ovulation induction[50,84,86] and IVF/ICSI.[25,56,87,88] These rates refer to preclinical losses,[25,87] clinical losses[25] and recurrent miscarriages.[85,89] The calculated OR for early pregnancy loss (up to the week 6 of gestation) in obese women undergoing IVF with respect to patients of normal weight is 1.69 (95% CI: 1.13-2.51).[25] However, Winter et al. related the higher risk of miscarriage in early pregnancy to poor-quality embryos rather than obesity.[20] That said, obesity has itself been linked to poor oocyte and embryo quality.[62,87,90]

Few reports have not found a relationship between high BMI and miscarriage, but this may be due to the variety of cut-off BMI values considered (≥25 kg/m2;[57] ≥27.9 kg/m2;[64] ≥27 kg/m2;[24] ≥28 kg/m2)[63] and the small sample sizes usually employed. A BMI of 30 kg/m2 or higher is the most appropriate cut-off for the definition of obesity, and is recommended by other authors and the WHO.[25,31,91,92] Although a BMI of 27 kg/m2 or higher is generally considered to have negative health implications, a BMI of 30 kg/m2 or higher has traditionally been the point at which the relative risk of death from all causes is considered to double and endocrinological abnormalities are, consequently, more common. A universal definition of obesity would aid research and would promote more uniform and reliable results.[93] However, an increased risk of early pregnancy loss after IVF or ICSI has even been reported in overweight patients when lower BMI cutoffs were applied.[87,94] A lack of differentiation of fat distribution or fat type could also explain the discrepancies between the results of the different studies.[20]

In the recent systematic review performed by Maheshwari et al., in which ten studies of overweight/obesity and IVF were evaluated, the OR for miscarriage was significantly higher in overweight (>25 kg/m2; OR: 1.33; 95% CI: 1.06-1.68) and obese women (>30 kg/m2; OR: 1.53; 95% CI: 1.27-1.84) than in nonoverweight (<25 kg/m2) and nonobese (<30 kg/m2) women, respectively.[83] Similarly, a meta-analysis of 16 studies performed by Metwally et al. regarding the effect of high BMI on risk of miscarriage after spontaneous or assisted conception determined that patients with a BMI of 25 kg/m2 or higher had a significantly higher probability of having a miscarriage, regardless of the method of conception (OR: 1.67; 95% CI: 1.25-2.25).[95] This increased risk was particularly identified in pregnancies obtained by ovulation induction and ovum donation. This evidence would suggest that an increased risk of miscarriage after IVF should be considered in overweight and obese women.

The high prevalence of PCOS among infertile obese women, which is itself associated with miscarriage, does not fully explain the relationship between obesity and miscarriage in assisted conception.[25,87,88] Indeed, Wang et al. suggested obesity to be an independent risk factor for miscarriage, attributing the higher numbers of spontaneous abortions observed in women with PCOS to their levels of obesity and the type of treatment they received.[91]

Some recent theories have postulated that the increased risk of biochemical and first-trimester clinical miscarriages in obese women undergoing IVF could be related to ovarian or endometrial factors. Regarding ovarian factors, miscarriage in obese women has been associated with impaired insulin resistance at the time of conception,[85] abnormal corpus luteum function,[87] impaired oocyte quality due to the reduced risk of miscarriage in cases of ICSI in which infertility is attributed to the male factor,[96] and poor oocyte/embryo quality and development.[20,75,85] Endometrial receptivity may also be impaired,[77,78] and exposure of the uterus to high estradiol concentrations produced by the higher doses of gonadotrophins administered in obese patients during ovarian stimulation in order to compensate for the state of gonadotrophin resistance[88,99] could also lie behind the tendency towards miscarriage.

Obese women tend to experience obstetrical complications in all three trimesters of pregnancy. Obesity is associated with 18% of obstetric causes of maternal mortality and 80% of anesthesiarelated deaths.[92] Pregnancy complications are higher in obese women, particularly during the third trimester, and include hypertension, gestational diabetes, preeclampsia, thromboembolism, fetal macrosomia, urinary tract infection, preterm labor and delivery, sudden and unexplained intrauterine death, operative vaginal deliveries, cesarean section delivery, shoulder dystocia, anesthetic and surgical complications, postpartum hemorrhage, postoperative wound infection and dehiscence, and endomyometritis in the puerperium.[92,98,99]

Defects of the CNS of the fetus (e.g., neural tube defects), great vessels, ventral wall and intestine[99-102] have been described more frequently in obese women. These findings could be explained by insufficient absorption or distribution of essential nutrients such as folic acid, the incipient hyperglycemia caused by insulin resistance at the time of organogenesis, or the poorer visualization of fetal organs by ultrasound, which may lead to subsequent errors in sonographic prenatal diagnosis.[103-105]

Obesity has also been related to an increased risk of chronic disease in the adolescence and adulthood of the offspring, such as obesity, cardiovascular disease and Type 2 diabetes.[106] As obesity can affect all aspects of maternal health, management of pregnancy in obese women is likely to be associated with a substantial increase in costs. For obese women, the cost of antenatal care is approximately five-times higher than the average.[86]

Impact of Obesity on Gametes, Embryos & Endometrium. Based on the aforementioned data, obesity seems to be related to lower fecundity, reduced implantation and pregnancy rates, increased biochemical pregnancy rates and clinical miscarriages, and more frequent second- and third-trimester pregnancy complications, all of which is regardless of how conception has been achieved (spontaneously, by ovulation induction or IVF/ICSI). The combination of all these trends leads to a reduced live birth rate.

Fedorcsak et al. (n = 383) reported a live birth rate of 75% in women with a BMI of less than 25 kg/m2 after IVF/ICSI, which dropped to 63% (p = 0.04) in patients with a BMI of 25 kg/m2 or higher.[87] Excess weight (defined as a BMI ≥ 27 kg/m2) was found to have a significant effect on the live birth rate per IVF cycle by Lintsen et al. (n = 8457), who calculated an OR of 0.67 (95% CI: 0.48.0.94).[94] Recently, Fedorsak et al. (n = 5019) detected a linear association between higher BMI and reduced live birth and cumulative live birth rates, reporting a live birth OR of 0.75 (95% CI: 0.57.0.95) in women with a BMI of 30 kg/m2 or higher with respect to those of normal weight.[25] Fedorcsak et al. found that obese patients had on average 3.9 fewer live births per 100 initiated IVF and ICSI cycles than controls of normal weight.[25] Calculated as a cumulative effect, 41 out of 100 obese women gave birth to living newborn(s) within three treatment cycles, compared with 50 out of 100 women with normal bodyweight.

Most complications in the second and third trimester of pregnancy are due to maternal manifestations of the metabolic syndrome of obesity. However, what occurs between conception and the end of the first trimester seems to be the result of an abnormal dialogue between the oocyte (and, thus, the resulting embryo) and the endometrium. Therefore, the logical next step should be to determine the influences of each of these two components in the final result of the equation, which is the ongoing pregnancy rate per cycle started.

Oocyte/Embryo. Several studies have shown a significantly reduced oocyte retrieval in overweight and obese women,[25,38,55,57,72,83,87] which is mainly due to their poorer ovarian response, and occurs even when PCOS is associated.[55] The lower bioavailability of injected hCG (intramuscular or subcutaneously) described in obese patients[107] could be partly responsible for this finding. Moreover, Fedorcsak et al. found a significant association between the lower number of collected oocytes in obese women and their increased risk of early pregnancy loss.[87] However, other authors have found no differences between the numbers of oocytes retrieved from different BMI groups.[63,64]

Oocyte quality may also be impaired as a result of obesity, with subsequent lower fertilization rates.[60,108] Dokras et al. reported lower numbers of mature oocytes in obese women undergoing IVF.[80] However, while some authors have reported a poorer oocyte and embryo quality in obese patients,[25,62,87,90,109] others have failed to demonstrate such an association.[63,82] Similarly, a lower incidence of embryo transfer and a lower mean number of transferred embryos have been observed in linear association with a rising BMI in some,[25,80,109] but not in all[63,64] studies. Hence, there is a current lack of consensus with regard to the supposed oocyte and embryo impairment in obese women undergoing IVF, and to what degree they are altered.

Some authors have hypothesized that increased gonadotrophin doses, administered in order to compensate for relative gonadotrophin resistance induced by obesity, might result in impaired oocyte/embryo quality, implantation failure and regnancy complications.[55] Indeed, superovulation in mice induces various defects, such as abnormal embryonic development and decreased invasional capacity of blastocysts in vitro, as well as lower implantation rates, delayed implantation, increased length of gestation, lower birthweight and developmental retardation in vivo.[110,109] Hence, gonadotrophin therapy could alter uterine receptivity,[112-114] explaining the impaired implantation and embryonic development after gonadotrophin treatment in mice[110,111] and the high incidence of spontaneous abortion in human beings,[115] which could be increased in obese women due to the high doses of gonadotrophins that they require.[87]

Recently, the role of male partner obesity in the poorer IVF outcome has been evaluated. In fact, three recent studies of young fertile populations have reported a significant alteration in the hormonal male pattern of obese men, leading to a significant reduction in some sperm parameters, including sperm concentration and total sperm count, and a trend towards an impaired morphology.[11,116,117] Therefore, the inferior sperm quality of obese men could also impair the quality of embryos after IVF. In fact, a recent study of 26,303 planned pregnancies, after controlling for other confounding variables, found an OR for infertility in overweight and obese men that was significantly higher (1.2-1.4) than that in normal weight men.[118] Similarly, Ramlau-Hansen et al. (n = 47,835 couples) observed a dose-response relationship between increasing BMI and subfecundity (time to pregnancy > 12 months) among women and men with a BMI of 18.5 kg/m2 or higher.[119] Therefore, couples ran a high risk of being subfecund if they were both obese. Couples often share similar lifestyle behaviors, so that some obese women have obese male partners, and the poor reproductive outcome of these couples could be the result of the combination of two low-quality gametes in a low-quality embryo, that may reach a low-quality endometrium.

At IVI-Valencia, we recently examined the outcome of 6500 IVF cycles according to women's BMI, while controlling for different confounding variables such as age, smoking habit, sperm quality, origin and duration of infertility, and protocol for ovarian stimulation. In the obese group (≥30 kg/m2), there was a significant increase in the dose of gonadotrophins during controlled ovarian stimulation, and significantly lower implantation (26.4 vs 32.2% when <30 kg/m2; p = 0.005), pregnancy (37.9 vs 44.4% when <30 kg/m2; p = 0.029) and live birth rates (23.7 vs 30.6% when <30 kg/m2; p = 0.004) than the other three groups. However, when oocyte and embryo quality were assessed, we found no significant differences among the different BMI groups [Bellver et al.; unpublished data]. These results indicate that the contribution for the poor reproductive outcome of obese women undergoing IVF could be related to the endometrium (or the uterine environment) or to the oocyte/embryo complex, but the conventional embryological criteria employed for selecting the best embryos to transfer in the IVF laboratories may be insufficient in such cases. This could explain the disagreement between different studies published to date regarding the oocyte and embryo quality of obese women undergoing IVF, despite a consensus about the poor reproductive outcome of these patients.

Endometrium. The endometrium may also be affected by obesity.[120] The best human model for dissecting both components (embryo and endometrium) s the ovum donation model, in which oocytes from healthy, young, nonobese donors are given to recipients with different BMIs and the subsequent outcome is studied. Postovum donation implantation, pregnancy and miscarriage rates with respect to the BMI of the recipient have been evaluated by only a few recent studies.[27,121-123] Miscarriage and ongoing pregnancy rates in these studies have varied considerably, mainly owing to statistical shortcomings including insufficient sample sizes, poor selection criteria or overestimation of fetal loss rates. The first of the studies in question reported a fourfold increase in the risk of spontaneous abortion in obese women,[121] but two later publications failed to detect any impact of obesity on pregnancy outcome.[122,123]

Our group performed the first of the three aforementioned studies[121] and, although we detected no significant differences in pregnancy or implantation rates with respect to BMI, we did observe a trend towards poorer results in obese women. The miscarriage rate, on the other hand, was significantly higher in obese women (38.1%) than in overweight and normal patients, and constituted an OR for miscarriage of 4.02 (95% CI: 1.53-10.57). However, the obese group sample size was somewhat small (n = 50), and not all the cycles were first cycles. Thus, an overestimation of repeated cycles in the same patient may have contributed to increase the number of miscarriages in the obese group, as later suggested by other reports.[123,124] The second study used the ovum donation model to evaluate uterine receptivity through endometrial implantation.[122] No effect of BMI on implantation rates was reported among first-cycle recipients of ovum donation. However, the number of subjects included was insufficient on which to base any solid conclusions; of a total of 96 cycles, the lean group consisted of only seven patients and the obese group only 12 patients. The third study employed a better methodology than the former two, as only first-cycle recipients of ovum donation were evaluated, and the number of cases was considerably larger (n = 536), including a total of 77 obese subjects.[123] No significant differences were detected between pregnancy, implantation and miscarriage rates in the different BMI groups. However, miscarriage rates were considerably high in the lean, normal and obese groups (25.0, 24.5 and 29.8%, respectively). Furthermore, when fetal loss rates were differentiated according to day of embryo transfer (day 3 versus blastocyst), miscarriage rates rose to 34.3 and 45.0% on day 3 in normal and obese women, respectively. A recent study of 3089 ovum donation cycles showed a global miscarriage rate of 17.6%, which fell to 16.8% in women aged under 45 years (n = 2683),[125] the age of most of the subjects in the study by Styne-Gross et al.[123] Therefore, the high miscarriage rate found by Styne-Gross et al.[123] calls into doubt their conclusions.[126]

Recently, we have studied a huge sample of first-cycle recipients of ovum donation without risk factors of miscarriage (n = 2656), of which 122 were obese. A tendency towards lower implantation and pregnancy rates and higher miscarriage and ectopic rates was linked to an increasing BMI. These differences were not statistically significant. However, this tendency led us to analyze the ongoing pregnancy rate per cycle initiated, and we found that the obese group demonstrated significantly lower values (36.1%) than lean (<20 kg/m2; 46.7%; p = 0.032) and normal (20-24.9 kg/m2) controls (45.2%; p = 0.046) (Figure 2). This effect was more pronounced when the cut-off value of 25 kg/m2 was considered for comparisons.[27] This study indicates that the endometrium, or its environment, plays a role in the poor reproductive outcome of obese women. This, in turn, suggests that the ovary should not be the only consideration in the fertility prognosis of these patients.

Figure 2. (click image to zoom) Reproductive outcome in ovum donation according to recipient's BMI. BMI = Body mass index; EP = Ectopic pregnancy rate; IR = Implantation rate; MR = Miscarriage rate; PR = Pregnancy rate; OPR = Ongoing pregnancy rate.

In Box 1 there is a summary of all the described deleterious effects of obesity on IVF outcome.

Improvement of Reproductive Performance in Obesity. The main mechanism of infertility in obese women is anovulation.[48] Despite the use of gonadotrophins or clomiphene citrate in isolated ovarian cycles to induce ovulation or superovulation for programmed coitus and intrauterine inseminations, the best option consists of developing strategies that could maintain ovulation chronically. Some of these strategies include weight loss by diet and exercise, pharmacological therapy and bariatric surgery.

Weight loss is the most important isolated measure to improve or even restore fertility in obese women, regardless of how conception is achieved. With just 5% or more loss of bodyweight the reproductive status of a patient can be improved significantly,[25] and even more so when abdominal fat is reduced.[127] Weight loss results in decreased testosterone and fasting insulin concentrations, decreased insulin response to 75 g of glucose orally, decreased hyperlipidemia and increased sex hormone-binding globulin (SHBG) concentrations.[25,128,129] Clinical consequences of weight loss include the regularization of the menstrual pattern, the reduction of hirsutism and the improvement of ovulation and pregnancy rates in up to 80-90% of patients.[130-133] The restoration of ovulatory cycles seems to be related to caloric restriction and is mediated by the reduction of insulin resistance which is more common in central obesity.[18,25,41,129] Weight reduction is achieved by diet and exercise which should be adapted to the physical condition of the patient so that energy expenditure exceeds energy intake. The key component of such a diet should be calorie restriction rather than the composition of the diet itself.[23] However, these measures are often insufficient when a long-term follow-up and psychological support do not form part of the strategy. Therefore, a multidisciplinary approach by endocrinologist, gynecologist, psychologist and nutritionist is advisable in obese and, in particular, morbidly obese women. The acquisition of sensible eating habits and the long-term compliance with a weight-reduction program (sometimes to be sustained for life) is essential for a significant effect on health, and complementary psychological behavior therapies are often necessary for the long-term maintenance of the improvements achieved.[18,30]

Appetite suppressants (e.g., sibutramine and orlistat) appear to aid long-term weight loss maintenance by undermining appetite and fat absorption and by increasing satiety. However, their use regarding fertility is controversial and poorly assessed; side-effects have been reported and a close follow-up is recommended.[23,30,134] In addition, studies evaluating the long-term efficacy of anti-obesity agents are limited.

Metformin, a biguanide oral antihyperglycemic agent belonging to the family of insulin-sensitizing drugs, can reduce fasting insulin and androgen concentrations, thereby improving ovulation, especially when hyperandrogenism is associated.[30,41,135] It seems to be less efficacious for ovulation in obese PCOS women than in normoweight PCOS women.[30] Its effect on weight loss seems to be only modest at high doses.[136] Tang et al. showed that metformin alone does not improve weight loss in obese patients with PCOS and that only weight loss through lifestyle modification improved menstrual frequency.[137] Metformin may complement a hypocaloric diet and counteract the metabolic and endocrine alterations of obesity, especially menstrual disturbances,[138] but its effect seems to be limited when there is excessive weight.[139] Finally, in PCOS, metformin alone does not seem to have a more positive effect on ovulation and live birth rates than clomiphene citrate (CC) alone[140,141] but may be useful when administered in combination with CC in CC-resistant women.[142]

Bariatric surgery has been proposed when all the previously described measures fail and particularly in cases in which BMI is 40 kg/m2 or higher, or 35 kg/m2 or higher with comorbid conditions.[134] Gastric bypass or banding could restore both menstruation and pregnancy,[143,144] but is associated with numerous surgical complications including a 1.year mortality rate of up to 4.6%,[145.147] and perinatal and maternal problems in pregnant women,[106,144] which may be avoided if there is an interval of 2 years between surgery and pregnancy.[148] Moreover, bariatric surgery is expensive and there are no long-term follow-up data regarding progress of offspring.[106,146] In addition, a recent study has even shown higher rates of infertility (OR: 4.7; 95% CI: 1.9-11.7) in obese women undergoing assisted reproduction and who have been operated on this way.[149] Currently, bariatric surgery for reproductive purposes is not usually recommended and should be considered as a last-line therapy.

In the context of IVF, there are no studies of ART outcomes with respect to weight management, and the role of different diets, pharmacological interventions and surgical procedures in improving reproductive parameters are not yet known.