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Abstract

Nongenetic, environmental factors contribute to maternal morbidity and mortality through chemical exposures via air, water, soil, food, and consumer products. Pregnancy represents a particularly sensitive window of susceptibility during which physiological changes to every major organ system increase sensitivity to chemicals that can impact a woman's long-term health. Nonchemical stressors, such as low socioeconomic status, may exacerbate the effects of chemical exposures on maternal health. Racial/ethnic minorities are exposed disproportionately to both chemicals and nonchemical stressors, which likely contribute to the observed health disparities for maternal morbidities and mortality. Epidemiological studies linking exposures to adverse maternal health outcomes underscore the importance of environmental health impacts, and mechanistic studies in model systems reveal how chemicals perturb biological pathways and processes. Environmental stressors are associated with a variety of immediate maternal health impacts, including hypertensive disorders of pregnancy, fibroids, and infertility, as well as long-term maternal health impacts, such as higher risk of breast cancer and metabolic disorders. Identifying and reducing a pregnant woman's environmental exposures is not only beneficial to her offspring but also important to preserve her short- and long-term health.

Introduction

Research on environmental exposures of pregnant women has focused on adverse health effects in their offspring, but relatively few studies have focused on the short- and long-term health of the mother. Preexisting conditions with links to environmental exposures and maternal gestational exposures pose risks to women's health both during pregnancy and after parturition. Environmental toxicants that play a role in maternal health are ubiquitous, with well over 70% of reproductive-age women and pregnant women having detectable levels of phenols, such as bisphenol A, persistent organic pollutants (POPs), and polycyclic aromatic hydrocarbons.¹ Levels of these toxicants are often higher in nonwhite women²; and these chemical stressors, in combination with nonchemical stressors, such as neighborhood conditions, contribute to health disparities in maternal morbidity and mortality, as well as to long-term postpregnancy health. In this review, we consider the role of environmental exposures on fertility, pregnancy, maternal morbidities, and women's health beyond the postpartum period. Examples from both environmental epidemiology and fundamental mechanistic research demonstrate a direct role of the environment during this window of susceptibility, as well as indirect impacts on comorbidities or health effects later in life (summarized in Table 1).

Table 1.

Examples of Environmental Stressors Linked to Maternal Health Outcomes and Potential Moderating Factors^a

Environmental stressors	Maternal outcomes
Air pollution	Hypertensive disorders of pregnancy^3,4
	Polycystic ovarian syndrome⁵
	Subfertility^6 –9
	Miscarriage^10,11
	ART failure^12 –17
Metals	Hypertensive disorders of pregnancy^18,19
	Uterine fibroids^20 –23
	Subfertility^24 –26
	Miscarriage^27,28
	Cardiometabolic health²⁹
PFAS^a	Breast development and lactation^30 –32
	Breast cancer^33,34
	Cardiometabolic health³⁵
Persistent pesticides (DDT and DDE)	Lactation impairment³⁶
Persistent pesticides (DDT and DDE)	Breast cancer risk in mother and female offspring³⁷
Persistent pollutants (dioxin/PCBs)	Breast cancer risk in mother by 50 years of age³⁸
Persistent pollutants (dioxin/PCBs)	Mammary development and lactation³⁹
EDCs (e.g., phthalates, phenols)	Uterine fibroids^40 –42
EDCs (e.g., phthalates, phenols)	Thyroid function, glucose metabolism and obesity, fertility, and carcinogenesis⁴³
Potential moderators
Race/ethnicity	Cardiometabolic health⁴⁴
Race/ethnicity	Uterine fibroids⁴⁵

Most exposures were associated with more adverse outcomes, but the strength and direction of effect varies. See cited references for details.

ART, assisted reproductive technology; DDE, dichlorodiphenyl dichloroethene; DDT, dichlorodiphenyltrichloroethane; EDC, endocrine-disrupting chemical; PCB, polychlorinated biphenyl; PFAS, perfluoroalkyl substance.

Maternal Environmental Health Disparities

A health disparity refers to differences in the prevalence of health conditions that adversely affect disadvantaged populations.⁴⁶ In the United States, racial/ethnic minorities, socioeconomically disadvantaged populations, underserved rural populations, and sexual and gender minorities are included in this definition. Often these populations experience higher disease incidence or prevalence, earlier onset, more aggressive progression, and premature or higher mortality.⁴⁶

Chemical and nonchemical exposures that adversely affect maternal health are not randomly distributed across the population; their distribution contributes to the widespread disparities observed across the health conditions described in this review. For example, racial/ethnic minorities live in largely different physical and social environments compared with the majority white population,⁴⁷ and racial differences in exposure to stressors emanating from institutional, personally mediated, and internalized discriminatory policies and practices lead to differential risk across the life span, including during the reproductive period.⁴⁸ Such conditions may subsequently contribute to the disproportionately increased risk of adverse maternal health behaviors (e.g., disrupted sleep) and outcomes (e.g., preeclampsia), along with a cascade of suboptimal health consequences (e.g., cardiovascular disease).^2,49
–51 Chemical exposures are higher, or their reported associations tend to be stronger, among racial/ethnic minorities compared to white populations for cardiometabolic health outcomes, such as obesity, hypertension, type 2 diabetes mellitus, chronic kidney disease, and cardiovascular disease.^{2,20,52

–58} For example, a recent review of the effects of synthetic chemicals on cardiometabolic health among vulnerable populations (defined broadly as pregnant women and children, the economically disadvantaged, and racial/ethnic minorities) found associations of some POPs (e.g., perfluoroalkyl/polyfluoroalkyl substances) and non-POPs (i.e., phenols, phthalates, and parabens) with gestational diabetes and dysregulated glucose metabolism.⁴⁴

Racial/ethnic minority women generally have a higher body burden of exposures from consumer products, occupations, and residential characteristics.^50,51 Exposure to potentially dangerous beauty product-related chemicals during reproductive ages can result from discriminatory practices and policies related to the marketing of chemical products to racial/ethnic minorities (e.g., hair relaxers with lye) and product preferences to achieve a culturally desirable Eurocentric beauty standard will influence product uptake/usage of hair relaxers and skin lighteners.⁵⁷ Disparate exposure to endocrine-disrupting chemicals (EDCs) can occur through discriminatory racial residential and labor market segregation policies and practices. Such practices place racial/ethnic minorities in closer proximity to sources of water and air pollution, and these minorities are less likely to benefit from remediation efforts after contamination is identified in a community.⁵⁹ Higher consumption of EDC-containing processed foods is due to “food deserts” or “food swamps,” with fewer healthy options available in low-income neighborhoods. Limited resources also drive the purchasing of cheaper, more chemically laden consumer products.⁵⁶ An important pursuit of minority health research is to identify health burdens of racial/ethnic minority groups that stem from environmental exposures and social disadvantages arising from discriminatory policies and practices that contribute to maternal health disparities.⁴⁶

Hypertensive Disorders of Pregnancy

Hypertensive disorders of pregnancy (HDP) comprise a spectrum of pregnancy complications that include gestational hypertension, preeclampsia/eclampsia, and chronic hypertension with/without superimposed preeclampsia and are leading causes of maternal morbidity and mortality.⁶⁰ In addition to pregnancy and postpartum complications, women who experience HDP are at significantly higher risk for diseases later in life.^61,62 Risk factors for HDP include comorbidities (e.g., diabetes) and maternal age >40 years; however, most cases of preeclampsia (the most common type of HDP) occur among first-time pregnancies with no other known risk factors,⁶³ suggesting a potential role of environmental exposures.

Air pollution has been the primary focus of many studies of HDP. Traffic emissions (e.g., particulate matter, nitrogen oxides) have been classified by the National Toxicology Program as a presumed hazard for HDP.³ Fewer studies have evaluated other environmental contaminants, limiting the ability to draw definitive conclusions. Evidence of an association with preeclampsia exists for cadmium and other heavy metals, POPs such as perfluoroalkyl substances (PFAS), and plasticizers (e.g., phthalates).^18,64 Despite the disproportionate burden of chemical exposures, few studies of HDP or other cardiometabolic health outcomes have focused on racial/ethnic minority populations.⁴⁴

The clinical manifestations of preeclampsia are largely attributed to (i) placental dysfunction due to incomplete remodeling of the uterine spiral arteries early in pregnancy and subsequent reduction of blood supply and nutrients to the fetoplacental unit; and (ii) dysregulated maternal hemodynamics. Numerous environmental factors plausibly could contribute to the onset and/or progression of either of these processes.

Remodeling of the spiral arteries is critical to the proper exchange of oxygen and nutrients to the fetus and removal of waste from the fetus during pregnancy. Improper remodeling leads to hypoxia of the placenta and the subsequent release of factors that activate oxidative stress and inflammation pathways. Many environmental contaminants cross the placenta and can disrupt the proper trophoblast migration and invasion necessary for spiral artery remodeling and, thus, normal placentation.^65,66 Epidemiologic studies demonstrate associations between contaminant exposures and angiogenic factors that are strong biomarkers of implantation and placental development^67,68 and epigenetic changes that may reflect perturbations in normal processes.⁶⁹

Many environmental contaminants, particularly air pollutants and heavy metals, have been linked to elevated blood pressure in both pregnant and nonpregnant populations.^3,70 In response to the growing demands of the fetus, maternal hormones mediate hemodynamic changes to increase blood volume and cardiac output while decreasing vascular resistance. Furthermore, endothelial cells play a critical role in these processes by sensing blood composition and by providing a physical barrier to the improper movement of water, ions, proteins, and cells from the blood into the vessel walls. Oxidative stress and inflammation play a causal role in endothelial cell dysfunction,⁷¹ and these pathways may be highly sensitive to environmental exposures. Epidemiologic evidence linking environmental exposures to HDP and the biological plausibility based on mechanistic studies support an important role for the environment in the etiology of HDP.

Breast Development and Health

The breast has the longest developmental window of any organ in women; beginning in the early prenatal period, continuing throughout puberty, with completion during the first full-term pregnancy.⁷² During pregnancy, the breast is particularly vulnerable to toxicant exposure as the body is undergoing complex changes in nutrient and toxicant metabolism and hormonal shifts.^73
–75 Pregnancy as a window of susceptibility for toxicant exposure adversely altering the human breast is understudied.^{58,74,76
–78}

Breast-specific glandular morphology and function are altered by exposure to environmental toxicants. Laboratory animal data demonstrate that dioxins and perfluorooctanoic acid (PFOA) interfere with maternal breast development during pregnancy and impair lactation.^30,39 Recent evidence suggests that PFOA and related chemicals also may shorten lactation or inhibit milk production in women,^31,32 similar to dichlorodiphenyl dichloroethene.³⁶ Breast density, a morphological factor strongly related to later breast cancer risk, has been poorly studied for environmental influences during this critical window of pregnancy.

Chemicals may alter epigenetic mechanisms to influence both transient and persistent effects on the breast. The breast undergoes a well-characterized differentiation process during pregnancy,^72,79 and exposures, such as to EDCs, during this critical window can affect breast growth and differentiation.⁷⁶ Morphological and cellular changes during pregnancy are linked to alterations in the epigenome, because chromatin structure is directly linked to development and cell fate.⁷⁹ Pregnancy-associated epigenetic signatures in the breast and other tissues persist after breast involution.^80,81 In addition, some chromatin remodeling complexes are responsive to estrogen and progesterone,^82,83 which are increased in pregnancy. Thus, during pregnancy, the breast is rewriting its epigenetic program to form new structures and complete its development.⁸⁴ Therefore, environmental contaminants, particularly during pregnancy, may act on the breast through numerous mechanisms—including endocrine disruption, alterations in chromatin structure, and cell-type-specific aberrations—to alter future risk of developing breast cancer.

Pregnancy is not only the last period of breast maturation for women but also the first developmental window for her offspring. For example, exposure to environmental chemicals during pregnancy—such as DDT, polychlorinated biphenyls, and polyfluoroalkyl and PFAS—alter breast cancer risk in perimenopausal female offspring.^33,34,37,38 Diethylstilbestrol (DES), a drug prescribed for women from 1938 to 1971 to prevent miscarriage, exemplifies how pregnancy is a susceptible time period for breast development in women and their daughters. One in six (vs. one in eight in the general population) DES-prescribed pregnant women developed breast cancer (relative risk = 1.27, 95% confidence interval [CI] = 1.07–1.52),⁸⁵ and a higher breast cancer risk in DES daughters over 40 years of age also is reported (hazard ratio = 1.82, 95% CI = 1.04–3.18),⁸⁶ among numerous other adverse health outcomes. Nongenetic risk factors, including contaminant exposures that can alter genetic and epigenetic programming to promote breast tumorigenesis, may contribute to observed racial disparities of earlier age of onset and higher rates of more aggressive breast cancer subtypes in African American women.⁸⁷

Subfertility, Pregnancy Complications, and Maternal Morbidity

Environmental exposures can interfere with a woman's fertility either directly, via disrupted endocrine signaling or reproductive axis function, or indirectly, via their influence on health conditions, such as polycystic ovarian syndrome (PCOS) or uterine fibroids, that can reduce fertility and increase maternal morbidity. Subfertility can compel the use of assisted reproductive technologies (ART), which increase morbidities, including Caesarean delivery, preeclampsia, hemorrhage, HDP, gestational diabetes, placental abnormalities, thromboembolism, and maternal death.^88

–92

Links have been documented between environmental exposures and conditions that impact fertility and maternal morbidity. Air pollution, including NO₂ and PM_2.5, has been associated with increased risk of PCOS.⁵ Uterine fibroids, benign tumors of the uterine muscle, may be influenced by environmental exposures as epidemiologic and laboratory studies indicate that EDCs and metals could play a role.^{21
–23,40
–42} Compared to white women, African American women have earlier onset of fibroids and worse symptomatology, resulting in an increased risk of pregnancy bleeding and Caesarean delivery.⁴⁵

Air pollution has been directly associated with reduced fertility.⁶ Specifically, NO₂,⁷ PM_2.5,⁷ and metals^12,24

–27 have been associated with reduced conception rates, infertility, or increased pregnancy loss. Exposure to NO₂ and ozone, particularly around ovulation, may reduce conception.⁸ Traffic pollution has been associated with increased risk of miscarriage among nonsmokers¹⁰ and an increased risk of infertility more broadly.⁹ Subfertility caused by air pollution may lead women to ART, which is less successful for exposed women. NO₂ and PM_2.5 are associated with increased ART cycle failure rates.¹³ Carbon monoxide¹⁴ and PM_2.5 ¹⁵ are associated with decreased conception rates. Decreased live birth rates are associated with NO₂,^12,15,16 SO₂,¹⁷ ozone,¹⁵ and PM_2.5.¹³ An ecologic association between air pollutant peaks and monthly in vitro fertilization pregnancy failure rates has been observed.¹¹

Metabolic Disorders

Metabolic disorders during pregnancy can impact a woman's short-term and long-term physiology. Women with gestational diabetes have a seven-fold increase in the risk of type 2 diabetes after the gestational period and the postpartum incidence of metabolic syndrome is as high as 12%.^88,93,94 The increase in metabolic syndrome also is observed in women without gestational diabetes and is greater among women with high prepregnancy body mass index⁹⁵ or elevated diastolic blood pressure during pregnancy.²⁹ Unequal burden of exposure to chemicals, such as EDCs, is an underresearched contributor to the unequal burden of metabolic disease risk in Latinos, African Americans, and low-income populations.⁵⁶

Exposure to environmental contaminants during pregnancy is implicated in metabolic changes. Repeated exposure to such EDCs as phthalates, parabens, and phenols results in dysregulated glucose metabolism/tolerance or changes in maternal thyroid hormone levels during pregnancy.^{44,52,96
–98} In addition, both experimental and epidemiologic evidence suggests that PFAS and certain metals are metabolic disruptors that may adversely influence cardiometabolic health, interfere with glucose control, and increase risk of hypertension and hyperlipidemia.^29,35 The impact of EDCs on thyroid function, glucose metabolism and obesity, fertility, and carcinogenesis mainly occurs through epigenetic mechanisms,⁴³ and their contributions to maternal metabolic issues likely impact long-term maternal health versus immediate postpartum effects.⁹⁹

Conclusion

Environmental exposures co-occurring in varying mixtures in the air we breathe, the food we eat, and beyond can affect maternal morbidity and mortality. Environmental health is an important component of maternal health, and observed health disparities in maternal health may be driven by elevated exposures to chemical and nonchemical stressors. In this review, we illustrate specific examples of maternal vulnerabilities to chemical exposures in pregnancy. HDP have been linked to a variety of environmental exposures, and mechanistic studies underscore the potential for such exposures to disrupt placentation and hemodynamic regulation. Breast development, particularly during the critical window of pregnancy, is sensitive to perturbation by environmental contaminants, which may contribute to impaired breastfeeding and later breast cancer risk. A variety of environmental exposures may lead to subfertility, increasing the risk of ART treatments, which are accompanied by numerous maternal health risks. Alterations during pregnancy may permanently alter metabolic and cardiovascular function.

Future research is needed addressing knowledge gaps in maternal environmental health to better understand pregnancy as a susceptible window and to understand the mechanisms underlying increased risk of disease (e.g., diabetes, cardiovascular events, obesity, or breast cancer). The maternal exposome must be assessed to characterize how the milieu of chemical and nonchemical stressors we encounter throughout life can adversely impact maternal health through exposure-outcome pathways. Capturing environmental exposures across diverse racial/ethnic populations in big data initiatives, such as the All of Us Research Program, will be crucial for accelerating maternal environmental health research. Biomarkers of exposure may inform the path for personalized exposure monitoring and interventions to prevent adverse maternal health outcomes. These efforts will require collaborative science across a variety of disciplines, with the ultimate goal of disseminating research that informs policy to prevent maternal mortality and morbidity.

In sum, these few examples show the ability of prenatal environmental exposures to exert influence on maternal morbidity and mortality across the life course. By taking steps to identify and reduce exposures in this critical window, pregnant women, aided by their health care providers, can protect their own health, not just the health of their children.

Resources for more information on environmental health issues relevant to pregnant women include the following:

National Institute of Environmental Health Sciences

https://factor.niehs.nih.gov/2020/1/papers/traffic/index.htm

https://factor.niehs.nih.gov/2019/12/community-impact/apple/index.htm

https://niehs.nih.gov/health/topics/population/whealth/index.cfm

https://niehs.nih.gov/health/topics/agents/cosmetics/index.cfm

https://niehs.nih.gov/health/materials/environmental_factors_and_breast_cancer_risk_508.pdf

https://niehs.nih.gov/health/materials/endocrine_disruptors_508.pdf

https://niehs.nih.gov/health/materials/flame_retardants_508.pdf

https://niehs.nih.gov/health/materials/perfluoroalkyl_and_polyfluoroalkyl_substances_508.pdf

https://niehs.nih.gov/health/materials/partnerships_for_environmental_public_health_peph_508.pdf

Partnerships for Environmental Public Health

https://niehs.nih.gov/research/supported/translational/peph/resources/index.cfm

Centers for Disease Control and Prevention

https://cdc.gov/reproductivehealth/maternalinfanthealth/pregnancy-relatedmortality.htm

https://cdc.gov/reproductivehealth/maternalinfanthealth/severematernalmorbidity.html

https://cdc.gov/mmwr/volumes/68/wr/mm6835a3.htm?s_cid=mm6835a3_w

https://cdc.gov/vitalsigns/maternal-deaths/

https://cdc.gov/mmwr/volumes/68/wr/mm6818e1.htm?s_cid=mm6818e1_w

Footnotes

Author Disclosure Statement

No competing financial interests exist.

Funding Information

This work was funded, in part, by the Intramural Program at the National Institutes of Health's National Institute of Environmental Health Sciences (Z1AES103325-01 [C.L.J.], Z01-ES102785 [S.E.F.], 1ZIAES103332 [A.J.W.], and Z01ES103333 [A.M.Z.J.]) and the Postdoctoral Research Associate Training Program (Fi2GM133546 [E.M.M.]).

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Environmental Factors Involved in Maternal Morbidity and Mortality

Abstract

Introduction

Maternal Environmental Health Disparities

Hypertensive Disorders of Pregnancy

Breast Development and Health

Subfertility, Pregnancy Complications, and Maternal Morbidity

Metabolic Disorders

Conclusion

Footnotes

Author Disclosure Statement

Funding Information

References