Early Pregnancy Study Research Articles

Preterm Birth in African American Women: A Multi-Omic Pilot Study in Early Pregnancy.

Preterm birth (PTB; <37weeks completed gestation) is a devastating problem affecting over 13 million live births worldwide. In the U.S., African Americans experience significantly higher rates of PTB compared to non-Hispanic Whites. PTB disparities have been linked to social determinants of health (e.g., socioeconomic status, discrimination). However, the biological underpinnings related to these associations are unclear. DNA methylation (DNAm) is subject to environmental influences, and DNAm modifications are known to affect gene expression. Using a multi-omic approach, we examined differences in combined DNA methylation (DNAm) and messenger RNA (mRNA) transcriptomic data from 20 pregnant African American women (12 PTB; 8 term birth) early in pregnancy (8-18weeks gestation). We found that the HLA-DQB2 gene was both differentially methylated (cg12296550; p = .02) and differentially expressed (p = .014; log2FC = 2.5) between women with PTB and term birth. Gene expression analysis showed HLA-DQB2 and HLA-DRB4 (p = .028; log2FC = -3.6) were the two most highly expressed genes. HLA-DQB2 expressed higher in PTB and HLA-DRB4 expressed higher in term birth. However, no genes remained significant (p < .05) after Bonferroni correction. HLA-DRB4 and AKR1C1 were identified as a potential biomarkers in dimensionality reduction models and are also important to immune function and allogenic breakdown. Altered gene expression may lead to inflammatory imbalances or allogenic intolerance resulting in PTB. This study provides proof-of-concept evidence for the feasibility and importance of future multi-omics studies with larger populations to further explore the genes and pathways identified here.

Serial Diurnal Salivary Cortisol Profiles in 667 Pregnant Women-Association With Cardiometabolic Complications.

Maternal obesity, hypertensive pregnancy disorders, and gestational diabetes (GDM) are linked to an increased risk of negative offspring health outcomes. This association may be mediated by maternal hypothalamic-pituitary-adrenal axis (HPA axis) activity, resulting in elevated maternal cortisol levels and fetal exposure, but evidence remains scarce. We (1) examined maternal diurnal cortisol profiles longitudinally across gestation, and (2) explored associations with maternal cardiometabolic complications. Women in the InTraUterine sampling in early pregnancy (ITU) study (n = 667) provided 7 salivary cortisol samples from awakening to bedtime up to 3 times during pregnancy (median gestational week 19.3, 25.7, and 38.1; n = 9356 samples). Changes in cortisol awakening response (CAR) and diurnal slope (indicative of HPA axis activity) and their associations with maternal body mass index (BMI), hypertensive pregnancy disorders and GDM were examined using linear mixed models. The CAR declined in 60% to 67% of women, and the diurnal slope attenuated from early to late pregnancy (b = 0.006; P = .001). Higher BMI was associated with less decline in CAR (b = 0.031; P = .0004) and less attenuation in diurnal slope from early to late pregnancy (b = -0.001; P = .006). Hypertensive pregnancy disorders and GDM were not significantly associated with diurnal cortisol profiles. The attenuation in CAR and diurnal slope support HPA axis hyporesponsivity during pregnancy. Less attenuation of both markers in women with a higher BMI may indicate reduced adaption of the HPA axis to pregnancy, presenting a mechanistic link to offspring health outcomes.

Urinary Paraben Concentrations and Associations with the Periconceptional Urinary Metabolome: Untargeted and Targeted Metabolomics Analyses of Participants from the Early Pregnancy Study.

Parabens, found in everyday items from personal care products to foods, are chemicals with endocrine-disrupting activity, which has been shown to influence reproductive function. This study investigated whether urinary concentrations of methylparaben, propylparaben, or butylparaben were associated with the urinary metabolome during the periconceptional period, a critical window for female reproductive function. Changes to the periconceptional urinary metabolome could provide insights into the mechanisms by which parabens could impact fertility. Urinary paraben concentrations were measured in paired pre- and postconception urine samples from 42 participants in the Early Pregnancy Study, a prospective cohort of 221 women attempting to conceive. We performed untargeted and targeted metabolomics analyses using ultrahigh-performance liquid chromatography quadrupole time-of-flight mass spectrometry. We used principal component analysis, orthogonal partial least-squares discriminant analysis, and permutation testing, coupled with univariate statistical analyses, to find metabolites associated with paraben concentration at the two time points. Potential confounders were identified with a directed acyclic graph and used to adjust results with multivariable linear regression. Metabolites were identified using fragmentation data. Seven metabolites were associated with paraben concentration (variable importance to projection score , false discovery rate-corrected ). We identified four diet-related metabolites to the Metabolomics Standards Initiative (MSI) certainty of identification level 2, including metabolites from smoke flavoring, grapes, and olive oil. One metabolite was identified to the class level only (MSI level 3). Two metabolites were unidentified (MSI level 4). After adjustment, three metabolites remained associated with methylparaben and propylparaben, two of which were diet-related. No metabolomic markers of endocrine disruption were associated with paraben concentrations. This study identified novel relationships between urinary paraben concentrations and diet-related metabolites but not with metabolites on endocrine-disrupting pathways, as hypothesized. It demonstrates the feasibility of integrating untargeted metabolomics data with environmental exposure information and epidemiological adjustment for confounders. The findings underscore a potentially important connection between diet and paraben exposure, with applications to nutritional epidemiology and dietary exposure assessment. https://doi.org/10.1289/EHP12125.

1187-P: Early Pregnancy Hyperglycemia and Glycemic Status at 24–28 Weeks in Indian Women

Introduction: Early pregnancy hyperglycemia threshold (FPG ≥92mg/dl (≥5.1mmol/l)) suggested by International Association of Diabetes and Pregnancy Study Groups (IADPSG) is debateable. There is no evidence of their glycemic status at 24-28 weeks in Indians. Aim: To understand the 24-28 weeks glycemic status in women with early pregnancy hyperglycemia. Methods: STratification of Risk of Diabetes in Early pregnancy (STRiDE) study, designed to identify the role of HbA1c in early pregnancy on incident GDM, recruited 2703 pregnant women from 7 centres in south India and 566 (20.9%) women had early pregnancy hyperglycemia. Of these 477 women underwent 24-28 weeks screening (OGTT n=150, FPG n=327) Results: Abnormal glucose values were present in 32.7% of women at 24-28 weeks (high FPG or GDM by OGTT). These women had higher weight, BMI, waist circumference, family history of diabetes, FPG, and HbA1c at booking compared to women who were normoglycaemic. In multiple regression analysis, early pregnancy FPG ≥95mg/dl (5.3mmol/l) was independently associated with abnormal glucose values at 24-28 weeks (aOR: 1.9; 95% CI: 1.3-3.0, p &amp;lt;0.001), adjusted for key covariates. Conclusion: Majority of women who had early pregnancy hyperglycaemia became normoglycaemic at 24-28 weeks. HAPO study FPG threshold for the adverse outcomes with aOR: 2.0 was ≥95mg/dl. It may be prudent to classify Indian women with this threshold in early pregnancy as abnormal. Disclosure W.Hannah: None. M.Deepa: None. C.Shivashri: None. H.Saite: None. U.Ram: None. R.Anjana: None. Y.Ghebremichael-weldeselassie: None. P.Saravanan: Other Relationship; Novo Nordisk, Research Support; Novo Nordisk, Amgen Inc., Abbott. V.Mohan: None. Funding Medical Research Council, UK (MR/N006232/1)

Urinary phenol concentrations and fecundability and early pregnancy loss.

Are urinary phenol concentrations of methylparaben, propylparaben, butylparaben, triclosan, benzophenone-3, 2,4-dichlorophenol or 2,5-dichlorophenol associated with fecundability and early pregnancy loss? 2,5-dichlorophenol concentrations were associated with an increased odds of early pregnancy loss, and higher concentrations of butylparaben and triclosan were associated with an increase in fecundability. Phenols are chemicals with endocrine-disrupting potential found in everyday products. Despite plausible mechanisms of phenol reproductive toxicity, there are inconsistent results across few epidemiologic studies examining phenol exposure and reproductive function in non-fertility treatment populations. Specimens and data were from the North Carolina Early Pregnancy Study prospective cohort of 221 women attempting to conceive naturally from 1982 to 1986. This analysis includes data from 221 participants across 706 menstrual cycles, with 135 live births, 15 clinical miscarriages and 48 early pregnancy losses (before 42 days after the last menstrual period). Participants collected daily first-morning urine specimens. For each menstrual cycle, aliquots from three daily specimens across the cycle were pooled within individuals and analyzed for phenol concentrations. To assess sample repeatability, we calculated intraclass correlation coefficients (ICCs) for each phenol. We evaluated associations between phenol concentrations from pooled samples and time to pregnancy using discrete-time logistic regression and generalized estimating equations (GEE), and early pregnancy loss using multivariable logistic regression and GEE. ICCs for within-person variability across menstrual cycles in pooled phenol concentrations ranged from 0.42 to 0.75. There was an increased odds of early pregnancy loss with 2,5-dichlorophenol concentrations although the CIs were wide (5th vs 1st quintile odds ratio (OR): 4.79; 95% CI: 1.06, 21.59). There was an increased per-cycle odds of conception at higher concentrations of butylparaben (OR: 1.62; 95% CI: 1.08, 2.44) and triclosan (OR: 1.49; 95% CI: 0.99, 2.26) compared to non-detectable concentrations. No associations were observed between these endpoints and concentrations of other phenols examined. Limitations include the absence of phenol measurements for male partners and a limited sample size, especially for the outcome of early pregnancy loss, which reduced our power to detect associations. This study is the first to use repeated pooled measures to summarize phenol exposure and the first to investigate associations with fecundability and early pregnancy loss. Within-person phenol concentration variability underscores the importance of collecting repeated samples for future studies. Exposure misclassification could contribute to differences between the findings of this study and those of other studies, all of which used one urine sample to assess phenol exposure. This study also contributes to the limited literature probing potential associations between environmental exposures and early pregnancy loss, which is a challenging outcome to study as it typically occurs before a pregnancy is clinically recognized. This research was supported by the National Institute of Environmental Health Sciences of the National Institutes of Health (award number F31ES030594), the Intramural Research Program of the National Institutes of Health, the National Institute of Environmental Health Sciences (project numbers ES103333 and ES103086) and a doctoral fellowship at the Yale School of Public Health. The authors declare they have no competing interests to disclose. N/A.

Abstract P203: Metabolomic Markers Of Gestational Weight Gain In Overweight And Obese Pregnant Women-a Longitudinal Study

Background: Optimal gestational weight gain (GWG) is critical for fetal development and maternal health. Few studies have investigated metabolomic markers of GWG. Thus, we performed a metabolome-wide association study with GWG among pregnant women in the US. Methods: This longitudinal study included overweight or obese pregnant women (pre-pregnancy BMI ≥ 25) enrolled in the Health in Pregnancy and Postpartum study in early pregnancy (mean gestational week (GW) at baseline=12). Fasting plasma samples were collected both at baseline (N=39) and 32 GW (N=29). Untargeted metabolomic profiling was conducted using three different analytical platforms, including GC-TOF MS, HILIC-QTOF MS/MS, and CSH-QTOF MS/MS. Linear regressions were performed to identify metabolites at each time point and the change between two time points (i.e., metabolites 32 wk - metabolites baseline )/metabolites baseline ) that were individually associated with total GWG, a difference between delivery weight and pre-pregnancy weight. The least absolute shrinkage and selection operator (LASSO) regressions were conducted to select metabolites that were jointly associated with total GWG. Results: The mean (SD) age of 39 women enrolled was 30.4 (5.4) years and 38.5% were Blacks. A total of 769 known metabolites were profiled and annotated. Eight metabolites at 32 GW, including PC (34:4), LPC (22:5), isoleucine, arachidonic acid, TAG (52:6), TAG (58:7), and glyceric acid were positively whereas 3-Hydroxybutyrylcarnitine was negatively associated with GWG in both linear regressions (FDR &lt; 0.1) and LASSO regressions (with no-zero coefficients) after adjusting for age, race, parity, and pre-pregnancy BMI (Figure 1). Metabolites at around 12 GW or changes between two time points were not associated with GWG (all FDRs ≥ 0.1). Conclusions: We identified eight metabolites at 32 GW that were significantly associated with total GWG in this longitudinal study of overweight and obese pregnant women. Future studies are warranted to replicate our findings.

Maternal phthalate and phthalate alternative metabolites and urinary biomarkers of estrogens and testosterones across pregnancy

Background/objectivesPregnant women are ubiquitously exposed to phthalates from food packaging materials and personal care products. Phthalates alter estrogen and testosterone concentrations in experimental models, but their ability to impact these hormones in human pregnancy is not well characterized. MethodsWe recruited women ages 18–40 into the Illinois Kids Development Study (I-KIDS) in early pregnancy. Participants provided up to 5 first-morning urine samples across pregnancy (8–40 weeks gestation) that we pooled for quantification of 19 phthalate or phthalate alternative metabolites. Either individual (ng/mL) or molar sums (nmol/mL) of metabolites were used as exposure biomarkers. We summed urinary concentrations (ng/mL) of eight major estrogen (SumEstrogens) and two major testosterone (SumTestosterones) metabolites measured at median 13, 28, and 34 weeks gestation. We also estimated the ratio of estrogens-to-androgens. Linear mixed-effects models assessed relationships of phthalates/alternatives as continuous measures or as concentration quartiles with SumEstrogens, SumTestosterones, and the Estrogen/Androgen ratio in 434 women. In our models, we controlled for age, race, education, parity, smoking in the first trimester, pre-pregnancy body mass index, diet quality, conception season, fetal sex, and gestational age at hormone assessment. We also explored whether gestational age at hormone assessment or fetal sex modified these associations. All biomarkers and outcomes were specific gravity-adjusted, and continuous exposures and outcomes were also natural log-transformed. ResultsMost participants were non-Hispanic white (80.9%), college educated (82.2%), and had urinary phthalate/alternative metabolite concentrations similar to those of reproductive-aged U.S. women. Overall, select phthalate metabolites were positively associated with SumEstrogens and SumTestosterones, but negatively associated with the Estrogen/Androgen ratio. For example, SumEstrogens was 5.1% (95%CI: 1.8, 8.5) higher with every 2-fold increase in sum of di(2-ethylhexyl) phthalate metabolites, while SumTestosterones was 7.9% (95%CI: 1.0, 15.3) higher and Estrogen/Androgen ratio was −7.7% (95%CI: −13.6, −1.4) lower with every 2-fold increase in monoethyl phthalate. However, phthalate alternatives were only positively associated with SumEstrogens, which was 2.4% (95%CI: 0.4, 4.5) and 3.2% (95%CI: 0.7, 5.8) higher with every 2-fold increase in sum of di(isononyl) cyclohexane-1,2-dicarboxylate metabolites and sum of di(2-ethylhexyl) terephthalate metabolites, respectively. Gestational age- and fetal sex-specific associations were only consistently observed for associations of phthalates/alternatives with SumEstrogens, where associations were strongest in mid-to-late pregnancy in women carrying females. ConclusionPhthalates/alternatives may impact gestational hormones, with potential for gestational age- and fetal sex-specific associations. Whether maternal urinary estrogens and testosterones mediate associations of phthalates/alternatives with pregnancy and fetal outcomes merits further investigation.

Maternal Hypertensive Pregnancy Disorders and Mental Disorders in Children.

The associations of maternal hypertensive pregnancy disorders with offspring mental disorders remain unclear. We examined whether maternal hypertensive disorders and maximum blood pressure during pregnancy predict offspring childhood mental disorders, whether the associations are independent of maternal and paternal mental disorders and paternal hypertensive disorders, independent of or additive with maternal early pregnancy overweight/obesity and diabetes mellitus disorders, and mediated or moderated by preterm birth, small-for-gestational-age birth and neonatal intensive care unit admission. Our prospective study comprised 4743 mother-child dyads of Prediction and Prevention of Preeclampsia and Intrauterine Growth Restriction study. Women were recruited to the study in early pregnancy at Finnish maternity hospitals. Children were born 2006 to 2010 and followed-up until December 31, 2016, to ages 6.4 to 10.8 years. Hypertensive pregnancy disorders were identified from medical records, Medical Birth Register, and Care Register for Health Care. Systolic and diastolic blood pressure were measured at antenatal clinics and hospital visits. Mental disorder diagnoses were identified from Care Register for Health Care. Maternal gestational and chronic hypertension, preeclampsia and its severity increased offspring hazard of any childhood mental disorder. The associations of preeclampsia (hazard ratio=1.66 [95% CI, 1.14-2.42]) and severe preeclampsia (hazard ratio=2.01 [95% CI, 1.08-3.73]) were independent of all covariates. Maternal hypertensive and diabetes mellitus disorders and overweight/obesity also additively increased offspring hazard of mental disorders. Preterm and small-for-gestational-age births and neonatal intensive care unit admission partially mediated the effects of any and severe preeclampsia on offspring mental disorders. To conclude, maternal hypertensive pregnancy disorders carry adverse consequences for offspring mental health.

Association between iron deficiency and prevalence of thyroid autoimmunity in pregnant and non-pregnant women of childbearing age: a cross-sectional study.

Background:Thyroid autoimmunity (TAI) is prevalent among women of reproductive age and associated with adverse pregnancy outcomes. This study aimed to investigate the association between iron nutritional status and the prevalence of TAI in women during the first trimester of pregnancy and in non-pregnant women of childbearing age.Methods:Cross-sectional analysis of 7463 pregnant women during the first trimester of pregnancy and 2185 non-pregnant women of childbearing age nested within the sub-clinical hypothyroid in early pregnancy study, a prospective collection of pregnant and non-pregnant women's data, was conducted in Liaoning province of China between 2012 and 2015. Serum thyrotropin, free thyroxine, thyroid peroxidase antibodies (TPOAbs), thyroglobulin antibodies (TgAbs), serum ferritin, and urinary iodine were measured. Iron deficiency (ID) was defined as serum ferritin <15 μg/L and iron overload (IO) was defined as ferritin >150 μg/L. TPOAb-positive was defined as >34 U/mL and TgAb-positive was defined as >115 U/mL. Multilevel logistic regression was conducted to examine the association between TAI and different iron nutritional status after adjusting for potential confounders.Results:The prevalence of isolated TPOAb-positive was markedly higher in women with ID than those without ID, in both pregnant and non-pregnant women (6.28% vs. 3.23%, χ2 = 10.264, P = 0.002; 6.25% vs. 3.70%, χ2 = 3,791, P = 0.044; respectively). After adjusting for confounders and the cluster effect of hospitals, ID remained associated with TPOAb-positive in pregnant and non-pregnant women (odds ratio [OR]: 2.111, 95% confidence interval [CI]: 1.241–3.591, P = 0.006; and OR: 1.822, 95% CI: 1.011–3.282, P = 0.046, respectively).Conclusion:ID was associated with a higher prevalence of isolated TPOAbs-positive, but not with isolated TgAb-positive, in both pregnant women during the first trimester of pregnancy and non-pregnant women of childbearing age, while IO was not associated with either isolated TPOAb-positive or isolated TgAb-positive.Clinical trial registration:ChiCTR-TRC-13003805, http://www.chictr.org.cn/index.aspx.

Diabetes and Pregnancy

Diabetes and Pregnancy

Effects of an antenatal dietary intervention in overweight and obese women on 6 month infant outcomes: follow-up from the LIMIT randomised trial

BackgroundThe immediate impact of providing an antenatal dietary intervention during pregnancy has been extensively studied, but little is known of the effects beyond the neonatal period. Our objective was to evaluate the effect of an antenatal dietary intervention in overweight or obese women on infant outcomes 6 months after birth.MethodsWe conducted a follow up study of infants born to women who participated in the LIMIT trial during pregnancy. Live-born infants at 6-months of age, and whose mother provided consent to ongoing follow-up were eligible. The primary follow-up study endpoint was the incidence of infant BMI z-score ≥90th centile for infant sex and age. Secondary study outcomes included a range of infant anthropometric measures, neurodevelopment, general health, and infant feeding. Analyses used intention to treat principles according to the treatment group allocated in pregnancy. Missing data were imputed and analyses adjusted for maternal early pregnancy BMI, parity, study centre, socioeconomic status, age, and smoking status. Outcome assessors were blinded to the allocated treatment group.ResultsA total of 1754 infants were assessed at age 6 months (Lifestyle Advice n = 869; Standard Care n = 885), representing 82.1% of the eligible sample (n = 2136). There were no statistically significant differences in the incidence of infant BMI z-score ≥90th centile for infants born to women in the Lifestyle Advice group, compared with the Standard Care group (Lifestyle Advice 233 (21.71%) vs. Standard Care 233 (21.90%); adjusted relative risk (aRR) 0.99; 95% confidence interval 0.82 to 1.18; p = 0.88). There were no other effects on infant growth, adiposity, or neurodevelopment.ConclusionProviding pregnant women who were overweight or obese with an antenatal dietary and lifestyle intervention did not alter 6-month infant growth and adiposity. Trial Registration: Australian and New Zealand Clinical Trials Registry (ACTRN12607000161426).

Long-term Recall of Pregnancy-related Events.

Early-life factors can be associated with future health outcomes and are often measured by maternal recall. 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. 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. 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.

Association of serum n-3 polyunsaturated fatty acids with psychological distress in the second and third trimesters of pregnancy: Adjunct Study of Japan Environment and Children's Study

The results of several epidemiological studies and clinical trials investigating the effects of n-3 polyunsaturated fatty acids (PUFAs) on antenatal and postnatal depression remain controversial. In a previous case-control study of early pregnancy in Japan, we found an inverse association between eicosapentaenoic acid and risk of psychological distress after adjusting for possible confounders. Here, in a 1:2 matched case-control study, we further investigated the possible relationship between serum n-3 PUFAs and risk of psychological distress in the second and third trimesters of pregnancy. The psychological distress group (n=71) consisted of subjects with a score of ≥13 on the Kessler Psychological Distress Scale. The control group (n=142) was matched for age, educational level, and family income. Fatty acid composition of total lipid was determined from serum samples by gas chromatography. Associations between fatty acid levels and incidence of psychological distress were evaluated by logistic regression. Sixty-six percent of blood samples were collected in the second trimester and the remainder in the third. There were no significant differences in any of the n-3 PUFAs between the two groups. After adjustment for possible confounders, none of the n-3 PUFAs showed an association with risk of psychological distress. Peripheral n-3 PUFA levels might not influence the risk of psychological distress in later pregnancy. Further research is warranted to clarify this finding.

Voices: A Conversation with Allen J. Wilcox.

Allen James Wilcox was born on 30 September 1946 in Columbus, OH. He studied medicine at the University of Michigan, graduated in 1973, and after a rotating internship, he completed a master's degree in maternal and child health (1976) and a PhD in epidemiology (1979) at the University of North Carolina in Chapel Hill. After graduation, he went to work at the National Institute of Environmental Health Sciences (NIEHS, one of the US National Institutes of Health) in Durham, NC, where he has spent his career. He developed a research program in reproductive and perinatal epidemiology, a relatively unexplored area at the time. His studies include the early pregnancy study, which documented the extent of subclinical pregnancy loss in humans and established the fertile days of a woman's menstrual cycle. He served as the Chief of the Epidemiology Branch from 1991 to 2001, and as Editor-in-Chief of the journal EPIDEMIOLOGY from 2001 to 2014. His textbook, Fertility and Pregnancy-An Epidemiologic Perspective, was published by Oxford University Press in 2010. He was elected to the American Epidemiological Society in 1989, and served as its president in 2003. He also served as president of the Society of Pediatric and Perinatal Epidemiological Research (1996) and the president of the Society of Epidemiological Research (1998). He holds adjunct teaching appointments at the University of North Carolina, Harvard University, and the University of Bergen (Norway), which awarded him an honorary doctoral degree in 2008.

Long-term Recall of Time to Pregnancy.

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. 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. 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). 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.

Personalised estimation of a woman’s most fertile days

Objectives: We propose a new, personalised approach of estimating a woman’s most fertile days that only requires recording the first day of menses and can use a smartphone to convey this information to the user so that she can plan or prevent pregnancy.Methods: We performed a retrospective analysis of two cohort studies (a North Carolina-based study and the Early Pregnancy Study [EPS]) and a prospective multicentre trial (World Health Organization [WHO] study). The North Carolina study consisted of 68 sexually active women with either an intrauterine device or tubal ligation. The EPS comprised 221 women who planned to become pregnant and had no known fertility problems. The WHO study consisted of 706 women from five geographically and culturally diverse settings. Bayesian statistical methods were used to design our proposed method, Dynamic Optimal Timing (DOT). Simulation studies were used to estimate the cumulative pregnancy risk.Results: For the proposed method, simulation analyses indicated a 4.4% cumulative probability of pregnancy over 13 cycles with correct use. After a calibration window, this method flagged between 11 and 13 days when unprotected intercourse should be avoided per cycle. Eligible women should have cycle lengths between 20 and 40 days with a variability range less than or equal to 9 days.Conclusions: DOT can easily be implemented by computer or smartphone applications, allowing for women to make more informed decisions about their fertility. This approach is already incorporated into a patent-pending system and is available for free download on iPhones and Androids.

Characterization of Pesticide Exposure in a Sample of Pregnant Women in Ecuador.

Few studies have detailed the prenatal pesticide exposure levels of women employed in or residing near large-scale agricultural industries. This study reports pesticide metabolite levels during and shortly after pregnancy in a pilot study of workers in Ecuador. Urine samples were collected for 16 rose workers and 10 nonagricultural workers enrolled into the study in early pregnancy. We measured six nonspecific organophosphatedialkylphosphate (DAP) pesticide metabolites, two alkylenebis-dithiocarbamate pesticide metabolites [ethylene thiourea (ETU) and propylene thiourea (PTU)], 3,5,6-trichloro-2-pyridinol (TCPy), malathion dicarboxylic acid, and two pyrethroid metabolites (2,2-dimethylcyclo propanecarboxylic acid and 3-phenooxybenzoic acid). We collected 141 urine samples (mean: 5.4 per woman). We observed high detection frequencies for five DAP metabolites and ETU, PTU, and TCPy. We report elevated levels of ETU in the entire sample (median 4.24ng/mL, IQR 2.23, 7.18), suggesting other possible non-occupational pathways of exposure. We found no statistical differences in pesticide levels by current employment status, although the highest pesticide levels were among rose workers. We observed within-woman correlation in TCPy and PTU levels, but not in ETU or DAP levels. The present study is the first to characterize prenatal pesticide exposure levels among working women in Ecuador. Limitations include a small sample size and use of a convenience sample. Strengths include a longitudinal design and multiple urine samples per woman. Results provide an initial characterization of prenatal pesticide exposure levels and how these levels vary over pregnancy in a community impacted by agricultural industry and will inform further studies in the region.

New understanding of TSH reference range during the first trimester of pregnancy

Guidelines of the American Thyroid Association (ATA) proposed two diagnostic criteria for subclinical hypothyroidism during the first trimester of pregnancy:criterion 1 was based on the pregnancy-specific TSH reference range and criterion 2 on serum TSH＞2.5 mIU/L level with normal serum FT4.According to the results of the Subclinical hypothyroidism during early pregnancy study,author proposed that criterion 2 is not appropriate for Chinese pregnant women because the TSH concentration has become significantly higher in whole Chinese population.By using criterion 2,the prevalence may be as high as 27.8％,which may result in over-diagnosis and over treatment. Key words: Subclinical hypothyroidism; Pregnancy; Thyrotropin

Functional clustering in nested designs: Modeling variability in reproductive epidemiology studies

We discuss functional clustering procedures for nested designs, where multiple curves are collected for each subject in the study. We start by considering the application of standard functional clustering tools to this problem, which leads to groupings based on the average profile for each subject. After discussing some of the shortcomings of this approach, we present a mixture model based on a generalization of the nested Dirichlet process that clusters subjects based on the distribution of their curves. By using mixtures of generalized Dirichlet processes, the model induces a much more flexible prior on the partition structure than other popular model-based clustering methods, allowing for different rates of introduction of new clusters as the number of observations increases. The methods are illustrated using hormone profiles from multiple menstrual cycles collected for women in the Early Pregnancy Study.

Adjusting to motherhood. The importance of BMI in predicting maternal well-being, eating behaviour and feeding practice within a cross cultural setting

Maternal body mass index (BMI) is associated with negative body image and restrained eating which are experienced differently across cultures. The present study aimed to: 1) examine if self-esteem, eating behaviours and body satisfaction changed from early pregnancy to 2–6 months after giving birth; 2) explore changes according to country (Israel vs. UK) and BMI; and 3) determine any relationship between these measurements and infant feeding. Participants completed questionnaires assessing self-esteem, body image and eating/feeding behaviours. Multilevel linear modelling was used to account for change and to assess the independent impact of BMI on outcomes. Seventy-three women and infants participated in the study in early pregnancy and again 16 (9) weeks following birth. Women gained 1.5 kg (range −12 + 23) and UK mothers reported significantly greater body dissatisfaction, but self-esteem and eating behaviours remained stable. BMI was the main predictor of self-esteem, eating behaviours and body satisfaction. Mothers’ perceptions of infant's eating did not vary according to BMI or country; however, heavier mothers reported feeding their infants according to a schedule. The first months after giving birth are a key time to assess adjustment to motherhood but later assessments are necessary in order to track changes beyond the early period post-pregnancy.