1 Department of Obstetrics and Gynaecology, Rikshospitalet University Hospital, Oslo, Norway
2 To whom correspondence should be addressed at: Department of Obstetrics and Gynaecology, Rikshospitalet University Hospital, Sognsvannsveien 20, 0027 Oslo, Norway. Email: peter.fedorcsak{at}klinmed.uio.no
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Abstract |
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Key words: body mass index/insulin resistance/IVF/PCOS
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Introduction |
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Clinical observations on the effects of body weight during IVF and ICSI are conflicting. In overweight/obese compared with normal weight women, increased FSH requirement during ovarian stimulation, fewer collected oocytes, decreased serum estradiol concentrations, frequent cycle cancellations and low pregnancy rate have been observed (Crosignani et al., 1994; Homburg et al., 1996
; Soderstrom-Anttila et al., 1996
; Wang et al., 2000
; Wittemer et al., 2000
; Carrell et al., 2001
; Loveland et al., 2001
; Mulders et al., 2003
; Nichols et al., 2003
). It has also been reported that obese women are at increased risk of miscarriage after IVF or ICSI, an association not fully explained by the high prevalence of polycystic ovary syndrome (PCOS), which is itself related to miscarriage, among obese infertile women (Fedorcsák et al., 2000b
; Wang et al., 2001
, 2002
). Confirming the harmful effect of obesity, weight loss was found to improve the outcome of assisted reproduction treatment in obese women (Clark et al., 1998
).
Other studies, however, find no significant effect of obesity on response to ovarian stimulation (Lewis et al., 1990; Lashen et al., 1999
; Loh et al., 2002
) or on pregnancy rate and outcome of pregnancies conceived by IVF and ICSI (Lewis et al., 1990
; Lashen et al., 1999
; Wittemer et al., 2000
; Winter et al., 2002
). It has also been suggested that abdominal fatness has a more important impact on IVF outcome than obesity itself (Wass et al., 1997
). This controversy among various reports, which is partly caused by the varying focus of investigators, differences in study designs and low sample size of some reports, led us to examine the impact of underweight and overweight on IVF and ICSI treatment in a large cohort of women.
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Patients and methods |
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Gamete handling, fertilization and embryo culture were performed according to standard IVF procedures. Briefly, Universal IVF medium (Medi-Cult, Copenhagen, Denmark) was used during oocyte insemination and embryo culture. In ICSI cycles, only ejaculated spermatozoa were microinjected. Embryos were scored from grade 1 (high quality) to grade 4 (poor quality) according to the number, size and shape of blastomeres and degree of fragmentation, using previously described criteria (Van den Abbeel et al., 1988). Embryos were transferred on day 3, except in cases with few embryos (
2), which were transferred on day 2. As a rule, and when available, two embryos were transferred. However, during the period 19961997, transfer of three embryos was sometimes allowed in selected older women (>35 years) with multiple prior unsuccessful cycles, after counselling the patient on the risks of multiple gestation. Luteal phase support up to 14 days after oocyte retrieval consisted of either daily i.m. injection of 25 mg progesterone in oil, Crinone® vaginal gel (90 mg, Serono) or intravaginal Progestan® (600 mg, Nourypharma, Germany) capsules.
The serum concentration of HCG was measured on day 14 after oocyte retrieval and, in the case of concentrations above 20 U/l, which indicated pregnancy, an ultrasound scan was performed 34 weeks later to verify the viability of pregnancy and count gestational sacs. Early pregnancy loss was defined as a biochemical pregnancy without subsequent ultrasound signs of viable pregnancy. The implantation rate was calculated as the ratio of the number of gestational sacs over the number of transferred embryos. Pregnancies were followed to term by general practitioners or obstetricians at the patients' local hospitals. Every pregnant woman was contacted on pregnancy outcome, and copies of original medical records were obtained.
Weight and height of women were measured with a calibrated balance and height rod at the first visit, a median 80 days before the first IVF or ICSI cycle. The main cause of infertility, as determined by the physician, was categorized as male factor (assessed by sperm analysis), tubal factor (assessed by hysterosalpingogram or laparoscopy), endometriosis (laparoscopy), PCOS (defined by polycystic ovaries on ultrasound scan, and two or more of the following criteria: oligo/amenorrhoea, hirsutism and hyperandrogenism), other specific diseases or unexplained infertility.
Data analysis
Data with normal distribution are presented as mean (SD); data with log-normal distribution are presented as geometric mean [95% confidence interval(CI)]. Data for IVF and ICSI cycles were analysed and compared for the following strata of BMI (kg/m2): underweight, BMI <18.5; normal weight, 18.524.9; overweight, 25.029.9; and obesity, 30.0. Generalized linear models were used to assess linear association between classes of BMI and continuous variables. In these analyses, age and main infertility diagnosis were included as covariates, to examine the independent effect of BMI.
2 test for linear trend was used to assess linear association between classes of BMI and rate variables. Logistic regression was used to calculate odds ratios for live birth and for miscarriage, using BMI classes, age and infertility diagnosis as explanatory variables. The fit of logistic models was assessed with HosmerLemeshow test. Cumulative live birth rates were calculated by the KaplanMeier method, and were compared across BMI classes with the log rank test for trend. SPSS version 10 (SPSS Inc., Chicago, IL) was used for data analysis. P<0.05 was considered statistically significant.
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Results |
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Linear association was observed between higher BMI and increased incidence of early pregnancy loss (before week 6 of gestation) and miscarriage during 612 weeks of pregnancy, and between higher BMI and lower live birth rate and cumulative live birth rate (Table II). After adjusting for differences in age and main diagnosis of infertility, the odds ratio of live birth was 0.75 (95% CI 0.570.98, P=0.05), while the odds ratio of early pregnancy loss was 1.69 (95% CI 1.132.51, P=0.003) in obese women (BMI 30.0 kg/m2) compared with women with normal weight (BMI 18.524.9 kg/m2).
Treatment outcome in the first IVF or ICSI cycle
During the first IVF or ICSI cycles of the treated couples (n=2660), a positive correlation was observed between BMI and total FSH dose and between BMI and frequency of cycle cancellations. Negative correlation was observed between BMI and the number of collected oocytes. No significant association was observed between BMI and pregnancy rate, but increased BMI was associated with higher incidence of early pregnancy loss and, although not statistically significant (P=0.09), with a lower live birth rate (Table III).
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Discussion |
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Compared with women with normal weight, obese women achieved on average 3.9 (95% CI 0.37.6) fewer live births per 100 started IVF and ICSI cycles. As a cumulative effect, 41 of 100 obese women gave birth to living newborn(s) within three treatment cycles, compared with 50 of 100 women who had normal body weight. Of the 3.9 missing live births per 100 started cycles, 3.2 could be attributed to an increased incidence of early pregnancy loss in obese women (Figure 1). These findings agree with earlier observations that overweight and obesity are related to lower chances of live birth due to an increased risk of miscarriage of early pregnancies conceived in vitro (Fedorcsák et al., 2000b
; Wang et al., 2002
). Miscarriage in obese women is probably not caused by the IVF procedure itself, since obesity also increases miscarriage rate in recipients of donated oocytes (Bellver et al., 2003
) and during natural conception (Hamilton-Fairley et al., 1992
). The cause of early pregnancy loss in obese women is not identified in this report, as we did not observe statistically significant differences in fertilization rate, cleavage stage and morphology of transferred embryos, or in implantation and biochemical pregnancy rates among women with different BMI. Other studies, however, suggest that obesity and the associated endocrine alterations may affect corpus luteum function (Sherman and Korenman, 1974
; Fedorcsák et al., 2000a
), early embryo development (Kawamura et al., 2002
; Fedorcsák and Storeng, 2003
), trophoblast function (Castellucci et al., 2000
) and endometrial receptivity (Alfer et al., 2000
; Gonzalez et al., 2000
).
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We observed an association between increased BMI and increased FSH requirement, fewer collected oocytes and increased risk of insufficient follicle development during ovarian stimulation for IVF and ICSI, suggesting that the response to FSH stimulation is attenuated by overweight and obesity. Although the starting dose of FSH was not fixed in this report, the correlation between BMI and length of stimulation suggests that the differences in FSH requirement were not caused solely by a deliberate subscription of higher FSH doses in obese women. Furthermore, the analysis of the 2660 first treatment cycles (one cycle per couple) yielded similar results to those obtained with all cycles, indicating that the association of increased BMI and increased FSH requirement was not due to a dose adjustment in successive cycles of the same couple.
During ovarian stimulation with FSH, selection of multiple growing follicles requires that the serum FSH concentration exceeds a threshold (Hillier, 2000). In obese women, the threshold effect of exogenous FSH is reduced (Imani et al., 2002
), which consequently may lead to fewer selected follicles, fewer collected oocytes and a requirement for larger FSH doses for stimulation, as observed in the present analysis.
To what extent this impaired response to stimulation contributes to the reduced live birth rate in obese women is uncertain. The contribution of increased cycle cancellations is probably small: assuming that cancelled cycles would have resulted in a similar live birth rate to non-cancelled cycles, the 3.6 excess cancellations per 100 started cycles would account for
0.8 of the 3.9 missing live births in obese women (Figure 1). Furthermore, although obese women had fewer oocytes collected, fewer embryos to select for transfer and fewer cycles that proceeded to embryo transfer, pregnancy and implantation rates were similar in obese and normal weight women. Consequently, alternative stimulation regimens that increase the number of available oocytes and reduce cancellation rate in obese womenassuming that oocyte quality and endometrial receptivity are not compromised and the risk of hyperstimulation is not increasedmay bring about only a marginal improvement of live birth rate after IVF and ICSI in obese women.
It has been suggested that the association of body weight and IVF outcome is of an inverted U shape, implicating that underweight has as deleterious an effect on IVF outcome as overweight and obesity (Wang et al., 2000; Winter et al., 2002
). Our data do not reveal a significant impact of underweight on clinical pregnancy rate or live birth rate during IVF. It remains to be examined whether differences between our study and Australian reports (Wang et al., 2000
; Winter et al., 2002
) are caused by true biological differences among patient populations or statistical phenomena due to infrequency of underweight.
In summary, we found that obesity is associated with a lower live birth rate after IVF and ICSI treatment, mainly because of an increased risk of early pregnancy loss in obese women. An impaired response to ovarian stimulation in obese women was also observed. Underweight was not related to an impaired outcome of IVF or ICSI in this analysis.
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Submitted on October 20, 2003; resubmitted on May 27, 2004; accepted on July 26, 2004.