Introduction

Parental exposures before a child is conceived can result in adverse reproductive effects, including

• infertility;
• spontaneous abortion; and
• genetic damage to the fetus, possibly resulting in birth defects.

Reproductive hazards can affect fertility, conception, pregnancy, delivery, or a combination of any or all of these. Studies in humans that have assessed the causal relationship between specific exposures and these outcomes have frequently faced limitations and challenges, including

• lack of accurate assessment of the dose of the exposure to mother or fetus or both;
• a need for proper control groups to take into account the other genetic, physical and socioeconomic factors affecting reproductive toxicity;
• inadequate assessment of the background prevalence of events;
• difficulties with reliable ascertainment of outcomes; and
• multiplicity of exposures [Goldman 2005; Schettler et al. 1999; Greaves and Soden 2003].

Exposures to hazardous substances during pregnancy can potentially affect the development of fetal organ systems. Such exposures can further lead to either gross structural changes or more subtle functional changes. During critical periods of organogenesis (i.e., the 6-week period that follows the establishment of the placental circulation). Exposures can cause profound systemic damage out of proportion with the dose response seen in adults.

Preconception-Maternal Effects

Exposure of ova to toxicants

Exposures to developing ova can have lifelong effects. The ovum from which the fetus is formed develops during the early fetal life of the mother. The ovum's development arrests in the prophase of the cell cycle until ovulation - this can occur many decades hence [AAP 2003]. Ova forming within a female fetus may be affected by exposures experienced by her mother during the mother's lifetime. Fetal ova may also be affected by the exposures of her grandmother. This is because the grandmother's exposures may have affected the mother's developing ova during the mother's fetal life.

After birth, ova rest dormant and are vulnerable to environmental insults until the time of ovulation.

Effects on fertility

Agents that interfere with the menstrual cycle and ovulation, such as hormonally active agents, may affect fertility [Windham and Osorio 2004]. Mothers who smoke cigarettes may have decreased fertility [AAP 2003].

Effects on sex ratio

A recent retrospective study [Hertz-Picciotto et al. 2008] showed a 33% relative decrease in male births in women who had suffered high environmental exposures to polychlorinated biphenyls (PCBs) in the 1960s (i.e., those with levels in the 90^th percentile). But the data from the Yusho and Yucheng episodes (i.e., excess PCBs and furan exposure in cooking oil) showed no effect on the sex ratio, even with very high maternal exposures [Gomez et al. 2002; Yoshimura et al. 2001; Rogan et al. 1999]. Few studies have been conducted of altered sex ratio with maternal exposure to persistent pollutants. More work on this area needs to occur.

Preconception-Paternal Effects

Effects on fertility

Agents that interfere with male hormones or with hormonal feedback (e.g., testosterone, luteinizing hormone [LH]) may also affect production of healthy sperm, thus affecting fertility [Osorio and Windham 2004]. Injury to spermatogonia can occur at any time and lead to infertility. Repeated, narrow windows of vulnerability occur in parallel with the continual postpubertal production of semen and regeneration of spermatozoa. Adverse reproductive outcomes may also result from transmission of toxicants in seminal fluid.

Effects on sex ratio

One study noted that children fathered by men exposed to dioxin after the Seveso, Italy accident showed a decrease in the expected male:female ratio [Mocarelli et al. 2000]. This same pattern was seen in a study of male workers at a 2,4,5-trichlorophenol plant in Ufa, Russia [Ryan et al. 2002]. More recent work has suggested that this effect occurs only when the exposure occurs in men before age 20 [Gomez et al. 2002]. But more research is needed on how male reproduction is affected by persistent organic pollutants such as dioxin.

Preconceptual Factors Affecting Either Parent

Preconception exposures to hazardous substances are one possible reason for a change in the normal male:female sex ratio at birth. Since 1970, a distinct and unexplained trend in reduced male-to-female birth ratio has been noted in Japan and in the United States. The difference, while very small, is significant on a population level. A decline of 37 males per 100,000 births occurred in Japan and a drop of 17 males per 100,000 per live births in the United States. The reasons for these population-wide declines are unknown, but one explanation may be parental exposures to low levels of environmental contaminants [Davis et al. 2007].

Preconception Counseling About Known Reproductive Hazards

Preconception counseling proactively addresses issues that can significantly affect the unborn child's health or development. Methylmercury in fish [Mahaffey 2005] and lead are examples of toxicants which, through maternal preconception exposures, can affect the developing fetus in utero. Anticipatory guidance includes encouraging prospective parents to protect their health and that of their unborn infant by reducing known dietary exposures to methylmercury in certain fish species. Prospective mothers who smoke should be encouraged to quit because of the effects of smoking on fertility and because of numerous effects on a pregnancy (see below).

For further information, please see the Case Studies in Environmental Medicine Reproductive and Developmental Toxicity(currently in development) and Case Studies in Environmental Medicine Taking a Pediatric Exposure History, http://www.atsdr.cdc.gov/csem/csem.asp?csem=26&po=0 .

In utero Effects from Past Maternal Exposures

Past and current exposures can affect a developing fetus in several ways. Contaminants in a pregnant woman's past and current diet can potentially harm the fetus. Physiologic changes during pregnancy can mobilize stored toxicants, such as lead from bone or PCBs from fat cells, resulting in fetal exposure. Maternal alcohol ingestion during pregnancy can lead to fetal alcohol syndrome.

Mobilization of toxicants stored in maternal tissues

Exposures experienced by the mother before pregnancy may affect her developing fetus. Exposure to some persistent or slowly excreted chemicals can lead to body burdens stored in such places as body fat or bone. For example, a woman who experienced a pre-pregnancy exposure to lead and who was inadequately treated for lead poisoning during childhood might give birth to an infant with congenital lead poisoning [Shannon and Graef 1992]. The most logical explanation for this would be storage of the lead in the mother's bones with subsequent mobilization during pregnancy [Silbergeld 1991].

A mother's intake before and during pregnancy of mercury-containing fish may affect her child's neurological development. According to the National Health and Nutrition Examination Survey (NHANES), exposures of concern to methylmercury in blood - a neurological toxicant found in certain fish - occurs among 6% of 16- to 49-year old women [CDC 2004]. Subgroups with high fish consumption include wives of sportfishers, coastal dwellers, and others who could have methylmercury exposures substantially higher than the U.S. norm [Mahaffey 2005].

Maternal smoking during pregnancy has been associated with

• stillbirth
• placental abruption,
• prematurity,
• lower mean birth weight,
• birth defects such as cleft lip and palate,
• increased risk of infant mortality,
• decrements in lung function later in the life of the exposed child, and
• sudden infant death syndrome (SIDs).

A child healthcare provider's anticipatory guidance can help stop maternal consumption of tobacco and alcohol. But other chemicals are known to have an adverse effect on pregnancies. A child healthcare provider can offer guidance on these chemicals as well.

Table 3. Examples of chemicals and their known adverse effects on pregnancy and neonatal outcomes. This partial list of chemicals is from studies that found evidence of specific chemicals' adverse human health effects. For the most current and complete list of drugs and chemicals affecting pregnancy, please refer to the US Food and Drug Administration classifications.

Adapted from [NIOSH 1999]

Placental Dependent Exposures

A fact of fetal life is that the fetus cannot escape transplacental transport of toxicants to which the mother is exposed. During gestation, past and current maternal exposures can affect the fetus. The placenta, whose circulation is established approximately 17 days after fertilization, acts as the most important route of exposure for genotoxins and carcinogens [Autrup 1993; Waalkes et al. 2003].

The placenta is a semipermeable membrane that permits easy transport of low-molecular-weight (i.e., carbon monoxide (CO)) and fat-soluble compounds (i.e., polycyclic aromatic hydrocarbons and ethanol), as well as compounds such as lead. Some water-soluble and high-molecular-weight compounds may also cross the placenta, albeit more slowly. The placenta has limited detoxification ability. Placental degradative enzymes include inducible catalase, superoxide dismutase, and mixed function oxidases. But these enzymes help to mitigate only very low toxicant concentrations.

For example, young infants and children have an increased susceptibility to CO toxicity because of their higher metabolic rates. The fetus is at especially high risk of acute toxicity from carbon monoxide. Maternal CO diffuses across the placenta and increases the levels of CO in the fetus. Fetal hemoglobin has a higher affinity for CO compared with adult hemoglobin. The elimination half-life of carboxyhemoglobin is longer in the fetus than in the adult. Exposure to CO results in a substantial decrease in oxygen delivery to the placenta and ultimately to fetal tissues [AAP 2003].

Healthcare professionals such as anesthetists, dental assistants, and hospital personnel, are often exposed to potentially embryotoxic hazards such as

• anesthetic gases,
• antineoplastic agents,
• ethylene oxide,
• mercury, and
• solvents.

Studies involving these professionals have revealed significant risks for spontaneous abortions and congenital malformations [Ahlborg and Hemminki 1995]. In a study of nurses and pharmacists with occupational exposure to antineoplastic agents, maternal exposure to antineoplastic agents during pregnancy resulted in a statistically significant increased risk of spontaneous abortions and stillbirths [Valanis et al. 1999].

Several occupations and industries have been associated with adverse outcomes in pregnancy, including an increased risk of spontaneous abortion and birth defects. Some of these occupations or industries include

• solderers and welders,
• bridge repainters,
• radiator repairers,
• battery makers,
• electronics and semi-conductor industries,
• health care workers involved in cancer chemotherapy [NIOSH 1999].

Placental Independent Exposures

Fetal exposures that can occur independently of the placenta include

• heat,
• ionizing radiation, and
• noise [Paulson 2001].

A mother's exposure to ionizing radiation can increase the likelihood of childhood leukemia and neurologic delays.

Fetal Exposure to Carcinogens

Rapidly dividing fetal cells may show increased sensitivity to carcinogens. Epidemiologic evidence, however, is contradictory on the relation between age of exposure and cancer risk. Apparently, childhood sensitivity to carcinogens increases in some organs and decreases in others. The only two generally accepted in utero carcinogens are diethylstilbestrol (DES) (via placenta) and ionizing radiation (acting directly on the fetus) [Anderson et al. 2000; DeBaun and Gurney 2001; Lemasters et al. 2000]. An increased risk of brain tumors in children was associated with the use of household flea/tick pesticide from the time of pregnancy to the time of diagnosis [Pogoda and Preston-Martin 1997]. Paternal occupational exposure to pesticides was found to have a statistically significant increased risk for Wilm's Tumor in offspring [Fear 1998].

Progress Check