The present study found a significant inverse association between DEHP metabolite levels in maternal, third-trimester, spot urine samples and gestational age at delivery. An inverse association also was seen between gestational age and DEHP concentrations in maternal personal air samples, but the association was not statistically significant. This was not unexpected; although inhalation is one route of exposure, diet is presumed to be the major route.33,34
Therefore, the biomarker is likely to provide a better indication of cumulative exposure. Only 1 previous study showed an inverse association between prenatal DEHP exposure and gestational age; gestational age was significantly lower among infants with MEHP levels in cord blood above versus below the LOD.9
Two additional studies measured DEHP metabolites in maternal, second- or third-trimester, spot urine samples in the same CDC laboratory as that used in the current study. However, findings were inconsistent with those presented here. In one study, involving 404 subjects from multiple racial/ethnic groups residing in New York City, gestational age increased by 1.1 days (95% CI: 0.1–2.0 days) for each 1-logarithmic unit increase in MEHP levels but was not associated with oxidative metabolite levels.15
In the other study, involving 284 subjects from 4 study sites (California, Iowa, Minnesota, and Missouri) enrolled as part of the Study for Future Families, a 1-logarithmic unit increase in urinary metabolite (MEHP, MEOHP, and MEHHP) concentrations was associated with an increase in gestational age of 1.1 to 1.3 days (95% CI: 0.7–2.5 days).16
However, when analyses were stratified according to geographic site, gestational age increased with higher metabolite concentrations in 3 sites but decreased in Minnesota.
Reasons for the discrepancies in these research findings might include differences in study design, exposure levels, race/ethnicity, underlying characteristics of the populations, or uncontrolled confounding. Differences in exposure levels might be particularly relevant, because dose-response curves for endocrine disruptors, including DEHP, frequently are nonlinear and can reverse at higher doses, with U-shaped or inverted U-shaped curves being seen.35–37
Exposures seem to have been considerably higher in the study by Latini et al,9
relative to the other cohorts (eg, the study by Wolff et al15
). Differences in exposures might explain some of the discrepancies in results across the 4 sites in the study by Adibi et al.16
Exposure differences also might explain discrepancies between the study by Adibi et al16
and our findings, because our metabolite concentrations were considerably higher. The geometric means for MEOHP and MEHHP differed by almost twofold, and the 95% concentration level differed by more than twofold. This may be particularly relevant because we saw associations principally among subjects with exposure levels in the highest quartile. However, metabolite concentrations in our study were similar to those seen in the study by Wolff et al15
; both studies were conducted in New York City, although there were racial/ethnic differences in the cohorts. It should be noted that the association between urinary MEHP concentrations and gestational age seen in our cohort was somewhat stronger among African American subjects than among Dominican subjects although exposure levels were similar, which suggests that effects may differ according to race/ethnicity.
Measurement errors in BMI and weight gain during pregnancy might result in residual confounding, which might be contributing to the discrepancies in the research findings. Recent research indicated that DEHP exposure might be associated with adiposity,17,38
and gestational weight gain can affect the risk of preterm birth.39
Although we assessed prepregnancy weight, height, BMI, and weight gain during pregnancy, our anthropometric measures, as well as those used in the study by Wolff et al,15
were based on maternal self-reports and might be subject to incorrect recall. Data on maternal BMI, height, and weight gain during pregnancy were not collected in the study by Adibi et al.16
Within-subject variability in urinary metabolite concentrations also might contribute to exposure misclassification, although this likely would be non-differential with respect to gestational age and would bias results toward the null hypothesis. In our study, urinary metabolite concentrations were adjusted with respect to specific gravity; in the studies by Adibi et al16
and Wolff et al,15
creatinine levels were used to control for dilution. Research findings from the CCCEH cohort suggest that variability in phthalate metabolite concentrations in repeat urine samples collected over the final 6 weeks of pregnancy are reduced when urinary concentrations are adjusted with respect to specific gravity versus creatinine levels.11
Finally, differences in race/ethnicity, education, and maternal age across the 3 studies might be proxies for other unmeasured effect modifiers, such as nutrition, coexposures, or other lifestyle factors.16
We are currently evaluating the relationship between prenatal phthalate exposures and expression of genes, including cyclooxygenase 2, PPAR-γ, and related genes, in placental tissue from the current cohort, which may provide insights into mechanisms through which prenatal DEHP exposure could alter the timing of labor.