In approximately 300 pregnant women from 4 US locations, we found that gestation was 1.1 days and 1.3 days longer with each log-unit increase in urinary concentrations of the DEHP metabolites MEHP and MEOHP, respectively. Women at the 75th percentile of urinary MEHP concentration had a duration of gestation that was 2.3 days (95% CI: 1.4, 3.3) longer than that of women at the 25th percentile of exposure, after we controlled for urinary creatinine concentration, demographic factors, maternal health, stress, and parity. DEHP exposure in this cohort was similar to the NHANES US population estimate for pregnant females.
The clinical or population significance of an exposure-related shift of 2–3 days in gestational length is difficult to evaluate. For this reason, we also estimated associations with clinical outcomes and saw increased odds of delivering after 41 weeks, decreased odds of preterm delivery, and increased odds of delivering by cesarean section. Delivery after 41 weeks is associated with an increase in perinatal mortality due to meconium aspiration, fetal distress, asphyxia, pneumonia, malformations, shoulder dystocia, and traumatic injuries (39
). Women who undergo cesarean section are at increased risk in subsequent pregnancies of malpresentation, abnormal placentation, antepartum hemorrhage, placenta accreta, prolonged labor, uterine rupture, preterm birth, low birth weight, and stillbirth (41
). The observed decrease in the risk of preterm delivery may be protective or may be indicative of abnormal function of the placenta (26
); in this study, we could not distinguish between these possibilities.
A prior study using MEHP concentration in umbilical cord blood from 84 Italian mother/newborn pairs found an association that pointed in the opposite direction than was observed here (8
). Latini et al. (8
) reported that gestational age was shorter by 1.2 weeks in the MEHP-positive pairs than in the MEHP-negative subjects. In that study, they measured MEHP and DEHP in umbilical cord blood, which may have been subject to contamination by DEHP in the sampling and analytic equipment (42
). Measuring MEHP in blood is not recommended because of its short half-life (14
). In that analysis, exposure status was dichotomized as exposed and nonexposed. Given that more than 95% of the general US population has detectable urinary metabolites of DEHP (5
), this approach could have resulted in misclassification among the nonexposed subjects. The discrepant results between these 2 studies could be due to differences in study design, exposure assessment, and/or the underlying characteristics of the populations.
When we stratified SFF subjects by geographic location, gestational age tended to increase with increasing phthalate metabolite concentrations for all sites except Minnesota, where it tended to remain flat or decrease slightly. The women from Minnesota tended to have higher MEOHP concentrations and %MEHP, higher gestational age, higher maternal age, and more education than women from other study centers, most markedly relative to California, and they were predominantly white (97%). We can speculate on 2 possible explanations. It is possible that the dose-response curve was nonlinear and essentially reversed at the higher doses among the Minnesota subjects. It is also possible that the site-specific populations differed in ways that modified the relation between DEHP exposure and placental function. The significant differences in race, education, maternal age, and parity between study centers could be proxies for other unmeasured effect modifiers, such as nutritional factors, coexposures, and/or lifestyle factors.
Other known causes of prolonged gestation include fish oil consumption during pregnancy (43
), deficiency in placental sulfatase, which is another cause of decreased estrogen synthesis (45
), and living in a highly polluted area (46
). Fish oil contains n-3 long-chain polyunsaturated fatty acids, which are also ligands of PPARγ and may contribute to a suppressed inflammatory response late in pregnancy (47
). If this were the case, it is possible that a competitive interaction between DEHP and fatty acids in the diet exists. We could not test this hypothesis, since fish consumption among our subjects was generally low (88% of those who consumed fish had 2 or fewer servings per week). We did not have information on the type of fish consumed or on how it was prepared.
We hypothesized that the association between DEHP exposure and timing of labor could also differ depending on a woman's ability to metabolize and excrete DEHP. To test this, we dichotomized %MEHP values at the median and compared metabolite associations within the low and high strata. The association of MEOHP concentrations with longer gestation was 3-fold stronger in the low-%MEHP group than in the high-%MEHP group. The association of MEOHP concentration with the timing of labor might be due to disruption in parturition and signaling by DEHP metabolites, but it might also be due to differences in a woman's ability to metabolize and excrete DEHP. In a previous report, we found %MEHP to be approximately twice as reproducible within a woman over the last 6 weeks of pregnancy as DEHP metabolites (10
), suggesting that %MEHP may reflect stable interindividual differences that could be relevant to the metabolism and excretion of these compounds in pregnancy.
Concern exists about the potential for systematic error in estimating gestational age using the last-menstrual-period approach (49
). We addressed this by also using the clinical estimate, which takes into account ultrasound data and examination of the newborn in cases where there are inconsistencies in last-menstrual-period dating and clinical presentation, but the clinical estimate may have been less precise, given that it was rounded up. We found results to be consistent using both measures when including all gestational ages and less consistent when modeling associations with preterm and postterm delivery. Misclassification of gestational age by last menstrual period is most problematic among preterm and postterm births, with the degree of misclassification being associated with maternal race, age, education, parity, month that prenatal care began (51
), and regularity of the menstrual period (52
). Given that some of these factors are also related to phthalate exposure and pregnancy outcomes, we relied on the clinical estimate to model associations with DEHP metabolite concentrations.
Some misclassification of DEHP exposure was present in our data, given that we had a single spot urine sample for characterizing exposure. In a previous analysis, we showed that DEHP metabolite concentrations are not highly reproducible in pregnant women over the last 6 weeks of pregnancy, probably because of physiologic changes occurring in the third trimester (10
). Of the SFF subjects, 55% were sampled in the third trimester. In addition to misclassification, there may have been other exposures and risk factors associated with urinary DEHP metabolite concentrations and birth outcomes that we were not able to adequately control for, resulting in residual confounding.
In conclusion, we observed an association between increased concentrations of DEHP metabolites in maternal urine measured during pregnancy and gestational age in a US multicenter pregnancy cohort study. The direction and size of the effect appeared to differ depending in part on geographic location and a woman's ability to metabolize and eliminate DEHP. Our results support the hypothesis that DEHP exposure may alter the dialogue between the maternal and fetal compartments that is essential for normal labor. Consistent with this hypothesis, urinary DEHP metabolite concentrations were associated with an increased risk of cesarean section delivery and of delivering at more than 41 weeks. The binding affinity of the metabolite MEHP for PPARγ and the central role PPARγ plays in regulating placental function may provide an explanation for this association, but this was not directly explored in the present study.
These results need to be replicated in other populations. There is likewise a need for more in vitro and in vivo research to better understand molecular mechanisms by which DEHP may alter placental development and/or function.