Human Reproduction Update Advance Access originally published online on June 21, 2007
Human Reproduction Update 2007 13(5):433-444; doi:10.1093/humupd/dmm017
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Effect of overweight and obesity on assisted reproductive technology—a systematic review
1 Assisted Reproduction Unit, University of Aberdeen, Aberdeen Maternity Hospital, Aberdeen AB25 2ZL, UK 2 Obstetrics and Gynaecology, Aberdeen Royal Infirmary, Aberdeen AB25 2ZL, UK 3 Department of Obstetrics and Gynaecology, Dugald Baird Centre for Research on Women’s Health, School of Medicine University of Aberdeen, Aberdeen AB25 2ZD, UK
4 Correspondence address. Tel: +44-1224-553582; Fax: +44-1224-551072; E-mail: abha.maheshwari{at}abdn.ac.uk
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Abstract |
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Obesity is known to be associated with sub-optimal reproductive performance but its direct effect on the outcome of assisted reproduction techniques (ART) is less clear. This present study aimed to perform a systematic review of the available evidence to assess the effects of obesity on the outcome of ART. A number of observational studies were identified. Interpretation of the results was compromised by variations in the methods used to define overweight and obese populations and inconsistencies in the choice and definition of outcome measures. Compared with women with a BMI of 25 kg/m2 or less, women with a BMI
25 kg/m2 have a lower chance of pregnancy following IVF [odds ratio (OR) 0.71, 95% CI: 0.62, 0.81], require higher dose of gonadotrophins (weighed mean differences 210.08, 95% CI: 149.12, 271.05) and have an increased miscarriage rate (OR 1.33, 95% CI: 1.06, 1.68). There is insufficient evidence on the effect of BMI on live birth, cycle cancellation, oocyte recovery and ovarian hyperstimulation syndrome. Further studies with clear entry criteria and uniform reporting of outcomes are needed to investigate the true impact of weight on the outcome of ART.
Key words: obesity / overweight / ART / systematic review / observational studies
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Introduction |
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The proportion of obese women (BMI
30) in the UK has increased from 16.4% in 1993 to 23.8% in 2004 (http://www.ic.nhs.uk/pubs/hlthsvyeng2004upd). In the 25–44 years age group, 
30% women are overweight (BMI 25–30) and 20% are obese. Along with the other conditions like diabetes, hypertension, cardiovascular diseases, pancreatitis and musculoskeletal diseases, obese women are more likely to experience reproductive problems (Clark et al., 1998
). Overweight women are known to be at a higher risk of menstrual dysfunction and anovulation, possibly due to altered secretion of pulsatile GnRH, resulting in altered sex hormone binding globulin (SHBG), ovarian and adrenal androgens and Luteinizing hormone (LH). Weight loss in these women is associated with the return of spontaneous ovulation and a reduced likelihood of requiring induction of ovulation (Clark et al., 1995).
In women undergoing assisted reproduction techniques (ART), obesity has been associated with the need for higher doses of gonadotrophins, increased cycle cancellation rates and fewer oocytes retrieved (Fedorcsak et al., 2004). Lower rates of embryo transfer, pregnancy and live birth have also been reported, as have higher miscarriage rates (Wang et al., 2000; Fedorcsak et al., 2004). However, other studies have been unable to find any negative impact of obesity on ART outcome (Lashen et al., 1999; Dechaud et al., 2006).
A recent survey of assisted reproduction clinics in UK demonstrates a wide variation in their approach towards obese infertile women (Zachariah et al., 2006). This is especially relevant at the present time when criteria for access to IVF in some health care settings include strict upper limits for BMI. Existing studies on the affect of obesity on ART population show variable results. The aim of this study is to perform a systematic review of the literature in order to determine whether increased BMI has an adverse effect on the outcome of ART, and if so, to assess the size of this effect.
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Materials and Methods |
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Search strategy
Medline (1966–2006), Embase (1966–2006) and the Cochrane Database of Systematic Reviews were searched using the key words ‘overweight’, or ‘obesity’ or ‘body mass index’, ‘BMI’ and ‘follicle stimulating hormone’ or ‘gonadotrophin’. ‘mp’, ‘oocytes’ or ‘oocyte quality’, ‘embryo transfer’ or ‘fertilization in vitro’ or ‘oocytes’ or ‘embryo’ or ‘embryo quality’ or ‘pregnancy rate’ ‘pregnancy’ or ‘sperm injections’, ‘intracytoplasmic’ ‘embryo.mp’, ‘fertilization in vitro’ or ‘mp IVF’, ‘, abortion’, ‘spontaneous’, ‘early pregnancy loss’, ‘mp live birth’, ‘pregnancy’, ‘infertility’ and ‘waist hip ratio’. Relevant journals in the specialty (Human Reproduction and Fertility and Sterility) were searched electronically and all cross references were hand searched. Contact with authors was attempted wherever appropriate. Guidelines for meta-analysis and systematic reviews of observational studies (MOOSE guidelines) were followed (Stroup et al., 2000).
Only published studies were included. Due to the nature of the question, randomized controlled trials were not anticipated. All observational studies on the effect of obesity/overweight on IVF and ICSI were included.
Studies were excluded if they investigated the effect of obesity/overweight in natural cycle conceptions/intrauterine insemination/ovulation induction. Where studies reported a combination of effects (i.e. smoking, advanced reproductive age, and raised FSH), only those which reported on the independent effect of BMI were included (as BMI is the most commonly used measure of obesity). Studies which exclusively investigated selected populations[e.g. only women with polycystic ovary syndrome (PCOS) or oocyte recipients] were excluded, as were studies which reported alternative parameters (i.e. waist hip ratio, WHR or body weight) for obesity, without providing any data on BMI.
Independent searches were conducted by two researchers (A.M. and L.S.) and all identified studies were reviewed separately by them. Any disagreement was resolved after discussion with S.B. Data were extracted according to a pre-designed proforma.
The primary outcome measure was live birth rate per woman. Secondary outcome measures included total dose of gonadotrophins, cancellation rates, number of oocytes retrieved, number of embryos obtained, pregnancy rate, miscarriage rate and ovarian hyperstimulation syndrome (OHSS) rate.
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Results |
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Identification
A total of 1843 studies were identified. Of them only 37 studied the effect of obesity on an ART population. All were in English except for two papers, one of which was in German (Munz et al., 2005) and the other in Czech (Krizanovska et al., 2002). These were translated in full by the University of Aberdeen translation service. Of these studies, only 21 fulfilled the inclusion criterion (Supplementary Fig.1). Details of included studies are provided in Table 1 and excluded studies are shown in Supplementary Table 1.
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Analysis and pooling of data
Of 21 studies fulfilling the inclusion criteria only 11 studies had cut-off values for BMI, to define overweight and obese groups, according to the WHO criteria (Table 2). Cut-off values for BMI, varied in nine studies (Lewis et al., 1990; Crosignani et al., 1994; Lashen et al., 1999; Loveland et al., 2001; Unkila-Kallio et al., 2001; Urbancsek et al., 2002; Nichols et al., 2003; Spandorfer et. al, 2004; Ku et al., 2006). As a consequence of this, results from these individual studies could not be compared and their data could not be aggregated. We tried to contact the authors of these studies via email and letters. Only one author (Nichols et al., 2003) re-analysed their data according to the BMI cut-offs specified in our review and their data were included in the final meta-analysis. Two authors indicated (Lashen et al., 1999; Urbancsek et al., 2002) that they cannot re-analyse the data. Two emails bounced back (Loveland et al., 2001; Ku et al., 2006) and we did not receive any reply from the authors of other studies (Lewis et al., 1990; Crosignani et al., 1994; Unkila-Kallio et al., 2001; Spandorfer et. al, 2004; Fig. 1). Frattarelli and Kodama (2004) have not reported the number of women/cycles in any BMI category. We tried to contact the corresponding authors but email bounced back and we did not receive any reply to the written letter.
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All the included studies were cohort studies except for two case control studies (Lashen et al., 1999
; Urbancsek et al., 2002). Data from the latter could not be aggregated due to the use of different ranges of BMI to define cases and controls (Table 1). Of the 12 studies included in the final meta-analysis, three (Fedrorcsak et al., 2000; Wang et al., 2002; Winter et al., 2002) only reported on the miscarriage rates in pregnancies conceived following ART. For each outcome, data were only pooled if there were at least two studies with similar range of BMI for the comparison groups. A random effect model was used (because of statistical heterogeneity in the outcome data) to calculate combined odds ratios (OR) (95% CI) with the help of Revman 4.2 software. Weighed mean differences (WMD) were calculated for continuous variables. Tests of heterogeneity were performed prior to pooling of data.
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Methodological quality of included studies |
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The recommended classification of overweight and obesity as suggested by National Institute of Health is shown in Table 2. In accordance with the suggested categories, outcomes were compared in the following groups, i.e. BMI < and
25, and BMI < and 30. Data on women with BMI 35 were only available in a single study (Wang et al., 2000), which did not report live birth rate. Only one study (Dokras et al., 2006) reported outcomes for women with BMI > 40. Wherever this was reported, women with low BMI (BMI < 18.5 or < 20) were excluded from analysis in order to provide an accurate comparison of normal versus increased BMI. However, this information is only provided in some studies (Wang et al., 2000; Wittemer et al., 2000; Krizanovska et al., 2002; Wang et al., 2002; Winter et al., 2002; Fedorcsak et al., 2004; Dechaud et al., 2006). Moreover, variable definition for low BMI is used by various authors [BMI < 18.5 (Fedorcsak et al., 2004) and BMI < 20 (Wittemer et al., 2000)].
Some authors have reported outcomes per cycle (Wittemer et al., 2000; Nichols et al., 2003; Dechaud et al., 2006), while others have chosen to report outcomes per woman (Wang et al., 2000; Krizanovska et al., 2002; Fedorcsak et al., 2004; van Swieten et al., 2005; Dokras et al., 2006). Except for three (Wang et al., 2000; Krizanovska et al., 2002; Nichols et al., 2003), all studies reporting outcomes per woman have only included one cycle per woman. Only Fedorcsak et al. (2004) provided data separately for both denominators (cycle and woman). We did not feel that we could combine data on outcomes per cycle with those per woman, as more than one cycle per woman may over-represent women who failed to conceive. Hence, outcomes have been presented per cycle as well as per woman.
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Description of outcome measures |
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 TOPAbstractIntroductionMaterials and MethodsResultsMethodological quality of... Description of outcome measures Results of the aggregated...DiscussionConclusionSupplementary materialReferences |
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Live birth rate
Live birth rate has been reported in a single study (Fedorcsak et al., 2004). Two other studies have reported on delivery rate (Wittemer et al., 2000; Dokras et al., 2006). For the purpose of this review, live birth rate and delivery rate has been combined and have been reported as per patient (Fedorcsak et al., 2004; Dokras et al., 2006) and per cycle (Wittemer et al., 2000; Fedorcsak et al., 2004).
There was a wide variation in the definition of clinical/ongoing pregnancy amongst various studies. Krizanovska et al. (2002) and van Swieten et al. (2005) reported all cases with positive b-hCG as clinical pregnancy, while Wittemer et al. (2000) have used ‘initiated pregnancies’ without a clear definition of this term. Wang et al. (2000) measured the probability of achieving at least one clinical pregnancy per woman whereas Nichols et al. (2003) defined clinical pregnancy as the presence of a gestational sac at 6–7 weeks gestation, identified via transvaginal scan. For the purpose of this review, we have aggregated all the pregnancies (biochemical, clinical, initiated and ongoing pregnancies) in order to calculate the total pregnancy rate.
Early pregnancy loss has been defined as miscarriage before 6 weeks (Winter et al., 2002; Fedorscak et al., 2004), before 12 weeks (Fedorcsak et al., 2000) and up to 20 weeks (Wang et al., 2002; Dokras et al., 2006). For the purpose of this review, we have combined all the miscarriages together. Some of the data from Winter et al. (2002) and Wang et al. (2002) were from the same series of women. Fedorcsak et al. (2000) included only miscarriages after first cycle while Winter et al. (2002) included more than one cycle per woman. However, in 38% of cycles (1421 cycles), in Winter et al. (2002) study, risk of early pregnancy loss could not be determined.
Data pertaining to the dose of gonadotrophins could only be pooled in a few studies where the mean (SD/SEM) of the total dose was provided (Fedorcsak et al., 2004; Deuchad et al., 2006).
Six studies have reported the number of oocytes retrieved (Nichols et al., 2003; Fedorcsak et al., 2004; Munz et al., 2005; van Swieten et al., 2005; Dechaud et al., 2006; Dokras et al., 2006). Only Dokras et al. (2006) reported the number of mature oocytes.
Cycle cancellation rate was reported in four studies (Fedorcsak et al., 2004; van Swieten et al., 2005; Dechaud et al., 2006; Dokras et al., 2006). Only two studies (Fedorcsak et al., 2004; van Swieten et al., 2005) differentiated between the cancellations due to poor response and those due to the risk of OHSS. Fedorcsak et al. (2004) also mentioned cancellation due to other causes, which were not specified.
Only two studies have included data on the number of embryos formed (Krizanovska et al., 2002; Munz et al., 2005). It was not possible to aggregate these data. None of the studies mentioned the quality of embryos obtained.
Ovarian hyperstimulation syndrome
Incidence of OHSS has been investigated in 4 studies (Krizanovska et al., 2002; Munz et al., 2005; van Swieten et al., 2005; Dokras et al., 2006). In this review it has not been possible to differentiate between mild, moderate or severe OHSS.
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Results of the aggregated data |
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Pooled results are described separately for BMI
25 versus < 25 and for BMI 30 versus < 30. Results, wherever possible, have been presented per woman. In addition, outcomes per cycle have been aggregated together and described separately.
In women with BMI of < 25, the odds of live birth per woman (Supplementary Fig.2a) were 1.08 (95%: CI 0.92, 1.26), and per cycle were 0.74 (95% CI: 0.27, 2.01) when compared with women with BMI of 25 (Data not shown). In women with BMI of < 30, the odds of live birth per woman (Supplementary Fig. 2b) were 1.12 (95% CI: 0.91, 1.37) when compared with women with BMI of 30. There was significant statistical heterogeneity in results from the different studies (P = 0.003).
In women with BMI of < 25, the odds of pregnancy rate per woman (Fig. 1a) were 1.24 (95% CI: 1.02, 1.50) and per cycle were 0.99 (95% CI: 0.88, 1.12) (data not shown) when compared with women with BMI of 25. Again the results showed significant statistical heterogeneity (P = 0.03).
In women with a BMI of < 30, the odds of pregnancy per woman (Fig. 1b) were 1.16 (95%: CI 0.95, 1.43), and per cycle were 1.05 (95% CI: 0.87, 1.28) (data not shown) when compared with women with a BMI of 30.
When only normal weight (BMI 20–25) women were included, the odds of pregnancy per woman were 1.40 (95% CI: 1.22, 1.60) as compared to woman with a BMI 25. Odds of pregnancy were 1.47 (95% CI: 1.20, 1.80) for a woman with a BMI < 30 as compared to women with BMI of 30 (Fig. 1c and d).
The dose of gonadotrophins 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 (Fig. 2a). The requirement for gonadotrophins was higher (WMD 361.94, 95% CI: 156.47, 567.40) in obese women (BMI 30 versus BMI < 30) (Fig. 2b).
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Number of oocytes retrieved
The WMD of the number of oocytes recovered in women with BMI < 25 was 0.58 (95% CI: 0.22, 0.94) in comparison with women with BMI 25. The WMD of the number of oocytes retrieved in women with BMI < 30 was 0.68 (95% CI: 0.11, 1.25) as compared to women with BMI of 30 (Fig. 3a and b).
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Pooled data from studies which have chosen to report the outcomes per cycle (data not shown), show no difference (WMD – 0.30, 95% CI: – 1.62, 1.02 & WMD 0.46, 95% CI: – 0.55, 1.47) in the number of oocytes recovered in a cycle in either comparison, i.e. BMI < 25 versus
25 and BMI < 30 versus 30.
In women with BMI of 25, the odds of cycle cancellation were 1.32 (95% CI: 0.96, 1.82), as compared to women with BMI of < 25 (Supplementary Fig.3a). When the data from studies which have reported the outcomes per cycle were pooled, the odds of cycle cancellation in women with BMI of 25 were 1.83 (95% CI: 1.36, 2.45), as compared to women with BMI < 25 (data not shown). The results displayed evidence of significant statistical heterogeneity (P = 0.05). BMI of 30 was associated with higher odds of cycle cancellation 1.35 (95% CI: 0.99, 1.84), than that of BMI of < 30 (Supplmentary Fig.3b). When the data from studies which have reported the outcomes per cycle were pooled, the odds of cycle cancellation in women with BMI of 30 were 1.59 (95%CI: 0.53, 4.80), as compared to women with BMI < 30 (Data not shown).
In a woman with BMI of 25, the odds of OHSS were 1.12 (95% CI: 0.74, 1.68), as compared to women with a BMI of < 25 (Supplementary Fig. 4a). In a woman with BMI of 30, the odds of OHSS were 1.16 (95% CI: 0.69, 1.96), as compared to women with BMI of < 30 (Supplementary Fig.4b).
In women with BMI of < 25, the odds of miscarriage (Fig. 4a) were 1.33 (95% CI: 1.06, 1.638), compared to women with BMI of 25. The results showed evidence of statistical heterogeneity (P = 0.05). The risk of miscarriage was higher (Fig. 4b) (OR = 1.53, 95% CI: 1.27, 1.84), in women with BMI 30 versus BMI < 30.
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Discussion |
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Our results show that overweight women face a lower likelihood of pregnancy and an increased risk of miscarriage after IVF. They also have reduced number of oocytes retrieved despite requiring higher doses of gonadotrophins. There is insufficient evidence of a difference in other outcomes including live birth, OHSS and cycle cancellation rates.
The strength of this systematic review lies in its comprehensive nature and ability to compare pooled data from a number of large studies according to the WHO classification of BMI. However, as a systematic review based on observational data, these results are not free from bias. The studies included in the review display considerable clinical, methodological and statistical heterogeneity. Despite fulfilling all the inclusion criteria, eight studies could not be included in the meta-analysis due to differences in their classification of overweight and obesity. Our meta-analysis, based on reported data, was unable to adjust for potential confounders such as age. Finally, the possibility of publication bias cannot be excluded. It was not feasible to generate a funnel plot based on live birth due to paucity of studies which reported this as an outcome.
The studies included in this review showed a wide variation in their choice of subjects. Some included all women undergoing assisted conception (Wang et al., 2000; Krizanovska et al., 2002; Fedorcsak et al., 2004), while others excluded those with a poor prognosis (Wittemer et al., 2000; van Swieten et al., 2005; Dechaud et al., 2006; Dokras et al., 2006). Women with PCOS were excluded by Wittemer et al. (2000). This may be relevant as PCOS (which is associated with obesity) has been shown to have an independent effect on pregnancy rates (Wang et al., 2000). Two studies excluded women on the basis of age (van Swieten et al., 2005; Dokras et al., 2006). Others adjusted for confounding factors such as age, year of treatment and diagnosis of PCOS (Wang et al., 2000; Nichols et al., 2003; Dokras et al., 2006).
Clinical protocols used for pituitary down-regulation and controlled ovarian hyperstimulation varied among studies and sometimes even within the same study. This could have had an impact on ovarian response and cancellation rates (Al-Inany et al., 2006). The starting dose of gonadotrophins was based on results of preliminary tests of ovarian reserve (Dokras et al, 2006), BMI and age (Fedorcsak et al., 2004; Dechaud et al., 2006) in some studies, but not in others (van Swieten et al., 2005).
Live birth, as an outcome measure, was only reported by a minority of studies. It is, however, possible to extrapolate from the available data and argue that a combination of higher miscarriage and lower pregnancy rates in overweight and obese women could result in a reduced expectation of live birth rate. Interpretation of our results is further complicated by differences in the definitions used for outcome measure such as miscarriage, pregnancy rate (Table 1) in individual studies. For instance, there is no consensus regarding the definition of poor response (van Swieten et al., 2005; Dechaud et al., 2006; Dokras et al., 2006) or clear criteria for cancellation due to the threat of OHSS.
Many studies have reported live birth/pregnancy rates per cycle rather than per woman. Using the latter as denominator is the more methodologically robust method (Johnson et al., 2003; Vail and Gardener, 2003) as it is the woman who is generally accepted to be the unit of analysis. Expressing outcomes per cycle can lead to significant bias—especially as many women can undergo more than one treatment cycle.
We were limited by the need to work with reported results from published papers rather than raw data from individual women. Thus, while some of the individual studies were able to adjust for confounders such as age, parity and duration of infertility, we were unable to adjust for these factors in our meta-analysis. Some of the studies measured the mean number of oocytes or units of gonadotrophins, but failed to provide any measure of the spread of the data (SD/SEM). This again influenced our ability to aggregate data.
Previously, individual studies on the outcome of IVF in women with high BMI showed conflicting results. There was sufficient concerns about risks in overweight/obese women to prompt organizations such as the British Fertility Society (BFS) to suggest withholding IVF from women with BMI of > 35 (Kennedy et al., 2006). The BFS has also suggested that women with BMI of > 30 should be referred to a weight loss programme. Our results show poorer outcomes even in women with a BMI of 25 and over—a group which includes 50% of women in the UK. The need to address this issue may have substantial resource implications.
We have been able to provide the estimate of difference in only two BMI groups (BMI < 25 versus 25 and < 30 versus 30). Few women in the higher BMI categories currently receive IVF, and this number is destined to shrink in future as clinics adopt a strict weight linked policy for access to IVF. Most of the units in UK have a cut-off of BMI < 35 for women to be able to access IVF (Zachariah et al., 2006).
In this review, we have considered BMI as a marker of obesity. There are suggestions that WHR is a better predictor of reproductive outcome (Wass et al., 1997; Zaadstra et al., 1993) as BMI does not differentiate between android and gynaecoid fat distribution.
More research in this area is needed with clearly defined patient populations, using standardized BMI criteria and uniform outcome measures. Access to individual patient data may allow more refined methods of analysis including the ability to adjust for confounders in generating combined OR. Further research is needed in determining the best measure of obesity for reproductive outcome.
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Conclusion |
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Obesity and overweight is associated with decreased pregnancy rates, increased requirement for gonadotrophins and a higher miscarriage rate. These differences are evident even at a BMI
25. More evidence is required in order to make a judgement about the effect on live birth. More prospective studies with clear entry criteria and uniform reporting of outcomes are needed. Meanwhile, weight loss should be considered in overweight women (i.e. BMI 25) before initiating assisted reproduction. |
Supplementary material |
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Supplementary material is available at http://humupd.oxfordjournals.org
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