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Current Studies at Motherisk
Neurodevelopment of Children Exposed in-Utero to Chemotherapy for Maternal Breast Cancer (Dr. I Nulman)
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Cancer in Pregnancy: Methotrexate
Methotrexate (MTX) is a folic acid antagonist used in the treatment of auto immune and neoplastic disease. It is closely related to aminopterin, another folic acid antagonist. Folic acid has a key role in replication of nucleic acids. It is retained for several weeks in the kidney and for months in the liver.
|Animal studies * 1-6||Mice, rats, rabbits and monkeys||Equivalent doses or greater than used in humans||Fetal death. Doses required to produce this effect are higher in monkeys.|
|Rats, mice, rabbits||Dose-dependent effect||Malformations, dose-dependent, mostly cleft palate, limb and central nervous system. CNS malformations in mice appeared only at 4-fold dose greater then used in humans.|
|Rhesus monkeys||Five-fold greater doses than used in humans||No evidence of teratogenicity|
|Human studies||Case reports||1st trim exposure||A peculiar
pattern of anomalies was described for at least seven children born to
women treated with MTX during the first trimester of pregnancy 7-11.
The main features of this syndrome are abnormal skull ("clover-leaf"
skull or oxycephaly) with a large head, craniosynostsis, large
fontanelles, ocular hypertelorism with proeminent eyes and wide nasal
bridge. Skeletal, limb and CNS defects were also described. This
pattern is quite similar to the described for aminopterin exposure in
There are, also, case reports 12,13 and case series (see below) of successful outcomes after first trimester exposure. The risk are probably time and dose dependent, being greater with larger doses and smaller or even non-existent with lower doses (less than 10 mg/wk) 14.
|2nd and 3rd trim exposures||1. A review of 5 cases of 2nd or 3rd trimester exposures without adverse effect 15.
2. A case of severe myelosupression in an infant exposed to combined therapy during 1st, 2nd and 3rd trim 16.
3. A healthy girl born to a woman who received combination therapy including MTX for acute lymphoblastic leukemia, from 22nd week to term. Karyotype revealed 46 chromosomes with the presence of gaps and a ring chromosome, which is similar to the observed in patients after cytotoxic chemotherapy 17. The clinical significance of this finding is still unknown but it can represent a risk of cancer, as well as a risk of genetic damage in the next generation 18
|Case series||A. Malformations:||No
epidemiological studies of congenital anomalies among the infants of
women treated with MTX during pregnancy were found. There is a number
of case series which included exposures during the first trimester.
1. No congenital anomalies were observed in one series among 9 children born to women treated during pregnancy with cancer chemotherapeutic regimens that included MTX. Five of these women were treated during the first trimester 19. Their growth, intellectual development and cytogenetic analysis were normal in ages ranging from 3 - 19 years at the time of follow-up.
2. In a series of 9 patients with acute leukemia during pregnancy, 5 of them with the use of methotrexate during the first trimester , no one was born with congenital malformation. 20, but 4 had a subnormal birth weight. One had severe pancytopenia and low birth weight. The mother of this patient received combination chemotherapy (cytosine arabinoside, prednisone, 6-mercaptorurine, methotrexate and vincristine) during 1st, 2nd and 3rd trimesters.
3. In a series of 10 pregnancies from 8 patients with MTX exposure prior to and during pregnancy, 3 ended as spontaneous abortions, 2 as elective abortions and 5 progressed to term with no congenital abnormalities found. All of them had first trimester exposure 21.
4. In a series of 21 prospectively ascertained cases of MTX exposure, 9 occurred within one year prior to conception and 5 occurred during pregnancy (4 during the first trimester), all with normal outcomes. Of the 9 exposures prior to conception, 4 resulted in full term healthy infants and 4 resulted in first trimester spontaneous losses 22.
|B. Pregnancy loss:||MTX increases the rate of miscarriage in women exposed early in pregnancy 21,22 (see details above) and it is used as an abortifacient 23,24 and in the treatment of ectopic pregnancy 25|
|Pre-pregnancy||A study of 445 long-term survivors treated with chemoterapy for gestational tumours including MTX did not show any increased incidence of congenital malformation in the children 26. Other studies also presented successful pregnancies after pre-conceptional chemotherapy 22,27,28.|
- Darab et al: Pathogenesis of median facial clefts in mice treated withmethotrexate. Teratology 36:77-88, 1987.
- De Sesso & Goeringer: Methotrexate-induced developmental toxicity in rabbits is ameliorated by 1-(p-tosyl)-3,4,4-trimethylimidazolidine, afunctional analog for tetrahydrofolate-mediated one-carbon transfer. Teratology 45:271-283, 1992.
- Jordan et al: Embryotoxicity of the folate antagonist methotrexate in rats and rabbits. Teratology 15:73-80, 1977.
- Lanoue & Sulik: Methotrexate (MTX) can induce neural tube defects (NTDs) in mouse embryos. Teratology 51: 189, 1995.
- Skalko & Gold: Teratogenicity of methotrexate in mice. Teratology 9:159-64, 1974.
- Wilson et al: Comparative distribution and embryo toxicity of methotrexate in pregnant rats and rhesus monkeys. Teratology 19:71-98,1979.
- Bawle et al: Phenotype of an adult with methotrexate embryophaty and of 2 children with exposure during fetal period. Am J Hum Genet 57(4 suppl): A83, 1995.
- Buckley et al: Multiple congenital anomalies associated with weekly low-dose methotrexate treatment of the mother. Arthritis & Rheumatism40:971-3, 1997.
- Diniz et al : Os efeitos do metotrexate no feto em desenvolvimento [The effects of methotrexate on the developing fetus] Rev Hosp Clin Fac MedSao Paulo 33: 286-90, 1978.
- Milunsky et al: Methotrexate-induced congenital malformations. J Pediatr 72:790-5, 1968.
- Powell & Eckert: Methotrexate-induced congenital malformations. MedJ Aust 2:1076-1077, 1971.
- Dara et al: Successful pregnancy during chemotherapy for acute leukemia. Cancer 47:845-6, 1981.
- Feliu et al: Acute leukemia and pregnancy. Cancer 61:580-4,1988.
- Feldkamp & Carey: Clinical teratology counseling and consultation case report: low dose methotrexate exposure in early weeks of pregnancy. Teratology 47:533-9, 1993.
- Nicholson: Cytotoxic drugs in pregnancy: review of reported cases. J Obstet Gynaecol Br Commonw 75:307-12, 1968.
- Pizzuto et al: Treatment of acute leukemia during pregnancy: presentation of nine cases. Cancer Treat Rep 64:679-83,1980.
- Mondello et al: Chromosomal effects of methotrexate on cultured human lymphocytes. Mutat Res 139-67-70, 1984.
- Schleuning & Clemm: Chromosomal aberrations in a newborn whose mother received cytotoxic treatment during pregnancy. New Engl J Med 317:1666-7, 1987.
- Aviles et al: Growth and development of children of mothers treated with chemotherapy during pregnancy: current status of 43 children. Am JHematol 36:243-8, 1991.
- Kozlowski et al: Outcome of first-trimester exposure to low-dose methotrexate in eight patients with rheumatic disease. Am J Med88:589-92, 1990.
- Donnenfeld et al: Methotrexate exposure prior to and during pregnancy. Teratology 49:79-81, 1994.
- Creinin et al: a randomized trial comparing misoprostol three and seven days after methotrexate for early abortion. Am J Obstet Gynecol173:1578-84.
- Hausknecht: Methotrexate and misoprostol to terminate early pregnancy. New Engl J Med 333:537-40, 1995.
- Zohav et al: Successful pregnancy following conservative treatment of cervical pregnancy with methotrexate. Int J Gynecol Obstet 48:97-8,1995.
- Rustin et al: Pregnancy after cytotoxic chemotherapy for gestational trophoblastic tumours. Br Med J 288: 103-6, 1984.
- Green et al: Congenital anomalies in children of patients who received chemotherapy for cancer in childhood and adolescence. New Engl J Med325: 141-6, 1991.
- van Thiel et al: Pregnancies after chemotherapy of trophoblastic neoplasms. Science 169:1326-7, 1970.