Academic journal article Environmental Health Perspectives

Conditioning on Parity in Studies of Perfluoroalkyl Acids and Time to Pregnancy: An Example from the Danish National Birth Cohort

Academic journal article Environmental Health Perspectives

Conditioning on Parity in Studies of Perfluoroalkyl Acids and Time to Pregnancy: An Example from the Danish National Birth Cohort

Article excerpt

Introduction

Since 2009, a number of studies have investigated associations between perfluoroalkyl acids (PFAAs) in women and fecundability, indicated by the time to pregnancy (TTP), with inconsistent results (Bach et al. 2015b, 2015a, 2016b; Buck Louis et al. 2013; Fei et al. 2009; J0rgensen et al. 2014; Velez et al. 2015; Vestergaard et al. 2012; Whitworth et al. 2012, 2016). Only one epidemiological study showed an association between higher PFAAs and longer TTP in nulliparous women (Fei et al. 2009), whereas three other studies found no association (Bach et al. 2015a; Vestergaard et al. 2012; Whitworth et al. 2016). A few other studies demonstrated associations in parous women or pooled samples of both parous and nulliparous women (Bach et al. 2016b). Thus, differences in whether and how the studies conditioned on parity could possibly, at least partly, explain the inconsistent results (Bach et al. 2016a). Some rodent studies suggest that PFAA exposure may cause impaired fertility, potentially through endocrine disruption. However, most animal studies applied exposure levels of PFAAs several orders of magnitude higher than for background-exposed humans (Bach et al. 2016b).

In this paper, we use causal directed acyclic graphs (DAGs) to illustrate confounding by factors related to previous pregnancies as well as potential dependent measurement error of the exposure in pregnancy-based studies of parous women. Further, we evaluate data from the Danish National Birth Cohort to exemplify these issues.

In a recent paper, Velez et al. (2015) argued that the association between PFAA exposure and the TTP may be described as illustrated by Howards et al. (2012) using a DAG. Figure 1, which is adapted from Howards et al. (2012), assumes that both fecundability and PFAA levels will be similar in two consecutive pregnancies, but this is not plausible for the following reasons. First, fecundity (the biological capability to conceive) and fecundability (the probability of conception in each cycle) depend on various factors such as age (Axmon et al. 2006; Joffe and Li 1994; Mutsaerts et al. 2012; Olsen 1990), body mass index (BMI) (Gesink Law et al. 2007; Ramlau-Hansen et al. 2007; Wise et al. 2010), and smoking (Bolumar et al. 1996; Joffe and Li 1994; Olsen 1991). Consequently, fecundity and fecundability are not expected to be constant over time at the individual level. Second, PFAA concentrations also change over time. Many PFAAs have half-lives of a year or more (Olsen et al. 2007), and a study of 100 women reported that concentrations measured during the same trimester were correlated between consecutive pregnancies (Papadopoulou et al. 2015). However, a study of 19 women reported that PFAA concentrations generally decrease during pregnancy (Glynn et al. 2012), and, on average, PFAA concentrations are lower in parous compared to nulliparous women (Berg et al. 2014; Brantsaeter et al. 2013; Papadopoulou et al. 2015), most likely due to the transfer of PFAAs to the fetus and their excretion in breast milk (Cariou et al. 2015; Kang et al. 2016; Mondal et al. 2014; Motas Guzman et al. 2016).

Velez et al. (2015) argued that conditioning on parity should be avoided in studies of PFAAs and TTP, and stated "In a sense, [previous TTP] is a proxy for parity and fecundability." In our opinion, however, the time-varying nature of PFAA exposures needs to be considered, and fecundability (or rather, its proxy measure, the TTP) and parity (previous births) should be treated as separate variables in causal models (Bach et al. 2015a). Consequently, we propose an alternative causal structure, shown in Figure 2. In all subsequent figures, the association of interest is the association between PFAAs at the time of starting to try to conceive and the TTP, independent of parity. For nulliparous women, this is illustrated by the association between PFAA 1 and impaired fecundity 1, and for parous women, by the association between PFAA 2 and impaired fecundity 2. …

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