Prophylaxis and Treatment of Pregnant Women for Emerging Infections and Bioterrorism Emergencies

Joanne Cono; Janet D. Cragan; Denise J. Jamieson; Sonja A. Rasmussen

Disclosures

Emerging Infectious Diseases. 2006;12(11) 

In This Article

Teratogenic Potential of Medications and Vaccines

Whether use of a medication or vaccine is harmful to the embryo or fetus depends on multiple factors, including the nature of the agent (e.g., live versus killed vaccine), its dose and route of administration, timing of use during gestation, concomitant use of other agents, nature of the infection being treated or prevented, and genetic susceptibility of the pregnant woman and of the embryo or fetus. Potential adverse effects of an exposure on the embryo or fetus include spontaneous pregnancy loss, structural malformations, intrauterine growth restriction, preterm delivery, hearing loss, and neurobehavioral abnormalities, among others. Timing of exposure during gestation is particularly critical. Organogenesis, the period of organ formation, extends from 15 to 60 days after fertilization (≈4-11 weeks after the start of the last menstrual period).[10] Before organogenesis, harmful exposures are most likely to result in spontaneous pregnancy loss, although some embryos that survive can be adversely affected.[11] After this time, structural abnormalities are less likely to occur, although damage to a normally formed organ is still possible.[12] In addition, some teratogenic medications have a narrow window of exposure when their use results in malformations. For example, thalidomide is believed to produce malformations only when used 34-50 days after the beginning of the last menstrual period.[13] In contrast, adverse outcomes such as growth retardation and functional abnormalities can result from later exposures. Angiotensin-converting enzyme inhibitors have been associated with impaired renal function in the newborn when used to treat maternal hypertension during the latter half of pregnancy.[13]

In the United States, the reproductive effects of medications and vaccines are usually assessed in animal studies before these products are licensed for human use. Efficacy in humans is evaluated in premarketing clinical trials. However, because of ethical concerns about exposing an embryo or fetus to an agent with unknown effects, reproductive studies are not performed in humans before licensure, and pregnant women have traditionally been excluded from clinical trials of efficacy.[14] Although animal studies can be useful in evaluating an agent's potential for adverse reproductive effects, they are not always predictive of the effects in humans.

For these reasons, information about the effects of medications and vaccines during pregnancy is usually obtained from data collected after these agents are in use in the population. These data take the form of adverse event reports, case series, prospective exposure registries, and cohort and case-control studies, each of which has its own methodologic strengths and limitations.[15] Conclusive information can be difficult to obtain from these studies because of low levels of use of individual medications or vaccines in the population outside of an emergency setting and the difficulty of separating reproductive effects of the medication or vaccine from those of the underlying infection or other genetic and environmental factors. A 2001 review of available information about medications approved by the US Food and Drug Administration (FDA) from 1980 through 2000 concluded that insufficient information existed to assess the teratogenic potential of >90% of these drugs.[16]

In 1979, to help healthcare providers assess potential risks and benefits of medications during pregnancy, FDA developed a use-in-pregnancy rating system (21 CFR 201.57). This system labels drugs on the basis of assessment of their relative risk to the fetus and their potential benefit to the mother.[17] Ranging from category A through X ( Table 1 ), this scale uses available data from animal reproductive and human studies. This rating system is used widely by clinicians in the United States, but it has several shortcomings. These include the fact that medications in the same letter category may have different magnitudes of fetal risk, most medications are rated category C (i.e., insufficient information is available to assess their potential risk and benefit during pregnancy), and the rating is not routinely updated when new information becomes available.[18] In addition, this rating system does not address the effects of gestational timing of exposure or of physiologic changes that occur during pregnancy.[18,19] FDA recognizes these limitations and is working to improve communication about the risks and safety of medication use during pregnancy.[20]

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