Phthalate Exposure During Pregnancy Linked to Shorter Gestation and Lower Birth Weight in Large US Cohort
核心洞察
A prospective cohort of 5,318 mother-child pairs across 18 US sites found that urinary phthalate and alternative plasticizer biomarkers were associated with shorter gestational length and lower birth weight-for-gestational-age z scores.
Each interquartile-range increase in summed diisononyl phthalate metabolites corresponded to roughly 0.6 fewer days of gestation, while detection of phthalic acid was linked to about 1.1 fewer days.
Summed phthalates (搜索) and alternative plasticizers were associated with a 0.06-point lower birth weight-for-gestational-age z score, with associations generally stronger among male newborns.
A large prospective US cohort study has found that urinary biomarkers of environmental chemical exposure during pregnancy—particularly phthalates (搜索) or alternative plasticizers and polycyclic aromatic hydrocarbons (搜索) (PAHs)—are associated with modest differences in gestational length and birth weight-for-gestational-age z scores. The findings, drawn from the Environmental influences on Child Health Outcomes (ECHO) Cohort, add to a growing body of evidence linking ubiquitous endocrine-disrupting chemicals to adverse pregnancy outcomes.
Researchers evaluated 5,318 mother-child pairs from 18 US sites enrolled from 2000 to 2021. A single midgestation urine sample, collected at a median of 25 weeks, was used to measure 113 analytes from 10 chemical classes, including insecticides, fungicides and herbicides, halogenated phenols, organophosphate esters, benzophenones, bisphenols, parabens, antimicrobials, phthalates (搜索) or alternative plasticizers, and polycyclic aromatic hydrocarbons (搜索).
The primary outcomes were gestational age at birth and birth weight-for-gestational-age z scores, with secondary outcomes including preterm birth and small-for-gestational-age status. Models accounted for site-level clustering and were adjusted for maternal age, race and ethnicity, prepregnancy body mass index, education, parity, season and year of urine collection, and tobacco use during pregnancy.
Widespread Chemical Exposure
Urinary biomarker detection was extensive across the cohort. Of the 113 analytes measured, 110 were detected in at least one sample, and 43 were detected in at least half of all samples. Samples had a median of 45 detected analytes, underscoring the near-universal nature of exposure to these environmental chemicals during pregnancy.
Phthalates and Gestational Length
The most consistent findings for gestational age involved phthalates (搜索) and alternative plasticizers. Eight analytes or sums were associated with younger gestational age at birth, all of which were metabolites of phthalates or alternative plasticizers. Each interquartile-range increase in summed diisononyl phthalate metabolites was associated with approximately 0.6 fewer days of gestation, and detection of phthalic acid was associated with about 1.1 fewer days of gestation.
In secondary analyses, summed diisononyl phthalate metabolites, mono(3-carboxypropyl) phthalate, and phthalic acid were associated with higher odds of preterm birth. Conversely, six analytes or sums were associated with older gestational age at birth or lower odds of preterm birth, including summed neonicotinoid insecticides, the insecticide metabolite 3,5,6-trichloro-2-pyridinol, the benzophenone BP1, the paraben ethyl paraben, the phthalate metabolite MnBP/MiBP, and a hydroxyphenanthrene biomarker. The study authors did not characterize these inverse associations as protective effects.
Birth Weight-for-Gestational-Age Findings
Associations with birth weight-for-gestational-age z scores were reported across several chemical classes. In adjusted models, 15 analytes or sums were associated with lower birth weight-for-gestational-age z scores, while two—a neonicotinoid metabolite and the benzophenone BP6—were associated with higher scores. Summed phthalates (搜索) and alternative plasticizers were associated with a 0.06-point lower birth weight-for-gestational-age z score, while summed polycyclic aromatic hydrocarbons (搜索) were associated with a 0.04-point lower score.
Several individual phthalate and polycyclic aromatic hydrocarbon biomarkers were associated with lower birth weight-for-gestational-age z scores, including monoethyl phthalate, mono-hexyl phthalate, hydroxynaphthalene, hydroxypyrene, hydroxylated phenanthrene, and hydroxylated fluorene biomarkers. Other analytes associated with lower scores included the neonicotinoid insecticide biomarker 6-chloronicotinic acid, two halogenated phenols, bis(1,3-dichloro-2-propyl) phosphate, benzophenone-8, and bisphenol F.
In categorical analyses, the continuous birth weight-for-gestational-age findings were generally directionally consistent but had wider uncertainty. One phenanthrene biomarker was associated with higher odds of small-for-gestational-age status. Summed phthalates (搜索) and alternative plasticizers were associated with numerically higher odds of small-for-gestational-age status, but the confidence interval crossed the null.
Sex-Specific Patterns
Subgroup analyses suggested that associations between phthalate and alternative plasticizer metabolites and younger gestational age or higher odds of preterm birth were generally stronger among male newborns than female newborns. Researchers also reported sex-specific findings for several individual analytes, although they noted that effect sizes were often similar and subtle sex differences could not be ruled out.
Sensitivity Analyses and Limitations
In sensitivity analyses, leave-one-site-out analyses did not meaningfully change effect sizes, and models including chemical class sums together produced similar estimates with wider confidence intervals. However, after correction for multiple comparisons, only associations of 2,3,4,6-tetrachlorophenol, benzophenone-8, 1-hydroxynaphthalene, and combined 2-, 3-, and 9-hydroxyfluorene with birth weight-for-gestational-age z scores remained.
The study had several limitations. Because it was observational, the findings cannot establish causality. Exposure assessment was based on a single midpregnancy urine sample, which may not reflect exposure across pregnancy. Sites selected urine samples based on availability and their own criteria, which may limit representativeness. Long-term urine storage may have influenced measurement for some analytes. The researchers also noted that both false-positive and false-negative findings were possible given the large number of analytes evaluated, and that chemical class sums assume equal toxic effects across analytes.
"Many of the urinary analytes that we measured, particularly phthalates (搜索) or alternative plasticizers and PAHs, were associated with shorter length of gestation or lower BW-GA z scores," wrote lead study author Jessie P. Buckley, PhD, of the University of North Carolina at Chapel Hill, and colleagues.