key: cord-0743822-gy6f4xud authors: Harville, Emily W.; Kruse, Alexandra N.; Zhao, Qi title: The Impact of Early-Life Exposures on Women’s Reproductive Health in Adulthood date: 2021-10-14 journal: Curr Epidemiol Rep DOI: 10.1007/s40471-021-00279-0 sha: 94f67272209beb9c8634b01e24c651151ecf83c2 doc_id: 743822 cord_uid: gy6f4xud PURPOSE OF REVIEW: To review the effects of early-life, preconception, and prior-generation exposures on reproductive health in women. RECENT FINDINGS: Women’s early-life factors can affect reproductive health by contributing to health status or exposure level on entering pregnancy. Alternately, they can have permanent effects, regardless of later-life experience. Nutrition, social class, parental smoking, other adverse childhood experiences, environmental pollutants, infectious agents, and racism and discrimination all affect reproductive health, even if experienced in childhood or in utero. Possible transgenerational effects are now being investigated through three- or more-generation studies. These effects occur with mechanisms that may include direct exposure, behavioral, endocrine, inflammatory, and epigenetic pathways. SUMMARY: Pregnancy is increasingly understood in a life course perspective, but rigorously testing hypotheses on early-life effects is still difficult. In order to improve the health outcomes of all women, we need to expand our toolkit of methods and theory. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s40471-021-00279-0. Traditionally research on pregnancy has been focused on the 9 months prior to birth. However, there is increasing recognition of the effects of preconception, early-life, and transgenerational exposures on reproductive outcomes. Such ideas have been developed from perspectives that range from sociological and life-course [1] to next-generation and technological (such as epigenetic analysis of DNA methylation [2] ), and are incorporated into the concept of the exposome, addressing the totality of particularly environmental exposures throughout the life course [3] . Preconception can be construed narrowly as the period when pregnancy is planned, or broadly, as any point in the life span prior to pregnancy, while "early-life" usually indicates a focus on childhood and adolescence [4] . Exposures from both time periods affect pregnancy and infant health (e.g., folic acid supplementation [5] or adverse childhood experiences [6] ). Adverse health behaviors, whether smoking, sedentary lifestyle, or poor diet, rarely start during pregnancy. They are usually in place well before pregnancy, so that pregnancy begins under less optimal conditions and potentially leads to chronic diseases for both mother and child [7] . In addition, social class, stress, and trauma, whenever experienced, affect both biology and behavior, with consequences for pregnancy health, fecundability, and fertility decisions [8] . Developmental Origins of Health and Disease theory and research, while primarily focused on cardiometabolic health, also have been applied to reproductive outcomes [9] . Early-life exposures (whether in childhood, adolescence, or a previous generation) set a trajectory of risk. In some cases, this trajectory indicates an association between the early-life risk factor and risk factor levels during pregnancy (or at conception attempt) (Fig. 1a) . Knowledge about early-life exposures is therefore important for understanding the course of disease, identifying women who are at high risk, and determining interventions that will have the greatest impact. However, measuring earlylife risk factors does not provide additional predictive power beyond what is measured during pregnancy; the threshold for risk is met only when the pregnancy happens. For example, adolescent smoking might predict reproductive outcomes, but only because it is associated with smoking during pregnancy. If a woman quit smoking prior to pregnancy, the early-life smoking would not predict outcomes. In other cases, early-life exposures have independent effects on reproductive and pregnancy outcomes (Fig. 1b) , and predict and cause these outcomes. For these, an early-life exposure has a permanent effect, regardless of later exposures: early-life smoking predicts reproductive outcomes, regardless of smoking during pregnancy. The exposures considered in this review may be of either type, but we will focus on possible mechanisms for independent, permanent effects of early-life exposures (Table 1) . Nutrition Childhood nutrition has long been recognized for its farreaching effects on adult health. At the most basic level, sufficient calories are necessary for menarche and normal gynecological development to occur [10] , and this can extend to lifelong influences; for example, low early-life crop yields in preindustrial societies [11] and early-life exposure to the Dutch Hunger Winter were associated with reduced fertility [12] . Other early deficiencies also cause long-term problems, e.g., rickets in early life leading to pelvic deformities inconsistent with carrying a pregnancy to term [13] . Other micronutrient deficiencies, including iron, thiamine, and vitamin B12, have long-term physiological sequelae that can be permanent [14] . Women with a history of eating disorders are at higher risk of miscarriage and low birthweight (LBW) [15] . High-calorie and low-nutrient density diets lead to obesity in childhood and later, associated with infertility, gestational diabetes, and complicated labor [16] . Early-life social class predicts reproductive health. Economic hardship during the mother's childhood is associated with negative outcomes in neonates, including lower birthweight, longer hospital stays, and higher rates of neonatal intensive care unit admissions [17] . Maternal socioeconomic decline from childhood has been associated with infant mortality and preterm birth (PTB) [18, 19] , while lifetime improved SES has been associated with reduced risk of small-for-gestational-age (SGA) and PTB [20, 21] . Recent work has extended this idea from individual SES to the wider community; for instance, neighborhood SES [22] modified age-related patterns of LBW and SGA [23] , while inequality and polarization in childhood neighborhood was associated with greater likelihood of PTB in adulthood [24] . Women who experience physical abuse in childhood are at increased risk of PTB and LBW [25] . Sexual abuse during childhood has a particularly strong association with pregnancy complications, including increased hospitalization, premature contractions, cervical insufficiency, and PTB [26] . Abuse is also strongly associated with mental health issues, which raise the risk for several poor outcomes, both directly and via health behaviors, substance use, and partner violence during the pregnancy [27] . Experiencing out-of-home care (foster or residential care) as a child is associated with increased risk of PTB [28] . More generally, adverse childhood experiences (ACEs), such as abuse, parental substance use, or neglect, are linked to adverse birth outcomes [29, 30] , unintended pregnancy [31] , and risky reproductive health behaviors, including early sexual debut and prenatal substance use [32] [33] [34] . It should be noted that positive experiences in earlier life may also have long-term effects; women with greater athletic opportunities in adolescence (due to Title IX) gave birth to babies with higher Apgar scores and who were less likely to be LBW [35] . Tobacco smoke is composed of hundreds of toxins, many of which affect reproduction. Exposure to parental smoking in childhood is associated with stillbirth, spontaneous abortion, and ectopic pregnancy, and reduced success in fertility treatment [36, 37] , even among women who never smoked themselves. In utero exposure to maternal smoking has been associated with reduced fertility [38] and miscarriage [39] , though effects are small and inconsistent [40] . Many environmental pollutants are retained in the body. Lipophilic chemicals accumulate in fat tissues and heavy metals are taken up in bones. Such toxicants may be released during pregnancy even if exposure occurred many years previously; this has been clearly demonstrated with studies of lead (Pb) isotopes [41] . Arsenic, to which several worldwide populations are highly exposed, is associated with alterations in hormonal levels and may cause anemia, exacerbated during pregnancy [42] . Preconception and prenatal exposure to endocrine disruptors can impact a woman's reproductive health, altering hormonal signaling in reproductive organs by, for instance, antiestrogenic effects. The focus of this research has generally been on organogenesis and neonatal periods, and then again during the reproductive years [43] ; for instance, prenatal exposure to dioxins and polychlorinated biphenyls (PCBs) has been associated with longer time to pregnancy [44] . Few studies have directly linked childhood and adolescent exposures to later-life pregnancy outcomes. Young women living in the Chernobyl region had a higher risk of miscarriage, premature birth, and menstrual disturbances approximately 20 years after the nuclear disaster there, although in that case there were long-lasting and ongoing exposures to radiation and other pollutants [45] . Proper treatment of chronic infections is crucial in management of infectious sequelae impacting reproductive health. Although research on non-congenitally inherited earlylife exposure to sexually transmitted diseases is extremely limited, infections occurring years prior to child-bearing can significantly impact fecundity. Women living with HIV are at increased odds of developing coinfection with other sexually transmitted infections including human papillomavirus, genital herpes, syphilis, trichomonas, gonorrhea, and chlamydia, which may progress to pelvic inflammatory disease, with deleterious effects on reproductive health and fecundity [46, 47] . Women with HIV are more likely to experience anovulation and amenorrhea [48] . Preconception treatment with antiretroviral therapy increases the risk of both PTB and LBW, compared to women treated with antiretroviral therapy after conceiving [49] . Other longterm infectious diseases, such as tuberculosis, also carry reproductive sequelae, including infertility, miscarriage, and ectopic pregnancy [50] . At this point, nothing can be said conclusively about the long-term effects of COVID-19 on reproductive health. Several changes in reproductive physiology observed with COVID-19 have effects on later fertility and pregnancy, but it will be many years before we can truly assess the effects of early-life exposure to COVID-19. Patients infected with COVID-19 have been found to have a prolonged menstrual cycle, but these changes did not extend beyond a few months after resolution of infection [51] . Alterations of Angiotensin-Converting Enzyme (ACE-2) have led to cases of orchitis and infertility in males with COVID-19 infection, and researchers have hypothesized that gonadotropin-dependent expression of ovarian ACE-2 could affect female gametogenesis including ovarian function, oocyte quality, and later pregnancy outcomes [46] , although initial studies of hormone concentrations are reassuring [51] . Pro-inflammatory ACE-2 can lead to damage of endometrial epithelial cells, which may affect early embryo implantation [52, 53] , and ACE-2 effects on angiotensin-II could also lead to dysfunctional uterine bleeding secondary to hyperplastic endometrium. Parental treatment of COVID-19-induced pneumonia, including antiviral therapy, has been hypothesized to influence later development of the fetus, leading to a recommendation that contraception be encouraged for a time after active infection [54] , although current evidence suggests no association between medical treatments and birth defects or preterm delivery [55] . Beyond possible effects of the virus and related treatments, the social, economic, educational, and emotional toll of the pandemic may be substantial and lifelong or transgenerational. The 1918 influenza pandemic led to reduced income and health for at least two generations [56] . Structural racism and discrimination produce a situation where the abovementioned risk factors are more likely to be seen in populations of color and disadvantaged populations. The high prevalence of these early-life risk factors is likely a major contributor to disparities in reproductive outcomes. Studies of lifetime experiences of interpersonal racism or ethnic discrimination have generally found associations with adverse birth outcomes [57] or with potential mediators of such associations, such as depressive symptoms or psychological distress [58] . Experiences of stigma and discrimination among sexual minority women contribute to worse reproductive health [59] . These early-life risk factors could lead to poorer reproductive and pregnancy outcomes through several pathways (Table 1) . Certain exposures (infectious agents or environmental pollutants) are retained in the body, so that the early-life exposure is still present during pregnancy even when there was no recent exposure. Others have direct effects on the structure of the reproductive system. Some exposures, particularly social ones, may lead to adverse health behaviors. Many types of exposures produce long-term hormonal or inflammatory changes [60] . For instance, micronutrient deficiencies cause subtle changes such as cortisol levels and rhythms [14] ; adverse childhood experiences have also been shown to alter hypothalamic-pituitary-adrenal axis function [61, 62] ; in utero exposure to maternal smoking changes ovarian developmental signaling [63] ; and prenatal exposure to perfluoroalkyl substances has been associated with anti-Müllerian hormone levels, associated with ovarian reserve [64] . Increasingly, there is interest in possible epigenetic changes that persist across the life course, carry into pregnancy, and impact reproduction [65] , although evidence for causal effects is still limited. Developmental origins of health and disease (DOHaD) research have made us aware that early life can encompass the period in utero, or even prior to conception, and studies are now beginning to address transgenerational effects. Such studies provide powerful evidence for life experiences affecting health and disease across the life course and generations, and how "life circumstances, health, and disease are linked at a molecular scale" [66] . PubMed, EMBASE, and CINAHL were searched for papers with keywords related to transgenerational effects (transgenerational, multigenerational, three-generation) and reproductive health (birthweight, preterm, gestational age, fertility, miscarriage; see supplementary material for details). Several three-or more-generation studies exist addressing reproductive health (Table 2) . Perhaps because the original focus among DOHaD studies was birthweight (and likely because it is easily measured and reported), this remains the primary reproductive outcome studied. However, a few studies have also addressed infant mortality, preterm birth, birth defects, or hypertensive disorders (Table 2) . Results from the multigenerational studies are inconclusive. Generally, grandparents' exposures were related to grandchildren's birth outcomes, but often that was mediated by known risk factors in the intermediate generation, such as maternal BMI, smoking, or birthweight. Conducting a multigenerational study is difficult. Randomized trials are impossible and prospective cohort studies are nearly as hard. The Uppsala study is the closest to a prospective design, identifying F0 births (first-generation, grandparents) at a single hospital (1915) (1916) (1917) (1918) (1919) (1920) (1921) (1922) (1923) (1924) (1925) (1926) (1927) (1928) (1929) , then linking to F1 (children) and F2 (grandchildren) [67] . Few other studies started with a multigenerational design, and many include both prospective and retrospective components. Several studies began as birth cohorts, enrolling either pregnant women or children at birth and following the children until they had their own children. Others are linkages of existing data sources (e.g., Swedish and Norwegian medical registries [68, 69] , vital statistics data [70] [71] [72] , or medical records [73] ). Some focus on a defined exposure (e.g., famine, traumatic experience, diethylstilbestrol (DES), the atomic bomb); others were developed as studies of social and economic development in youth, and expanded to include biological measures [74] . For some, the focus is on change in risk factors across generations, particularly those with a focus on social or neighborhood exposures [18, 19] . All the study designs share issues with completeness of measurement across generations and informative missing data [75] . Interpretation of these studies is additionally complex in that it is generally easier to follow the maternal line, but many epigenetic and transgenerational effects in both humans and animals have been shown to be paternal [76] . Perhaps because of these difficulties, many studies that have collected information on three generations appear to have published primarily on two-generation associations. Pregnancy is increasingly understood in a life course perspective, but rigorous methods for researching this are still difficult. Retrospective studies are subject to recall bias and selective fertility [77] . Prospective life course studies require a long-term investment of time and money, and information relevant to hypotheses of most interest decades or generations later may not have been measured initially. Even when data are collected at regular time points, statistical methods may not be sufficient for determining critical periods, while measurement error may not allow determining independent effects [78] . Parental -particularly paternal -information may be missing, especially for important confounders. These concerns are magnified in multigenerational studies. Technological developments in both statistical methods [75] and epigenetics [79] will be Generations are referred to as F0 (grandparent), F1 (parent), F2 (child) for consistency, regardless of how they were referred to in the paper. Last column blank for studies that present a 3-generation study design but for which we did not find papers on effects of F0 exposures on F2 outcomes LBW, low birthweight; PTB, preterm birth; SES, socioeconomic status; DES, diethystilbestrol needed to improve our understanding of patterns of disease and of mechanisms. However, given the lack of efficacy for many interventions implemented during pregnancy, improving health in this crucial period may not be possible without improving health throughout life. The online version contains supplementary material available at https:// doi. org/ 10. 1007/ s40471-021-00279-0. Improving maternal and child health across the life course: where do we go from here? 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Developing a maternally linked birth dataset to study the generational recurrence of low birthweight in Virginia Discriminatory mass de-housing and low-weight births: scales of geography, time, and level The Washington State Intergenerational Study of Birth Outcomes: methodology and some comparisons of maternal birthweight and infant birthweight and gestation in four ethnic groups We thank Elaine Hicks for assistance in conducting the literature review. The authors declare no competing interests. This article does not contain any studies with human or animal subjects performed by any of the authors.