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. 2021 Nov:156:106714.
doi: 10.1016/j.envint.2021.106714. Epub 2021 Jun 17.

Early pregnancy exposure to metal mixture and birth outcomes - A prospective study in Project Viva

Mohammad L Rahman  1 , Emily Oken  1 , Marie-France Hivert  2 , Sheryl Rifas-Shiman  1 , Pi-I D Lin  1 , Elena Colicino  3 , Robert O Wright  4 , Chitra Amarasiriwardena  4 , Birgit G Claus Henn  5 , Diane R Gold  6 , Brent A Coull  7 , Andres Cardenas  8
Affiliations

Early pregnancy exposure to metal mixture and birth outcomes - A prospective study in Project Viva

Mohammad L Rahman et al. Environ Int. 2021 Nov.

Abstract

Background: Prenatal exposure to metals has been individually associated with birth outcomes. However, little is known about the effect of metal mixture, particularly at low exposure levels.

Objectives: To estimate individual and joint effects of metal mixture components on birth outcomes.

Methods: We used data from 1,391 mother-infant pairs in Project Viva (1999-2002). We measured 11 metals in maternal 1st trimester erythrocyte; abstracted birth weight from medical records; calculated gestational age from last menstrual period or ultrasound; and obtained birth length (n = 729) and head circumference (n = 791) from research measurements. We estimated individual and joint effects of metals using multivariable linear and Bayesian kernel machine regressions.

Results: In both single metal and metal mixture analyses, exposure to higher concentrations of arsenic was associated with lower birth weight in males, zinc with higher head circumference in females, and manganese with higher birth length in sex-combined analysis. We also observed sex-specific metal interactions with birth outcomes. Arsenic and manganese showed a synergistic association with birth weight in males, in whom an interquartile range (IQR) increase in arsenic was associated with 25.3 g (95% CI: -79.9, 29.3), 47.9 g (95% CI: -98.0, 2.1), and 72.2 g (95% CI: -129.8, -14.7) lower birth weight when manganese concentrations were at 25th, 50th, and 75th percentiles, respectively. Lead and zinc showed an antagonistic association with head circumference in males, where an IQR increase in lead was associated with 0.18 cm (95% CI: -0.35, -0.02), 0.10 cm (95% CI: -0.25, 0.04), 0.03 cm (95% CI: -0.2, 0.14) smaller head circumference when zinc concentrations were at 25th, 50th, and 75th percentiles, respectively. Exposure to higher concentrations of arsenic was also associated with lower gestational age in males when concentrations of manganese and lead were higher.

Discussion: Maternal erythrocyte concentrations of arsenic, manganese, lead, and zinc were individually and interactively associated with birth outcomes. The associations varied by infant sex and exposure level of other mixture components.

Keywords: Arsenic; Birth outcome; Environmental exposure; Lead; Manganese; Metals; Mixture analysis; Pregnancy.

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Conflict of interest statement

Competing Financial Interests: The authors declare they have no actual or potential competing financial interests.

Figures

Figure 1.
Figure 1.
Adjusted associations of an IQR increase in erythrocyte concentrations of individual metal on birth outcomes in Project Viva in infant sex-combined and sex stratified analyses. Models were adjusted for gestational age at delivery (except when gestational age was an outcome) and potential confounders. The sex-combined analysis was also adjusted for infant sex.
Figure 2.
Figure 2.
Mixture analyses with BKMR illustrating the effect of metal mixture components on birth outcomes (estimates and 95% confidence intervals, gray dashed line at the null) in Project viva in sex-combined and sex-stratified analyses. This plot compares birth measurements when a mixture component is at the 75th percentile vs. 25th percentile, when all the other mixture components are fixed at the 25th, 50th, and 75th percentiles. Models were adjusted for gestational age (except when gestational age is an outcome) and potential confounders. The sex-combined analysis was also adjusted for infant sex.
Figure 3.
Figure 3.
Multiple metal linear regression analyses illustrating interactions between metal mixture components with respective birth measurements (estimates and 95% confidence intervals, gray dashed line at the null) in Project viva in sex-combined and sex-stratified analyses. The plot illustrates the marginal effect for an IQR increase in A) As on birth weight at quartiles of Mn; B-C) Mn and Zn on birth length at quartiles of Hg, respectively; D) Pb on head circumference at quartiles of Zn; E) Pb on gestational age at quartiles of Zn; and F) As on gestational age at quartiles of Pb and Mn. All six metals (As, Cd, Mn, Pb, Zn, and Hg) were included in the same model along with their two- or three-way interactions. Models were adjusted for gestational age (except when gestational age is an outcome) and potential confounders. The sex-combined analysis was also adjusted for infant sex.
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