Ectopic Pregnancy: A Clinical Casebook

10. Effect of Methotrexate Treatment for Ectopic Pregnancy on Current and Subsequent Pregnancy

Shirin Namouz-Haddad  and Gideon Koren 


The Hospital for Sick Children, 555 University Ave, M5G 1X8 Toronto, ON, Canada

Shirin Namouz-Haddad (Corresponding author)


Gideon Koren



Methotrexate toxicityTeratogenAminopterin syndromeMethotrexate embryopathy

Case Study

A 30-year-old woman was referred to a high-risk clinic, to discuss the consequences of 80 mg intramuscular (IM) methotrexate (MTX) given due to an erroneous diagnosis of ectopic pregnancy at 6 weeks’ gestation of a planned pregnancy.

Two days prior to her referral, a transvaginal ultrasound examination revealed a viable intrauterine pregnancy, 8.3 gestational weeks based on crown–rump length (CRL) measurement of 18.9 mm with a positive and normal fetal heartbeat, with no abnormal findings on adnexas (Fig. 10.1).


Fig. 10.1

Transvaginal ultrasound examination revealed a normal intrauterine pregnancy of 8 weeks + 3 days. Transvaginal ultrasound image of 8 weeks + 3 days fetus

The couple was very concerned about the risks of an adverse pregnancy outcome in the current and subsequent pregnancies due to MTX treatment.

My Management



Diagnosis and Assessment

Different regimens of delivering high-dose MTX (60–100 mg or more) to a patient with ectopic pregnancy have been described [1]. Typically, misdiagnosed intrauterine pregnancy which is treated as ectopic pregnancy exposes the fetus to high-dose MTX during critical stages of embryogenesis. This is the only situation in medicine where a highly teratogenic dose of a drug is given to a pregnant woman.

MTX, a folic acid antagonist and DNA synthesis inhibitor in rapidly dividing cells, has been implicated in as a human teratogen , particularly when used in a high dose during the first trimester of pregnancy. MTX embryopathy (the aminopterin syndrome) is characterized by intrauterine growth restriction, miscarriage, stillbirth, cardiac defects, dysmorphic facial features, neural tube and skeletal anomalies, and mental retardation [12] (Table 10.1).

Table 10.1

The aminopterin embryopathy. [313]

Spontaneous abortion

Wide set eyes

Intrauterine growth restriction

Wide set nasal bridge


Oral cleft


Micrognathia and retrognathia


Low set ears


Short extremities

Spina bifida

Abnormal bone ossification

Mental retardation

Fingers syndactyly

Developmental delay

Thumb and fibular hypoplasia

Lambdoid suture synostosis

Club foot

Large fontanelles


Until recently it was believed that the low oral weekly dose of MTX, given in rheumatological conditions, did not result in the aminopterin syndrome; however, such a case was described in Argentina in 2013 [3].

The absolute risk of MTX embryopathy can only be estimated due to underreporting of cases because of medicolegal fears of erroneous of ectopic pregnancy. The largest observational study by our group included eight pregnant women who were misdiagnosed as an ectopic pregnancy and treated with 50–184 mg MTX. None of these pregnancies resulted in the birth of healthy newborn (two newborns had major malformations compatible with MTX embryopathy (one of them had a stillbirth at 30 gestational weeks), three of eight pregnancies resulted in spontaneous miscarriage less than 2 weeks after MTX treatment , and three of eight women terminated the pregnancy based on their physician advice) [1].

Overall, the risk of this patient having a baby with birth defects is substantially increased when compared to the population baseline of 1–3 % [4].


Theoretically, MTX embryopathy may be attenuated by folinic acid coadministration by countering the antifolate effect MTX. Leucovorin injection (a structural analogue of folinic acid) in animals ameliorated MTX teratogenic effect [5]. In a rabbit model, leucovorin was administered up to 24 h after MTX injection.

In a clinical setting, often by the time an accurate pregnancy location is diagnosed, 1–2 weeks have elapsed since MTX treatment. Importantly, folinic acid treatment in human pregnancy following MTX exposure has not been studied in humans.

The MTX teratogenicity and the lack of evidence to improve the pregnancy outcome should be thoroughly discussed with the patient. Should the woman choose to continue the pregnancy, based on religion or psychological reasons, a detailed fetal ultrasound study should be done. It may detect major malformations but cannot rule out completely such abnormalities or mental retardation. In such cases, giving folinic acid may make sense, provided that the family is advised that there is no evidence of efficacy beyond the mechanistic support.

Future Aspects

Recommendations for future conception after MTX exposure call for ensuring undetectable MTX levels which should be reached [67]. On the other hand, a safe interval for conception with no risk of residual MTX effect has not been established, and commonly the advice is to avoid pregnancy for 3 months [7], due to the fact that residual MTX may be stored in the kidney and liver for months, despite its short elimination half-life of 8–15 h [8].

The safety of subsequent pregnancy after much higher doses of MTX for treatment of gestational trophoblastic tumor is controversial. Chemotherapy for gestational trophoblastic tumors may include MTX as a single agent, other cytotoxic drugs, or MTX in combination with different drugs. A retrospective study, in which all women were treated with high doses of MTX (mean 1.2 g, up to 6.8 g), showed that the risk for congenital malformation in subsequent pregnancy was not associated with the time interval between treatment completion and conception [9]. The risks for malformation and stillbirth were not statistically increased when compared to an expected background group [9]. In contrast, in another study, the risk of abnormal pregnancy outcome (spontaneous abortion, stillbirth, and repeat mole) was significantly increased in women who conceived in a time interval of less than 6 months after chemotherapy completion (6/15; 40 %) compared to interval  > 12 months (10/95; 10.5 %; p =  0.028) [10]. However, only 4 out of 15 cases who conceived in a time interval < 6 months had been treated with MTX.

To date, the largest prospective observational study failed to show an increased risk of abnormal pregnancy outcomes (stillbirth, spontaneous abortion, major, and minor birth defects) in women chronically treated with low dose MTX (median weekly dosage 15 mg; range 2.5–30 mg) up to 10 weeks prior to LMP compared to healthy control and disease matched women unexposed to MTX [11]. In contrast, those treated during the first trimester had a higher risk of congenital malformations, although not compatible with the aminopterin syndrome .

None of the aforementioned studies addressed the typical MTX dosage used for ectopic pregnancy. Only one retrospective study compared 45 women who conceived  < 6 months (mean 3.6 ± 1.7 months) after MTX treatment for an ectopic pregnancy with 80 women conceiving  > 6 months (23.6 ± 14.7 months) after MTX treatment. Pregnancy adverse outcomes were comparable between the two groups (odds ratio (OR) 1.00, 95 % confidence interval (CI) 0.98–1.02), including congenital malformation, spontaneous abortion, preterm delivery, and low birth weight. In logistic regression, the interval between conception and MTX exposure had no effect on fetal adverse outcomes [12].

Management in Subsequent Pregnancy

The lack of evidence of prolonged teratogenic effect of MTX on subsequent pregnancy, coupled with the short elimination half-life of the drug, is reassuring. Even if the woman conceives less than 3 months after the treatment, there is no evidence to advise her on increased teratogenic risk. However, the limitations of the small published studies must be acknowledged, since they do not have sufficient power to detect small increase in teratogenicity following ectopic pregnancy treatment by MTX.


The family decided to terminate the pregnancy. Following her gynecologist’s advice, she conceived 6 months after pregnancy termination. The following pregnancy was followed up by a low-risk pregnancy clinic. A healthy girl was born at term.

Clinical Pearls/Pitfalls

·               Erroneous diagnosis of an intrauterine pregnancy as ectopic and MTX treatment pose a significant increased risk of adverse fetal outcome.

·               Erroneous MTX treatment during pregnancy should prompt a thorough discussion and counseling of the patient regarding the risks of fetal exposure to MTX.

·               A 6-month interval before conception following MTX treatment should be advised.

·               Conception within less than 3–6 months subsequent to MTX treatment should not be considered as a definite indication for pregnancy termination, and a detailed follow-up of fetal anatomy scan should be advised.



Nurmohamed L, Moretti ME, Schechter T, Einarson A, Johnson D, Lavigne SV, et al. Outcome following high-dose methotrexate in pregnancies misdiagnosed as ectopic. Am J Obstet Gynecol. 2011;205:533 e1–3.CrossRefPubMed


Del Campo M, Kosaki K, Bennett FC, Jones KL. Developmental delay in fetal aminopterin/methotrexate syndrome. Teratology. 1999;60:10–2.CrossRefPubMed


Martin MC, Barbero P, Groisman B, Aguirre MA, Koren G. Methotrexate embryopathy after exposure to low weekly doses in early pregnancy. Reprod Toxicol. 2014;43:26–9


Heinonen OP, Slone D, Shapiro S. Birth defects and drugs in pregnancy. Littleton: Pub. Sciences Group; 1977.


DeSesso JM, Goeringer GC. Amelioration by leucovorin of methotrexate developmental toxicity in rabbits. Teratology. 1991;43:201–15.


American College of O, Gynecologists. ACOG practice bulletin no. 94: medical management of ectopic pregnancy. Obstet Gynecol. 2008;111:1479–85.CrossRef


Practice Committee of American Society for Reproductive Medicine. Medical treatment of ectopic pregnancy: a committee opinion. Fertil Steril. 2013;100:638–44.


Charache S, Condit PT, Humphreys SR. Studies on the folic acid vitamins. IV. The persistence of amethopterin in mammalian tissues. 1960;13:236–40.


Rustin GJ, Booth M, Dent J, Salt S, Rustin F, Bagshawe KD. Pregnancy after cytotoxic chemotherapy for gestational trophoblastic tumours. BMJ. 1984;288:103–6.CrossRefPubMedCentralPubMed


Matsui H, Iitsuka Y, Suzuka K, Yamazawa K, Tanaka N, Seki K, et al. Risk of abnormal pregnancy completing chemotherapy for gestational trophoblastic tumor. Gynecol Oncol. 2003;88:104–7.CrossRefPubMed


Weber-Schoendorfer C, Chambers C, Wacker E, Beghin D, Bernard N, Shechtman S, et al. Pregnancy outcome after rheumatologic methotrexate (MTX) treatment prior to or during early pregnancy: a prospective multicenter cohort study. Arthritis Rheumatol. 2014;66(5):1101–10.


Svirsky R, Rozovski U, Vaknin Z, Pansky M, Schneider D, Halperin R. The safety of conception occurring shortly after methotrexate treatment of an ectopic pregnancy. Reprod Toxicol (Elmsford, NY). 2009;27:85–7.CrossRefPubMed


Lloyd ME, Carr M, McElhatton P, Hall GM, Hughes RA. The effects of methotrexate on pregnancy, fertility and lactation. QJM. 1999;92:551–63.CrossRefPubMed