RECURRENT PREGNANCY LOSS

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1 RECURRENT PREGNANCY LOSS FERTILITY AND STERILITY VOL. 79, NO. 5, MAY 2003 Copyright 2003 American Society for Reproductive Medicine Published by Elsevier Inc. Printed on acid-free paper in U.S.A. Obesity and the risk of spontaneous abortion after oocyte donation José Bellver, M.D., a Luis P. Rossal, M.D., a Ernesto Bosch, M.D., a Andrés Zúñiga, M.D., b José T. Corona, M.D., b Fernando Meléndez, M.D., c Emilio Gómez, Ph.D., c Carlos Simón, M.D., a,d José Remohí, M.D., a,d and Antonio Pellicer, M.D. a,d,e Instituto Valenciano de Infertilidad, Valencia, Spain Received June 24, 2002; revised and accepted October 3, Reprint requests: Antonio Pellicer, M.D., Instituto Valenciano de Infertilidad, Plaza de la Policía Local 3, 46015, Valencia, Spain (FAX: ; apellicer@ivi.es). a Instituto Valenciano de Infertilidad (IVI). b IVI, Madrid, Spain. c IVI, Murcia, Spain. d Department of Pediatrics, Obstetrics and Gynecology, School of Medicine of Valencia, Valencia, Spain. e Department of Obstetrics and Gynecology, Hospital Dr. Peset, Valencia, Spain /03/$30.00 doi: /s (03) Objective: To determine whether obesity increases the risk of spontaneous abortion. Design: Retrospective study. Setting: Oocyte donation program at the Instituto Valenciano de Infertilidad in Spain. Patient(s): Seven hundred twelve cycles of recipients of ovum donation with known body mass index (BMI), good-quality embryo transfer, and absence of uterine pathology or clinical history of antiphospholipid antibodies or recurrent abortion. Intervention(s): Recipients were divided in four BMI (kg/m 2 ) groups: lean, with BMI 20 (n 92; 12.9%); normal, with BMI (n 398; 55.9%); overweight, with BMI (n 172; 24.2%); and obese, with BMI 30 (n 50; 7%). Clinical parameters were compared among the groups. Main Outcome Measure(s): Spontaneous abortion rates according to BMI. Result(s): No difference was found among the four BMI groups in any of the parameters of the cycle analyzed. The overall abortion rate was 15.8% (57 of 360). There were significant differences in abortion rates between the obese (38.1%), and the normal (13.3%) and overweight (15.5%) groups. When several cutoff BMI values were established (20, 25, and 30), only the obese women demonstrated a greater risk of abortion. Compared with the normal population, the obese group showed a significant fourfold increase in the risk of spontaneous abortion. Conclusion(s): Our findings confirm that obesity (BMI 30) is an independent risk factor for spontaneous abortion. Therefore, it would be advisable for obese patients to reduce weight before becoming pregnant. (Fertil Steril 2003;79: by American Society for Reproductive Medicine.) Key Words: Body mass index, obesity, abortion, oocyte donation Obesity is a serious health problem that is more frequently seen in women (1). It has been related to an increased risk of atherosclerosis, hypertension, heart and cerebrovascular disease, diabetes, cancer, and death (2 4). In addition, many reports have shown a poor pregnancy outcome in obese patients (5 8), including an increased risk of spontaneous or recurrent abortion (8 13), although others have not found a real link between obesity and early pregnancy loss (14 17). The close relationship between polycystic ovary syndrome (PCOS) and infertility is well documented. It has also been described that women with PCOS may have a greater risk of spontaneous abortion (16, 18 22), but the mechanisms involved are still not well understood. The rates of first trimester pregnancy losses in women with PCOS are reported to be 30% 50% (18, 23, 24), three times higher than those described for normal women (25, 26). It is well known that women with PCOS have a high prevalence of obesity (7, 27, 28). Thus, a cause-effect relationship between both entities has been established (11, 12). In one study, women with PCOS had a significantly greater risk of spontaneous abortion compared with women without PCOS, and after adjusting for obesity and the type of treatment received, this effect was reduced to a nonsignificant level (11). Moreover, both disorders share endocrine alterations that may be responsible for early pregnancy loss such as hyperandrogenemia 1136

2 (13, 29, 30), hyperinsulinemic insulin resistance (12, 24, 31, 32), or altered leptin levels (33 36). Successful implantation depends on a close relationship between the endometrium and the embryo. Whereas environmental factors may affect endometrial receptivity, the quality of the embryo is also of paramount importance. In this context, the replacement of embryos derived from oocytes of PCOS donors suggests no effect of the disease on the oocyte (37, 38), except for in patients with insulin resistance and associated obesity, in whom a poor IVF outcome due to oocyte and embryo quality has been documented (39). Based on the above information, obesity could be an independent risk factor for spontaneous abortion, affecting the embryo, the endometrium, or both. The aim of this work was to investigate this issue by studying successful implantation in the ovum donation model to discern the role of the endometrium and the embryo. After excluding poor embryo quality and other known risk factors for early pregnancy loss, we compared the abortion rates in a large cohort of women who became pregnant after ovum donation according to their body mass index (BMI [kg/m 2 ]). MATERIALS AND METHODS The patients included in this study were treated in three centers of the Instituto Valenciano de Infertilidad (IVI) in Spain (IVI-Valencia, IVI-Madrid, and IVI-Murcia). Every cycle of ovum donation registered in the computer database was considered, and only those recipients with a known BMI 1 year before the treatment were included. The cases were recruited retrospectively from January 1999 to February Institutional Review Board approval was obtained. A total of 1,148 cycles of ovum recipients with known BMI were initially included, but 436 cycles were discarded for a number of reasons. First, we paid careful attention to select replacements with good embryo quality, i.e., embryos with 2 4 cells and 15% of fragmentation on day 2 of development; embryos with 6 8 cells and 15% of fragmentation on day 3 of development; cavitated or expanded blastocysts on day 5 of development; or expanded or hatching blastocysts on day 6 of development. A total of 222 cycles were discarded because of poor embryo quality. Similarly, cases with uterine pathology (submucous or more than 2 cm intramural fibroids, polyps, adhesions, adenomyosis, or müllerian defects) (n 31) or a clinical history of antiphospholipid antibodies (lupus anticoagulant or anticardiolipin IgG-IgM) or recurrent abortion (except for the cases of a known maternal chromosomal abnormality) (n 52) were also eliminated. Finally, cases in which the oocytes came from donors with more than four previous donations (n 131) were also not considered. Donors were years of age and always in normal BMI ranges ( ). None of them presented phenotypic features or ultrasound appearance of PCOS. The ovaries were stimulated for ovum pickup as described elsewhere (40). A total of 712 cycles was accepted for the study. To compare the abortion rates according to the BMI (calculated as weight in kilograms divided by height in meters squared), these cycles were divided into four groups: lean, with BMI 20 (n 92; 12.9%); normal, with BMI (n 398; 55.9%); overweight, with BMI (n 172; 24.2%); and obese, with BMI 30 (n 50; 7%). The comparison was also carried out taking into account different cutoff BMI values (20, 25, and 30). The protocol of steroid replacement has been described elsewhere (40). ET was performed 2, 3, 5, or 6 days after oocyte recovery using the vaginal route. The transfer of frozen-thawed embryos was not included in this study. The daily administration of 6 mg of estradiol valerate and 800 mg micronized P was maintained for 14 days, after which a -hcg (AxSYM System; Abbott Laboratories, Abbott Park, IL) in blood was performed. In case of positive results, the hormone therapy was continued at the same dosage until day 80 of pregnancy. Pregnancy was defined as the presence of an embryonic sac(s) by an ultrasound scan performed 4 6 weeks after ET. Spontaneous abortion was defined as a pregnancy failing to reach 20 weeks of gestation, excluding losses due to ectopic pregnancy or induced abortion. The statistical analysis was performed using the Statistical Package for the Social Sciences, version 10.0 (SPSS Inc., Chicago, IL). Categorical data were expressed as number and percentage, and numerical data as mean and standard deviation. One-way analysis of variance with the Bonferroni test and nonparametric tests (Kruskal-Wallis and Mann-Whitney U-test) were used when appropriate. P.05 was considered statistically significant. RESULTS The overall pregnancy rate in this cohort was 50.6% (360 of 712). As Table 1 shows, there was no significant difference among the four established BMI groups in any of the assisted reproductive technology parameters analyzed. This included the comparison of severe sperm pathology such as severe teratozoospermia ( 5% normal forms), severe oligozoospermia ( 5 million of fresh spermatozoids/mm 3 ) and nonobstructive azoospermia, analyzed either as a whole entity (severe male factor) or separately. There was a trend toward lower pregnancy and implantation rates in the obese group, but no significant difference appeared. The overall abortion rate was 15.8% (57 of 360). The comparison of the abortion rate among the different BMI groups showed significant differences between the obese and the normal women (P.003) and between the obese and the overweight patients (P.02) (Table 2). Moreover, when several cutoff BMI values were established (20, FERTILITY & STERILITY 1137

3 TABLE 1 Descriptive characteristics of the study group (n 712). BMI 20 (n 92) BMI (n 398) BMI (n 172) BMI 30 (n 50) Age of recipient (y) No. of donated oocytes Cycle of the donor Use of GnRH agonist (%) 76 (82.6) 296 (74.4) 125 (72.7) 38 (76.0) Days of estrogen therapy Severe sperm pathology (%) 18 (19.6) 49 (12.3) 19 (11.1) 8 (16.0) No. of ETs Day of embryo development Transferred blastocysts (%) 17 (18.5) 48 (12.1) 23 (13.4) 4 (8.0) Implantation rate (%) Pregnancy rate (%) 44 (47.8) 211 (53.0) 84 (48.8) 21 (42) Spontaneous embryo reduction (%) a 2 (2.2) 12 (3.0) 12 (7.0) 1 (2.0) Note: Unless otherwise indicated, values are means SD. BMI body mass index. P was not significant for all entries. a All spontaneous embryo reductions were of one embryonic sac, except for two cases with reduction of two sacs (one in the BMI group, and the other in the BMI group). 25, and 30 kg/m 2 ), only the obese women ( 30 kg/m 2 ) demonstrated a greater risk of abortion than the rest of the patients (P.009) (Table 2). The odds ratio (OR) was calculated by taking as normal the incidence of abortion in the normal group (13.3%) to determine the increased risk of spontaneous abortion in obese women. The OR was 1.45 ( ) for the lean women, 1.20 ( ) for the overweight women, and 4.02 ( ) for the obese patients. As Figure 1 shows, with a BMI 30, there was a significant (P.005) fourfold increase in the risk of spontaneous abortion compared with the normal population. DISCUSSION The aim of the present study was to determine whether obesity could be an independent risk factor for spontaneous FIGURE 1 Risk of spontaneous abortion according to BMI, taking as normal the incidence of abortion in the normal group (13.3%). Open squares signify odds ratios; the bars show the 95% confidence interval. TABLE 2 Abortion rates according to body mass index (BMI). BMI groups (kg/m 2 ) Pregnancy (n) Abortion rate (%) a b a,b Cutoff BMI values (kg/m 2 ) Pregnancy (n) Abortion rate (%) P a P.003. b P Bellver et al. Obesity and spontaneous abortion Vol. 79, No. 5, May 2003

4 abortion. The ovum donation model was used to rule out possible confounding variables, especially the age of the mother and the quality of the embryos replaced, as well as other causes of abortion in women. The data show that obesity was associated with a significant increase in early pregnancy losses. Specifically, the obese group showed a significant fourfold increase in the risk of abortion compared with the normal group of patients (38.1% vs. 13.3%). Thus, the risky BMI cutoff for spontaneous abortion probably would be 30 instead of 25 as others have suggested (12, 13). In addition, a trend toward lower implantation and pregnancy rates was also observed. The next question to be addressed is, what is the intrinsic alteration associated with obesity that could be responsible for the increased abortion rates? Since there is such a close association between PCOS and obesity (7, 11, 27, 28), and since PCOS is also associated with increased miscarriage (10, 18 22), both entities should be discussed together. In a recent publication, Wang et al. (11) suggested that the higher risk of spontaneous abortion observed in women with PCOS was likely to be due to their high prevalence of obesity and the type of treatment they received. After adjusting for these two factors, the greater risk of spontaneous abortion of the women with PCOS compared with the women without PCOS was reduced to a nonsignificant level. From the data presented herein and previous reports of the literature (37, 38), bad-quality oocytes and resulting embryos should be rejected as the cause of pregnancy loss in these women. Rather, an environmental factor affecting endometrial receptivity seems to be the most plausible cause (41). In this sense, some factor/s related to PCOS could also be responsible for the higher incidence of abortion such as hyperandrogenemia (29, 30), hyperinsulinemic insulin resistance (12, 24, 31), high plasminogen activator inhibitor activity (20), or elevated leptin levels (36). These factors are not exclusive to this syndrome and can be seen in obese women in whom insulin resistance (32), hyperandrogenism (13), elevated serum phosphatidyl inositol (42), and leptin deficiency or resistance (33 36) have been described. Three of these factors are coincident in obese patients and those with PCOS. The first factor is hyperandrogenemia. However, we know that the elevated serum concentrations of LH and T, as well as polycystic ovarian morphology as assessed by ultrasound, are not risk factors for early pregnancy loss in PCOS (14, 43, 44). Moreover, most of our patients herein were treated with a depot preparation of GnRH that should maintain low ovarian serum androgen levels. The second factor is insulin resistance. The use of metformin, an insulin sensitizer that lowers serum levels of insulin, androgens, and PAI-1 activity (PAI-Fx) and reduces the weight of the patient (21), has been reported to be of tremendous impact in decreasing early pregnancy loss in women with PCOS (22, 45, 46). Insulin resistance is an endocrine alteration that deserves to be further explored in obese women. However, it may affect the quality of the oocyte as well (39). The third option is leptin. At the paracrine level, the leptin system has been involved in embryonic implantation and placentation. The amount of body fat stores is known to influence fertility, indicating a link between adipose tissue and the reproductive system (47). An interesting hypothesis is that leptin is a peripheral signal indicating the adequacy of nutritional status for reproductive function (48). One early indication came from the observation that ob/ob female mice (which lack functional leptin) or db/db mice (which lack functional leptin receptors) are characterized by obesity and sterility (49, 50). Fertility in the ob/ob animals can be restored by exogenous administration of leptin but not by food restriction, indicating that leptin per se is required for normal reproductive functioning (51, 52). Although the leptin system clearly influences reproduction, whether leptin acts as an endocrine or paracrine mediator to exert its effect is not yet resolved. In summary, whatever the subjacent cause, obesity without PCOS seems to be an independent risk factor for abortion. Our findings confirm those published in previous reports about the link between obesity and spontaneous abortion and encourage a search for the underlying mechanism(s), which are probably not only associated with weight excess but may sometimes be isolated from or linked to other pathologies such as PCOS. 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