Environmental and Occupational Concerns in Pregnancy

Environmental and occupational hazards are challenging for the clinician because of the intense concern expressed by many potentially exposed women and their families. Although it is true that some types of exposures can cause birth defects and other problems, in many cases there is little to no risk for the patient or the fetus because the exposure dose is negligible. Establishing exposure levels can be challenging because many toxicants have no readily available assay to assess the dose absorbed into the body. Even if a blood or urine test is available, compounds may be rapidly metabolized so that an exposure last week or last month cannot be detected by a test today. A careful environmental and occupational history can provide an estimate of exposure levels.

Another challenge is reducing exposures that are identified in the history. The clinician cannot ensure that the patient will be able to take appropriate exposure remediation steps. Environmental hazards may be unavoidable when contamination of air, water or soil is widespread. For occupational exposures, the patient may wish to follow the clinician's advice, but the workplace may refuse to modify the patient's work duties. A work restriction may cause the woman to lose her job, especially in countries that have not enacted maternity protection legislation. This barrier to managing the patient can be overcome, in part, by using work restrictions judicially.

The number of potential environmental and occupational exposures is enormous, so the clinician will need information resources. The reproductive and developmental effects of all agents cannot be described in a single textbook chapter. Caution should be exercised when reviewing the health information on the material safety data sheets that patients may bring to clinic. Several studies have demonstrated that the known adverse health effects of a compound may be missing from these sheets, particularly the reproductive effects.^{1, 2}

To assess an agent for any associations with adverse health outcomes, a literature search should be conducted or an expert should be consulted. Information resources available by telephone in North America include the Organization of Teratology Information Services (http://www.otispregnancy.org) and Motherrisk (http://www.motherisk.org). The web pages of these organizations provide links to resources in other parts of the world. Reproductive toxicity data syntheses are available by subscription from services such as REPROTOX (http://www.reprotox.org/) or the Teratogen Information System, TERIS (http://depts.washington.edu/terisweb/teris/index.html). Poison control centers, medical school libraries, and hospital emergency departments may have subscriptions to these and other computerized databases that contain health information about hazardous agents.

Environmental pollutants can cause developmental effects at prenatal exposure levels that do not cause symptoms in the mother. Trace amounts of toxicants can be found in food, air, and water, but there are a number of laws and regulations in place in the United States to limit toxicants to levels that are unlikely to be harmful. There are circumstances, however, when environmental exposures can exceed recommended levels and the woman can take steps to lower her exposure.

Methylmercury is a contaminant that can be found in fish. Its toxic properties were noted during poisonings in Japan and Iraq and in more recent epidemiologic studies; these findings have been further confirmed by studies in laboratory animals.^{3, 4, 5, 6, 7} In Japan, pregnant women consumed fish poisoned by methylmercury released as industrial waste into Minamata Bay. In Iraq, pregnant women consumed grain that had been treated with pesticides containing the compound. Their infants had microcephaly, learning deficits, abnormal gait, dysarthria, ataxia, visual problems, and deafness, whereas the mothers showed little to no toxic effects. Pregnant women in the Faeroe Islands had exposures from consuming pilot whale meat, and their children at age 7 had neuropsychologic dysfunction that included problems with language, attention, and memory.⁷

Mercury is currently found in many fish species.  Sport fish that are smaller contain fewer pollutants than larger, older fish.  Bluegill, perch, stream trout and smelt that feed on insects contain lower levels of pollutants than fish that feed on the bottoms of lakes and streams, such as catfish or carp.  When cleaning and cooking fish, removal of the fat reduces pollutant levels.^{8, 9, 10, 11, 12} 

Warnings about fish consumption were issued in the United States during 2001 by the Environmental Protection Agency and the Food and Drug Administration.^{8, 9}  Women who may become pregnant or who are pregnant or breastfeeding were advised not to eat shark, swordfish, king mackerel or tilefish.  Avoidance of these fish was recommended because long-lived, large fish that feed on other fish accumulate methylmercury over their lifetimes.  In addition, the women were advised to limit intake of all other fish to 12 oz per week on average.  Health Canada has recommended a limit of 150 g per month of fresh and frozen tuna, shark, swordfish, escolar, marlin and orange roughy for women who may become pregnant and women who are pregnant or breastfeeding.¹²

Canned tuna is one of the most commonly consumed fish preparations.  Mercury levels are generally lower in canned tuna than in tuna steak because canned tuna is prepared from smaller fish.  Canned light tuna has less mercury than canned albacore tuna.^{9, 12}  Health Canada says that women who may become pregnant and women who are pregnant or nursing may eat up to four Food Guide Servings of canned albacore tuna each week; one Food Guide Serving is 75 g, 2.5 oz, 125 mL or half a cup. 

Another example of an environmental exposure that can affect pregnancy and fetal development is lead. Approximately 1 in 200 childbearing-aged women in the United States have blood lead levels exceeding the recommended level of 10 μg/dL (0.483 μmol/L).^{13, 14} Women at greater risk for elevated blood levels include those whose children were found to have an elevated lead level during screening or those who live in a house built before 1960 that was recently renovated or currently has peeling or chipped paint. Other risk factors include engaging in hobbies involving lead or having a household member who works in a job with lead exposure, eating or chewing nonfood items, being a current smoker, or consuming more than nine servings of canned food per week. In a study of pregnant women, the presence of at least one of these risk factors had a sensitivity of 89.2% and a positive predictive value of 96.4% for exceeding the recommended blood lead level.¹⁴

Multiple sources of information about terrorism and disasters have been developed to assist the clinician to manage patients, including pregnant women.^{15, 16, 17, 18, 19, 20, 21, 22, 23} The Centers for Disease Control and Prevention provides fact sheets, guidelines and links to information about biologic, nuclear, and chemical terrorism at http://www.bt.cdc.gov.

Women who are considered at high risk for exposure to agents used for bioterrorism, especially smallpox and anthrax, can be counseled about vaccination and antibiotic prophylaxis based on published guidelines.^{15, 16, 24} It is advisable to consult the most recent bulletins from the Centers for Disease Control and Prevention, the American College of Obstetricians and Gynecologists and similar organizations. Fact sheets available on the Internet cover topics such as providing routine prenatal care during a disaster, treating emerging infections and other topics.^{17, 23}  Immunization during pregnancy is further discussed in the chapter on "Immunization in Pregnancy".

Smallpox vaccine should not be administered to women who are pregnant, and vaccinated women should avoid pregnancy for 4 weeks after vaccine administration. Smallpox vaccine should not be administered to anyone who has close physical contact with a pregnant woman, such as household members and sexual partners. To ascertain the magnitude of risk from smallpox vaccine exposure during pregnancy, new data are being assembled from a registry of pregnant women inadvertently exposed to smallpox vaccine. Breastfeeding is also a contraindication to receiving smallpox vaccine, although people who are in close contact with a breastfeeding woman may be vaccinated.¹⁷

Anthrax vaccine is an inactivated bacterial vaccine and its use should be reserved for situations in which there is a risk for serious maternal illness or death if the vaccine is not administered.^{17, 25, 26} The American College of Obstetricians and Gynecologists has stated that the risk of teratogenicity from anthrax vaccine is theoretical and that vaccination of pregnant women is “not routinely recommended unless pregnant women work directly with Bacillus anthracis, imported animal hides, potentially infected animals in high incidence areas (not United States), or for military personnel deployed to high-risk exposure areas.”²⁶ Antibiotic prophylaxis of asymptomatic pregnant and lactating women should be limited to those exposed to a confirmed environmental contamination or high-risk source as determined by the local Department of Health.²⁴ Ciprofloxacin 500 mg orally every 12 hours is recommended for 60 days, although if the bacteria is found to be penicillin-sensitive, the patient should use amoxicillin instead. For exposed pregnant women who are allergic to penicillin and ciprofloxacin, doxycycline should be administered or penicillin desensitization should be considered. Guidelines stress that benefits of therapy should outweigh risks. While human teratogenicity with fluoroquinolones has not been confirmed, some studies have shown irreversible drug-induced arthropathy in adolescent animals administered ciprofloxacin, and doxycycline can cause dental staining of the primary teeth and possibly decrease bone growth.²⁴

Substantial environmental exposure to radiation could occur as a result of a disaster or terrorism incident, although small-scale releases (e.g., "dirty bombs") may generate more fear than actual exposure. Some of the issues to discuss with patients after an environmental radiation release are similar to those that arise in context of diagnostic tests (see the chapter "Potential Effects on the Conceptus from Diagnostic Roentgenographic and Radionuclide Studies"). If the exposure was negligible, then the clinician will be able to reassure the patient that termination of pregnancy is not necessary and that no increase in adverse health consequences is anticipated.

When the nuclear plant at Chernobyl exploded, a huge amount of fallout migrated to the surrounding regions. When the cloud reached Finland, radiation exposure was twice the background level.²⁷ Although there was an increase in spontaneous abortions in Finland after the incident, reporting bias or confounding could not be ruled out. In the Czech Republic, a deficit of male births was correlated with fallout exposure dose.²⁸ Studies of childhood leukemia incidence in the areas surrounding the plant were inconclusive, but a definite increase in thyroid cancer was found among children in Belarus who were exposed in utero or during infancy.²⁹ The increase in childhood thyroid cancer occurred in the context of low-level iodine deficiency because iodinization of salt was not used in the former Soviet Union.³⁰ This finding emphasizes the importance of iodine prophylaxis among pregnant women if a nuclear incident occurs.^{20, 31, 32} Iodine reduces the risk for thyroid cancer by binding to receptors in the thyroid, which prevents uptake of radioactive iodine isotopes. The Centers for Disease Control and Prevention recommends that, in the event of a nuclear disaster, pregnant and breastfeeding women should be administered the same dose of potassium iodide as other young adults.³¹

Any chemical could theoretically result in population exposures during a terrorist attack or disaster. Chemicals that are regarded as likely agents for terrorist attacks include sarin nerve gas, mustard gas and the poisons ricin or VX. Very little information is available about caring for pregnant women exposed to these agents. The general principles of decontamination and supportive management would apply to pregnant women. A significant issue during an incident will be the high level of fear among pregnant women whose exposures are negligible. Education can help to address this fear. Psychiatric morbidity has been studied after natural disasters such as earthquakes.^{33, 34} These studies suggest that pregnant women who may need the most intensive psychosocial support include those who were injured, had a family member who was injured, or are earlier in gestation when the disaster occurred.

The occupational history can be used to assess whether the patient works with chemicals, biological agents or physical hazards such as noise and radiation. Other common concerns are ergonimic job demands and circadian disturbances from working frequently rotating shifts. In clinical practice, the woman is the patient and the history focuses on her health and her risk factors. The male partner's occupational exposures can also impact reproductive outcomes, so it is important to assess his history. Examples of associations between paternal exposures and pregnancy outcomes are provided below.

In addition to obtaining a complete list of the couple's occupational exposures, the history should also be used to estimate exposure levels. Working with an agent is not the same as being exposed to it internally. Chemical and biological agents in the workplace are typically absorbed into the body through inhalation, dermal absorption, or contamination of tobacco products or food or drinks that are ingested.

If a chemical used in the workplace is heated, or is or is agitated or sprayed (aerosolization), or if it is in the form of a fine powder, inhalation of the substance often increases. Agents that are agitated, sprayed or poured may have more opportunities to contact the skin, increasing the risk for dermal absorption among those agents for which the skin is not an effective barrier, such as certain organic solvents and pesticides. If a large amount of the agent is used and the work task involving the chemical is frequently performed, there is a greater chance of internal body exposure. If no gloves or protective clothing is used, dermal exposure risk is increased. All gloves are not equally impermeable, so the proper type of gloves must be worn for specific chemicals. Efficient workplace ventilation is preferable to use of a respirator. Pregnant women may wear most lightweight respirators for limited periods, and a properly designed respiratory protection program can minimize inhalational exposures. However, respirators do not prevent all exposures. Breaks in technique occur, leading to potentially significant exposures and a false sense of security.

Employees with potential exposure to radiation often wear badges, and historical data can be reviewed early in pregnancy to ascertain whether past exposures have exceeded recommended levels.  If so, the job should be evaluated to determine ways to reduce exposure to recommended limits for pregnant women.  Women may be required to wear hearing protection for moderately elevated noise levels (e.g., 85 decibels time weighted average over 8 hours) that are not thought to cause harm to the fetus.  Few data are available to estimate the noise threshold at which fetal hearing may be compromised by maternal noise exposure late in pregnancy, but loud noise will be transferred through the mother's abdominal wall.  

Examples of occupational and environmental exposures that have been linked with various reproductive and developmental endpoints are described below. This information highlights the fact that birth defects are not the only adverse effect that can occur from hazardous exposures to parents.  Although the critical period for the development of birth defects of many organ systems is in the first trimester, hearing, descent of the testicles, and development of the brain can be harmed by certain toxicants even if exposure only occurs after the first trimester.  In addition, many hazardous chemicals to which a mother is exposed can be found in breast milk. Very few epidemiologic studies have assessed the effect of lactational exposures on infants.  If the mother's exposure level is low, then the toxicant level in breast milk is probably very low. The benefits of breastfeeding may outweigh any risk of exposure to the infant.

Difficulty in achieving a successful pregnancy is fairly common.  About 7% of women aged 15–44 in the United States report that they suffer from fertility problems.³⁵  Assisted reproductive technologies such as in vitro fertilization are used to conceive 1% of births in the United States, and the rate of use of these technologies is similar or higher in Western Europe.^{36, 37} 

Some studies have found worsening secular trends in semen parameters, urogenital tract anomalies and testicular cancer.³⁸  Although other studies have not found such trends, the positive studies have raised concerns that environmental exposures may be affecting reproductive health. Confounding by increasing rates of obesity among men and prenatal exposure of male infants to tobacco smoke are alternate or complimentary explanations for observed trends in semen parameters.^{39, 40} When male infertility is diagnosed in clinical settings, non-toxicological explanations such as varicocele, post-pubertal viral infections such as mumps, cryptorchidism and other medical conditions are more common than etiologies related to chemical exposures.  Heavy exposure to persistent organochlorine pollutants such as dichloro-diphenyl-trichloroethane (DDT) and polychlorinated biphenyls (PCB), however, can affect male fertility;  occupational exposure to certain pesticides such as dibromochloroethane (DBCP) or certain other agents can also impair male fertility.^{41, 42, 43, 44, 45}

 In women, tubal disorders, polycystic ovary syndrome, ovarian dysfunction related to aging and uterine factors such as leiomyoma or Mullerian anomalies are more frequently implicated in the etiology of infertility than toxic exposures.  The risk for fertility problems can be increased by handling antineoplastic drugs and organic solvents such as n-hexane, methyl ethyl ketone, ethyl acetate and dichloromethane (also known as methylene chloride) without using optimal equipment and work practices.^{44, 46, 47}  Exposure to a variety of pesticides have also been associated with prolonged time to pregnancy.^{43, 45, 48}

Spontaneous abortion can be related to toxicant exposures, although the miscarriage rate is high (about 15% of clinically recognized pregnancies) among women with no known hazardous exposures. Many recent epidemiologic studies have been able to control for the main confounders and suggest that the clinician should be concerned when the patient's history reveals certain types of hazardous exposures. The biologic plausibility of findings from epidemiologic studies among women and men is supported by experimental studies among laboratory animals.

The critical period during which a parental exposure to a hazardous agent may increase the risk for spontaneous abortion probably includes not only the early weeks of pregnancy but also the preconception period. Paternal factors unrelated to environmental exposures, such as older age, can increase the risk for spontaneous abortion.⁴⁹ The mechanisms by which male exposure to toxicants may cause spontaneous abortion are thought to include genetic alterations in sperm, transfer of toxic exposures to the mother through soiled clothing, or other mechanisms. Spontaneous abortion and other types of fetal death have been increased in populations in which the father was exposed to organic solvents, lead, mercury, welding fumes or pesticides.^{50, 51, 52, 53, 54, 55}

Among women, some preconception exposures take time to be cleared from the body (e.g., heavy metals and chlorinated pesticides), so prudent avoidance during the preconception period is warranted. During early pregnancy, intensive exposure to organic solvents increases the risk for miscarriage.^{56, 57, 58} Some of these agents are carbon disulfide, dimethylformamide, methylene chloride, toluene, and xylene. Maternal lead exposure, certain pesticides, the more toxic of the disinfectants, like formaldehyde, and other exposures increase the risk of spontaneous abortions among exposed women.^{56, 57}

Maternal exposures in health care workplaces that can increase the risk for miscarriage include certain medications, sterilants such as ethylene oxide, and waste anesthetic gases.^{59, 60, 61, 62}  Some evidence suggests that prolonged working hours and shift work may increase miscarriage risk.^{63, 64} Drugs of concern include antiviral agents like acyclovir and zidovine, antineoplastic agents, and others. Pharmaceuticals are further discussed in the chapter.: "Teratology and Drugs in Pregnancy". A very large dose of ionizing radiation soon after conception may be embryolethal, causing a subclinical or clinical miscarriage. Ionizing radiation is further discussed in the chapter "Potential Effects on the Conceptus from Diagnostic Roentgenographic and Radionuclide Studies".

Hazardous exposures can cause birth defects, although a substantial proportion of congenital anomalies remain unexplained. Occupational exposure to pesticides has been shown to increase aneuploidy in sperm cells, suggesting a genetic mechanism by which such preconception exposures to the father could cause birth defects.⁶⁵ Agents that have been associated in epidemiologic studies with birth defects in offspring after paternal exposure include pesticides, welding fumes, and possibly lead and organic solvents.^{66, 67, 68, 69, 70, 71}

Because many women are not sure they are pregnant until organogenesis is well underway, reducing hazardous exposures is best accomplished in the preconception period. Maternal exposure to methylmercury is a well-known cause of congenital anomalies. Several studies suggest that maternal lead exposure increases the risk for neural tube defects.^{72, 73} The mechanism by which this might occur is that lead exposure can precipitate zinc deficiency, and this in turn impairs absorption of folic acid.⁷²

Organic solvent use at work increases risk for birth defects, probably by about 60%.^{74, 75} Workplace exposure measurements from industrial hygiene sampling can be very helpful, but commonly are not available to the physician.  Solvent exposure estimates from the patient's history that are most worrisome are those that are high enough to cause sensory irritation,⁷⁶ although with chronic exposure, sensory symptoms often attenuate. In animals, ethylene glycol monomethyl ether and the glycol ether metabolite, methoyxacetic acid, cause limb defects.^{77, 78} Occupational exposure to glycol ethers occurred twice as frequently among mothers of infants with neural tube defects, cleft lip or multiple anomalies in a large European study.⁷⁹

Pesticides vary in their reproductive toxicity from negligible or low to relatively high. Many epidemiologic studies of pesticide contact during pregnancy are limited by inexact assessment of exposure. Birth defects have been associated with certain pesticides in studies of animals and in some studies of mothers who had occupational or environmental pesticide exposure.^{80, 81, 82} In registry studies in Norway that involved more than 190,000 births, limb reduction defects and other congenital anomalies were associated with agriculture, especially grain farming.^{67, 83} Increases in limb defects have been found in some studies of agricultural workers in the United States and Spain.^{84, 85, 86} Grain is often treated with fungicides, but not all agricultural workers would come in contact with these compounds.  Hence, using occupation as a proxy for fungicide exposure is imprecise.  Animal research, however, has shown an increase in limb defects on exposure to certain fungicides.⁸⁷

Compounds that impair reproductive hormone function are suspected causes of chryptorchidism and hypospadias.  Support for this concern has been provided by studies that found associations between the congenital anomalies and employment in agriculture, possibly implicating pesticides that can disrupt endocrine function in experimental studies in animals or in vitro systems, or alternatively, mycotoxins from fungi that grow on damp grain.^{83, 88, 89, 90}  The epidemiologic research includes studies that controlled for non-toxicologic etiologic factors in the genesis of these birth defects such as fetal growth restriction and preterm birth.  In some populations, there is no association between maternal serum levels of persistent pollutants and male genital defects in their infants.^{91, 92}  A breast milk study showed that environmentally persistent pesticides such as DDT and hexachlorobenzene were more common among cases with these congenital anomalies than among controls.⁹³

Ionizing radiation exposure during pregnancy can cause microcephaly and other defects. The likelihood of malformation and the organs affected depends on the dose of radiation and the stage of development at which the radiation is received. Workplaces that follow governmental mandates, such as those of the Nuclear Regulatory Commission in the United States, will keep exposures at a protective level; the maximum exposures allowed for a woman in the United States who reports her pregnancy to her employer are less than 50 mrem in any gestational month and less than 500 mrem throughout the pregnancy.

Paternal exposure to organic solvents or lead in the workplace has been associated with fetal growth retardation and preterm birth, perhaps because of a genetic effect on male gametes. ^{94, 95} Although not all studies agree, increased risk has been implicated if the father's exposure level was high, of long duration or to a mixture of toxicants.^{94, 96, 97} Men's lead-contaminated work clothes may be a source of secondary lead exposure to women.  

Among women, many epidemiologic studies have found a modest adverse effect on birthweight of intensive job physical demands such as usually standing more than 6 hours per shift, working longer than 8 hours daily and working more than 40 hours per week.^{98, 99, 100, 101, 102, 103} Some of the studies have been prospective and have controlled for multiple other risk factors to assess the independent effect of physically heavy work on preterm birth or fetal growth restriction. Intensive job physical demands and highly stressful work may increase the risk for preeclampsia.¹⁰⁴ Frequently rotating shifts have been correlated with having a small-for-gestational-age or preterm infant in some studies.^{103, 105, 106} This information can be useful in counseling women about potential risks, but whether all women should receive routine restrictions on job physical demands is debatable. There are no randomized trials to assess the benefits and consequences of prescribing various restrictions on physical exertion in the workplace.

Occupational exposure to ethylene oxide, nitrous oxide, lead, organic solvents and environmental exposure to air pollution have also been linked to conditions resulting in low birthweight.^{60, 107, 108, 109, 110, 111, 112, 113} Regarding mechanisms by which organic solvents or lead may exert these effects, it is known that both can harm renal function and affect blood pressure.  Preterm delivery is sometimes indicated because of preeclampsia. Women who were exposed to solvents during pregnancy were shown in one study to have 3.9-times the frequency of preeclampsia as unexposed women.¹¹⁴ Occupational exposure to solvents has been associated with increased risk of gestational hypertension.^{115, 116} A blood lead level of 6.9 μg/dL or greater significantly increased the risk of hypertension during pregnancy in one study.¹¹⁷ Other studies have also noted that overexposure to lead in the workplace, and perhaps even airborne lead pollution, may restrict fetal growth.^{118, 119, 120}

Hazardous exposures that result in fetal growth restriction could theoretically increase the infant's risk for chronic hypertension, diabetes and heart disease later in life through fetal programming because small-for-gestational-age infants are at increased risk for these conditions.^{121, 122}  There are currently no data from follow-up studies to test this hypothesis.

The fetal brain is vulnerable to neurotoxic exposures throughout pregnancy.¹²³ Children with low-level prenatal lead exposure may demonstrate cognitive deficits well into late childhood even after adjustment for the most important confounding influences on brain function.¹²⁴ Similar effects have been seen for gestational exposure to polychlorinated biphenyls (PCBs), mercury, pesticides and organic solvents.^{13, 125, 126, 127, 128, 129}

Polybrominated diphenyl ethers are environmentally persistent compounds used as flame retardants.  They cause developmental neurotoxicity in animals at levels that are similar to those seen in highly exposed infants in the United States.¹³⁰ Exposure to mothers and infants occurs from house dust and through the food chain, where the compounds bioaccumulate in animals.  In North America, population exposures are higher than in some European countries where the use of polybrominated diphenyl ethers has been banned because of these health concerns.^{131, 132, 133, 134}

Whether attention deficit hyperactivity disorder (ADHD) in children is related to pollution or hazardous occupational exposures of their parents is unclear. Many epidemiologic studies have shown that maternal smoking during pregnancy increases the risk of ADHD as well as aggressive and oppositional behavior.^{135, 136, 137, 138} The findings persisted in studies that controlled for parental ADHD, parental IQ and socioeconomic status. The tobacco studies show that a toxic mechanism could play a role in the genesis of neurodevelopmental problems in children and provide indirect support for the biologic plausibility of studies linking pollutants such as lead, polyaromatic hydrocarbons and the pesticide, chlorpyrifos, to ADHD.^{138, 139, 140}  Fetal chemical exposure levels from smoking, however, are relatively high compared with population exposures to environmental pollution. 

Autism spectrum disorders are increasingly recognized, and this has led to a concern that environmental exposures may play a role in their etiology.¹⁴¹ Autism is believed to be a disorder with multifactorial etiology in which gene–environment interaction may be a causal pathway.  Advanced maternal and paternal age are risk factors for autism.¹⁴²  The initial window of vulnerability for developing autism is early in gestation.  During this period, neural tube closure occurs and the brainstem forms.¹⁴³  Since some toxicants can cause neural tube defects, this reinforces the importance of minimizing hazardous exposures in the periconceptual period and the first weeks of pregnancy.^{72, 73, 79} Other vulnerable periods may include later pregnancy when brain structures develop that are responsible for executive functions, as well as the postnatal period when synaptic pruning occurs.

Prenatal rubella infection and postnatal herpes encephalitis can cause autism, but prospective studies have shown no association with the measles, mumps, rubella vaccine.^{141, 144, 145, 146} Daily prenatal smoking increases the risk for autism by approximately 40%.¹⁴⁷ Drugs that can cause autistic disorders in humans include thalidomide and valproate, and the critical period for exposure is at neural tube closure (gestational days 20 to 24). Autism has a strong genetic component, with 66% concordance in monozygotic twins compared with a background rate of approximately one per 1,000 in the general population. Knockout mice lacking Hoxa-1 and Hoxb-1 genes have some of the same abnormalities as rats exposed prenatally to valproate and people with autism, notably brainstem abnormalities and a decrease in cerebellar Purkinje cells.^{141, 143, 144} Clusters of autism have been investigated in communities with pollution concerns in New Jersey and Massachusetts, but no consensus exists implicating a causal relationship with toxicants.^{141, 148} A case-control study also raised concerns about pollutants as contributors to the development of autism.¹⁴⁹  Research funding on the determinants of autism increased after passage of the Children's Health Act of 2000 (United States Public Law No. 106-310), so new findings may someday help address concerns about the possible contribution of pollutants to autism incidence.

In schizophrenia, the anatomic anomalies of the brain suggest that neuronal migration and apoptosis did not occur normally during the second trimester of pregnancy.^{150, 151} This has led to hypotheses that the disorder may sometimes be caused by prenatal noxious exposures among genetically susceptible individuals. Conditions associated with fetal hypoxia have been linked to later schizophrenia by several groups of researchers.^{152, 153, 154} No studies of parental exposures to environmental or workplace contaminants and later development of schizophrenia in offspring were located.

The fetal immune system can be affected by toxicants, including chemical exposures from maternal smoking and possibly urban air pollution and other chemical exposures.^{155, 156, 157} One study assessed maternal PCB blood levels for 982 newborns near PCB manufacturing facilities in Eastern Slovakia.¹⁵⁸  Higher levels of prenatal PCB exposure were associated with smaller thymic volume among the infants, suggesting that immunologic development may have been affected by exposure.  In a study from Japan, higher levels of persistent halogenated pollutants in breast milk were associated with alterations in T lymphocyte subpopulation ratios.¹⁵⁹  Although developmental immunotoxicants could theoretically increase the risk for childhood asthma or atopy during childhood, the clinical significance of the immune alterations seen in these studies has not been determined.

Childhood cancer risk may be increased by paternal preconception exposure to tobacco, certain metal compounds or petroleum products.^{160, 161, 162, 163} Some results in the studies of male exposures have conflicted and confounders were not always well controlled, but the ability of paternal exposures before conception to cause cancer in offspring is supported by studies in laboratory animals.^{164, 165, 166}

Transplacental carcinogenesis among women who were exposed prenatally to diethylstilbestrol exposure is well known.  Other hazardous agents administered to female animals during gestation can cause malignancies in offspring.¹⁶⁴ One example is exposure to products of combustion such as dibenzopyrene and diesel exhaust particles.^{167, 168} These experiments support the plausibility of the epidemiologic associations found between childhood cancer and exposure to smoke from tobacco or traffic exhaust during pregnancy, although results of studies in human populations are mixed.^{169, 170, 171, 172} In a study that examined sensitive subpopulations of children, maternal prenatal smoking was correlated with leukemia in children who carry CYP1A1 or GSTM1 genotypes which increase fetal exposure to reactive metabolites of polycyclic aromatic hydrocarbons.¹⁷³

Prenatal exposure to nuclear fallout causes childhood thyroid cancer.¹⁷⁴  Maternal prenatal organic solvent exposure has been linked to increased risk of childhood leukemia,^{169, 175, 176, 177} and correlation of maternal solvent exposure during pregnancy with K-ras mutations in children with acute lymphoblastic leukemia suggests that the association could be causal.¹⁷⁸ A large number of studies have linked maternal pesticide exposure, particularly to insecticides, to increased rates of leukemia.  These associations include not only exposure to pesticides from agricultural work but also exposure from residential use.^{163, 179, 180, 181, 182, 183} Pesticide exposure assessment remains imprecise in many epidemiologic studies but some studies include biologic measurements.  For example, meconium levels of the insecticide, propoxur, have been correlated with presence of the leukemia-associated chromosomal translocation t(8;21)(q22;q22) in fetal cord blood cells.¹⁸⁴

Labor regulations and workplace health and safety law are the purview of a number of federal and state agencies in the United States, and expertise in all aspects is beyond the scope of clinical practice. Pregnant women should be advised to obtain information about the policies at their company for implementing these laws and regulations. Further information can be obtained from external sources such as the United States Department of Labor and the Occupational Safety and Health Administration (OSHA). Most workplaces are regulated by OSHA, which has promulgated several standards that explicitly aim to protect reproductive health. Like the enforcement of speed limit laws, however, OSHA enforcement is unable to ensure that all employers comply with all the standards all the time. In addition, some of the legally binding occupational exposure limits were set in the 1970s and have not kept pace with new research on reproductive and developmental hazards that occur at lower exposure levels. Because of this phenomenon, sometimes the patient and the clinician determine that a modification of duties is warranted to reduce reproductive risks.

In Canada, the European Union, and many other countries, a woman who needs time off from work because of pregnancy complications or hazardous exposures can receive temporary income support from a governmental program that is like the social security disability system in the United States. The United States has the Family and Medical Leave Act, which provides for 12 weeks of unpaid leave each year. There are certain exclusions from the Act, and it only applies to women who work in companies with 50 or more employees. Some employers may interpret the Act to mean that a medical complication has to have arisen in the pregnancy before the leave can be used, excluding its use for reducing risk.¹⁸⁵

The US Department of Labor reported that as of 2007, laws that relate to the Federal Family and Medical Leave Act had been enacted in 11 states and the District of Columbia.¹⁸⁶  These states were California, Connecticut, Hawaii, Maine, Minnesota, New Jersey, Oregbon, Rhode Island, Vermont, Washington and Wisconsin.  In Oregon, medical leave related to pregnancy and childbirth may be added to family or medical leave taken for other reasons under the Act. Some state laws have mandated salary support during periods of leave to care for a newborn.  In Washington state, such leave will be paid for up to 5 weeks at $250 per week beginning in 2009.¹⁸⁷ In California, employees are eligible to receive 55 percent of their wages during family and medical leave, up to a maximum of $728 per week.¹⁸⁶

The Americans with Disabilities Act explicitly excludes pregnancy because the Act only applies to permanent conditions. The Pregnancy Discrimination Act has no provisions to require employers to provide more access for pregnant women to limited duty or medical leave than would be provided for other employees. Case law interpreting the Act in relation to hazardous exposures includes the Supreme Court decision commonly known as the Johnson Controls case.¹⁸⁵ The Court struck down the fetal protection policy used by the company, because the policy did not allow any women capable of bearing children to work with lead. The Court found that the policy was discriminatory in part because men are also susceptible to reproductive effects from lead. A better way to handle reproductive hazards is to reduce exposure levels for all workers and to provide supervisors with training to avoid discriminatory behavior against pregnant employees.¹⁸⁸ When an infant health problem may have been caused by work, workers' compensation does not apply because the fetus is not an employee. Civil and criminal suits may be brought against health care providers, employers, or manufacturers of products used in the workplace if harm occurs.¹⁸⁵

The goal of counseling is to educate patients about potential risks while keeping these risks in perspective. Commonly in clinical practice patients will ask about avoidance of risk from a future exposure or about the magnitude of risk from an exposure that has already occurred. When it comes to reproductive hazards in the workplace or environment, exposures to both the woman and her male partner are important.  The history and any data from biologic or workplace monitoring can be used to assess whether internal exposure to hazardous agents is likely. A thorough evaluation may discover that a job that initially seemed hazardous actually entails negligible risk. Then reassurance can be provided and the woman can avoid the social and economic losses that may accompany unnecessarily restrictive medical recommendations. If an exposure to a reproductive toxicant at a significant dose has already occurred during the pregnancy, then counseling should include not only the potential risk but also the best estimate of the magnitude of risk. For example, it may help to explain that because birth defects are relatively uncommon, a 50% increase in risk means that most exposed pregnancies will still not be affected by anomalies. The patient, her family and the clinician may elect to follow-up the pregnancy closely rather than automatically elect voluntary termination.

If exposure has not already occurred, the best decision may be to make job changes to prevent future exposures, preferably before conception. Workers can often modify their technique to reduce future exposures, for instance, by fully complying with use of gloves and protective clothing. A written work restriction or a medical leave may be warranted in some cases. Many companies have generous programs to assist employees who need medically related work modifications or temporary medical leave. Even if the patient will experience economic hardship, in some cases it is better to recommend strongly that the patient avoid further exposures from an unsafe job. The patient should provide consent before the employer is contacted to obtain workplace exposure data or to recommend changes in job duties.

Occupational and environmental exposures can affect both men and women. When the male partner has intensive occupational exposure to certain pesticides, heavy metals, organic solvents or other agents, pregnancy outcomes such as spontaneous abortion and birth defects may be increased. Among women, adverse effects of exposure include spontaneous abortion, congenital anomalies, fetal growth restriction, gestational hypertension, and preterm birth. When infants are followed-up into childhood, certain prenatal exposures are associated with neurobehavioral effects. Laboratory animal studies confirm the biologic plausibility of these associations and also have documented transplacental carcinogenesis and fetal immune system changes. Health effects from maternal exposure have been linked to certain heavy metals, organic solvents, pesticides, and pharmaceuticals such as antineoplastic and antiviral agents. Hazardous maternal exposures also include certain biologic agents, radiation, and ergonomic stressors such as prolonged standing, long working hours, and excessive shift work. The rate of adverse reproductive effects is dose-dependent. Clues from the occupational history that substantial internal exposure may be occurring include frequent use of large quantities of the agent, and work practices that promote inhalational or dermal exposure, as well as contamination of food or drink. Personal protective equipment may fail, giving a false sense of security. Counseling can assist the couple to ascertain the level of risk, put their risk from occupational and environmental exposures into perspective and find ways to reduce exposures when warranted.