CASE A 28-year-old woman, gravida 4, para 3, requested medical termination of her pregnancy at approximately 7 weeks’ gestation. She was given intramuscular methotrexate 50 mg/m2 and oral misoprostol 400 mcg. Nine weeks later, she presented at our primary care clinic complaining of mild pelvic pain. Given her history, we ordered transvaginal ultrasound, which showed a viable pregnancy with an average ultrasound age of 16 weeks’ gestation and grossly normal fetal anatomy. We counseled the patient regarding the risks associated with maintaining the pregnancy after exposure to methotrexate, and she and her husband elected to proceed with the pregnancy.
Throughout the pregnancy, a perinatologist conducted serial 2-dimensional ultrasounds. At 30 weeks’ gestation, ultrasound revealed mild hydrocephalus but yielded poor visualization of the kidneys, heart, and spine. A repeat ultrasound at 34 weeks demonstrated unchanged hydrocephalus and normal fetal anatomy with appropriate interval growth. A fetal echocardiogram in utero showed no cardiac anomalies. At 39 weeks, the patient underwent induction of labor due to severe oligohydramnios. A viable female infant weighing 2456 g was delivered by spontaneous vaginal delivery, with Apgar scores of 8 and 9 at 1 and 5 minutes, respectively.
The infant was small for her gestational age. Her hands had 4 digits each, including the thumb (FIGURE 1A). The upper extremities were shorter than expected in relation to the infant’s torso and were locked in 90 degrees of flexion at the elbow (FIGURE 1B). Her lower extremities were both normal in length, but her left ankle joint was everted with considerable laxity at the tibiotalar joint. The infant’s mandible deviated to the right. An ultrasound of her head showed dilation of the lateral ventricle, consistent with nonobstructive hydrocephalus. A skeletal survey revealed bilateral radial-humeral synostosis at approximately 90 degrees of flexion. The second day after birth, the infant was transferred to a tertiary medical facility for further evaluation by pediatric subspecialists.
A pediatric orthopedic surgeon noted bilateral hip dysplasia and fitted the infant for a Pavlik harness. Ultrasound of the spine identified a dysmorphic sacrum with a thickened conus medullaris ending at the level of L2-L3, with increased risk for a tethered spinal cord. To correct the hydrocephalus, a neurosurgeon recommended intervention in the neonatal period. The parents were counseled to expect some degree of developmental disability, and karyotyping was performed to rule out potential genetically linked syndromes.
FIGURE 1
Methotrexate exposure led to these congenital anomalies
Methotrexate exposure at 7 weeks’ gestation resulted in this child having 4 digits on each hand (A), shortened arms locked in 90 degrees of flexion at the elbow, and an everted left ankle joint (B).
Risks associated with methotrexate
In the 1960s, methotrexate was commonly used as an abortifacient.1 Its use for that purpose became rare, however, after multiple reports from the 1950s to the 1970s of congenital malformations in infants exposed to the drug in utero, either inadvertently or after attempted abortion.1 In the 1990s, its use increased again in conjunction with misoprostol, primarily for medical management of suspected ectopic pregnancies and less often for elective terminations. Use of the combination resulted in fewer reports of congenital anomalies.1
The failure rate of medical abortion using methotrexate varies. In 1999, one study reported an 8% failure rate when methotrexate was used with misoprostol.2 In 2004, methotrexate alone led to a failure rate of 31% in medical termination of early pregnancy.3 In 2005, another study of methotrexate and misoprostol used in combination for elective termination reported a failure rate of 2% to 10%.4
Risk is not always foreseen
Methotrexate is widely used to treat such conditions as neoplastic disease and autoimmune disorders. Unintended exposure of a fetus to methotrexate is a very real possibility when the drug is used to treat a mother’s rheumatoid arthritis, psoriasis, or systemic lupus erythematosus. Methotrexate is a folic acid antagonist that produces its most teratogenic effects between 6 and 8 weeks postconception.4 Anomalies associated with methotrexate exposure include skull defects, central nervous system abnormalities, limb defects, gastrointestinal and cardiopulmonary defects, developmental delay, and cognitive impairment.4 Even at low doses and with short-term exposure, methotrexate can cause substantial fetal anomalies. In 2002, a woman who was unknowingly 3.5 weeks pregnant used oral methotrexate 7.5 mg/d for 2 days to treat her psoriasis.5 During a fetal anatomy sonogram at 18 weeks’ gestation, multiple anomalies were noted and later confirmed at fetopsy.