Introduction

Per- and polyfluoroalkyl substances (PFAS) are a group of synthetic fluorine-containing chemicals that are widespread and persistent in the environment (Houde et al. 2006; Lau et al. 2007). PFAS have been applied in a variety of commercial products since the 1940s, such as in the treatment of paper, clothing, carpets, food packing material, and kitchenware (Houde et al. 2006). Dietary exposure and contaminations from drinking water, food packaging material, indoor air, and household environments are likely the major exposure routes in humans (D’eon and Mabury 2011). The most frequently detected PFAS have estimated biological half-lives in humans of about 3 to 5 y or longer (Olsen et al. 2007). Perfluorooctanesulfonic acid (PFOS) and perfluorooctanoic acid (PFOA) were the two most commonly used PFAS that have now been gradually phased out in production, but these compounds are still detectable globally (Bjerregaard-Olesen et al. 2016; Calafat et al. 2019; Kato et al. 2011). Meanwhile, human exposures to other types of PFAS, such as perfluorononanoic acid (PFNA), have been reported to be increasing (Bjerregaard-Olesen et al. 2016; Kato et al. 2011). Moreover, newer types of fluorinated compounds, such as GenX (also named PFPrOPrA or HFPO–DA) (Gebbink et al. 2017), designed as substitutes for PFOA in manufacturing processes, have recently been detected in the biota and drinking water sources (Gebbink et al. 2017; Sun et al. 2016). Continuing research efforts to evaluate potential adverse health effects resulting from human exposures to these synthetic fluorinated compounds are still needed.

Experimental studies have demonstrated a rather strong developmental toxicity of PFOA and PFOS; for example, exposure to high doses of PFOS and PFOA can cause pregnancy loss, infant mortality, birth defects, and impaired fetal growth in mice (Lau et al. 2006; Luebker et al. 2005). In humans, considerable amounts of PFAS from the mothers can cross the placental barrier and accumulate in the fetus (Fei et al. 2007; Manzano-Salgado et al. 2015). Numerous epidemiological studies have suggested that prenatal PFAS exposure might affect fetal growth (Bjerregaard-Olesen et al. 2019; Fei et al. 2008; Liew et al. 2018a) and increase risk for preterm birth (Meng et al. 2018).

Miscarriage, defined as fetal loss prior to 20 or 22 wk of gestation, is common and estimated to affect about 10–20% of all clinically recognized pregnancies (Nybo Andersen et al. 2000; Wilcox et al. 1988). Epidemiological evidence regarding the possible link between PFAS exposure and miscarriage is sparse. The C8 Health Project that surveyed a community highly exposed to PFOA from contaminated drinking water reported no associations for the history of miscarriage and stillbirths according to the geospatial modeled PFOA and PFOS levels (Darrow et al. 2013; Savitz et al. 2012; Stein et al. 2009). A more recent report in the C8 Health Project, which employed a prospective design and assessed serum PFOA and PFOS concentrations in 1,129 women during 2005–2006 and their self-reported pregnancy outcomes between 2008 and 2011, found 20–30% higher odds for miscarriage per log ng/mL increase of PFOS level in the women prior to pregnancy, while no association was found for PFOA (Darrow et al. 2014). Another small case–control study, which included 56 cases of miscarriage selected from a pregnancy cohort among women who resided in the municipality of Odense, Denmark, during 2010–2012, estimated an unexpectedly high 2- to 16-fold odds for miscarriage in the highest tertile of two types of PFAS [PFNA and perfluorodecanoic acid (PFDA)], measured in first-trimester maternal serum, while no association was found for PFOA and PFOS (Jensen et al. 2015).

We conducted a nested case–control study using maternal blood samples collected in the Danish National Birth Cohort (DNBC) and evaluated the associations between prenatal exposure to seven types of PFAS and the risk of miscarriage.

Materials and Methods

Cases and Controls

The DNBC enrolled 100,413 pregnancies at the first antenatal visit (weeks 6 to 12) through general practitioners from 1996–2002 in all regions of Denmark (Olsen et al. 2001). Pregnant women who completed the first telephone interview invited approximately at week 12 of gestation and with a stored prenatal blood sample available for PFAS analyses were eligible for this study. All participating women enrolled in the DNBC intended to carry their pregnancies to term. Information on miscarriage and the gestational age of event was obtained from the Danish National Hospital Discharge Register (Andersen et al. 1999; Bech et al. 2005). We randomly selected 220 cases among 760 eligible pregnancies ending in miscarriage during weeks 12–22. We also randomly selected 220 controls from 80,375 eligible pregnancies ending in singleton live births registered in the Danish Medical Birth Register (Bliddal et al. 2018). The sample size was predefined and limited by the study cost to conduct PFAS measurement. Two control samples failed the PFAS extraction process; thus, the final sample size for statistical analysis was 220 cases and 218 controls.

The research protocol for this study was approved by the Danish data inspectorate (2015-57-0002) and the Danish ethical review committee (1-10-72-134-17)…

*Read the full study online at https://ehp.niehs.nih.gov/doi/10.1289/EHP6202