Systemic inflammation and menstrual cycle length in a prospective cohort study.

BACKGROUND: Local inflammation plays an important role in normal folliculogenesis and ovulation, and conditions of chronic systemic inflammation, such as obesity and polycystic ovarian syndrome, can disrupt normal follicular dynamics. OBJECTIVE: This study aimed to determine the association between systemic inflammation, as measured by C-reactive protein levels, and menstrual cycle length. STUDY DESIGN: This study was a secondary analysis using data from Time to Conceive, a prospective time-to-pregnancy cohort study. The association between cycle length and C-reactive protein was analyzed using multivariable linear mixed and marginal models adjusted for age, race, education, body mass index, time since oral contraceptive use, alcohol, smoking, caffeine consumption, and exercise. Time to Conceive enrolled women aged 30 to 44 years with no history of infertility who were attempting to conceive for <3 months. Serum C-reactive protein levels were measured on cycle day 2, 3, or 4. Participants recorded daily menstrual cycle data for ≤4 months. RESULTS: Main outcome measures included menstrual cycle length and follicular and luteal phase lengths. Multivariable analysis included 1409 cycles from 414 women. There was no linear association between C-reactive protein levels and menstrual cycle length. However, compared with <1 mg/L, a C-reactive protein level >10 mg/L was associated with >3 times the odds (adjusted odds ratio, 3.7; 95% confidence interval, 1.67-8.11) of long cycles (defined as ≥35 days). When evaluating follicular phase length, a C-reactive protein level of >10 mg/L was associated both with follicular phases that were 1.7 (95% confidence interval, 0.23-3.09) days longer and with >2 times the odds of a long follicular phase (adjusted odds ratio, 2.2; 95% confidence interval, 1.05-4.74). CONCLUSION: There is a potential pathophysiological association between systemic inflammation and menstrual cycle changes. Further studies are needed to determine if systemic inflammation alters the menstrual cycle or if long menstrual cycles are a marker for elevated systemic inflammation.

Families with children resulting from ART: psychosocial and financial implications.

STUDY QUESTION: What are the psychosocial and financial issues experienced among families with children 2-12 years of age conceived by ART? SUMMARY ANSWER: Our results suggest that families with children, 2-12 years of age, conceived via ART are doing well, although impacts were identified on parents of twins and higher-order multiples. WHAT IS KNOWN ALREADY: Multiple births have been associated with higher morbidity and mortality of children, as well as financial costs to families and society. STUDY DESIGN SIZE DURATION: This study was an assessment of familial response to birth of singletons, twins and higher order multiples at child's ages of 2-12. PARTICIPANTS/MATERIALS SETTING METHODS: Semi-structured interviews and surveys were conducted with mothers (n = 348) and fathers (n = 338) of singletons, twins and higher-order multiple gestations who received fertility services. MAIN RESULTS AND THE ROLE OF CHANCE: No significant differences were observed between the groups in domains of primary caregiving or parental separation/divorce. Impacts were identified on parent's ability to maintain employment. The revised 15-item scores of the Impact on Family Scale were significantly lower, reflecting more negative impacts, among families with twins (beta = -2.6, 95% confidence interval (CI), -4.7, -0.5, P = 0.014) and multiples (beta = -7.4, 95% CI, -10.4, -4.5, P < 0.001) than among families with singletons. Similarly, the Parenting Stress Index total scores were significantly lower among families with twins and multiples, indicating greater levels of stress, when compared to those with singletons. In addition, the Beck Depression Inventory total score were significantly higher for twins and multiples, and the Child Behaviour Checklist for ages 1.5-5 total problem score was significantly higher for twins when compared to singletons. LIMITATIONS REASONS FOR CAUTION: The study was limited to families who received fertility treatment and constitutes a population that was well educated and had higher incomes. Additionally, interview data was self-reported. STUDY FUNDING/COMPETING INTERESTS: This work was supported by National Institutes of Health (NIH)/Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) U10 HD39005 (to M.P.D.), U10 HD077680 (to K.R.H.), U10 HD077844 (to A.Z.), U10 HD077841 (to M.C.), U10 HD38992 (to R.S.L.), U10 HD27049 (to C.C.), U10 HD055925 (to H.Z.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NICHD or NIH.Dr Virginia Miller-no conflicts; Dr Michael P. Diamond-NIH Funding, AbbVie, Bayer and ObsEva Funding; Board of Directors and Stockholder for Advanced Reproductive Care; Dr Karl R. Hansen-Yale University/Reproductive Medicine Network/NICHD, Roche Diagnostics and Ferring International Pharmascience Center US funding; Dr Anne Steiner-NIH Funding; Dr Marcelle I. Cedars-no conflicts; Dr Richard Legro-consultant for Ogeda, Millendo, Kindex and Bayer; Ferring and Astra Zeneca funding; Dr Stephen A. Krawetz-no conflicts; Dr Christos Coutifaris-NIH Funding; Dr Hao Huang-no conflicts; Dr Nanette Santoro-no conflicts; Dr Heping Zhang-NIH Funding. TRIAL REGISTRATION NUMBER: N/A.

Polycystic Ovary Syndrome Signs and Metabolic Syndrome in Premenopausal Hispanic/Latina Women: the HCHS/SOL Study.

CONTEXT: Polycystic ovary syndrome (PCOS), a condition of androgen excess in women, is associated with cardiometabolic risk factors; however, this association is not fully characterized in a population-based sample of premenopausal women and high-risk groups such as Hispanics/Latinas. OBJECTIVE: We examined the association of PCOS signs and metabolic syndrome (MetS) in premenopausal Hispanic/Latina women. METHODS: This cross-sectional analysis includes 1427 women age 24 to 44 years from the Hispanic Community Health Study/Study of Latinos. PCOS signs included menstrual cycle greater than 35 days or irregular, self-reported PCOS, and oral contraceptive use to regulate periods or acne, and a composite of 1 or more PCOS signs. We calculated odds ratios (OR) and 95% CI for MetS, accounting for sociodemographic factors and the complex survey design; an additional model included body mass index (BMI). RESULTS: The mean age was 34 years and 30% reported any PCOS sign. The odds of MetS were higher in women reporting cycles greater than 35 days or irregular (OR 1.63; CI: 1.07-2.49) vs cycles 24 to 35 days, self-reported PCOS (OR 2.49; CI: 1.38-4.50) vs no PCOS, and any PCOS sign (OR 1.58; CI: 1.10-2.26) vs none. We found no association between OC use to regulate periods or acne and MetS (OR 1.1; CI: 0.6-1.8). When adjusting for BMI, only the association of self-reported PCOS and MetS was attenuated (OR 1.78; CI: 0.92-3.44). CONCLUSIONS: In Hispanic/Latina women, irregular menstrual cycles, self-reported PCOS, and any PCOS sign were associated with MetS and could indicate women at metabolic disease risk.

Analgesic use at ovulation and implantation and human fertility.

BACKGROUND: Studies investigating the effects of pain-relieving medication use on conceiving a pregnancy have shown conflicting results. Furthermore, no previous study has examined medication use around ovulation or implantation and the associations with the probability of conception, fecundability. OBJECTIVE: The objective of the study was to explore the association between fecundability and analgesic use in 3 different menstrual cycle windows (preovulation, periovulation, and implantation) as well as across the entire menstrual cycle. STUDY DESIGN: We analyzed data from a prospective cohort study of women between 30 and 44 years of age who were trying to conceive naturally from 2008 through 2015. Using daily diaries, medication usage was classified as acetaminophen, aspirin, or nonaspirin nonsteroidal antiinflammatory drug during 4 time periods of interest (preovulatory, periovulatory, and implantation) as well as the overall nonmenstrual bleeding days of the cycle. Menstrual cycles during the prospective attempt to become pregnant were enumerated using daily diary menstrual bleeding information. Conception was defined as a positive home pregnancy test. Discrete time fecundability models were used to estimate the fecundability ratio and 95% confidence interval in each of the 4 time windows of interest and for each pain reliever (aspirin use, nonaspirin nonsteroidal antiinflammatory drug use, acetaminophen) compared with no medication use after adjustment for several covariates including age, race, education, body mass index, alcohol and caffeine use, frequency of intercourse, and a history of migraines or uterine fibroids. RESULTS: Medication use was infrequent in the 858 women and 2366 cycles in this analysis. Use of nonaspirin nonsteroidal antiinflammatory drugs or acetaminophen was not associated with fecundability in any of the time windows of interest. Although the sample size was small, aspirin use during the implantation window was associated with increased fecundability (adjusted fecundability ratio [confidence interval]: 2.05 [1.23-3.41]). This association remained when limiting the analysis to cycles with minimal missing data or when adjusting for gravidity. None of the other medications were associated with fecundability. CONCLUSION: Aspirin use around implantation was associated with increased fecundability. These results expand previous literature to suggest the following: (1) implantation may be an important target for the effects of aspirin on conception and (2) aspirin may be beneficial, regardless of pregnancy loss history. These observations should be tested with a clinical trial.

Fertility Related Quality of Life, Gonadal Function and Erectile Dysfunction in Male Partners of Couples with Unexplained Infertility.

PURPOSE: We sought to determine whether lower fertility related quality of life or depression in men of couples with unexplained infertility is associated with low total testosterone levels, abnormal semen quality or erectile dysfunction. MATERIALS AND METHODS: This study is a secondary analysis of a large, multicenter, randomized controlled trial in couples with unexplained infertility. Male partners underwent baseline semen analysis with measurement of fasting total testosterone and gonadotropin. They also completed surveys, including the FertiQOL (Fertility Quality of Life), the PHQ-9 (Patient Health Questionnaire-9) and the IIEF (International Index of Erectile Function). The primary study outcomes were total testosterone with low total testosterone defined as less than 264 ng/dl, semen parameters and the IIEF score. We performed multivariable logistic regression analyses adjusted for patient age, race, body mass index, education, smoking, alcohol use, infertility duration and comorbidity. RESULTS: A total of 708 men with a mean ± SD age of 34.2 ± 5.6 were included in study. Of the men 59 (8.3%) had a PHQ-9 score of 5 or greater, which was consistent with depression, 99 (14.0%) had low total testosterone and 63 (9.0%) had mild or worse erectile dysfunction. Neither the FertiQOL score nor depression was associated with total testosterone or any semen parameter. The FertiQOL score was inversely associated with erectile dysfunction (for every 5-point score decline AOR 1.30, 95% CI 1.16-1.46). Depressed men were significantly more likely to have erectile dysfunction than nondepressed men (AOR 6.31, 95% CI 3.12-12.77). CONCLUSIONS: In men in couples with unexplained infertility lower fertility related quality of life and depression are strongly associated with erectile dysfunction. However, neither is associated with spermatogenesis or testosterone levels. Erectile dysfunction in infertile men merits longitudinal investigation in future studies.

Major depression, antidepressant use, and male and female fertility.

OBJECTIVE: To determine if maternal major depression (MD), antidepressant use, or paternal MD are associated with pregnancy outcomes after non-IVF fertility treatments. DESIGN: Cohort study. SETTING: Clinics. PATIENT(S): Participants in two randomized trials: PPCOS II (clomiphene citrate versus letrozole for polycystic ovary syndrome), and AMIGOS (gonadotropins versus clomiphene citrate versus letrozole for unexplained infertility). INTERVENTION(S): Female and male partners completed the Patient Health Questionnaire (PHQ-9). Female medication use was collected. PHQ-9 score ≥10 was used to define currently active MD. MAIN OUTCOME MEASURE(S): Primary outcome: live birth. SECONDARY OUTCOMES: pregnancy, first-trimester miscarriage. Poisson regression models were used to determine relative risks after adjusting for age, race, income, months trying to conceive, smoking, and study (PPCOS II versus AMIGOS). RESULT(S): Data for 1,650 women and 1,608 men were included. Among women not using an antidepressant, the presence of currently active MD was not associated with poorer fertility outcomes (live birth, miscarriage), but rather was associated with a slightly increased likelihood of pregnancy. Maternal antidepressant use (n = 90) was associated with increased risk of miscarriage, and male partners with currently active MD were less likely to achieve conception. CONCLUSION(S): Currently active MD in the female partner does not negatively affect non-IVF treatment outcomes; however, currently active MD in the male partner may lower the likelihood of pregnancy. Maternal antidepressant use is associated with first-trimester pregnancy loss, which may depend upon the type of antidepressant. CLINICAL TRIAL REGISTRATION NUMBERS: NCT00719186 and NCT01044862.

Cycle day, estrogen level, and lead follicle size: analysis of 27,790 in vitro fertilization cycles to determine optimal start criteria for gonadotropin-releasing hormone antagonist.

OBJECTIVE: To determine the optimal criteria at which to start GnRH antagonists during controlled ovarian hyperstimulation (COH) for in vitro fertilization (IVF). DESIGN: Retrospective clinical cohort. SETTING: IVF clinics. PATIENT(S): Women undergoing fresh autologous IVF using GnRH antagonist for ovulation suppression during COH. INTERVENTION(S): Measurement of lead follicle size, E2 level, and cycle day of stimulation on day of antagonist initiation. MAIN OUTCOME MEASURE(S): Clinical pregnancy rate (PR). RESULT(S): The highest clinical PR was achieved when the antagonist was started when a lead follicle reached 14-15.9 mm in size (mean clinical PR 21.3; 95% confidence interval [CI] 19.3, 23.6) on cycle day 6 (mean clinical PR 22.2; 95% CI 17, 28.4), or when the E2 level was between 500 and 599 pg/mL (mean clinical PR 25.4; 95% CI 19.5, 32.4). Starting antagonists when the E2 level was <300 or >1,100 pg/mL reduced the odds of clinical pregnancy by 40% (odds ratio 0.60, 95% CI 0.5, 0.7). CONCLUSION(S): Cycle day, E2 level, and follicle size at time of antagonist start are all independent predictors of a clinical pregnancy after IVF. Initiating antagonists when the E2 level is extremely low (<300 pg/mL) or extremely high (>1,100 pg/mL) significantly reduces the odds of pregnancy.

Anti-Müllerian hormone levels and incidence of early natural menopause in a prospective study.

STUDY QUESTION: Are anti-Müllerian hormone (AMH) levels assessed in women aged 32-44 associated with risk of incident early natural menopause? SUMMARY ANSWER: We observed strong, significant associations between lower AMH levels and higher risk of early menopause. WHAT IS KNOWN ALREADY: The ability to predict risk early menopause, defined as menopause before age 45, prior to fertility decline would improve options for family planning and cardiovascular disease prevention. Though AMH is an established marker of menopause timing in older reproductive-aged women, whether AMH is associated with risk of early menopause has not been evaluated. STUDY DESIGN, SIZE, DURATION: We assessed these relations in a nested case-control study within the prospective Nurses' Health Study II cohort. Premenopausal blood samples were collected in 1996-1999. Participants were followed until 2011 for early natural menopause, with follow-up rates >94%. PARTICIPANTS/MATERIALS, SETTING, METHODS: Early menopause cases (n = 327) were women reporting natural menopause between blood collection and age 45. Controls (n = 491) experienced menopause after age 45 and included 327 cases matched to controls on the basis of age at blood draw (±4 months) and other factors. AMH levels up to 12 years before early menopause were assayed in 2016. MAIN RESULTS AND THE ROLE OF CHANCE: In multivariable conditional logistic regression models adjusting for matching factors, body mass index, smoking, parity, oral contraceptive use, and other factors, each 0.10 ng/ml decrease in AMH was associated with a 14% higher risk of early menopause (95% confidence interval (CI) 1.10 to 1.18; P < 0.001). In polynomial regression models including linear and quadratic terms for AMH, odds ratios for early menopause for women with AMH levels of 1.5, 1.0 and 0.5 ng/ml compared to 2.0 ng/ml were 2.6, 7.5 and 23 (all P < 0.001). Significant associations were observed irrespective of smoking status, adiposity, infertility history and menstrual cycle characteristics. Furthermore, models assessing the predictive ability of AMH showed high concordance, and C-statistics were high, ranging from 0.68 (age ≤35) to 0.93 (age 42). LIMITATIONS, REASONS FOR CAUTION: Our population was relatively homogenous with respect to race/ethnicity. Further work in more ethnically diverse populations is needed. WIDE IMPLICATION OF THE FINDINGS: To our knowledge, this is the first prospective study to evaluate whether AMH levels are associated with early menopause. These findings support the utility of AMH as a clinical marker of early menopause in otherwise healthy women. STUDY FUNDING/COMPETING INTEREST(S): This project was supported by UM1CA176726, R01CA67262, and R01HD078517 from the U.S. Department of Health and Human Services, National Institutes of Health. No competing interests declared.

25-Hydroxyvitamin D (25(OH)D) and biomarkers of ovarian reserve.

OBJECTIVE: The aim of the study was to examine the associations between 25-hydroxyvitamin D (25(OH)D) and biomarkers of ovarian reserve in a large community-based sample of women. METHODS: In 2010 to 2016, women aged 30 to 44 years without any known fertility problems were recruited from the Chapel Hill, NC area for a prospective time-to-pregnancy cohort study. At enrollment 561 women provided a blood sample that was used to measure 25(OH)D, anti-Müllerian hormone (AMH), follicle-stimulating hormone, and inhibin-B. Unadjusted associations were estimated with Spearman correlation coefficients. Multivariable linear regression was used to estimate associations of 25(OH)D with ovarian reserve biomarkers, after adjusting for age, race, body mass index, smoking history, and recent use of hormonal birth control. RESULTS: The mean 25(OH)D was 36 ng/mL (SD = 11 ng/mL). 25(OH)D was not correlated with AMH, follicle-stimulating hormone, or inhibin-B (all r < 0.03). Multivariable results with continuous hormonal outcomes were also null. For dichotomous outcomes, there was a tendency for insufficient 25(OH)D (<30 ng/mL) to be associated with low AMH (<0.7 ng/mL) (odds ratio [95% CI]: 1.8 [0.9-4]). CONCLUSIONS: For the most part, 25(OH)D was not associated with ovarian reserve biomarkers in a group of women trying to become pregnant. We found some evidence that low 25(OH)D (<30 ng/mL) was associated with low AMH, but this should be confirmed in studies with a higher prevalence of low 25(OH)D.

Association Between Biomarkers of Ovarian Reserve and Infertility Among Older Women of Reproductive Age.

Importance: Despite lack of evidence of their utility, biomarkers of ovarian reserve are being promoted as potential markers of reproductive potential. Objective: To determine the associations between biomarkers of ovarian reserve and reproductive potential among women of late reproductive age. Design, Setting, and Participants: Prospective time-to-pregnancy cohort study (2008 to date of last follow-up in March 2016) of women (N = 981) aged 30 to 44 years without a history of infertility who had been trying to conceive for 3 months or less, recruited from the community in the Raleigh-Durham, North Carolina, area. Exposures: Early-follicular-phase serum level of antimüllerian hormone (AMH), follicle-stimulating hormone (FSH), and inhibin B and urinary level of FSH. Main Outcomes and Measures: The primary outcomes were the cumulative probability of conception by 6 and 12 cycles of attempt and relative fecundability (probability of conception in a given menstrual cycle). Conception was defined as a positive pregnancy test result. Results: A total of 750 women (mean age, 33.3 [SD, 3.2] years; 77% white; 36% overweight or obese) provided a blood and urine sample and were included in the analysis. After adjusting for age, body mass index, race, current smoking status, and recent hormonal contraceptive use, women with low AMH values (<0.7 ng/mL [n = 84]) did not have a significantly different predicted probability of conceiving by 6 cycles of attempt (65%; 95% CI, 50%-75%) compared with women (n = 579) with normal values (62%; 95% CI, 57%-66%) or by 12 cycles of attempt (84% [95% CI, 70%-91%] vs 75% [95% CI, 70%-79%], respectively). Women with high serum FSH values (>10 mIU/mL [n = 83]) did not have a significantly different predicted probability of conceiving after 6 cycles of attempt (63%; 95% CI, 50%-73%) compared with women (n = 654) with normal values (62%; 95% CI, 57%-66%) or after 12 cycles of attempt (82% [95% CI, 70%-89%] vs 75% [95% CI, 70%-78%], respectively). Women with high urinary FSH values (>11.5 mIU/mg creatinine [n = 69]) did not have a significantly different predicted probability of conceiving after 6 cycles of attempt (61%; 95% CI, 46%-74%) compared with women (n = 660) with normal values (62%; 95% CI, 58%-66%) or after 12 cycles of attempt (70% [95% CI, 54%-80%] vs 76% [95% CI, 72%-80%], respectively). Inhibin B levels (n = 737) were not associated with the probability of conceiving in a given cycle (hazard ratio per 1-pg/mL increase, 0.999; 95% CI, 0.997-1.001). Conclusions and Relevance: Among women aged 30 to 44 years without a history of infertility who had been trying to conceive for 3 months or less, biomarkers indicating diminished ovarian reserve compared with normal ovarian reserve were not associated with reduced fertility. These findings do not support the use of urinary or blood follicle-stimulating hormone tests or antimüllerian hormone levels to assess natural fertility for women with these characteristics.

Immediate ureterovaginal fistula following oocyte retrieval: A case and systematic review of the literature.

The aim of this study is to report a case of acute ureterovaginal fistula (UVF) formation with immediate symptomatic presentation after transvaginal ultrasound-guided oocyte retrieval (TVOR) for in vitro fertilization (IVF) and to perform a systematic literature review of ureteral injuries during TVOR. A 33-year-old woman with a history of anovulatory infertility presented with severe abdominal pain and vaginal leakage immediately following TVOR for IVF. We systematically reviewed the current literature regarding ureteral injury resulting from TVOR and present a case of timely identification and management of a UVF followed by a successful pregnancy. Computed tomography cystogram with intravenous contrast and left retrograde pyelogram confirmed the diagnosis of UVF which was managed by placement of the left ureteral stent. The IVF cycle was converted to a freeze-all cycle. The ureteral stent was removed 4 weeks later, and a subsequent frozen embryo transfer cycle resulted in pregnancy. We present the 13th case of ureteral injury and the fourth case of UVF following TVOR. UVF formation is a rare complication after TVOR and may result in serious long-term morbidity if it is not identified and treated promptly. Clinicians must exercise a high degree of suspicion and prompt evaluation for potential ureteral injuries in women presenting with abdominal pain, urinary symptoms, or vaginal leakage following TVOR.

Thyroid Autoimmunity and Reproductive Function.

Thyroid hormones are important for normal reproductive function, and maternal thyroid dysfunction has been associated with infertility, miscarriage, preterm birth, and poor neurodevelopment in the offspring. Thyroid autoimmunity is the leading cause of thyroid dysfunction in women of reproductive age. Women with thyroid autoimmunity, even with normal thyroid function, appear to be at a higher risk for poor reproductive outcomes, including miscarriage and preterm birth. Thyroxine replacement in women with thyroid autoimmunity with or without appreciable thyroid dysfunction may improve pregnancy outcomes. Thus, identification and treatment of women with thyroid autoimmunity may optimize reproductive success.

Baseline AMH Level Associated With Ovulation Following Ovulation Induction in Women With Polycystic Ovary Syndrome.

CONTEXT: Anti-Müllerian hormone (AMH) reduces aromatase activity and sensitivity of follicles to FSH stimulation. Therefore, elevated serum AMH may indicate a higher threshold for response to ovulation induction in women with polycystic ovary syndrome (PCOS). OBJECTIVE: This study sought to determine the association between AMH levels and ovulatory response to treatment among the women enrolled into the Pregnancy in PCOS II (PPCOS II) trial. DESIGN AND SETTING: This was a secondary analysis of data from a randomized clinical trial in academic health centers throughout the United States Participants: A total of 748 women age 18-40 years, with PCOS and measured AMH levels at baseline, were included in this study. MAIN OUTCOME MEASURES: Couples were followed for up to five treatment cycles to determine ovulation (midluteal serum progesterone > 5 ng/mL) and the dose required to achieve ovulation. RESULTS: A lower mean AMH and AMH per follicle was observed among women who ovulated compared with women who never achieved ovulation during the study (geometric mean AMH, 5.54 vs 7.35 ng/mL; P = .0001; geometric mean AMH per follicle, 0.14 vs 0.18; P = .01) after adjustment for age, body mass index, T, and insulin level. As AMH levels increased, the dose of ovulation induction medication needed to achieve ovulation also increased. No associations were observed between antral follicle count and ovulation. CONCLUSIONS: These results suggest that high serum AMH is associated with a reduced response to ovulation induction among women with PCOS. Women with higher AMH levels may require higher doses of medication to achieve ovulation.

Chlamydia trachomatis immunoglobulin G3 seropositivity is a predictor of reproductive outcomes in infertile women with patent fallopian tubes.

OBJECTIVE: To determine if Chlamydia trachomatis (C. trachomatis) seropositivity, as detected by the C. trachomatis elementary body (EB)-based enzyme-linked immunosorbent assay [EB ELISA] predicts pregnancy and pregnancy outcome among infertile women with documented tubal patency. DESIGN: Cohort study. SETTING: Outpatient clinics. PATIENT(S): In all, 1,250 infertile women with documented tubal patency enrolled in 1 of 2 randomized controlled trials: Pregnancy in Polycystic Ovary Syndrome II; and the Assessment of Multiple Intrauterine Gestations From Ovarian Stimulation. INTERVENTION(S): Sera were analyzed for anti-C. trachomatis immunoglobulin G (IgG)1 and IgG3 antibodies, using a research C. trachomatis EB ELISA. The optical density (OD)405 readings of ≥ 0.35 and ≥ 0.1 were considered positive for IgG1 and IgG3, respectively. MAIN OUTCOME MEASURE(S): Primary outcomes included pregnancy, live birth, and ectopic pregnancy. Log-linear regression was used to determine the relative risk after adjusting for age, race, treatment medication, smoking status, and current alcohol use. RESULT(S): A total of 243 (19%) women were seropositive for anti-C. trachomatis IgG3. They tended to be nonwhite and smokers. Anti-C. trachomatis IgG3 seropositive women were significantly less likely to conceive (risk ratio [RR] 0.65, 95% confidence interval [CI] 0.52-0.83) or to have a live birth (RR 0.59, 95% CI 0.43-0.80); these associations were weakened after adjusting for number of hysterosalpingography-documented patent tubes (RR 0.73, 95% CI 0.56-0.97) and (RR 0.73, 95% CI 0.50-1.04), respectively. Anti-C. trachomatis IgG3 seropositive women who conceived had a ×2.7 risk (95% CI 1.40-5.34) of ectopic pregnancy. CONCLUSION(S): Even in the presence of tubal patency, anti-C. trachomatis IgG3 seropositivity is associated with a lower likelihood of pregnancy. Anti-C. trachomatis IgG3 seropositive women have as high as 3 times the risk of ectopic pregnancy. CLINICAL TRIAL REGISTRATION NUMBER: PPCOSII: NCT00719186 and AMIGOS: NCT01044862.

Anti-Müllerian hormone concentrations in premenopausal women and breast cancer risk.

Laboratory models support an inverse association between anti-Müllerian hormone (AMH) and breast tumor development. Human studies are lacking; one study (N = 105 cases, 204 controls) with prospectively collected serum reported the opposite-an approximate 10-fold increase in breast cancer risk comparing fourth with first quartile AMH levels. We investigated the relation between serum AMH levels and breast cancer risk in a case-control (N = 452 cases, 902 controls) study nested within the prospective Sister Study cohort of 50,884 women. At enrollment, participants were ages 35 to 54, premenopausal, and completed questionnaires on medical and family history, lifestyle factors, and demographics. AMH (ng/mL) was measured by ultrasensitive ELISA in serum collected at enrollment and log-transformed for analysis. Multivariate conditional logistic regression was used to calculate ORs and 95% confidence intervals (CI) to account for matching on age and enrollment year. Mean age at enrollment was 46.8 years with an average 2.9 years from blood draw to breast cancer diagnosis (SD = 1.9). AMH concentrations were below the limit of detection (0.003 ng/mL) for approximately 25% of samples. Compared with samples below the LOD, women with AMH >2.84 ng/mL (90th percentile among controls) had a 2-fold increase in breast cancer odds (OR, 2.25; 95% CI, 1.26-4.02). For each 1-unit increase in lnAMH, overall breast cancer odds increased by 8% (OR, 1.08; 95% CI, 1.02-1.15) and odds of estrogen receptor-positive, invasive disease increased by 15% (OR, 1.15; 95% CI, 1.05-1.25). Our findings demonstrate an overall positive relation between AMH and breast cancer.

Lower plasma 25-hydroxyvitamin D is associated with irregular menstrual cycles in a cross-sectional study.

BACKGROUND: In animals, low levels of vitamin D are associated with estrus cycle disturbances, but there are virtually no human data. We examined the association of 25-hydroxyvitamin D (25(OH)D) (a biomarker for vitamin D status) with menstrual cycle characteristics. METHODS: Women aged 35-44 were randomly selected from a Washington D.C. health plan and invited to participate in the Uterine Fibroid Study (1996-1999). Our analysis includes 636 women (57% were African-American) who provided a blood sample and completed a telephone interview that included gynecologic history. Women were asked their usual cycle length in the preceding year. Women who reported it was "too irregular to estimate" were classified as having irregular cycles (N=48). Women were excluded if they currently or recently used hormonal contraception or any other medication that influences menstrual cycles. 25(OH)D was measured by radioimmunoassay in stored plasma samples. RESULTS: The median 25(OH)D level was 12.0 ng/mL (interquartile range: 7.6, 19.7 ng/mL). After controlling for age, race, BMI, education, age of menarche, current smoking, alcohol use, and physical activity, a decrease in 25(OH)D of 10 ng/mL was associated with 1.9 times the odds of irregular cycles (Odds ratio (OR) (95% confidence interval (CI)): 1.9 (1.0, 3.4), p=0.04). 25(OH)D was not associated with the occurrence of short cycles (OR(CI): 1.08 (0.79, 1.48, p=0.6) or long cycles (OR(CI): 1.31 (0.66, 2.60), p=0.4). CONCLUSIONS: Lower levels of 25(OH)D were associated with irregular cycles, but not with short or long cycles. Vitamin D may play a role in regulating ovulatory function. Further investigation of potential mechanisms is warranted.

Association between serum 25-hydroxyvitamin D and ovarian reserve in premenopausal women.

OBJECTIVE: Vitamin D has been linked to antimüllerian hormone levels, suggesting a possible association with greater ovarian reserve, but large population-based studies are lacking. Our objective was to explore the association between vitamin D and follicle-stimulating hormone (FSH) in premenopausal women. METHODS: The Uterine Fibroid Study (1996-1999) enrolled randomly selected 30- to 49-year-old members of a Washington, DC, health plan (N = 1,430). Women provided blood and urine samples in addition to questionnaire data. The vitamin D metabolite 25-hydroxyvitamin D (25(OH)D) was measured in stored plasma samples. Urinary FSH (mIU/mg creatinine) was measured by immunofluorometric assay. To obtain baseline measures, we limited this investigation to urine samples collected in the first 5 days of the menstrual cycle or 5 days before menses onset. In addition, postmenopausal women and women using oral contraceptives were excluded, leaving 527 women for analysis. FSH was creatinine-adjusted, normalized by log transformation, and modeled with multivariable linear regression. RESULTS: The median 25(OH)D level was 12 ng/mL, with approximately 75% of participants below the recommended level of 20 ng/mL. FSH and 25(OH)D were inversely related. For every 10-ng/mL increase in 25(OH)D, urinary FSH decreased by 14% (95% CI, -23 to -5; P = 0.003). CONCLUSIONS: Vitamin D is inversely related to FSH. This is consistent with literature relating low vitamin D levels to lower antimüllerian hormone levels. Prospective studies should investigate whether low vitamin D levels contribute to decreased ovarian reserve.

Short-term effects of salpingectomy during laparoscopic hysterectomy on ovarian reserve: a pilot randomized controlled trial.

OBJECTIVE: To examine the short-term effects of salpingectomy during laparoscopic hysterectomy on ovarian reserve when ovarian preservation is planned in view of determining the feasibility of conducting the study on a larger scale. DESIGN: Pilot randomized controlled trial. SETTING: Tertiary care, academic medical center. PATIENT(S): Thirty premenopausal women aged 18 to 45 years undergoing laparoscopic hysterectomy with ovarian preservation for benign indications from April 2012 to September 2012. INTERVENTION(S): Bilateral salpingectomy (n = 15) versus no salpingectomy (n = 15) at the time of laparoscopic hysterectomy with ovarian preservation. MAIN OUTCOME MEASURE(S): Antimüllerian hormone (AMH) measured preoperatively, at 4 to 6 weeks postoperatively, and at 3 months postoperatively, with operative time and estimated blood loss abstracted from the medical records. RESULT(S): The mean AMH levels were not statistically significantly different at baseline (2.26 vs. 2.25 ng/ml), 4 to 6 weeks postoperatively (1.03 vs. 1.25 ng/ml), or 3 months postoperatively (1.86 vs. 1.82 ng/ml) among women with salpingectomy versus no salpingectomy, respectively. There was also no statistically significant temporal change in the mean AMH level from baseline to 3 months postoperatively (-0.07 vs. -0.08 ng/ml) between the two groups. No difference in operative time (116 vs. 115 minutes) or estimated blood loss (70 vs. 91 mL) was observed. CONCLUSION(S): Salpingectomy at the time of laparoscopic hysterectomy with ovarian preservation is a safe procedure that does not appear to have any short-term deleterious effects on ovarian reserve, as measured by AMH level. Conducting a trial of this nature that is adequately powered with long-term follow-up evaluation would be feasible and is required to definitively confirm these results.

Efficient use of early obstetric sonography in the emergency department setting.

OBJECTIVES: Transvaginal sonography is frequently used in the emergency department (ED) to triage pregnancies of unknown location. The purpose of this study was to examine the utility of sonography in clinically stable patients with ß-human chorionic gonadotropin (ß-hCG) values below the discriminatory zone. METHODS: We conducted a retrospective cohort study of 408 consecutive ED patients who presented with pregnancies of unknown location and serum ß-hCG levels between 5 and 2500 mIU/mL and underwent transvaginal sonography. Women were classified as receiving immediate treatment or expectant management. Predictors associated with immediate treatment were assessed by bivariate analyses and logistic regression. RESULTS: Of the cohort, 361 women (88.5%) received expectant management, and 6.9%, 3.1%, and 0% of patients with pregnancies of unknown location and ß-hCG levels below 1000, 200, and 75 mIU/mL, respectively, received immediate treatment. Compared to the expectant management group, women receiving immediate treatment (n=47) were further from the last menstrual period (7.86 versus 6.10 weeks; P <.01), were more likely to report pain (59.6% versus 40.2% P = .01), had higher ß-hCG levels(1183 versus 608 mIU/mL; P <.01), and had lower hematocrit levels (35.7% versus 37.0%; P < .01), with pain the most predictive factor for immediate treatment (odds ratio,5.97; 95% confidence interval, 2.45-14.53). A model combining symptoms, ß-hCG, hematocrit, and weeks since the last menstrual period predicted the likelihood of sonography changing management from expectant management to immediate treatment with specificity of 98%. CONCLUSIONS: The diagnostic utility of sonography in clinically stable patients presenting to the ED in very early pregnancy is limited. A model using symptoms, ß-hCG, hematocrit, and the last menstrual period may aid clinicians to triage those who would benefit from immediate sonography.