Obesity does not impact implantation rates or pregnancy outcome in women attempting conception through oocyte donation

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1 IN VITRO FERTILIZATION Obesity does not impact implantation rates or pregnancy outcome in women attempting conception through oocyte donation Allison Styne-Gross, M.D., a Karen Elkind-Hirsch, Ph.D., b and Richard T. Scott, Jr., M.D. b a Division of Reproductive Endocrinology and Infertility, Emory University School of Medicine, Atlanta, Georgia; and b Reproductive Medicine Associates of New Jersey, Morristown, New Jersey Objective: To independently evaluate the effect of body mass index (BMI) on implantation, pregnancy, and incidence of spontaneous miscarriage using the donor oocyte recipient model. Design: Institutional Review Board-approved retrospective data analyses of donor oocyte cycles from 1999 to Setting: Private assisted reproductive technology (ART) center. Patient(s): Five hundred thirty-six first cycle recipients of donor oocytes. Intervention(s): Data were collected from the first cycle of each donor oocyte recipient included in the study. The body mass index (BMI) of each recipient was calculated using the formula weight (in kilograms)/height (in meters squared). Patients were divided into four groups based on BMI: underweight, normal, overweight, and obese. Pregnancy outcomes in each group were compared. Main Outcome Measure(s): Body mass index, implantation rate, pregnancy rate (PR), miscarriage rate. Result(s): There were no statistically significant differences in the implantation rates, ongoing PRs, or spontaneous abortion rates among patients in the four BMI groups. When further divided into those patients receiving blastocyst vs. day 3 transfers, there was still no effect of BMI on implantation rate, PR, or loss rate among the blastocyst or day 3 donor oocyte recipients. Conclusion(s): Body mass index has no adverse impact on implantation or reproductive outcome in donor oocyte recipients. Therefore, obesity does not appear to exert a negative effect on endometrial receptivity. (Fertil Steril 2005;83: by American Society for Reproductive Medicine.) Key Words: Body mass index, oocyte donation, obesity, implantation, pregnancy rate, miscarriage Maternal obesity is associated with reduced fertility in the general population and with lower live birth rate after IVF and intracytoplasmic sperm injection (ICSI) (1 4). Several studies analyzing patients treated by assisted reproductive technology (ART) find an inverse relationship between obesity, pregnancy rate (PR), and implantation rate (2, 5). Other reports more specifically showed that very obese women have half the odds of conception compared to moderately overweight women (6, 7). Obesity, independent of hyperinsulinemia, is related to an increased risk of insufficient follicle development, a lower oocyte count, and increased gonadotropin requirement (4, 8, 9). In contrast, other studies find no significant effect of obesity on implantation rate and PR in pregnancies conceived in vitro (10, 11). Weight excess is associated with an increased risk of miscarriage during natural conception (12). Likewise, a Received September 17, 2004; revised and accepted January 3, Reprint requests: Richard T. Scott, Jr., M.D., Reproductive Medicine Associates of New Jersey, 111 Madison Ave, Ste 100, Morristown, New Jersey (FAX: ; rscott@rmanj.com). marked increase in the risk of miscarriage in pregnancies achieved by IVF or ICSI in overweight and obese women has been attributed to obesity. Several reports confirm that higher body mass index (BMI) is associated with a higher incidence of early pregnancy loss, before week 6 of gestation among women undergoing IVF or ICSI (3, 13 15). Other studies failed to show significant effects of obesity on spontaneous abortion in a similar group of women (6, 11). Thus, the reported relationship between BMI and the risk of spontaneous abortion is inconsistent. The question remains as to the mechanism in which obesity may affect fecundity in women. Is it exclusively an ovarian effect, endometrial effect, or a combined effect? The cause of the reduced PR or higher spontaneous loss rate in obese women is not identified in any of these reports, rather inferred from their association. Factors other than follicular development, such as altered receptivity of the uterus after transfer of embryos, could explain reduced fecundity. In our review of the literature, there were only a few studies in which the effects of BMI on implantation and /05/$30.00 Fertility and Sterility Vol. 83, No. 6, June 2005 doi: /j.fertnstert Copyright 2005 American Society for Reproductive Medicine, Published by Elsevier Inc. 1629

2 pregnancy outcome, independent of oocyte development, were compared. Using a donor recipient model, these investigators evaluated the independent effects of BMI on implantation rate and PR per cycle under strictly controlled conditions (16 18). Both Cano et al. (16) and Wattanakumtornkul et al. (17) observed no association between BMI and PR or loss rate in oocyte donation cycles, whereas Bellver et al. (18) found obesity to be an independent risk factor for miscarriage in women receiving donated oocytes. This discrepancy can be explained by the fact that Bellver et al. (18) allowed the same patient to contribute more than one cycle, thereby weighing the data to over-represent patients with failed cycles. The prevalence of obesity in infertile women is high, but there is conflicting data regarding the association of BMI with reduced PRs in women receiving ART. The oocyte donation model is a unique model in which to distinguish ovarian from uterine receptivity effects on reproductive outcome under conditions of programmed hormonal support and standardized embryo quality. To that end, we retrospectively analyzed our donor oocyte recipient database to determine the potential effect of obesity on implantation rate, PR, and spontaneous loss rate and more specifically, analyze endometrial receptivity as a possible etiology. MATERIALS AND METHODS The Western Institutional Review Board approved the study protocol and waived consent. A retrospective analysis of the charts of 536 patients who were recipients of oocyte donation at the IVF program of the Reproductive Medicine Associates of New Jersey from November 1999 until June 2004 was performed. Oocyte donors consisted of paid anonymous volunteers or unpaid volunteers known to the recipient. All donors were healthy young women ( 32 years old). Only the first cycle for each recipient was included. The data collected included the following parameters: age, weight, height, number of embryos transferred, day of embryo transfer (ET), peak endometrial thickness, PR, implantation rate, and pregnancy losses. A patient was considered pregnant if a gestational sac was visualized on ultrasound. Implantation rate is defined as number of sacs per embryo transferred. Spontaneous abortion included both gestational sacs passed spontaneously and missed abortion on transvaginal ultrasound requiring dilatation and curettage. The BMI was calculated on the basis of height and weight measurements obtained at the time of the initial patient consultation. The BMI of each subject was calculated using the formula weight (in kilograms)/height (in meters squared). The BMI was used as an indicator of obesity, and subjects were stratified into four BMI groups: underweight, normal, overweight, and obese using a modification of the World Health Organization (WHO) classification (19). Group 1 consisted of underweight patients with BMI 20 kg/m 2. Group 2 were normal weight with a BMI between 21 and 25 kg/m 2. Group three were considered overweight with a BMI of kg/m 2, and group 4 were obese (BMI 30 kg/m 2 ). Before stimulation, all recipients were screened for uterine pathology with either saline sonogram or hysterosalpingogram. They were not started if any uterine pathology was noted. All recipients underwent endometrial preparation with an established hormone replacement protocol and received ET on either day 3 or day 5. Patients were excluded from analysis if their peak endometrial thickness was less than 6 mm, if they were using adjunctive therapies (i.e., Viagra), or if they had a prior history of recurrent pregnancy loss. These variables would potentially skew an independent effect of BMI on pregnancy outcome. Statistical Analyses For comparisons of group differences in recipient age and mean number of embryos transferred, data were evaluated by one-way analysis of variance (ANOVA). Data are reported as mean one standard deviation with P.05 as the significance cutoff for ANOVA data. Receiver operating characteristic (ROC) curve analyses were carried out to establish the appropriate cutoff levels of BMI for defining overweight as a negative risk for pregnancy and miscarriage. Complex 2 tests were performed to analyze the incidence of spontaneous abortion and ongoing PR among patients in the four different BMI categories. The Bonferroni correction procedure for multiple comparisons was applied to avoid type 1 error for the 10 2 comparisons. Data are presented as percentages, with a corrected P value of.005 or less as the significance cutoff adjusted for multiple comparisons. All P values presented are two-sided. The statistical analyses were performed using the Statistical Package Analyze-it for Microsoft Excel (Microsoft, Redmond, WA). RESULTS There were 536 donor oocyte recipients included in the study, each contributing one cycle for analysis. Donors were years of age and had an average BMI of kg/m 2. The screening of oocyte donors included basal FSH and E 2 levels to assess ovarian reserve, screening ultrasound including the assessment of antral follicle counts, and thyroid function screening. Recipients were stratified into groups based on a modification of the WHO criteria (19) described previously. Nineteen percent of the patients had a BMI of less than or equal to 20 kg/m 2 (underweight), 53% had a BMI of kg/m 2 (normal weight), 14% had a BMI of kg/m 2, and the remaining 14% were obese (BMI of 30 kg/m 2 or more). Both recipient age and number of embryos transferred in each BMI group were similar (Table 1). The percentage of cycles with day 3 ETs vs. blastocyst transfers did not differ among the BMI groups (P.46). When separated into groups based on day of transfer, without regard to BMI, blastocyst trans Styne-Gross et al. Recipient BMI does not impact implantation Vol. 83, No. 6, June 2005

3 TABLE 1 Pregnancy outcome and BMI P value N Mean age (y) Implantation rate (%) Pregnancy rate (%) Loss rate (%) Mean no. of embryos % Blastocyst transferred 55.4 a 60.6 a 51.4 a 59.7 a % Day 3 transferred 44.6 b 39.4 b 48.6 b 40.3 b a vs. b P.46. fers had higher implantation rate and PR than day 3 transfers (80.7% vs. 62.5%, respectively; P.0001). No statistically significant differences in the implantation rate or ongoing PR were determined for the four different BMI categories (Table 1). The ROC curve of PR vs. BMI further illustrates this point (Fig. 1). It is essentially a diagonal line, suggesting no predictive relationship between BMI and implantation rate. As shown in Table 1, the incidence of spontaneous loss among patients in the four different BMI categories did not differ statistically. Data were further analyzed by 2 comparisons of the four BMI groups within the two subsets of patients the first, consisting of recipients who received ET on day 3 after retrieval and the second receiving blastocyst transfers. Table 2 summarizes the results of implantation rate, PR per ET, and miscarriage rate in each BMI group, FIGURE 1 Receiver operator characteristic curve of body mass index and pregnancy rate SENSITIVITY SPECIFICITY Fertility and Sterility 1631

4 TABLE 2 Pregnancy outcome and BMI analyzed by day of transfer P value a Blastocyst D3 Blastocyst D3 Blastocyst D3 Blastocyst D3 Blastocyst D3 N Mean age (y) Implantation rate (%) Pregnancy rate (%) Loss rate (%) Mean no. of embryos transferred a Significant, defined as P.05 for ANOVA analyses and P.005 for Bonferroni-corrected 2 analyses. D3 day 3. broken down by day of transfer. Again, the mean age between BMI groups was similar. Among the blastocyst and day 3 recipients analyzed separately, there was no effect of BMI on implantation rate, PR, or loss rate. Separate ROC curves for predicting spontaneous loss were derived from plotting sensitivity against 1-specificity for a range of BMI strata using day 3 transfers alone, blastocyst transfer alone, and all recipient transfers, as shown in Figure 2. Based on ROC curves of miscarriage vs. BMI constructed for each group as well as the combined data, BMI does not appear to be a risk indicator of spontaneous loss. Again the ROC curves (Fig. 2) follow a diagonal path indicating that BMI has effectively 50% sensitivity and 50% specificity in predicting miscarriage. DISCUSSION The impact of BMI on pregnancy has been addressed in several studies that demonstrate that obesity is associated with increased incidence of poor pregnancy outcome after IVF treatment (2, 4, 5, 7). The present study sought to determine the impact of obesity on endometrial receptivity using a donor recipient model. This model was selected because it allows exclusion of obesity effects on ovarian follicular maturation and focuses independently on the role of the endometrium. In our study, elevated BMI was not associated with implantation failure, decreased PR, or higher spontaneous loss rate. Our findings are consistent with those of other investigators who found that extremes of body mass did not affect reproductive outcome in patients who had undergone IVF cycles (6, 11, 20). However, these other studies all looked at the impact of obesity on pregnancy outcome without making a distinction between its effects on oocyte quality or endometrial receptivity. To distinguish between the impact of obesity on the oocyte from its endometrial effect, a handful of investigators used a donor oocyte recipient model (16 18). Bellver and colleagues (18) reported a higher rate of spontaneous abortion in patients with BMI 30 kg/m 2 from a sample of 712 cycles of recipients of ovum donation. One limitation to that study, however, was that the difference found between obese and nonobese patients is not accurately represented because patients have contributed more than one cycle to the analysis, thereby weighing the data to over-represent those patients who had more than one cycle because of failure to conceive or miscarriage. This is a common mistake that we have found in our review of the literature and it may explain why there is so much controversy regarding this topic. Our results do not agree with those published in this and previous reports about the link between obesity and spontaneous abortion. In contrast, our findings confirm the retrospective analyses of Wattanakumtornkul et al. (17) who report no differences in implantation rate or live births in consecutive first cycle donor oocyte recipients after controlling for age, endometrial thickness, and number and quality of transferred embryos Styne-Gross et al. Recipient BMI does not impact implantation Vol. 83, No. 6, June 2005

5 FIGURE 2 Receiver operator characteristic curve of body mass index and miscarriage rate. From the data presented herein and previous reports of the literature (10, 11, 20), poor quality oocytes and resulting embryos may account for pregnancy loss in obese women undergoing fertility treatments. We clearly attempted to control for the oocyte effect by using oocytes donated by young women with a normal BMI. It has been suggested that the etiology behind early miscarriage, higher gonadotropin requirements in IVF, and decreased PRs in women with polycystic ovarian syndrome (PCOS) and concurrent obesity is due to the altered hormonal environment of the developing oocyte (15). Wittemer et al. (6) showed that by theoretically eliminating this steroidogenic milieu using a GnRH downregulation protocol to suppress the natural GnRH pulsatile surges, more gonadotropin is required and fewer oocytes are retrieved, but there is no effect of obesity on PR or spontaneous loss. As observed in this study, obesity appears to have no effect on an already fertilized embryo grown in culture. Although some recent reports have suggested a link between maternal obesity and poor pregnancy outcome, our data eliminate obesity acting on the endometrium as an etiology. In quantifying pregnancy outcome in each BMI group, we can explicitly comment more accurately on the effect of obesity on endometrial receptivity. Based on this information we can comfortably counsel our oocyte recipients that elevated BMI will have no direct effect on their implantation rate and ability to sustain a pregnancy. By default, this effect appears more likely to be ovarian, primarily acting at the level of the developing oocyte. However, this information has been concluded strictly in the background of a controlled steroidogenic environment, where stimulation is regulated by giving a fixed regimen of E 2 and P. Recognizing these limitations, we cannot extrapolate these data to the natural cycle where other factors that may impact the endometrium are regulated by fluctuations in the natural steroidogenic milieu. Furthermore, it remains plausible that a detrimental effect of high BMI would be observed among recipients with morbid obesity (BMI 40 kg/m 2 ) as only a small number of the patients studied were morbidly obese (n 13; 9 conceived, 4 did not). Continued work in this area in which the uterine environment is controlled and the impact of obesity on folliculogenesis is studied still needs to be done. Acknowledgments: We acknowledge the efforts of Brooke Bonser, Janet Behnke (data collections), and Paul Bergh, M.D., (scientific advisor) at the Reproductive Medicine Associates of New Jersey. REFERENCES 1. Norman RJ, Clark AM. Obesity and reproductive disorders, a review. Reprod Fertil Dev 1998;10: Wang JX, Davies M, Norman RJ. Body mass and probability of pregnancy during assisted reproduction treatment: retrospective study. Brit Med J 2000;321: Wang JX, Davies MJ, Norman RJ. Obesity increases the risk of spontaneous abortion during infertility treatment. Obstet Res 2002;10: Fedorcsak P, Dale PO, Storeng R, Ertzeid G, Bjercke S, Oldereid N, et al. Impact of overweight and underweight on assisted reproduction treatment. Hum Reprod. 2004;19: Loveland JB, McClamrock H, Malinow A, Sharara F. Increased body mass index has a deleterious effect on in vitro fertilization outcome. J Assist Reprod Genet 2001;18: Wittemer C, Ohl J, Bailly M, Bettahar-Lebugle K, Nisand I. Does body mass index of infertile women have an impact on IVF procedure and outcome? J Assist Reprod Genet 2000;17: Nichols JE, Crane MM, Higdon HL, Miller PB, Boone WR. Extremes Fertility and Sterility 1633

6 of body mass index reduce in vitro fertilization pregnancy rates. Fertil Steril 2003;79: Fedorcsak P, Dale PO, Storeng R, Tanbo T, Abyholm T. The impact of obesity and insulin resistance on the outcome of IVF or ICSI in women with polycystic ovarian syndrome. Hum Reprod 2001;16: Mulders AG, Laven JS, Eijkemans MJ, Hughes EG, Fauser BC. Patient predictors for outcome of gonadotropin ovulation induction in women with normogonadotrophic anovulatory infertility: a meta-analysis. Hum Reprod Update 2004;9: Lewis CG, Warnes GM, Wang XJ, Matthews CD. Failure of body mass index or body weight to influence markedly the response to ovarian hyperstimulation in normal cycling women. Fertil Steril 1990;53: Lashen H, Ledger W, Bernal AL, Barlow D. Extremes of body mass do not adversely affect the outcome of superovulation and in-vitro fertilization. Eur Soc Hum Reprod Embryol 1999;14: Hamilton-Fairley D, Kiddy D, Watson H, Paterson C, Franks S. Association of moderate obesity with a poor pregnancy outcome in women with polycystic ovary syndrome treated with low dose gonadotropin. Br J Obstet Gynaecol 1992;99: Wang JX, Warnes GW, Davies MJ, Norman RJ. Polycystic ovarian syndrome and the risk of spontaneous abortion following assisted reproductive technology treatment. Hum Reprod 2001;16: Fedorcsak P, Storeng R, Dale PO, Tanbo T, Abyholm T. Obesity is a risk factor for early pregnancy loss after IVF or ICSI. Acta Obstet Gynecol Scand 2000;79: Bussen S, Sutterlin M, Steck T. Endocrine abnormalities during the follicular phase in women with recurrent spontaneous abortion. Hum Reprod 1999;14: Cano F, Landeras J, Molla M, Gomez E, Ballesteros A, Remohi J. The effect of extreme of body mass on embryo implantation at oocytes donation program. Fertil Steril 2001;76:S Wattanakumtornkul S, Damario MA, Stevens Hall SA, Thornhill AR, Tummon IS. Body mass index and uterine receptivity in the oocyte donation model. Fertil Steril 2003;80: Bellver J, Rossal LP, Bosch E, Zúñiga A, Corona JT, Meléndez F, et al. Obesity and the risk of spontaneous abortion after oocyte donation. Fertil Steril 2003;79: World Health Organization. Obesity: preventing and managing the global epidemic. Report of a WHO consultation on obesity. World Health Organization: Geneva, Switzerland, Roth D, Grazi RV, Loebel SM. Extremes of body mass index do not affect first-trimester pregnancy outcome in patients with infertility. Am J Obstet Gynecol 2003;188: Styne-Gross et al. Recipient BMI does not impact implantation Vol. 83, No. 6, June 2005