Date of Award


Document Type


Degree Name

Medical Doctor (MD)

First Advisor

Laura Ment


Establishing Prevalence Rate of Major Malformations after In Utero Exposure: A Challenge for Pregnancy Registries. Ephat H. Russcol and Lewis B. Holmes, M.D., Genetics Unit, Department of Pediatrics, Massachusetts General Hospital, Boston, MA. (Sponsored By Dr. Laura Ment, Department of Pediatrics, Yale University School of Medicine). Baseline rates of malformations are affected by many different factors, and it is often difficult to determine what the actual rate of malformations is. A meta-analysis of rates of major malformations in the general population was performed. Several search terms were used and strict criteria were utilized to select well-investigated studies that discussed the baseline prevalence of malformations in the population. Twenty-nine studies comprising 6,828,658 births were found, and twelve countries were represented. The mean (± standard deviation) malformation rate was 2.4537 ± 1.2982 with a standard error of 0.2370. The malformation rate ascertained at birth or shortly after was 1.8188 ± 0.6517 with a standard error of 0.1881. The malformation rate at age one year or later was 2.7561 ± 1.0121 with a standard error of 0.2530. The malformation rate at birth was found to be significantly lower than the malformation rate ascertained at one year or later (p<0.05). This study is the first to show the statistically significant importance of age of ascertainment when looking across multiple studies. Pregnancy registers studying the effect of a prenatal exposure often do not have the resources needed to recruit an internal control group and therefore must choose an external control group. Many studies of 3 baseline rates of malformations do not exclude chromosomal or genetic anomalies and ascertain malformations at birth and also later in life rather than only at birth. This results in a relatively high baseline or comparison malformation rate. In contrast, many pregnancy registers appropriately exclude chromosomal and genetic anomalies and, due to resource constraints, they ascertain the malformation rate at birth or shortly thereafter. When malformation rates following an exposure are compared to a baseline rate that is erroneously higher than it should be, the teratogenic effect of the investigated exposure may be missed. It is dangerous to judge a medication's exposure as irrelevant when in fact it may be associated with a slightly higher malformation rate. Ideally, in the future, pregnancy registers will have internal control groups; the North American AED (antiepileptic drug) Pregnancy Registry has already begun to do so.


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