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Obesity does not adversely affect results in patients who are undergoing in vitro fertilization and embryo transfer
European Journal of Obstetrics & Gynecology and Reproductive Biology 127 (2006) 88–93 www.elsevier.com/locate/ejogrb
Obesity does not adversely affect results in patients who are undergoing in vitro fertilization and embryo transfer Herve Dechaud a,*, Tal Anahory b, Lionel Reyftmann a, Vanessa Loup b, Samir Hamamah b, Bernard Hedon a a
Service de Gyne´cologie-Obste´trique et Me´decine de la Reproduction, CHU Arnaud De Villeneuve, Faculte´ de Me´decine, Universite´ Montpellier I, 371 avenue du Doyen Gaston GIRAUD, 34295 Montpellier Cedex 5, France b Laboratoire de Biologie du De´veloppement et de la Reproduction B, CHU Arnaud De Villeneuve, Faculte´ de Me´decine, Universite´ Montpellier I, 371 avenue du Doyen Gaston GIRAUD, 34295 Montpellier Cedex 5, France Received 5 August 2005; received in revised form 11 October 2005; accepted 12 December 2005
Abstract Objective: To examine the outcome of in vitro fertilization according to the body mass index of infertile patients. Study design: Between September 2003 and May 2005, 573 patients underwent 789 in vitro fertilization cycles or ICSI because of male factor, tubal factor, and unexplained infertility were retrospectively included from our IVF database. The patients were classified in four groups: BMI < 20 kg/m2 (264 cycles), 20 BMI < 25 (394 cycles), 25 BMI < 30 (83 cycles), and BMI 30 (48 cycles). All patients had a long protocol for IVF with a combination of the GnRH agonist and recombinant FSH. Results: All parameters of ovarian response were comparable except the total required r-FSH dose. This dose was statistically higher in the group of BMI 30 compared to the other groups ( p = 0.0003). All parameters of IVF outcome were comparable, including the cancellation rate, the implantation rate, and pregnancy rates. Conclusion: Obese patients require a higher r-FSH dose to achieve follicular maturation than normal weight patients. Obesity does not affect negatively results of in vitro fertilization. # 2006 Elsevier Ireland Ltd. All rights reserved. Keywords: Body mass index; In vitro fertilization; Ovarian stimulation; Pregnancy rate; Weight
1. Introduction Excess body weight and obesity are associated with alterations in the reproductive system in women and frequently accompany obesity in experimental animals [1,2]. Epidemiological evidence clearly shows that being overweight contributes to menstrual disorders, infertility, poor pregnancy outcome, impaired fetal well-being, and mother diabetes mellitus [3]. Weight and body mass are known to be important parameters in determining the potential of woman’s reproductive system [4,5]. However, their influence on ovarian response to exogenous gonadotropins is still controversial. In the literature, several studies * Corresponding author. Tel.: +33 467 336 536; fax: +33 467 336 468. E-mail address: [email protected] (H. Dechaud).
show patient obesity adversely affects the outcome of superovulation [6,7]. Conversely, the absence of an adverse effect of excess body mass on in vitro fertilization (IVF) outcome was described in few publications [8–11]. Nevertheless, the body fat distribution represents an important parameter considering the response of treatment and the probability of conception per cycle [12,13]. If pathogenesis of this phenomenon is still unclear, weight loss programmes were known to restore menstrual regularity and spontaneous ovulation [14–16]. Moreover, it is well known that obesity could enhance endometrial benign pathologies, as well as malignant [17]. Because of these concerns, we have conducted a study based on our prospectively collected database to ascertain the extent to which infertile patient body mass index (BMI) affects superovulation and IVF outcome.
0301-2115/$ – see front matter # 2006 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ejogrb.2005.12.009
H. Dechaud et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 127 (2006) 88–93
2. Materials and methods Five hundred seventy three patients referred to the Department of Reproductive Medicine for IVF between September 2003 and May 2005 were included in this retrospective study. The protocol for pituitary down-regulation, controlled ovarian hyperstimulation and human chorionic gonadotropin (hCG) administration remained consistent throughout the study period. 2.1. Selection of patients Inclusion criteria were patients who undergoing IVF because of tubal infertility (n = 322, 56.1%) or unexplained infertility (n = 43, 7.6%) or male infertility (n = 208, 36.3%). Patients with PCOS (according to the Rotterdam criteria) were not excluded from the data. Women with a history of uterine surgery, who had apparent endometrial pathologies (submucous myoma, synechia, polyps, uterus septum) or hydrosalpinges evidenced by ultrasonography, who had had three or more failed attempts at IVF and embryo transfer, or who received frozen-thawed embryos were not included. Ovarian stimulations other than long protocol GnRH agonist/r-FSH (i.e., unstimulated cycle, antagonist/r-FSH protocol, or in vitro maturation protocol) and patients referred to our center for preimplantation genetic diagnosis were excluded from the analysis. A woman was considered as smoker if she smokes five or more cigarettes a day. All couples had undergone routine fertility investigation. Male semen analysis was considered as normal according to the WHO criteria. Hormonal assessment included measurement of the serum progesterone level on cycle days 19 and 23. Prolactin, TSH, testosterone, androstenedione, DHEA, 17-hydroxyprogesterone, LH, and FSH were assayed on day 3 of a spontaneous cycle. We considered sperm–mucus interaction to be normal if mobile sperm were present throughout the Huhner postcoital test. All patients had hysterosalpingographic and ultrasonographic examination to assess the uterine cavity and fallopian tubes. Then, all, except for infertility with severe male factor, had a laparoscopic and hysteroscopic examination before the first IVF procedure. Patients with endometriosis diagnosed during the laparoscopic procedure were excluded. At the time of the initial patient consultation (a median 60 days before the first IVF or ICSI cycle), BMI values for individual woman were calculated by the ratio of body weight (in kilograms)/height (in meters squared). According to their BMI, the patients were stratified into four groups: BMI < 20 kg/m2 (264 cycles), 20 BMI < 25 (394 cycles), 25 BMI < 30 (83 cycles), and BMI 30 (48 cycles). 2.2. IVF protocol All patients were stimulated with a combination of the gonadotropin releasing hormone agonist (GnRH-a) (Dec-
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apeptyl LP 31, Ipsen, Paris, France) and recombinant FSH (r-FSH) (Puregon1, Organon, Paris, France or Gonal F1, Serono, Paris, France) to obtain multiple follicular development. Each patient received the GnRH-a (3 mg i.m.) on day 1 or 2 of a normal cycle. Fourteen days later, pituitary desensitization was evaluated by ultrasound (US) examination (no follicle of >10 mm in diameter) and by serum estradiol levels (<50 pg/mL). Then, as a rule, r-FSH was administered s.c. every evening at a starting dose of 150 IU, with the exception of women older than 38 years and those with BMI 30 kg/m2 who received 300 IU, and women with polycystic ovaries who received 125 IU starting r-FSH dose. Seven days later, the r-FSH dose was modified in accordance with the ovarian response, which was evaluated by serum estradiol levels and daily US examination to observe follicular development. The criteria for hCG administration (5000 IU i.m.) included an estradiol level of >1500 pg/mL and at least three follicles of >18 mm in diameter. Retrieval of oocytes occurred 35 h after hCG administration and was performed by guidance of vaginal US. Conventional fertilization was performed. In case of extremely poor sperm quality, intracytoplasmic sperm injection (ICSI), which at our unit gives the same pregnancy rate as conventional fertilization, was used. The embryos were evaluated and classified as previously reported [18] as follows: grade 1: perfectly symmetrical with no fragmentation; grade 2: perfectly symmetrical with slight fragmentation (<20% fragmentation of the total embryonic volume); grade 3: uneven blastomeres with no fragmentation; grade 4: uneven blastomeres with gross fragmentation (>20% fragments). Grade 1 or 2 embryos were considered high quality. Embryo transfer took place 2 or 3 days later in all patients in whom embryos were obtained. The number of embryos replaced was determined according to the following criteria: the age of the patient, the ovarian response to exogenous stimulation, the fertilization rate, morphologic aspect of the embryos, and proper counselling of the couple. Micronized vaginal progesterone (600 mg a day, started on the day of oocytes pick-up and up to 14 days) was used for luteal support. The outcome measures were the duration of ovarian stimulation, the total required r-FSH dose, the peak estradiol concentration on day of hCG, the number of oocytes retrieved, the number of embryos obtained, the fertilization rate (number of embryos obtained/total number of oocytes), the percentage of each type of embryos obtained, and the number of embryos transferred. During the ovarian stimulation, cycles could be cancelled for insufficient follicular development or for imminent ovarian hyperstimulation syndrome. The outcome measures were the implantation rate (i.e., the ratio of the number of gestational sacs seen on US scan over the number of transferred embryos), the pregnancy rates, and the ongoing pregnancy rates (after 12 weeks of gestation).
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Table 1 Characteristics of the patients in each group according to the BMI (kg/m2) Parameter
BMI < 20, 186 patients
20 BMI < 25, 283 patients
25 BMI < 30, 68 patients
BMI 30, 36 patients
p
Age (years) BMI (kg/m2) Duration of infertility (years) Unexplained infertility (%) Tubal infertility (%) Male infertility (%) Associated PCOS (%) Smoker (%) Day 3 FSH (IU/L) Day 3 LH (IU/L)
32.8 4.6 (21–42) 18.6 0.9 4.8 2.3 23.5 30.7 45.8 8.7 25.7 7.3 2.7 5.5 2.9
33.1 4.4 (21–43) 22 1.3 4.8 2.7 22.1 26.1 52 7.2 20.8 6.9 2.2 5 3.4
34 4.4 (24–42) 26.7 1.4 4.6 2.8 15.7 31.3 51.8 13.2 30.1 6.8 2 6 2.7
31.6 5.5 (20–42) 33.9 3.2 5.6 3.6 25 29.2 45.9 14.5 20.8 5.7 2.2 5.1 4.1
NS <0.0001 NS NS NS NS NS NS NS NS
Values are means S.D.; NS, not significant; BMI, body mass index; FSH, follicle stimulating hormone; LH, luteinizing hormone. Table 2 Result of ovarian stimulation and IVF outcome in each group according to the BMI (kg/m2) Parameter
BMI < 20, 264 cycles
20 BMI < 25, 394 cycles
25 BMI < 30, 83 cycles
BMI 30, 48 cycles
p
Cancellation rate (%) Duration of r-FSH stimulation (days) Total r-FSH dose (IU) Peak estradiol (pg/mL) Number of oocytes collected Number of embryos obtained Fertilization rate (%) Number of embryos transferred Mean grade of transferred embryos
14.7 10.2 1.6 2045 868 2477 1380 12.3 5.8 6.9 4.1 66.3 2.4 0.8 2.5
15.7 10.7 2 2047 888 2349 1357 10.9 5.1 6.3 3.9 67.2 2.3 0.8 2.4
20.4 10.9 1.9 2281 967 2298 1660 11.8 5.4 6.7 4 66.6 2.5 1.2 2.6
14.5 10.9 1.4 2454 757 2022 1057 12.1 7.6 6.4 4.7 65.2 2.2 0.9 2.4
NS NS 0.0003 NS NS NS NS NS NS
Values are means S.D.
2.3. Statistical analysis The statistical tests applied to the data were Kruskall– Wallis non-parametric method or Chi-square test when appropriate. If the Kruskall–Wallis test indicated a significant difference among several groups, the Mann– Whitney test was used to compare two groups to determine whether these two groups differed significantly. Then, in order to show a possible trend across the groups, we applied the Spearman correlation test for the quantitative variables and the Cochran-Armitage trend test for the qualitative ones. Significance was set at p < 0.05.
3. Results During a period of 20 months, 1298 IVF or ICSI cycles were performed in our unit. According to the classification
by BMI, 32.4% of women were lean, 49.4% have a normal weight, 11.9% were overweight, and 6.3% were obese. There was no difference between the four groups for the age of the patients, the duration of the infertility, smoking, and day 3 FSH and LH levels (Table 1). No significant difference was noted for the cause of infertility. The results of ovarian stimulation were reported in Table 2. All parameters of ovarian response were comparable in the four groups except the total required r-FSH dose to achieve the follicular maturation. The duration of the ovarian stimulation and the peak estradiol concentration on day of hCG were comparable. Fertilization rates and the number of embryos transferred were comparable between the four groups. The statistical analysis using the Spearman’s correlation test shows the same results. For the total dose of r-FSH required, p is equal to 0.006 and r = 0.09. All parameters of IVF outcome were comparable and reported in Table 3. Biochemical pregnancy rates were,
Table 3 Pregnancy outcome in each group according to the BMI (kg/m2) Parameter
BMI < 20, 264 cycles
20 BMI < 25, 394 cycles
25 BMI < 30, 83 cycles
BMI 30, 48 cycles
p
Implantation rate (%) Miscarriage rate (%) Ongoing pregnancy rate/cycle Ongoing pregnancy rate/oocyte pick-up Ongoing pregnancy rate/transfer
45/522 (8.6%) 6/54 (11.1%) 33/264 (12.5%) 33/225 (14.6%) 33/214 (15.4%)
114/738 (15.4%) 8/105 (7.7%) 76/394 (19.3%) 76/332 (22.9%) 76/314 (24.2%)
17/160 (10.6%) 3/20 (15%) 11/83 (13.2%) 11/66 (16.6%) 11/62 (17.7%)
10/89 (11.2%) 1/8 (12.5%) 6/48 (12.5%) 6/41 (14.6%) 6/40 (15%)
NS NS NS NS NS
H. Dechaud et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 127 (2006) 88–93
respectively, 27.7%, 20%, 30%, and 12.5% ( p = not significant). Pregnancy rates per transfer were, respectively, 25.2%, 33.4%, 32.6%, and 20%. The statistical analysis using the Cochran-Armitage trend test does not find any significant difference in terms of pregnancy. In the group of lean women, there was 27 singletons and 6 twins; in normal weight patients, 50 singletons, 23 twins, 2 triplets and 1 quadruplet; in overweight women, 8 singletons and 3 twins; and in the group of obese patients, 3 singletons and 3 twins.
4. Discussion 4.1. Ovarian stimulation in obese women The rationale for this study was that obesity is questioned about giving lower pregnancy rates during IVF cycles than normal weight patients [7,13,19,20]. The findings of our study confirm those of others who found a relationship between patient weight and the total dose gonadotropin required to achieve follicular maturation [21]. The total r-FSH dose increases between lean or normal weight to overweight or obese patients. There was no difference between lean and normal weight patients. It is tempting to speculate that obesity could influence the results of stimulated ovulation, since increased body fat has been associated with disorders of spontaneous ovulation [22]. Weight and body mass are known to be important parameters in determining the potential of a woman’s reproductive system but their influence on ovarian response to exogenous gonadotropins is still controversial [23,24]. In non-PCOS patients, the response to gonadotropininduced ovulation induction is inversely related to BMI [25,26]. Moreover, in non-PCOS obese patients, it was suggested that a doubling of gonadotropin dose was necessary for adequate ovarian stimulation [12]. Nevertheless, few studies could not find a clear relationship between body mass and response to ovarian stimulation or to IVF outcome [8]. The relationship between BMI and the ovarian response to hyperstimulation as determined by the serum estradiol level before the day of hCG, indicated only a tendency to increase the number of days of treatment required in subjects with highest BMI. The peak serum estradiol concentration reached was highest within the normal BMI range when compared with the BMI > 27.6. In a non-PCOS and PCOS patients case–control study, apart from significantly lower peak estradiol concentrations in the obese patients, there were no significant difference for results of superovulation and IVF outcome between the obese patients and their control group [8]. However, obese patients and their controls received similar gonadotropin doses. 4.2. Total r-FSH dose required in obese patients Exactly why patients with greater body mass require higher FSH or hMG dose is unclear. It may be related to the greater amount of body surface, inadequate estradiol
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metabolism and decreased sex hormone-binding globulin (SHBG). A few studies about gonadotropin absorption and its metabolic clearance rate in normal and obese patients are available. Fat tissue is both a steroidal reservoir and a site of steroid metabolism. In PCOS patients, a difference was found between lean and obese women with regard to resorption or metabolism of sub-cutaneous injected FSH [27,28]. Using recombinant FSH, heavier patients may require a higher dose than 225 IU to achieve follicular maturation due to their high distribution volume and fat tissue. The pharmacokinetic of rFSH was studied, indicating that after sub-cutaneous or intramuscular injection, the pharmacokinetic of a single injection of r-FSH does not appear to be remarkably different among women with higher body mass indices [29]. Nevertheless, some papers show that reduced ovarian sensitivity to exogenous gonadotropins in obese patients is not related to different absorption and distribution of the drug but could be better explained by altered peripheral steroid metabolism [30]. Moreover, the FSH concentration during hMG treatment was higher in overweight women, suggesting that the relative hMG resistance is not the result of a decreased bioavailability. The increased requirement of hMG with increasing BMI in PCOS is not merely determined by obesity alone but by insulin and insulin-like growth factor binding protein-1 concentrations [21]. Finally, this problem remains unclear and drug absorption and metabolic clearance large-scale controlled studies, in obese women, would be helpful to clarify these controversies. 4.3. IVF outcome in obese women This study shows that the IVF outcome is not affected by an increased BMI, in terms of embryo implantation rate or pregnancy rate. In vitro fertilization offers the opportunity to study human fecundity under strictly controlled conditions. A retrospective study reported significant differences between pregnancy and implantation rates after IVF procedures in patients with BMI > 25 compared to those with BMI 25, despite of similar results of ovarian stimulation [31]. Oocyte or embryo poor quality may explain these results [32]. Comparing android and gynaecoid body fat distribution, a possible reason of the decreased pregnancy rate in women with an android body fat distribution is endometrial changes due to hormonal dysfunction. Similarly, uterine factors could be involved in the decreased pregnancy rate in patients weighing 10% more than their ideal weight [26]. Recent studies show that obesity does not impact implantation rates in women attempting conception through oocyte donation [33,34]. These works eliminate obesity acting on the endometrium as an etiology of impaired results of IVF. It is well known that obesity, particularly the abdominal– visceral phenotype, is associated with supranormal estrogen production, due to increased activity of the aromatase system. Moreover, several authors have reported that PCOS women with central adiposity have higher estrone concentrations compared to women with a peripheral fat distribution [35]. In
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addition, reduced SHBG values, which usually accompany obesity, may favor greater amounts of free estradiol to be delivered to target tissues. Obese women are also characterized by reduced formation of inactive estrogen metabolites, and by greater availability of estrone in the target tissues. All these conditions concur in favoring a hyperestrogenic state in obese women. Furthermore, upper body fat, rather than lower body fatness, is associated with increased serum concentrations of testosterone, free testosterone, and estradiol [36]. It may be possible that the altered steroid milieu could affect the endometrium. Nevertheless, androgen effects on the endometrium are at present unknown. In obese women with predominant upper body segment obesity, estrogen receptors in endometrium were found greater amounts. This fact is probably due to inadequate progesterone action as well as an influence of other steroid precursors or hormones such as androgens, estrogens, and insulin [37]. In addition, little is known about the expression of estrogen receptors in infertile patients, offering the opportunity of developing many hypotheses about the impaired embryo implantation phenomenon [38]. 4.4. Weight loss programmes Previous authors recommended weight loss as the best, cheapest, and cause-related therapy of infertile, obese women [16,22]. Our results continue to support the view that all who treat infertility should consider weight loss to be a prerequisite for obese women prior to any assisted reproduction programmes. Weight loss often restores normal cycle regulatory and sex hormone concentrations in obese women, which indicates that obesity itself and not primary endocrine dysfunction is the cause of the reproductive problems. In addition, emotional problems associated with obesity may play a role in menstrual abnormalities. Although it is not known if these specific psychological differences are sufficient to affect fertility, improvements of mood, self-esteem, and weight reduction are essential to increase the outcome of infertility treatments [39]. 4.5. Obstetrical outcome and obesity Despite the increased r-FSH dose required to achieve follicular maturation, the ovarian stimulation in obese patients is possible with appropriate results. However, several questions remain controversial, such as the risk of miscarriage with the consecutive effect on the live birth rate. In our study, there is no significant difference between the four groups of patients in terms of miscarriage. Nevertheless, a larger study would be necessary to address this point without controversy. A recent matched case–control study shows obesity is associated with increased risk of miscarriage (odd ratio 1.2 and confidence interval 1.01– 1.46) [40]. For PCOS patients, many hypotheses could explain the pathogenesis of pregnancy loss such as hypersecretion of luteinizing hormone, hyperandrogenae-
mia, or hyperinsulinaemia [41]. But obesity itself could impair fertility and pregnancy. Beyond the IVF results, obesity increases morbidity for both mother and fetus. There is an increased risk in pregnancy hypertension, toxaemia, gestational diabetes, caesarean section, and increased hospitalization. For all of these reasons, programmes of weight loss are absolutely necessary for obese women undergoing in vitro fertilization. In the future, studies have to emphasize the potential negative impact of obesity on fertility in selected patients, and have to evaluate accurately the impact of weight loss, in order to further improve IVF and pregnancy outcome.
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Obesity does not adversely affect results in patients who are undergoing in vitro fertilization and embryo transfer Herve Dechaud a,*, Tal Anahory b, Lionel Reyftmann a, Vanessa Loup b, Samir Hamamah b, Bernard Hedon a a
Service de Gyne´cologie-Obste´trique et Me´decine de la Reproduction, CHU Arnaud De Villeneuve, Faculte´ de Me´decine, Universite´ Montpellier I, 371 avenue du Doyen Gaston GIRAUD, 34295 Montpellier Cedex 5, France b Laboratoire de Biologie du De´veloppement et de la Reproduction B, CHU Arnaud De Villeneuve, Faculte´ de Me´decine, Universite´ Montpellier I, 371 avenue du Doyen Gaston GIRAUD, 34295 Montpellier Cedex 5, France Received 5 August 2005; received in revised form 11 October 2005; accepted 12 December 2005
Abstract Objective: To examine the outcome of in vitro fertilization according to the body mass index of infertile patients. Study design: Between September 2003 and May 2005, 573 patients underwent 789 in vitro fertilization cycles or ICSI because of male factor, tubal factor, and unexplained infertility were retrospectively included from our IVF database. The patients were classified in four groups: BMI < 20 kg/m2 (264 cycles), 20 BMI < 25 (394 cycles), 25 BMI < 30 (83 cycles), and BMI 30 (48 cycles). All patients had a long protocol for IVF with a combination of the GnRH agonist and recombinant FSH. Results: All parameters of ovarian response were comparable except the total required r-FSH dose. This dose was statistically higher in the group of BMI 30 compared to the other groups ( p = 0.0003). All parameters of IVF outcome were comparable, including the cancellation rate, the implantation rate, and pregnancy rates. Conclusion: Obese patients require a higher r-FSH dose to achieve follicular maturation than normal weight patients. Obesity does not affect negatively results of in vitro fertilization. # 2006 Elsevier Ireland Ltd. All rights reserved. Keywords: Body mass index; In vitro fertilization; Ovarian stimulation; Pregnancy rate; Weight
1. Introduction Excess body weight and obesity are associated with alterations in the reproductive system in women and frequently accompany obesity in experimental animals [1,2]. Epidemiological evidence clearly shows that being overweight contributes to menstrual disorders, infertility, poor pregnancy outcome, impaired fetal well-being, and mother diabetes mellitus [3]. Weight and body mass are known to be important parameters in determining the potential of woman’s reproductive system [4,5]. However, their influence on ovarian response to exogenous gonadotropins is still controversial. In the literature, several studies * Corresponding author. Tel.: +33 467 336 536; fax: +33 467 336 468. E-mail address: [email protected] (H. Dechaud).
show patient obesity adversely affects the outcome of superovulation [6,7]. Conversely, the absence of an adverse effect of excess body mass on in vitro fertilization (IVF) outcome was described in few publications [8–11]. Nevertheless, the body fat distribution represents an important parameter considering the response of treatment and the probability of conception per cycle [12,13]. If pathogenesis of this phenomenon is still unclear, weight loss programmes were known to restore menstrual regularity and spontaneous ovulation [14–16]. Moreover, it is well known that obesity could enhance endometrial benign pathologies, as well as malignant [17]. Because of these concerns, we have conducted a study based on our prospectively collected database to ascertain the extent to which infertile patient body mass index (BMI) affects superovulation and IVF outcome.
0301-2115/$ – see front matter # 2006 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ejogrb.2005.12.009
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2. Materials and methods Five hundred seventy three patients referred to the Department of Reproductive Medicine for IVF between September 2003 and May 2005 were included in this retrospective study. The protocol for pituitary down-regulation, controlled ovarian hyperstimulation and human chorionic gonadotropin (hCG) administration remained consistent throughout the study period. 2.1. Selection of patients Inclusion criteria were patients who undergoing IVF because of tubal infertility (n = 322, 56.1%) or unexplained infertility (n = 43, 7.6%) or male infertility (n = 208, 36.3%). Patients with PCOS (according to the Rotterdam criteria) were not excluded from the data. Women with a history of uterine surgery, who had apparent endometrial pathologies (submucous myoma, synechia, polyps, uterus septum) or hydrosalpinges evidenced by ultrasonography, who had had three or more failed attempts at IVF and embryo transfer, or who received frozen-thawed embryos were not included. Ovarian stimulations other than long protocol GnRH agonist/r-FSH (i.e., unstimulated cycle, antagonist/r-FSH protocol, or in vitro maturation protocol) and patients referred to our center for preimplantation genetic diagnosis were excluded from the analysis. A woman was considered as smoker if she smokes five or more cigarettes a day. All couples had undergone routine fertility investigation. Male semen analysis was considered as normal according to the WHO criteria. Hormonal assessment included measurement of the serum progesterone level on cycle days 19 and 23. Prolactin, TSH, testosterone, androstenedione, DHEA, 17-hydroxyprogesterone, LH, and FSH were assayed on day 3 of a spontaneous cycle. We considered sperm–mucus interaction to be normal if mobile sperm were present throughout the Huhner postcoital test. All patients had hysterosalpingographic and ultrasonographic examination to assess the uterine cavity and fallopian tubes. Then, all, except for infertility with severe male factor, had a laparoscopic and hysteroscopic examination before the first IVF procedure. Patients with endometriosis diagnosed during the laparoscopic procedure were excluded. At the time of the initial patient consultation (a median 60 days before the first IVF or ICSI cycle), BMI values for individual woman were calculated by the ratio of body weight (in kilograms)/height (in meters squared). According to their BMI, the patients were stratified into four groups: BMI < 20 kg/m2 (264 cycles), 20 BMI < 25 (394 cycles), 25 BMI < 30 (83 cycles), and BMI 30 (48 cycles). 2.2. IVF protocol All patients were stimulated with a combination of the gonadotropin releasing hormone agonist (GnRH-a) (Dec-
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apeptyl LP 31, Ipsen, Paris, France) and recombinant FSH (r-FSH) (Puregon1, Organon, Paris, France or Gonal F1, Serono, Paris, France) to obtain multiple follicular development. Each patient received the GnRH-a (3 mg i.m.) on day 1 or 2 of a normal cycle. Fourteen days later, pituitary desensitization was evaluated by ultrasound (US) examination (no follicle of >10 mm in diameter) and by serum estradiol levels (<50 pg/mL). Then, as a rule, r-FSH was administered s.c. every evening at a starting dose of 150 IU, with the exception of women older than 38 years and those with BMI 30 kg/m2 who received 300 IU, and women with polycystic ovaries who received 125 IU starting r-FSH dose. Seven days later, the r-FSH dose was modified in accordance with the ovarian response, which was evaluated by serum estradiol levels and daily US examination to observe follicular development. The criteria for hCG administration (5000 IU i.m.) included an estradiol level of >1500 pg/mL and at least three follicles of >18 mm in diameter. Retrieval of oocytes occurred 35 h after hCG administration and was performed by guidance of vaginal US. Conventional fertilization was performed. In case of extremely poor sperm quality, intracytoplasmic sperm injection (ICSI), which at our unit gives the same pregnancy rate as conventional fertilization, was used. The embryos were evaluated and classified as previously reported [18] as follows: grade 1: perfectly symmetrical with no fragmentation; grade 2: perfectly symmetrical with slight fragmentation (<20% fragmentation of the total embryonic volume); grade 3: uneven blastomeres with no fragmentation; grade 4: uneven blastomeres with gross fragmentation (>20% fragments). Grade 1 or 2 embryos were considered high quality. Embryo transfer took place 2 or 3 days later in all patients in whom embryos were obtained. The number of embryos replaced was determined according to the following criteria: the age of the patient, the ovarian response to exogenous stimulation, the fertilization rate, morphologic aspect of the embryos, and proper counselling of the couple. Micronized vaginal progesterone (600 mg a day, started on the day of oocytes pick-up and up to 14 days) was used for luteal support. The outcome measures were the duration of ovarian stimulation, the total required r-FSH dose, the peak estradiol concentration on day of hCG, the number of oocytes retrieved, the number of embryos obtained, the fertilization rate (number of embryos obtained/total number of oocytes), the percentage of each type of embryos obtained, and the number of embryos transferred. During the ovarian stimulation, cycles could be cancelled for insufficient follicular development or for imminent ovarian hyperstimulation syndrome. The outcome measures were the implantation rate (i.e., the ratio of the number of gestational sacs seen on US scan over the number of transferred embryos), the pregnancy rates, and the ongoing pregnancy rates (after 12 weeks of gestation).
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Table 1 Characteristics of the patients in each group according to the BMI (kg/m2) Parameter
BMI < 20, 186 patients
20 BMI < 25, 283 patients
25 BMI < 30, 68 patients
BMI 30, 36 patients
p
Age (years) BMI (kg/m2) Duration of infertility (years) Unexplained infertility (%) Tubal infertility (%) Male infertility (%) Associated PCOS (%) Smoker (%) Day 3 FSH (IU/L) Day 3 LH (IU/L)
32.8 4.6 (21–42) 18.6 0.9 4.8 2.3 23.5 30.7 45.8 8.7 25.7 7.3 2.7 5.5 2.9
33.1 4.4 (21–43) 22 1.3 4.8 2.7 22.1 26.1 52 7.2 20.8 6.9 2.2 5 3.4
34 4.4 (24–42) 26.7 1.4 4.6 2.8 15.7 31.3 51.8 13.2 30.1 6.8 2 6 2.7
31.6 5.5 (20–42) 33.9 3.2 5.6 3.6 25 29.2 45.9 14.5 20.8 5.7 2.2 5.1 4.1
NS <0.0001 NS NS NS NS NS NS NS NS
Values are means S.D.; NS, not significant; BMI, body mass index; FSH, follicle stimulating hormone; LH, luteinizing hormone. Table 2 Result of ovarian stimulation and IVF outcome in each group according to the BMI (kg/m2) Parameter
BMI < 20, 264 cycles
20 BMI < 25, 394 cycles
25 BMI < 30, 83 cycles
BMI 30, 48 cycles
p
Cancellation rate (%) Duration of r-FSH stimulation (days) Total r-FSH dose (IU) Peak estradiol (pg/mL) Number of oocytes collected Number of embryos obtained Fertilization rate (%) Number of embryos transferred Mean grade of transferred embryos
14.7 10.2 1.6 2045 868 2477 1380 12.3 5.8 6.9 4.1 66.3 2.4 0.8 2.5
15.7 10.7 2 2047 888 2349 1357 10.9 5.1 6.3 3.9 67.2 2.3 0.8 2.4
20.4 10.9 1.9 2281 967 2298 1660 11.8 5.4 6.7 4 66.6 2.5 1.2 2.6
14.5 10.9 1.4 2454 757 2022 1057 12.1 7.6 6.4 4.7 65.2 2.2 0.9 2.4
NS NS 0.0003 NS NS NS NS NS NS
Values are means S.D.
2.3. Statistical analysis The statistical tests applied to the data were Kruskall– Wallis non-parametric method or Chi-square test when appropriate. If the Kruskall–Wallis test indicated a significant difference among several groups, the Mann– Whitney test was used to compare two groups to determine whether these two groups differed significantly. Then, in order to show a possible trend across the groups, we applied the Spearman correlation test for the quantitative variables and the Cochran-Armitage trend test for the qualitative ones. Significance was set at p < 0.05.
3. Results During a period of 20 months, 1298 IVF or ICSI cycles were performed in our unit. According to the classification
by BMI, 32.4% of women were lean, 49.4% have a normal weight, 11.9% were overweight, and 6.3% were obese. There was no difference between the four groups for the age of the patients, the duration of the infertility, smoking, and day 3 FSH and LH levels (Table 1). No significant difference was noted for the cause of infertility. The results of ovarian stimulation were reported in Table 2. All parameters of ovarian response were comparable in the four groups except the total required r-FSH dose to achieve the follicular maturation. The duration of the ovarian stimulation and the peak estradiol concentration on day of hCG were comparable. Fertilization rates and the number of embryos transferred were comparable between the four groups. The statistical analysis using the Spearman’s correlation test shows the same results. For the total dose of r-FSH required, p is equal to 0.006 and r = 0.09. All parameters of IVF outcome were comparable and reported in Table 3. Biochemical pregnancy rates were,
Table 3 Pregnancy outcome in each group according to the BMI (kg/m2) Parameter
BMI < 20, 264 cycles
20 BMI < 25, 394 cycles
25 BMI < 30, 83 cycles
BMI 30, 48 cycles
p
Implantation rate (%) Miscarriage rate (%) Ongoing pregnancy rate/cycle Ongoing pregnancy rate/oocyte pick-up Ongoing pregnancy rate/transfer
45/522 (8.6%) 6/54 (11.1%) 33/264 (12.5%) 33/225 (14.6%) 33/214 (15.4%)
114/738 (15.4%) 8/105 (7.7%) 76/394 (19.3%) 76/332 (22.9%) 76/314 (24.2%)
17/160 (10.6%) 3/20 (15%) 11/83 (13.2%) 11/66 (16.6%) 11/62 (17.7%)
10/89 (11.2%) 1/8 (12.5%) 6/48 (12.5%) 6/41 (14.6%) 6/40 (15%)
NS NS NS NS NS
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respectively, 27.7%, 20%, 30%, and 12.5% ( p = not significant). Pregnancy rates per transfer were, respectively, 25.2%, 33.4%, 32.6%, and 20%. The statistical analysis using the Cochran-Armitage trend test does not find any significant difference in terms of pregnancy. In the group of lean women, there was 27 singletons and 6 twins; in normal weight patients, 50 singletons, 23 twins, 2 triplets and 1 quadruplet; in overweight women, 8 singletons and 3 twins; and in the group of obese patients, 3 singletons and 3 twins.
4. Discussion 4.1. Ovarian stimulation in obese women The rationale for this study was that obesity is questioned about giving lower pregnancy rates during IVF cycles than normal weight patients [7,13,19,20]. The findings of our study confirm those of others who found a relationship between patient weight and the total dose gonadotropin required to achieve follicular maturation [21]. The total r-FSH dose increases between lean or normal weight to overweight or obese patients. There was no difference between lean and normal weight patients. It is tempting to speculate that obesity could influence the results of stimulated ovulation, since increased body fat has been associated with disorders of spontaneous ovulation [22]. Weight and body mass are known to be important parameters in determining the potential of a woman’s reproductive system but their influence on ovarian response to exogenous gonadotropins is still controversial [23,24]. In non-PCOS patients, the response to gonadotropininduced ovulation induction is inversely related to BMI [25,26]. Moreover, in non-PCOS obese patients, it was suggested that a doubling of gonadotropin dose was necessary for adequate ovarian stimulation [12]. Nevertheless, few studies could not find a clear relationship between body mass and response to ovarian stimulation or to IVF outcome [8]. The relationship between BMI and the ovarian response to hyperstimulation as determined by the serum estradiol level before the day of hCG, indicated only a tendency to increase the number of days of treatment required in subjects with highest BMI. The peak serum estradiol concentration reached was highest within the normal BMI range when compared with the BMI > 27.6. In a non-PCOS and PCOS patients case–control study, apart from significantly lower peak estradiol concentrations in the obese patients, there were no significant difference for results of superovulation and IVF outcome between the obese patients and their control group [8]. However, obese patients and their controls received similar gonadotropin doses. 4.2. Total r-FSH dose required in obese patients Exactly why patients with greater body mass require higher FSH or hMG dose is unclear. It may be related to the greater amount of body surface, inadequate estradiol
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metabolism and decreased sex hormone-binding globulin (SHBG). A few studies about gonadotropin absorption and its metabolic clearance rate in normal and obese patients are available. Fat tissue is both a steroidal reservoir and a site of steroid metabolism. In PCOS patients, a difference was found between lean and obese women with regard to resorption or metabolism of sub-cutaneous injected FSH [27,28]. Using recombinant FSH, heavier patients may require a higher dose than 225 IU to achieve follicular maturation due to their high distribution volume and fat tissue. The pharmacokinetic of rFSH was studied, indicating that after sub-cutaneous or intramuscular injection, the pharmacokinetic of a single injection of r-FSH does not appear to be remarkably different among women with higher body mass indices [29]. Nevertheless, some papers show that reduced ovarian sensitivity to exogenous gonadotropins in obese patients is not related to different absorption and distribution of the drug but could be better explained by altered peripheral steroid metabolism [30]. Moreover, the FSH concentration during hMG treatment was higher in overweight women, suggesting that the relative hMG resistance is not the result of a decreased bioavailability. The increased requirement of hMG with increasing BMI in PCOS is not merely determined by obesity alone but by insulin and insulin-like growth factor binding protein-1 concentrations [21]. Finally, this problem remains unclear and drug absorption and metabolic clearance large-scale controlled studies, in obese women, would be helpful to clarify these controversies. 4.3. IVF outcome in obese women This study shows that the IVF outcome is not affected by an increased BMI, in terms of embryo implantation rate or pregnancy rate. In vitro fertilization offers the opportunity to study human fecundity under strictly controlled conditions. A retrospective study reported significant differences between pregnancy and implantation rates after IVF procedures in patients with BMI > 25 compared to those with BMI 25, despite of similar results of ovarian stimulation [31]. Oocyte or embryo poor quality may explain these results [32]. Comparing android and gynaecoid body fat distribution, a possible reason of the decreased pregnancy rate in women with an android body fat distribution is endometrial changes due to hormonal dysfunction. Similarly, uterine factors could be involved in the decreased pregnancy rate in patients weighing 10% more than their ideal weight [26]. Recent studies show that obesity does not impact implantation rates in women attempting conception through oocyte donation [33,34]. These works eliminate obesity acting on the endometrium as an etiology of impaired results of IVF. It is well known that obesity, particularly the abdominal– visceral phenotype, is associated with supranormal estrogen production, due to increased activity of the aromatase system. Moreover, several authors have reported that PCOS women with central adiposity have higher estrone concentrations compared to women with a peripheral fat distribution [35]. In
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addition, reduced SHBG values, which usually accompany obesity, may favor greater amounts of free estradiol to be delivered to target tissues. Obese women are also characterized by reduced formation of inactive estrogen metabolites, and by greater availability of estrone in the target tissues. All these conditions concur in favoring a hyperestrogenic state in obese women. Furthermore, upper body fat, rather than lower body fatness, is associated with increased serum concentrations of testosterone, free testosterone, and estradiol [36]. It may be possible that the altered steroid milieu could affect the endometrium. Nevertheless, androgen effects on the endometrium are at present unknown. In obese women with predominant upper body segment obesity, estrogen receptors in endometrium were found greater amounts. This fact is probably due to inadequate progesterone action as well as an influence of other steroid precursors or hormones such as androgens, estrogens, and insulin [37]. In addition, little is known about the expression of estrogen receptors in infertile patients, offering the opportunity of developing many hypotheses about the impaired embryo implantation phenomenon [38]. 4.4. Weight loss programmes Previous authors recommended weight loss as the best, cheapest, and cause-related therapy of infertile, obese women [16,22]. Our results continue to support the view that all who treat infertility should consider weight loss to be a prerequisite for obese women prior to any assisted reproduction programmes. Weight loss often restores normal cycle regulatory and sex hormone concentrations in obese women, which indicates that obesity itself and not primary endocrine dysfunction is the cause of the reproductive problems. In addition, emotional problems associated with obesity may play a role in menstrual abnormalities. Although it is not known if these specific psychological differences are sufficient to affect fertility, improvements of mood, self-esteem, and weight reduction are essential to increase the outcome of infertility treatments [39]. 4.5. Obstetrical outcome and obesity Despite the increased r-FSH dose required to achieve follicular maturation, the ovarian stimulation in obese patients is possible with appropriate results. However, several questions remain controversial, such as the risk of miscarriage with the consecutive effect on the live birth rate. In our study, there is no significant difference between the four groups of patients in terms of miscarriage. Nevertheless, a larger study would be necessary to address this point without controversy. A recent matched case–control study shows obesity is associated with increased risk of miscarriage (odd ratio 1.2 and confidence interval 1.01– 1.46) [40]. For PCOS patients, many hypotheses could explain the pathogenesis of pregnancy loss such as hypersecretion of luteinizing hormone, hyperandrogenae-
mia, or hyperinsulinaemia [41]. But obesity itself could impair fertility and pregnancy. Beyond the IVF results, obesity increases morbidity for both mother and fetus. There is an increased risk in pregnancy hypertension, toxaemia, gestational diabetes, caesarean section, and increased hospitalization. For all of these reasons, programmes of weight loss are absolutely necessary for obese women undergoing in vitro fertilization. In the future, studies have to emphasize the potential negative impact of obesity on fertility in selected patients, and have to evaluate accurately the impact of weight loss, in order to further improve IVF and pregnancy outcome.
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