The limits of small-for-gestational-age as a high-risk category.

SGA (small for gestational age) is widely used to identify high-risk infants, although with inconsistent definitions. Cut points range from 2.5th to 10th percentile of birthweight-for-gestational age. We used receiver operator characteristic curves (ROC) to identify the cut point with maximum sensitivity and specificity (Youden Index), and the area under the curve (AUC), which assesses overall discriminating power. Analysis was conducted on 3,836,034 US births (2015) and 292,279 Norwegian births (2010-14). Birthweight percentiles were calculated using exact birthweights at each week of gestational age, and then summarized across gestational ages. We also conducted a companion analysis of gestational age itself to consider the predictive power of gestational week of birth. Outcomes were neonatal mortality and cerebral palsy, both strongly associated with birthweight. Birthweight percentiles performed poorly in all analyses. The AUC for birthweight percentiles as a discriminator of neonatal mortality was 60% (where 50% is no better than a coin-toss). At such low discrimination, the Youden Index provides no useful SGA cut point. Results in Norway were virtually identical, with an AUC of 58%. The AUC with cerebral palsy as the outcome was even lower, at 54%. In contrast, gestational age had an AUC of 85% as a predictor of neonatal mortality, with < 37 weeks as the optimum cut point. SGA provides surprisingly poor identification of at-risk infants, while gestational age performs well. Similar results in two countries that differ in mean birthweight, percent preterm, and neonatal mortality suggest robustness across populations.

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.

Association of urinary concentrations of early pregnancy phthalate metabolites and bisphenol A with length of gestation.

BACKGROUND: Environmental exposure to phthalates and bisphenol A (BPA) may have endocrine disrupting effects that alter length of gestation. We assessed the association between the urinary concentrations of 11 phthalate metabolites and BPA with length of gestation in a cohort of women followed from before conception with daily 1st-morning urinary hormone measures that identified day of implantation. METHODS: Pre-implantation and post-implantation urinary phthalate metabolites and BPA concentrations were measured in pooled urine samples designed to limit single-measure variability due to the likely episodic nature of these exposures and the short half-life of these compounds. We estimated associations between these exposure biomarkers early in pregnancy with length of gestation from implantation to spontaneous birth. Cox proportional hazards models were used to estimate the hazard of birth among 125 naturally-conceived, singleton live births with censoring for medical interventions that artificially shortened pregnancy. RESULTS: Higher concentrations of mono (2-ethyl-5-hydroxyhexyl) phthalate (a metabolite of di (2-ethylhexyl) phthalate (DEHP)) during the pre-implantation window were associated with reduced probability of birth, i.e., longer gestations (hazard ratio (HR): 0.55, 95% CI: 0.35, 0.86; p = 0.01). The HR for the molar sum of the four DEHP metabolites measured showed a similar association (HR: 0.67, 95% CI: 0.43, 1.05). Higher concentrations of mono (3-carboxypropyl) phthalate (MCPP), a non-specific metabolite of several high molecular-weight phthalates, measured post-implantation were associated with increased risk of earlier birth, i.e. shorter length of gestation, HR: 1.59, CI: 1.02, 2.49. CONCLUSIONS: Early gestational exposure to DEHP and possibly other high-molecular weight phthalates, (as reflected by urinary MCPP concentrations) may influence the length of pregnancy. Such effects could have consequences for neonatal and maternal health.

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 (∑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.

25-Hydroxyvitamin D and Long Menstrual Cycles in a Prospective Cohort Study.

BACKGROUND: Vitamin D insufficiency is associated with subfertility and prolonged estrus cycles in animals, but humans have not been well studied. METHODS: A prospective time-to-pregnancy study, Time to Conceive (2010-2015), collected up to 4 months of daily diary data. Participants were healthy, late reproductive-aged women in North Carolina who were attempting pregnancy. We examined menstrual cycle length as a continuous variable and in categories: long (35+ days) and short (≤25 days). Follicular phase length and luteal phase length were categorized as long (18+ days) or short (≤10 days). We estimated associations between those lengths and serum 25-hydroxyvitamin D (25[OH]D) using linear mixed models and marginal models. RESULTS: There were 1,278 menstrual cycles from 446 women of whom 5% were vitamin D deficient (25[OH]D, <20 ng/ml), 69% were between 20 and 39 ng/ml, and 26% were 40 ng/ml or higher. There was a dose-response association between vitamin D levels and cycle length. Compared with the highest 25(OH)D level (≥40 ng/ml), 25(OH)D deficiency was associated with almost three times the odds of long cycles (adjusted odds ratio [aOR] = 2.8 [95% confidence interval (CI) = 1.0, 7.5]). The aOR was 1.9 (1.1, 3.5) for 20 to <30 ng/ml. The probability of a long follicular phase and the probability of a short luteal phase both increased with decreasing 25(OH)D. CONCLUSIONS: Lower levels of 25(OH)D are associated with longer follicular phase and an overall longer menstrual cycle. Our results are consistent with other evidence supporting vitamin D's role in the reproductive axis, which may have broader implications for reproductive success.

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.

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.

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.

Ultraviolet radiation intensity predicts the relative distribution of dermatomyositis and anti-Mi-2 autoantibodies in women.

OBJECTIVE: Because studies suggest that ultraviolet (UV) radiation modulates the myositis phenotype and Mi-2 autoantigen expression, we conducted a retrospective investigation to determine whether UV radiation may influence the relative prevalence of dermatomyositis and anti-Mi-2 autoantibodies in the US. METHODS: We assessed the relationship between surface UV radiation intensity in the state of residence at the time of onset with the relative prevalence of dermatomyositis and myositis autoantibodies in 380 patients with myositis from referral centers in the US. Myositis autoantibodies were detected by validated immunoprecipitation assays. Surface UV radiation intensity was estimated from UV Index data collected by the US National Weather Service. RESULTS: UV radiation intensity was associated with the relative proportion of patients with dermatomyositis (odds ratio [OR] 2.3, 95% confidence interval [95% CI] 0.9-5.8) and with the proportion of patients expressing anti-Mi-2 autoantibodies (OR 6.0, 95% CI 1.1-34.1). Modeling of these data showed that these associations were confined to women (OR 3.8, 95% CI 1.3-11.0 and OR 17.3, 95% CI 1.8-162.4, respectively) and suggests that sex influences the effects of UV radiation on autoimmune disorders. Significant associations were not observed in men, nor were UV radiation levels related to the presence of antisynthetase or anti-signal recognition particle autoantibodies. CONCLUSION: This first study of the distribution of myositis phenotypes and UV radiation exposure in the US showed that UV radiation may modulate the clinical and immunologic expression of autoimmune disease in women. Further investigation of the mechanisms by which these effects are produced may provide insights into pathogenesis and suggest therapeutic or preventative strategies.

Accuracy of reporting of menstrual cycle length.

There are many studies based on self-reported menstrual cycle length, yet little is known about the validity of this measure. The authors used data collected in 1990 from 352 women born in Chicago, Illinois, aged 37-39 years. Women reported their usual cycle length and behavioral and reproductive characteristics at study enrollment and then completed daily menstrual diaries for up to 6 months. The authors compared this observed cycle length (geometric mean) with the reported length by using kappa coefficients. To assess systematic effects, they performed linear regression of the difference between reported and observed cycle length. Agreement between observed and reported cycle length was moderate. The crude overall kappa coefficient was 0.33; the kappa adjusted for within-woman sampling variability was 0.45 (95% confidence interval: 0.36, 0.55). On average, women overestimated their cycle length by 0.7 days (95% confidence interval: 0.3, 1.0). Reporting by sexually active women and women with a history of infertility was more accurate. Parity, body mass index, prior medical evaluation for irregular cycles, and exercise were all associated with systematic reporting differences. Studies that rely on self-reported cycle length could be prone to artifactual findings because of systematic covariate effects on reporting.

Parent's occupation and isolated orofacial clefts in Norway: a population-based case-control study.

PURPOSE: Occupational factors have been associated with risk of orofacial clefts in offspring, although data are limited. We explored associations between parent's occupation and isolated orofacial clefts using a population-based case-control study. METHODS: Cases were restricted to infants born with an isolated orofacial cleft in Norway during the period 1996 to 2001 (314 with cleft lip with or without palate [CLP] and 118 with cleft palate only [CPO]). Controls (n = 763) were chosen randomly from all Norwegian live births. We considered full-time employment during the first 3 months of pregnancy. RESULTS: Several maternal occupations previously associated with clefts showed some evidence of association, including hairdressers (CLP; adjusted odds ratio = 4.8; 95% confidence interval [CI]: 0.99-23). Mothers working in manufacturing and in food production had increased odds for babies with CPO (3.8; 1.3-11, and 7.1; 1.5-33, respectively). Among fathers' occupations previously associated with clefts, an association was suggested for woodworking both for CLP (1.7; 0.85-3.2) and for CPO (2.0; 0.82-4.7). Fathers working as professional housekeepers showed substantial increased odds of CPO (12; 3.3-46). CONCLUSIONS: Taken together with previous studies, these results suggest that exposures in certain occupations may influence the risk of orofacial clefting in offspring. Specific exposures accompanying these occupations warrant exploration.

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 (> or =400 microg/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.

Intact HCG, free HCG beta subunit and HCG beta core fragment: longitudinal patterns in urine during early pregnancy.

BACKGROUND: Detecting and monitoring early pregnancy depend on the measurement of HCG. Little is known about how production of various forms of HCG may evolve over the earliest weeks of pregnancy, particularly in naturally conceived pregnancies. METHODS: We describe the daily excretion of three urinary HCG analytes during the first 6 weeks post-conception in 37 naturally conceived pregnancies ending in singleton birth. We assayed daily first morning urine samples for intact HCG, free beta subunit and beta?core fragment, plus the combined measurement of these HCG forms. We calculated doubling times for each analyte and the inter- and intra-subject day-to-day variation. RESULTS: Intact HCG and the free beta subunit were initially the predominant forms of HCG, with the beta core fragment emerging as the predominant form in the fifth week after conception. Intact HCG and the free beta subunit showed the most day-to-day variability, and were transiently undetectable even 10 days after detection of pregnancy. The most stable estimate of doubling time was provided by the combined measurement of all these forms. CONCLUSIONS: Although intact HCG is usually regarded as the main analyte for detection and monitoring of early pregnancy, it can fluctuate markedly during early pregnancy. This variability could affect pregnancy test results based on early pregnancy urine, and may distort estimates of doubling time. Assays that combine several forms of HCG may be more reliable.

On the frequency of intercourse around ovulation: evidence for biological influences.

BACKGROUND: Intercourse in mammals is often coordinated with ovulation, for example through fluctuations in libido or by the acceleration of ovulation with intercourse. Such coordination has not been established in humans. We explored this possibility by examining patterns of sexual intercourse in relation to ovulation. METHODS: Sixty-eight sexually active North Carolina women with either an intrauterine device or tubal ligation provided data for up to three menstrual cycles. These women collected daily urine specimens and kept daily diaries of intercourse and menstrual bleeding. Major estrogen and progesterone metabolites excreted in urine were used to identify the day of ovulation. The fertile days of the cycle were defined as the 6 consecutive days ending with ovulation. Women contributed a total of 171 ovulatory cycles. Menstrual bleeding days were excluded from analysis. RESULTS: The frequency of intercourse rose during the follicular phase, peaking at ovulation and declining abruptly thereafter. The 6 consecutive days with most frequent intercourse corresponded with the 6 fertile days of the menstrual cycle. Intercourse was 24% more frequent during the 6 fertile days than during the remaining non-bleeding days (P < 0.001). CONCLUSIONS: There apparently are biological factors that promote intercourse during a woman's 6 fertile days.

Rescue of the corpus luteum in human pregnancy.

Rescue of the corpus luteum from its programmed senescence maintains progesterone production required for pregnancy. In primates, chorionic gonadotropin produced by the developing conceptus acts as the primary luteotrophic signal. The purpose of this research was to assess corpus luteum rescue by examining changes in daily urinary progesterone metabolite levels during the first week after implantation. We determined the variability in progesterone metabolite profiles and evaluated its relationship to early pregnancy loss in 120 naturally conceived human pregnancies, including 43 early pregnancy losses. In other primates, an abrupt increase in the progesterone metabolite occurs at the time of implantation. This pattern occurred in an estimated 45% of the pregnancies in the present study. In the remaining pregnancies, there was a delayed rise (18%), neither a rise or decline (22%), or a decline (15%) during the week after implantation. The estimated rate of early pregnancy loss increased across these categories (from 5% loss with an abrupt rise at implantation to 100% loss with progesterone metabolite decline). Low urinary hCG levels in early pregnancy were significant determinants of a decline in postimplantation progesterone metabolite. However, preimplantation steroid metabolite levels were not significant, suggesting no inherent problem with the corpus luteum. Examination of individual progesterone metabolite profiles in relation to hCG profiles also indicated that few losses were caused by corpus luteum failure. Delineating the functional importance of an abrupt progesterone rise at the time of implantation may provide new strategies for promoting successful implantation in assisted reproduction.