Obesity has a strong association with subfertility and is a major risk factor in pregnancy. In pregnancy, obesity may cause early foetal loss, congenital malformations and poor perinatal outcomes.

Women can be classified on the basis of BMI as overweight when: BMI 25-29.9 kg/m2 and obese BMI >30. A female waist circumference of < 80 cm is considered low-risk, while 80-88 cm is moderate-risk and >88 cm are categorised as high-risk, and very high-risk.

Overweight Singapore women contribute to 28.6% of the population while obese women form 7.9%. Among the ethnic groups in Singapore, 20.7% of Malays, 14.0% of Indians and 5.9% of Chinese were considered obese with the highest prevalence of obesity in the 30 to 39-year-old age group (11.5%).

THE PATHOPHYSIOLOGY OF OBESITY AND INFERTILITY

In women with a high caloric intake, insulin, GLP-1 and leptin act on the hypothalamus and lead to a satiety response by inhibiting neuropeptide Y (NPY) and stimulating proopiomelanocortin (POMC) neurons. This also promotes gonadotropin- releasing hormone (GnRH) secretion.

Leptin, in addition, selectively facilitates luteinising hormone (LH) release through kisspeptin release. Peripherally, leptin potentiates insulin-induced theca cell proliferation and androgen production from the ovaries. Chronic GnRH production with a propensity towards more LH can contribute to a polycystic ovary syndrome (PCOS) phenotype.

Alternatively, obesity may be due to leptin resistance or mutant leptin leading to an absence of the satiety response. Obesity per se can increase peripheral aromatisation of androgens, increase insulin resistance and decrease sex hormone- binding globulin (SHBG), contributing to chronic anovulation.

In patients with malnutrition and low calorie intake, Ghrelin from the gut and adiponectin from the fat inhibit GnRH secretion and stimulate feeding. This mechanism conserves energy during famine and promotes procreation only when food is available.

Obesity can cause a systemic inflammation due to interaction between the immune cells in adipose tissue and adipocytes, resulting in the release of free fatty acids (FFA) and cytokines. These FFA can increase reactive oxygen species (ROS) and cause dysfunction of the oocyte’s mitochondria and endoplasmic reticulum. These oocytes may not form viable embryos or implant.

Obesity may also affect implantation by an endometrial effect and is associated with increased endometrial polyps. Increased BMI can double the miscarriage rate as compared to women with a normal BMI (38% versus 20%; odds ratio [OR] 2.4, 95% CI 1.6–3.8). Miscarriages in young overweight women may not be associated with aneuploidy suggesting alternative mechanisms.

SYMPTOMS

Obese women with PCOS usually present with oligomenorrhoea and clinical hyperandrogenaemia. Clinical hyperandrogenaemia manifests differently in the various races as hirsutism, acne or rarely androgenic alopecia in the crown of the head.

ASSISTED REPRODUCTION TREATMENT (ART) IN OBESE WOMEN

Overweight or obese women had significantly lower clinical pregnancy rates, live-birth rates and higher miscarriage rates following ART compared with normal BMI women.

Pre-term deliveries are higher in both singletons (1.5 fold) and in twins (2-3 fold) of obese women (BMI >35 kg/m2) after IVF compared with normal weight women. Younger women with a higher BMI have a more pronounced negative influence on fertility than older women.

POTENTIAL INTERVENTIONS IN OBESE WOMEN

Conservative/Expectant Management
Diet and increased exercise would be the first line management of obesity. A daily caloric intake of 600 kcal less than the caloric requirement to maintain a stable body weight is recommended. Dietary restrictions lower than 800 kcal/day are not recommended beyond 12 weeks even if nutritionally complete. Although treatment with metformin can facilitate weight loss by appetite suppression, it should not be used for this purpose.

Exercise must be of moderate intensity at least 5 times a week for 60-90 minutes. Exercise activities should preferably be a daily routine like brisk walking or gardening to promote sustainability. The target weight loss should be no more than 0.5-1 kg/week.

Cognitive and behavioural interventions like goal-setting, slower eating and social support can sustain long-term adherence to both diet and exercise regimens.

Short-term low calorie diet and exercise for a period of 6-8 weeks prior to IVF has no statistically-significant difference in live birth rates in spite of a weight reduction and lower BMI. However, improvement in the Preconception Dietary Risk Score (PDRS), which is a measure of nutritional habits and dietary quality (higher scores indicate higher dietary quality), by one point, was associated with a 65% increase in the ongoing pregnancy rate after IVF.

Medical Management
Orlistat may be offered as an adjunct to women who have achieved partial success in losing weight and persevered with lifestyle changes for 6 months. There is no evidence of any increase in the relative risk of major malformation when orlistat was used in early pregnancy. However anti-obesity drugs should be stopped once pregnancy is achieved.

Insulin-sensitising agents, such as metformin, decrease circulating insulin and androgen levels and may be associated with a modest decrease in body weight and visceral fat.

Metformin is used in patients with PCOS especially if they have impaired glucose tolerance or features of metabolic syndrome. All women with PCOS would benefit from an oral glucose tolerance test at presentation and thereafter every two years. Evaluations should also include blood pressure, waist circumference and a lipid profile.

Metformin is more effective with a hypocaloric diet for reducing weight and visceral fat. The recommended dose is 1500- 2000 mg/day and the main side-effects are gastrointestinal upset (i.e. nausea and vomiting) and rarely, lactic acidosis in patients with hepatic and renal impairment.

Clomiphene is commonly used for ovulation induction for subfertility. Clomiphene resistance is treated by ovulation induction with gonadotropins or laproscopic ovarian drilling. Metformin is not a first line drug for fertility in patients with PCOS.

Surgical Management
Bariatric surgery is recommended for inpatients with a new diagnosis of type 2 diabetes and a BMI 30-35 kg/m2, and a lower BMI in patients of Asian origin. Women with a preoperative BMI of >40 kg/m2 can be expected to lose 20-40 kg over 2 years and to maintain their reduced weight for 10 years.

Pregnancy is not recommended for 12-18 months after bariatric surgery, when most of the weight loss occurs, to avoid nutritional deficiencies. There are no reports of randomised controlled trials (RCTs) assessing the impact of bariatric surgery in infertile populations or in patients undergoing ART; however, a recent observational study has shown an improvement in the number of oocytes retrieved in obese women after bariatric surgery.

IS IT COST-EFFECTIVE TO OFFER ART TO OBESE SUBFERTILE WOMEN?

The costs per live birth in overweight and obese women are at least 44% higher than those in their normal weight counterparts. However, in a single cycle of IVF treatment, there is no statistically significant difference in the obstetric costs of a woman with normal BMI woman or a BMI of 30-35.

IS IT ETHICAL TO WITHHOLD FERTILITY TREATMENT AND ART OPTIONS FROM OBESE WOMEN?

Spontaneously pregnant obese women are only offered careful monitoring. Assisted Reproduction in obese women increases the risks of deep vein thrombosis due to an hyperestrogenic environment and is associated with a suboptimal outcome.

Weight loss benefits both the mother and the child and it is not unethical for fertility specialists to insist on a certain target before commencing treatment. Numerous guidelines suggest a BMI < 30 for a younger woman and < 35 for an older woman prior to conception. From a societal perspective, this would reduce the increased demand on resources.

Respect for a patient’s autonomy dictates that it is reasonable to offer treatment to a woman willing to accept an unfavourable outcome. This must be considered for older women with declining fertility for whom outcomes are compromised due to body weight.

CONCLUSION

In summary, obesity has a significant adverse effect on fertility and ART outcome, especially in younger women less than 35 years. This effect may be mediated by both oocyte and endometrial effects.

There is not enough evidence on the effectiveness and cost of different interventions on the outcome of fertility treatment in obese women.

Being a modifiable risk factor, it is ethically justifiable to require obese women to lose weight before receiving ART.

GPs can call for appointments through the GP Appointment Hotline at 6321 4402 for more information.

Dr Hemashree Rajesh is a Senior Consultant with the Department of Obstetrics and Gynaecology at Singapore General Hospital.

She specialises in male and female infertility, polycystic ovarian syndrome (PCOS), fertility preservation and is an accredited IVF specialist (in-vitro fertilisation). She is a trained console surgeon to perform robotic procedure for endometriosis.