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Assisted Conception Unit, Guy’s and St. Thomas’ Hospital NHS Foundation Trust, 11th Floor Tower Wing, Guy’s Hospital, St. Thomas Street, Great Maze Pond, London SE1 9RT, United Kingdom
Assisted Conception Unit, Guy’s and St. Thomas’ Hospital NHS Foundation Trust, 11th Floor Tower Wing, Guy’s Hospital, St. Thomas Street, Great Maze Pond, London SE1 9RT, United Kingdom
Assisted Conception Unit, Guy’s and St. Thomas’ Hospital NHS Foundation Trust, 11th Floor Tower Wing, Guy’s Hospital, St. Thomas Street, Great Maze Pond, London SE1 9RT, United Kingdom
Assisted Conception Unit, Guy’s and St. Thomas’ Hospital NHS Foundation Trust, 11th Floor Tower Wing, Guy’s Hospital, St. Thomas Street, Great Maze Pond, London SE1 9RT, United Kingdom
Assisted Conception Unit, Guy’s and St. Thomas’ Hospital NHS Foundation Trust, 11th Floor Tower Wing, Guy’s Hospital, St. Thomas Street, Great Maze Pond, London SE1 9RT, United Kingdom
Assisted Conception Unit, Guy’s and St. Thomas’ Hospital NHS Foundation Trust, 11th Floor Tower Wing, Guy’s Hospital, St. Thomas Street, Great Maze Pond, London SE1 9RT, United Kingdom
There is conflicting evidence regarding the effect of raised body mass index (BMI) on the outcome of assisted reproductive technology. In particular, there is insufficient evidence to describe the effect of BMI on live birth rates. We carried out a systematic review and meta-analysis of studies to evaluate the effect of raised BMI on treatment outcome following IVF/ICSI treatment. Subgroup analysis on overweight and obese patients was performed. Literature searches were conducted on MEDLINE, EMBASE and the Web of Science from 1966 to 2010. Thirty-three studies including 47,967 treatment cycles were included. Results indicated 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) and significantly higher miscarriage rate (RR = 1.31, P < 0.0001) compared to women with a BMI < 25 following treatment. A subgroup analysis of overweight women (BMI ⩾ 25–29.9) revealed lower clinical pregnancy (RR = 0.91, P = 0.0003) and live birth rates (RR = 0.91, P = 0.01) and higher miscarriage rate (RR = 1.24, P < 0.00001) compared to women with normal weight (BMI < 25). In conclusion, raised BMI is associated with adverse pregnancy outcome in women undergoing IVF/ICSI treatment, including lower live birth rates. This effect is present in overweight as well as obese women.
There is conflicting evidence regarding the effect of raised body mass index (BMI) on the outcome of fertility treatment. In particular, there is insufficient evidence to describe the effect of BMI on live-birth rates. We carried out a systematic review and meta-analysis of studies to evaluate the effect of raised BMI on the clinical pregnancy, miscarriage and live-birth rates following IVF and intracytoplasmic sperm injection treatment (ICSI). Subgroup analysis on overweight (BMI ⩾25–29.9 kg/m2) and obese (BMI ⩾30 kg/m2) patients was performed. Literature searches were conducted from 1966 to 2010. Thirty-three studies including 47967 treatment cycles were included. Results indicated that women who were overweight or obese (BMI ⩾25 kg/m2) had significantly lower clinical pregnancy (RR = 0.90) and live-birth rates (RR = 0.84) and significantly higher miscarriage rate (RR = 1.31) compared with women with a BMI < 25 kg/m2 following treatment. A subgroup analysis comparing women who were overweight (BMI ⩾25–29.9 kg/m2) with women who had a normal weight (BMI < 25 kg/m2) revealed significant lower clinical pregnancy (RR = 0.91) and live-birth rates (RR = 0.91) and significantly higher miscarriage rate (RR = 1.24) in overweight women. In conclusion, raised BMI is associated with adverse pregnancy outcome in women undergoing IVF/ICSI treatment, including lower live-birth rates. This effect is present in overweight as well as obese women.
). In many European countries, over half of women of reproductive age are either overweight (body mass index (BMI) 25–29.9 kg/m2) or obese (BMI ⩾30 kg/m2) (
International Obesity Task Force and European Association for the Study of Obesity 2002. Obesity in Europe. The case for action. London. Available from: <http://www.iotf.org/media/euobesity.pdf>.
Obesity is associated with a range of health consequences, including a detrimental effect upon reproductive health. Compared with women with normal BMI (18.5–24.9 kg/m2), women with a raised BMI are known to have a threefold greater risk of infertility due to disturbances in the hypothalamic–pituitary axis, menstrual cycle alterations and anovulation as well as psychological and social factors (
). Nevertheless, there is conflicting evidence regarding the effect of raised BMI on the outcome of assisted reproduction technology. Although some studies have reported no adverse effect of raised BMI on IVF outcome (
), others have linked raised BMI with a negative impact on outcome. This included the need for higher doses of gonadotrophins, fewer oocytes collected, higher cancellation rate and reduced pregnancy and live-birth rates, as well as higher miscarriage rates (
). Two recent systematic reviews found insufficient evidence regarding the impact of raised BMI on the live-birth and miscarriage rates after IVF treatment (
). Since the publication of these two reviews, numerous studies have been published investigating the link between raised BMI and IVF outcome. The aim of this study was to perform an up-to-date systematic review of existing literature to evaluate the impact of BMI on the pregnancy outcome after IVF treatment and, if possible, to determine the impact of overweight (BMI ⩾25–29.9 kg/m2) and obesity (BMI ⩾30 kg/m2) on IVF outcome separately.
Materials and Methods
Search strategy and identification of literature
Literature searches were conducted via Medline (1966–2010) and Embase (1966–2010) and the Institute for Scientific Information conference proceedings. A combination of medical subject headings (MeSH) and text words were used to generate two subsets of citations, one including studies of body mass index (‘overweight’, ‘obesity’, ‘body mass index’, ‘BMI’, ‘hip-waist ratio’) and the other including studies of IVF and intracytoplasmic sperm injection (ICSI) (‘in-vitro fertilization’, ‘embryo transfer’, ‘intracytoplasmic sperm injection’, ‘assisted reproduction techniques’). These subsets were combined with ‘AND’ to generate a subset of citations relevant to the research question. No language restrictions were placed on any search. The searches were conducted independently by VR and SKS.
Study selection and data extraction
Studies were included if they investigated the effect of BMI on pregnancy outcome in women undergoing IVF treatment with or without ICSI. Studies involving natural cycle conception, oocyte donation, intrauterine insemination or induction of ovulation were excluded. In addition, studies reporting alternative parameters for obesity (e.g. waist/hip ratio) were also excluded.
Studies were selected in a two-stage process. In the first instance, two reviewers (VR and SKS) independently scrutinized the titles and abstracts from the electronic searches and full manuscripts of all citations that definitely or possibly met the predefined selection criteria were obtained. Following examination of the full manuscripts, final inclusion or exclusion decisions were made. Assessment of the manuscripts was performed independently by two reviewers (VR and SKS), and any disagreements about inclusion were resolved by consensus after consultation with two co-authors (SS and TE).For each study included, information was obtained regarding population size, study design, BMI categories used and population numbers in each category, exclusion criteria and outcome measures.
The data collected was initially combined into one study group that had BMI ⩾25 kg/m2 (overweight and obese patients) and compared with a control group BMI < 25 kg/m2. The latter did not exclude underweight women (BMI < 18.5 kg/m2), as most authors studying this BMI category did not report if underweight women were included in their analysis. Thereafter, a subgroup analysis on overweight (BMI ⩾25–29.9 kg/m2) and obese (BMI ⩾30 kg/m2) patients was performed and each compared with the normal BMI group (BMI < 25 kg/m2).
Outcome measures
The outcome measures of interest were clinical pregnancy, miscarriage and live-birth rates. For the purpose of this review, clinical pregnancy was defined as the observation of a pregnancy sac on ultrasound at least 4 weeks after embryo transfer. Miscarriage was defined as any pregnancy loss, including biochemical pregnancies, occurring before 20 weeks of gestation. Other outcome measures, such as duration and dose of gonadotrophin used for ovarian stimulation, number of oocytes retrieved and peak oestradiol concentrations were also studied.
Statistical analysis
Outcome data from each study were pooled and expressed as risk ratio (RR) with 95% confidence interval (CI) by using either a fixed-effect model (
). An I2 value <50% was considered evidence of significant heterogeneity. Exploration of clinical heterogeneity was conducted using variation in features of the study population, intervention and study quality. Statistical analyses were performed with RevMan 5.0 software.
Results
The search strategy yielded 422 citations, all captured from electronic citations (Figure 1). Of these, 346 publications were excluded, as it was clear from the title and/or abstract that they did not fulfill the selection criteria. From the remaining 76 articles, 17 were excluded, as they were duplicate publications, two of which (
) and 23 studies were excluded as the WHO criteria for BMI classification was not used. The authors of the three abstracts with insufficient information for inclusion eligibility were contacted via email to obtain more information. No reply was received and therefore these three studies were excluded (
For the remaining 33 articles, full manuscripts were obtained for scrutiny and data necessary for the analysis were then extracted. The main characteristics of the studies are presented in Table 1.
Amount of FSH No. of oocytes recovered Abortion before 6 weeks Abortion between week 6 and 12 Abortion after week 12 Life-birth rate
Inclusion of first pregnancy for each couple only Different stimulation cycles (including clomiphene citrate with FSH) 1–3 embryos transferred day 2, 3 or 4 after oocyte collection Measurement of HCG day 14, ultrasound scan at 6 weeks and 12 weeks of gestation
<18.5: 26 Women 18.5–25: 701 Women 25.1–30: 243 Women 30.1–35: 107 Women >35: 46 Women
None stated
Early pregnancy loss
Pregnancy defined as HCG ⩾10 IU/l on day 16 after ovulation
Pregnancy loss defined as miscarriage before 6 weeks of gestation, either by self reported miscarriage or absence of embryonic sac or gestational sac on ultrasound at 6–7 weeks of gestation
Dose and duration of FSH No. of cancelled cycles No. of oocytes collected No. of biochemical pregnancies Early pregnancy loss Miscarriage 6–12 weeks Miscarriage >12 weeks Live-birth rate
Starting FSH dose adapted for age and BMI > 35 kg/m2 Embryo transfer day 2 or 3 Up to three embryos transferred Pregnancy defined as HCG > 20 U/l on day 14 after oocyte retrieval Early pregnancy loss defined as biochemical pregnancy without ultrasound signs of viable pregnancy BMI measured a median 80 days before treatment cycle
Cancelled cycles if poor response or OHSS Clinical pregnancy defined as biochemical pregnancy Abortion defined as spontaneous abortion <12 weeks Only first stimulation cycles studied
Women with a history of uterine surgery, who had apparent endometrial pathologies or hydrosalpinges, who had 3 or more attempts of IVF and embryo transfer, or who received frozen–thawed embryos Women not on long protocol PGD patients
Duration and dose of FSH No. of oocytes collected Implantation rate Clinical pregnancy rate Miscarriage rate
PCOS patients included BMI at initial consultation
<25: 683 Women 25–29.9: 295 Women 30–39.9: 236 Women ⩾40: 79 Women
Women ⩾38 years of age Day-2 embryo transfer cycles Cryopreserved embryo transfers Donor oocyte cycles GIFT cycles
Cancellation rate Days of stimulation No. of follicles aspirated No. of mature oocytes Fertilization rate Transfer rate OHSS Clinical pregnancy rate Miscarriage rate Delivery rate
Women during their first fresh IVF cycle Long protocol or microdose flare protocol Day-3 or day-5 embryo transfer Miscarriage defined as pregnancy loss up to 20 weeks of gestation
Different stimulation cycles used Clinical pregnancy defined as presence of gestational sac Early miscarriage defined as <15 weeks of gestation Later miscarriage defined as ⩾15 weeks of gestation
Freeze–thaw cycles Female age > 40 years History of irregular menstrual cycle Presence of PCOS Patients suspected of having a poor ovarian response
Dose and duration of FSH No. of oocytes Fertilization rate Clinical pregnancy rate No. of miscarriages
BMI immediately prior to initiating ICSI cycle Day-3 embryo transfer Clinical pregnancy defined as presence of intrauterine gestational sac with heartbeat at ultrasonography and/or presence of trophoblastic tissue in dilatation and curettage pathology specimen
<18.5: 21 Women 18.5–24.9: 267 Women 25–29.9: 77 Women ⩾30: 52 Women
Women > 35 years old Only women included with cycle day-3 FSH < 10 IU/l and oestradiol < 80 pg/ml
No. of oocytes retrieved Implantation rate Clinical pregnancy rate
First cycles only Clinical pregnancy defined as presence of a gestational sac Ongoing pregnancy defined as the presence of fetal heart tones at 8–9 weeks of gestation Division into PCOS and non-PCOS patients
Rittenberg, V., Sobaleva, S., Ahmad, A., Oteng-ntim, E., Bolton, V., Khalaf, Y., Braude, P., El-Toukhy, T., 2011. Influence of BMI on risk of miscarriage after single blastocyst transfer. Hum. Reprod. [Epub ahead of print].
<18.5 Women > 40 years old PGD cycles Donated oocyte cycles Embryos frozen for fertility preservation Pregnancies in women with Müllarian duct anomalies Pregnancies resulting in monozygotic twin gestation
Dose and duration of FSH No. of oocytes retrieved Fertilization rate Embryo quality Clinical pregnancy rate Implantation rate Miscarriage rate Ongoing pregnancy rate
Single blastocyst transfers only following fresh and cryo–thawed cycles Only first pregnancy during the study period included Miscarriage defined as pregnancy loss <20 weeks Clinical pregnancy defined as gestational sac with fetal heart beat on ultrasound scan week 4–5 after embryo transfer BMI measured within 1 month of starting treatment
Women ⩾38 years old ⩾3 previous IVF attempts Other than 2 high-quality embryos Women with hydrosalpinx, fibroid uterus, congenital uterine anomaly, chronic illness
Dose and duration of gonadotrophins No. of oocytes retrieved Implantation rate Pregnancy rate
Only data for first cycle included Different stimulation cycles used Day-2 or -3 embryo transfers Clinical pregnancy defined as intrauterine gestational sac with fetal pole with heart beat on scan 4 weeks after embryo transfer Only embryo transfers included when 2 top-quality could be transferred (two 4-cell grade I on day 2 or two 7–8 cell on day 3)
18.5–25: 2222 Women >25–29.9: 379 Women ⩾30: 27 Women
Endometriosis stage III or IV >2 failed IVF or ICSI cycles PGD cycles Frozen–thawed embryo transfers
Days and dose of stimulation No. of oocytes retrieved Pregnancy rate Miscarriage rate Ongoing pregnancy rate Live-birth rate
Long stimulation protocols only PCOS patients included Only first treatment cycles included Clinical pregnancy defined by visualization of gestational sac and cardiac activity 6 weeks after embryo transfer Miscarriage defined as pregnancy loss <12 full weeks of gestation Only Chinese women
There were only two studies that were prospective observational studies and the remaining studies were retrospective. Out of the 33 studies, only one study was a case-control study, the remaining were cohort studies. They were all single-centre studies. There were 25 studies in the group with BMI < 25 versus BMI ⩾25 kg/m2, 16 studies in the group BMI 18.5–24.9 and BMI 25–29.9 kg/m2 and 15 studies in the group BMI 18.5–24.9 and BMI ⩾30. In total, 33 studies including 47,967 IVF/ICSI cycles were included in the review: BMI < 25 kg/m2, n= 32,496; and BMI ⩾25 kg/m2, n= 15,471.
Primary outcome
Live-birth rate per IVF/ICSI cycle
BMI < 25 kg/m2 versus BMI ⩾25 kg/m2: the pooled results from nine studies showed a statistically significant reduction in the live-birth rate in women with BMI ⩾25 kg/m2 compared with women with BMI < 25 kg/m2 (RR 0.84, 95% CI 0.77–0.92, P= 0.0002; Figure 2A). There was no significant heterogeneity between the included studies (I2 = 21.3%).
Figure 2Meta-analysis of live-birth rate data for different body mass index (BMI) categories: (A) BMI < 25 kg/m2 versus BMI ⩾25 kg/m2; (B) normal BMI versus BMI 25–29.9 kg/m2; and (C) normal BMI versus BMI ⩾30 kg/m2.
Normal BMI versus BMI 25–29.9 kg/m2: the pooled results from five studies showed a statistically significant reduction in the live-birth rate in women with BMI 25–29.9 kg/m2 compared with women with normal BMI (RR 0.91, 95% CI 0.85–0.98, P= 0.01; Figure 2B). There was no significant heterogeneity between the included studies (I2 = 0%).
Normal BMI versus BMI ⩾30 kg/m2: pooling the results from five studies that reported live birth as an outcome showed a statistically significant reduction in the live-birth rate in women with BMI ⩾30 kg/m2 compared with women with normal BMI (RR 0.80, 95% CI: 0.71–0.90, P= 0.0002; Figure 2C). There was no significant heterogeneity between the included studies (I2 = 0%).
Secondary outcome
Clinical pregnancy rate
BMI < 25 kg/m2 versus BMI ⩾25 kg/m2: pooled analysis from 25 studies showed a significant reduction in the clinical pregnancy rate in women with BMI < 25 kg/m2 compared with women with BMI ⩾25 kg/m2 (RR 0.90, 95% CI 0.85–0.94, P< 0.0001; Figure 3A). There was significant heterogeneity between the included studies (I2 = 50.8%, P= 0.002).
Figure 3Meta-analysis of clinical pregnancy rate data for different body mass index (BMI) categories: (A) BMI < 25 kg/m2 versus BMI ⩾25 kg/m2; (B) normal BMI versus BMI 25–29.9 kg/m2; and (C) normal BMI versus BMI ⩾30 kg/m2.
Normal BMI versus BMI 25–29.9 kg/m2: pooled analysis from 16 studies showed a significant reduction in the clinical pregnancy rate in women with BMI 25–29.9 kg/m2 compared with women with normal BMI (RR 0.91, 95% CI 0.86–0.96, P= 0.0003; Figure 3B). There was no significant heterogeneity between the included studies (I2 = 34.6%).
Normal BMI versus BMI ⩾30 kg/m2: pooled studies from 15 studies showed that there was a significant reduction in the clinical pregnancy rate in women with BMI ⩾30 kg/m2 compared with those with normal BMI (RR 0.87, 95% CI 0.80–0.95, P= 0.002; Figure 3C). There was significant heterogeneity between the included studies (I2 = 61.8%, P= 0.0008).
Miscarriage rate
BMI < 25 kg/m2 versus BMI ⩾25 kg/m2: pooled analysis from 22 studies showed a statistically significant increase in the miscarriage rate in women with BMI ⩾25 kg/m2 compared with women with BMI < 25 kg/m2 (RR 1.31, 95% CI 1.18–1.45, P< 0.00001; Figure 4A). The I2 value was 47.9% indicating no significant heterogeneity in the included studies.
Figure 4Meta-analysis of miscarriage rate data for different body mass index (BMI) categories: (A) BMI < 25 kg/m2 versus BMI ⩾25 kg/m2; (B) normal BMI versus BMI 25–29.9 kg/m2; and (C) normal BMI versus BMI ⩾30 kg/m2.
Normal BMI versus BMI 25–29.9 kg/m2: pooled analysis from 14 studies showed a statistically significant higher rate of miscarriage in women with BMI 25–29.9 kg/m2 compared with women with normal BMI (RR 1.24, 95% CI 1.13–1.35, P= 0.001; Figure 4B). There was no significant heterogeneity between the included studies (I2 = 22.4%).
Normal BMI versus BMI ⩾30 kg/m2: pooled analysis from 14 studies showed that the miscarriage rate was significantly higher in the group with BMI ⩾30 kg/m2 (RR 1.36, 95% CI 1.13–1.64, P= 0.001 Figure 4C). There was significant heterogeneity between the included studies (I2 = 56.4%, P= 0.005).
Other outcome measures
Duration of gonadotrophin stimulation
BMI < 25 kg/m2 versus BMI ⩾25 kg/m2: pooled analysis from two studies (
Rittenberg, V., Sobaleva, S., Ahmad, A., Oteng-ntim, E., Bolton, V., Khalaf, Y., Braude, P., El-Toukhy, T., 2011. Influence of BMI on risk of miscarriage after single blastocyst transfer. Hum. Reprod. [Epub ahead of print].
) showed that the duration of gonadotrophin stimulation was significantly longer in women with BMI ⩾25 kg/m2 compared with women with BMI < 25 kg/m2 (Weighted mean difference (WMD) 0.88, 95% CI 0.49–1.27, P< 0.0001). There was no significant heterogeneity between the included studies (I2 = 0%).
Normal BMI versus BMI 25–29.9 kg/m2: pooled analysis from five studies (
) showed that the duration of gonadotrophin stimulation was significantly longer in women with BMI 25–29.9 kg/m2 compared with women with normal BMI (WMD 0.22, 95% CI 0.21–0.23, P< 0.00001). There was no significant heterogeneity between the included studies (I2 = 0%).
Normal BMI versus BMI ⩾30 kg/m2: pooled analysis from five studies (
) showed that the duration of gonadotrophin stimulation was significantly longer in women with BMI ⩾30 kg/m2 compared with women with normal BMI (WMD 0.27, 95% CI 0.26–0.28, P< 0.00001). There was no significant heterogeneity between the included studies (I2 = 0%).
Dose of gonadotrophin stimulation
BMI < 25 kg/m2 versus BMI ⩾25 kg/m2: pooled analysis from two studies (
) showed that there was no statistically significant difference in the dose of gonadotrophin stimulation in women with BMI ⩾25 kg/m2 compared with women with BMI < 25 kg/m2.
Normal BMI versus BMI 25–29.9 kg/m2: pooled analysis from five studies (
) showed a higher dose of gonadotrophin stimulation in women with BMI 25–29.9 kg/m2 compared with women with normal BMI (WMD 137.92, 95% CI 41.25–234.60, P= 0.005). There was a significant heterogeneity between the included studies (I2 = 61.2%).
Normal BMI versus BMI ⩾30 kg/m2: pooled analysis from five studies (
) showed a higher dose of gonadotrophin stimulation in women with BMI ⩾30 kg/m2 compared with women with normal BMI (WMD 406.77, 95% CI 169.26–644.2, P= 0.0008). There was significant heterogeneity between the included studies (I2 = 80.8%).
Number of oocytes retrieved
There was no significant difference in number of ooctyes retrieved in the different study groups.
Peak oestradiol concentrations
There was no significant difference in peak oestradiol concentrations in the different study groups.
Discussion
Obesity has become a worldwide epidemic. Consequently, an increasing number of overweight and obese women are seeking fertility through assisted reproduction technology. Thus, the impact of raised BMI on the outcome of IVF treatment is of interest to patients, clinicians and policy makers.
The results of this review indicate that women who are overweight or obese (BMI ⩾25 kg/m2) have a poorer outcome following IVF treatment compared with women with normal BMI. Unlike the previous systematic reviews (
), the current review and meta-analysis is able to clearly demonstrate that raised BMI is associated with a significantly reduced live-birth rate and increased miscarriage rate after IVF treatment.
This review has also allowed separate evaluation of the impact of being overweight or obese on IVF outcome. The results demonstrate that the poorer outcome of IVF treatment is not limited to women with BMI ⩾30 kg/m2; overweight women (BMI 25–29.9 kg/m2) also have significantly lower pregnancy and live-birth rates and higher miscarriage rate after IVF treatment compared with women with normal BMI. The study results also confirm the trend towards a poorer outcome with rising BMI. This dose–effect relationship has been previously suggested (
). The current data show that, on average, the live-birth rate is reduced by 9% (95% CI 2–15%) in overweight women compared with a 20% reduction (95% CI 12–29%) in the obese group.
The validity of the current results depends on the quality of individual studies included in this review. Data were aggregated from a considerable number of large observational studies and only studies which adopted the WHO classification of BMI were included. However, like previous reviews, these results are not completely free from bias and should be interpreted with caution. For example, considerable methodological and clinical heterogeneity was encountered amongst the included studies, particularly in relation to study population characteristics and definition of the relevant outcome measures.
In addition, this study was not able to adjust for important confounders such as patient age, cause and duration of infertility, ovarian stimulation protocol used and number and quality of embryos transferred, all of which varied among the included studies. In an attempt to reduce heterogeneity, 23 studies that did not follow the WHO classification of BMI or did not have any results in the overweight or obese group analysis that could be used for analysis were excluded (
A prospective, randomized, controlled study to compare two doses of recombinant human chorionic gonadotropin in serum and follicular fluid in woman with high body mass index.
Although it was not possible to exclude women who had BMI < 18.5 kg/m2 from the group of women who were reported as having BMI < 25 kg/m2 from the data provided in 18 studies (
), including these women in the current analysis has probably resulted in underestimation of the detrimental effect of raised BMI, as a low BMI (<18.5 kg/m2) is known to be associated with a poorer IVF outcome (
). Furthermore, the subgroup analysis followed the WHO criteria for overweight (BMI ⩾25–29.9 kg/m2) and obese (BMI ⩾30 kg/m2) in order to provide an accurate comparison of normal versus increased BMI (
Despite the methodological shortcomings of the available literature, there was limited statistical heterogeneity in this study’s results, which corroborates those of previous reviews and confirms the detrimental effect of raised BMI on IVF outcome. In support of the current findings, the negative impact of raised BMI on IVF outcome was also confirmed in a recent meta-analysis of randomized controlled trails evaluating the use of single-embryo transfer in IVF (
), which showed that for every unit increase in BMI the odds of a preterm birth ⩽32 weeks increased by 16% (1.16, 1.04–1.30, P= 0.01).
Successful implantation and continuation of pregnancy depend on close interactions between the embryo and the endometrium. Raised BMI is associated with a variety of key endocrine and paracrine changes which could adversely affect oocyte maturation and embryonic competence. These include hyperandrogenaemia (
). In addition, alterations in serum concentrations of insulin-like growth factors, which are involved in cell proliferation and differentiation, and their binding proteins could influence folliculogenesis, oocyte maturation and embryo development (
Insulin-like growth factor-II (IGF-II), IGF-binding protein-3 (IGFBP-3), and IGFBP-4 in follicular fluid are associated with oocyte maturation and embryo development.
). Furthermore, BMI correlates with endometrial and intra-follicular concentrations of the inflammatory markers, interleukin 6 and tumor necrosis factor α, both of which have been associated with poor oocyte quality, impaired implantation and increased risk of miscarriage, and thus could mediate the effect of obesity on IVF outcome (
Future studies examining the relationship between BMI and IVF outcome should strictly conform with WHO standardized classification of BMI categories and account for important confounders such as age, cause of infertility, particularly polycystic ovary syndrome, and quality of embryos transferred (
). In addition, since only one cycle per women should be included in these studies, reporting rates per woman rather than per cycle would provide a more robust analysis.
The findings of this review can empower clinicians to provide more detailed advice regarding the impact of raised BMI on treatment outcome before starting an IVF cycle. Ideally, the advice given can be complemented with information on the effect of weight loss on IVF treatment outcome.
have reported that for each unit reduction in BMI the odds of achieving a pregnancy following IVF could improve by 19%. Therefore, weight loss should be encouraged in overweight and obese women, while at the same time clinicians should facilitate access to effective weight-loss programmes to enable women to achieve a better treatment outcome.
In conclusion, this systematic review and meta-analysis clearly demonstrates that raised BMI has an adverse effect on IVF treatment outcome. It significantly reduces pregnancy and live-birth rates and increases miscarriage rate. This effect is present in overweight as well as obese women. Further studies are needed to enhance the understanding of the underlying mechanisms for this effect.
References
Anderson A.N.
Wohlfahrt J.
Christens P.
Olsen J.
Melbye M.
Maternal age and fetal loss: population based register linkage study.
International Obesity Task Force and European Association for the Study of Obesity 2002. Obesity in Europe. The case for action. London. Available from: <http://www.iotf.org/media/euobesity.pdf>.
A prospective, randomized, controlled study to compare two doses of recombinant human chorionic gonadotropin in serum and follicular fluid in woman with high body mass index.
Rittenberg, V., Sobaleva, S., Ahmad, A., Oteng-ntim, E., Bolton, V., Khalaf, Y., Braude, P., El-Toukhy, T., 2011. Influence of BMI on risk of miscarriage after single blastocyst transfer. Hum. Reprod. [Epub ahead of print].
Insulin-like growth factor-II (IGF-II), IGF-binding protein-3 (IGFBP-3), and IGFBP-4 in follicular fluid are associated with oocyte maturation and embryo development.
Declaration: The author reports no financial or commercial conflicts of interest.
Footnotes
Vivian Rittenberg graduated in 2002 from the Université Libre de Bruxelles, following which she completed her specialization in obstetrics and gynecology in 2007. She then worked on the differentiation of human embryonic stem cells before moving to the Manchester Fertility Services. Since 2009 she has worked as a clinical research fellow in the assisted conception unit of Guy’s and St. Thomas’ NHS Foundation Trust. Her special research interests are in factors influencing IVF treatment outcomes.
This study investigated the impact of women’s body mass index (BMI) on the outcome after consecutive IVF/intracytoplasmic sperm injection cycles in 487 patients initiating treatment with 5-year follow-up. The total number of cycles was 1417. In total 103 (21.1%) were overweight (BMI 25–29.9 kg/m2) and 59 (12.1%) were obese (BMI ⩾30 kg/m2). Number of initiated cycles/woman (P = 0.01), number of cancelled cycles/woman (P < 0.01) and the total dose of gonadotrophin used/cycle (P < 0.01) rose with increasing BMI.
Vivian Rittenberg graduated in 2002 from the Université Libre de Bruxelles, following which she completed her specialization in obstetrics and gynecology in 2007. She then worked on the differentiation of human embryonic stem cells before moving to the Manchester Fertility Services. Since 2009 she has worked as a clinical research fellow in the assisted conception unit of Guy’s and St. Thomas’ NHS Foundation Trust. Her special research interests are in factors influencing IVF treatment outcomes.
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