High serum luteinizing hormone and testosterone concentrations do not predict pregnancy outcome in women with recurrent miscarriage

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1 FERTILITY AND STERILITY VOL. 77, NO. 2, FEBRUARY 2002 Copyright 2002 American Society for Reproductive Medicine Published by Elsevier Science Inc. Printed on acid-free paper in U.S.A. High serum luteinizing hormone and testosterone concentrations do not predict pregnancy outcome in women with recurrent miscarriage Luciano G. Nardo, M.D., Raj Rai, M.D., May Backos, M.R.C.O.G., Safaa El-Gaddal, M.R.C.O.G., and Lesley Regan, M.D. Department of Reproductive Science and Medicine, Imperial College School of Medicine, St Mary s Hospital, London, United Kingdom Received June 6, 2001; revised and accepted August 28, Presented in part at the 17th Annual Meeting ESHRE, Lausanne, Switzerland, July 1 4, Reprint requests: Raj Rai, M.D., Department of Reproductive Science and Medicine, Imperial College School of Medicine, St Mary s Hospital, Praed Street, Mint Wing, London W2 1PG, United Kingdom (FAX: ; r.rai@ic.ac.uk) /02/$22.00 PII S (01) Objective: To investigate the relationship between Day 8 serum luteinizing hormone (LH) and testosterone (T) concentrations, and body mass index (BMI) with pregnancy outcome in women with recurrent miscarriage. Design: Prospective observational study. Setting: National recurrent miscarriage clinic. Patient(s): Three hundred forty-four women (median age 32 years; range 18 44) with a history of recurrent first trimester miscarriage (median 4; 3 14; 12 weeks gestation) who conceived spontaneously and who received no pharmacological treatment during pregnancy were studied. All women were antiphospholipid antibody negative and had a normal peripheral karyotype as did their partners. Intervention(s): Outcome of untreated pregnancies. Main Outcome Measure(s): Day 8 serum LH and T concentrations and BMI were correlated with pregnancy outcome. Result(s): One hundred and ninety-two (55.8%) women had a live birth and 152 (44.2%) women miscarried. Polycystic ovarian morphology was diagnosed in 174 women (50.6%). There was no significant relationship between follicular phase LH concentrations and pregnancy outcome. Pregnancy outcome was similar in women with normal and high serum T concentrations. BMI value was not significantly different between women who had a live birth and those who miscarried. Conclusion(s): The analysis of this large cohort of women with recurrent miscarriage demonstrates that prepregnancy Day 8 serum LH and T concentrations, and BMI do not have a statistically significant relationship with pregnancy outcome. (Fertil Steril 2002;77: by American Society for Reproductive Medicine.) Key Words: Recurrent miscarriage, pregnancy outcome, luteinizing hormone, testosterone, body mass index Recurrent miscarriage, the loss of three or more consecutive pregnancies, is a heterogeneous condition affecting approximately 1% of couples trying to conceive (1, 2). A variety of endocrine abnormalities hypersecretion of luteinizing hormone (LH) (3, 4), hyperandrogenaemia (5 7), obesity (8), retarded endometrium (9), and short duration of the luteal phase of the cycle (10) have been cited as being either associated with or causal for pregnancy loss; however, there is a paucity of data on the prospective outcome of untreated pregnancies in women with recurrent miscarriage identified as having any of these endocrinopathies. Hormonal events before ovulation, particularly the fluctuation of LH, androgens, and follicle-stimulating hormone (FSH) during the early follicular phase, may significantly influence the development of the oocyte and determine its subsequent meiotic capability and fertilization ability. Tonic LH hypersecretion is frequently encountered in patients with polycystic ovary syndrome (PCOS) (11, 12), and elevated follicular phase LH concentration has been associated with detrimental effects on reproductive function irregular menstrual cycles, reduced rates of ovulation, infertility, and increased rates of recurrent miscarriage (13 18). 348

2 The objective of this prospective, observational study was to determine the relationship between follicular phase serum LH and testosterone (T) concentrations, and body mass index (BMI) with pregnancy outcome in women with recurrent miscarriage. MATERIALS AND METHODS The St. Mary s Hospital Local Research Ethics Committee gave IRB approval for this study. Subjects The future pregnancy outcome of 344 women (median age 32 years; range 18 44) with a history of recurrent first trimester miscarriage (median 4; 3 14; 12 weeks gestation) who conceived spontaneously and who received no pharmacological treatment during pregnancy was studied. All women were antiphospholipid antibody (apl) negative, had normal uterine anatomy and a normal peripheral blood karyotype as did their partner. The BMI of each women was also calculated using the formula weight (kg)/height (m 2 ). Women with a BMI 28 kg/m 2 were considered obese. Ultrasound Scan Uterine anatomy and ovarian morphology were determined by pelvic ultrasonography in the early to mid-follicular phase of the menstrual cycle. Trained ultrasonographers performed ultrasonography with an Ultramark 9 (Advanced Technology Laboratories, Bothel, Seattle, Washington) and either a 3.5 MHz abdominal or a5mhzvaginal probe. A diagnosis of polycystic ovary (PCO) morphology was made if the ovarian volume was enlarged ( 9 ml), and there were more than 10 follicles with a diameter between 2 8 mm arranged peripherally in one plane and there was increased echodensity of the stroma (19). These ultrasound criteria have been widely used in European studies to define PCO morphology (20). Hormonal Assays Serum LH and T levels were measured on Day 8 of the menstrual cycle. LH was assayed using a heterogeneous sandwich magnetic separation assay, and T with a competitive magnetic separation assay on the Technicon Immuno 1 Immunoanalyser System (Bayer Corporation, Tarrytown, New York). The coefficient of variation for the LH assay was 3% and for the T assay 8%. T levels were considered as normal ( 3 ng/ml) or high ( 3 ng/ml), respectively. On the basis of serum LH levels, women were divided into three groups: high serum LH levels ( 10 IU/L), normal serum LH levels ( 4 and 10 IU/L), and low serum LH levels ( 4 IU/L). Antiphospholipid Antibodies Assays All women were screened for apl on at least two occasions more than 8 weeks apart prior to pregnancy. Lupus anticoagulant (LA) was detected using the dilute Russell s viper venom time (drvvt) together with a platelet neutralization procedure. Patient samples with a drvvt ratio (test/ control) of 1.1 were retested with a platelet neutralization procedure. A decrease of 10% in the ratio was considered positive for LA (21). Anticardiolipin antibodies (acl) were identified using a standardized enzyme linked immunosorbent assay (ELISA). An IgG anticardiolipin level 5 GPL units and an IgM anticardiolipin level 3 MPL were considered to be positive (22). Women with persistently positive tests for either LA or acl were diagnosed as having the primary antiphospholipid syndrome were treated with aspirin and heparin during pregnancy and were excluded from this study (23). Management during Pregnancy All women attended a dedicated early pregnancy clinic (5 to 12 weeks gestation), where they received supportive care and serial first trimester ultrasound scans were performed. No woman received pharmacological treatment during pregnancy except for folic acid (400 g daily) as prophylaxis against neural tube defects. The outcome of all pregnancies was available for analysis. Statistical Analysis Discrete variables were analysed using either Fisher s exact test or the 2 test and continuous variables using the Mann Whitney U test. Multivariate logistic regression analysis was performed to assess the independent effect of age, previous number of miscarriages, ovarian morphology, serum LH and T concentrations, and BMI to predict the pregnancy outcome. Significance was assumed at P.05. RESULTS Of the 344 women included in this study, 192 (55.8%) had a live birth and 152 (44.2%) miscarried. In accordance with the morphological criteria defined above, the prevalence of PCO in women studied was 50.6% (174/344). There was no significant difference in the live birth rate between women with PCO (58.6%) and those with normal ovarian morphology (50%; P.3). Day 8 serum LH levels were low in 70 (20.4%) women, and 38 (54.2%) of those who had a live birth; normal in 242 (70.3%) women, and 141 (58.2%) of those who had a live birth; high in 32 (9.3%) women, and 13 (40.6%) of those who had a live birth. No statistically significant differences were found among the three groups of women in terms of maternal age and number of previous miscarriages (Table 1). Analysis of the relationship between follicular phase LH concentrations with pregnancy outcome shows no statistically significant results between the three groups of women. Similarly, there was no significant difference in the pregnancy outcome between women with a normal and those with a high serum T concentration. Women with a normal T concentration had a live birth rate of 51.5% and those with a high testosterone concentration had a live birth rate of 56.5% FERTILITY & STERILITY 349

3 TABLE 1 Demographic details and serum LH concentrations of the study population. Low LH Normal LH High LH P value No. of women Median maternal age (range) 32 (22 42) 32 (18 44) 32 (22 42) NS Median no. of previous miscarriages (range) 4(3 12) 4 (3 14) 5 (3 10) NS Note: LH luteinizing hormone; NS not significant (Mann Whitney U test). (P.55). There was no significant difference in BMI value between those women who subsequently miscarried again compared with those who subsequently delivered a live infant (Fig. 1). Among all variables considered, age and previous number of miscarriages were the only independent variables to predict the probability of pregnancy outcome among women with recurrent first trimester miscarriage (Table 2). DISCUSSION This prospective observational study reports that there is no significant relationship between [1] polycystic ovary morphology, [2] hypersecretion of LH, [3] high T concentrations, and [4] BMI with pregnancy outcome in women with a history of unexplained recurrent miscarriage who conceive spontaneously. The miscarriage rate of 44% in this study is similar to the rate that the authors have previously reported in a cohort of 486 women with unexplained recurrent miscarriage (40%; P.27) (24). The findings of this study contrast with earlier data obtained from pregnancies achieved spontaneously or following ovulation induction, suggesting that high serum LH concentrations are associated with a significant impairment of fertility and an increased risk of miscarriage FIGURE 1 Body mass index (BMI) and pregnancy outcome. 350 Nardo et al. LH, T, and pregnancy outcome Vol. 77, No. 2, February 2002

4 TABLE 2 Multivariate logistic regression analysis of variables considered against the pregnancy outcome. Variable Odds ratio (95% confidence interval) P value Age No. of previous miscarriages Ovarian morphology Normal morphology PCO morphology Day 8 LH concentrations Low Normal High Day 8 T concentrations Normal High BMI Note: PCO polycystic ovary; LH luteinizing hormone; T testosterone; BMI body mass index. (14 16, 25, 26). These early studies also reported that suppression of high endogenous LH levels using gonadotrophinreleasing hormone (GnRH) analogues were effective in reducing the detrimental effects of high LH (3). More recent studies, however, have provided contrary evidence reporting no statistically significant differences in pregnancy outcome in women with recurrent miscarriage who have a high serum LH concentration compared with those with a normal serum LH concentration (6, 27). Two important clinical studies have demonstrated that suppression of high endogenous LH secretion using GnRH analogues does not improve the pregnancy outcome (26, 28). With regard to serum T, although the authors found that women who miscarried had a higher serum T concentration compared with those who had a live birth, this difference did not reach statistical significance. Although Liddell et al. (29) made a similar observation, other studies have highlighted an association among high T concentrations, abnormal endometrial development, and adverse pregnancy outcome (6, 7). Further studies are needed to understand the role of androgens on the uterine luminal epithelium and their relationship to early pregnancy loss. No significant relationship existed between BMI and pregnancy outcome. This is in agreement with a previous report (30) but in contrast with others (31). This discrepancy may be explained in part by patient selection and treatment. All women in this study conceived spontaneously. In conclusion, analysis of this large cohort of women with recurrent miscarriage demonstrates that mid-follicular serum LH concentrations, T concentrations, and BMI values are not predictive of the prospective outcome of untreated pregnancies. A causal relationship between multifactorial endocrinopathies and recurrent miscarriage remains to be established. References 1. Coulam CB. Recurrent pregnancy loss (foreword). In: Greenshaw C, ed. Clinical Obstetrics and gynecology. Philadelphia: Harper and Row, 1986: Stirrat GM. Recurrent miscarriage. Lancet 1990;336: Balen AH, Tan SL, Jacobs HS. Hypersecretion of luteinizing hormone: a significant cause of infertility and miscarriage. Br J Obstet Gynaecol 1993;100: Homburg R. Adverse effects of luteinizing hormone on fertility: fact or fantasy. Baillieres Clin Obstet Gynaecol 1998;12: Li TC, Serle E, Warren MA, Cooke ID. 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