Introduction

Obesity is widely regarded as a major global pandemic that has far-reaching implications well beyond the ramifications of the patient’s health . Obesity rates have increased dramatically in developed countries, and this trend is also now evident in developing countries. For example, in Australia in 1995, 5% of the population was determined to be overweight or obese. Less than two decades later, these levels have surpassed 60%. These figures closely reflect the trends in the United States and other developed countries . Obesity has overtaken smoking as the leading cause of premature death in most developed counties, to the extent that it is now regarded as the single largest threat to public health. With these trends in sight, it is estimated that the current generation of children will have a shorter life expectancy than earlier generations simply because of obesity.

On an economic level, the direct and indirect medical costs associated with obesity are truly staggering . Conventionally, obesity is linked to conditions such as hypertension, type 2 diabetes, hypercholesterolaemia, coronary heart disease (CHD), stroke, asthma and arthritis. In practice, however, it is recognised that obesity will have direct implications on virtually every medical specialty. The practice of obstetrics and gynaecology has had to undergo a rapid transformation in recent years in order to adapt to this patient demographic.

Obesity is a major contributor to a variety of underlying aetiologies associated with infertility . No longer controversial, most of the recent evidence categorically demonstrates that obese women are at an increased risk of sub-fecundity and infertility. This is mediated by an interplay between derangements in the hypothalamic–pituitary–ovarian axis, oocyte quality and endometrial receptivity . Indeed, poorer reproductive outcomes have been demonstrated to impact obese women regardless of the mode of conception, encompassing natural conception, pregnancies achieved by ovulation induction, in vitro fertilisation (IVF)–intra-cytoplasmic sperm injection (ICSI) and from ovum donation programmes. Moreover, a direct correlation has been demonstrated between a higher body mass index (BMI) and a poorer fertility prognosis . Therefore, it is of paramount importance that the initial presentation of infertility should act as a barometer of a patient’s general state of health. As such, it is incumbent on treating clinicians to make a significant mind shift and avoid the temptation to solely concentrate on the presenting complaint of infertility; instead, clinicians must adopt a more holistic approach when considering the long-term health sequelae of patients.

Biochemical effect of obesity on fertility

Obesity has profound effects on sex hormone secretion and metabolism resulting in changes to the bioavailability of oestrogen and androgens. With increasing adiposity, there is an increase in peripheral aromatisation of androgens to oestrogens with a concurrent decease in the hepatic synthesis of sex hormone-binding globulin (SHBG). This results in an increase in free oestradiol and testosterone levels. This is further exacerbated by an associated hyperinsulinaemia resulting in a further decrease of SHBG and stimulation of ovarian androgen production. The resultant hypersecretion of luteinising hormone (LH) and the increased androgen to oestrogen ratio and the overall altered endocrine milieu in turn lead to impaired folliculogenesis and follicular atresia. It is clear that obesity is associated in varying degrees with insulin resistance, hypertension, dyslipidaemia and varying components of metabolic syndrome . The way these interplay with folliculogenesis and endometrial receptivity is yet to be fully elucidated; notwithstanding this, it is clear that obesity has a direct and deleterious impact on fertility. Analysis of follicular fluid assayed for various hormones and metabolites from patients undergoing IVF cycles demonstrates significant differences in obese patients compared with their normal-BMI counterparts. Furthermore, the systemic alterations associated with obesity, namely, hyperinsulinaemia, dyslipidaemia and inflammatory responses, are evident from the ovarian follicular microenvironment . By extension, on observing the plasma serum levels of obese subjects, varying levels of insulin resistance are noted, known to have profound physiological ramifications. The overall adiposity is further associated with changes related to inflammation, coagulation and fibrinolysis . Various such markers including C-reactive protein, interleukin-6, tumour necrosis factor-α and plasminogen activator inhibitor type-1 are found in increased levels in obese patients. It is stipulated that these have a deleterious effect on the reproductive cycle.

In a study by Metwally et al. (2007) , comparing IVF outcomes in obese and lower-BMI groups of patients under the age of 35 revealed some interesting results. Age is, of course, a very sensitive marker of oocyte quality and a prognostic marker of assisted reproductive technology (ART) success. The rationale of focussing on women under the age of 35 is that one would expect the quality of oocytes to be consistently better than in an older age group. This study revealed that women who are obese had significantly lower oocyte utilisation rates and significantly more embryos discarded than the normal or overweight subgroups being analysed. Furthermore, there were fewer embryos cryopreserved and, overall, a poorer mean embryo grade was attained whilst a higher dose of gonadotropins was used. This study, in conjunction with many others , supports the idea that, on a biochemical level, obesity impacts oocyte quality and this is further compounded by obesity affecting uterine receptivity.

Biochemical effect of obesity on fertility

Obesity has profound effects on sex hormone secretion and metabolism resulting in changes to the bioavailability of oestrogen and androgens. With increasing adiposity, there is an increase in peripheral aromatisation of androgens to oestrogens with a concurrent decease in the hepatic synthesis of sex hormone-binding globulin (SHBG). This results in an increase in free oestradiol and testosterone levels. This is further exacerbated by an associated hyperinsulinaemia resulting in a further decrease of SHBG and stimulation of ovarian androgen production. The resultant hypersecretion of luteinising hormone (LH) and the increased androgen to oestrogen ratio and the overall altered endocrine milieu in turn lead to impaired folliculogenesis and follicular atresia. It is clear that obesity is associated in varying degrees with insulin resistance, hypertension, dyslipidaemia and varying components of metabolic syndrome . The way these interplay with folliculogenesis and endometrial receptivity is yet to be fully elucidated; notwithstanding this, it is clear that obesity has a direct and deleterious impact on fertility. Analysis of follicular fluid assayed for various hormones and metabolites from patients undergoing IVF cycles demonstrates significant differences in obese patients compared with their normal-BMI counterparts. Furthermore, the systemic alterations associated with obesity, namely, hyperinsulinaemia, dyslipidaemia and inflammatory responses, are evident from the ovarian follicular microenvironment . By extension, on observing the plasma serum levels of obese subjects, varying levels of insulin resistance are noted, known to have profound physiological ramifications. The overall adiposity is further associated with changes related to inflammation, coagulation and fibrinolysis . Various such markers including C-reactive protein, interleukin-6, tumour necrosis factor-α and plasminogen activator inhibitor type-1 are found in increased levels in obese patients. It is stipulated that these have a deleterious effect on the reproductive cycle.

In a study by Metwally et al. (2007) , comparing IVF outcomes in obese and lower-BMI groups of patients under the age of 35 revealed some interesting results. Age is, of course, a very sensitive marker of oocyte quality and a prognostic marker of assisted reproductive technology (ART) success. The rationale of focussing on women under the age of 35 is that one would expect the quality of oocytes to be consistently better than in an older age group. This study revealed that women who are obese had significantly lower oocyte utilisation rates and significantly more embryos discarded than the normal or overweight subgroups being analysed. Furthermore, there were fewer embryos cryopreserved and, overall, a poorer mean embryo grade was attained whilst a higher dose of gonadotropins was used. This study, in conjunction with many others , supports the idea that, on a biochemical level, obesity impacts oocyte quality and this is further compounded by obesity affecting uterine receptivity.

Effects of obesity on miscarriage rates

The aim of this review was to highlight that obesity has a profound impact on female reproductive performance. Obesity increases the rate of miscarriage regardless of the mode of conception. The exact mechanism mediating this is multifaceted and difficult to categorise. The link between obesity and polycystic ovarian syndrome (PCOS) is well documented and is further discussed below. However, with its association with miscarriage, it appears that obesity is an independent risk factor for miscarriage regardless of the presence of PCOS . In a meta-analysis by Metwally et al. (2008) , data from 16 studies were combined, and the results from a total of >16,000 patients revealed that there was a significant increase in the miscarriage rates in women with a BMI ≥25 kg/m ² (odds ratio (OR) 1.67; 95% confidence interval (CI) 1.25–2.25). Similarly, pregnancies achieved following oocyte donation had significantly higher odds of miscarriage in the overweight and obese groups. This trend was further seen in patients conceived following ovulation induction (OR 5.11; 95% CI 1.76–14.83), and the risk of recurrent miscarriage is more prevalent in the obese group (OR 4.68; 95% CI 1.21–18.13). The National Institute of Clinical Excellence (NICE) in the United Kingdom suggests that pregnancy is best achieved with a BMI <29 kg/m ² . On the basis of available data, most guidelines are set arbitrarily and based primarily on expert opinions. There is a lack of consensus on ideal BMIs as demonstrated when examining guidelines of different countries. As such, the authors feel that setting strict restrictions based solely on BMI is unjustified and international consensus should be reached in the first instance. Clearly, treatment needs to be individualised to the patient’s circumstances and decisions need to be made when considering all the various facets. Age, being a sensitive marker of fertility success, should be brought into consideration when determining the feasibility of rapid weight reduction preconceptually. On a larger scale, the question of whether BMI is the best means of assessing adiposity should be addressed. This question is, however, beyond the scope of this report.

The oocyte, the embryo and the risks of birth defects

Women are born with a finite number of oocytes, and obesity appears to play a pivotal role in the outcome of this precarious and very finely balanced cell line. Both human and animal studies have demonstrated that all stages of gamete maturation and embryo development are directly influenced by extrinsic nutritional and intrinsic hormonal status. Preconception obesity has been shown to be associated with increased follicular fluid levels of insulin, lactate, triglycerides and C-reactive protein levels .

Female obesity and infertility are inextricably linked and, therefore, it is incumbent on treating clinicians to educate patients to adopt behavioural changes. Empowering patients preconceptually to understand the implications of obesity and the long-term health consequences both for them and for their future children should be an integral part of a fertility workup. As fertility specialists, we are congruent with the various modifiable risk factors that contribute to birth defects. As facilitators of fertility, a great deal of consideration is placed preconceptually on mitigating these risks. For this reason, patients are typically screened for measles, mumps, rubella and varicella prior to commencing treatment and immunisation provided if required. In a similar fashion, folic acid is commenced preconceptually in order to reduce the risks of neural tube defects and diabetic care is tightly controlled in order to improve outcomes. There is an extensive list of teratogenic medications that also need to be considered prior to embarking on conception, and these need to be either altered or stopped if safe to do so.

Despite the fact that major structural defects affect one in 33 newborns , identifiable risk factors account for approximately 35% of major birth defects; thus, we are missing the underlying cause of defects in a significant majority of cases. A meta-analysis of maternal obesity and birth defects published in 2008 reported that preconceptual obesity was associated with an increased risk of neural tube defects. This was supported by a second meta-analysis published the following year by Stothart et al. who also suggested a possible increased risk of congenital heart defects; indeed, increased rates of birth defects have been associated with increased BMI and these are summarised in Table 1 .

Regardless of the fact that there is uncertainty regarding the causal relationship between pre-pregnancy obesity and birth defects, it goes without saying that obesity, being a modifiable risk factor, should be considered by both patients and clinicians when performing the initial workup of infertile patients.

Effects of obesity on uterine receptivity

The previous section focussed on the correlation between obesity and birth defects; the underlying causal effect of this, if any, is yet to be elucidated. As described, it is clear that oocytes and embryos are exposed to alterations in their paracrine, endocrine and biochemical environments depending on BMI parameters. Therefore, the question arises whether the innate quality of oocytes are affected by BMI or whether the environmental milieu within the uterus is affected by BMI.

Elucidating whether the endometrial environment represents a variable in implantation success in relation to BMI, the oocyte donation–recipient model was investigated. In this model, a consistently homogeneous population of women donating their oocytes was selected as controls. By focussing on fertility outcomes in the corresponding recipients, the ovarian effects are mitigated; as such, extra-ovarian factors can be looked at in greater detail. Analysis of this model indicates a relationship between recipients’ BMI and poor reproductive outcomes. Gene expression analysis during the implantation window suggests endometrial dysregulation in obese PCOS women as compared with normal-BMI controls . It is, however, important to point out that not all studies have demonstrated the same results, presumably due to the complex nature of the questions being asked.

In order to address this question further, an important study by Bellver et al. (2013) analysed the outcome of >9500 ovum donation cycles from normal-BMI donors, and these results were correlated with the recipient weights. The outcome of this study demonstrated that in relation to normal-BMI recipients there was a statistically poorer outcome in terms of implantation, pregnancy and clinical pregnancy rates in the obese population. The live birthweights from the obese population were 27% lower than the normal-BMI oocyte recipients.