Ectopic Pregnancy: A Clinical Casebook

9. Inadvertent Methotrexate Administration

Togas Tulandi  and Senem Ates 


McGill University Health Center, H3A 1A1, 687 Pine Ave West, Montreal, QC, Canada

Togas Tulandi (Corresponding author)


Senem Ates



Ectopic pregnancyhCG discriminatory zoneMethotrexateCongenital malformationPregnancy of unknown location

Case Study

A 32-year-old woman presented to the emergency department with left-sided low abdominal pain and a positive pregnancy test. Her last menstrual period had started 6 weeks prior to this presentation. Past medical history revealed a right salpingectomy for tubal ectopic pregnancy a year ago. Physical examination indicated a stable patient with a mildly tender abdomen. Serum human chorionic gonadotropin (hCG) level was 1700 IU/L. Transvaginal ultrasound examination showed absence of intrauterine pregnancy and a 2-cm adnexal mass in the left adnexa. With these findings, the consulting gynecologist advised the emergency physician to administer methotrexate and the patient was instructed to see the consulting gynecologist 3 days later.

My Management




Diagnosis and Assessment

The patient was indeed at risk to have a second ectopic pregnancy and the index of suspicion was high, as the incidence of recurrence after one tubal ectopic pregnancy is 12–15 % [1]. In general, the discriminatory zone of hCG for a detected intrauterine pregnancy by transvaginal ultrasound is 1500 mIU/mL [2]. However, there is a variation in the level of hCG and the discriminatory levels are not always reliable. Although uncommon, laboratory error can also occur. An adnexal mass could simply represent a corpus luteum.

In addition, the hCG levels in multiple pregnancies are higher at a given gestational age than those in singleton pregnancies. In women with an intrauterine multiple pregnancy, the serum hCG level could be higher than 1500 mIU and yet ultrasound examination will not reveal an intrauterine pregnancy. For example, Usta et al. reported an inadvertent methotrexate administration to a woman who, at 5 gestational weeks, presented with signs and symptoms suspicious of ectopic pregnancy, after being treated with an ovulation induction agent. At 8 weeks of gestation, she was found to be carrying a triplet pregnancy, which eventually spontaneously reduced to a singleton pregnancy. However, the baby was born with multiple congenital anomalies [3].

Therefore, it is possible that the above clinical findings do not rule out the presence of an intrauterine pregnancy. It has been estimated that only around 20 % of patients initially diagnosed with pregnancies of unknown location are ultimately diagnosed with ectopic pregnancies [4].


In a patient who is hemodynamically stable with an uncertain diagnosis of ectopic pregnancy, one should repeat the serum measurement of hCG as well as the ultrasound examination a few days later. There is no urgency to treat the patient at this stage, and administering methotrexate could harm an intrauterine pregnancy. Before methotrexate treatment, it is crucial to ask ourselves whether there is a possibility of a viable intrauterine pregnancy. Without doubt, failure to diagnose the possibility of an intrauterine pregnancy and administering methotrexate poses more serious consequences than delaying a diagnosis of an ectopic pregnancy [5].

Methotrexate is a cytotoxic drug that inhibits the action of dihydrofolate reductase, an enzyme that reduces dihydrofolate to tetrahydrofolate. Tetrahydrofolate is necessary for thymidylate synthesis; therefore, methotrexate acts to prevent DNA synthesis [6]. It is classified as category X (contraindicated in pregnancy), and clearly should not be given to women with a viable intrauterine pregnancy. Otherwise, there is a risk of severe congenital anomalies, collectively known as methotrexate or aminopterin (a close structural analog of methotrexate) syndrome. This syndrome includes skeletal anomalies, central nervous system and cardiac abnormalities, as well as intrauterine growth restriction and developmental delay [78].

Specific findings in an affected fetus or newborn include microcephaly, skull bone hypoplasia, wide fontanels, craniosynostosis, broad nasal bridge, shallow supraorbital ridges, prominent eyes, low set ears, maxillary hypoplasia, epicanthal folds, short limbs, talipes, hypodactyly, and syndactyly [7]. Fetal death has also been reported [7]. Even a single dose of methotrexate can be harmful, especially during the critical window between the sixth and eighth embryonic weeks [4]. Figures show images of a female child who was exposed to methotrexate in utero. Despite the report of a successful perinatal outcome in a woman with heterotopic pregnancy treated with local injection of methotrexate, the risks of methotrexate outweigh its benefit [9]. It appears that fetuses exposed to methotrexate intended to treat ectopic pregnancy are at particular risk for tetralogy of Fallot [6].


Fig. 9.1

Note short forearms (From Seidahmed et al., A Case of methotrexate embryopathy with holoprosencephaly, expanding the phenotype, Birth Defects Research (Part A) 2006;76:138–142. Reproduce with permission.)


Fig. 9.2

A female child with multiple dysmorphic features related to methotrexate exposure in utero (From Seidahmed et al., A Case of methotrexate embryopathy with holoprosencephaly, expanding the phenotype, Birth Defects Research (Part A) 2006;76:138–142. Reproduce with permission.)


Fig. 9.3

Magnetic resonance imaging of the brain revealed absent corpus callosum and cerebellar hypoplasia, and prominence cisterna magna. (From Seidahmed et al., A Case of methotrexate embryopathy with holoprosencephaly, expanding the phenotype, Birth Defects Research (Part A) 2006;76:138–142. Reproduced with permission)

Absolute contraindications to methotrexate include breast-feeding, evidence of immunodeficiency, blood dyscrasias including significant anemia, sensitivity to methotrexate, active pulmonary or pelvic ulcer disease, hepatic or renal dysfunction, or alcoholism. Kelly et al. reported a fatal outcome after methotrexate treatment for an ectopic pregnancy in a woman with renal insufficiency [10].

Up to 30 % of patients who receive a single dose of methotrexate and 40 % who receive multiple doses will experience side effects. The most common side effects are stomatitis and conjunctivitis, which are usually mild and self-limiting. Other rare side effects include pleuritis, dermatitis, alopecia, gastritis, enteritis, elevated liver enzymes, and bone marrow suppression. Therefore, even if there is no viable intrauterine pregnancy developing that is at risk for embryopathy, as in the case of a miscarriage, unnecessary methotrexate administration (or surgery) can cause unjustified morbidity to the patient.


The patient received an intramuscular injection of methotrexate. The consulting gynecologist performed another ultrasound 3 days later, which, to his dismay, detected an intrauterine pregnancy. Termination of the pregnancy was discussed but the patient declined, and she subsequently gave birth to a male baby. Unfortunately, the baby had a cleft palate and bone deformities. The family took legal action against the gynecologist, the emergency physician, and the hospital.

Clinical Pearls/Pitfalls

·               The discriminatory hCG levels are not always reliable.

·               In multiple pregnancies, the hCG levels are higher than those in singleton pregnancies at a given gestational age.

·               Although uncommon, laboratory error can occur.

·               Before methotrexate treatment, one has to be sure that there is no possibility of a viable intrauterine pregnancy.

·               Failure to diagnose the possibility of an intrauterine pregnancy and administering methotrexate poses more serious consequences than delaying a diagnosis of an ectopic pregnancy.

·               Inadvertent methotrexate administration can lead to serious medical litigation against the physician and the institution.



Tulandi T. Clinical manifestations, diagnosis, and management of ectopic pregnancy. Accessed 2 December 2014.


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