Principles and Practice of Controlled Ovarian Stimulation in ART 1st ed.

4. Obesity and Its Impact on Ovarian Stimulation

Surveen Ghumman  and Pinkee Saxena2

(1)

Department of IVF and Reproductive Medicine, Department of Obstetrics and Gynecology, MAX Multispecialty Hospitals, Saket, Panchsheel, and Patparganj, New Delhi, Delhi, 110017, India

(2)

Department of Obstetrics and Gynecology, Deen Dayal Upadhyay Hospital, New Delhi, Delhi, India

Surveen Ghumman

Email: surveen12@gmail.com

Abstract

Increased body mass index (BMI) has effect on various aspects of infertility treatment and assisted reproductive technology (ART) procedures. The extent of this influence is, however, conflicting in literature. Overweight and obese women require a higher dose of gonadotropin with greater number of days of stimulation and yet have lower peak oestradiol levels with an increased risk of cycle cancellation due to poor follicular development. On controlled ovarian stimulation, there is less number and poor quality of oocytes reported in these women. They have lower fertilization and pregnancy rates. The effect of obesity upon implantation rate has also been inconsistently reported. Some studies have identified a reduction in implantation rates among the obese women. Weight loss results in regularization of the menstrual pattern, a decrease in cancellation rates, an increase in the number of embryos available for transfer, a reduction in the number of ART cycles required to achieve pregnancy and a decrease in miscarriage rates. There are higher obstetric complications with a lower live birth rate in these women. Obesity is a modifiable risk factor. It has an effect on fertility, its treatment and obstetrics outcome. Women with increased BMI should be first encouraged to reduce weight before starting any treatment for infertility or planning conception.

Keywords

ObesityControlled ovarian stimulationGonadotropinsOverweightBMIFertilityOocyte qualityWeight loss

4.1 Incidence

In the last few decades, there has been a change in lifestyle and socioeconomic conditions globally. This has led to rise in obesity. Obesity has now become a major epidemic. Rising incidence of obesity is seen both in developed and developing countries. In England, it is seen that 56 % of women are either overweight or obese [1]. More than 30 % of women in the United States are found to be obese [2]. Prevalence of obesity is rising even in developing countries. Over the last 20 years, the obesity rates have tripled in the developing world, and now it is seen that 10 % of all children across the world are overweight or obese [3].

The World Health Organization has defined obesity as body mass index (BMI) more than or equal to 30 kg/m2 [4]. Obesity poses a major health challenge, as it is a risk factor for cardiovascular disease, diabetes mellitus, arthritis and cancers of oesophagus, colon and endometrium. In addition to this, in women of child-bearing age it is associated with infertility and increased complication during pregnancy [5].

4.2 Obesity and Its Impact on Fertility

Infertility issues are more commonly seen in obese women. Thirty to seventy-five percent of women with polycystic ovary syndrome (PCOS) are also found to be obese [6]. Anovulation is a major cause of infertility among obese women, the relative risk being 3.1 (95 % confidence interval (CI) 2.2–4.4) when compared to those with a normal BMI [7]. Body fat distribution in women of reproductive age also has an impact on fertility in addition to age or obesity. Zaadstra observed that a 0.1 unit increase in waist-hip ratio (WHR) leads to a 30 % decrease in probability of conception per cycle (hazard ratio 0.706; 95 % CI 0.562–0.887) [8].

Obesity is found to decrease successful pregnancy rates in both natural and assisted conception cycles [9]. Ovulation and conception requires a fine complex balance of hormones released by reproductive organs. Obesity interferes with this in many ways. Insulin resistance is commonly seen in most obese women. Elevated levels of insulin lead to a reduction in hepatic synthesis of sex hormone-binding globulin (SHBG), an elevated level of circulating free androgens and high levels of free insulin-like growth factor 1 [10]. This relative hyperandrogenemia found in obese women has undesirable effects on ovarian function and contributes towards oligo-anovulation. Insulin also stimulates LH receptor expression on theca and granulosa cells resulting in LH hypersecretion and unfavourable folliculo-genesis.

Increased levels of circulating leptin are found in obese women. Leptin plays a regulatory role at hypothalamus-pituitary-ovarian axis and, influences ovarian folliculo-genesis and endometrium development. A high level of leptin leads to sub-fertility in them. Low levels of adiponectin and altered levels of TNF, plasminogen activator inhibitor (PAI) and type-1 interleukin-6 (IL6) are found in obese women, which reduces conception rate. Other potential mechanisms of infertility in the obese include poor-quality oocytes and a defect in endometrial receptivity.

It is seen that a weight loss of 5 % or more in obese women leads to a decrease in insulin and IGF levels and increase in SHBG levels, resulting in regular menstruation in women with PCOS [11]. Weight loss leads to reduction in insulin resistance and central adiposity [12]. Also, obese women who lose weight tend to have spontaneous ovulation and improved response to ovarian stimulation in infertility treatment. It is therefore advocated that for overweight and obese infertile women after initial assessment for infertility, weight management interventions like lifestyle change, diet, exercise or drug to decrease weight should be recommended first before embarking on any treatment modality.

4.3 Impact of Obesity in Infertility Treatment

Increased body mass index (BMI) has effects on various aspects of infertility treatment and assisted reproductive technology (ART) procedures. The extent of this influence is, however, conflicting in literature.

4.3.1 Ovulation Induction

Clomiphene citrate is commonly used as first line of ovulation induction drug in obese women. It is, however, found to be associated with low ovulation and pregnancy rates [13].

Obesity and insulin resistance have been implicated to lead to suboptimal response even when gonadotropins were used for ovulation induction. Studies have shown that women with high BMI need higher total doses of FSH to achieve ovulation [weighted mean difference 771 IU (95 % CI, 700–842)]. These women also face a higher risk of cycle cancellation [OR 1.86 (95 % CI: 1.13–3.06)] and are less likely to ovulate [OR 0.44 (95 % CI: 0.31–0.61)] [14]. A multicentre randomized controlled trial also showed that with increasing BMI, a higher threshold dose of gonadotropins was required with more days of stimulation; however, despite greater gonadotropin requirements, no difference was seen in overall outcome of ovulation induction and clinical pregnancy in women with anovulatory polycystic ovary syndrome and a BMI of less than 35 kg/m2 [15].

Insulin sensitizers have been frequently used in obese women with PCOS. Tang et al. updated the Cochrane review on the role of metformin for women with PCOS. They concluded that metformin is beneficial in improving clinical pregnancy and ovulation rates. However, there is no evidence that metformin improves live birth rates whether it is used alone or in combination with clomiphene or when compared with clomiphene, and hence it has limited role in PCOS [16]. Neil P. Johnson observed that in women with PCOS undergoing IVF metformin when added reduces the risk of ovarian hyperstimulation syndrome [17].

Rosiglitazone has been found to be effective. Short-term rosiglitazone therapy enhances both spontaneous and clomiphene-induced ovulation in overweight and obese women with PCOS. Rosiglitazone therapy improves insulin sensitivity and decreases hyperandrogenemia primarily through increase in SHBG but is hepatotoxic [18]. Pioglitazone appears to be effective as well; however, the study is still limited. Since foetal safety for both these drugs has not been established (pregnancy category C of the US FDA guidelines), these drugs when used should be discontinued as soon as pregnancy has been established.

4.3.2 Impact of Obesity on ART

Obesity has influence on all aspects of ART. There is inconsistent evidence regarding the effect of raised BMI on the outcome of assisted reproductive technology.

4.3.2.1 Ovarian Stimulation

As already stated, overweight and obese women require a higher dose of gonadotropin with greater number of days of stimulation and yet have lower peak oestradiol levels, with an increased risk of cycle cancellation due to poor follicular development [19]. The dose of gonadotropins was higher in women with BMI of ≥25 (WMD 210.08, 95 % CI: 149.12, 271.05) in comparison with those with BMI of <25 and in obese women (BMI ≥30 versus BMI <30) (WMD 361.94, 95 % CI: 156.47, 567.40) [20].

4.3.2.2 Oocyte Recovery

Ovum pickup in obese women can at times be technically more difficult to perform. Also general anaesthesia in them poses challenges like difficult endotracheal intubation due to excessive tissue and oedema and hypoxia from failed or difficult intubation.

4.3.2.3 Oocyte Number and Quality

The maturing oocyte is very vulnerable to changes in its micro-environment, the follicular fluid. Valckx et al. showed that differences in BMI are associated with alterations in the fatty acid composition of the follicular fluid. This variation possibly affects granulosa cell viability, oocyte development and subsequent embryo quality, possibly explaining differences in oocyte quality in obese patients [21].

Increased LH and altered LH: FSH ratio affects ovulation and the resumption of oocyte maturation in obese women. Frequently, obese women require greater amounts of gonadotropins for IVF and a longer period of stimulation leading to alterations in oocyte development [22]. Obesity affects oocyte competence and maturation through alterations in various hormones, particularly those hormones that trigger oocyte maturation [23].

Esinler et al. in their study found that in women with BMI >30 the number of cumulus-oocyte complexes collected was lower and stage of oocyte maturation delayed. Fertilization rate, embryos transferred, implantation and pregnancy rates, however, were not influenced by obesity. The number of cycles with good-quality cryo-preservable embryos was significantly lower in them (P < 0.05) [24]. Carrell et al. in their study have shown that there is impairment in oocyte maturation with increasing BMI [25]. Ronit et al. studied the characteristics of failed fertilized oocytes. They found that compared to women with normal BMI, severely obese women had a greater prevalence of spindle anomalies and non-aligned chromosomes in failed fertilized oocytes [26].

Zang et al. also showed that the number of oocytes obtained by obese women was significantly lower than normal-weight women (oocytes retrieved 2.98 ± 6.91 vs. 14.49 ± 7.96 respectively, P < 0.001) [27]. This result was supplemented by another systematic review where the weighted mean difference (WMD) of the number of oocytes recovered in women with BMI >25 kg/m2 was 0.58 (95 % CI: 0.22, 0.94) in comparison with women with BMI <25 kg/m2 [20]. A study done by Metwally et al., however, reported that oocyte quality assessed by number of oocytes considered suitable for injection or the number that fertilized was unaffected by BMI [28].

4.3.2.4 Oocyte Fertilization and Embryo Quality

Oocyte fertilization rates have been shown to be lower in morbidly obese women (59 % vs. 69 %; P < 0.03) [29]. In a large cohort study, it was seen that in comparison with women of normal weight, overweight women (BMI >25<30 kg/m2) have lower fertilization rates (60.8 ± 23.3 vs. 61.1 ± 23.0, P < 0.001), fewer cleaved embryos (7.55 ± 4.86 vs. 8.67 ± 5.90, P < 0.001), fewer high-grade embryos (4.65 ± 3.96 vs. 5.59 ± 4.81, P < 0.001) and fewer cryo-preserved embryos (4.44 ± 4.55 vs. 5.49 ± 5.55, P < 0.001) [27]. A conflicting report was found by Bellver et al. in their retrospective study on 6,500 IVF/ICSI cycles. They concluded that the fertilization rate or embryo quality was not impaired in overweight and obese women. However, implantation, pregnancy and live birth rates were poorer in obese women. In fact, pregnancy and live birth rates were reduced progressively with each unit of BMI with a significant odds ratio of 0.984 (95 % confidence interval 0.972–0.997) and 0.981 (95 % confidence interval 0.967–0.995), respectively. In addition, the cumulative pregnancy rate after four IVF cycles was reduced as BMI increased [30].

4.3.2.5 Cycle Cancellation

Several studies have looked at the cycle cancellations in overweight and obese women. Maheshwari et al. in their systematic review suggest that the odds of cycle cancellation in women with BMI of >25 kg/m2 were 1.83 (95 % CI: 1.36, 2.45) as compared to women with BMI <25 kg/m2. However, there was significant statistical heterogeneity (P < 0.05) in the pooled data, and hence results were inconclusive [20].

4.3.2.6 Ovarian Hyperstimulation Syndrome

Ovarian hyperstimulation syndrome (OHSS) is an avoidable complication of ovarian stimulation. In a review of women with BMI of ≥25, the odds of OHSS were 1.12 (95 % CI: 0.74, 1.68), and with BMI of ≥30, the odds of OHSS were 1.16 (95 % CI: 0.69, 1.96) [20]. The higher incidence of ovarian hyperstimulation may be due to the increased incidence of PCOS in overweight women. In another review, none of the studies included found any significant difference between the risk of OHSS in normal and overweight women. The pooled OR for overweight women was 1.0 (95 % CI 0.77–1.3) [31].

4.3.2.7 Implantation, Pregnancy and Live Birth Rates

The end result of ovarian stimulation is implantation, pregnancy and live birth rates. The effect of obesity upon implantation rate has also been inconsistently reported. Some authors have identified a reduction in implantation rates among the obese women [3233]. Bellever et al. reported that implantation, pregnancy, twin pregnancy and live birth rates were significantly reduced as BMI increased [30]. An unfavourable intrauterine milieu, compromised oocyte quality and impaired endometrial receptivity may be contributing factors for this.

Meta-analyses have been done by various authors to find the association between increased BMI and pregnancy or live birth rate following assisted ART treatment. Rittenberg et al. reviewed 33 studies including 47,967 treatment cycles to evaluate the effect of raised BMI on treatment outcome following IVF/ICSI treatment. They concluded that women who were overweight or obese (BMI ≥25) had significantly lower clinical pregnancy (RR = 0.90, P < 0.0001) and live birth rates (RR = 0.84, P = 0.0002). Rittenberg et al. found that the probability of live birth after ART was reduced by 9 % (95 % CI: 2–15 %) in overweight women compared with a reduction of 20 % (95 % CI: 12–29 %) in the obese group [34].

Koning et al. analyzed 27 studies. They reported that clinical pregnancy rates were not different for overweight and normal-weight women [OR 0.94 (95 % CI 0.69–1.3)] or for obese women when compared with normal-weight women [OR 0.97 (95 % CI 0.59–1.6)]. However, overweight women undergoing ART had a significant lower live birth rate after ART than women with a normal weight [OR 0.90 (95 % CI 0.82–1.0)]. They found an OR of 0.90 for the association between overweight and live birth, indicating a 10 % reduction in the success rates of IVF in overweight women [31]. Similarly, Maheshwari et al. analyzed 37 studies and found lower pregnancy (odds ratio [OR]: 0.71; 95 % CI: 0.62–0.81) [20]. Another retrospective cohort study was done of 1,721 women to study effects of BMI in women undergoing IVF. They found that the odds of clinical pregnancy (odds ratio [OR] 0.50, 95 % confidence interval [CI] 0.31–0.82) and live birth (OR 0.51, 95 % CI 0.29–0.87) were 50 % lower in women with class III obesity as compared with women of normal BMI [35].

Luke et al. found that maternal obesity is associated with lower live birth rates in women receiving ART treatments. This was seen with use of both the autologous oocyte as well as donor oocytes; however, the effect was most severe among treatments using autologous oocytes suggesting a detrimental effect of obesity on the foetal environment [36]. Data from another study suggests that obesity does not affect IVF outcomes in women using donor oocytes. Oocyte quality rather than endometrial receptivity may be the overriding factor influencing IVF outcomes in obese women using autologous oocytes [37].

Overall, studies indicate that overweight or obesity result in poorer ART outcomes.

4.3.3 Obesity and Its Impact on Pregnancy

Overweight and obese women have increased risk of miscarriage in all types of conception, be it in spontaneous cycle, induced cycle, IVF or oocyte donation cycle. A systematic review of literature done by Maheswari et al. showed that when compared with women of BMI <25, the odds of miscarriage in women with BMI of ≥25 kg/m2 were 1.33 (95 % CI: 1.06–1.638) and 1.53 (95 % CI: 1.27–1.84) in women with BMI ≥30 kg/m2 when compared to women of BMI <30 kg/m2. The results, however, showed evidence of statistical heterogeneity. Koning also found a significantly higher miscarriage rate in overweight women (RR = 1.31, P < 0.0001) compared to women with BMI <25. This has been supported by few others [3839].

Another recent meta-analysis of the available evidence suggested that there was a significant increase in the odds of miscarriage in women with a BMI of ≥25 kg/m2 (OR 1.67; 95 % CI, 1.25–2.25) following spontaneously conceived pregnancies as well as following ovulation induction (OR, 5.11; 95 % CI, 1.76–14.83) but not in women who underwent IVF/ICSI (OR, 1.52, 95 % CI, 0.88–2.61). This may be due to differences in the nature of the included studies and the type of denominator used to calculate the prevalence of miscarriage [40].

Relation between BMI and multiple pregnancies for women undergoing ART was reviewed by Koning. The pooled OR expressing the association between overweight and the risk of multiple pregnancies was 0.97 (95 % CI 0.91–1.04). Only retrospective cohort study a significantly higher risk of multiple pregnancies was observed in women with normal weight following ART, whereas the six other studies did not. They also studied the association between BMI and ectopic pregnancies but found no significant difference in risk of ectopic pregnancy [31].

However, obese and morbidly obese subjects have a significantly higher risk for obstetric complications during pregnancy like gestational diabetes mellitus, pre-eclampsia, thromboembolism, caesarean delivery and foetal anomaly [41].

Age is an important factor that has a bearing on live birth rates following IVF in relation to female age for women with a BMI of <25 and >25 kg/m2. It is observed that live birth rates decrease from 26 % for younger women to 10 % for women aged 40 [20]. Koning stated that the profound effect of age is much stronger when compared with the moderate effect of excessive weight on the live birth rate following IVF [31].

IVF treatment in women with increased BMI has reduced live pregnancy rate. Cost is a major factor involved in infertility treatment. Due to this risk, there are guidelines that regulate access to fertility care for overweight and obese women in various countries. In New Zealand, women with a BMI of >32 kg/m2 are excluded from any fertility treatment under public IVF funding. RANZCOG considers a BMI >35 kg/m2 to be a contraindication to assisted reproduction. The British Fertility Society recommends deferring IVF treatment for BMI of >35 [42]. Current 2013 NICE guidelines also recommend an ideal BMI between 19 and 30 kg/m2 before commencing IVF treatment.

4.4 Weight Loss and Fertility

Since obesity has a detrimental effect on reproductive outcome, studies have evaluated the impact of weight loss on fertility. A systematic review was done by Sim et al. to assess the effect of weight loss achieved by various modalities like diet, lifestyle changes, non-surgical medical interventions and bariatric surgery. They found that weight loss in the obese and overweight did significantly increase pregnancy rates and live birth rates. In addition to this, weight loss also resulted in regularization of the menstrual pattern, a decrease in cancellation rates, an increase in the number of embryos available for transfer, a reduction in the number of ART cycles required to achieve pregnancy and a decrease in miscarriage rates. They also reported a number of natural conceptions with weight loss [43].

As little as 5–10 % weight loss can improve fertility outcomes and lead to an improvement in endocrine parameters, such as decrease in free testosterone, lower fasting insulin levels and increased frequency of ovulation [1112]. In addition, weight loss causes a significant reduction in central fat deposits (11 %) and serum luteinizing hormone levels [44].

Drugs have been used to bring about change in weight. In a large randomized controlled trial with metformin, there were no significant changes in insulin sensitivity or lipid profiles; however, a significant reduction in waist circumference and free androgen index was seen with metformin. An improvement in menstruation was only seen when there was associated weight loss [45]. Orlistat, in a small prospective trail, has been found to be effective in the obese both with and without PCOS [46].

Bariatric surgery has maximum effect of weight loss. In a study done, it was found that post bariatric surgery there was a significant improvement in the number of follicles seen and number of oocytes retrieved [47]. Weight loss in women with increased BMI improves their reproductive outcomes; however, in order for this to be effective, it has to be gradual and sustained.

Conclusion

Obesity is a modifiable risk factor. It has an effect on fertility, its treatment and obstetrics outcome. Women with increased BMI should be first encouraged to reduce weight before starting any treatment for infertility or planning conception.

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