Pre-conception urinary levels of phthlates may up risk of preterm birth

The presence of multiple phthalate metabolites in maternal urine was tied to a 50% increase in the risk of preterm birth, and a mother’s exposure to phthalates before conception may be a risk factor for preterm birth, researchers reported.

After controlling for other known risk factors, maternal pre-conception ΣDEHP metabolite concentrations were associated with an increased risk of preterm birth (risk ratio 1.50, 95% CI 1.09-2.06, P=0.01), according to Carmen Messerlian, PhD, of Harvard T.H. Chan School of Public Health in Boston, and co-authors.

In addition, maternal pre-conception concentrations of MHiNCH, a metabolite of a non-phthalate plasticizer substitute, was linked with an increased risk of preterm birth (RR 1.70, 95% CI 0.89-3.24, P= 0.11), they stated in JAMA Network Open.

However, while the former finding “remained robust” after adjustment for prenatal ΣDEHP or MHiNCH concentrations (RR 1.69, 95% CI 1.17-2.44, P=0.006), the latter finding was attenuated (RR 1.17, 95% CI 0.49-2.81, P=0.72), the authors noted.

Nonetheless, “Our results suggest that female exposure to ΣDEHP before conception might be an unrecognized risk factor for adverse pregnancy outcomes, often overlooked in clinical practice,” they emphasized.

Links between preterm birth and exposure to phthalates during pregnancy are not new, such as those seen in a 2019 study out of China done in over 3,000 pregnant women, but the current results seem “novel” because they describe “an association between pre-conception exposure to specific phthalate metabolites and preterm birth,” noted Ruth A. Etzel, MD, PhD, of the Milken Institute School of Public Health at George Washington University in Washington, DC, in an invited commentary accompanying the study.

She pointed out that many foods can be sources of high concentrations of phthalates (poultry, oils, fats,) and low concentrations (fruits and vegetables, eggs, yogurt, rice), yet intervention studies have shown the difficulty of cutting phthalate concentrations through dietary changes.

Etzel also noted that, based on current and previous data, “reducing risk factors for preterm birth during the first trimester of pregnancy may be too late…it may now be time to consider a stronger focus on primordial prevention,” rather than “primary prevention” that is left up to the individual. She explained that “primordial prevention consists of population-level actions and measures that inhibit the emergence and establishment of adverse environmental, economic, and social conditions,” such as curbing air pollution and “prohibiting endocrine-disrupting chemicals in food-handling equipment and food contact materials.”

Messerlian and co-authors conducted the study using participants in the ongoing EARTH study, and included a prospective pre-conception cohort of subfertile couples:

  • 419 mothers, mean age 34.7 years, mean BMI 24.1 kg/m2.
  • 229 fathers, mean age 36 years, mean BMI 27.7 kg/m2.
  • 420 live-born singleton offspring born between January 2005 and December 2018, mean age 39.3 weeks, 8% born preterm, mean birth weight 3,363 g (about 7.4 lbs), 5% born with birth weight <2,500 g.

Statistical analysis was performed from August through October 2019. The RR of preterm birth (live birth <37 completed weeks’ gestation) was estimated in association with urinary concentrations of 11 individual phthalate metabolites, the molar sum of SDEHP metabolites, and two metabolites of the non-phthalate plasticizer substitute.

“All statistical models were adjusted for ART [assisted reproductive technology] vs non-ART to control for mode of conception and indirectly for the underlying cause of infertility,” the authors noted.

They reported that the association between pre-conception urinary SDEHP metabolite concentrations and risk for preterm birth appeared to be stronger for male infants (RR 2.01, 95% CI 1.17-3.45) versus female infants (RR 1.22; 95% CI 0.79-1.88, P=0.17 for effect-measure modification).

In sensitivity analyses, maternal pre-conception MHiNCH concentrations above the median were tied to a suggested increased risk of preterm birth (RR 4.02, 95% CI 0.84 to 19.30, P=0.08), and reduced gestational age (ß = −2.01 days, 95% CI −3.74 to −0.29 days, P=0.02).

As for paternal urinary SDEHP metabolite concentrations, they were associated with an increased risk of preterm birth in covariate-adjusted models (RR 1.41, 95% CI 0.94-2.11, P=0.09), but the association was “markedly attenuated toward the null in models accounting for maternal pre-conception SDEHP concentrations,” Messerlian’s group found (RR 1.06, 95% CI 0.66-1.68, P=0.82).

In analyses of only 228 couples, associations of maternal pre-conception ΣDEHP metabolite concentrations with preterm birth were prominent in covariate-adjusted models (RR 2.30, 95% CI 1.46-3.60, P<0.001), and also in models additionally adjusting for prenatal (RR 4.98, 95% CI 2.31 to 10.75, P<0.001) or paternal pre-conception (RR 2.37, 95% CI 1.39 to 3.70, P=0.001) ΣDEHP concentrations.

Study limitations included the small number of preterm birth cases, which prevented analysis of clinical subtypes of preterm birth, and “limited power to detect sex-specific differences,” so “these results should be interpreted with caution,” the authors wrote. Etzel added that “it is too early to assess whether the association [the authors] found between phthalate exposure before conception and preterm birth is causal. The study will need to be replicated, especially among couples who are not seeking treatment for infertility.”

The authors agreed “future studies should validate these associations,” but that “it is appropriate to inform couples planning conception about measures to reduce phthalate exposure.”

  1. Maternal pre-conception urinary concentrations of phthalate metabolites were associated with an increased risk of preterm birth.

  2. Female exposure to some plasticizers during the preconception period may be a potential risk factor for adverse pregnancy outcomes.

Shalmali Pal, Contributing Writer, BreakingMED™

The study was funded by the National Institute of Environmental Health Sciences (NIEHS).

Messerlian reported funding from the Canadian Institutes of Health Research. Co-authors reported grants from the NIEHS, the NIH, and a relationship with Quest Diagnostics.

Etzel reported no relationships relevant to the contents of this paper to disclose.

Cat ID: 40

Topic ID: 83,40,40,41,142,192,149,151,925

References

Zhang Y, et al “Association of parental preconception exposure to phthalates and phthalate substitutes with preterm birth” JAMA Network Open 2020; 3(4):e202159.

Etzel RA “Is the environment associated with preterm birth?” JAMA Network Open 2020; 3(4):e202239.