Many, if not most, major teratogens were irst described by clinicians who observed a rare defect occurring after a rare exposure. his has been termed the "astute clinician model" (Carey, 2009). Congenital rubella syndrome was identiied in this way by Gregg (1941), an Australian ophthalmologist whose observations challenged the view that the uterine environment was impervious to noxious agents. Other teratogens identiied through case series include thalidomide and alcohol a ones, 1973; Lenz, 1962). Shepard (2002a) recommended that establishment of teratogenicity in this way requires proven exposure at a critical time in development and probably at least three such cases, each carefully delineated. Unfortunately, teratogens are less likely to be identiied if the exposure is uncommon, if the defects are relatively nonspeciic, or if abnormalities develop in only a small proportion of exposed fetuses. A major limitation of case series is their lack of a control group.
hese studies begin with groups of afected infants (cases) and unafected controls and are structured to allow retrospective assessment of prenatal exposure to particular substances. Casecontrol studies are an eicient way to study rare outcomes (Alwan, 2015). These permit investigators to evaluate associations and generate useful hypotheses. However, case-control studies have inherent potential for recal bias. Namely, parents of an afected infant are often more likely to recall exposure than those whose child is not ill. Confounding by indication is another concern, that is, the indication for the medication may be the cause of the birth defect. And importantly, birth defect registries have statistical power to detect small diferences that may not be clinically meaningful. Grimes and Schulz (2012) have cautioned that unless odds ratios in case-control studies are above three-to fourfold, the observed associations may not be correct.
The National Birth Defects Prevention Study n excellent example of a population-based case-control study is the National Birth Defects Prevention Study (NBDPS). Funded by Congress and coordinated by the National Center on Birth Defects and Developmental Disabilities, the NBDPS . took place between 1997 and 2013 across ten states with active birth defects surveillance programs. Clinical geneticists reviewed each potential case, and standardized telephone interviews were conducted with mothers whose pregnancies were afected or unafected to obtain information regarding medication exposure and risk factors (Mitchell, 2011i; Reehuis, 2015). Live births, stillbirths, and terminated pregnancies were included and totaled approximately 32,000 cases and nearly 12,000 controls.
he NBDPS has yielded more than 200 scientiic manuscripts. It identified novel-although often small-associations between individual birth defects and the following classes of medications: antibiotics, antidepressants, antiemetics, antihypertensives, asthma medications, nonsteroidal antiinlammatory drugs (NSAIDs), and opioids (Ailes, 2016; Broussard, 2011; Fisher, 2017; Hernandez, 2012; Lin,
Teratology, Teratogens, and Fetotoxic Agents 237 2012; Munsie, 201i1). he NBDPS also found associations between birth defects and exposures such as secondhand smoke, pesticides, and nitrogen oxide, which is a marker of traic-related air pollution (Hoyt, 2016; Rocheleau, 2015;
Stingone,i2017).
The NBDPS did have limitations related to study design.