Maternal Plasma Perfluoroalkyl Substances and Miscarriage: A Nested Case–Control Study in the Danish National Birth Cohort

Abstract

BACKGROUND: Per-and polyfluoroalkyl substances (PFAS) are widespread persistent organic pollutants and endocrine disruptors. High doses of perfluorooctanesulfonic acid (PFOS) and perfluorooctanoic acid (PFOA) exposure can cause pregnancy loss and infant deaths in animals, but the associations between PFAS exposures and risk of miscarriage in humans are not well studied. METHODS: Using a case-control study nested within the Danish National Birth Cohort (DNBC, 1996-2002), we compared 220 pregnancies ending in miscarriage during weeks 12-22 of gestation, with 218 pregnancies resulting in live births. Levels of seven types of PFAS [PFOS, PFOA, perfluorohexane sulfonate (PFHxS), perfluoroheptane sulfonate (PFHpS), perfluorononanoic acid (PFNA), perfluorodecanoic acid (PFDA), and perfluorooctanesulfonic acid (PFOSA)] were measured in maternal plasma collected in early gestation (mean gestational week 8). We estimated the odds ratios (ORs) and 95% confidence intervals (CIs) for miscarriage and each PFAS as a continuous variable or in quartiles, controlling for maternal age, parity, socio-occupational status, smoking and alcohol intake, gestational week of blood sampling, and maternal history of miscarriage. Stratification by parity and PFAS mixture analyses using weighted quantile sum (WQS) regression were also conducted. RESULTS: We observed a monotonic increase in odds for miscarriage associated with increasing PFOA and PFHpS levels. The ORs comparing the highest PFOA or PFHpS quartile to the lowest were 2.2 (95% CI: 1.2, 3.9) and 1.8 (95% CI: 1.0, 3.2). The ORs were also elevated for the second or third quartile of PFHxS or PFOS, but no consistent exposure-outcome pattern emerged. An interquartile range (IQR) increment in the WQS index of seven PFAS was associated with 64% higher odds for miscarriage (95% CI: 1.15, 2.34). The associations were stronger in parous women, while findings were inconsistent among nulliparous women. CONCLUSION: Maternal exposures to higher levels of PFOA, PFHpS, and PFAS mixtures were associated with the risk of miscarriage and particularly among parous women. Larger replication studies among nulliparous women are needed to allay concerns about confounding by reproductive history.

Thyroid Disrupting Effects of Old and New Generation PFAS

“…A very recent paper from the same Danish group of the study by Preston et al. ( 73 ). describes the results of a nested case-control study performed on the same aforementioned national cohort of pregnant women.…”

Exposure to perfluoroalkyl substances in early pregnancy and risk of sporadic first trimester miscarriage

“…The positive association between early pregnancy PFOA exposure and miscarriage during the first trimester is a novel finding. Recently, a nested case-control study within the Danish National Birth Cohort, DNBC (sampled during years 1996 through 2002), reported an association between maternal PFOA and second trimester miscarriage 20 . The association was strongest among parous women, when investigating in total n = 220 cases of miscarriage.…”

“…This makes it important to study also associations between PFAS exposure and miscarriage, since abnormal placentation www.nature.com/scientificreports/ is important in the aetiology also of miscarriage. Despite this, human investigations of PFAS exposure as risk factor of miscarriage are limited 8,10,[17][18][19][20] and findings are highly divergent. The aim of this study was hence to investigate whether maternal exposure to eight PFASs in early pregnancy is associated with unexplained, sporadic first trimester miscarriage of the same pregnancy.…”

<p>Epidemiological Studies on Fetal Loss – Better Data and Research Methods are Needed</p>

“…32,33 If couples were not enrolled prior to conception, such as in pregnancy planner studies, adjustment on the time of study entry during pregnancy is recommended when the endpoint is pregnancy loss. 34 However, we should not blindly adjust for any strong predictors of the outcome in analyses. "Birth weight paradox" is a well-known example of "collider bias" due to an inappropriate adjustment of an intermediate variable (low birth weight) in the analyses of maternal smoking and infant mortality.…”