Correspondence

Central Nervous System and Limb Anomalies in Case Reports of First-Trimester Statin Exposure

N Engl J Med 2004; 350:1579-1582April 8, 2004

Article

To the Editor:

The cholesterol-lowering statin drugs are contraindicated in pregnancy1; therefore, few data exist regarding their safety in human gestation. We reviewed 178 cases of first-trimester statin exposure reported to the Food and Drug Administration (FDA) from 1987 through 2001 for patterns suggesting possible drug-related effects on embryogenesis. After the exclusion of cases involving first-trimester elective or spontaneous abortions (46 and 42 cases, respectively), pregnancy loss due to maternal illness (15), fetal genetic disorders (3), transient neonatal disorders (5), or loss to follow-up (15), 52 cases were considered evaluable (Table 1Table 1Congenital Anomalies Associated with First-Trimester Statin Exposure.).

Among these cases, there were 20 reports of malformation, including 5 severe defects of the central nervous system (2 of which were holoprosencephaly) and 5 unilateral limb deficiencies; one patient had both of these malformations. The two simvastatin-exposed cases of limb deficiency were complex lower-limb anomalies including both long-bone shortening and aplasia or hypoplasia of the foot structures. The infant in one of these cases and a lovastatin-exposed infant also had rare forms of the VACTERL association (i.e., three or more of the following findings: vertebral, anal, cardiac, tracheal, esophageal, renal, and limb defects).

In all cases of adverse outcomes at birth, the associated statin was lipophilic. Cerivastatin, simvastatin, lovastatin, and atorvastatin all achieve embryoplacental concentrations similar to those of maternal plasma.1 In studies in animals, lipophilic statins have been shown to have adverse reproductive effects in the axial skeleton, viscera, or central nervous system. No malformations were reported among 14 infants exposed to pravastatin; this statin is hydrophilic, has low tissue penetration, and has not caused reproductive toxic effects in animals.1

Holoprosencephaly and the VACTERL association have been linked to inhibition of cholesterol biosynthesis, down-regulation of the cholesterol-dependent sonic hedgehog morphogenetic pathway, or both.3,4 These malformations as well as neural-tube and cardiac defects are also associated with maternal diabetes; thus, diabetes might confound the association between statin use and these malformations. However, maternal diabetes was identified in only 7 of 178 case reports and 1 of 20 cases of malformation (spina bifida).

It is thought that only a small proportion of adverse events are reported to the FDA2; however, reports are likely to be biased toward severe outcomes. The number of births after first-trimester exposures to statin are unknown. Table 1 presents both the number of reported exposures and the predicted number of exposures on the basis of prescription data and birth rates. There would be no expected cases of most of the malformations listed in the table, even allowing for the imprecision of estimating exposures; yet three rare anomalies3-5 are each observed twice in this small series.

Data from case series cannot be used to test hypotheses of teratogenicity. However, these findings support the need for controlled epidemiologic studies evaluating the potential teratogenic effects of individual drugs in this class.

Robin J. Edison, M.D., M.P.H.
Maximilian Muenke, M.D.
National Institutes of Health, Bethesda, MD 20892-1852
muenke@nih.gov

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