Ebstein's malformation of the tricuspid valve: Genetic and environmental factors

Abstract

Ebstein's anomaly is a specific structural deformity of the tricuspid valve, and its rarity has hampered etiologic evaluation. Cases of Ebstein's anomaly registered in the Baltimore Washington Infant Study (BWIS), a regional case-control study of cardiovascular malformations (CVM) in infancy, are reviewed. Between 1981 and 1989 a total of 4,390 CVM cases, including 47 Ebstein cases, and 3,572 controls were registered. The prevalence of Ebstein's anomaly was 5.2 per 100,000 livebirths. Additional cardiac anomalies were present in 38.3% of Ebstein cases. Non-cardiac malformations were present in 19.1% of Ebstein cases vs. 25.5% of other CVM, and 1.7% of controls. Case-fatality by 1 year of age was 23.4% in Ebstein vs. 18.1% in other CVM. Interviews of parents of Ebstein cases, other CVM, and controls (n = 44, 3,335, and 3,572, respectively) elicited information on family history of malformations, maternal illnesses, reproductive history, therapeutic drugs, parental lifestyle, and environmental exposures during the periconceptional period. Case-control analyses suggest genetic, reproductive, and environmental risk factors: twins [odds ratio (OR) 8.2, 95% confidence interval (CI) 2.6-25.3]; family history of CVM (OR 6.4, 95% CI 1.8-22.2); white race (OR 2.9 with non-whites as reference, 95% CI 1.2-7.0); previous miscarriages (OR 2.0, 95% CI 1.2-3.3); maternal exposure to benzodiazepines (OR 5.4, 95% CI 1.5-19.1); and varnishing (OR 3.4, 95% CI 1.3-9.1). Additional multicenter investigations are warranted to elucidate the role of genetic, reproductive, and environmental factors in the etiology of this anomaly.

Ebstein’s Anomaly

“…Case-control studies suggest genetic, reproductive, and environmental risk factors (eg, the anomaly is more common in twins, in those with a family history of congenital heart disease, and in those with maternal exposure to benzodiazepines). 4 Maternal lithium therapy can rarely lead to Ebstein's anomaly in the offspring. 20 Most cases are sporadic; familial Ebstein's anomaly is rare.…”

“…[2][3][4][5][6] This anomaly was described by Wilhelm Ebstein in 1866 in a report titled, "Concerning a very rare case of insufficiency of the tricuspid valve caused by a congenital malformation." 7,8 The patient was a 19-year-old cyanotic man with dyspnea, palpitations, jugular venous distension, and cardiomegaly.…”

A Case of Pregnancy with Ebstein’s Anomaly

“…Environmental factors implicated in aetiology include maternal ingestion of lithium or benzodiazepine and maternal history of miscarriage. 2 Increased incidence is observed in Caucasians.…”

Lithium Use in Pregnancy and the Risk of Cardiac Malformations

“…8,9 Other than the findings among lithium-exposed infants in the International Register, most of the information on the safety of lithium during pregnancy that has accumulated in the past 40 years is based on case reports [10][11][12][13][14] and small studies (Table S1 in the Supplementary Appendix, available with the full text of this article at NEJM.org). Several small casecontrol studies failed to show an association between lithium and Ebstein's anomaly, [15][16][17][18][19] overall cardiac defects, 20 or any congenital malformations. 21 In two uncontrolled cohort studies of lithium-exposed pregnancies, no cardiac malformations were detected in the 82 newborns examined 22,23 ; another uncontrolled study showed four mild cardiac defects in 79 exposed infants.…”