Dataset Information

Association between the pregnancy exposome and fetal growth.

ABSTRACT:

Background

Several environmental contaminants were shown to possibly influence fetal growth, generally from single exposure family studies, which are prone to publication bias and confounding by co-exposures. The exposome paradigm offers perspectives to avoid selective reporting of findings and to control for confounding by co-exposures. We aimed to characterize associations of fetal growth with the pregnancy chemical and external exposomes.

Methods

Within the Human Early-Life Exposome project, 131 prenatal exposures were assessed using biomarkers and environmental models in 1287 mother-child pairs from six European cohorts. We investigated their associations with fetal growth using a deletion-substitution-addition (DSA) algorithm considering all exposures simultaneously, and an exposome-wide association study (ExWAS) considering each exposure independently. We corrected for exposure measurement error and tested for exposure-exposure and sex-exposure interactions.

Results

The DSA model identified lead blood level, which was associated with a 97 g birth weight decrease for each doubling in lead concentration. No exposure passed the multiple testing-corrected significance threshold of ExWAS; without multiple testing correction, this model was in favour of negative associations of lead, fine particulate matter concentration and absorbance with birth weight, and of a positive sex-specific association of parabens with birth weight in boys. No two-way interaction between exposure variables was identified.

Conclusions

This first large-scale exposome study of fetal growth simultaneously considered >100 environmental exposures. Compared with single exposure studies, our approach allowed making all tests (usually reported in successive publications) explicit. Lead exposure is still a health concern in Europe and parabens health effects warrant further investigation.

SUBMITTER: Agier L

PROVIDER: S-EPMC7266545 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:ImportanceFexofenadine hydrochloride is a frequently used drug for treatment of allergic conditions during pregnancy, but the fetal safety of fexofenadine use has not been well studied.ObjectiveTo investigate the risk of adverse fetal outcomes associated with fexofenadine use during pregnancy.Design, setting, and participantsA nationwide registry-based cohort study was conducted on pregnancies in Denmark from January 1, 2001, to December 31, 2016. Data analysis was performed from March 21, 2019, to January 29, 2020. From a cohort of 1 287 668 pregnancies, fexofenadine use was compared with cetirizine hydrochloride use during pregnancy, matched in a 1:1 ratio on propensity scores. Distinct study cohorts and exposure time periods were applied according to each outcome analysis. Sensitivity analyses included comparing pregnancies with vs without fexofenadine exposure during pregnancy but with previous use before pregnancy and with loratadine use during pregnancy as additional comparator groups.ExposureFilled prescription for fexofenadine.Main outcomes and measuresMajor birth defects and spontaneous abortion. Secondary outcomes were preterm birth, small size for gestational age (SGA), and stillbirth. Logistic regression was used to estimate prevalence odds ratios (ORs) of major birth defects, preterm birth, and SGA, and Cox proportional hazards regression was used to estimate hazard ratios (HRs) of spontaneous abortion and stillbirth.ResultsFor the analyses of major birth defects and spontaneous abortion, a total of 2962 and 4901 pregnancies with fexofenadine use were included, respectively, matched in a 1:1 ratio with pregnancies with cetirizine use. Mean (SD) age of the fexofenadine cohort for analyses of major birth defects was 30.6 (4.8) years and, for analysis of spontaneous abortion, 30.4 (5.5) years. Infants born with major birth defects occurred in 118 pregnancies (4.0%) with fexofenadine use compared with 112 pregnancies (3.8%) with cetirizine use. Spontaneous abortion occurred in 413 pregnancies (8.4%) with fexofenadine use compared with 439 pregnancies (9.0%) with cetirizine use. Fexofenadine use during pregnancy was not associated with an increased risk of major birth defects (prevalence OR, 1.06; 95% CI, 0.81-1.37) or spontaneous abortion (HR, 0.93; 95% CI, 0.82-1.07) compared with cetirizine use during pregnancy. Preterm birth occurred in 370 pregnancies (7.5%) with fexofenadine use compared with 382 pregnancies (7.7%) with cetirizine use (prevalence OR, 0.97; 95% CI, 0.83-1.12), SGA occurred in 515 pregnancies (10.1%) with fexofenadine use compared with 523 pregnancies (10.2%) with cetirizine use (prevalence OR, 0.98; 95% CI, 0.87-1.12), and a total of 16 pregnancies (0.3%) with fexofenadine use ended in stillbirth compared with 24 pregnancies (0.4%) with cetirizine use (HR, 0.67; 95% CI, 0.36-1.27). Sensitivity analyses of the primary outcomes, including the comparisons of pregnancies with loratadine use and pregnancies unexposed to fexofenadine during pregnancy but with prior use of fexofenadine, showed similar results.Conclusions and relevanceUse of fexofenadine during pregnancy does not appear to be associated with an increased risk of adverse fetal outcomes.

Project description:INTRODUCTION:The objective was to evaluate the association between fetal sex and adverse pregnancy outcome, while correcting for fetal growth and gestational age at delivery. MATERIAL AND METHODS:Data from the Netherlands Perinatal Registry (1999-2010) were used. The study population comprised all white European women with a singleton delivery between 25+0 and 42+6 weeks of gestation. Fetuses with structural or chromosomal abnormalities were excluded. Outcomes were antepartum death, intrapartum/neonatal death (from onset of labor until 28 days after birth), perinatal death (antepartum death or intrapartum/neonatal death), a composite of neonatal morbidity (including infant respiratory distress syndrome, sepsis, necrotizing enterocolitis, meconium aspiration, persistent pulmonary hypertension of the newborn, periventricular leukomalacia, Apgar score <7 at 5 minutes, and intracranial hemorrhage) and a composite adverse neonatal outcome (perinatal death or neonatal morbidity). Outcomes were expressed stratified by birthweight percentile (<p10 [small for gestation], p10-90 [normal weight], >p90 [large for gestation]) and gestational age at delivery (25+0 -27+6 , 28+0 -31+6 , 32+0 -36+6 , 37+0 -42+6 weeks). The association between fetal sex and outcome was assessed using the fetus at risk approach. RESULTS:We studied 1 742 831 pregnant women. We found no increased risk of antepartum, intrapartum/neonatal and perinatal death in normal weight and large-for-gestation males born after 28+0 weeks compared with females. We found an increased risk of antepartum death among small-for-gestation males born after 28+0 weeks (relative risk [RR] 1.16-1.40). All males born after 32+0 weeks of gestation suffered more neonatal morbidity than females regardless of birthweight percentile (RR 1.07-1.34). Infant respiratory distress syndrome, sepsis, persistent pulmonary hypertension of the newborn, Apgar score <7 at 5 minutes, and intracranial hemorrhage all occurred more often in males than in females. CONCLUSIONS:Small-for-gestation males have an increased risk of antepartum death and all males born after 32+0 weeks of gestation have an increased risk of neonatal morbidity compared with females. In contrast to findings in previous studies we found no increased risk of antepartum, intrapartum/neonatal or perinatal death in normal weight and large-for-gestation males born after 28+0 weeks.

Project description:It is widely recognized that exogenous factors play an important role in the development of hypertensive disorders of pregnancy (HDP). However, only a few external environmental factors have been studied, often separately, with no attempt to examine the totality of the external environment, or the external exposome. We conducted an external exposome-wide association study (ExWAS) using the Florida Vital Statistics Birth Records including 819,399 women with live births in 2010-2013. A total of 5784 factors characterizing women's surrounding natural, built, and social environment during pregnancy from 10 data sources were collected, harmonized, integrated, and spatiotemporally linked to the women based on pregnancy periods using 250 m buffers around their geocoded residential addresses. A random 50:50 split divided the data into discovery and replication sets, and a 3-phase procedure was used. In phase 1, associations between HDP and individual factors were examined, and Bonferroni adjustment was performed. In phase 2, an elastic net model was used to perform variable selection among significant variables from phase 1. In phase 3, a multivariable logistic regression model including all variables selected by the elastic net model was fitted. Variables that were significant in both the discovery and replication sets were retained. Among the 528 and 490 variables identified in Phase 1, 232 and 224 were selected by the elastic net model in Phase 2, and 67 and 48 variables remained statistically significant in Phase 3 in the discovery and replication sets, respectively. A total of 12 variables were significant in both the discovery and replication sets, including air toxicants (e.g., 2,2,4-trimethylpentane), meteorological factors (e.g., omega or vertical velocity at 125mb pressure level), neighborhood crime and safety (e.g., burglary rate), and neighborhood sociodemographic status (e.g., urbanization). This is the first large external exposome study of HDP. It confirmed some of the previously reported associations and generated unexpected predictors within the environment that may warrant more focused evaluation.

Project description:BACKGROUND:Fetal growth patterns in pregnancy-associated hypertensive disorders is poorly understood because prospective longitudinal data are lacking. OBJECTIVE:The objective of the study was to compare longitudinal fetal growth trajectories between normotensive women and those with pregnancy-associated hypertensive disorders. STUDY DESIGN:This is a study based on data from a prospective longitudinal cohort study of fetal growth performed at 12 US sites (2009-2013). Project gestational age was confirmed by ultrasound between 8 weeks 0 days and 13 weels 6 days, and up to 6 ultrasounds were performed across gestation. Hypertensive disorders were diagnosed based on 2002 American College of Obstetricians and Gynecologists guidelines and grouped hierarchically as severe preeclampsia (including eclampsia or HELLP [hemolysis, elevated liver enzymes, and low platelet count] syndrome), mild preeclampsia, severe gestational hypertension, mild gestational hypertension, or unspecified hypertension. Women without any hypertensive disorder constituted the normotensive group. Growth curves for estimated fetal weight and individual biometric parameters including biparietal diameter, head circumference, abdominal circumference, and femur and humerus length were calculated for each group using linear mixed models with cubic splines. Global and weekly pairwise comparisons were performed between women with a hypertensive disorder compared with normotensive women to analyze differences while adjusting for confounding variables. Delivery gestational age and birthweights were compared among groups. RESULTS:Of 2462 women analyzed, 2296 (93.3%) were normotensive, 63 (2.6%) had mild gestational hypertension, 54 (2.2%) mild preeclampsia, 32 (1.3%) severe preeclampsia, and 17 (0.7%) unspecified hypertension. Compared with normotensive women, those with severe preeclampsia had estimated fetal weights that were reduced between 22 and 38 weeks (all weekly pairwise values of P < .008). Women with severe preeclampsia compared with those without hypertension also had significantly smaller fetal abdominal circumference between 23-31 and 33-37 weeks' gestation (weekly pairwise values of P < .04). Scattered weekly growth differences were noted on other biometric parameters between these 2 groups. The consistent differences in estimated fetal weight and abdominal circumference were not observed between women with other hypertensive disorders and those who were normotensive. Women with severe preeclampsia delivered significantly earlier (mean gestational age 35.9 ± 3.2 weeks) than the other groups (global P < .0001). Birthweights in the severe preeclampsia group were also significantly lower (mean -949.5 g [95% confidence interval, -1117.7 to -781.2 g]; P < .0001) than in the normotensive group. CONCLUSION:Among women with pregnancy-associated hypertensive disorders, only those destined to develop severe preeclampsia demonstrated a significant and consistent difference in fetal growth (ie, smaller estimated fetal weight and abdominal circumference) when compared with normotensive women.

Project description:ImportancePodophyllotoxin is an antimitotic agent primarily used in the local treatment of anogenital warts. Data that enable the assessment of the fetal safety of podophyllotoxin use during pregnancy are lacking.ObjectiveTo investigate the association between local podophyllotoxin exposure during pregnancy and risk of adverse fetal outcomes.Design, setting, and participantsThis cohort study obtained individual-level pregnancy data from various nationwide registries in Denmark from the study period of January 1, 1997, through December 31, 2016, resulting in a cohort of 1 650 649 pregnancies. Pregnancies with multiple records on overlapping dates and pregnancy records with implausible or missing information on gestational age were excluded. Local podophyllotoxin-exposed pregnancies were compared with unexposed pregnancies and matched in a 1:10 ratio according to propensity scores on a wide set of baseline characteristics. Five distinct study cohorts were constructed, one for each outcome analysis. Sensitivity analyses included a comparison of podophyllotoxin-exposed pregnancies with pregnancies with podophyllotoxin use only before pregnancy onset. Data analyses were performed from April 27, 2019, to June 26, 2019.ExposuresFilled prescription for local podophyllotoxin.Main outcomes and measuresPrimary outcomes were major birth defects and spontaneous abortions. Secondary outcomes were preterm births, small-for-gestational-age (SGA) size, and stillbirths. Logistic regression was used to estimate the prevalence odds ratios (ORs) of major birth defects, preterm births, and SGA size, and Cox proportional hazards regression modeling was used to estimate hazard ratios (HRs) of spontaneous abortions and stillbirths.ResultsThis study included 9229 pregnancies (mean [SD] maternal age at pregnancy onset, 27.7 [5.2] years) for the analyses of major birth defects and 18 590 pregnancies (mean [SD] maternal age at pregnancy onset, 26.4 [6.0] years) for the analyses of spontaneous abortions. Among the podophyllotoxin-exposed pregnancies, 29 infants (3.5%) were diagnosed with major birth defects, compared with 286 (3.4%) among the unexposed pregnancies. A total of 141 podophyllotoxin-exposed pregnancies (8.3%) ended in spontaneous abortion, compared with 1626 (9.6%) among the unexposed pregnancies. No statistically significant associations were found between podophyllotoxin exposure during pregnancy and major birth defects (prevalence odds ratio [OR], 1.02 95% CI, 0.69-1.50), spontaneous abortions (HR, 0.87; 95% CI, 0.73-1.04), preterm births (prevalence OR, 1.08; 95% CI, 0.86-1.35), SGA size (prevalence OR, 1.01; 95% CI, 0.85-1.22), or stillbirths (HR, 0.58; 95% CI, 0.18-1.86). Sensitivity analyses of the primary outcomes achieved similar results.Conclusions and relevanceFindings from this study suggest that podophyllotoxin use during pregnancy may be safe, as it did not appear to be associated with an increased risk of adverse fetal outcomes. These findings may help guide clinicians, patients, and drug regulatory authorities when prescribing podophyllotoxin.

Project description:To compare the rates of fetal growth restriction (FGR) in singleton and twin pregnancies using singleton and twin-specific birthweight standards. The study included liveborn twin and singleton pregnancies between January 2000 and January 2019. Hypertensive disorders of pregnancy (HDP) included gestational hypertension and pre-eclampsia. The study outcomes were FGR or small-for-gestational-age (SGA) at birth as assessed using singleton and twin reference charts. The analysis included 1473 twin and 62,432 singleton pregnancies. In singleton pregnancies the risk of PTB <34 weeks without HDP (OR 2.82, p < 0.001), delivery ≥34 weeks with HDP (OR 2.38, p < 0.001), and PTB <34 weeks with HDP (OR 13.65, p < 0.001) were significantly higher in the pregnancies complicated by FGR compared to those without. When selective fetal growth restriction (sFGR) was assessed using the singleton standard, the risk of PTB <34 weeks without HDP (OR 1.03, p = 0.872), delivery ≥34 weeks with HDP (OR 1.36, p = 0.160) were similar in the pregnancies complicated by sFGR compared to those without, while the risk of PTB <34 weeks with HDP (OR 2.41, p = 0.025) was significantly higher in the pregnancies complicated by sFGR compared to those without. When sFGR was assessed using the twin-specific chart, the risk of PTB <34 weeks without HDP (OR 3.55, p < 0.001), delivery ≥34 weeks with HDP (OR 3.17, p = 0.004), and PTB <34 weeks with HDP (OR 5.69, p < 0.001) were significantly higher in the pregnancies complicated by sFGR compared to those without. The stronger and more consistent association persisted in the subgroup analyses according to chorionicity. The strength of association in dichorionic twin pregnancies resembles that of the singletons more closely and consistently when the FGR was diagnosed using the twin-specific charts. FGR in twin pregnancies has a stronger and more consistent association with HDP and PTB when using twin-specific rather than singleton charts. This study provides further evidence supporting the use of twin-specific charts when assessing fetal growth in twin pregnancies.

Project description:ImportancePrenatal exposure to persistent organic pollutants (POPs) has been associated with birth size, but data on fetal growth and among racially/ethnically diverse pregnant women remain scarce.ObjectivesTo assess the association between maternal plasma POPs in early pregnancy and fetal growth and by infant sex and maternal race/ethnicity.Design, setting, and participantsThis cohort study used the National Institute of Child Health and Human Development Fetal Growth Studies-Singleton cohort, which recruited nonobese, low-risk pregnant women before 14 weeks' gestation between July 1, 2009, and January 31, 2013, in 12 community-based clinics throughout the United States. Participants self-identified their race/ethnicity, self-reported their behavioral risk factors, and were followed up throughout their pregnancy. Data were analyzed from July 31, 2018, to June 3, 2019.ExposuresLevels of 76 POPs in early gestation plasma were measured: 11 perfluoroalkyl and polyfluoroalkyl substances, 1 polybrominated biphenyl, 9 polybrominated diphenyl ethers (PBDEs), 44 polychlorinated biphenyls (PCBs), and 11 organochlorine pesticides (OCPs). The bayesian kernel machine regression method was used to examine chemical class mixtures, and generalized additive mixed model was used to analyze individual chemicals.Main outcomes and measuresFourteen fetal biometrics were measured, including head circumference, abdominal circumference, and femur length, within 5 ultrasonography appointments.ResultsA total of 2284 low-risk pregnant women were included: 606 women (26.5%) self-identified as white with a mean (SD) age of 30.3 (4.4) years, 589 (25.8%) as black with a mean (SD) age of 25.5 (5.5) years, 635 (27.8%) as Hispanic with a mean (SD) age of 27.1 (5.5) years, and 454 (19.9%) as Asian with a mean (SD) age of 30.5 (4.5) years. A comparison between the 75th and 25th percentile of exposure revealed that the OCP mixture was negatively associated with most fetal growth measures, with a reduction of 4.7 mm (95% CI, -6.7 to -2.8 mm) in head circumference, 3.5 mm (95% CI, -4.7 to -2.2 mm) in abdominal circumference, and 0.6 mm (95% CI, -1.1 to -0.2 mm) in femur length. Higher exposure to the PBDE mixture was associated with reduced abdominal circumference (-2.4 mm; 95% CI, -4.0 to -0.5 mm) and femur length (-0.5 mm; 95% CI, -1.0 to -0.1 mm), and the dioxin-like PCB mixture was associated with reduced head circumference (-6.4 mm; 95% CI, -8.4 to -4.3 mm) and abdominal circumference (-2.4 mm; 95% CI, -3.9 to -0.8 mm). Associations with individual chemicals were less consistent. There were some interactions by fetal sex, although most of the results did not vary by maternal race/ethnicity. For example, oxychlordane (-0.98 mm; 95% CI, -1.60 to -0.36 mm; P for interaction <.001), trans-nonachlor (-0.31 mm; 95% CI, -0.54 to -0.08 mm; P for interaction = .005), and p,p'-dichlorodiphenyldichloroethylene (-0.19 mm; 95% CI, -0.22 to -0.09 mm; P for interaction = .006) were associated with shorter femur length among boys only.Conclusions and relevanceThis study found that, among pregnant women with low POP levels, a mixture of OCPs was negatively associated with most fetal growth measures and that mixtures of PBDEs and dioxin-like PCBs were associated with reduced abdominal circumference. These findings suggested that, although exposures may be low, associations with fetal growth are apparent.

Project description:IntroductionBirth weight is described as one of the main determinants of newborns' chances of survival. Among the associated causes, or risk factors, the mother's nutritional status strongly influences fetal growth and birth weight outcomes of the concept. This study evaluates the association between food deserts, small for gestational age (SGA), large for gestational age (LGA) and low birth weight (LBW) newborns.DesignThis is a cross-sectional population study, resulting from individual data from the Live Birth Information System (SINASC), and commune data from mapping food deserts (CAISAN) in Brazil. The newborn's size was defined as follows: appropriate for gestational age (between 10 and 90th percentile), SGA (< 10th percentile), LGA (> 90th percentile), and low birth weight < 2,500 g. To characterize food environments, we used tertiles of the density of establishments which sell in natura and ultra-processed foods. Logistic regression modeling was conducted to investigate the associations of interest.ResultsWe analyzed 2,632,314 live births in Brazil in 2016, after appropriate adjustments, women living in municipalities with limited availability of fresh foods had a higher chance of having newborns with SGA [OR2nd tertile: 1.06 (1.05-1.07)] and LBW [OR2nd tertile: 1.11 (1.09-1.12)]. Conversely, municipalities with greater availability of ultra-processed foods had a higher chance of having newborns with SGA [OR3rd tertile: 1.04 (1.02-1.06)] and LBW [OR2nd tertile: 1.13 (1.11-1.16)]. Stratification by race showed that Black and Mixed/Brown women had a higher chance of having newborns with SGA [OR3rd tertile: 1.09 (1.01-1.18)] and [OR3rd tertile: 1.06 (1.04-1.09)], respectively, while Mixed-race women also had a higher chance of having newborns with LBW [OR3rd tertile: 1.17 (1.14-1.20)]. Indigenous women were associated with LGA [OR3rd tertile: 1.20 (1.01-1.45)].ConclusionThe study found that living in areas with limited access to healthy foods was associated with an increased risk of SGA and low birth weight among newborns, particularly among Black and Mixed/Brown women. Therefore, urgent initiatives aimed at reducing social inequalities and mitigating the impact of poor food environments are needed in Brazil.

Project description:BackgroundPerturbations in fetal growth may have adverse consequences for childhood and later life health. Organophosphate pesticide (OP) exposure has been associated with reduced birth weight at delivery but results are not consistent. We investigated this question by utilizing ultrasound measures of size in utero in combination with measures from delivery.MethodsWithin Generation R, a population-based prospective cohort conducted between 2002 and 2006 in Rotterdam, Netherlands, we measured dialkyl phosphates (DAPs), OP metabolites, in urine samples from early, middle, and late pregnancy and created a subject-specific average to estimate OP exposure ([Formula: see text]). Ultrasound measures of head circumference, femur length, and estimated fetal weight from middle and late pregnancy and delivery measures were converted to standard deviation scores (SDS). Associations with DAP average were examined in linear mixed effects models that included an interaction term between gestational age at measurement and DAP average to investigate whether the relationship differed over time. Windows of vulnerability to exposure were assessed by modeling urinary DAPs from each visit in relation to growth measurements.ResultsA 10-fold increase in average DAPs was associated with a [Formula: see text] SDS decrease in fetal length (95% [Formula: see text], [Formula: see text]) and a [Formula: see text] SDS decrease in estimated fetal weight (95% [Formula: see text], [Formula: see text]) at 20 weeks of gestation. These differences corresponded to 5% and 6% decreases relative to the mean. Effect estimates were greatest in magnitude for DAP concentrations measured early in pregnancy. Associations between average DAPs and growth measures at delivery were positive but not significant for head circumference and length and were null for weight.ConclusionsMaternal urinary DAPs were associated with decreased fetal weight and length measured during mid-pregnancy, but not at delivery. https://doi.org/10.1289/EHP4858.