Environmental chemicals and preterm birth: Biological
mechanisms and the state of the science
Kelly K. Ferguson, PhD, MPH
1,*
and Helen B. Chin, PhD, MPH
1
1
Epidemiology Branch, National Institute of Environmental Health Sciences, Research Triangle
Park, North Carolina
Abstract
Purpose of review—Preterm birth is a significant worldwide health problem of uncertain
origins. The extant body of literature examining environmental contaminant exposures in relation
to preterm birth is extensive but results remain ambiguous for most organic pollutants, metals and
metalloids, and air pollutants. In the present review we examine recent epidemiologic studies
investigating these associations, and identify recent advances and the state of the science.
Additionally, we highlight biological mechanisms of action in the pathway between chemical
exposures and preterm birth, including inflammation, oxidative stress, and endocrine disruption,
that deserve more attention in this context.
Recent findings—Important advances have been made in the study of the environment and
preterm birth, particularly in regard to exposure assessment methods, exploration of effect
modification by co-morbidities and exposures, and in identification of windows of vulnerability
during gestation. There is strong evidence for an association between maternal exposure to some
persistent pesticides, lead, and fine particulate matter, but data on other contaminants is sparse and
only suggestive trends can be noted with the current data.
Summary—Beyond replicating current findings, further work must be done to improve
understanding of mechanisms underlying the associations observed between environmental
chemical exposures and preterm birth. By examining windows of vulnerability, disaggregating
preterm birth by phenotypes, and measuring biomarkers of mechanistic pathways in these
epidemiologic studies we can improve our ability to detect associations with exposure, provide
additional evidence for causality in an observational setting, and identify opportunities for
intervention.
Keywords
Preterm birth; gestational age; environment; contaminants; toxicity; epidemiology
*
Corresponding Author: Kelly K. Ferguson, Epidemiology Branch, National Institute of Environmental Health Sciences, 111 TW
Alexander Drive, PO Box 12233, MD A3-05, Research Triangle Park, NC 27709, USA, kelly.ferguson2@nih.gov. .
Conflict of interest
The authors declare that they have no conflict of interest.
Human and animal rights and informed consent
This article does not contain any studies with human or animal subjects performed by any of the authors.
HHS Public Access
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Curr Epidemiol Rep
. Author manuscript; available in PMC 2018 March 01.
Published in final edited form as:
Curr Epidemiol Rep
. 2017 March ; 4(1): 56–71. doi:10.1007/s40471-017-0099-7.
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Introduction
Preterm birth (PTB) is an extensively studied perinatal outcome due to its prevalence, high
societal costs, and poorly understood origins. Defined as delivery prior to 37 weeks
gestation, PTB occurs in approximately 1 in 10 pregnancies worldwide and is one of the
strongest predictors of neonatal mortality and morbidity (1). Furthermore, PTB may mediate
numerous later life adverse health outcomes, such as neurodevelopmental delays, asthma
and allergy, and metabolic disease. There are known predictors, presentations, and
hypothesized mechanisms of PTB, but knowledge of concrete
causes
remains minimal. The
prevalence, costliness, and ambiguity surrounding this disease has led to scientific curiosity
in the potential contribution of environmental chemical factors.
Exposures to organic pollutants, metals and metalloids, and air pollutants have the potential
to increase risk of PTB through multiple pathways. Some of the most important mechanisms
of action that have been include inflammation, oxidative stress, and endocrine disruption,
and each of these in turn has been linked to PTB. A large body of literature is devoted to this
research (2-4), and, importantly, there have been recent efforts to identify the relevant
biological mechanisms underlying these relationships in epidemiologic studies. By
measuring biomarkers of mechanism, assessing windows of vulnerability to exposure, and
examining associations with PTB phenotypes, research on environmental chemicals and
PTB has advanced significantly.
The intention of this review is first to describe inflammation, oxidative stress, and endocrine
disruption as three potential pathways of chemical action in the pathway to PTB (Figure 1),
and to highlight recent studies that have advanced understanding of these mechanisms
within the context of pregnancy (Table 1). Next, we present the state of the epidemiologic
evidence examining the relationship between organic pollutants, metals and metalloids, and
air pollutants. We review recent studies and discuss the major findings that support or refute
an association with PTB and that point toward mechanisms.
Mechanisms of chemical action in the etiology of PTB
While rodent studies can be helpful for understanding biological processes that may be
related to PTB, they offer an insufficient model, as it is very difficult to cause them to deliver
preterm (5, 6). Thus, epidemiologic studies are especially valuable for studying this health
outcome. This is true for studying associations with chemical exposures and for elucidating
mechanisms. Beyond the utility of this model, studies of environmental chemicals and PTB
that additionally investigate mechanisms can provide stronger arguments for causation in the
observational setting, identify opportunities for interventions when remediating exposure is
difficult or impossible, and improve the understanding of chemical toxicities in humans that
may be extended to other disease. Here we examine three potential mechanistic pathways
that have received some attention in the study of environmental chemicals and PTB, and
deserve additional exploration in the future, including inflammation, oxidative stress, and
endocrine disruption (Figure 1). Additionally, we highlight consequences of these disrupted
processes in pregnancy, potentially sensitive windows of vulnerability to exposure, and
phenotypic presentations of PTB that would be expected to be more strongly associated with
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each pathway (e.g., spontaneous preterm labor, preterm premature rupture of the membranes
[PPROM], preeclampsia, and intrauterine growth restriction [IUGR]).
Inflammation
Intrauterine bacterial infection is perhaps the best established cause of PTB (7).
Inflammatory pathways are thus one of the most well-studied mechanisms in the preterm
pathway. Environmental contaminants have the potential to generate circulating or tissue-
specific inflammation in several ways. First, particulate matter (metallic, endotoxin, or
otherwise) may be engulfed by phagocytosis and lead to activation of T helper cells and
release of cytokines (8). Second, xenobiotic binding to certain receptors, such as peroxisome
proliferator activated receptors, can influence cytokine production as in the example of
phthalate monoesters (9, 10).Third, environmental chemicals have demonstrated capacity to
cause epigenetic modification by way of DNA methylation, histone modifications, and/or
perturbations in miRNA expression which can lead to changes in inflammatory responses
(11). Finally, these exposures can have adjuvant effects, exemplified by phthalates (12),
which can increase the inflammation response to other stimuli.
While in many cases the exact cellular processes by which chemicals create inflammation
are unknown, many exposures have been associated with inflammation in epidemiologic
studies (13-15). Changes in the systemic maternal or the intrauterine inflammatory milieu
could have downstream consequences that precipitate PTB, e.g. by initiating a cascade of
events leading to cervical ripening, rupture of the amniotic sac, or increased myometrial
contractility (16). These changes—sensitive to exposures later in pregnancy—may all
precipitate spontaneous PTB either by initiating preterm labor or by causing PPROM.
Oxidative Stress
Oxidative stress, which can cause or be consequence of increased inflammation, is another
important mechanism that could link environmental chemical exposures to PTB. Many
chemicals have the capacity to induce oxidative stress, either through: overproduction of
reactive oxygen species (ROS) generated enzymatically (e.g., through upregulation of
cytochrome P450 pathways) or non-enzymatically (e.g., through the Fenton reaction) (17,
18); changes in mitochondrial membrane potential and permeability (19-21); and impaired
antioxidant function (22, 23). Disturbance of the delicate balance between ROS and
antioxidant defenses can have numerous downstream consequences in pregnancy. Early in
gestation, oxidative stress can cause impaired invasion of the spiral arterioles into the
maternal myometrium, resulting in poor placentation that can lead to preeclampsia or IUGR
(24). Elevated levels later in pregnancy could: activate the maternal endothelium, part of a
two-stage hypothesis underlying the onset of preeclampsia (25); cause damage to the
membranes resulting in premature rupture (26, 27); create signaling changes in the cervix
leading to shortening and spontaneous labor (28, 29); and/or impact placental protein
synthesis and nutrient transport that again lead to fetal growth restriction which can result in
medically indicated PTB (30, 31).
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Endocrine disruption
Hormones carefully regulate nutrient transfer in pregnancy essential for growth of the fetus
as well as timing of parturition. Disrupted fetal and placental thyroid hormone signaling has
been observed in cases of IUGR (32). Additionally, animal studies show that glucocorticoid
administration during pregnancy leads to a clear dose-dependent decrease in size of the fetus
(30), and similar associations have been observed in human populations (33). Thus, thyroid
and glucocorticoid hormones (e.g., cortisol) may be involved in the pathway to PTB with
presentation of IUGR. Many chemicals have been linked to thyroid hormone disruption,
potentially through receptor activity, particularly polychlorinated biphenyls (PCBs) and
perfluorinated compounds (34, 35). Additionally, extensive
in vitro
and animal evidence
demonstrates that environmental contaminants have the potential to interfere with
glucocorticoid signaling. For example, bisphenol A (BPA) and other phenols, phthalates,
perfluorinated compounds, and some pesticides can inhibit enzymes involved in the
metabolism of glucocorticoids, thus raising circulating levels (37). Hormonal activity, and
particularly that of the hypothalamic pituitary adrenal (HPA) axis, is additionally important
in the timing of delivery. Corticotropin releasing hormone (CRH) in the placenta has been
hypothesized as crucial for timing of spontaneous parturition (38, 39). Progesterone,
estrogen, and cortisol pathways in the mother and fetus that interact to maintain homeostasis
of CRH in pregnancy may thus be sensitive targets of chemical exposure (40).
Lastly, it is important to recognize that these pathways do not operate independently.
Inflammation is tightly tied to hormonal regulation in pregnancy (16), and oxidative stress
and inflammation have the potential to induce one another. These mechanisms may explain
in part some of the associations observed in the following sections.
Environmental chemicals and PTB
Organic pollutants
Water disinfection byproducts (DBP)—A common method to disinfect drinking water
is through the process of chlorination (41, 42). The most abundant byproducts of this process
are trihalomethanes (THMs) and exposure to these along with haloacetic acids (HAAs) have
been studied in relation to PTB (43). Grellier and colleagues reviewed the literature on
exposure to water DBP and PTB in 2010 and concluded no association (44).
Since 2010 there have been seven additional studies (45-51). Three, conducted in Europe,
used a method of exposure assessment that incorporated both measurements of THMs from
public drinking water sources and individual level information on personal routes of
exposure including ingestion, inhalation, and dermal absorption (45-48). The study by
Costet and colleagues was novel in that exposure was quantified from a biomarker of
trichloroacetic acid measured in maternal urine (45). None of these studies found an
association between total THM and PTB.
The remaining three studies were US based and found small positive associations with water
DBP and PTB (49-51). In New York, total THM were measured from the public water
source at multiple time points during pregnancy (49). Although exposure was determined
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from public water source measures, this study was able to link the source with maternal
residence, lending more confidence to the level of exposure being assigned to each woman.
A modest association was detected between low levels of total THMs and PTB, but a null
association was observed at higher levels. The remaining two studies did incorporate an
individual component and used a representative water source to assign exposure, but also
found similar small positive associations with some of the water DBP (51).
Persistent organic pollutants—Most of the literature examining an association between
organic pollutants and PTB has focused on chemicals that persist in the environment and
human body. Evidence of a relationship between persistent pesticides and PTB come from
studies of populations with high levels of exposure (52, 53). A subset of studies from a
recent review of environmental chemicals and PTB (54) were published since 2010 and
show that overall the literature supports an association between high levels of
organochlorine pesticide exposure (55-57) and PTB with weaker or null associations for the
remaining persistent pollutants (54, 58-65).
Studies published since that review (54) show consistent findings of the association between
persistent pesticides and PTB with high exposures associated with increased risk, whereas
the relationship with lower exposures is less clear. In a study conducted in Guadeloupe
where there is widespread chlordecone use and environmental contamination, authors found
an association with exposure as measured by maternal blood sample at delivery and
increased risk of PTB (
66). However, a study conducted in Spain, where pesticide exposure
was much lower, failed to show an association between 1
st
trimester maternal
hexachlorobenzene levels and PTB (67).
Exposure to high levels of non-pesticide persistent pollutants do not show the same
relationship, with generally null findings for dioxin exposure and PTB regardless of
exposure burden. A chemical explosion in Seveso, Italy led to unprecedented residential
dioxin exposure providing the opportunity to investigate the health effects of high levels of
this chemical (68). Despite exposure to elevated levels of dioxin, an association with PTB
could not be established in this cohort (68). Similarly, in a population highly exposed to
perfluorooctanoic acid as a result of industrial contamination of the drinking water, no
association with PTB was found.(69) In contrast, a study of flame retardants showed a dose
response relationship with PTB (70). Maternal blood samples were taken at the time of
delivery and an increased risk of PTB was observed with increasing levels of
polybrominated diphenyl ethers.
Non-persistent organic pollutants—Investigation of organophosphate pesticides in
relation to PTB has been limited and no associations with PTB have been reported (71, 72).
Atrazine, another chemical used in agriculture, is applied as an herbicide, and can
contaminate water supplies (73). Early studies looking at atrazine assigned exposure based
on measurements from water sources and found null or weak non-significant positive
associations with PTB (74, 75). Recent studies continue to use drinking water levels to
assign atrazine exposure despite the ability to measure individual exposure from urine
samples (76), and the evidence for atrazine being associated with increased PTB remains
inconclusive (77).
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