Overview of occupational and environmental risks to reproduction in females

INTRODUCTION — Preconception and prenatal exposures to some environmental conditions and toxicants can have lasting effects on health throughout the life cycle [1,2]. Reproductive hazards can affect fertility, conception, pregnancy, and/or delivery as well as the development of the embryo, fetus, infant, and child [3,4]. Although harmful environmental exposures may be widespread, there are often disproportionate exposures and effects in underserved and minority populations [5,6]. Reproductive hazards also exist in the workplace [7-9]. It is critical that clinicians providing obstetric/gynecological care be knowledgeable about environmental reproductive hazards pertinent to their locations and patient population and provide relevant screening and counseling [5].

This topic will provide an overview of the types of reproductive environmental hazards, categories of adverse outcomes, and the mechanisms by which environmental factors may impact female reproduction. Related information on occupational and environmental health, as well as the impact of specific agents on reproduction, is presented in detail separately. (See "Overview of occupational and environmental health" and "Occupational and environmental risks to reproduction in females: Specific exposures and impact".)

BACKGROUND — Some of the adverse impacts of toxicants on the developing fetus became recognized from past disasters, such as children born with severe motor and cognitive problems related to maternal consumption of methyl mercury contaminated fish (Minamata Bay, Japan). In the last decades, more attention has focused on the growing evidence regarding low-level exposures and their associations with adverse outcomes, such as low birth weight, intellectual deficits, mental health issues, cancer, and endocrine problems (obesity, diabetes), in childhood and beyond [2]. Studies have also demonstrated that for some well-known toxicants, such as lead and mercury, there may not be an actual threshold level, but rather a continuum of dose-related effects, that are more apparent on a population rather than individual level [2].

World chemical manufacturing has increased the number of chemicals present in our daily life, with an estimated 70,000 to 100,000 commercially available and about 5000 in volumes greater than one million tons per year [3]. These existing and newly created industrial chemicals can enter the marketplace, communities, and workplaces with only limited or no assessment of potential reproductive or child-related side effects [3,10].

Exposure to small amounts of potentially toxic chemicals is ubiquitous. In a study of lead, mercury, and polychlorinated biphenyl (PCB) blood levels among women of childbearing age (16 to 49 years) who participated in the National Health and Nutrition Examination Survey (NHANES), 33 percent had levels at or above the median for two of these chemicals and another 23 percent had blood levels at or above the median for three of these chemicals [11]. Although the levels of each individual agent were well below levels usually considered of clinical significance, the authors pointed out the need to study the effects of combinations of low-level chemicals.

Recent concerns have been raised, for example, about contaminants from plastics and consumer products (such as bisphenol A and phthalates), chemicals that act as endocrine disruptors [3]. There is emerging information about reproductive effects from long lasting "forever" chemicals, such as poly- and perfluoroalkyl substances (PFAS) [3,12,13]. PFAS exposure presents frustrating situations for clinicians and patients since there is poor correlation between blood tests for selected PFAS and outcomes, some have a half-life in the body for years, and there is no agent known to enhance excretion. (See "Occupational and environmental risks to reproduction in females: Specific exposures and impact".)

TYPES OF REPRODUCTIVE HAZARDS — The three general categories of reproductive hazards are (1) physical factors (eg, radiation, exposure to electrical shock, excessive vibration or heat, working conditions, and physical demands), (2) biological factors (eg, viruses, parasites), and (3) toxic agents (eg, toxicant exposure via ingestion, inhalation, or contact with skin). Some fetal toxicant exposures are concurrent with the pregnancy; however, others are the result of a previous (nonconcurrent) exposure, with ongoing maternal elimination of the toxicant or from mobilization of stored toxicants from the maternal body chemical burden (eg, polychlorinated biphenyls from fat stores, lead from bone stores) [14]. Reproductive exposures to medications are reviewed elsewhere. (See "Prenatal care: Patient education, health promotion, and safety of commonly used drugs", section on 'Safety of selected common medications used transiently in pregnancy'.)

TYPES OF ADVERSE OUTCOMES — Adverse reproductive and developmental outcomes from exposure to toxic agents include:

●Menstrual disorders and other hormonal influences

●Premature menopause

●Infertility or subfertility

●Delayed conception

●Spontaneous abortion

●Stillbirth or infant death

●Low birth weight and/or fetal growth restriction

●Preterm birth

●Hypertensive disorders of pregnancy

●Congenital malformations

●Cognitive changes and reduced IQ

●Neurodevelopmental delays (such as autism)

●Childhood cancer

●Childhood and adult obesity, endocrine problems

Accurate data on baseline rates of specific adverse outcomes in the general population are difficult to assemble because of the absence of a national monitoring system in the United States and lack of comparability among epidemiologic studies. Estimated frequencies of various adverse outcomes in the United States are listed in the table (table 1) [7].

ASSESSING RISK — Specific environmental exposures have been linked to increased risks of the adverse outcomes discussed above. Yet the strength of the causal associations among exposures and outcomes also varies with the strength of the available data [15] (table 2). Detailed summaries that list chemicals, exposure sources and pathways, and selected health impacts have been published [3]. Studies in humans that assess the causal relationship between specific exposures and reproductive outcomes frequently face limitations and challenges, including [7,15-18]:

●Difficulty in accurately assessing the dose and timing of the exposure to mother and/or fetus

●Difficulties in accurate ascertainment of multiple co-exposures

●Frequent lack of proper control groups since a variety of other genetic, physical, and socioeconomic factors affect reproductive toxicity

●Inadequate assessment of the background prevalence of events

●Difficulties with reliable ascertainment of the outcome or endpoint (eg, early abortion versus late heavy menses)

●Incomplete ascertainment of potential confounders

The effect of ascertainment bias was illustrated by a large cohort study that assessed occupational exposures mid-pregnancy by self-report of chemical agents and by use of a job-exposure matrix that linked job titles to workplace chemical exposures according to expert judgment [17]. After adjustment of confounders, the authors noted that self-reported exposures were not associated with an increased risk of adverse outcomes, but expert judgment-based exposure to phthalates was associated with prolonged time to pregnancy (odds ratio [OR] 2.16, 95% CI 1.02-4.57) and pesticides were associated with decreased birth weight (OR 2.42, 95% CI 1.10-5.34), although the population attributable fractions were quite small (0.7 percent).

Potential problems also arise from study design [7]. Ideally, a prenatal developmental toxicity study and a one-, two-, or multi-generation reproduction toxicity study are recommended for evaluating the reproductive hazard of a substance [19]. These types of studies are both cost- and time-intensive; thus, they are infrequently performed. A cross-sectional study that examines the relationship between adverse reproductive outcomes and exposures among current employees at a workplace may suffer from selection bias ("healthy worker effect") due to the lack of a representative population, since individuals with health problems may not be working, thus leaving only healthy individuals remaining at work. Alternatively, if workers able to conceive were out on pregnancy leave or performing child care, then the population remaining at work may be biased toward those with fertility problems.

A case-control design would be a good method for studying rare outcomes, such as congenital defects. Case control studies, however, are sometimes limited by the focus on one specific outcome (as reflected in the case definition), and thus miss identifying other potential adverse reproductive outcomes. They may also lack optimal exposure information. A prospective cohort design allows for better measurement of exposures and confounders from the outset, but may subsequently be limited if there is excessive drop out of study participants over time. Given the limited number of human studies, efforts have been made to look at pooled data, either using a strength of the evidence approach, or a more formal meta-analysis, in order to determine or rate the strength of the evidence in support of (or against) associations between specific exposures and adverse pregnancy outcomes [3,15,20,21].

Given limitations to high quality human data about adverse reproductive outcomes from specific agents and the large number of as yet untested chemicals, clinicians and governmental and regulatory agencies often turn to animal studies for information about potential toxicants. In evaluating the relevance of animal literature to humans, it is necessary "to consider the species tested; route, timing, and dose of exposure; end points examined; systemic or maternal toxicity; litter effects; consistency among animal studies; concordance with reproductive biology; and biological plausibility of a mechanism of action" [7].

With these caveats in mind, information concerning relationships of environmental exposures to adverse reproductive and developmental outcomes is discussed below. A general overview of occupational and environmental health, including how to take an environmental exposure history, is available separately. (See "Overview of occupational and environmental health".)

PATHOGENESIS — There are multiple physiologic events of reproduction that could be affected by environmental exposures [7,8].

Interference with oogenesis — It is thought that all primary oocytes of the human ovaries are formed by the fifth month of gestation [22]. The oocytes begin their first meiotic division in utero, and then remain arrested until puberty when ovulation commences. Damage to oocytes during fetal development from toxicants, chemotherapy, or radiation may be manifested later in life as reduced fertility [7,14,23]. Toxic exposures during the woman's lifetime also may induce genetic or cytotoxic harm to oocytes, even though they are equipped with an excellent (although not foolproof) repair system. (See "Ovarian development and failure (menopause) in normal women".)

Interference with the menstrual cycle and fertility — The menstrual cycle involves exquisitely timed rises and falls of follicle-stimulating hormone, luteinizing hormone, estrogen, and progesterone (figure 1) [7,8,23]. (See "Normal menstrual cycle".)

Toxicants may interfere with hormonal synthesis and secretion and thus lead to menstrual disorders, particularly disturbances in ovulation. In addition, some chemicals can mimic or disrupt the action of naturally occurring hormones and, as a consequence, lead to reproductive or developmental effects (see "Occupational and environmental risks to reproduction in females: Specific exposures and impact", section on 'Bisphenol A and other phenols'). Examples include:

●Menstrual disorders – Menstrual disorders have been reported among women in various occupations, including athletes, agricultural workers, lead exposed women, hairdressers, shift workers, and nurses handling antineoplastic drugs [24] and in association with specific environmental exposures (air pollution, parabens, polybrominated biphenyls) [25].

●Reduced fertility – Reduced fertility has been reported in dental assistants exposed to high levels of nitrous oxides [26], cleaners exposed to elevated levels of organic solvents, such as dry cleaning chemicals [27-29], and industrial workers exposed to drugs or chemicals during manufacture [24].

These relationships were illustrated in a study of ovarian function in Southeast Asian immigrant women in which daily urine samples were tested for organochlorine compounds (including DDT, its metabolite DDE, and 10 polychlorinated biphenyl [PCB] congeners) and hormone levels; menstrual cycle parameters were also assessed [30]. DDE had effects on ovarian function (changes in cycle length, luteal phase length, level of progesterone metabolites) that could influence other endpoints such as fertility, pregnancy, and reproductive cancers.

Interference with fetal development — The dividing zygote reaches the uterus approximately three days after fertilization; implantation begins approximately three days later and takes approximately one week to complete. Toxic exposures during these first two weeks postconception usually result in fetal loss, which may appear as late menstrual flow. During this two-week period, the embryo is less sensitive to structural damage because sublethal damage can be corrected by cellular repair processes of the rapidly dividing cells.

From the third through the eighth week of development (the period of organogenesis), the embryo is very sensitive to teratogenic insults that cause abnormalities in form or function of a developing fetus. Environmental teratogens can produce cell death, alter normal growth of tissues, or interfere with normal cellular differentiation or other morphologic processes. The consequences of these actions can be fetal loss, fetal growth restriction, birth defects, or impaired neurologic performance.

Dose and timing are important determinants of fetal effects [2,31]. Thus, exposures occurring at "critical periods" in development have specific effects related to the developmental stage of the fetal organs (figure 2) and exposure to the same agent at different times may cause different anomalies. Exposures after the first trimester may induce only minor structural abnormalities, but can still impair growth (through effects on cell division and hypertrophy) and development (through effects on cell differentiation) occurring during the second and third trimesters. (See "Congenital anomalies: Approach to evaluation".)

The fetal central nervous system (CNS) is the organ system most vulnerable to developmental injury throughout pregnancy [10,11,32]. The fetal brain is particularly sensitive to toxins because of the incomplete blood-brain barrier; continued myelination, proliferation and pruning of neurons; and sensitivity to hypoxia [2]. Exposure to a neurotoxin can adversely affect both structural and cognitive development. Some toxins, such as mercury, lead, and tobacco, can exert these effects throughout gestation [33]. Prenatal exposure to numerous (low-level) environmental toxicants have been implicated as contributors to the development of neurodevelopmental disabilities, including autism, attention-deficit hyperactivity disorder, and other cognitive/behavioral impairments [10].

The relationship of genetic susceptibility, epigenetic changes, environmental exposures, and reproductive outcomes is an active area of investigation. As an example, a study in China observed that organic solvent exposure was significantly related to shortened gestation and that certain combined maternal-infant gene polymorphisms modified the effect of exposure to organic solvents on gestational age [34]. Gene-environment interactions, particularly DNA methylation and histone modifications ("epigenetic mechanisms"), also appear to have a role in the development of neurologic and behavior function [35] and on development of asthma and allergic disease [36]. Researchers are also evaluating whether epigenetic modification in response to a disproportionate burden of prenatal environmental exposures may account for some of the disparities in adverse pregnancy outcomes observed in minority populations [37].

Effect of pregnancy — The physiologic changes of pregnancy may alter the amount of toxin absorbed and delivered to the fetus. As examples:

●Delayed gastric emptying and reduced intestinal motility increase absorption of ingested agents

●Increased minute ventilation and tidal volume increase absorption of respiratory toxins

●Increased plasma volume and total body water decrease the blood concentration of toxins

●Increased body fat decreases blood concentration, but increases fat storage, of lipid soluble agents

●Increased renal blood flow leads to increased renal excretion

Effect of maternal factors — The pregnant mother's overall health is also an important factor. If an exposure leads to direct toxicity to the mother, there may be indirect (as well as direct) adverse effects on the fetus. For example, a mother with carbon monoxide poisoning or a severe asthma attack may not adequately perfuse the placenta or release oxygen to the fetus. Some substances, such as lead and per- and polyfluoroalkyl substances (PFAS), have been associated with hypertensive disorders of pregnancy [38,39]. In addition, job-related physical or emotional stresses could impact the course of the pregnancy [7,40]. (See "Working during pregnancy".)

Effect of lactation — The American Academy of Pediatrics (AAP), the United States Preventive Medicine Task Force and the Centers for Disease Control and Prevention promote breastfeeding as the optimal form of nutrition for infants because of its advantages for general health and growth, and for its role in reducing risks of various acute and chronic illnesses [41,42]. Unfortunately, breast milk can sometimes be a source of contaminants [43-45]. This occurs when lactation mobilizes previously stored fat-soluble toxicants, such as dioxins, PCBs, some pesticides, and lead, which then diffuse into the mother's breast milk [46].

Maternal toxicokinetics, the solubility and binding properties of the toxicant, and the characteristics of breast milk determine the milk-maternal plasma (M/P) ratio [47]. The higher the ratio, the more substance is transferred into the breast milk. The M/P ratios for lipophilic substances like PCBs range from 4 to 10, whereas the ratio for organic and inorganic mercury is 0.9 [44]. Since infants rarely develop problems due to contaminants in breast milk, it is generally believed that the many benefits provided by breastfeeding outweigh risks from possible contaminants [48]. The best approach is to strive for elimination of exposure to persistent bio-accumulating toxic chemicals in our environment. A study that measured volatile organic compounds (VOCs) in samples from a milk bank, in milk from three mothers in nonsmoking households, and from air in their homes found that their infants' average daily dose of VOCs was 25- to 135-fold higher by inhalation than by ingestion [49].

Of note, formula feeding does not guarantee an absence of contaminants, since water used in the formula can also contain contaminants, a particularly important consideration in lower-resource countries.

IMPACT OF SPECIFIC ENVIRONMENTAL EXPOSURES — The impact of various exposures on reproduction are presented in detail separately. (See "Occupational and environmental risks to reproduction in females: Specific exposures and impact".)

PREVENTION — Clinicians can be involved with counseling patients about actions they can take to minimize their risk of exposure to occupational and environmental reproductive hazards [5]. Some examples include:

●Ask patients to identify potential hazardous exposures at work or at home, what protective measures (if any) are being used, and consider using available screening questionnaires or guides [50].

●Ask key questions concerning diet, such as ingestion of predator fish (swordfish, tuna) that might be high in mercury, and then advise about wiser choices of fish.

●Inquire about use of any supplements or Ayurvedic medications. Advise that these agents may contain lead and discontinue taking them.

●If living in an older home, advise about potential lead in the paint and against doing self-home renovation that could involve exposure to lead dust.

●For workplace exposures, request copies of and read the Safety Data Sheets (SDS) for products to which they may be exposed. However, MSDS frequently have inadequate information about reproductive or developmental toxicity. Furthermore, the information may be inaccurate due to inherent limitations in acquiring these types of data [16]. Further information may be obtained by contacting one of the resources below.

●Use a safer product, if possible, to replace one that may be harmful in women planning pregnancy.

●Reduce or eliminate exposure through engineering controls or use of personal protection, such as protective clothing and respirators. Respirator usage later in pregnancy, however, may become difficult.

●When exposures cannot be controlled or eliminated, transfer to a different job without the exposure.

●Avoid exposure to excessive vibration, temperature extremes, and ionizing and non-ionizing radiation.

●If chemical contact with the skin occurs, wash the area thoroughly as soon as possible.

●In general, work in well-ventilated areas and with proper control of chemical vapors or other toxicants.

RESOURCES — The number of agents with potential reproductive risks is too large to allow discussion of each within a monograph. The clinician can consult any of several resources that provide this information in a database. As an example:

●MotherToBaby hotline: 1.866.626.6847 (phone) or 855.999.3525 (text message). This group is affiliated with the Genesis Foundation and provides information, at no cost, on potential pregnancy risks from exposure to medications, chemicals, infections, radiation, and other agents. Many patient-oriented fact sheets are available for specific exposures.

●The University of California's (San Francisco) Program on Reproductive Health and the Environment focuses on the intersection of science, medicine, policy, and community engagement in each of our areas of activity: targeted research, expanding clinical practice, and advancing science-based policy solutions. Their website contains useful information at http://prhe.ucsf.edu/.

●REPROTOX is an information system developed by the Reproductive Toxicology Center. It contains commentaries on the potentially harmful effects of chemicals and physical agents on human pregnancy, reproduction, and development. It is available for a fee online (https://reprotox.org/).

●Pediatric Environmental Health Specialty Unit (PEHSU), located in each of the 10 United States Environmental Protection Agency (EPA) regions. These provide education and consultation for health professionals, public health professionals and others about the topic of children's environmental health, including reproductive and developmental toxicity. Contact information for the sites can be found at www.pehsu.net.

●American College of Obstetricians and Gynecologists Expert View and Frequently Asked Questions (FAQ) sites

SUMMARY AND RECOMMENDATIONS

●Adverse reproductive and developmental outcomes from exposure to toxic agents include menstrual disorders, infertility, spontaneous abortion, stillbirth or infant death, low birth weight and fetal growth restriction, preterm birth, congenital malformations, developmental delays, and childhood cancer. (See 'Types of adverse outcomes' above.)

●While specific environmental exposures have been linked to increased risks of the adverse outcomes, the strength of the causal associations among exposures and outcomes also varies with the strength of the available data (table 2). Human studies frequently face limitations and challenges, including lack of accurate assessment of the dose of the exposure to mother and/or fetus; a need for proper control groups; inadequate assessment of the background prevalence of events; difficulties with reliable ascertainment of the outcome or endpoint (eg, early abortion versus late heavy menses); and difficulties in accurate ascertainment of exposures and multiplicity of exposures. (See 'Assessing risk' above.)

●Multiple physiologic events that could be affected by environmental exposures include oogenesis, menstrual cyclicity, pregnancy, fetal development, and lactation. (See 'Pathogenesis' above.)

●Individuals should take action to minimize their risk of exposure to occupational and environmental reproductive hazards. Such actions include (see 'Prevention' above):

•Identify potential hazardous exposures and reduce or eliminate exposure to these agents

•Request copies and read the Material Safety Data Sheets (MSDS) for relevant products

•Use the safest products available

•Avoid exposure to lead, mercury, excessive vibration, temperature extremes, and ionizing and nonionizing radiation

•Consider measures to avoid exposures to plastic contaminants

•If chemical contact with the skin occurs, wash the area thoroughly as soon as possible

•Work in well-ventilated areas and with proper control of chemical vapors or other toxicants