Obesity: Fertility and Pregnancy

 

Normal body mass index BMI is 18.5-24.9Kg/M2 and overweight is 25to29.9Kg/M2. Obesity is BMI 30kg/M2. Obesity is classified as Class-I-(30.0–34.9Kg/M2), Class-II-(35.0–39.9Kg/M2) and Class-III-(≥40Kg/M2). Obesity has reached epidemic proportions. One third of women are obese, one half of pregnant women are overweight or obese, and 8-10% of reproductive-aged women are extremely obese, putting them at a greater risk of pregnancy complications.

 

Obesity is associated with no-ovulation, menstrual disorders, hirsutism, infertility, miscarriage and obstetric complications. It impairs human reproduction through insulin resistance, excess-androgen and elevated leptin levels.

 

Obese women have an increased incidence of insulin resistance; associated with non-insulin dependent diabetes mellitus (non-IDDM), hypertension, lipid abnormalities, and atherosclerotic cardiovascular disease. High insulin blood level (hyperinsulinemia) appears to be present in a significant number of polycystic ovary syndrome (PCOS) patients, independent of obesity, while others associate hyperinsulinemia in PCOS with only obese patients.

 

In obese women with insulin resistance, it is important to assess for metabolic syndrome if there is present three or more of the following: hypertension ≥130/85mmHg; triglyceride ≥1.7mmol/L, HDL-cholesterol <1.3mmol/L; abdominal obesity >90cm or fasting glucose ≥6mmol/L. Hypertension develops later in life. Cardiovascular risk increases if waist-circumference is >90cm.

 

PCOS in obese woman is diagnosed with at least 2 of the following: polycystic ovary on ultrasound (US); infrequent or no ovulation or symptoms and tests of androgen excess after excluding other causes of androgen excess.

 

Obesity is associated with response failure to clomiphene citrate (CC), gonadotropins and laparoscopic ovarian surgery diathermy-LOS.

 

Weight loss is first-line therapy. Losing 5% of body weight can result in a pregnancy. A low-calorie diet reduces weight by 12% in six months and improves reproductive outcome. Weight loss prior to conception improves the live birth rate in obese women with or without PCOS.

 

Regular exercise helps long-term weight loss, but has orthopaedic and cardiovascular limitations in obese women.

 

Bariatric surgery in the morbidly obese may sustain weight loss. Appetite suppressant sibutramine and intestinal fat absorption-blocker orlistat reduce androgens and insulin resistance independently of weight-loss.

 

In obese women with normal levels of the follicle stimulating hormone (FSH) and not ovulating CC is the first choice to induce ovulation. CC is orally ingested and economic, safe and requires little monitoring.

 

A woman’s weight, androgen levels and age predict treatment success. Pregnancy rates when BMI>30 are significantly less compared with BMI<30. CC produces ovulation in 75%–80% of PCOS-patients, but pregnancy is 22% per ovulation and differences are due to CC antioestrogenic effects. Multiple pregnancies occur in less than 10% and ovarian hyperstimulation is rare.

 

There is an apparent advantage to adding metformin to CC in women with BMI>35kg/m2 and in those with CC resistance. Metformin use in PCOS should be restricted to the obese and insulin resistant.

 

Gonadotropins injections are a second possible therapy in CC resistant patients. Gonadotropins induce ovulation and achieve a fertilisable follicle but the drawbacks are ovarian hyperstimulation and the increased likelihood of multiple pregnancies (which can be reduced with US and oestradiol monitoring).  No response after six gonadotropins cycles signifies resistance. The most clinically useful predictors of gonadotropin ovulation induction outcome in women with normal gonadotropin level are obesity and insulin resistance.

 

In women with PCOS who have failed to conceive despite successful ovulation induction, intra-uterine insemination may be considered if there is an associated male factor.

 

Ovulation induction by LOS is an option in CC resistant women or those with an excess of the lutinising hormone. It is also available if a laparoscopic assessment of the pelvis is required or if the woman lives too far away for monitoring required during gonadotropin therapy. RCT comparing LOS with gonadotropins for CC resistant PCOS showed a similar ongoing pregnancy rate and live birth rate, but multiple pregnancy rates were significantly higher in gonadotrophin compared with LOS. Treating CC resistant PCOS by LOS resulted in reduced costs. LOS does not reduce ovarian reserve.

 

 

 

Because of inherent risks of laparoscopy particularly in the obese and the lack of long-term evidence from randomised controlled trials (RCT), LOS cannot be recommended. Adjuvant therapy CC or FSH will be required in 50% of LOS treated women. In addition to laparoscopic complications, ovarian adhesions as a late complication are common.

 

In principle, anovulation is not an indication for IVF.

 

IVF is used when weight reduction, CC, gonadotropins, LOS and metformin have failed. Risk of multiple pregnancies is markedly reduced in IVF with single embryo transfer.

 

After a failure of weight reduction, CC or LOS, it may be argued that gonadotropin should be omitted and replaced by ovarian stimulation and IVF.

 

PCOS associated with tubal damage, severe endometriosis, preimplantation genetic diagnosis and male infertility indicate IVF. Women with PCOS undergoing IVF have more cycle cancellation. The usage of metformin in IVF improves viable pregnancy rates and reduces the incidence of ovarian hyperstimulation syndrome (OHSS). PCOS does not intervene in embryo implantation as IVF success is similar in patients with or without PCOS.

 

It is important to assess the endometrium with a biopsy to exclude cancer after prolonged exposure of unopposed oestrogen.

 

Infertility assessment includes: age, duration, previous evaluations/therapy, prevailing menstrual, medical, surgical, gynaecological, obstetric and sexual conditions; personal and lifestyle history. The physical assessment includes: BMI; thyroid gland; galactorrhoea; hirsutism; acne; male-pattern baldness and pelvic examination. Infertility in obese women should be assessed fully to identify other causes of infertility; tubal damage, severe endometriosis, preimplantation genetic diagnosis and male infertility all indicate IVF. Prompt evaluation should be offered to women older than 35-37.

 

In obese infertile women undergoing assisted reproduction technology (ART) the ovary plays a leading role in the fertility prognosis. The endocrine and metabolic environment may affect oocyte quality, embryo development, implantation and pregnancy outcome.

 

Obesity in women affects the endometrium which plays a negative role in ART even when the ovum is donated. Obesity impairs the outcome of ART. The lower probability of a healthy live birth in obese women seems to be the result of a combination of lower implantation and pregnancy rates, higher preclinical and clinical miscarriage rates and increased complications during pregnancy for both mother and foetus.

 

In infertile obese patients undergoing IVF/ICSI; class-II has lower pregnancy rates when compared to class-I. Compared to normal weight women; Class-III obese women are 35% less likely to become pregnant; Class-II has 28% less chance; 9% for Class-I; and 3% for overweight women. Stillbirth in obese women was more than doubled and premature birth paralleled increasing obesity: from 16% for overweight to 34% for Class-III obesity.

 

Women with BMI>35Kg/M2 because of high complications risk’ generally are not offered IVF until they had lost weight unless they are older than 35. A flexible approach is recommended and cases are looked at individually. There is a view that women should not be discriminated against because of their size. While obesity has a powerful effect on fertility, women can overcome it with fertility drugs.

 

Anovulatory women (particularly PCOS) pose a greater risk for hyperstimulation. Women with PCOS undergoing IVF had more cycle cancellation. Full-blown OHSS has serious maternal complications: thrombosis; stroke; hepato-renal failure; cardio-pulmonary compromise and even death. In PCOS patients the GnRH-antagonist protocol is associated with comparable pregnancy outcome but a lower risk for OHSS when compared with GnRH-agonist long protocol.

 

Obesity is an independent risk factor for early pregnancy loss, late pregnancy loss, hypertension, pre-eclampsia and gestational diabetes, thrombo-embolism, caesarian section (CS), postpartum haemorrhage, maternal and foetal deaths and post-partum weight retention.

 

Obese women should attend preconception assessment and counselling. Maternal and foetal risks of obesity in pregnancy are stressed. A weight loss program including diet, exercise, and behavioural therapy is encouraged before attempting pregnancy.

 

At the initial antenatal visit and throughout pregnancy women are advised of their appropriate weight gain. Nutrition consultation is offered and an exercise program is implemented. Those who have had bariatric surgery may need iron, vitamin B12, folate, vitamin D, and calcium supplements if indicated. A gastric band may need adjustment during pregnancy.

 

The The foetus of a pregnant woman who is overweight or obese is at an increased risk of prematurity, stillbirth, congenital anomalies i.e. neural tube defect, macrosomia with possible birth injury, and childhood obesity. Critically, obesity makes it harder to diagnose foetal anomalies by ultrasound during pregnancy. Large-for-gestational-age infants are at an increased risk of childhood and adolescent obesity.

 

Obese women are less likely to initiate and sustain breastfeeding.

 

Assessing foetal weight even with an ultrasound and interpreting foetal heart monitoring or uterine contraction patterns poses difficulties in obese women during labour.

 

Anaesthesia management is difficult. An anaesthetist consultation late in pregnancy or early in labour is important. Epidural or spinal anaesthesia is recommended if needed or elected, however it may be technically difficult or impossible because of excess fat. General anaesthesia can be challenging due to difficult endotracheal intubation and associated respiratory complications.

 

CS in obese women can lead to increased blood loss, prolonged operative time, wound infection, sleep apnea and venous thromboembolism (thromboprophylaxis is indicated). Extremely obese women should be counselled regarding increased likelihood of complicated and emergency CS. They require specific resources including blood products and a large operating table.

 

Bariatric surgery in obese reproductive-aged women is increasing. Maternal gastrointestinal obstruction and haemorrhage can complicate this procedure however the incidence is infrequent. Pregnancies after bariatric surgery are less likely to be complicated by gestational diabetes mellitus, hypertension, preeclampsia and macrosomia than are pregnancies of obese women who have not undergone such surgery. Bariatric surgery is not an independent indication for caesarean delivery.

 

Nutrition and exercise counselling should continue postpartum and before attempting another pregnancy.

 

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