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.

Keywords: Biomarkers; chemical exposures; cohort; environment; exposome; fetal growth; mixtures.

Figure 1

Birth weight distribution displayed overall among all cohorts (A) and as boxplots by cohort (B).

Figure 2

Adjusted effect measure of exposures on birth weight by cohort (ExWAS approach). Estimates are given as a change in mean birth weight (g) for each inter-quartile range (defined over all observations) increase in exposure (normalized and corrected for measurement error). Only exposures with an uncorrected P-value < 5% in the main ExWAS (i.e. without cohort–exposure interaction) are reported. Black squares display the coefficient estimates, and the horizontal lines their 95% CIs. The values of the coefficients (95% CI) are given on the right-hand side of the graphs; on the left-hand side, a symbol displays the proportion of missing values that were imputed for the given exposure variable in each cohort (*** <10% of imputed values, **10–50% of imputed values, * 50–80% of imputed values, no symbol indicates more than 80% of imputed values). The exposures distribution is displayed in Supplementary Figure S3, available as Supplementary data at IJE online. Associations were adjusted for gestational duration (simple and quadratic terms), sex of the newborn, parity, maternal height, maternal weight before pregnancy (using a broken stick model with a knot at 60 kg), maternal smoking during the second trimester of pregnancy, maternal education, season of conception and cohort (fixed effect variable). T3, averaged over the third trimester of pregnancy.

Figure 3

Adjusted effect measure of exposures on birth weight by offspring sex (ExWAS approach). Estimates are given as a change in mean birth weight (g) for each inter-quartile range (defined over all observations) increase in exposure (normalized and corrected for measurement error). Only exposures with an uncorrected sex interaction or sex-specific P-value < 5% are reported. The dot displays the coefficient estimate, and the vertical line its 95% CI. Associations were adjusted for gestational duration (simple and quadratic terms), sex of the newborn, parity, maternal height, maternal weight before pregnancy (using a broken stick model with a knot at 60 kg), maternal smoking during the second trimester of pregnancy, maternal education, season of conception and cohort (fixed effect variable). DDT, dichlorodiphenyltrichloroethane; PFOS, perfluorooctane sulfonate; T3, averaged over the third trimester of pregnancy.