D. Robert McConnaughey

Folic acid supplements and risk of facial clefts: national population based case-control study

Objective To explore the role of folic acid supplements, dietary folates, and multivitamins in the prevention of facial clefts. Design National population based case-control study. Setting Infants born 1996-2001 in Norway. Participants 377 infants with cleft lip with or without cleft palate; 196 infants with cleft palate alone; 763 controls. Main outcome measures Association of facial clefts with maternal intake of folic acid supplements, multivitamins, and folates in diet. Results Folic acid supplementation during early pregnancy (≥400 �g/day) was associated with a reduced risk of isolated cleft lip with or without cleft palate after adjustment for multivitamins, smoking, and other potential confounding factors (adjusted odds ratio 0.61, 95% confidence interval 0.39 to 0.96). Independent of supplements, diets rich in fruits, vegetables, and other high folate containing foods reduced the risk somewhat (adjusted odds ratio 0.75, 0.50 to 1.11). The lowest risk of cleft lip was among women with folate rich diets who also took folic acid supplements and multivitamins (0.36, 0.17 to 0.77). Folic acid provided no protection against cleft palate alone (1.07, 0.56 to 2.03). Conclusions Folic acid supplements during early pregnancy seem to reduce the risk of isolated cleft lip (with or without cleft palate) by about a third. Other vitamins and dietary factors may provide additional benefit.

Preimplantation urinary hormone profiles and the probability of conception in healthy women

OBJECTIVE To examine hormonal predictors of conception in menstrual cycles from normal women. DESIGN Longitudinal study. SETTING Community. PATIENT(S) Two hundred fifteen healthy female volunteers with no known fertility problems who were trying to conceive. INTERVENTION(S) Participants recorded menstrual bleeding, sexual intercourse, and collected first morning urine specimens daily from when they stopped contraception until they became pregnant or for 6 months if no clinical pregnancy was achieved. Measurements were made of urinary LH and urinary metabolites of estrogen and progesterone. MAIN OUTCOME MEASURE(S) Conception was identified by a sensitive and specific immunoradiometric assay for urinary hCG. RESULT(S) Statistical analyses of 189 conception and 409 nonconception cycles controlled for sexual intercourse and interdependence of cycles from the same woman. Conception was more likely in cycles with lower baseline progesterone metabolite levels, higher ovulatory LH, and higher midluteal progesterone. Midluteal estrogen also was elevated in conception cycles when examined without adjusting for other hormone levels, but this finding did not persist after multivariate adjustment. CONCLUSIONS Menstrual cycles in normal women vary in their hormonal quality in ways that are predictive of cycle fertility.

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

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.

Association of urinary concentrations of phthalate metabolites and bisphenol A with early pregnancy endpoints

Background: Phthalates and bisphenol A (BPA) are environmental contaminants that may affect early embryonic development. Objective: To assess the association between phthalate metabolites and BPA with early pregnancy endpoints in a cohort of women followed from before conception. Methods: We quantified 11 phthalate metabolites and BPA in 137 conception cycles from naturally conceived clinical pregnancies. Phthalate metabolites and BPA concentrations were measured in a pooled sample of three daily morning urine specimens. Daily urinary hormone measurements had previously been used to define ovulation, implantation, and corpus luteum rescue. We assessed associations between conception cycle exposures (phthalate biomarkers and BPA) and 1) time from ovulation to implantation; 2) type of corpus luteum rescue (timing and pattern of rise in progesterone: early, late, or no rise); and 3) rate of initial rise in hCG. Results: Mono(3‐carboxypropyl) phthalate (MCPP) and mono‐isobutyl phthalate (MiBP) were associated with earlier implantation (6–8 days vs. 9 days (the most commonly observed); per natural log‐unit, OR (95% CI) = 2.8 (1.2, 6.7) and OR (CI) = 2.1 (1.2, 3.7), respectively). Monoethyl phthalate (MEP) was associated with later implantation (10–12 days vs. 9 days); OR (CI) = 1.5 (1.0, 2.1). Compared with implantation on day 9, BPA was significantly associated with both earlier and later implantation (OR=2.2 for both). Women with concentrations above the median of monobenzyl phthalate (MBzP) (p = 0.04) or above the median of the molar sum of four di(2‐ethylhexyl) phthalate metabolites (&Sgr;DEHP) (p = 0.08) had a slower initial rise in hCG. Increasing MCPP was associated with an increased odds of a late rise rescue (OR (CI) = 2.9 (1.0, 8.5); late rise vs. early rise), while increasing MEP was associated with a no rise rescue (OR (CI) = 1.6 (0.9, 2.8); no rise vs. early rise). Conclusions: The reported associations varied in their direction of effect, some potentially protective, others adverse. This may reflect the complexity with which these potential endocrine disrupting chemicals can be acting, but chance findings are also possible. Given that women continue to be exposed to these compounds (or their precursors), continued research on the effects they may have on pregnancy is warranted.

Long-term Recall of Pregnancy-related Events

Background: Early-life factors can be associated with future health outcomes and are often measured by maternal recall. Methods: We used data from the North Carolina Early Pregnancy Study and Follow-up to characterize long-term maternal recall. We used data from the Early Pregnancy Study as the gold standard to evaluate the accuracy of prepregnancy weight, early pregnancy behaviors, symptoms and duration of pregnancy, and child’s birthweight reported at follow-up, for 109 women whose study pregnancies had resulted in a live birth. Results: Most (81%) participants reported a prepregnancy weight at follow-up that correctly classified them by BMI category. Women reported experiencing pregnancy symptoms later at follow-up than what they reported in the Early Pregnancy Study. Accuracy of reporting of early pregnancy behaviors varied based on exposure. Overall, women who had abstained from a behavior were more likely to be classified correctly. Sensitivity of reporting was 0.14 for antibiotics, 0.30 for wine, 0.71 for brewed coffee, and 0.82 for vitamins. Most misclassification at follow-up was due to false-negative reporting. Among women who gave birth to singletons, 94% could report their child’s correct birthweight within ½ pound and 86% could report duration of pregnancy within 7 days at follow-up. Conclusions: Self-report of prepregnancy weight, duration of pregnancy, and child’s birthweight after almost 30 years was good, whereas self-reported pregnancy-related exposures resulted in higher levels of reporting error. Social desirability appeared to influence women’s report of their behaviors at follow-up. Self-reported assessment of confidence in the recalled information was unrelated to accuracy.