Mild obesity does not affect perinatal outcome in gestational carrier cycles.

STUDY QUESTION: Does BMI of gestational carriers (GCs) affect perinatal outcomes after embryo transfer? SUMMARY ANSWER: Overweight and class I obesity in GCs does not affect the rate of good perinatal outcomes. WHAT IS KNOWN ALREADY: The use of GCs is increasing, but uniform guidance regarding optimal BMI for GCs is lacking. Women with obesity who conceive without fertility treatment or through autologous or donor in vitro fertilization are at higher risk of adverse maternal and fetal outcomes, but data on obesity in GCs are very limited. STUDY DESIGN, SIZE, DURATION: We performed a retrospective cohort study of 1121 GC cycles from January 2015 to December 2020 at US Fertility, the largest national partnership of fertility practices in the USA. PARTICIPANTS/MATERIALS, SETTING, AND METHODS: All GC cycles performed at a large network of fertility practices were reviewed. Same-sex partners undergoing co-IVF were excluded. The primary outcome was good perinatal outcome from the first embryo transfer, defined as a singleton live birth at ≥37 weeks of gestation with birth weight between 2500 and 4000 g. Secondary outcome measures included frequencies of live birth, clinical pregnancy, miscarriage, full-term birth, low birth weight, large for gestational age, and cesarean delivery. A generalized linear model (log-binomial) was used for each to compare outcomes across BMI groups using normal BMI (20-24.9 kg/m2) as the reference group. Risk ratios and 95% CIs were estimated for each category group relative to normal BMI. MAIN RESULTS AND THE ROLE OF CHANCE: We identified 1121 cycles in which GCs underwent first embryo transfer, of which 263 (23.5%) were in GCs with BMI >30. Demographics and reproductive history for GCs did not differ by BMI groups. The age of intended parents, use of frozen eggs, and fresh embryo transfers were higher with increasing BMI group. There were no statistically significant associations between BMI and good perinatal outcomes, live birth, clinical pregnancy, biochemical, spontaneous abortion, or low birth weight. However, among live births, higher BMI was significantly associated with birth by cesarean (P = 0.015) and large for gestational age infants (P = 0.023). LIMITATIONS, REASONS FOR CAUTION: This was a retrospective study, and there may be unmeasured confounders. The number of patients with BMI <20 or ≥35 was small, limiting the power for these groups. We were not able to assess all maternal and fetal outcomes. WIDER IMPLICATIONS OF THE FINDINGS: In this study, we did not identify any significant impact of BMI on the chances of having a good perinatal outcome. Prior research studies have been inconsistent and this is the largest study to date. STUDY FUNDING/COMPETING INTEREST(S): No external funding was received for this work. The authors do not have any conflicts of interest to declare. TRIAL REGISTRATION NUMBER: N/A.

Does AMH relate to timing of menopause? Results of an Individual Patient Data meta- analysis.

CONTEXT: Anti-Müllerian hormone based (AMH) age at menopause predictions remain cumbersome due to predictive inaccuracy. OBJECTIVE: To perform an Individual Patient Data (IPD) meta-analysis, regarding AMH based menopause prediction. DATA SOURCES: A systematic literature search was performed using PubMed, Embase and Cochrane databases. STUDY SELECTION: Prospective cohort studies regarding menopause prediction using serum AMH levels were selected by consensus discussion. DATA SELECTION: Individual cases were included if experiencing a regular cycle at baseline. Exclusion criteria were hormone use and gynecological surgery. DATA SYNTHESIS: 2596 women were included, 1077 experienced menopause. A multivariable Cox regression analysis assessed time to menopause (TTM) using age and AMH. AMH predicted TTM, however, added value on top of age was poor (age alone C-statistic 84%; age + AMH HR 0.66 95% CI 0.61-0.71, C-statistic 86%). Moreover, the capacity of AMH to predict early (≤45 years) and late menopause (≥55 years) was assessed. An added effect of AMH was demonstrated for early menopause (age alone C-statistic 52%; age + AMH HR 0.33, 95% CI 0.24-0.45, C-statistic 80%). A Weibull regression model calculating individual age at menopause revealed that predictive inaccuracy remained present and increased with decreasing age at menopause. Lastly, a check of non-proportionality of the predictive effect of AMH demonstrated a reduced predictive effect with increasing age. CONCLUSION: AMH was a significant predictor of TTM and especially of time to early menopause. However, individual predictions of age at menopause demonstrated a limited precision, particularly when concerning early age at menopause, making clinical application troublesome.

Induction, labor length and mode of delivery: the impact on preeclampsia-related adverse maternal outcomes.

OBJECTIVE: The objectives were to evaluate whether induction, specifically prolonged labor, was associated with adverse maternal outcomes related to preeclampsia with severe features (PEC-S) and whether cesarean affected the rate. STUDY DESIGN: This was a retrospective cohort study of women with PEC-S ⩾34 weeks who were diagnosed either before planned cesarean or before induction/latent labor. The primary outcome was a composite adverse maternal outcome related to PEC-S. RESULTS: The final cohort comprised 193 women (n=172 with labor and n=21 with planned cesarean). The prevalence of the outcome was 15.5%. Women exposed to labor did not have a higher rate compared with planned cesarean (16.3% vs 9.5%, P=0.4). Adjusting for confounders, women with a cesarean after prolonged labor had a 10-fold higher adverse outcome risk compared with women with a planned cesarean (adjusted odds ratio (aOR) 9.7 (1.2 to 78.6), P=0.03) or with a vaginal delivery <24 h (aOR 9.7 (1.4 to 67.4), P=0.02). CONCLUSION: Prolonged labor and cesarean in labor were both associated with an increase in our outcome.

Macrosomia has its roots in early placental development.

INTRODUCTION: We sought to determine if early placental size, as measured by 3-dimensional ultrasonography, is associated with an increased risk of delivering a macrosomic or large-for-gestational age (LGA) infant. METHODS: We prospectively collected 3-dimensional ultrasound volume sets of singleton pregnancies at 11-14 weeks and 18-24 weeks. Birth weights were collected from the medical records. After delivery, the ultrasound volume set were used to measure the placental volume (PV) and placental quotient (PQ = PV/gestational age), as well as the mean placental and chorionic diameters (MPD and MCD, respectively). Placental measures were analyzed as predictors of macrosomia (birth weight ≥4000 g) and LGA (birth weight ≥90th percentile). RESULTS: The 578 pregnancies with first trimester volumes included 44 (7.6%) macrosomic and 43 (7.4%) LGA infants. 373 subjects also had second trimester volumes available. A higher PV and PQ were both significantly associated with macrosomia and LGA in both the first and second trimesters. Second trimester MPD was significantly associated with both outcomes as well, while second trimester MCD was only associated with LGA. The above associations remained significant after adjusting for maternal demographic variables such as race, ethnicity, age and diabetes. Adjusted models yielded moderate prediction of macrosomia and LGA (AUC: 0.71-0.77). CONCLUSIONS: Sonographic measurement of the early placenta can identify pregnancies at greater risk of macrosomia and LGA. Macrosomia and LGA are already determined in part by early placental growth and development.

Randomized controlled trial of benzocaine versus placebo spray for pain relief at hysterosalpingogram.

Many women experience pain during hysterosalpingogram (HSG). This prospective, randomized, double-blinded, placebo-controlled study assessed whether the use of benzocaine spray during HSG is associated with reduced pain as compared with placebo. Thirty women presenting for HSG were enrolled and randomized to either benzocaine or saline spray. Treatment groups were similar in age, race, parity, pre-procedure oral analgesic use and history of dysmenorrhoea and/or chronic pelvic pain. Median change in pain score from baseline to procedure was 50.6mm (-7.4 to 98.8mm) in the benzocaine group and 70.4mm (19.8 to 100mm) in the placebo group. There was no difference between groups after adjusting for history of dysmenorrhoea. There was no difference in resolution of pain in benzocaine versus placebo groups at 5 min post procedure--median pain score difference -11.1 (-90.1 to 18.5) versus -37.0 (-100 to 1.2)--or at 30 min post procedure. Satisfaction scores did not differ by treatment and did not correlate with pain score during the procedure (rho=0.005). The use of benzocaine spray does not significantly improve pain relief during HSG nor does it hasten resolution of pain post HSG. Of interest, patient satisfaction was not correlated with pain. Many women experience pain during hysterosalpingogram (HSG), which is a test used to evaluate the uterine cavity and fallopian tube. We conducted a prospective, randomized, double-blinded, placebo-controlled study to assess whether the use of benzocaine spray during HSG is associated with reduced pain as compared with placebo. Thirty women presenting for HSG were enrolled and randomized to either benzocaine or saline spray. Treatment groups were similar in age, race, previous pregnancies, pre-procedure oral analgesic use and history of dysmenorrhoea (painful periods) and/or chronic pelvic pain. There was no difference in pain scores or resolution of pain between the two groups. Satisfaction scores did not differ by treatment group and did not correlate with the pain score during the procedure. We conclude that the use of benzocaine spray does not significantly improve pain relief during HSG nor does it hasten resolution of pain post HSG. Of interest, patient satisfaction was not correlated with pain.

Antibiotic residues in milk from small dairy farms in rural Peru.

The use of antibiotics in livestock can pose a public health threat, especially if antibiotic residues remain in the food product. Understanding how often and why farmers sell products with antibiotic residues is critical to improving the quality of these products. To understand how often milk with antibiotic residues is sold on small farms in a major dairy-producing region of Peru and identify factors associated with selling milk with antibiotic residues, we tested milk samples for antibiotic residues from every provider on three routes of commercial milk companies and from bulk tanks of farmers currently treating cows with antibiotics. We also asked farmers if they sold milk from treated cows and examined factors associated with the tendency to do so. The prevalence of milk contamination with antibiotic residues on commercial routes was low (0-4.2%); however, 33/36 farmers treating their animals with antibiotics sold milk that tested positive for antibiotic residues. The self-reported sale of milk from treated cows had a sensitivity, specificity, and positive and negative predictive values of 75.8%, 100%, 100% and 27.2%, respectively (with testing of milk for residues as the gold standard). Finally, 69/156 randomly selected farmers reported selling milk from treated cows, and farmers' knowledge of antibiotics and the milk purchaser were significantly associated with a farmer's tendency to report doing so. Educating farmers on the risks associated with antibiotics and enforcement of penalties for selling contaminated milk by milk companies are needed to improve milk quality.

Comparison of two methods for collecting antibiotic use data on small dairy farms.

Antibiotics are commonly used in animal agriculture; they can improve animal health and productivity, but their use may also represent a public health threat. Very little is known about antibiotic use on small farms in lower/middle income countries. To understand antibiotic use on these farms and promote the judicious use of these drugs, pharmacoepidemiologic data are necessary. However, acquiring such data can be difficult, as farmers are often illiterate (and therefore cannot participate in written surveys or keep treatment records), antibiotics can be obtained over-the-counter (in which case no prescriptions are generated) and monitoring and surveillance systems for drug use are often non-existent. The goal of this study was to compare two methods of acquiring pharmacoepidemiologic data pertaining to antibiotics that are well-adapted to farms in lower-middle income countries: self-report and the collection of discarded drug packaging. A convenience sample of 20 farmers in Cajamarca, Peru, participated in the study. Farmers placed discarded antibiotic packaging in bins for six months. At the end of the six-month period, farmers were interviewed and asked to recall the antibiotic usage that occurred on their farm over the past month and past six months; these self-reported data were quantitatively and qualitatively compared to the bin contents collected in the last month and previous six months. We found that the agreement between the bins and self-report was relatively poor for both the quantity and types of antibiotics used. The bins appeared to perform better than self-report when bottles and mLs of antibiotics were measured, while self-report appeared to perform better for intra-mammary infusions. The bins also appeared to perform better when data pertaining to an extended time period (six months) were collected. The results of this study will provide guidance to investigators seeking to collect pharmacoepidemiologic data in similar environments.

The use of antibiotics on small dairy farms in rural Peru.

Very little is known about the use of antibiotics on small dairy farms in lower/middle-income countries. The use of these drugs can have profound impacts on animal health, farmer income and public health. A survey of 156 farmers was conducted in Cajamarca, a major dairy-producing center in the highlands of Peru characterized by small farms (<15 cows) to assess patterns and determinants of antibiotic use and farmers' knowledge of antibiotics. The reported incidence of disease on these farms was relatively low (0.571 episodes of disease per cow-year), but more than 83% of the reported episodes were treated with antibiotics. The most commonly used antibiotics were oxytetracycline, penicillin and trimethoprim-sulfamethoxazole drugs; antiparasitic drugs were also used to treat what were likely bacterial infections. An increased incidence of treated disease was significantly associated with smaller farm size, lower farmer income, the previous use of the Californian Mastitis test on the farm and antibiotic knowledge. Farmers' knowledge of antibiotics was assessed with a series of questions on antibiotics, resulting in a "knowledge score". Increased knowledge was significantly associated with the use of antibiotics for preventative reasons, the purchase of antibiotics from feed-stores, the experience of complications in animals after having administered antibiotics, the number of workers on the farm and the educational level of the farmer. Overall, antibiotics appeared to be used infrequently, most likely because therapeutic interventions were sought only when the animal had reached an advanced stage of clinical disease. Few farmers were able to define an antibiotic, but many farmers understood that the use of antibiotics carried inherent risks to their animals and potentially to the consumers of dairy products from treated animals. The results of this study are useful for understanding the patterns of antibiotic use and associated management, demographic and knowledge factors of farmers on small dairy farms in rural Peru.

Hormone variations associated with quantitative fat measures in the menopausal transition.

OBJECTIVE: Reproductive hormone levels are associated with body size, and the association between estradiol and body size varies over the menopausal transition. This study aims to delineate these relationships using quantitative measures of visceral and subcutaneous fat. METHODS: Early follicular hormones (follicle stimulating hormone (FSH), estradiol, luteinizing hormone, dehydroepiandrosterone sulfate, testosterone) and T-1 weighted abdominal MRI images were obtained in a cross-sectional assessment of 77 women in the Penn Ovarian Aging Study. Fat volume (cm(3)) was quantified using validated software (Amira) and divided into tertiles of visceral and subcutaneous fat volume for analysis. Multivariable linear regression models compared hormone values between tertiles adjusting for race, age, and menopausal status. RESULTS: In adjusted models, estradiol was positively associated with visceral fat tertiles (geometric mean (GM) estradiol (pg/ml): Low 13.0, Mid 17.5, High 26.7, p = 0.006) while FSH was inversely associated with visceral fat tertiles (GM FSH (mIU/ml): Low 42.8, Mid 43.2, High 30.8, p = 0.03). The association of estradiol with visceral and subcutaneous fat tertiles varied by menopausal status (p < 0.001). In the early transition, estradiol was similar across tertiles of fat; postmenopause, estradiol was positively associated with visceral fat. Other hormones were not associated with fat measures. CONCLUSIONS: Estradiol was associated with quantitative measures of visceral fat and varies by menopausal status. This finding suggests that visceral fat may be an important mediator in hormone changes over the menopausal transition.

Ectopic pregnancy prediction in women with a pregnancy of unknown location: data beyond 48 h are necessary.

STUDY QUESTION: Are there improvements in the accuracy of prediction of ectopic pregnancy (EP) in women with early symptomatic pregnancy using human chorionic gonadotrophin (hCG) curves when clinicians consider visits beyond the first 48 h after initial presentation? SUMMARY ANSWER: Two hCG values, measured 48 h (2 days) apart, are often not sufficient to accurately predict the outcome of a woman with a pregnancy of unknown location (PUL), but adding a third visit on Day 4 or 7 significantly improved the prediction for 1 in 15 women. WHAT IS KNOWN ALREADY: The use of serial hCG values is commonly used to aid in the prediction of the final diagnosis in women with a PUL. Initial outcome predictions based on two hCG values may often be incorrect. STUDY DESIGN, SIZE, DURATION: This retrospective multicenter cohort study included 646 women with a PUL, recruited over 2 years. Of these women, 146 were ultimately diagnosed with EP. PARTICIPANTS/MATERIALS, SETTING, METHODS: Women presenting to the emergency room with first trimester pain or bleeding, with a PUL, at least 2 hCG values and a definitive final diagnosis from the University of Pennsylvania, University of Miami and University of Southern California, were recruited from 2007 to 2009. MAIN RESULTS AND THE ROLE OF CHANCE: Using currently recommended prediction rules, adding a third hCG evaluation on Day 4 after initial presentation significantly improved the accuracy of initial prediction from the first two values (48 h apart, or Day 2) by 9.3% (P = 0.015). Adding a third value on Day 7 improved prediction significantly by 6.7% (P = 0.031), compared with prediction based on first two values. The improvement in prediction by assessing four hCG values (Days 0, 2, 4 and 7) compared with three values (Days 0, 2 and 4) was 1.3% and not statistically significant. LIMITATIONS, REASONS FOR CAUTION: Missing data imputation likely biased results toward the null; predicted outcomes may not match those made by clinicians; and the study does not predict intrauterine pregnancy and spontaneous miscarriage separately. WIDER IMPLICATIONS OF THE FINDINGS: This study provides useful information for the prediction of outcomes for women with a symptomatic first trimester pregnancy of unknown location, but may not be generalizable to all pregnant women. STUDY FUNDING/COMPETING INTEREST(S): Supported by NIH grant numbers R01-HD036455 to Dr Barnhart and Dr Sammel, K24HD060687 to Dr Barnhart, and 5T32MH065218 to Ms. Zee. The authors have no conflicts of interest to declare.

A decrease in serum estradiol levels after human chorionic gonadotrophin administration predicts significantly lower clinical pregnancy and live birth rates in in vitro fertilization cycles.

BACKGROUND: Although close observation of serum estradiol (E2) levels remains a mainstay of assessing clinical response to controlled ovarian stimulation, the prognostic value of any change in E2 levels after administration of hCG remains unclear. The objective of this study is to evaluate the relationship between serum E2 response after hCG administration and the clinical pregnancy and live birth rates in fresh IVF cycles. METHODS: We conducted a retrospective cohort study of women aged 21-45 years undergoing their first IVF cycle from 1999 to 2008 at a single practice. We compared the post-hCG serum E2 level with values on the day of hCG trigger. IVF cycles were stratified by post-hCG E2 response and appropriate parametric and non-parametric statistics were performed. Clinical intrauterine pregnancy and live births were the primary outcomes of interest. Multivariable logistic regression models were created to identify predictive factors associated with outcomes while adjusting for potential confounders. RESULTS: Among the 1712 IVF cycles, 1065 exhibited a >10% increase (Group A), 525 had a plateau (± 10%, Group B) and 122 showed a >10% decrease (Group C) in post-hCG E2 levels. While the E2 levels on the day of hCG were similar across groups, Group C had more patients with diminished ovarian reserve, required higher gonadotrophin doses and had the lowest implantation rates. After adjusting for age, total gonadotrophin dose, infertility diagnosis, number of oocytes and number of transferred embryos, the associations between post-hCG E2 decline (Group C) and clinical pregnancy [adjusted odds ratio (aOR): 0.53; 95% confidence interval (CI): 0.33-0.84, P= 0.007] and live birth (aOR: 0.40; 95% CI: 0.22-0.71, P= 0.002) were significant. We also found significant associations between E2 plateau (Group B) and clinical pregnancy (aOR: 0.73; 95% CI: 0.57-0.94, P= 0.013) and live birth (aOR: 0.74; 95% CI: 0.56-0.97, P= 0.032) when adjusting for the same factors. CONCLUSIONS: In our study, >10% decrease in E2 levels after hCG administration was associated with 40-50% reduction in clinical pregnancy and live birth rates. Similarly, post-hCG E2 plateau (± 10%) lowered the clinical pregnancy and live birth rates by >25%. Our study suggests that the change in the post-hCG E2 level is another parameter that can be used by clinicians to counsel patients regarding their likelihood of success with assisted reproductive technologies prior to oocyte retrieval.

Does a prediction model for pregnancy of unknown location developed in the UK validate on a US population?

BACKGROUND: A logistic regression model (M4) was developed in the UK to predict the outcome for women with a pregnancy of unknown location (PUL) based on the initial two human chorionic gonadotrophin (hCG) values, 48 h apart. The purpose of this paper was to assess the utility of this model to predict the outcome for a woman (PUL) in a US population. METHODS: Diagnostic variables included log-transformed serum hCG average of two measurements, and linear and quadratic hCG ratios. Outcomes modeled were failing PUL, intrauterine pregnancy (IUP) and ectopic pregnancy (EP). This model was applied to a US cohort of 604 women presenting with symptomatic first-trimester pregnancies, who were followed until a definitive diagnosis was made. The model was applied before and after correcting for differences in terminology and diagnostic criteria. RESULTS: When retrospectively applied to the adjusted US population, the M4 model demonstrated lower areas under the curve compared with the UK population, 0.898 versus 0.988 for failing PUL/spontaneous miscarriage, 0.915 versus 0.981 for IUP and 0.831 versus 0.904 for EP. Whereas the model had 80% sensitivity for EP using UK data, this decreased to 49% for the US data, with similar specificities. Performance only improved slightly (55% sensitivity) when the US population was adjusted to better match the UK diagnostic criteria. CONCLUSIONS: A logistic regression model based on two hCG values performed with modest decreases in predictive ability in a US cohort for women at risk for EP compared with the original UK population. However, the sensitivity for EP was too low for the model to be used in clinical practice in its present form. Our data illustrate the difficulties of applying algorithms from one center to another, where the definitions of pathology may differ.

Rethinking IUGR in preeclampsia: dependent or independent of maternal hypertension?

OBJECTIVE: Chronic hypertension (CHTN) is a risk factor for both intrauterine growth restriction (IUGR) as well as preeclampsia. This study was performed to: (1) describe the prevalence of IUGR in women with preeclampsia (with and without CHTN) compared with controls, (2) investigate the relationship between preeclampsia and maternal CHTN with IUGR, and (3) investigate the relationship between IUGR and severity of preeclampsia. STUDY DESIGN: A case-control study was performed. Cases were patients identified with preeclampsia. Controls were patients presenting for delivery at term (>or=37 weeks). IUGR prevalence by case-control status, or severity of disease was evaluated using Pearson chi(2) tests. Multivariable logistic regression was used to control for confounders. RESULT: In all, 430 cases and 568 controls were studied. Preeclamptic women have a 2.7 (CI (1.94 to 3.86)) and 4.3 (CI (2.58 to 7.17)) times increased odds of having a fetus with IUGR at <10 and <5% compared with controls in adjusted analyses. There was a significant interaction between CHTN and IUGR. Therefore, in women without CHTN, women with PEC had increased odds of IUGR, whereas in women with CHTN, there was no difference in odds of IUGR in women with or without preeclampsia. Within the cases, severe preeclampsia was associated with IUGR<10% (AOR=1.82 (1.11 to 2.97)) but not IUGR<5% (AOR=1.6 (0.85 to 2.86)). CONCLUSION: Preeclampsia is independently associated with the development of IUGR. As suggested earlier, women with CHTN do not have the highest prevalence of IUGR, suggesting disparate pathways by which IUGR develops in women with superimposed preeclampsia compared with preeclampsia alone.

Adverse reproductive outcomes in urban women with adeno-associated virus-2 infections in early pregnancy.

BACKGROUND: We demonstrated recently that adeno-associated virus-2 (AAV-2) DNA was detected significantly more frequently in placental trophoblast cells from cases of severe pre-eclampsia than from normal term deliveries. Here, we sought to determine if maternal AAV-2 infection early in pregnancy preceded adverse outcomes resulting from placental dysfunction. METHODS: We collected first trimester maternal serum samples and compared anti-AAV-2 IgM antibody levels (indicating primary infection or reactivation of latent AAV-2) between controls delivered at term (n = 106) and three groups of cases: spontaneous abortions (n = 34), spontaneous preterm deliveries (n = 24) and women with at least one outcome usually attributed to placental dysfunction, including pre-eclampsia, intrauterine growth restriction (IUGR) or stillbirth (n = 20). The seroprevalence of immunoglobulin G (IgG) antibodies against AAV-2 and IgM antibodies against viruses that promote AAV-2 replication [adenovirus and cytomegalovirus (CMV)] were also determined. RESULTS: First trimester maternal IgM seropositivity was 5.6 times more prevalent among pre-eclampsia/IUGR/stillbirth cases (P = 0.0004) and 7.6 times more prevalent among preterm deliveries (P < 0.0001) than among controls. CMV and adenovirus IgM antibodies and chronic AAV-2 infections (IgG seropositivity) were not associated with adverse pregnancy outcomes. CONCLUSIONS: Primary or reactivated AAV-2 infection (maternal IgM seropositivity) early in pregnancy was associated with adverse reproductive outcomes associated with placental dysfunction, including pre-eclampsia, stillbirth and spontaneous preterm delivery.

Follicular phase hormone levels and menstrual bleeding status in the approach to menopause.

OBJECTIVE: (1) Characterize the relationship between follicular phase hormone levels and menstrual bleeding patterns in the approach to menopause; (2) identify racial differences in hormone levels; (3) determine independent contributions of menstrual status, race, age, BMI, and smoking to hormone levels. DESIGN: Randomly identified, population-based cohort, stratified to obtain equal numbers of African American and Caucasian women, prospectively followed for 5 years. SETTING: Women in Philadelphia County, PA, identified by random-digit telephone dialing. PARTICIPANT(S): Women aged 35 to 47 years with regular menstrual cycles at enrollment (N = 436). DATA COLLECTION: Blood sampling twice in each of 7 assessment periods during days 1-6 of the cycle, menstrual dates identified through structured interview and daily symptom reports, anthropometric measures and standardized questionnaires at each assessment period. MAIN OUTCOME MEASURE(S): Serum levels of follicular E(2), FSH, inhibin B, and LH. RESULT(S): The mean levels of E(2), FSH, inhibin B, and LH were differentially associated with the 5 menstrual status groups defined by changes in bleeding patterns. Significant changes in hormone levels occurred prior to missed menstrual cycles for inhibin B, FSH, and LH. All hormones had a highly significant interaction between menstrual status and BMI. African American women had significantly lower levels of E(2) and LH compared to Caucasian women in univariate analyses. The interaction of race, menstrual status, and BMI was highly significant (P<.001) for E(2), with African American women having lower E(2) levels until postmenopause, when E(2) levels were higher in AA women with BMI > or =25 and BMI > or =30. CONCLUSION(S): Levels of E(2), FSH, LH, and inhibin B are significantly associated with menstrual bleeding patterns in late reproductive age women and differentiate the earliest stages of the menopausal transition. Racial differences in mean levels of E(2) appear strongly mediated by BMI.

Premenstrual syndrome as a predictor of menopausal symptoms.

OBJECTIVE: To estimate whether premenstrual syndrome (PMS) predicts common menopausal symptoms assessed longitudinally for 5 years among women in the transition to menopause. METHODS: Data were obtained from a structured interview questionnaire, daily symptom ratings, and standard measures of depressive symptoms and sleep quality at 7 assessment periods in a population-based cohort of 436 women. Menstrual status was determined by menstrual bleeding dates. Hormones were measured in the early follicular phase, with a maximum of 14 measures per subject. Multivariate logistic regression models for repeated measures were used to estimate the effects of study variables. RESULTS: Premenstrual syndrome significantly decreased with age (P <.001) and with changes in menstrual bleeding status (P =.003). Women with PMS at enrollment were more likely over the 5-year period to report menopausal hot flushes (odds ratio [OR] 2.09; confidence interval [CI] 1.42, 3.08; P <.001); depressed mood (OR 2.34; CI 1.60. 3.43; P <.001); poor sleep (OR 1.72; CI 1.16, 2.53; P =.007), and decreased libido (OR 1.54; CI 1.06, 2.24; P =.024) after adjusting for age, race, diagnosis of major depression, and estradiol. Subjects' fluctuations in estradiol were significantly associated with hot flushes, depressive symptoms, and poor sleep. CONCLUSION: Premenstrual syndrome decreased in the transition to menopause. Women who reported PMS at baseline were at greater risk of menopausal hot flushes, depressed mood, poor sleep, and decreased libido. Further studies of the associations of symptoms and changes in ovarian function are needed to elucidate the underlying symptom physiology and aid in the development of effective treatments for women during the menopausal transition.

DHEA-S levels and depressive symptoms in a cohort of African American and Caucasian women in the late reproductive years.

BACKGROUND: The objective of this study was to elucidate the associations of dehydroepiandrosterone sulfate (DHEA-S) levels and depressive symptoms in African American and Caucasian women in the late reproductive years, a transitional age zone preceding the perimenopause, in which ovarian aging and associated endocrine changes begin. We had hypothesized that lower levels of DHEA-S would be associated with depressive symptoms and that, because DHEA-S levels decline with increasing age, older women would have an increased prevalence of depressive symptoms. METHODS: This cross-sectional study used a population-based urban sample recruited through random digit telephone dialing. The sample was 338 women between the ages of 35 and 47 years with regular menses. Half the sample was African American and half was Caucasian. RESULTS: Higher DHEA-S levels were associated with depressive symptoms in women in the younger half of this cohort. Lower DHEA-S levels were associated with depressive symptoms in the women in the older half of this cohort. The direction of the relationship of DHEA-S and depressive symptoms changes with age, being a positive relationship in younger women and an inverse relationship in the older women in this cohort. This change in the direction of the relationship appears to occur at a younger age in African American women. CONCLUSIONS: Our hypothesis of a relationship between low DHEA-S levels and elevated depressive symptoms was supported only in the older women in this cohort. Unexpectedly, younger women in this cohort demonstrated a positive association between DHEA-S levels and depressive symptoms. Changes in DHEA-S levels, depressive symptoms, and the relationship of other hormones in the hypothalamic-pituitary-adrenal axis need to be better understood in premenopausal women approaching perimenopause.

Amniotic fluid matrix metalloproteinase-8 indicates intra-amniotic infection.

OBJECTIVE: This study was undertaken to determine whether matrix metalloproteinase-8, which is produced by neutrophils, is a useful marker for the detection of intra-amniotic infection. STUDY DESIGN: We performed a case-control study using enzyme-linked immunosorbent assays to detect matrix metalloproteinase-8 in 77 amniotic fluid specimens that were obtained by amniocentesis from women with preterm contractions or preterm labor and intact fetal membranes (n = 66) and from women with preterm premature rupture of membranes (n = 11). RESULTS: Thirty women had culture-proven intra-amniotic infection (cases), 21 of whom had intact membranes. After constructing receiver operating characteristic curves to establish the optimal threshold concentration of matrix metalloproteinase-8 for a positive test result, we detected matrix metalloproteinase-8 in 27 of 30 women with intra-amniotic infection; only 10 of 47 control specimens contained matrix metalloproteinase-8 (P <.001; odds ratio, 33.3; 95% CI, 8.4, 132.7). Matrix metalloproteinase-8 was present in 20 of 21 women with intact membranes and intra-amniotic infection and in only 10 of 45 control subjects (P <.001; odds ratio, 70.0; 95% CI, 8.3, 587.6). Among women with intact membranes, the sensitivity of the assay was 0.95 and the specificity was 0.78. CONCLUSION: Our results indicate that matrix metalloproteinase-8 is highly correlated with intra-amniotic infection and that enzyme-linked immunosorbent assay for matrix metalloproteinase-8 may be a clinically useful test for the diagnosis of intra-amniotic infection in women with preterm contractions and preterm labor.

Sleep quality, estradiol levels, and behavioral factors in late reproductive age women.

OBJECTIVE: To estimate the prevalence of perceived poor sleep in women aged 35-49 years and to correlate sleep quality with levels of gonadal steroids and predictors of poor sleep. METHODS: A cohort of 218 black and 218 white women aged 35-47 years at enrollment (aged 37-49 at final follow-up) with regular menstrual cycles was identified through random digit dialing for a longitudinal study of ovarian aging correlates. Data obtained at four assessment periods, including enrollment, over a 2-year interval were collected between days 1 and 6 (mean = 3.9) of the menstrual cycle. The primary outcome measure was subjects' rating of sleep quality at each assessment period. Associations of sleep quality with hormone levels (estradiol, follicle-stimulating hormone, luteinizing hormone, testosterone, and dehydroepiandrosterone sulfate) and other clinical, behavioral, and demographic variables were examined in bivariable and multivariable analyses. RESULTS: Approximately 17% of subjects reported poor sleep at each assessment period. Significant independent associations with poor sleep included greater incidence of hot flashes (odds ratio [OR] 1.52; 95% confidence interval [CI] 1.08, 2.12, P =.02), higher anxiety levels (OR 1.03; 95% CI 1.00, 1.06, P =.04), higher depression levels (OR 1.05; 95% CI 1.02, 1.07, P <.001), greater caffeine consumption (OR 1.25; 95% CI 1.04, 1.49, P =.02), and lower estradiol levels in women aged 45-49 (OR 0.53; 95% CI 0.34, 0.84, P =.006), after adjustment for current use of sleep medications. CONCLUSION: Both hormonal and behavioral factors were associated with sleep quality. Estradiol levels are an important factor in poor sleep reported by women in the 45-49 age group. Further evaluation of estrogen treatment for poor sleep of women 45 years and older is warranted.

Exposure to soy-based formula in infancy and endocrinological and reproductive outcomes in young adulthood.

CONTEXT: A large body of evidence documents the role of phytoestrogens in influencing hormone-dependent states. Infants fed soy formula receive high levels of phytoestrogens, in the form of soy isoflavones, during a stage of development at which permanent effects are theoretically possible. However, a paucity of data exists on the long-term effects of infant soy formulas. OBJECTIVE: To examine the association between infant exposure to soy formula and health in young adulthood, with an emphasis on reproductive health. DESIGN, SETTING, AND PARTICIPANTS: Retrospective cohort study conducted from March to August 1999 among adults aged 20 to 34 years who, as infants, participated during 1965-1978 in controlled feeding studies conducted at the University of Iowa, Iowa City (248 were fed soy formula and 563 were fed cow milk formula during infancy). MAIN OUTCOME MEASURES: Self-reported pubertal maturation, menstrual and reproductive history, height and usual weight, and current health, compared based on type of formula exposure during infancy. RESULTS: No statistically significant differences were observed between groups in either women or men for more than 30 outcomes. However, women who had been fed soy formula reported slightly longer duration of menstrual bleeding (adjusted mean difference, 0.37 days; 95% confidence interval [CI], 0.06-0.68), with no difference in severity of menstrual flow. They also reported greater discomfort with menstruation (unadjusted relative risk for extreme discomfort vs no or mild pain, 1.77; 95% CI, 1.04-3.00). CONCLUSIONS: Exposure to soy formula does not appear to lead to different general health or reproductive outcomes than exposure to cow milk formula. Although the few positive findings should be explored in future studies, our findings are reassuring about the safety of infant soy formula.