© Springer India 2015
Surveen Ghumman (ed.)Principles and Practice of Controlled Ovarian Stimulation in ART10.1007/978-81-322-1686-5_44. Obesity and Its Impact on Ovarian Stimulation
(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
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 loss4.1 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 [32, 33]. 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].
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