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.
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
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
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
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
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
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
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.
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
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
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
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
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
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.
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.
By: Dr Hemashree Rajesh, Senior Consultant, Department of Obstetrics & Gynaecology, Singapore General Hospital
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.