Objective
The objective of this study was to report the outcomes of intrauterine pregnancies misdiagnosed as ectopic and exposed to methotrexate, a major teratogen.
Study Design
We report the outcomes of all subjects who sought consultation after exposure to high-dose methotrexate to induce abortion in presumed ectopic pregnancies, which were later identified as viable intrauterine pregnancies by 3 North American Teratology Information Services between 2002 and 2010.
Results
Eight women with normal, desired pregnancies were administered high-dose methotrexate in the first trimester because of presumed, misdiagnosed ectopic pregnancies. All pregnancies resulted in catastrophic outcomes. Two pregnancies resulted in severely malformed newborns with methotrexate embryopathy; 3 women miscarried shortly after exposure, and in 3 the erroneous diagnosis led the physicians to advise and perform surgical termination.
Conclusion
Erroneous diagnosis of intrauterine pregnancies as ectopic with subsequent first-trimester exposure to methotrexate may result in the birth of severely malformed babies or fetal demise.
Ectopic pregnancies, accounting for about 2% of all pregnancies (over 125,000 pregnancies/year in the United States alone), are the leading cause of first-trimester maternal death. Medical termination of ectopic pregnancies with methotrexate has more than tripled in the United States during the last decade (from 11% in 2002 to 35% in 2007), as it minimizes the risks, complications, and costs associated with surgical terminations. The latter has declined from 73.9% in 2002 to 64.9% in 2007 (with 21.5% laparotomies and 43.5% laporoscopies). Methotrexate, a folic acid antagonist, is a major human teratogen which induces a well-defined malformation pattern, first described nearly 50 years ago. Affected newborns typically demonstrate intrauterine growth retardation, cardiac malformations, craniofacial, and skeletal abnormalities. In early ectopic pregnancies (5-10 weeks’ gestation), methotrexate is administered intramuscularly (50 mg/m 2 /dose to 1 mg/kg/dose in a single or repeated doses) to induce fetal death. This regimen typically delivers a high dose (60-90 mg) of methotrexate to the patient, constituting the only medical scenario, where a potent teratogen is intentionally administered to pregnant women to cause fetal death.
For Editors’ Commentary, see Table of Contents
Diagnosing an early ectopic pregnancy remains difficult despite advances in imaging. The process may be long, distressing, and expensive, and about half of suspected cases require 4 visits or more to confirm or exclude this diagnosis. In about 40% of cases, the initial diagnosis of ectopic pregnancy is erroneous and a nonviable intrauterine pregnancy is later found.
Because a proportion of presumed ectopic pregnancies, based on early ultrasound, may be subsequently identified as viable intrauterine pregnancies on follow-up exam, healthy and desired intrauterine pregnancies may be exposed to methotrexate during critical stages of embryogenesis. The objective of the present report was to study this tenuous situation by reporting the experience of 3 North American Teratology Information Services.
Methods
We collected cases among callers (both physicians and patients), who sought consultation by one of 3 Teratology Information Service Centers: The Motherisk Program, The Hospital for Sick Children, Toronto; The California Teratogen Information Service, University of California, San Diego; and the Connecticut Pregnancy Exposure Information Service, West Hartford, between January 1, 2002 and April 30, 2010. All of the callers who were seeking advice in regards to first-trimester exposure to high-dose methotrexate to induce abortion, in intrauterine pregnancies misdiagnosed as ectopic, were captured. Information regarding patient age, indication, dose, route, timing, and effectiveness of methotrexate administration was recorded by each center. For cases in which the initial contact occurred before the outcome was known (n = 6) a subsequent follow-up call was made to the patient or physician, to obtain pregnancy outcome information.
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