Reproductive and perinatal principles in toxicology are often derived from basic science studies and are applied cautiously to clinical practice. This chapter reviews several principles of reproductive medicine that have implications for toxicology, including the physiology of pregnancy and placental xenobiotic transfer, the effects of xenobiotics on the developing fetus and the neonate, and the management of poisoning or overdose in pregnant women.
One of the most dramatic effects of exposure to a xenobiotic during pregnancy is the birth of a child with congenital malformations. Teratology, the study of birth defects, has principally been concerned with the study of physical malformations. A broader view of teratology includes “developmental” teratogens—xenobiotics that induce structural malformations, metabolic or physiologic dysfunction, or psychological or behavioral alterations or deficits in the offspring, either at or after birth.291 Only 4% to 6% of birth defects are attributable to known pharmaceuticals or occupational and environmental exposures.291,302
Some reproductive effects of xenobiotics occur before conception. Female germ cells are formed in utero; adverse effects from xenobiotic exposure theoretically occur from the time of a woman’s own intrauterine development to the end of her reproductive years. An example of a xenobiotic that had both teratogenic and reproductive effects is diethylstilbestrol (DES), which was most notable for causing vaginal or cervical adenocarcinoma (or both) in some women who were exposed to DES in utero and which also had adverse effects on fertility and pregnancy outcome in the same cohort of women exposed in utero.239,263
Men generally receive less attention with respect to reproductive risks. Male gametes are formed after puberty; only from that time on are they susceptible to xenobiotic injury. An example of a xenobiotic affecting male reproduction is dibromochloropropane, which reduces spermatogenesis and, consequently, fertility. In general, much less is known about the paternal contribution to teratogenesis.63,130,152
Occupational exposures to xenobiotics are potentially important but are often poorly defined. In 2015, there were approximately 43 million women of reproductive age in the workforce.331 Although approximately 90,000 chemicals are used commercially in the United States, only a few thousand of them have been specifically evaluated for reproductive toxicity. Many xenobiotics have teratogenic effects when tested in animal models, but there are relatively few well-defined human teratogens (Table 30–1).302 Thus, most tested xenobiotics do not appear to present a human teratogenic risk, but most xenobiotics have not been tested. Some of the presumed safe xenobiotics have other reproductive, nonteratogenic toxicities. Several excellent reviews and online resources are available.39,106,266,302,325
TABLE 30–1Known and Possible Human Teratogens ||Download (.pdf) TABLE 30–1 Known and Possible Human Teratogens
|Xenobiotic ||Reported Effects ||Comments |
|Alkylating agents (eg, busulfan, chlorambucil, cyclophosphamide, mechlorethamine, nitrogen mustard) ||Growth retardation, cleft palate, microphthalmia, hypoplastic ovaries, ...|