Anne Marie Z. Jukic

Urinary Concentrations of Phthalate Metabolites and Bisphenol A and Associations with Follicular-Phase Length, Luteal-Phase Length, Fecundability, and Early Pregnancy Loss

Background Certain phthalates and bisphenol A (BPA) show reproductive effects in animal studies and potentially affect human ovulation, conception, and pregnancy loss. Objectives We investigated these chemicals in relation to follicular- and luteal-phase lengths, time to pregnancy, and early pregnancy loss (within 6 weeks of the last menstrual period) among women attempting pregnancy. Methods Women discontinuing contraception provided daily first-morning urine specimens and recorded days with vaginal bleeding for up to 6 months. Specimens had previously been analyzed for estrogen and progesterone metabolites and human chorionic gonadotropin. A total of 221 participants contributed 706 menstrual cycles. We measured 11 phthalate metabolites and BPA in pooled urine from three specimens spaced throughout each menstrual cycle. We analyzed associations between chemical concentrations and outcomes using linear mixed models for follicular- and luteal-phase lengths, discrete-time fecundability models for time to pregnancy, and logistic regression for early pregnancy loss. Results Higher concentrations of monocarboxyoctyl phthalate (MCOP) were associated with shorter luteal phase [2nd tertile vs. 1st tertile: –0.5 days (95% CI: –0.9, –0.1), 3rd vs. 1st: –0.4 days (95% CI: –0.8, 0.01), p = 0.04]. BPA was also associated with shorter luteal phase [2nd vs. 1st: –0.8 days (95% CI: –1.2, –0.4), 3rd vs. 1st: –0.4 days (95% CI: –0.8, 0.02), p = 0.001]. Conclusions BPA and MCOP (or its precursors) were associated with shorter luteal phase. Menstrual cycle–specific estimates of urinary BPA and phthalate metabolites were not associated with detrimental alterations in follicular-phase length, time to pregnancy, or early pregnancy loss, and in fact, DEHP [di(2-ethylhexyl) phthalate] metabolites {MEOHP [mono(2-ethyl-5-oxohexyl) phthalate] and ΣDEHP} were associated with reduced early loss. These findings should be confirmed in future human studies. Citation Jukic AM, Calafat AM, McConnaughey DR, Longnecker MP, Hoppin JA, Weinberg CR, Wilcox AJ, Baird DD. 2016. Urinary concentrations of phthalate metabolites and bisphenol A and associations with follicular-phase length, luteal-phase length, fecundability, and early pregnancy loss. Environ Health Perspect 124:321–328; http://dx.doi.org/10.1289/ehp.1408164

Physical activity during pregnancy and language development in the offspring

BACKGROUND In rodents, physical activity during pregnancy has been associated with improved learning and memory in the offspring. We used data from the Avon Longitudinal Study of Parents and Children (born in 1991-92) to investigate maternal physical activity during pregnancy and offspring language development. METHODS At 18 weeks of gestation, women reported the hours per week they participated in 11 leisure-time physical activities and the hours per week spent in general physical activity (leisure, household and occupational). Caregivers completed a modified MacArthur Infant Communication scale at 15 months. Verbal intelligence quotient (IQ) was measured at age 8 years. Regression analysis was used to examine the associations of physical activity with MacArthur score (more than 75th percentile) and verbal IQ. The number of participants available for analyses ranged from 4529 to 7162. RESULTS Children of women in the two highest quintiles of leisure activity (compared with no leisure activity) were more likely to have high 15-month MacArthur scores (adjusted odds ratio 1.2 [95% confidence interval 0.9, 1.4] and adjusted odds ratio 1.4 [95% CI 1.1, 1.7], respectively). Leisure activity was not associated with IQ, while general physical activity was linked with lower verbal IQ (1 and 3 points lower for the two highest quintiles). CONCLUSIONS The most robust finding was a transient increase in offspring vocabulary score at young ages with maternal leisure activity. Differences in the associations with leisure-time physical activity compared with general physical activity need further exploration.

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

ObjectiveVitamin 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. MethodsThe 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. ResultsThe 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). ConclusionsVitamin 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.

The association of maternal factors with delayed implantation and the initial rise of urinary human chorionic gonadotrophin

BACKGROUND Late implantation and the pattern of early rise in hCG have been associated with early pregnancy loss. We explored factors that might be predictive of these markers of poor embryonic health in spontaneously conceived pregnancies. METHODS Participants in the North Carolina Early Pregnancy Study collected daily first-morning urine specimens while attempting to conceive. Samples were assayed for estrogen and progesterone metabolites (to identify day of ovulation) and hCG (to detect conception). Data were available for 190 pregnancies, 48 of which ended in early loss (within 6 weeks of the last menstrual period). We used logistic regression to identify characteristics associated with late implantation (≥10 days post-ovulation). For pregnancies surviving at least 6 weeks (n= 142), we used linear mixed models to identify factors associated with variations in hCG rise in the first 7 days from detection. RESULTS Later implantation was associated with current maternal smoking [odds ratio (OR): 5.7; 95% confidence interval (CI): 1.1-30] and with oocytes that were likely to have been fertilized late in their post-ovulatory lifespan (OR: 5.1; CI: 1.9-16). Older women had a faster rise in hCG (P= 0.01), as did women who had relatively late menarche (P for trend = 0.02). Women exposed in utero to diethylstilbestrol showed an unusual pattern of slow initial hCG rise followed by a fast increase, a pattern significantly different from that of unexposed women (P= 0.002). CONCLUSIONS Although limited by small numbers and infrequent exposures, our analyses suggest that a womans exposures both early in life and at the time of pregnancy may influence early development of the conceptus.

Measuring Menstrual Discomfort : A Comparison of Interview and Diary Data

Background: Menstrual discomfort is common among women of reproductive age and can be debilitating. The accuracy of self-report of menstrual discomfort is unknown. Methods: At enrollment into the DES Reproductive Health Study in 1990, premenopausal women classified their frequency of any menstrual discomfort as “always,” “often,” “sometimes,” and “never.” Subsequently, women provided daily diary information for up to 6 months regarding any menstrual discomfort and medication used for menstrual pain. Results: A total of 324 women contributed data on 4 or more menstrual cycles in the prospective study. At enrollment, 10% had reported never having menstrual discomfort. Of these, 65% recorded at least 1 day of menstrual discomfort during follow-up. For the 27% who had reported always having discomfort, 88% recorded discomfort in all cycles. The enrollment statement of discomfort was more strongly correlated with the percentage of cycles in which women took medication for menstrual pain; respondents who said they never had menstrual discomfort reported use of pain medication in 3% of cycles; sometimes, 36%; often, 67%; and always, 92%. The average number of days per cycle with prospectively recorded menstrual discomfort was also correlated with the enrollment response. Conclusions: A single question regarding frequency of menstrual discomfort was positively correlated with prospectively recorded menstrual discomfort and especially with pain requiring medication.

Measurement of Vitamin D for Epidemiologic and Clinical Research: Shining Light on a Complex Decision

Vitamin D is a fat-soluble vitamin that is synthesized in the skin with exposure to sunlight or is ingested from dietary supplements or food. There has been a dramatic increase in research on vitamin D, linking it with health outcomes as varied as reproductive function, infection, cardiovascular disease, and cancer. The study of vitamin D has generated much excitement, partly because there is an ideal intervention: Low levels may be common and can be remedied with widely available supplements. Determination of vitamin D status is complex and has advanced dramatically in the past 5 years. In this paper, we begin by describing important considerations for measurement of total 25-hydroxyvitamin D (25(OH)D), the biomarker traditionally assessed in epidemiologic studies. While 25(OH)D remains the most commonly measured biomarker, emerging evidence suggests that other related analytes may contribute to the characterization of an individuals vitamin D status (e.g., vitamin D-binding protein, bioavailable and free 25(OH)D, the C-3 epimer of 25(OH)D, 1,25-dihydroxyvitamin D, and 24,25-dihydroxyvitamin D). The measurement of these analytes is also complex, and there are important considerations for deciding whether their measurement is warranted in new research studies. Herein we discuss these issues and provide the reader with an up-to-date synthesis of research on vitamin D measurement options and considerations.

Long-term Recall of Time to Pregnancy

Background: Despite the widespread use of retrospectively reported time to pregnancy to evaluate fertility either as an outcome or as a risk factor for chronic disease, only two small studies have directly compared prospective data with later recall. Methods: The North Carolina Early Pregnancy Study (1982–1986) collected prospective time-to-pregnancy data from the beginning of participants’ pregnancy attempt. In 2010, (24–28 years later) women were sent a questionnaire including lifetime reproductive history that asked about all prior times to pregnancy. Of the 202 women with prospective time-to-pregnancy data, 76% provided recalled time to pregnancy. Results: A lower proportion of women with times to pregnancy ≥3 cycles provided a recalled time to pregnancy than women with times to pregnancy <3 cycles. Also, high gravidity or parity was associated with a lower likelihood of providing a recalled time to pregnancy. Women with very short or very long times to pregnancy (1 cycle or ≥13 cycles) had good recall of time to pregnancy. Positive predictive values of 1 or ≥13 cycles were 73% and 68%, respectively, while positive predictive values for other categories of time to pregnancy ranged from 38% to 58%. The weighted kappa statistic for recalled versus prospective time to pregnancy was 0.72 (95% confidence interval: 0.65, 0.79). Conclusions: Recalled time to pregnancy showed good agreement with prospective time to pregnancy. Informative missingness must be considered when imputing recalled time to pregnancy. Associations observed in future studies can be corrected for misclassification.

Correlates of self-reported physical activity at 3 and 12 months Postpartum

BACKGROUND Postpartum women are encouraged to participate in ≥ 150 min/week of moderate-intensity aerobic activity, but few women achieve this recommendation. This study sought to identify factors associated with participation in physical activity after pregnancy. METHODS We examined correlates of any self-reported moderate-to-vigorous physical activity (MVPA) (≥ 10 min/week across all modes) and any recreational MVPA (≥ 10 min/week) among women enrolled in the Pregnancy, Infection, and Nutrition Postpartum study at 3 months postpartum (n = 667) and at 12 months postpartum (n = 530). Potential correlates were identified according to the socioecological framework. RESULTS At 3 and 12 months postpartum, lower odds of participation in any MVPA were associated with lower education, breastfeeding, and minimal emotional support. Low exercise self-efficacy, receipt of advice about physical activity, and warmer seasons were associated with higher odds of any MVPA. For recreational MVPA, lower odds of participation were associated with unmarried status, lower education, employment, low income, preeclampsia, and minimal emotional support. Involvement in child/adult care activities, transportation MVPA, and warmer seasons were associated with higher odds of recreational MVPA. CONCLUSION These findings suggest that several modifiable intrapersonal and interpersonal factors are associated with postpartum MVPA and should be considered when developing interventions to help women maintain or increase MVPA after pregnancy.

Effects of early pregnancy loss on hormone levels in the subsequent menstrual cycle

Previous studies of hormone patterns after clinical miscarriage suggest reduced pituitary function. Hormonal effects of very early pregnancy loss (before 6 weeks gestation) have not been described. We used within-woman differences between menstrual cycles in urinary hormone measurements from women in the North Carolina Early Pregnancy Study to describe hormonal changes after very early pregnancy loss (n = 28 early losses; 80 non-conception comparison cycles). We found lower pre-ovulatory luteinising hormone and shorter luteal phase length after very early pregnancy loss, but the differences were non-significant (p > 0.3) and smaller than those reported in the spontaneous miscarriage literature. Consistent with the reduced pituitary function reported post-spontaneous miscarriage, we found a slower rate of oestrogen rise (p = 0.08). There was no evidence of lower mid-luteal steroid levels as has been suggested for post-spontaneous miscarriage cycles. Very early pregnancy losses do not appear to influence subsequent menstrual cycles to the same degree as spontaneous miscarriages.

The impact of systematic errors on gestational age estimation

Gestational age is considered the fundamental measure of pregnancy. It is the clock by which we interpret all other markers of pregnancy development. Variability in gestational age at delivery has been documented, with only about 85% of women delivering within 14 days of their ultrasound-derived due date (Økland Ultrasound Obstet Gynecol 2011;37: 207–13). Some portion of this total variability may be arise from natural variability (Jukic et al. Hum Reprod 2013;28:2848–55). Pathologies that trigger the birth of a premature fetus or fail to trigger the birth of a mature fetus, and systematic errors in gestational age assignment, also contribute to apparent variability. Systematic errors occur when maternal characteristics are associated with the consistent underor overestimation of gestational age. The paper by van Oppenraaij et al. in this issue gives examples of systematic differences in the recall of the last menstrual period (LMP). Women living in deprived neighbourhoods were more likely to exhibit digit preference in reporting their LMP, which in turn was associated with a higher frequency of postterm birth. Using this example, a naive study could find an association between deprived neighbourhoods and post-term birth, as a result of the