31: Reproductive and Perinatal Principles

INTRODUCTION

Reproductive and perinatal principles in toxicology are derived from basic science and are applied 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 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.²⁷⁴ Only 4% to 6% of birth defects are attributable to known pharmaceuticals or occupational and environmental exposures.^44,274

Reproductive effects of xenobiotics may occur before conception. Female germ cells are formed in utero; adverse effects from xenobiotic exposure can 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 caused vaginal or cervical adenocarcinoma (or both) in some women who had been exposed to DES in utero and also had effects on ­fertility and pregnancy outcome.^26,33

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.³³⁶

Occupational exposures to xenobiotics are potentially important but are often poorly defined. In 2004, it was estimated that there were 41 million women of reproductive age in the workforce.³¹³ 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 relatively few well-defined human teratogens have been identified (Table 31–1).²⁸⁶ 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 may have other reproductive, nonteratogenic toxicities. Several excellent reviews and online resources are available.^{45,104,238,249,274,286}