Hum. Reprod. Advance Access originally published online on May 24, 2008
Human Reproduction 2008 23(8):1835-1839; doi:10.1093/humrep/den188
Body mass index: impact on IVF success appears age-related 
1 Department of Obstetrics and Gynecology, Lutheran General Hospital, 1775 Dempster Street, Park Ridge, IL 60068, USA 2 Fertility Center of Illinois, 900 North Kingsbury Street, Suite RW6, Chicago, IL 60610, USA 3 EMD Serono, Inc., One Technology Place, Rockland, MA 02370, USA
4 Correspondence address. Fertility Center of Illinois, 2056 Westings Avenue, Suite 130, Naperville, IL 60563, USA. Fax: +1-630-305-7990; E-mail: meike.uhler{at}integramed.com
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Abstract |
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BACKGROUND: The objective of this study was to examine the effect of BMI on IVF outcomes.
METHODS: This was a retrospective analysis of all patients undergoing IVF from 1st January 2005 to 1st March 2006 in a large private practice using a single IVF laboratory. The patients underwent standard protocols for controlled ovarian hyperstimulation and embryology parameters. The main outcome measure was clinical pregnancy rate.
RESULTS: A total of 2167 fresh, non-donor IVF cycles were queried, but to minimize bias, only the first treatment cycle for each patient was analyzed (n = 1273). The data were examined by multiple regression models that included BMI and Age as main effects plus a BMI x Age interaction. When examined as a main effect, BMI did not appear to have a major effect on IVF outcome, but there was a significant BMI x Age interaction. At younger ages, a high BMI had a pronounced negative influence on fertility, but this effect diminished as the patient age increased. Clinical pregnancy rates decreased with increasing BMI and increasing Age.
CONCLUSIONS: In younger patients undergoing IVF, BMI has a significant negative impact on fertility that diminishes as patients reach their mid thirties. After Age 36, BMI has a minimal impact on fertility.
Key words: age/fertility/obesity/body mass index/IVF
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Introduction |
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Recent estimates in the USA highlight the prevalence of obesity in society, with
61% of women considered overweight, 33% obese and 6.9% morbidly obese (Ogden et al., 2006
). The deleterious effects of obesity on general heath are well known, and the reproductive consequences include menstrual disorders, infertility and maternal complications in pregnancy (Sharpe and Franks, 2004; American College of Obstetricians and Gynecologists, 2005). Reduced fecundity in obese women is probably related to multiple factors including aberrations in endocrine and metabolic functions that in turn can affect follicular growth, implantation and development of a clinical pregnancy (Pasquali et al., 2003; Fedorcsak et al., 2004). In some studies, obesity is associated with reduced fertility in the normal population (Pasquali et al., 2003) and with lower success rates for patients undergoing IVF.
Clinical observations on the effects of body weight during IVF are more controversial. Several investigators have shown a decrease in pregnancy and live birth rates in overweight and obese compared with normal weight women (Loveland et al., 2000; Wang et al., 2000; Nichols et al., 2003; Fedorcsak et al., 2004; Ferlitsch et al., 2004; Lintsen et al., 2005), whereas others have found no difference (Lashen et al., 1999; Wittemer et al., 2000; Frattarelli and Kodama, 2004; Spandorfer et al., 2004; van Swieten et al., 2005; Dokras et al., 2006). Possible reasons for the differences include: increased gonadotrophin requirement during ovarian stimulation (Wittemer et al., 2000; Fedorcsak et al., 2004), fewer retrieved oocytes (Wittemer et al., 2000; Fedorcsak et al., 2004), decreased serum estradiol concentrations (Lashen et al., 1999; Dokras et al., 2006), increased cycle cancellations (Fedorcsak et al., 2004; Spandorfer et al., 2004; van Swieten et al., 2005; Dokras et al., 2006) and lower fertilization rates (van Swieten et al., 2005). In contrast, other studies have found that obesity exerts no effect on, or actually decreases, the need for gonadotrophins (Frattarelli and Kodama, 2004; Spandorfer et al., 2004) and the number of days of ovarian stimulation (Lewis et al., 1990; Frattarelli and Kodama, 2004) and does not affect the estradiol levels (Lewis et al., 1990). Additionally, obese women who conceive following IVF have been found to be at an increased risk of spontaneous abortion (Wang et al., 2002; Fedorcsak et al., 2004) and a significant risk of obstetrical complications (Dokras et al., 2006).
Based on the relatively small number and heterogeneity of published reports, the impact of body mass index (BMI) on IVF outcomes warranted further investigation. Thus, the objective of this study was to examine the effects of body mass index (BMI) on IVF success in a large assisted reproductive technology (ART) program in an attempt to expand previous findings. In addition, Age was examined as an independent variable and the BMI x Age interaction was analyzed to determine if these two factors have independent or interdependent effects on pregnancy rates.
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Materials and Methods |
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Study design
This retrospective analysis was conducted in a large group practice using a single IVF laboratory. All patients undergoing IVF from 1st January 2005 to 1st March 2006 were available for review, and this included more than 2100 fresh, non-donor IVF cycles. This group encompassed a broad spectrum of patients representing typical infertility patients presenting for assisted reproduction. In order to minimize bias, only the first treatment cycle for a particular patient was included in the analysis (n = 1273). Institutional Review Board approval was obtained to retrospectively query the database.
Patients
All patients presenting for IVF ranged in age from 21 to 44, and their etiologies for infertility included tubal disease, ovulatory dysfunction, male factor, endometriosis and unexplained infertility. Patients were excluded from the study if they were undergoing frozen embryo transfer, donor oocyte or gestational surrogacy cycles. All patients had their weight measured, and their height was self-reported. BMI was determined by the ratio of weight divided by the height squared in metric units.
Treatment
Patients underwent controlled ovarian hyperstimulation (COH) by standard mid-luteal phase GnRH agonist down-regulation with leuprolide acetate (Lupron®, Tap Pharmaceuticals, Deerfield, IL, USA) at a dose of 0.5 mg daily or a GnRH antagonist protocol (Ganarelix Acetate®, Organon, Inc., West Orange, NJ, USA, or Cetrotide®, Serono, Inc., Rockland, MA, USA) where the GnRH antagonist was given as either 0.25 mg daily doses or a 3 mg dose followed by daily 0.25 mg injections after 96 h. The GnRH antagonist was initiated when the lead follicle was 12–14 mm in diameter. COH used recombinant FSH alone (Follistim®, Organon or Gonal-f®, EMD Serono) or in combination with hMG (Repronex®, Ferring Pharmaceuticals, Suffern, NY, USA) or recombinant LH (Luveris®, EMD Serono). About 4% of the patients in each BMI category were treated with recombinant LH. Adjustments were made based on individual responses.
When two or more follicles had attained a minimum mean diameter of 20 mm, follicular maturation was achieved with either recombinant hCG 250 µg SQ (Ovidrel®, Serono, Inc.) or urinary hCG 10 000 IU IM. Transvaginal ultrasound guided oocyte retrieval was performed 36 h after hCG injection.
Standard laboratory protocols were followed, including intracytoplasmic sperm injection, assisted hatching for cleavage stage embryos and extended culture for blastocyst transfer, as clinically appropriate. Ultrasound guided transfer was performed, and all patients received luteal phase progesterone supplementation administered as progesterone in oil, 50 mg IM daily. Serum hCG levels were measured 15 days after retrieval, and a clinical pregnancy was defined as the presence of a gestational sac on ultrasound.
Assessments
The primary end-point assessed was clinical pregnancy rate. The secondary end-points included: cycle cancellation rate, the number of oocytes retrieved, mature oocytes, implantation rate and live birth rate.
Statistical analyses
Patients were initially grouped into four BMI categories using the criteria specified by the Centers for Disease Control: underweight, BMI <18.5; normal, BMI >18.5–24.9; overweight, BMI 25–29.9; or obese: BMI 
30. Preliminary statistical comparisons were made by analysis of variance (ANOVA) and Chi-square tests using data grouped according to these four BMI categories. The data presented in Tables I–III represent group means (±SD) and frequencies from the preliminary analyses (ANOVA and Chi-square). Because fertility declines with age, particularly above Age 35, more comprehensive tests were undertaken to assess the effects of BMI and whether the effects of BMI were independent or interrelated to Age. First, in order to determine whether BMI and Age were independent or interrelated variables, a simple Pearson correlation coefficient was calculated. The correlation coefficient for BMI and Age was 0.02 (NS), indicating that BMI is independent and unrelated to Age. Second, in order to adjust for the known decline in fertility associated with age, each response or outcome was then analyzed using multiple linear (continuous variables) or logistic (categorical variables) regression where the main effects were BMI and Age (Tables II and III). Regression analyses also included a BMI x Age interaction term. The initial hypothesis was that the BMI x Age interactions would not be significant and recalculation of the models without the interaction term would be necessary. However, for the primary and secondary outcomes examined, BMI x Age interactions were significant and thus revealed that the effects of BMI on patient responses and outcomes were age-dependent. The best fit regression lines calculated by multiple logistic regression were used to illustrate the age-dependent effect of BMI on clinical pregnancy rates (Fig. 1) Statistical calculations were performed with JMP software (version 6.0; SAS Institute, Cary, NC, USA). In all cases, a P < 0.05 was considered statistically significant.
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Results |
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A total of 2167 fresh, non-donor IVF cycles were queried from the database, but to minimize bias, only the first treatment cycle for each patient was included in the statistical analysis (n = 1273). The mean age of the patients was 34.4 ± 4.7, and the ages of the patients were similar in each BMI category (Table I). The patients included in each BMI group were similar with respect to diagnoses and type of gonadotrophin stimulation protocol, indicating minimum bias in classifying patients among the various BMI categories.
There appeared to be a higher percentage of cancelled cycles in the underweight group, but when analyzed by multiple regression, only age had a significant effect on the percentage of cancelled cycles (Table II). Thus, the percentage of cancelled cycles increased with Age but it was independent of BMI, and in this particular case, the BMI x Age interaction was not significant.
As expected, each measure of fertility declined with age (Tables II and III). When examined as a main variable, BMI did not appear to have a major effect on IVF responses or outcomes; however, for most variables analyzed, there was a significant BMI x Age interaction (Tables II and III). The BMI x Age interaction was significant for numbers of retrieved oocytes, mature oocytes, fertilized oocytes, and for implantation, pregnancy, clinical pregnancy and live birth rates (Tables II and III; Fig. 1). Thus, the effects of BMI are highly dependent on age, and the effects of BMI on fertility change in relation to the Age of the patient.
A closer examination of the BMI x Age interaction demonstrated that at younger ages, fertility decreased markedly with increasing BMI but with advancing age, the effects of BMI were attenuated. Thus, the relationship between BMI and fertility is not straightforward. At younger ages, a higher BMI has a pronounced negative influence on fertility but the effect diminished as the patients increased in age (Fig. 1). The clinical pregnancy rates decreased with increasing BMI and increasing Age. BMI has a much less profound effect on fertility as patients reach the age of 36 and higher.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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This study demonstrated that the effect of BMI on IVF success appeared to be related to age. At younger ages, a higher BMI has a pronounced negative influence on pregnancy rate, but this effect is attenuated as age increased. When examined as a main variable alone, BMI did not appear to have a significant effect on IVF responses or outcomes, but when BMI x Age interaction was analyzed, there was a marked decrease in pregnancy rates with increasing BMI for younger patients. The BMI x Age interaction was significant for retrieved, mature and fertilized oocytes, and for implantation, pregnancy, clinical pregnancy and live birth rates. Thus, the effects of BMI are highly dependent on age. BMI has a much less profound impact on fertility as patients reach the age of 36 and older. These findings continue to underscore the importance of the dominating effect of age on IVF success, particularly above the age of 35.
The results presented in this study confirm the findings of published reports that have shown an adverse effect on clinical pregnancy rates in women with high compared with normal BMI (Loveland et al., 2000; Wang et al., 2000; Nichols et al., 2003; Fedorcsak et al., 2004; Ferlitsch et al., 2004; Lintsen et al., 2005). Our study demonstrated a decrease in retrieved and fertilized oocytes when the BMI x Age interaction was examined. Other investigators have also found a decrease in the number of retrieved oocytes (Wittemer et al., 2000; Fedorcsak et al., 2004), most likely due to decreased response to COH with increased BMI (Crosignani et al., 1994). A need for higher gonadotrophin dosage in obese women has been reported in both ovulation induction (Loh et al., 2002) and IVF cycles (Wittemer et al., 2000; Fedorcsak et al., 2004). Although this study did not find an increase in cancellation rates with high BMI, several authors have noted an increased frequency of cycle cancellation due to insufficient follicular development (Fedorcsak et al., 2004; Spandorfer et al., 2004; van Swieten et al., 2005; Dokras et al., 2006). A recent study of almost 1300 patients found a cancellation rate of 25% in the morbidly obese group compared with 10.9% in normal weight women, and morbidly obese women without polycystic ovarian syndrome (PCOS) had an even higher cancellation rate of 33% (Dokras et al., 2006).
In contrast to the findings in this study, six articles have found no significant differences in clinical pregnancy rates between obese and non-obese women (Lashen et al., 1999; Wittemer et al., 2000; Frattarelli and Kodama, 2004; Spandorfer et al., 2004; van Swieten et al., 2005; Dokras et al., 2006). The discrepancy between the various reports may be due to differences in study design, low samples sizes and varying focus of the investigators. Three studies demonstrated a decrease in the number of retrieved oocytes, but in spite of the lower response, there was no difference in pregnancy rates (Wittemer et al., 2000; Spandorfer et al., 2004; van Swieten et al., 2005). Only one article found that obesity was associated with an increase in the number of follicles observed on ultrasound, a decrease in the dosage of gonadotrophin used and a decrease in the number of days of stimulation (Frattarelli and Kodama, 2004).
Our results demonstrated a trend toward decreasing spontaneous abortion rates with increasing BMI, but this finding was not statistically significant. This observation is in contrast to two investigators who showed an increase in early pregnancy loss (Wang et al., 2000; Fedorcsak et al., 2004). These two articles cited (Wang et al., 2000; Fedorcsak et al., 2004) had higher numbers of patients than our study, and it may be possible that when examining spontaneous abortion rates, a larger number of patients may be necessary to find significance. The mechanisms for these findings have been postulated, and they include possible effects of obesity on endocrine and biochemical factors that may affect corpus luteum function, endometrial receptivity and early embryo development (Wang et al., 2000; Fedorcsak et al., 2004). In addition, the findings of a recent retrospective study of obstetric outcomes after IVF in obese and morbidly obese women demonstrated a significant linear trend for risk of pre-eclampsia, gestational diabetes and caesarean delivery with increasing BMI (Dokras et al., 2006).
The strength of this study included the large database queried, which encompassed a broad spectrum of patients representing typical infertility patients presenting for assisted reproduction. A total of almost 1300 IVF cycles were analyzed with nearly half of the patients in the overweight or obese category. Furthermore, this is the first study to demonstrate that the effect of BMI on IVF success is related to age.
This study is limited by its retrospective design. The small number of patients in the underweight group prevented any meaningful interpretation of the data, although other investigators have examined the impact of overweight and underweight on IVF pregnancy rates (Lashen et al., 1999; Nichols et al., 2003; Fedorcsak et al., 2004). Weight loss has been well established to improve reproductive outcomes in overweight and obese women. Even modest weight loss of 5–10% of initial body weight can effectively improve menstrual cycle regularity, ovulation and pregnancy rates (Norman et al., 2004). Our study, however, suggests that this recommendation may only be true in patients of Age 36 and younger. In older patients, the dominating effect of age on fertility and IVF outcomes became more important than the effects of BMI. Our findings confirmed a recent study that concluded elevated Day 3 FSH levels and obesity were independent risk factors for failure in assisted reproduction (Ferlitsch et al., 2004). Although this study did not examine pretreatment weight loss as an outcome, the finding that the effect of BMI on IVF success is related to age remains highly significant and clinically relevant. Therefore, it may be reasonable to delay treatment in younger women and recommend weight loss in an effort to increase their chance of success with IVF, as long as the delay does not put the younger women at risk for an age-related decline in fertility. Weight loss in older women seeking assisted reproduction should not postpone treatment as the effect of age clearly predominates.
It is important to note that early pregnancy loss and significant obstetrical morbidity may be associated with obese women undergoing IVF. These additional potential complications further emphasize the importance of early initiation of weight reduction prior to beginning fertility treatment (Dokras et al., 2006).
In conclusion, in younger patients undergoing IVF, BMI has a significant impact on pregnancy rates; however, as patients reach their mid thirties, the effects of age appear to be stronger than BMI. For patients in the normal and elevated BMI groups, BMI has a significant age-dependent influence on fertility and IVF outcomes. It appears that it may be appropriate to recommend weight loss prior to IVF in patients under Age 36, whereas in older patients, a more immediate and aggressive approach to ART may be warranted.
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Footnotes |
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Presented in part at the Annual Meeting of the American Society for Reproductive Medicine, New Orleans, LA, USA, 21–25 October 2006. 
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Submitted on November 9, 2007; resubmitted on March 20, 2008; accepted on April 8, 2008.
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