Adiposity and Endometriosis Severity and Typology.

STUDY OBJECTIVE: Prior research has collectively shown that endometriosis is inversely related to women's adiposity. The aim of this study was to assess whether this inverse relationship holds true by disease severity and typology. DESIGN: Cross-sectional study among women with no prior diagnosis of endometriosis. SETTING: Fourteen clinical centers in Salt Lake City, UT, and San Francisco, CA. PATIENTS: A total of 495 women (of which 473 were analyzed), aged 18-44 years, were enrolled in the operative cohort of the Endometriosis, Natural History, Diagnosis, and Outcomes (ENDO) Study. INTERVENTIONS: Gynecologic laparoscopy/laparotomy regardless of clinical indication. MEASUREMENTS AND MAIN RESULTS: Participants underwent anthropometric assessments, body composition measurements, and evaluations of body fat distribution ratios before surgery. Surgeons completed a standardized operative report immediately after surgery to capture revised American Society for Reproductive Medicine staging (I-IV) and typology of disease (superficial endometriosis [SE], ovarian endometrioma [OE], and deep infiltrating endometriosis [DIE]). Linear mixed models, taking into account within-clinical-center correlation, were used to generate least square means (95% confidence intervals) to assess differences in adiposity measures by endometriosis stage (no endometriosis, I-IV) and typology (no endometriosis, SE, DIE, OE, OE + DIE) adjusting for age, race/ethnicity, and parity. Although most confidence intervals were wide and overlapping, 3 general impressions emerged: (1) women with incident endometriosis had the lowest anthropometric/body composition indicators compared with those without incident endometriosis, (2) women with stage I or IV endometriosis had lower indicators compared with women with stage II or III, and (3) women with OE and/or DIE tended to have the lowest indicators, whereas women with SE had the highest indicators. CONCLUSION: Our research highlights that the relationship between women's adiposity and endometriosis severity and typology may be more complicated than prior research indicates.

Characterization of Thermal and Mechanical Indices from Serial Ultrasound Exams and Associations with Neonatal Anthropometry: The NICHD Fetal Growth Studies.

OBJECTIVE: This article aims to determine if the number of maternal ultrasound scans where the highest thermal (TI) or mechanical (MI) indices recorded during obstetrical ultrasound exceed 1.0 were associated with neonatal anthropometric measurements. STUDY DESIGN: A prospective cohort of 2,334 nonobese low-risk pregnant women from 12 U.S. clinical sites underwent a total of six ultrasound scans, for which the highest TI and MI values were recorded. Neonatal anthropometric measurements were obtained within 12 to 24 hours of delivery. Multiple linear regression models adjusted for maternal race/ethnicity, body mass index, weight gain, and gestational age were used to examine associations between the number of maternal ultrasounds during gestation with a TI or MI exceeding 1.0 and the mean change in neonatal anthropometry. RESULTS: Ultrasounds with TI or MI >1.0 were not associated with birth weight, neonatal length, nor head, chest, and abdominal circumferences. TI >1.0 was negatively associated with neonatal mid-upper arm and mid-upper thigh circumferences. MI >1.0 was negatively associated with neonatal skinfold measurements of the anterior thigh and triceps, and neonatal circumferences of the mid-upper thigh and umbilicus. CONCLUSION: Prenatal ultrasound examinations in which TI or MI intermittently exceeded 1.0 did not identify a pattern of alterations of birth size.

Parental urinary biomarkers of preconception exposure to bisphenol A and phthalates in relation to birth outcomes.

BACKGROUND: Bisphenol A (BPA) and phthalates are ubiquitous non-persistent endocrine disrupting chemicals whose relation with infant birth size is not clearly understood. METHODS: We examined associations between maternal and paternal preconception urinary concentrations of total BPA and 14 phthalate metabolites and birth size for 233 infants. Multiple linear regression models were used to estimate parental quartiles of BPA and phthalates in relation to birth weight, length, head circumference, and ponderal index with separate models run for each parent adjusting for age, smoking, body mass index, education, alcohol, parity, and creatinine. Models also included an interaction term for each chemical and infant sex and were further adjusted to include the other partner's chemical concentrations. RESULTS: In maternal models adjusted for partner's exposure and covariates, reductions in birth weight (range: 178-215 g; p < 0.05) were observed for the 2nd quartile of maternal monomethyl phthalate, mono-[(2-carboxymethyl) hexyl] phthalate and mono-n-octyl phthalate when compared with the 1st quartiles. The 3rd quartile of monoethylhexyl phthalate (mEHP) was also associated with a 200.16 g (95 % CI: -386.90, -13.42) reduction. Similar reductions in birth weight were observed for the 2(nd) quartile of paternal mEHP (ß = -191.93 g; 95 % CI: -381.61, -2.25). Additionally, select maternal urinary metabolites were associated with decreased head circumference, birth length and gestational age. However, paternal concentrations were generally associated with increased birth length and gestational age. CONCLUSIONS: We observed some suggestion that preconception maternal and paternal urinary concentration of BPA and specific phthalate metabolites may be associated with smaller birth size and increased gestational age, though the findings appeared to be parent and chemical specific.

Higher urinary lignan concentrations in women but not men are positively associated with shorter time to pregnancy.

Phytoestrogens have been associated with subtle hormonal changes, although effects on fecundity are unknown. Our objective was to evaluate the association between male and female urinary phytoestrogen (isoflavone and lignan) concentrations and time to pregnancy (TTP) in a population-based cohort of 501 couples desiring pregnancy and discontinuing contraception. Couples were followed for 12 mo or until pregnancy. Fecundability ORs (FORs) and 95% CIs were estimated after adjusting for age, body mass index, race, site, creatinine, supplement use, and physical activity in relation to female, male, and joint couple concentrations. Models included the phytoestrogen of interest and the sum of the remaining individual phytoestrogens. FORs <1 denote a longer TTP and FORs >1 a shorter TTP. Urinary lignan concentrations were higher, on average, among female partners of couples who became pregnant during the study compared with women who did not become pregnant (median enterodiol: 118 vs. 80 nmol/L; P < 0.10; median enterolactone: 990 vs. 412 nmol/L; P < 0.05) and were associated with significantly shorter TTP in models based on both individual and couples' concentrations (couples' models: enterodiol FOR, 1.13; 95% CI: 1.02, 1.26; enterolactone FOR, 1.11; 95% CI: 1.01, 1.21). Male lignan concentrations were not associated with TTP, nor were isoflavone concentrations. Sensitivity analyses showed that associations observed are unlikely to be explained by potential unmeasured confounding by lifestyle or other nutrients. Our results suggest that female urinary lignan concentrations at levels characteristic of the U.S. population are associated with a shorter TTP among couples who are attempting to conceive, highlighting the importance of dietary influences on fecundity.

Analysis of polychlorinated biphenyls and organochlorine pesticides in archived dried blood spots and its application to track temporal trends of environmental chemicals in newborns.

Dried blood spots (DBS) collected from infants shortly after birth for the newborn screening program (NSP) in the United States are valuable resources for the assessment of exposure to environmental chemicals in newborns. The NSP was debuted as a public health program in the United States in the 1960s; and the DBS samples collected over a period of time can be used in tracking temporal trends in exposure to environmental chemicals by newborns. In this study, polychlorinated biphenyls (PCBs) and organochlorine pesticides (OCPs) were measured in DBS samples collected from newborns in Upstate New York from 1997 to 2011 by gas chromatography-high resolution mass spectrometry (GC-HRMS). Twelve PCBs and two OCPs were found in DBS samples at a detection rate above 50% (n=51). The mean whole blood concentration of ΣPCBs (sum of 12 congeners) over the 15-year period was 1.06 ng/mL, followed by p,p'-DDE (0.421 ng/mL) and HCB (0.065 ng/mL). The measured concentrations of PCBs and p,p'-DDE in infants'blood were comparable to those reported in cord blood, suggesting maternal/trans-placental transfer of these compounds from mothers to fetuses. The concentrations of ΣPCBs and p,p'-DDE in blood samples of infants decreased significantly between 1997 and 2001, and no significant reduction was found thereafter. This observation is consistent with the trends reported for these chemicals in other human tissues in the United States.

Trace element analysis of human urine collected after administration of Gd-based MRI contrast agents: characterizing spectral interferences using inorganic mass spectrometry.

Analysis of human urine is commonly used in biomonitoring studies to assess exposure to essential (e.g., Cu, Zn, Se) and non-essential (Pb, Cd, Pt) trace elements. These data are also used in epidemiological studies to evaluate potential associations between trace element exposure and various health outcomes within a population. Today most trace element analyses are typically performed using quadrupole-based inductively coupled plasma mass spectrometry (Q-ICP-MS). However, there is always the potential for spectral interferences with Q-ICP-MS instrumentation, especially when analyzing human specimens that may contain medications and other exogenous substances. Moreover, such xenobiotics may be unknown to the investigators. In a recent study focusing on environmental exposures and endometriosis: Endometriosis: Natural History, Diagnosis, and Outcomes (ENDO Study), urine specimens (n=619) were collected from participating women upon enrollment into the study or prior to surgery or pelvic magnetic resonance imaging (MRI), and analyzed for 21 trace elements by Q-ICP-MS. Here we report on some anomalous results observed for Se and Pt with elevated concentrations up to several orders of magnitude greater than what might be expected based on established reference intervals. Further investigations using Sector Field (SF-) ICP-MS instrumentation led to identification of doubly charged and polyatomic gadolinium (Gd) species traced to a Gd-based contrast agent that was administered to some subjects just prior to urine collection. Specifically, interferences from Gd2+ and several minor polyatomics were identified as interferences on all of the major isotopes of Se including 74Se, 76Se, 77Se, 78Se, 80Se, and 82Se. While trace amounts of Pt were present in the urine, a number of Gd-containing polyatomic species were also evident as major interferences on all isotopes of Pt (190Pt, 192Pt, 194Pt, 195Pt, 196Pt, and 198Pt), including Gd-chlorides, Gd-argides, and Gd-oxides. These observations underscore the importance of considering potential isobaric interferences when interpreting unusual trace element results for clinical specimens.

Perfluorochemicals and endometriosis: the ENDO study.

BACKGROUND: Environmental chemicals may be associated with endometriosis. No published research has focused on the possible role of perfluorochemicals (PFCs) despite their widespread presence in human tissues. METHODS: We formulated two samples. The first was an operative sample comprising 495 women aged 18-44 years scheduled for laparoscopy/laparotomy at one of 14 participating clinical sites in the Salt Lake City or San Francisco area, 2007-2009. The second was a population-based sample comprising 131 women matched to the operative sample on age and residence within a 50-mile radius of participating clinics. Interviews and anthropometric assessments were conducted at enrollment, along with blood collection for the analysis of nine PFCs, which were quantified using liquid chromatography-tandem mass spectrometry. Endometriosis was defined based on surgical visualization (in the operative sample) or magnetic resonance imaging (in the population sample). Using logistic regression, we estimated odds ratios (ORs) and 95% confidence intervals (CIs) for each PFC (log-transformed), adjusting for age and body mass index, and then parity. RESULTS: Serum perfluorooctanoic acid (PFOA; OR = 1.89 [95% CI = 1.17-3.06]) and perfluorononanoic acid (2.20 [1.02-4.75]) were associated with endometriosis in the operative sample; findings were moderately attenuated with parity adjustment (1.62 [0.99-2.66] and 1.99 [0.91-4.33], respectively). Perfluorooctane sulfonic acid (1.86 [1.05-3.30]) and PFOA (2.58 [1.18-5.64]) increased the odds for moderate/severe endometriosis, although the odds were similarly attenuated with parity adjustment (OR = 1.50 and 1.86, respectively). CONCLUSIONS: Select PFCs were associated with an endometriosis diagnosis. These associations await corroboration.

Does Older Age Modify Associations between Endocrine Disrupting Chemicals and Fecundability?

Urinary concentrations of several endocrine disrupting chemicals, including phthalate metabolites, bisphenol A (BPA), and benzophenone (BP)-type ultraviolet (UV) filters, have been associated with a longer time-to-pregnancy (TTP). Potential modification of these associations by couple's age has not been studied. TTP was defined as the number of prospectively observed menstrual cycles a couple attempted pregnancy until the occurrence of a human chorionic gonadotropic-detected pregnancy. Urinary concentrations of two BP-type UV filters and three phthalate metabolites were measured at baseline. Fecundability odds ratios (FORs) and 95% confidence intervals (CIs) were estimated for each chemical adjusting for age, body mass index, serum cotinine, creatinine, and accounting for right censoring and left truncation. Models evaluated effect modification between EDC concentrations and TTP by partner's age, dichotomized at 35 years. Separate models were run for male and female partners. No significant effect modification was observed for any EDC for either partner, but data were suggestive of a longer TTP among females aged ≥35 years, particularly for BP-2 (FOR = 0.61, 95% CI 0.36, 1.05) and 4-hydroxybenzophenone (FOR = 0.71, 95% CI: 0.46, 1.09) reflecting 39% and 29% reductions in fecundability, respectively. We saw no evidence of effect modification by couples' age on associations between TTP and urinary phthalate or BPA metabolite concentrations. Across the EDCs we examined, we found little evidence that age modifies TTP-exposure associations.

The birth certificate as an efficient means of identifying children conceived with the help of infertility treatment.

Recent work suggests that infertility treatment is associated with adverse child health outcomes. In exploring various methods of assembling a cohort of children conceived by infertility treatment, the authors conducted a validation study of the assisted reproductive technology and infertility drug use check boxes on the Massachusetts birth certificate. Using 2001 and 2002 data, the authors conducted telephone interviews with 399 women whose child's birth certificate had at least one of the boxes checked along with 185 women who were over age 42 years or who delivered twins or higher order multiples to compare the check box information with maternal report. Among the 579 women with available information, the birth certificate was fully concordant with respect to infertility treatment status for 271 (47%) women, partially concordant for 248 (43%) women, and discordant for 60 (10%) women. Agreement between the birth certificate and maternal report was good for singletons (weighted kappa = 0.66) but was found to be very poor among twins and higher order multiples (weighted kappa = 0.05). The authors concluded that birth certificates are an efficient means of locating children conceived with the help of infertility treatment but that they are not appropriate for identifying type of treatment.

Validity of retrospectively reported behaviors during the periconception window.

OBJECTIVE: To assess the validity of retrospectively reported maternal behaviors while attempting pregnancy. STUDY DESIGN: Participants in a prospective pregnancy cohort study with periconception enrollment were queried about use of cigarettes, alcohol, vitamins and caffeine and the consumption of sport fish while attempting pregnancy. Prospective longitudinal data reported in daily diaries (gold standard) were compared with data obtained a decade later using a self-administered questionnaire. Agreement was assessed by percent agreement and Kappa coefficients. RESULTS: Among the 82 participating women, percent agreement ranged from 54-74% for the 5 behaviors. Validity was highest for smoking (Kappa = 0.43, 95% confidence interval [CI]: 0.22, 0.65) followed by fish consumption (Kappa = 0.32, 95% CI: 0.09, 0.55), caffeine (Kappa = 0.21, 95% CI: 0.09, 0.51) and alcohol (Kappa = 0.20, 95% CI: 0.08, 0.33). There were no systematic differences in agreement by time to pregnancy or pregnancy outcome. Associations between smoking and alcohol consumption and pregnancy outcomes were highly sensitive to the levels of misclassification observed in this study. CONCLUSION: Validity was poor to moderate for the 5 behaviors, though higher for more regular behaviors such as smoking and caffeine consumption. The potential for misreporting of periconception behaviors can affect inferences, and thus efforts to capture information prospectively should be promoted.

Metal(loid)s and human semen quality: The LIFE Study.

Multiple studies have demonstrated a global population-wide decline in semen quality, with sperm concentrations having fallen 50 % over the past 50 years. Several metal and metalloid ("metal(loid)") compounds are known to have testicular toxicity, raising concerns about their contribution to rising infertility. In the male reproductive tract, metal(loid)s can reduce semen quality and disturb function both directly, by inducing tissue damage, and indirectly, by disrupting hormone production and secretion. This study assessed associations between 15 creatinine-adjusted metal(loid)s and 7 measures of semen quality among 413 reproductive-aged men recruited from 16 U.S. counties between 2005-2009. Multi-metal(loid) multivariable linear regression models estimated associations between semen quality endpoints and urinary concentrations of chromium, cobalt, copper, molybdenum, selenium, zinc, antimony, arsenic, barium, cadmium, lead, thallium, tin, tungsten, and uranium. LASSO regression was employed to select model variables and account for multicollinearity of the metal(loid)s. A positive association was observed between tin and sperm morphology (ß = 4.92 p = 0.045). Chromium (ß = 1.87, p = 0.003) and copper (ß= -1.30, p = 0.028) were positively and negatively associated with total sperm count, respectively. With respect to DNA fragmentation, cadmium (ß = 12.73, p = 0.036) was positively associated and chromium was negatively associated (ß = -5.08, p = 0.001). In this cohort of U.S. population-based men, there was evidence of both positive and negative associations between specific metal(loid)s and semen quality. Additional research is needed to determine interactions between metal(loid)s within a mixture, consistent with typical human exposure, and identify sperm effects resulting from cumulative metal(loid) exposures.

Nutrition during Pregnancy: Findings from the National Institute of Child Health and Human Development (NICHD) Fetal Growth Studies-Singleton Cohort.

BACKGROUND: Accumulating evidence indicates that maternal diets are important for optimizing maternal and offspring health. Existing research lacks comprehensive profiles of maternal diets throughout pregnancy, especially in a racially/ethnically diverse obstetrical population. OBJECTIVE: The aim was to characterize diets in a longitudinal US pregnancy cohort by trimester, race/ethnicity, and prepregnancy BMI. METHODS: Data were obtained from pregnant women in the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Fetal Growth Studies-Singleton cohort (2009-2013). A food-frequency questionnaire (FFQ) at 8-13 wk of gestation assessed periconception and first-trimester diet (n = 1615). Automated, self-administered, 24-h dietary recalls targeted at 16-22, 24-29, 30-33, and 34-37 wk of gestation assessed second- and third-trimester diets (n = 1817 women/6791 recalls). The Healthy Eating Index-2010 (HEI-2010) assessed diet quality (i.e., adherence to US Dietary Guidelines). Variations in weighted energy-adjusted means for foods and nutrients were examined by trimester, self-identified race/ethnicity, and self-reported prepregnancy BMI. RESULTS: Mean (95% CI) HEI-2010 was 65.9 (64.9, 67.0) during periconception to the first trimester assessed with an FFQ and 51.6 (50.8, 52.4) and 51.5 (50.7, 52.3) during the second trimester and third trimester, respectively, assessed using 24-h recalls. No significant differences were observed between the second and third trimester in macronutrients, micronutrients, foods, or HEI-2010 components (P ≥ 0.05). Periconception to first-trimester HEI-2010 was highest among Asian/Pacific Islander [67.2 (65.9, 68.6)] and lowest among non-Hispanic Black [58.7 (57.5, 60.0)] women and highest among women with normal weight [67.2 (66.1, 68.4)] and lowest among women with obesity [63.5 (62.1, 64.9)]. Similar rankings were observed in the second/third trimesters. CONCLUSIONS: Most pregnant women in this cohort reported dietary intakes that, on average, did not meet US Dietary Guidelines for nonpregnant individuals. Also, diet differed across race/ethnic groups and by prepregnancy BMI, with the lowest overall dietary quality in all trimesters among non-Hispanic Black women and women with obesity. No meaningful changes in dietary intake were observed between the second and third trimesters.

Empirical and parametric likelihood interval estimation for populations with many zero values: application for assessing environmental chemical concentrations and reproductive health.

BACKGROUND: Understanding the health effects associated with environmental chemicals is challenging when individuals have concentrations at or below the laboratory limits of detection as well as when the values may round to zero or are presented in the form of 0 to substitute for missing values, which may result in many zeros in the database. Comparison of mean concentrations between individuals with and without disease necessitates estimation procedures that allow for data with many zero values. The main aim of this article is to propose and examine parametric and distribution-free methods for comparing data sets containing many zero observations. An important application of this approach is related to assessing environmental chemical concentrations and reproductive health. METHODS: We extended the empirical likelihood technique for estimating confidence intervals (CIs) in data sets with many zeros. We examined the proposed empirical likelihood interval estimations via a broad Monte Carlo study that compares the proposed method with parametric techniques. Certain characteristics of Monte Carlo simulations were chosen to be close to parameters of the real data set. We applied the method to a cohort study comprising 84 women aged 18-40 years who had undergone laparoscopy between 1999 and 2000 in whom serum concentrations of 2 organochlorine pesticides--Aldrin and beta-Benzene hexachloride (ß-BHC) were measured using gas chromatography with electron capture. RESULTS: When applied to the cohort study, the method produced efficient 95% CIs, allowing for the comparison of mean serum Aldrin concentrations for women with and without endometriosis (0.000338, 0.003561) and (0.000803, 0.004211), respectively. Mean ß-BHC concentrations also could be compared (0.000493, 0.005869) and (0.000680, 0.003807) based on individuals with and without the disease, respectively. Differences in mean concentrations for Aldrin and ß-BHC could be estimated (-0.001563, 0.003025) and (-0.003522, 0.002890), respectively. CONCLUSIONS: We found the empirical likelihood method for estimating CIs robust when data sets contain many zeros. In so doing, mean concentrations of Aldrin or ß-BHC did not differ by endometriosis diagnosis.

Luteinizing hormone, testosterone and inhibin B levels in the peripubertal period and racial/ethnic differences among boys aged 6-11 years: analyses from NHANES III, 1988-1994.

OBJECTIVE: To determine whether the initial physical findings of puberty are accompanied by hormonal evidence of pubertal activation of the hypothalamic-pituitary-gonadal (HPG) axis and whether racial/ethnic differences exist, we have analysed hormone levels in relation to age, onset of puberty and race/ethnicity. DESIGN: Cross-sectional analysis of luteinizing hormone (LH), testosterone (T) and inhibin B from banked sera from a representative sample of US boys aged 6·0-11·99 years who participated in the National Health and Nutrition Examination Survey (NHANES) III. PATIENTS: Eight hundred and twenty-eight boys having sera including 228 non-Hispanic white (NHW), 266 non-Hispanic black (NHB), 288 Mexican-American (MA) and 46 'other'. MEASUREMENTS: Using analysis of variance and linear regression techniques, concentrations of LH, T and inhibin B were compared by race/ethnicity for all boys and pubertal status (Tanner's Staging 1, 2 and 3+) for boys aged 8 years and older. Receiver operating curves were utilized to identify cut-points predictive of pubertal HPG status. RESULTS: Mean hormones levels progressively increased with age. Receiver operating characteristic (ROC) curves indicate hormones are consistent with pubertal onset as indicated by Tanner stage 2, except for T and genital stage 2. Inhibin B and LH levels increased significantly by genital stage after adjusting for age and race/ethnicity, while LH and T concentrations increased significantly across pubic hair stages. Levels of inhibin B were significantly higher for NHB boys compared with other racial/ethnic groups. CONCLUSIONS: In these cross-sectional findings, hormone levels rise gradually as boys approach the peripubertal age, whereas an abrupt rise was not associated with the onset of physical changes of puberty.

Characteristics of prospectively measured vaginal bleeding among women trying to conceive.

MikolajczykPrevious research has described variability in menstrual cycle lengths within and across women, though less attention has focused on characterising patterns of bleeding. While clinical definitions for menstrual bleeding are often given in standard textbooks, the validity of conventional definitions has not been empirically evaluated in epidemiological studies. The definition of menstrual bleeding may affect the analysis of time to pregnancy and pregnancy dating that relies upon the last menstrual period. We used daily records of vaginal bleeding from a prospective cohort study that included 74 women trying to become pregnant who reported 430 bleeding episodes. A longitudinal mixture model (PROC TRAJ) was used to classify patterns of bleeding. Among the first 74 bleeding episodes, 15% comprised only days with spotting or light bleeding (possibly representing non-menstrual bleeding given the length of the cycle defined by these bleeding episodes). When all 430 bleeding episodes were analysed, four distinct bleeding patterns emerged: (1) episodic bleeding comprising 1-3 days of spotting (10%), (2) bleeding lasting 3-6 days (40%), (3) bleeding lasting 6-8 days (33%), and (4) bleeding lasting 8-12 days (17%). These findings suggest that non-menstrual bleeding may be relatively common. Considerable variation in menstrual bleeding patterns is evident, and as such is likely to impact fecundity-related endpoints or gestational age estimates that rely upon menstrual cycle dates. The association between bleeding patterns and female fecundity awaits future research.

Glycaemic status during pregnancy and longitudinal measures of fetal growth in a multi-racial US population: a prospective cohort study.

BACKGROUND: The timepoint at which fetal growth begins to differ by maternal glycaemic status is not well understood. To address this lack of data, we examined gestational diabetes, impaired glucose tolerance, and early pregnancy glucose concentrations in relation to fetal growth trajectories. METHODS: This cohort study included 2458 pregnant women from the NICHD Fetal Growth Studies-Singletons study, which took place between 2009 and 2013. Women were recruited from 12 clinical centres in the USA. Women aged 18-40 years without major chronic conditions when entering pregnancy were included and those with records of neither glucose screening test or glucose tolerance test were excluded from the study. Women were enrolled at gestational weeks 8-13 and randomly assigned to four ultrasonogram schedules (Group A; weeks 16, 24, 30, 34; Group B: weeks 18, 26, 31, 35, 39; Group C: weeks 20, 28, 32, 36; Group D: weeks 22, 29, 33, 37, 41) to capture weekly fetal growth. Gestational diabetes, impaired glucose tolerance, and normal glucose tolerance were defined by medical record review. Glucose was measured in a subsample of women at weeks 10-14. We modelled fetal growth trajectories using linear mixed models with cubic splines. This study is registered with ClinicalTrials.gov, NCT00912132. FINDINGS: Of the 2458 women included in this study, 107 (4·4%) had gestational diabetes, 118 (4·8%) had impaired glucose tolerance, and 2020 (82·2%) had NGT. 213 women were excluded from the main analysis. The cohort with gestational diabetes was associated with a larger estimated fetal weight that started at week 20 and was significant at week 28-40 (at week 37: 3061 g [95% CI 2967-3164] for women with gestational diabetes vs 2943 g [2924-2962] for women with normal glucose tolerance, adjusted p=0·02). In addition, glucose levels at weeks 10-14 were positively associated with estimated fetal weight starting at week 23 and the association became significant at week 27 (at week 37: 3073 g [2983-3167] in the highest tertile vs 2853 g [2755-2955] in the lowest tertile, adjusted p=0·0009. INTERPRETATION: Gestational diabetes was associated with a larger fetal size that started at week 20 and became significant at gestational week 28. Efforts to mitigate gestational diabetes-related fetal overgrowth should start before 24-28 gestational weeks, when gestational diabetes is typically screened for in the USA. FUNDING: National Institutes of Health.

Sex differences in the associations of placental epigenetic aging with fetal growth.

Identifying factors that influence fetal growth in a sex-specific manner can help unravel mechanisms that explain sex differences in adverse neonatal outcomes and in-utero origins of cardiovascular disease disparities. Premature aging of the placenta, a tissue that supports fetal growth and exhibits sex-specific epigenetic changes, is associated with pregnancy complications. Using DNA methylation-based age estimator, we investigated the sex-specific relationship of placental epigenetic aging with fetal growth across 13-40 weeks gestation, neonatal size, and risk of low birth weight. Placental epigenetic age acceleration (PAA), the difference between DNA methylation age and gestational age, was associated with reduced fetal weight among males but with increased fetal weight among females. PAA was inversely associated with fetal weight, abdominal circumference, and biparietal diameter at 32-40 weeks among males but was positively associated with all growth measures among females across 13-40 weeks. A 1-week increase in PAA was associated with 2-fold (95% CI 1.2, 3.2) increased odds for low birth weight and 1.5-fold (95% CI 1.1, 2.0) increased odds for small-for-gestational age among males. In all, fetal growth was significantly reduced in males but not females exposed to a rapidly aging placenta. Epigenetic aging of the placenta may underlie sex differences in neonatal outcomes.