Occupational and environmental risks to reproduction in females: Specific exposures and impact

INTRODUCTION — There has been growing awareness of the prevalence of chemical and metal exposures to pregnant women [1]. At the same time, there has been increasing concerns about the potential effects of these exposures on female reproductive health and the need for health professionals to play a role in preventing harmful exposures [2-4]. A Committee Opinion by the American College of Obstetricians and Gynecologists and the American Society for Reproductive Medicine emphasizes the need to identify and reduce exposures to this multitude of environmental agents and to address the consequences of such exposures [5,6]. Fundamental to this process is understanding the conditions leading to exposure, interpretation of exposure markers, the scientific evidence supporting potential adverse effects, and options for exposure reduction.

This topic will focus on the reproductive impact of selected agents that are particularly timely or controversial and a clinical approach to evaluating and managing women with potential or confirmed exposures. Detailed discussions of specific exposures and approaches to poisoning in general are presented separately.

●(See "Lead exposure, toxicity, and poisoning in adults".)

●(See "Childhood lead poisoning: Clinical manifestations and diagnosis".)

●(See "Mercury toxicity".)

●(See "Arsenic exposure and chronic poisoning".)

●(See "General approach to drug poisoning in adults".)

●(See "Approach to the child with occult toxic exposure".)

In this topic, when discussing study results, we will use the terms "woman/en" or "patient(s)" as they are used in the studies presented. However, we encourage the reader to consider the specific counseling and treatment needs of transgender and gender expansive individuals.

CLINICAL AND COUNSELING CHALLENGES — The clinical provider faces many challenges when trying to address environmental exposures. For one, there are a huge number of toxic agents and potential exposures. As of 2023, the United States Environmental Protection Agency (EPA) listed 86,685 manufactured or processed chemical substances in its Toxic Substances Control Act (TSCA) Chemical Substance Inventory [7]. This inventory does not encompass all toxic substances, and most substances enter the marketplace with little regulatory oversight. There are over 350,000 chemicals registered and in use worldwide [8]. Additional challenges include the limited amount and quality of the scientific data, extrapolation of animal data to humans, timing of exposures, confounding variables, contributions of other social determinants of disease and medical illnesses, and exposures occurring as mixtures and not individual agents. These issues related to study design, assessment of exposure, and determination of the various reproductive end points and outcomes are presented in greater detail separately. (See "Overview of occupational and environmental risks to reproduction in females", section on 'Assessing risk'.)

OUR APPROACH — Given the numerous potential exposures and exposure combinations, copious amounts of data of varying quality and at times conflicting in nature, and the lack of a test or proven intervention in many instances, it is unclear how best to provide meaningful information to patients and families. Professional societies emphasize the need to identify and reduce exposures to this multitude of environmental agents and address the consequences of such exposures, which may disproportionately affect vulnerable and underserved populations [2,5,6,9]. While decreased exposure seems prudent, there is a tension between educating patients with the limited available information and creating patient stress about exposures over which the patient may have little control. In the work setting, providing information about work-related exposures may actually lead to implementation of strategies to reduce or prevent potentially harmful exposures [10].

In our practice, we have found the following actions helpful:

●Assess exposures – We ask patients about common exposures, particularly hazards at work, as well as metals such as lead (manufacturing and paint) and mercury (consumption of large predator fish). As time is limited during prenatal appointments and there are competing priorities, standardized printed or web-based questionnaires [11] may be useful to aid the clinician with assessment (see 'Assessment of environmental risk' below). We also advise clinicians to educate themselves about specific exposures that may be more prevalent in their geographic regions.

●Discuss impact of agent – For possible exposures, we discuss the potential impact of the agent on the patient, her fertility, the developing fetus, and the child. For patients with a specific known exposure, supporting written and web-based information can be helpful. (See 'Patient brochures about toxic exposures' below.)

●Discuss preventive measures – Opportunities to discuss environmental exposure arise frequently in clinical practice and often do require a lot of time to address. Examples include providing information (verbal, printed, online) when a woman expresses desire for pregnancy or when a patient presents with a specific history or question (ie, a woman asks about exposure to lead paint during house renovation).

●Provide additional resources – For patients and families with potential or confirmed exposures, we refer them to specialty providers for evaluation and/or management (ie, maternal-fetal medicine or occupational/environmental medicine specialists). In addition, we offer our patients counseling services to help them cope with the stress from the experience. Lastly, we provide them with websites that offer additional information relevant to their care. (See 'General information' below.)

METALS

Lead

Exposure sources — Lead, in the form of inorganic lead, is a commonly encountered agent (table 1). Work-related exposures include storage battery manufacturing, use of pigments, soldering, welding, use or production of ammunition, construction, and painting [12]. Non-work exposures can come from paint dust, cookware, cosmetics, some remedies or supplements (eg, Ayurvedic medications), and, to a lesser extent, water from leaded pipes [13]. Detailed discussions of acute lead exposure and management in adults and children, unrelated to reproduction, are presented separately.

●(See "Lead exposure, toxicity, and poisoning in adults".)

●(See "Childhood lead poisoning: Exposure and prevention".)

●(See "Childhood lead poisoning: Clinical manifestations and diagnosis".)

●(See "Childhood lead poisoning: Management".)

●(See "Lead nephropathy and lead-related nephrotoxicity".)

Inorganic lead can be absorbed through the intestinal tract (ingestion) or lungs (inhalation). Organic lead, found in leaded gasoline, can also be absorbed from the skin. Once absorbed, lead is bound to red blood cells and distributed to the soft tissues, brain, and skeleton and can also cross the placenta. Although inorganic lead is excreted via the urine with a half-life of months, some of the lead remains in the bone for decades, in equilibrium with the blood, thus serving as an internal, ongoing source of lead. Conditions that promote bone turnover, such as hyperthyroidism as well as pregnancy and breastfeeding, can lead to a release of lead to the blood and to higher blood lead levels (BLL), along with release of lead into breast milk during breastfeeding [14-16]. BLLs, therefore, reflect both current external exposures as well as past exposures from mobilization of lead previously stored in bones.

Exposure assessment

●History – The history is the key first step: Are there any current or prior sources of lead exposure (table 2)? A common scenario is that a person becomes pregnant and then commences with a home renovation project to make room for the new family addition. This renovation project may involve removal or disruption of painted surfaces and the consequent generation of lead dust. If the house was built before 1978, and has not been de-leaded, it is highly likely that the paint has lead. Past exposures are also important since lead may be stored in the bones, and that lead could be additionally mobilized to the blood during pregnancy and breastfeeding, which causes more bone turnover (figure 1).

●Biological monitoring – For patients at risk of lead exposure, lead can be reliably measured through a biological monitoring test: the venous blood lead concentration, which is reported as microgram/dL. This measurement will reflect current exposures, as well as small amounts of lead stored in bone and then released over time into the blood. The United States Preventive Services Task Force (USPSTF) concluded that current evidence is insufficient to assess the balance of benefits and harms for routine screening for elevated BLLs in asymptomatic pregnant persons, but both the United States Centers for Disease Control and Prevention (CDC) and the American College of Obstetricians and Gynecologists (ACOG) recommend targeted screening in pregnant and lactating women with risk factors for lead exposure, such as environmental, occupational, or pica [16-18]. (See "Lead exposure, toxicity, and poisoning in adults", section on 'When to measure blood lead levels'.)

Some research studies can test for the quantity of lead in cortical (tibia) and trabecular bone (patella) through radiograph fluorescence, which is an indication of long-term lead exposure, but this is not a test that is clinically available.

●Environmental sampling – Lead can also be measured in air samples or wipe samples, more commonly done in work settings.

Reproductive health impacts

●Adverse pregnancy outcomes – Maternal lead exposure appears to increase the risk of spontaneous abortion, preterm birth, and small for gestational age (SGA) [18-22]. One prospective study of 650 pregnant women reported the risk of spontaneous abortion increased with every 5 mcg/dL increase in BLL (range 5 to 20 mcg/dL) [19]. Maternal BLL of ≥10 mcg/dL have been associated with reduced gestational length, increased risk for preterm birth, and SGA [20].

Some cross-sectional studies have suggested that blood lead is associated with increased risk of hypertensive complications of pregnancy including preeclampsia. A meta-analysis of 11 studies including over 6000 women found that blood lead concentrations in pregnant women presented an important risk factor for preeclampsia, with an increase of 1 mcg/dL associated with a 1.6 percent increase in the likelihood of preeclampsia [23]. (See "Preeclampsia: Clinical features and diagnosis".)

●Effects on offspring – Studies have reported that young children with lead exposure have reduced neurobehavioral function and IQ, with no evidence of threshold effects [24-27]. Impaired cognitive development has also been demonstrated in children even with low levels of prenatal lead exposure [28]. Attempts to determine the impact of timing of lead exposure during pregnancy and subsequent cognitive impairment in offspring have reported inconsistent findings, including greatest correlation with first trimester exposure [29], greatest correlation with third trimester exposure [30], and no effect [31]. While mechanism of action is not fully understood, alternations in DNA methylation have been reported in children following prenatal lead exposure [32,33]. Additional information on childhood lead poisoning can be found in related content:

•(See "Childhood lead poisoning: Exposure and prevention".)

•(See "Childhood lead poisoning: Clinical manifestations and diagnosis".)

•(See "Childhood lead poisoning: Management".)

Practical clinical approach — We find the following strategies helpful to assess the possibility of exposure and need for blood lead test.

●Question – We ask about risk for lead exposure. Potential exposures include living in or renovating a home built before 1978, using imported pottery for cooking and eating, using Ayurvedic medication or supplements, using imported cosmetics (as those containing vermillion [sindoor]) or spices, or working in occupations with exposure. Additional discussion can be found in related content. (See "Childhood lead poisoning: Exposure and prevention".)

●Test – Since many of the above risk factors may not be readily elicited, our approach is to have a very low threshold for ordering a venous blood level. The test is relatively inexpensive and could have a significant impact on the individual patient. Background blood levels for United States (2017 to 2018) adults age 20 years and older is, on average, <1 mcg/dL, and the 95^th percentile is approximately 2.62 mcg/dL [34]. Looking at background BLL in women of childbearing age, from 1976 to 2016, there has been a downward trend. From 2011 to 2016, 0.7 percent of women of childbearing age had BLL ≥0.5 mcg/dL (representing approximately 500,000 women), with higher BLL associated with various factors [35]. The usual venous BLL is not a "serum" level, which is used more for research purposes. While independent reviews by the USPSTF and ACOG concluded that data were insufficient to recommend routine universal blood lead testing of all pregnant women, ACOG advises clinicians to consider venous BLL in women with risk factors, such as those who live in housing built before 1978, have an occupational exposure (or a partner with occupational exposure), or take alternative therapies that may contain lead (table 2) [17,18].

Evaluation of children with suspected lead poisoning is presented separately. (See "Childhood lead poisoning: Clinical manifestations and diagnosis".)

●Counsel – We provide information based on guidance from the CDC (figure 2) and ACOG (table 3) [13,18].

•For women with BLL around background (1 to 3 mcg/dL), we provide general advice about avoiding lead exposure, such as not starting renovation projects in an old house, avoiding imported glazed cookware, using proper protective measures for potential work exposures, and not taking Ayurvedic therapies.

•For women who have a BLL greater that 5 mcg/dL, first and most importantly, we emphasize the need to identify, reduce, or eliminate exposures. Some states have a lead program that will do home inspections for lead paint hazards and offer recommendations. Medical removal from a work lead exposure is recommended at BLL of 5 mcg/dL or more for pregnant women.

•Chelation therapy is generally avoided during pregnancy because of concern for possible teratogenic effects of the chelation agents. However, chelation therapy could be considered for BLL around 45 mcg/dL, and particularly at higher levels (>70) where there are also health risks to the mothers [13]. There are some case reports that demonstrate a lowering of BLL in the mother with chelation, but there is no definitive information on effects for the fetus. For BLL of >45 mcg/dL, consultation with an expert is advised: Poison Control Centers or to experts in the Pediatric Environmental Health Specialty Units. (See "Lead exposure, toxicity, and poisoning in adults", section on 'Pregnancy and breastfeeding'.)

•Nutritional supplement with 2000 mg of calcium daily through the diet or by supplementation. Some studies reported a decrease in maternal lead with supplementation of 1200 mg/day while pregnant [13]. Iron deficiency should be corrected if identified [13].

Useful resources

●Centers for Disease Control and Prevention (CDC): Guidelines for the Identification and Management of lead exposure in pregnant and lactating women

●Centers for Disease Control and Prevention (CDC): Breastfeeding, Environmental and Chemical Exposures, Lead

●American College of Obstetricians and Gynecologists (ACOG): Lead Screening during pregnancy and lactation

Mercury

Exposure sources — Mercury exists in three forms: organic, elemental, and inorganic salts, which all have different routes of exposure and potential toxicity [36-38]. (See "Mercury toxicity".)

●Organic mercury – The organic form, methyl mercury, is found in fish or contaminated foods, is one of the most commonly absorbed forms, and is typically of greatest concern and relevance among patients. Methyl mercury in these sources forms when inorganic mercury (as from industrial sources) enters the sea (also via air from coal-fired power plants), and sea microorganisms add a methyl group, which is ingested by fish eating smaller fish, so that it bioaccumulates among the larger predatory fish, such as tuna and swordfish, that have among the highest amounts of mercury. The mercury is present in the fish tissues and is not eliminated with cooking. The amount of methyl mercury in fish and seafood, therefore, varies, and concentrations for different fish are listed in resources such as the US Food and Drug Administration (FDA) web site. It is absorbed easily by ingestion. Per the US Fourth National Report on Human Exposure to Environmental Chemicals, blood methyl mercury levels have been gradually decreasing since 2011 [34]. The reported geometric means for total blood mercury for females were 0.489 (2011 to 2012), 0.422 (2013 to 2014), and 0.399 (2015 to 2016).

Another form of organic mercury is ethyl mercury (thimerosal), which has been used as a preservative for decades in multidose vials of medicines and vaccines [39]. Ethyl mercury is eliminated more quickly from the body than methyl mercury. Numerous studies have not shown any significant adverse effects in children (including no evidence of autism) or adults related to the small quantity added to vaccines. Most childhood vaccines never contained thimerosal, and in 2001, thimerosal was removed from vaccines in the United States [39]. Influenza vaccine is available in both thimerosal-containing (for multidose vials) and thimerosal-free versions [39], and there is a chart that lists all ingredients in vaccines [39]. The CDC provides a useful resource for patients: Understanding Thimerosal, Mercury, and Vaccine Safety [40].

●Elemental mercury – Elemental mercury refers to the liquid metallic (elemental) mercury that is used in dental amalgams, fluorescent lights, and some artisanal gold mining processes. Elemental mercury vaporizes at room temperature and is mainly absorbed through vapor inhalation and not by oral ingestion of the liquid. For women with mercury-containing dental amalgams, exposure could occur during chewing or teeth grinding when the element is vaporized and then inhaled. One study of pregnant women with amalgams and restorations, overall, did not report an association with negative birth outcomes [41]. Overall, the exposure is very small. Women should not have fillings removed just to reduce mercury exposure.

Of greater concern is the potential high exposure to elemental mercury in pregnant women around or working in artisanal gold mining [42]. This type of small-scale mining, usually performed by poorly educated individuals in low-resource settings, is carried out in 70 countries by approximately 10 to 15 million miners, including approximately 4 to 5 million women and children [42]. The work involves crushing possible gold-containing rocks or river sediment and adding elemental mercury (usually in large quantities) to form a gold-mercury "amalgam." This mixture is then heated to vaporize the mercury, leading to air, soil, and water contaminated with mercury. Women make up to 10 to 50 percent of the small-scale mining population directly but could also be contaminated indirectly, and such a level of mercury exposure could pose a threat to a developing fetus.

●Inorganic salts – Inorganic salts are formed when mercury combines with other elements such as sulfur or oxygen. Exposures can occur through industrial work. In addition, these compounds are sometimes added to cosmetic creams for skin lightening and can be absorbed through the skin [43,44].

Exposure assessment

●History – In the clinical setting, we begin with questions primarily concerning fish/seafood intake, particularly the type of fish. We also ask about occupation (exposure to any mercury type sources), use of elemental mercury in any cultural practices, use of skin lightening cosmetic creams [43,44], and recent dental work to remove mercury/silver amalgams. Clinicians who see patients from a community involved in gold mining are advised to ask about mercury exposure related to mining practices.

●Biological monitoring – For patients with possible mercury exposure based on history, blood mercury level is the most common test and reflects the concentration of total mercury (microgram/L). The test does not distinguish among the different forms of mercury. The half-life of mercury, in general, is approximately one to two months. Methyl mercury is excreted predominately through the gastrointestinal tract, and some is metabolized to the inorganic form that may then be excreted in the urine. Elemental and inorganic mercury have a much greater excretion in the urine. For screening, we order blood and spot urine mercury levels along with a urine creatinine (to correct for concentration on a spot sample). Urine mercury is reported both as mcg/L, as well as microgram per gram of creatinine. Finding the majority of mercury in the blood sample with little to none in the urine is suggestive of methyl mercury. Mercury can also be measured in hair, but a significant quantity may be required, and the result may be no more useful than a blood level given the half-life of one to two months.

Reproductive health impact — Once absorbed, all forms of mercury cross the placenta and can result in exposure to the developing fetus. Severe neurodevelopmental toxicity has been described with severe methyl mercury poisoning from consumption of fish highly contaminated with industrial mercury waste (Minamata disease) as well as from bread made from contaminated seeds [45,46]. The offspring from minimally symptomatic mothers with high exposure in Minamata, Japan, gave birth to offspring with severe neurologic manifestations resembling cerebral palsy, sometimes with seizures and cognitive impairment. It is important to note that exposure levels from these industrial disasters are many times greater than from routine fish consumption (10 to 60 ppm Hg versus <1 ppm).

Since these severe mercury poisoning events, subsequent studies of high fish-eating populations have examined mercury levels in pregnant women and neurobehavioral outcomes in offspring and, at times, reported conflicting results [47,48]. Studies of a population in the Faroe Islands found statistically significant effects on motor, attention, and verbal tests in neurobehavioral testing at ages 7 and 14 years after in utero exposure [47,49], whereas another study in the Seychelles Islands, a population chronically eating reef fish, did not find these effects [48,50]. To develop guidance, the US National Research Council Committee relied on data from the Faroe Islands and other data to arrive at a reference dose of 0.1 mcg Hg/kg/day for the whole population, including pregnant individuals or females of childbearing age. In addition, they utilized the lowest confidence interval of a mean cord blood mercury level associated with a statistical difference on a neurobehavioral test divided by an uncertainty factor (10) to come up with an "acceptable" level of blood mercury of 5.8 mcg/L for pregnant persons, which has also been adopted by the Environmental Protection Agency (EPA) [51]. However, because of differences between maternal blood mercury and cord blood due to the bioconcentration of methyl mercury across the placenta, some propose a goal below 3.5 and 5.8 mcg/L [52]. These studies and others have been the basis for guidelines around mercury exposure during pregnancy.

The impact of mercury exposure on the developing fetus, mercury levels in fish, and benefits of fish consumption are presented in detail separately. (See "Fish consumption and marine omega-3 fatty acid supplementation in pregnancy", section on 'Methylmercury in fish'.)

Practical clinical approach — We take the following approach in our practice:

●Inquire about possible sources of mercury exposure; the most common source is consumption of large predator-type fish (eg, shark, swordfish, tilefish, king mackerel).

●Counsel patients on the benefits and risks of fish consumption during pregnancy, including the benefits of omega-3 fatty acids [53-56]. We discuss the ACOG Practice Advisory that suggests women eat two to three servings a week (8 to 12 ounces total) of fish in the best category, one serving a week (no more than 6 ounces) of fish in the good category, and avoid fish with the highest mercury levels [57]. The FDA provides guidance with a chart that can be printed in English or Spanish. Patients with internet access can also check a list of mercury levels in commercial fish and shellfish and choose lower-mercury species. (See "Fish consumption and marine omega-3 fatty acid supplementation in pregnancy".)

●Monitor when clinically indicated. In situations in which a high level of mercury from any source is suspected, the clinician may choose to do a biological monitoring test. We advise a blood mercury, accompanied by a urine spot test for mercury, and urine creatinine (to adjust for concentration). An elevated blood mercury with much less in the urine is suggestive of methyl mercury. Interpretation and counseling regarding a test result are critical. Many fish eaters will have blood mercury levels greater than 5.8 mcg/L. The key actions are to identify the source and to decrease or eliminate the exposure. If fish is the likely source, the patient can switch to the very low mercury seafood. If the patient is preconception, advice could be given to wait until blood mercury levels decline, if elevated. As with lead, use of chelators during pregnancy is not advised unless there is evidence of very high mercury. Chelating agents also do not work well for methyl mercury and are more effective for inorganic mercury. In these situations, we advise consultation with an expert specialist. (See "Mercury toxicity", section on 'Treatment'.)

Useful resources

●(See "Fish consumption and marine omega-3 fatty acid supplementation in pregnancy".)

●US Food and Drug Administration (FDA): Advice about Eating Fish (For persons who are or might become pregnant, breastfeeding mothers, and young children).

●Agency for Toxic Substances and Disease Registry (ATSDR): Mercury and your health.

Arsenic

Exposure sources — There are different forms of arsenic, including inorganic (toxic) compounds (trivalent and pentavalent), organic, and relatively nontoxic organoarsenates (primarily arsenobetaine and arsenocholine). (See "Arsenic exposure and chronic poisoning".)

Inorganic arsenic is a naturally occurring element found in the earth's crust that can leach into drinking water and sometimes into food such as brown algae and rice (the latter, typically in low doses) [58]. Potential occupational exposure occurs in pesticide manufacturing, smelting, and other industrial processes.

Worldwide, the most important environmental exposures occur in certain geographic areas that have high levels of inorganic arsenic in groundwater. The inorganic forms are highly toxic and, with sufficient doses, can cause acute and sometimes deadly poisoning. Inorganic arsenic exists in trivalent and pentavalent forms that can be ingested, absorbed, and then metabolized by the liver to less toxic organic forms that are quickly excreted through the urine with a half-life of approximately 48 to 72 hours for the majority. Chronic exposures can also occur and, if in high enough amounts, can cause a variety of skin lesions as well as increase the risk for cancers, such as skin, lung, and bladder [59].

Exposure assessment

●History – We inquire about the patient's occupation, source of drinking water, diet, and use of any supplements. Drinking water, particularly from well water, is a common environmental source of arsenic.

●Biological monitoring – Arsenic can be measured in the urine, usually as "total arsenic," but it is important to speciate (fractionate) the sample to measure inorganic arsenic since there are other forms of arsenic (arsenobetaine, arsenosugars) from fish, shellfish, and other foods that are of minimal to no toxicity but add to the total arsenic measured and give a false impression of the presence of toxic exposure [60]. Urine is generally the preferred biomarker for recent arsenic exposure because arsenic is rapidly excreted into urine and can be speciated. Although it can also be measured in blood, it is cleared quickly from this reservoir.

For screening, a spot urine sample is obtained for both urine arsenic and urine creatinine. Urine creatinine is used to adjust for urine concentration. The initial arsenic result is reported as micrograms of arsenic per liter. The clinician then adjusts for urine concentration to determine the micrograms of arsenic per gram of creatinine (divide the microgram arsenic per liter by gram of creatinine per liter, and one arrives at microgram of arsenic per gram of creatinine). Some labs will do this if an arsenic profile is ordered.

After absorption, inorganic arsenic is distributed through the body, metabolized in the liver, and accumulated in the skin, hair, and nails. Advantages of using hair for testing include that it binds the inorganic (toxic) forms, but not the seafood-derived, less toxic, organic forms, and it can reflect exposures from the past (pending the length of the hair). Disadvantages of using hair for arsenic monitoring include that it will also bind external arsenic sources, such as from air (smelter) or from bathing with arsenic-contaminated water, and thus may not reflect the true internal dose. Hair samples tend to be more used in the research setting.

●Environmental assessment – Arsenic can be measured in well water and is usually assumed to be in inorganic form. Both the EPA and the World Health Organization currently have a guideline of 10 mcg/L for drinking water in order to decrease risks for future arsenic-related cancers.

Reproductive health impact — Despite estimates that over 300 million people globally have been exposed to arsenic contamination by way of drinking water, air, food, and beverages, few data are available on reproductive outcomes of exposure [61]. Inorganic arsenic can cross the placenta, so there is the potential for adverse reproductive and developmental outcomes. A meta-analysis of 16 studies found arsenic levels >50 mcg arsenic/L in groundwater were associated with nearly twice the risk of spontaneous abortion and stillbirth (odds ratio [OR] 1.98, 95% CI 1.27-3.10 and OR 1.77, 95% CI 1.32-2.36, respectively) [61]. The risks of neonatal and infant mortality were also increased (OR 1.51, 95% CI 1.28-1.78 and OR 1.35, 95% CI 1.12-1.62, respectively). The study was unable to assess the impact of lower doses of arsenic exposure because of paucity of data. A subsequent prospective cohort study of 200 pregnant women in Mexico reported maternal urinary concentrations of mono-methylated metabolites were negatively associated with newborn birth weight and gestational age [62]. The model adjusted for maternal age, education level, and maternal tobacco and alcohol use. Arsenic exposures during pregnancy and early childhood have also been associated with increased risks for latent health problems, including lung and cardiovascular disease and cancer [63]. At least one study has reported the impact of arsenic exposure varies by gestational age, with a protective effect reported for exposure between weeks 9 and 12 but a negative effect reported between weeks 25 to 28, which may indicate that arsenic toxicity differs across gestational ages [64].

Practical clinical approach — We find the following strategies helpful in clinical practice:

●Ask about source of drinking water and, if from well water, if it has been tested for arsenic. If not, a wise approach may be to drink and cook with other water (bottled) until the level of arsenic is known. If elevated, the patient is advised to stop drinking that water and using it for cooking.

●Ask about rice intake or concerns about rice. For most people who eat a variety of grains, exposure to inorganic arsenic will not be significant. If there are questions, we refer to available resources. (See 'Useful resources' below.)

●In most cases, biological monitoring tests for arsenic are not necessary. If there is a concern about continued exposure, such as from drinking water or from work exposures, then we order a urine arsenic (a spot sample is usually adequate for adults) that is speciated in order to know the amount of inorganic arsenic. In addition, we check a urine creatinine to correct for concentration, reported as micrograms of arsenic per gram of creatinine (ideally, micrograms of inorganic arsenic per gram of creatinine).

●For situations of chronic inorganic arsenic exposure, the treatment is to stop the exposure. Arsenic is quickly cleared from the blood. However, chronic arsenic exposure is associated with cancer and other adverse health outcomes. (See "Arsenic exposure and chronic poisoning", section on 'Clinical features and latent effects of chronic exposure'.)

Useful resources

●World Health Organization (WHO): Fact Sheet on Arsenic (2018)

●US Food and Drug Administration (FDA): Testing and analysis of arsenic in rice and rice products

●Pediatric Environmental Health Specialty Units (PEHSU): Fact sheet – Information on Arsenic in Food (2012)

PLASTICS — The term "plastics" includes a wide array of compounds. "Microplastics," which refers to particles less than 5 mm in size, have been reported in human placentas [65].

Phthalates — Phthalates are a large class of high-production synthetic chemicals used extensively in a diverse array of industrial and consumer applications, typically as a plasticizers or solvents [66,67].

Sources — As a plasticizer, phthalates are used to make products more flexible and harder to break and can be found in such items as tubing, food wraps, food packaging, vinyl shower curtains, rainwear, and some toys. The diet becomes a major source of exposure to phthalates from food or water contaminated during the production and storage processes [68]. In addition, dermal exposure can occur from phthalates used as solvents in cosmetics, perfumes, and personal care products (soaps, shampoos). Medical tubing can be a significant exposure source, particularly among sick neonates. Phthalates can leach or evaporate into the environment resulting in inhalation as an additional exposure route. Human exposure appears ubiquitous as documented in the National Health and Nutrition Examination Survey [69]. This includes pregnant women in whom greater than 98 percent had measurable exposure above the limit of detection [1]. Notably, adult women had higher exposure level to phthalate metabolites originating from personal care products [70].

Assessment — Common phthalates in production include di-2-ethylhexyl phthalate (DEHP) and dibutyl phthalate (DBP). The half-life of phthalates is quite short, with rapid metabolism and subsequent clearance from the body in urine or feces typically within 24 hours of exposure. Thus, phthalates do not tend to accumulate in the body [71]. Key metabolites include mono-(2-ethylhexyl) phthalate (MEHP) and 2-ethylhexanol, which are both biologically active. Metabolites can cross the placenta. Urine and serum are the preferred sources for measuring phthalates in humans, but measurement is typically limited to specific labs for biomonitoring or research purposes and not performed in clinical practice.

Impact on reproductive health — Phthalates are considered endocrine-disrupting chemicals (see "Endocrine-disrupting chemicals").

●Animal data – The potential that phthalates could adversely impact reproductive health was first recognized from experimental animal studies. Among rodents, in utero phthalate exposure was found to be embryo- and fetotoxic, with fewer litters achieved, fewer live pups per litter, and reduced pup weight [72]. Prenatal exposure among rats also has been linked with a constellation of teratogenic effects demonstrable in male rats known as the "phthalate syndrome" [73]. This is characterized by a reduced anogenital distance, hypospadias, testicular malformations, and reduced semen quality bearing a striking resemblance to testicular dysgenesis among humans. It is important to emphasize that animal studies demonstrating the reproductive toxicity of phthalates used much higher phthalate concentrations than the range of typical human exposure. Furthermore, there is strong evidence of species-specific toxicity, with rats being particularly vulnerable to phthalate exposure, underscoring the need for human-specific data.

●Human data – In contrast to a fairly extensive animal literature, only limited data are available to inform our understanding about the potential reproductive toxicity of phthalates among humans, although some studies suggest negative impacts on both fertility and pregnancy outcomes. Reduced anogenital distance among male infants, which is a marker of reduced androgen exposure during fetal life and associated with male subfertility in later life, has been demonstrated in association with prenatal phthalate exposure in some but not all studies [74,75]. Similarly, an increased risk for male newborn genital anomalies (hydrocele, hypospadias, and undescended testes) has been observed in some, but not all, studies [76,77].

•Fertility and birth outcomes – Among a cohort of couples undergoing infertility treatment, increasing preconceptual phthalate exposure was associated with reduced antral follicle counts [78], lower oocyte yield [79], fewer mature oocytes [79], lower fecundity [80], a higher risk of early biochemical loss and total pregnancy loss [81], and preterm birth (live birth before 37 completed weeks of gestation) [82]. In a prospective cohort study of 382 subfertile couples, prenatal phthalate metabolite concentrations were associated with an increased risk for preterm birth, with exposure in the third trimester associated with the highest risk (risk ratio [RR] 1.51, 95% CI 1.17-1.95) [83]. In a separate case-control study including 482 women, the odds of preterm birth increased across quartiles of DEHP metabolite exposure and were three- to fivefold higher among those in the highest compared with lowest quartiles [84]. Systematic reviews of the reproductive and developmental effects of phthalate exposure in females concluded that epidemiologic research supports a potential relationship between exposure and infertility, aneuploidy, pregnancy loss, preterm birth, and reduced birth weight, although additional research is needed to provide more definitive conclusions [85-87].

•Neurodevelopment – Association of prenatal phthalate exposure with an adverse impact on neurodevelopment is less clear. A systematic review of studies evaluating six phthalates with cognition, motor effects, and behavior including attention deficit hyperactivity disorder and autism spectrum disorder identified only slight to null associations with prenatal exposure, with the exception of an inverse association of butyl benzyl phthalate with motor skills [88].  

Counseling — Despite our limited understanding of the impact of phthalate exposure on human reproduction and pregnancy outcomes, it is reasonable to limit exposure, particularly around the time of conception and during pregnancy. We advise our patients that exposure can be reduced by minimizing the use of PVC (vinyl) plastic (Number 3) and minimizing ingestion of highly processed foods. When plastic products are necessary, products should be aired out before use. Patients interested in minimizing exposure from personal care products can evaluate the phthalate content through nonprofit online resources such as cosmetic database and Campaign for Safe Cosmetics.

Additional education and training for clinicians is available through the Pediatric Environmental Health Specialty Units (PEHSU) webinar on Phthalates and Phenols. A PEHSU fact sheet on Phthalates and Bisphenol A for Healthcare Providers can be found here.

Bisphenol A and other phenols — Bisphenol A (BPA), an endocrine disruptor with estrogen-like activity, is a synthetic chemical sold in high volume (>6 billion pounds per year) and added to plastics to make them clear [89-91]. BPA is also used in epoxy resins to line water pipes and the inside of food and beverage cans and a component of thermal paper used for printed receipts.

Acquisition — The primary route of exposure to BPA is through dietary ingestion, from leaching of the chemical from polycarbonate plastic storage containers or from the liners in food and beverage cans [92]. Dermal exposure can occur from handling of cash register receipts [93]. Exposure appears ubiquitous among the United States population, with detectable levels of BPA in more than 90 percent of urinary samples from the 1988 to 1994 National Health and Nutrition Examination Survey (NHANES III) [94]. The half-life of BPA is short, with near elimination within 24 hours [95]. That said, given the ubiquity of use, exposure is essentially continuous. Exposure levels can be measured in urine and serum samples, but such testing is typically limited to biomonitoring or research protocols and is not available for clinical use.

Reproductive health and consensus statements — The BPA animal literature demonstrates a wide range of adverse developmental and reproductive effects, including an increase in insulin resistance and obesity, altered brain development, altered mammary gland development, altered prostate development, decreased spermatogenesis, and neurobehavioral problems from in utero or early life exposure [90,91,96]. In vitro studies also raise the possibility that BPA exposure might interfere with meiosis and mitosis, which may translate in vivo to a higher prevalence of subfertility and early pregnancy loss [97-99].

Human epidemiologic data are more limited, and reviews of these data in addition to animal data have reached slightly different conclusions, as evidenced by the following regulatory statements:

●In 2006, the National Institutes of Health (NIH) and the United States Environmental Protection Agency (EPA) convened a meeting of experts to address concerns that the negative health effects identified in experimental in vitro and animal studies occurred at "low-dose" exposure levels (ie, within the range of typical human exposure). The 2007 NIH/EPA consensus panel statement concluded that, even in the absence of extensive human data, it was prudent to reduce exposure in the interim while human research continued to advance (the precautionary principle) [91]. They also emphasized that the consequences of exposure may not occur until much later in life (developmental origins of adult health and disease [DOHaD] hypothesis).

●A separate expert panel convened in 2007 by the National Toxicology Program, part of the United States National Institute of Environmental Health Sciences, reached the following conclusions about current levels of human exposure among fetuses, infants, and children [100]:

•"Some concern" for effects of BPA on "brain, behavior, and prostate in fetuses, infants, and children."

•"Minimal concern" for "effects on mammary gland and earlier age at puberty."

•"Negligible concern" that "exposure will result in neonatal mortality, birth defects, or reduced birth weight or growth."

•"Negligible concern" for "reproductive effects in non-occupationally exposed adults" and only "minimal concern" for reproductive effects among workers exposed to higher levels than average.

●A 2016 review of literature published between 2007 and 2016 concluded that BPA was associated with negative effects upon female fertility [89]. In one included study, among a cohort of couples undergoing infertility treatment, both urinary and serum BPA concentration was inversely correlated with both the number of oocytes retrieved and the peak estradiol during in vitro fertilization cycles [101].

●In 2018, the US Food and Drug Administration (FDA) released a statement that authorized levels of BPA use were safe for consumers based on data from a pre-peer review draft report of a two-year study involving rats performed by the National Toxicology Program (NTP) [102]. Members of the Endocrine Society, including over 18,000 researchers and clinicians, released a counter-statement that the FDA's conclusions were "premature and incomplete," in part because the conclusion included only the one guideline study and excluded other published grantee studies [103].

These conflicting studies and summaries highlight some of the challenges of studying BPA's impact on reproduction and development, including the differing impacts of different doses, importance of critical periods of development to exposure, and differing responses across animal models and sex-dependency [90].

Exposure assessment — Exposure to BPA and its metabolites (BPA glucuronide and BPA sulfate) are typically measured in urine specimens using liquid chromatography-tandem mass spectrometry (LC-MS/MS) techniques. As with phthalate exposures, measurement is typically limited to specific labs for biomonitoring or research purposes and not performed in clinical practice [104].

Counseling — In our practice, we take a precautionary approach and advise women to reduce exposure, if possible, during pregnancy and in products intended for their infants. Simple steps to limit BPA intake include:

●Avoid plastic polycarbonate plastic (recycle number 7 and some number 3 plastics) [92].

●Do not microwave or otherwise heat food and drinks in polycarbonate plastic.

●Hand wash polycarbonate containers rather than putting them in the dishwasher with harsh detergents at high temperatures.

●Avoid canned foods and seek nonplastic storage materials for food and beverages (eg, glass or stainless steel).

●Consider alternatives to plastic bags for storage of breast milk, such as small glass bottles or freezing the breast milk in silicone ice cube trays and then storing as cubes that can be defrosted in glass (instead of plastic).

In the United States, the FDA banned BPA from baby bottles and children's sippy cups (2012) and from infant formula (2013). This action was not based on safety concerns but rather reflected "industry abandonment of the chemical for these uses" [103]. Of note, many products using BPA-free plastic alternatives still leach chemicals that have estrogenic activity, and it is not at all clear what the potential impact these substitute products have on human reproductive health [105]. European authorities similarly restricted BPA from use in infant feeding bottles as early as 2011 and voted in early 2018 to extend this restriction of BPA to the production of bottles and drinking cups intended for use in young children up to three years of age (in addition to the restrictions already in place for infant feeding bottles). The ban also includes restriction on the use of BPA in varnishes or coatings in contact with food intended for young children [106].

●Other phenols – Other chemicals in the phenol class include BPA substitutes, triclosan (used for its antibacterial properties in personal care and cleaning products), and parabens (used as preservatives in cosmetics and creams). Even less is known about the potential impact of these agents on human reproductive health. Given the absence of data to support safety or harm of these chemicals during conception and pregnancy, we advise pregnant women to avoid exposure to these products as much as reasonably possible.

●Useful resources – Additional education and training for clinicians is available through the PEHSU webinar on Phthalates and Phenols. A PEHSU factsheet on Phthalates and Bisphenol A for Healthcare Providers can be found here. A FAQ document have been prepared for the public by the National Toxicology Program out of the National Institute of Environmental Health Sciences.

FLAME RETARDANTS — Flame retardants refer to synthetic chemicals that have been used in consumer and industrial products since the 1970s to reduce flammability [107].

Exposure sources — Flame retardants have been applied widely to textiles, furnishing, upholstery, carpets, electronics, and construction materials. There are hundreds of distinct flame retardants with differing chemical structures used over the past 40 years. Exposure to these organophosphate flame retardants is on the rise and demonstrable in more than 90 percent of subjects in the 2013-14 National Health and Nutrition Examination Survey [108].

One of the original classes of flame retardants were the polybrominated diphenyl ethers (PBDEs), which are notable for easy volatilization into the environment (air, dust, soil, surface water) because they do not bond with the material to which they are applied. In contrast to phthalates and phenols, which are nonpersistent chemicals, PBDEs persist in the environment for years and can bioaccumulate in adipose tissue (including breast milk) in living organisms [109,110]. Although PBDEs were phased out in the early 2000s, exposure continues because the chemicals are still present. The primary routes of exposure in humans are through ingestion of dust contaminated food and hands, inhalation from environmental release, or dermal contact. Exposure may be highest among young children with hand-to-mouth behaviors.

Reproductive health impact — Animal research suggests that PBDEs can cause reproductive and neurodevelopmental toxicity as well as other adverse nonreproductive effects [111]. Reproductive effects observed in animal species include impaired embryo development, increased resorption after conception, altered pubertal onset, structural changes to ovaries, reduced follicular counts among females, and impaired spermatogenesis and reduced semen quality in males [110].

Human data are even more limited than for the endocrine disruptors discussed above. A meta-analysis of four studies that compared prenatal and early childhood PBDE exposure with neurodevelopmental outcomes found that a 10-fold increase in PBDE exposure was associated with a nearly four point drop in IQ (-3.70 IQ points, 95% CI -6.56 to -0.83) [112]. A separate meta-analysis of seven different studies demonstrated a relationship between PBDE concentrations and reduced birth weight (-50.1 grams, 95% CI -95.9 to -5.3), although the clinical significance of this reduction is not yet known [113]. We know less about the potential impact of flame retardants that were introduced as alternatives to PBDEs. Some, including the organophosphate flame retardants, are short-lived and do not persist in the environment, but it is not known if this difference will be relevant to human development and reproduction or not.

Assessment and counseling — Exposure reduction for persistent chemicals is more challenging than for short-lived chemicals. Nonetheless, advice to patients interested in reducing exposure includes removing dust, vacuuming with high efficiency particulate air (HEPA) filters, cleaning air filters, and replacing any ripped or broken upholstered furniture, particularly foam containing products, to reduce indoor air levels. Hand washing can also remove PBDE dust contamination from hands. Biological testing is not available in the clinical setting at this time.

Useful resources — Fact sheets on flame retardants have been created by the National Institute of Environmental Health Sciences and the Environmental Protection Agency that may be useful for clinicians to provide to interested patients.

PESTICIDES — A pesticide is any substance used to control pests including insecticides, herbicides, rodenticides, and fungicides.

Types and mechanisms — Pesticide chemicals are widely used in agriculture for food production, and therefore, a primary route of human exposure is through the ingestion of pesticide residues in the diet. Pesticides are additionally used in the home or workplace for control of pests, which creates additional exposure routes through inhalation, dermal absorption, and ingestion, particularly if food is handled after touching surfaces contaminated with pesticides. Occupational exposure among agricultural workers and their families has been a concern. We focus here specifically on insecticides, as the health effects of these chemicals have been more widely studied.

Insecticides are typically classified by their mode of action and persistence in the environment. The organochlorines were the first insecticides synthesized and include compounds like dichlorodiphenyltrichloroethane (DDT), chlordane, and methoxychlor. Organochlorines interfere with nerve sodium channels and were widely used for insect control in the middle of the 20^th century for mosquito control but banned secondary to extensive neurotoxicity to other living organisms, not just insects. While exposure continues to this day as these chemicals persist in the environment for extended periods, there is little individuals can do to alter their own exposure. DDT is still used in some countries for control of mosquitoes in the fight against malaria [114]. Organophosphates and carbamates were introduced as alternatives to the organochlorines. While they are also neurotoxicants, their mechanism of action is through acetylcholinesterase inhibition, and they are less persistent in the environment than the organochlorines. The pyrethroids are an additional class of nonpersistent insecticide chemicals that interfere with sodium channels; these are often a component of residential pest (insect) control products. Newer insecticides include the neonicotinoids and the ryanoids. The variety of products and mechanisms of action are challenges to fully understanding the potential health hazards of insecticides.

Health impacts

●Reproductive health – Although the available data are less consistent than that for neurotoxic effects, insecticides also appear to adversely impact pregnancy outcomes (birth weight, gestational age at delivery) [115-120]. A study of 314 mother-newborn pairs reported an inverse association between chlorpyrifos levels and both birth weight and newborn length [119]. The decrease in birth weight (-186 grams per log increase in chlorpyrifos levels) was similar in magnitude to that attributed to maternal smoking. Other studies have evaluated specific or nonspecific organophosphorus pesticide (OP) metabolites in maternal urine as an integrating dosimeter of exposure to OP insecticides. Additional studies that evaluated the relationship between OPs and gestational age at birth also reported significant negative associations, which suggests the outcome of preterm birth merits additional research [117,121]. Pyrethroids have also been associated in cohort studies with negative impact on birth outcomes, such as preterm birth or low birth weight [122,123].

In addition to an impact on female reproduction, pesticide exposure has been linked with poor semen quality and reduced fertility among males following both occupational and lower-level environmental exposure [124-126].

●Neurotoxicity – There is animal and epidemiologic evidence that non-DDT insecticides also adversely impact neurodevelopment [127-134]. This is not surprising given that the chemicals were initially designed as nerve agents. Evidence for neurotoxicity is strongest for organophosphate pesticides with demonstrable deficits in cognition, memory, behavior, and motor reflexes; the greatest effects appear to occur following prenatal exposure (compared with postnatal) [127] and is not limited to women exposed occupationally. Yet, experimental and preliminary epidemiologic studies suggest prenatal exposure to pyrethroid insecticides also adversely affects learning and behavior in offspring [128-133].

Assessment and counseling — Women with acute significant exposure to pesticides are evaluated and treated as indicated. Biologic measurements are typically limited to specific labs for biomonitoring (eg, Centers for Disease Control and Prevention) or research purposes and not performed in clinical practice. If acute toxicity is suspected, clinicians should contact a local poison control center for help in managing the suspected poisoning. Confirmation of toxicity with biologic measurements is often recommended but may not be available in a clinically relevant timeframe, so treatment is instituted based upon symptoms, signs, and exposure history. For suspected organophosphate toxicity, acetylcholinesterase activity can be measured, but this would not be common in a typical clinical visit. (See "Organophosphate and carbamate poisoning" and "Paraquat poisoning" and "Overview of rodenticide poisoning".)

To assess exposure, we ask our patients during prenatal care about their use of pesticides inside the home, outside the home in the yard, and on pets. We also take an occupational history and, for those in agricultural work, will follow up with questions about use of personal protective equipment. We counsel our patients attempting conception to reduce exposure to pesticides if possible. Potential measures include [135,136]:

●Avoid application of residential pesticides both indoors and outdoors, and stay out of areas that have been recently treated.

●Choose baits and traps over sprays, dusts, and bombs to control residential pests.

●Seal cracks and holes in homes to reduce influx of insects.

●Remove shoes at the door.

●Avoid chemical tick and flea collars on pets.

●Wash fruits and vegetables (although this removes only surface pesticide residues).

●Consider purchase of organic fruits and vegetables, with a focus on the dirty dozen (reported by the Environmental Working Group each year). We recognize this option may be unavailable to all patients given potentially prohibitive pricing of such products.

●Insect repellants, such as DEET, do not appear to pose a significant concern to human health, including during pregnancy, when used as directed, although data remain limited [137].

Useful resources — Useful fact sheets have been created by MotherToBaby. Additional resources for interested clinicians have been collated by PRHE and are listed at the website Pesticides Matter.

PERFLUOROALKYL SUBSTANCES (PFAS)

Exposure sources and testing — Perfluoroalkyl substances (PFAS), previously called perfluorochemicals (PFCs), are used in nonstick cookware, carpet, stain resistant treatments for clothing, aqueous film-forming foam concentrate (AFFF) firefighting foam, nonstick packaging, and various industrial processes [138,139]. This class of chemicals, which includes more than 12,000 compounds such as perfluorooctanoate (PFOA), perfluorooctane sulfonate (PFOS), and perfluorohexanoate (PFHX), can be ingested or inhaled, are not metabolized in the body, and have estimated half-lives ranging from two to nine years. Recent concerns have arisen, as some of the chemicals have been found and measured in the drinking water of communities.

●Testing – The 2022 the US National Academies of Sciences, Engineering, and Medicine (NASEM) consensus study on PFAS suggests a role for possible PFAS blood testing in certain situations for those patients "who are likely to have a history of elevated exposure." This includes those with occupational exposure (eg, firefighters), those who live in communities where PFAS contamination has been documented (eg, drinking water exceeding regulatory limits), or those who live near PFAS-contaminated facilities. Although some of these chemicals can be measured in the blood and compared with population levels, there are currently only limited human correlations of the measured level and risk of adverse outcomes. Therefore, we have been hesitant to advise routine blood testing since it is difficult to interpret, or offer advice, other than to stop the exposure.

●Test interpretation and treatment – The above recommendations remain challenging to interpret as there are different definitions of what constitutes elevated exposure or PFAS contamination given variations in state and national guidelines [140]. In addition, there is no way (as yet) to remove or enhance excretion of the PFAS chemicals from the body.

●Role in establishing exposure – One justification for getting some blood testing, particularly for the specific PFAS found in elevated levels in the drinking water, would be to have a baseline measurement that would be available if at some later time new information arises that would be useful.

Clinical impact — In 2022 NASEM released a consensus study on PFAS exposure, testing, and clinical follow-up and found sufficient evidence of an association in humans between PFAS exposure and [140]:

●Decreased antibody response (adults and children) [139-141]

●Dyslipidemia (adults and children)

●Decreased infant and fetal growth

●Increased risk of kidney cancer (adults)

They also found suggestive evidence of an association with:

●Increased risk of breast cancer (adults)

●Liver enzyme alterations (adults and children)

●Increased risk of gestational hypertension and preeclampsia

●Increased risk of testicular cancer (adults)

●Thyroid disease and dysfunction (adults)

●Increased risk of ulcerative colitis (adults)

Impact on reproduction and pregnancy — There are numerous animal and human studies in progress, but most information at present has relied on animal studies. Per the CDC, "developmental and reproductive effects, including reduced birth weight, decreased gestational length, structural defects, delays in postnatal growth and development, increased neonatal mortality, and pregnancy loss have all been associated with prenatal rodent exposure to PFOS and PFOA" [142]. Some human studies suggest that exposure to high levels of certain PFAS may lead to increased risk of high blood pressure or preeclampsia in pregnant women and small decreases in infant birth weight [139,143], both of which were cited by the 2022 NASEM committee as associated with PFAS exposure; evidence was sufficient for the association with decreased fetal growth and suggestive for an increased risk of preeclampsia or gestational hypertension.

If a patient is documented to have elevated PFAS blood levels during pregnancy, the relevant screening tests should be considered. A lipid panel may be deferred until the postpartum period. Screening for preeclampsia should occur at all prenatal visits and warning signs of preeclampsia reviewed. There is insufficient evidence as to whether ultrasound(s) for fetal growth should be considered.

In a prospective cohort study of United States women that measured serum concentrations of PFAS and classified the concentrations by quartiles, the highest quartile group had a 60 percent increased hazard ratio for median time to natural menopause, which translated to natural menopause occurring approximately two years earlier compared with the lowest quartile group [144].

Counseling — The first step in counseling involves discussion of PFAS, potential health effects, and the pros and cons of blood testing, and then prevention. If not feasible to test seven PFAS chemicals (per the NASEM committee guide), one could choose a more limited approach and test only for the chemicals found most elevated in the contaminated water.

●For those found to have elevated levels, counsel about currently known associations to increased risks and perform relevant screening for related potential health issues.

●The most important guidance is to stop or reduce exposure.

•For those with known water contamination, use an alternative safe water for drinking and cooking, or install a filter certified to remove PFAS from a water system with high levels.

•Reduce, to the extent possible (particularly if pregnant), other potential sources, such as contaminated food (from contaminated soil or water) or food in contact with materials containing PFAS (such as microwave popcorn bags, packaged fast foods, or processed foods).

•Reduce use of or replace nonstick pots and utensils, and if using, do not clean in the dishwasher.

•Discard damaged stain-resistant carpeting and upholstery.

●For occupational exposures, identify and reduce potential sources of exposure, which may also include inhalation.

Additional educational resources specific to PFAS can be found at:

●Agency for Toxic Substances and Disease Registry (ATSDR) website on Per- and Polyfluoroalkyl Substances (PFAS) and your health

●ASTDR: PFAS – An Overview of the Science and Guidance for Clinicians on Per- and Polyfluoroalkyl Substances (PFAS) (revised December 6, 2019)

●United States Environmental Protection Agency (EPA): Research on Per- and Polyfluoroalkyl Substances (PFAS)

●Pediatric Environmental Health Specialty Units (PEHSU): Per- and polyfluoroalkyl substances (PFAS) resources

AIR POLLUTION

Exposure sources and assessment — Air can be polluted with a number of agents, including fine particulate matter (PM_2.5, PM₁₀) but also carbon monoxide (CO), sulfur dioxide (SO₂), polycyclic aromatic hydrocarbons (PAHs), ozone, and nitrous dioxide (NO₂). While air quality has improved in industrialized countries as a result of legislative efforts, there is evidence that continued low-level exposure to air pollution can negatively influence health at the population level, increasing the risk for morbidity and mortality from cardiovascular and pulmonary disease, both of which have the potential to negatively impact pregnancy. (See "Overview of possible risk factors for cardiovascular disease", section on 'Air pollution' and "Risk factors for asthma", section on 'Air pollution' and "Chronic obstructive pulmonary disease: Risk factors and risk reduction", section on 'Pollution, biomass, and occupational exposures'.)

There are no clinical tests to measure pollution exposure. Reducing exposure to ambient air pollution is best accomplished through policy and legislation. That said, on particularly high pollution days as defined by the air quality index, individuals could elect to stay inside and filter indoor air, although the implications of high exposures over short durations in pregnancy is not entirely understood [145].

Reproductive impact — The possibility that ambient air pollution might additionally affect female fertility and reproductive outcomes stems from extensive and mostly consistent literature documenting the association of cigarette smoking and environmental tobacco exposure with increases in subfertility and a host of adverse pregnancy outcomes including miscarriage, reduced birth weight, stillbirth, preterm birth, and abruption. (See "Cigarette and tobacco products in pregnancy: Impact on pregnancy and the neonate".)

Given the overlap in constituents of tobacco smoke with air pollution, a number of epidemiologic investigations have been undertaken to evaluate the association of ambient air pollution and human reproduction. Study designs are heterogeneous and include consideration of a variety of constituents of air pollution as the exposure of interest, most commonly fine particulate matter (PM_2.5, PM₁₀) but also CO, SO₂, PAHs, and NO₂. How exposure is quantified also differs from study to study ranging from direct personal air sampling to estimations from stationary air quality monitoring sites coupled with geospatial information on an individual.

Despite the heterogeneity of study designs, several systematic reviews summarizing the body of evidence with respect to reproductive health and air pollution have demonstrated increases in the risks for preterm birth, miscarriage and stillbirth, low birth weight, decrements in birth weight, and hypertensive disorders of pregnancy [146-152]. The association with preterm birth has been less consistent in studies. That said, even when associations were significant, estimates were typically modest (odds ratio <1.3). Such modest association nevertheless can have a significant impact at the population level. There are emerging data suggestive that pre- and early childhood exposure to ambient air pollution may increase the risk for autism spectrum disorders with ongoing confirmatory studies underway [153].

Carbon monoxide poisoning — In contrast to CO present in ambient air pollution, high levels of CO can accumulate in a dwelling due to incomplete combustion of an energy source (like a gas furnace) with inadequate ventilation. CO binds more tightly to hemoglobin than to oxygen (approximately 200 times) and is bound even more tightly to fetal hemoglobin. CO crosses the placenta, and given the relative affinity of fetal hemoglobin for CO compared with adult hemoglobin, CO can accumulate in the fetus and take longer to clear than in the adult. Hyperbaric oxygen treatment may need to be extended in the setting of CO poisoning in pregnancy to accomplish fetal CO elimination [154]. The presentation, diagnosis, and management of patients with CO poisoning is discussed in detail separately. (See "Carbon monoxide poisoning".)

RESOURCES FOR PATIENTS AND CLINICIANS

Assessment of environmental risk — The Agency for Toxic Substances and Disease Registry (ATSDR) of the Centers for Disease Control and Prevention provides training on taking an environmental exposure history.

Patient brochures about toxic exposures

●The Program on Reproductive Health and the Environment at the University of California San Francisco provides free online patient brochures, including:

•Toxic Matters – Protecting Our Families from Toxic Substances

•Work Matters – When You Work With or Around Toxic Chemicals What You Know Really Matters

•Pesticides Matter – Steps to Reduce Exposure to Protect Your Health

•What to Eat – A Guide to Your Daily Food Choice

●The ATSDR provides Patient Education and Care Instruction Sheets that address exposure to arsenic, asbestos, beryllium, carbon tetrachloride toxicity, nitrate/nitrite, polychlorinated biphenyls (PCBs), and radon.

●The American College of Obstetricians and Gynecologists Frequently Asked Questions on Toxic Chemicals: Steps to Stay Safer Before and During Pregnancy.

General information

●Environmental exposures and reproduction

•American Academy of Pediatrics, Pediatric Environmental Health (Green Book). A textbook on environmental health for clinicians that discusses sources of exposure and potential developmental susceptibility. The book can be purchased online through the American Academy of Pediatrics.

•American Association of Poison Control Centers supports 55 poison centers in their efforts to prevent and treat poison exposures. They also offer a free and confidential Poison Help Line at 1-800-222-1222.

•Pediatric Environmental Health Specialty Unit (PEHSU) is a national network of physicians with expertise in pediatric and reproductive environmental health.

●Environment and general health

•US Environmental Protection Agency provides information and training on Drinking Water Information for Health Care Providers.

•American College of Occupational and Environmental Medicine (ACOEM) provides guidelines that help clinicians evaluate and manage potential occupational health hazards.

•The United States Department of Labor Occupational Safety and Health Administration requires employers to provide safety data sheets for employees. This information is also available online.

SUMMARY AND RECOMMENDATIONS

●Counseling challenges and data limitations – Challenges in counseling women about the reproductive effects of chemical agents include the vast number of exposures and exposure combinations, limited applicability of animal data to humans, the inability to assume causation from association, the variable impact of agent dose and timing on reproductive and developmental outcomes, and the numerous potentially confounding variables (eg, maternal substance use, socioeconomic level, nutrition). (See 'Clinical and counseling challenges' above.)

●Exposure reduction and management – To help reduce the risk of environmental exposure, we discussed preventive measures, assess potential exposure risks, discuss the impact of any identified agents, and provide information and counseling resources for our patients. (See 'Our approach' above.)

•Lead – Lead, in the form of inorganic lead, is a commonly encountered agent (table 1). Inorganic lead can be absorbed through the intestinal tract (ingestion) or lungs (inhalation). Maternal lead exposure appears to increase the risk of spontaneous abortion, preterm birth, and small for gestational age birth weight as well as negatively impact neurobehavioral function and cognitive development. We ask all pregnant women about possible lead exposure and have a low threshold for checking a venous blood lead level (table 2). (See 'Lead' above.)

•Mercury – Mercury exposure typically comes from organic methyl mercury (ingested with fish intake) and elemental mercury (dental amalgams and artisanal gold mining). Exposure to methylmercury in fetal life in sufficient quantities can cause neurologic injury. (See 'Mercury' above.)

•Arsenic – Arsenic is a naturally occurring element found in the earth's crust that can leach into drinking water and sometimes into food such as rice (for rice, the doses are typically low doses). There are potential occupational exposures (such as in smelters, mining) and environmental exposures (frequently from contaminated drinking water). Elevated arsenic levels in drinking water have been associated with increased risk of spontaneous abortion, stillbirth, neonatal death, and the potential for future increased risks for some cancers. (See 'Arsenic' above.)

•Plastics (including phthalates and phenols) – Plastics, including phthalates and phenols (eg, bisphenol A) are synthetic chemicals used extensively in a diverse array of industrial and consumer applications, typically used as a plasticizers or solvents. These agents are considered endocrine disrupting chemicals, and initial studies suggest that they negatively impact fertility, reproductive outcomes, and development. (See 'Plastics' above.)

•Synthetic flame retardants – Synthetic flame retardants have been applied widely to textiles, furnishing, upholstery, carpets, electronics, and construction materials. There are hundreds of distinct flame retardants with differing chemical structures used over the past 40 years. While animal research suggests that some can cause reproductive and neurodevelopmental toxicity as well as other adverse nonreproductive effects, human data are limited. (See 'Flame retardants' above.)

•Pesticides – Pesticides include insecticides, herbicides, and fungicides. Organochlorines, the first insecticides synthesized, include dichlorodiphenyltrichloroethane (DDT), chlordane, and methoxychlor. Organochlorines interfere with nerve sodium channels and were widely used for mosquito control but subsequently banned secondary to extensive neurotoxicity to other living organisms, not just insects. There is animal and epidemiologic evidence that non-DDT insecticides adversely impact neurodevelopment. Negative reproductive effects include lower birth weight and gestational age at delivery as well as male subfertility. (See 'Pesticides' above.)

•Perfluoroalkyl substances (PFAS) – Perfluoroalkyl substances (PFAS), also called PFCs, are used in nonstick cookware, carpet, stain resistant treatments for clothing, AFFF fire-fighting foam, nonstick packaging, and various industrial processes. Significant exposures have been identified in contaminated drinking water sources. Initial studies have suggested an association between elevated maternal blood and cord blood concentrations of PFAS (primarily perfluorooctane sulfonate [PFOS] and perfluorooctanoate [PFOA]) and decreased birth weight. More studies are ongoing. (See 'Perfluoroalkyl substances (PFAS)' above.)

•Air pollution – There is evidence that continued low-level exposure to air pollution can negatively influence health at the population level by increasing the risk for morbidity and mortality from cardiovascular and pulmonary disease. Several systematic reviews assessing reproductive health and air pollution have demonstrated increases in the risk for stillbirth, low birth weight, and decrements in birth weight with increasing exposure. (See 'Air pollution' above.)