The Impact of Sample Timing and Study Confidence on Mean Birth Weight Differences Detected in a Meta-analysis of PFHxS
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Background: Steenland et al. (2018) showed that timing differences in PFOA biomarker sampling may result in reverse causality or confounding due to pregnancy-related hemodynamic changes. In a meta-analysis of epidemiologic data from 16 studies of birth weight identified in a systematic review of the health effects of PFHxS exposure, we examined whether results differed by study quality and by timing of exposure measurement.
Methods: Using a random effects model, we examined studies with maternal blood samples collected during first trimester (T1), second trimester (T2), third trimester (T3), post-partum (PP), or umbilical cord blood (UCB). Three grouping strategies were used: 1); early and mid-pregnancy sampling (T1; T1/T2; T2, n=7) versus later sampling (n=9); 2) early pregnancy sampling (T1; T1/T2, n=4) versus later sampling (n=12); 3) early (T1; T1/T2, n=4), mid- and late-pregnancy (T2; T2/T3; T3, n=7), and post-pregnancy (UBC; PP, n=5).
Results: The summary mean birthweight deficit was -12 grams (95%CI: -25, 0.1; I2=0%) per ln-unit PFHxS increase with no differences across study confidence level (High/Medium/Low). We saw minimal differences in pooled deficits with the first two dichotomized grouping strategies (-11 vs -15 g for early/mid-pregnancy versus late/post-pregnancy; -10 vs -13 g for early pregnancy versus other periods). The third analysis showed comparable pooled estimates for maternal samples collected during pregnancy (early: -10 g, mid-/late-pregnancy: -8 g); but a larger deficit for UCB or PP (-28 g; 95%CI: -69, 13).
Conclusion: Although we saw larger deficits for post-pregnancy samples based on a few studies, we consistently saw elevated birth weight deficits for pregnancy-based measures regardless of timing. Additionally, the few PFHxS studies adjusting for hemodynamics did not show evidence of confounding. Thus, more work is needed to determine whether reverse causality is a plausible explanation of these differences and to determine the most relevant grouping strategies based on hemodynamic expectations.