Risk factors for spontaneous abortion in menotropintreated

Transcription

1 FERTILITY AND STERILITY Copyright ~ 1987 The American Fertility Society Vol. 48, No. 4, October 1987 Printed in U.S.A. Risk factors for spontaneous abortion in menotropintreated women Michael Bohrer, M.D.* Ekkehard Kemmann, M.D. Department of Obstetrics and Gynecology, University of Medicine & Dentistry of New Jersey (UMDNJ), Robert Wood Johnson Medical School, New Brunswick, New Jersey Women who conceive with human gonadotropins have a high rate of spontaneous abortions. The causes for this poor outcome are unknown. In a retrospective analysis, the authors analyzed potential factors ~n 45 menotropin-treated patients with spontaneous first-trimester miscarriages. Data were compared with 119 menotropin-treated patients who conceived and delivered viable infants. Patient factors that were analyzed included the following: age, history of past miscarriages, duration of infertility, diagnostic category, weight, body surface area, duration and weight-corrected dose of menotropin administration, maximum estradiol level, estradiol pattern, human chorionic gonadotropin (hcg) dose, presence or absence of hcg support in the luteal phase, results of postcoital testing, methods of insemination, and results of husband's semen analysis. There was a significant difference between the miscarriage group and the control group in regard to age and weight distribution. All other characteristics were not significantly different. Patients over 81.8 kg as well as patients aged 35 years and older were both significantly (P < 0.01) at increased risk to have a spontaneous first-trimester miscarriage. The data suggest that obesity and advanced age contribute to the high miscarriage rate in menotropin-treated patients. It appears reasonable to suggest that women weighing more than 81.8 kg should make every effort to lose weight before beginning menotropin therapy. Fertil Steril 48:571, 1987 Approximately one fourth of those patients who conceive on a regimen of human menopausal gonadotropins (hmg) with human chorionic gonadotropin (hcg) will have a spontaneous miscarriage.1 2 This miscarriage rate is markedly higher than that of the general population. 3 Explanations for this observation include increased diagnostic surveillance and an increase in multiple gestations.1 The development of severe ovarian hyperstimulation may also place a patient at a higher risk for a miscarriage.2 Boue and Boue 4 suggested Received December 10, 1986; revised and accepted May 28, *Reprint requests: Michael Bohrer, M.D., Department of Obstetrics and Gynecology, UMDNJ Robert Wood Johnson Medical School, One Robert Wood Johnson Place, CN 19, New Brunswick, New Jersey an increased frequency of chromosomal aberrations in aborted pregnancies following induction of ovulation. Other explanations include corpus luteum insufficiency and selection of patients. 5 The miscarriage rate with hmg-hcg therapy was 25.6% at our institution, confirming the general experience. We were interested in analyzing possible risk factors in the genesis of spontaneous first-trimester miscarriages of menotropin-treated patients. As a control, we studied the data of hmg-treated patients whose pregnancy went on to a successful, viable birth. It was hoped that a comparative analysis might lead to the identification of specific risk factors in the miscarriage group. MATERIALS AND METHODS Subjects were patients who conceived on a regimen of hmg-hcg between 1978 and The age Vol. 48, No. 4, October 1987 Bohrer and Kemmann Menotropin treatment and miscarriage 571

2 of these patients ranged from 21 to 37 years (mean, 29.8 years). These patients had been trying to conceive for 1 to 10 years (mean, 2.8 years) and had undergone evaluation and treatment for infertility. Tubal patency had been demonstrated by hysterosalpingography or laparoscopy. Ovulation analysis had been done by menstrual history plus serum progesterone (P) levels, and/or endometrial biopsies. The indications for hmg use included hypogonadotropic amenorrhea (16.9%), polycystic ovaries (43.5%), short luteal phase (9.7%), unclassified ovulation dysfunction (18.8% ), and unexplained infertility (2.6% ). All patients had been treated unsuccessfully with clomiphene citrate (CC) in the past. Patients with ovulation dysfunction in association with endometriosis had undergone medical or surgical therapy for endometriosis before hmg therapy. Husbands had been evaluated by semen analysis, and all identified male infertility factors were attempted to be corrected prior to hmg therapy. Also, insemination with husband's semen was done for persistent male factor infertility or coexisting cervical factor infertility. Insemination methods included intracervical insemination and intrauterine insemination. Severe oligospermia was treated with donor insemination. The hmg treatment protocol consisted of an individualized daily regimen of hmg under serum 17~-estradiol (E 2 ) monitoring performed every other day. The initial hmg dose was usually 150 IU hmg (Pergonal, Serono Laboratories, Randolph, MA) and modified in subsequent cycles according to past response. During therapy, the hmg dose was adjusted to attain a linear E 2 rise on a semilog plot. At E 2 levels of 800 pg/ml, no further hmg was given, and, after 1 day of coasting, 10,000 IU hcg (Profasi, Serono Laboratories) was given to trigger ovulation. Sonographic follicle assessment was not performed. One week after the hcg administration, patients returned for a pelvic examination. If no ovarian enlargement was noted, luteal phase support of 1000 IU hcg was given. A pregnancy was diagnosed by rising hcg titers, the first titer done at least 17 days from ovulation. Patients were discharged to their private obstetrician usually after documentation of a gestational sac on sonography. Pregnancy outcome was determined from all patients who conceived in the study period using these methods: direct patient follow-up or patient information either by return of a written questionnaire sent to patients, or telephone follow-up (when necessary). Patients were grouped on the basis of outcome as follows. The study group consisted of patients who had a spontaneous miscarriage between 2.5 and 10 weeks after ovulation (corresponding to the first trimester). The control group was composed of patients who delivered one or more viable infants. A third group consisted of patients who either had an ectopic pregnancy or a fetal loss after the first trimester (these patients were excluded from further analysis). The study and control groups were compared regarding general characteristics of the patient population such as age, height, weight, body surface area, duration of infertility, diagnostic category, history of past miscarriages, and results of husband's semen analysis, as well as factors limited to the conception cycle such as treatment cycle number, duration of menotropin administration, weight-corrected dose of menotropins, maximum E 2 level, E 2 pattern (rising/falling), ovulatory hcg dose, results of postcoital testing, methods of insemination, presence or absence of ovarian cysts 1 week after ovulation, and administration of hcg support during luteal phase. Chi-square analysis, Fisher's exact test, and Student's t-test were used for statistical analysis of significance. In factors of significant difference between study and control groups, further analysis was made to determine quantitative relationships. RESULTS One hundred seventy-six pregnancies occurred in 154 patients during the study period. Forty-five (25.6%) of these 176 pregnancies ended in a spontaneous miscarriage and thus formed the study group, whereas 119 pregnancies (67.7%) were delivered and constituted the control group. Sixteen of these 119 patients (13.4%) had deliveries of twin or triplet pregnancies. In addition, an ectopic pregnancy was noted in four patients, and, in eight patients, a second or third trimester fetal loss occurred. These 12 patients (6.8%) were excluded from further analysis. Study and control groups did not differ in these factors: duration of infertility, history of past miscarriages, reason for hmg use (diagnostic category), and husband's semen analysis. There was no difference in the induction phase of conception cycles between groups in regard to weight-adjusted 572 Bohrer and Kemmann Menotropin treatment and miscarriage Fertility and Sterility

3 Table 1 Abortion Rate in Relation to Maximum Serum E 2 Level at or 24 Hours Before hcg Administration Total Viable Spontaneous Spontaneous Estradiol pregnancies pregnancies abortion abortion rate ng/ml % daily hmg dose, duration of hmg dose, maximum E 2 level, rising or falling E 2 pattern at time of hcg delivery, insemination methods, presence or absence of palpable ovarian cysts in the luteal phase, and administration or withholding of 1000 IU hcg booster injection. Table 1 shows the maximum serum E 2 levels at or 24 hours before hcg administration in the conception cycles and the absent relationship to the miscarriage rate. While the abortion was lowered when E 2 levels were between 1000 and 1399 pg/ml, we did not demonstrate a significant difference (Fisher's exact test) in the occurrence of spontaneous abortions in this subset compared with other subsets with lower or higher E 2 levels. Study and control groups differed significantly in two categories: study patients were either older or heavier than control patients. These relationships were explored further. Age Study and control patients were compared within progressive age categories. Table 2 shows that, in patients between 35 and 39 years, the miscarriage rate was 60%, significantly higher than in the younger patients. No patient aged 40 or older conceived during the duration of the study. Weight Study and control patients were compared within progressive weight categories. Table 3 shows that, with a weight of 54.5 to 68.1 kg, the lowest miscarriage rate occurred. Miscarriage rates were increased with lower and higher weights. Beyond 81.8 kg, the miscarriage rate was significantly (P < 0.001) increased, and patients over 95.5 kg had a 64% chance of miscarriage after conception. Age and weight were independent factors of significance (Table 3). Also, E 2 levels did not differ significantly in the different weight categories (Table 3). Thirteen patients who had a spontaneous miscarriage with hmg-hcg therapy conceived again with a subsequent hmg-hcg treatment. Five of these women (38%) had a second first-trimester miscarriage while the others carried the pregnancy to viability. DISCUSSION Our data identify two apparently independent factors that may affect the miscarriage rate of women who conceive on hmg-hcg therapy. Age as one of these factors is consistent with the general experience of increased miscarriage rates in older women. 3 While the general experience also implies that previous abortion experience is a predictor of subsequent abortion risks, our data in the study group were not significant for our specific infertile population. Perhaps the significance of this contribution might become evident with a larger population. The second factor, obesity, has not previously been implicated in the genesis of miscarriage. The association between weight and miscarriage in our data appears quite clear, is independent of age and E 2 level at ovulation, and gets stronger with higher weights. It is unclear to us whether obese women in the general population are also prone to higher miscarriage rates too, or whether such women, by the nature of their spontaneous ovulation, would represent a different population. Nevertheless, hmg-treated obese patients appear to be at increased risk for miscarriage. Data that compare miscarriage rates in hmg-treated patients to the general population need to be cognizant of age and weight factors. It is not readily clear why obesity should be associated with higher miscarriage rates. However, obesity affects steroid hormone metabolism and Table 2 Abortion Rate in Relation to Age of Menotropin-Treated Patients Total Viable Spontaneous Age pregnancies pregnancies abortion yr years versus 35+ years, P < , Fisher's exact test. Spontaneous abortion rate % " Vol. 48, No.4, October 1987 Bohrer and Kemmann Menotropin treatment and miscarriage 573

4 Table 3 Abortion Rate, Age, and Maximum E 2 in Relation to Weight of Menotropin-Treated Patients Mean Mean Weight age (SD) maximum E 2 (SD) kg yr (pglm 2 ) (3.6) 920 (463) (3.4) 1048 (578) (3.5) 1018 (317) (3.2)" 1221 (479)" (3.W 811 (245)d " kg versus kg, no significant difference, t-test. b kg versus kg, P = 0.021, Fisher's exact test. Total Viable Spontaneous Spontaneous pregnancies pregnancies abortions abortion rate b,c c c kg versus kg, P = 0.001, Fisher's exact test. d kg versus kg, no significant difference, t test. % ovulation. 6 Thus, there is an increase in the conversion of precursor hormone to estrone, and significant peripheral contribution to the estrogen pool. 7 The estrone/e 2 ratio may increase with peripheral conversion. Estrogen metabolism is altered and may affect endogenous gonadotropins. 8 Also, baseline androgen levels are relatively increased in obese women. 9 With hmg therapy, androgen levels are further augmented secondary to thecal cell stimulation. 10 It may be possible that the altered steroid milieu could affect the endometrium or the developing ovum and conceptus at some stage to increase the risk for a spontaneous miscarriage. Oelsner et al. 5 have shown a higher miscarriage rate in hmg-treated women who had endogenous gonadotropin activity versus those who were hypogonadotropic. While they did not report on the weight oftheir subjects, it is quite plausible that the former group is of higher weight. Thus, it appears that obese patients have a detrimental endogenous milieu with abnormalities in estrogen metabolism, increased androgen levels, and interfering endogenous gonadotropins. A quiescent endogenous hormone milieu, steroidal and gonadotropic, may be desirable to reduce the miscarriage rate in hmgtreated patients. It was interesting to note that a number of suspected factors were not associated with a higher miscarriage rate. Specifically, data pertaining to the induction cycle did not show any significant difference in study and control populations. Duration- and weight-adjusted hmg doses were similar in both groups (obviously, obese patients required more hmg). Maximum serum E 2 levels at or before hcg administration were comparable. Neither falling nor rising estrogen levels at hcg administration could be associated with increased miscarriages. Luteal phase ovarian enlargement and ab- sence of delivery of a luteal phase hcg booster did not affect miscarriage rate. Neither a male factor nor methods of insemination affected the miscarriage rate. Our data do not directly address the question of whether an increased occurrence of multiple gestations contributes to the miscarriage rate. Indeed, in our experience, a well-formed gestational sac or evidence of fetal activity is often not noted in patients who we followed up through the abortion. Instead, hcg levels already tended to be relatively low during early pregnancy. We believe that other factors, perhaps ovum quality and formation of the blastocyst, are most critical. Ben Rafael et al. 2 indicated that a high miscarriage rate occurred in a small number of patients with severe hyperstimulation. We aimed for serum E 2 levels of 800 pg/ml, and only a few patients received hcg with levels of more than 1400 pg/ml (Table 1). We therefore did not see enough patients with ovarian hyperstimulation to analyze this matter. Our data suggest that those patients who have one miscarriage with hmg-hcg therapy have an increased risk of a miscarriage with a subsequent hmg-hcg-related conception. This observation is in agreement with observations on recurrent miscarriage risks in general. 5 In conclusion, increased age and weight in this study could be identified as risk factors for the occurrence of a spontaneous first-trimester miscarriage in a population of women who conceived with hmg-hcg. Our findings imply that appropriate weight reduction should be recommended to patients before hmg therapy. REFERENCES 1. Schwartz M, Jewelewicz R, Dyrenfurth I, Tropper P, Vande Wiele RL: The use of human menopausal and choronic go- 574 Bohrer and Kemmann Menotropin treatment and miscarriage Fertility and Sterility

5 nadotropins for induction of ovulation. Am J Obstet Gynecol 138:801, Ben-Rafael Z, Dor J, Mashiach S, Blankstein J, Lunenfeld B, Serr DM: Abortion rate in pregnancies following ovulation induced by human menopausal gonadotropin/human chorionic gonadotropin. Fertil Steril 39:157, Jansen RP: Spontaneous abortion incidence in the treatment of infertility. Am J Obstet Gynecol 143:451, Boue JG, Boue A: Increased frequency of chromosomal anomalies in abortions after induced ovulation. Lancet 1:679, Oelsner G, Serr DM, Mashiach S, Blankstein J, Snyder M, Lunenfeld B: The study of induction of ovulation with menotropins: analysis of results of 1897 treatment cycles. Fertil Steril 30:538, Bates GW, Lucas JA: Hyperandrogenism and obesity. Semin Reprod Endocrinol 4:189, Siiteri PK, MacDonald PC: Role of estraglandular estrogen in human endocrinology. In Handbook of Physiology: Endocrinology, Vol II, Edited by RO Greep, E. Astwood. Washington, D.C., American Physiological Society, 1973, p Schneider J, Bradlow HL, Strain G, Levin J, Anderson K, Fishman J: Effects of obesity on estradiol metabolism: decreased formation of nonuterotropic metabolites. J Clin Endocrinol Metab 56:973, Bates GW, Whitworth NS: Effect of body weight reduction on plasma androgens in obese, infertile women. Fertil Steril 38:406, Skaf RA, Shelden R, Kemmann E: Androgenic response in anovulatory women during menotropins stimulation. Obstet Gynecol 58:714, 1981 Vol. 48, No.4, October 1987 Bohrer and Kemmann Menotropin treatment and miscarriage 575