Risk Factor: XM
Class: Immunologic agents/ Antirheumatic agents
Fetal Risk Summary
Methotrexate is a folic acid antagonist. References describing the use of this antineoplastic agent in 27 pregnancies, 11 in the 1st trimester, have been located (1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16 and 17). Three of the 11 1st trimester exposures resulted in malformed infants (2,3,6) and one in a spontaneous abortion (SAB) (17). Methotrexate-induced congenital defects are similar to those produced by another folic acid antagonist, aminopterin (see also Aminopterin) (6). Anomalies in two infants were: Absence of lambdoid and coronal sutures, oxycephaly, absence of frontal bone, low-set ears, hypertelorism, dextroposition of heart, absence of digits on feet, growth retardation, very wide posterior fontanelle, hypoplastic mandible, multiple anomalous ribs (2) Oxycephaly caused by absent coronal sutures, large anterior fontanelle, depressed and wide nasal bridge, low-set ears, long webbed fingers, wide-set eyes (3) A 1999 report from France described the outcomes of pregnancies in 20 women with breast cancer who were treated with antineoplastic agents (17). The first cycle of chemotherapy occurred at a mean gestational age of 26 weeks, with delivery occurring at a mean 34.7 weeks. A total of 38 cycles were administered during pregnancy, with a median of two cycles per woman. None of the women received radiation therapy during pregnancy. The pregnancy outcomes included two SAB (both exposed in the 1st trimester), one intrauterine death (exposed in the 2nd trimester), and 17 live births, one of whom died at 8 days of age without apparent cause. The 16 surviving children were developing normally at a mean follow-up of 42.3 months (17). Methotrexate, in combination with epirubicin and vincristine, was administered to one woman (25 mg/m2) at 6 weeks’ gestation. The pregnancy ended in a SAB (17).
Possible retention of methotrexate in maternal tissues before conception was suggested as the cause of a rare pulmonary disorder in a newborn, desquamating fibrosing alveolitis (18). The infant’s mother had conceived within 6 months of completing treatment with the antineoplastic. (Note: A later publication from these investigators, which included this case, noted that the newborn was conceived within 2 months of treatment termination [see Reference 30]. In addition, a sister of the infant born 3 years later developed the same disorder, although a third child born from the mother 1 year later developed normally.) Previous studies have shown that methotrexate may persist for prolonged periods in human tissues (19). However, conception occurred 3 months after discontinuance of therapy in one case (20), after 6 months in a second (13), and after 7 months in a third (21). Four (one set of twins) normal infants resulted from these latter pregnancies. Thus, the association between methotrexate and the pulmonary disorder is unknown.
Two cases of severe newborn myelosuppression have been reported after methotrexate use in pregnancy. In one case, pancytopenia was discovered in a 1000-g male newborn after exposure to six different antineoplastic agents, including methotrexate, in the 3rd trimester (4). The second infant, delivered at 31 weeks’ gestation, was exposed to methotrexate only during the 12th week of pregnancy (9). The severe bone marrow hypoplasia was most likely caused by the use of mercaptopurine near delivery.
Data from one review indicated that 40% of the infants exposed to cytotoxic drugs were of low birth weight (1). This finding was not related to the timing of the exposure. Long-term studies of growth and mental development in offspring exposed to antineoplastic agents during the 2nd trimester, the period of neuroblast multiplication, have not been conducted (22,23). Several studies, however, have followed individual infants for periods ranging from 2 to 84 months and have not discovered any problems (9,10,11,12 and 13,15,16).
Methotrexate crosses the placenta to the fetus (14). A 34-year-old mother was treated with multiple antineoplastic agents for acute lymphoblastic leukemia beginning in her 22nd week of pregnancy. Weekly intrathecal methotrexate (10 mg/m2) was administered from approximately 26 to 29 weeks’ gestation, then the dose was increased to 20 mg/m2 weekly until delivery at 40 weeks’ gestation. Methotrexate levels in cord serum and red cells were 1.86 109 mol/L, and 2.6 109 mol/g of hemoglobin, respectively, with 29% as the polyglutamate metabolite.
In the case described above, chromosomal analysis of the newborn revealed a normal karyotype (46,XX), but with gaps and a ring chromosome (14). The clinical significance of these findings is unknown, but because these abnormalities may persist for several years, the potential existed for an increased risk of cancer as well as for a risk of genetic damage in the next generation (14).
Successful pregnancies have followed the use of methotrexate before conception (13,18,20,21,24,25,26,27,28,29 and 30). Apparently, ovarian and testicular dysfunction are reversible (23,31,32,33 and 34). Two studies, one in 1984 and one in 1988, both involving women treated for gestational trophoblastic neoplasms, have analyzed reproductive function after methotrexate therapy and are described below (30,35).
In 438 long-term survivors treated with chemotherapy between 1958 and 1978, 436 received methotrexate either alone or in combination with other antineoplastic agents (30). This report was a continuation of a brief 1979 correspondence that discussed some of the same patients (18). The mean duration of chemotherapy was 4 months, with a mean interval from completion of therapy to the first pregnancy of 2.7 years. Conception occurred within 1 year of therapy completion in 45 women, resulting in 31 live births, 1 anencephalic stillbirth, 7 spontaneous abortions, and 6 elective abortions. Of the 436 women, 187 (43%) had at least one live birth (numbers given in parentheses refer to mean/maximum methotrexate dose in grams when used alone; mean/maximum dose in grams when used in combination) (1.26/6.0; 1.22/6.8), 23 (5%) had no live births (1.56/2.6; 1.33/6.5), 7 (2%) failed to conceive (1.30/1.6; 1.95/4.5), and 219 (50%) did not try to conceive (1.10/2.0; 2.20/34.5). The average ages at the end of treatment in the four groups were 24.9, 24.4, 24.4, and 31.5 years, respectively. Congenital abnormalities noted were anencephaly (2), spina bifida (1), tetralogy of Fallot (1), talipes equinovarus (1), collapsed lung (1), umbilical hernia (1), desquamative fibrosing alveolitis (1; same case as described above), asymptomatic heart murmur (1), and mental retardation (1). An 11th child had tachycardia but developed normally after treatment. One case of sudden infant death syndrome occurred in a female infant at 4 weeks of age. None of these outcomes differed statistically from that expected in a normal population (30).
The 1988 report described the reproductive results of 265 women who had been treated from 1959 to 1980 for gestational trophoblastic disease (35). Single-agent chemotherapy was administered to 91 women, only 2 of whom received methotrexate. Sequential (single-agent) and combination therapy were administered to 67 and 107 women, respectively, but the individual agents used were not specified. Further details of this study are provided in the monograph for mercaptopurine (see Mercaptopurine).
The long-term effects of combination chemotherapy on menstrual and reproductive function have also been described in women treated for malignant ovarian germ cell tumors (36). Only 2 of the 40 women treated received methotrexate. The results of this study are discussed in the monograph for cyclophosphamide (see Cyclophosphamide).
A 34-year-old man, being treated with oral methotrexate for Reiter’s syndrome, fathered a normal full-term female infant (37). The man had been receiving treatment with the drug intermittently for approximately 5 years and continuously for 5 months before conception.
Occupational exposure of the mother to antineoplastic agents during pregnancy may present a risk to the fetus. A position statement from the National Study Commission on Cytotoxic Exposure and a research article involving some antineoplastic agents are presented in the monograph for cyclophosphamide (see Cyclophosphamide).
Breast Feeding Summary
Methotrexate is excreted into breast milk in low concentrations (38). After a dose of 22.5 mg/day, milk concentrations of 6 109 M (0.26 g/dL) have been measured with a milk:plasma ratio of 0.08. The significance of this small amount is not known. However, because the drug may accumulate in neonatal tissues, breast feeding is not recommended. The American Academy of Pediatrics considers methotrexate to be contraindicated during breast feeding because of several potential problems, including immune suppression, neutropenia, adverse effects on growth, and carcinogenesis (39).
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