Antineoplastic/Immunologic Agent (Antirheumatic)
PREGNANCY RECOMMENDATION: Contraindicated
BREASTFEEDING RECOMMENDATION: Contraindicated
PREGNANCY SUMMARY
The use of methotrexate during organogenesis is associated with a spectrum of congenital defects collectively called methotrexate embryopathy or the fetal aminopterin-methotrexate syndrome. The critical period of exposure is 6–8 weeks postconception (8–10 weeks after the first day of the last menstrual period) and the critical dose is thought to be ≥10 mg/week. Typical characteristics of the syndrome are intrauterine growth restriction (IUGR); a marked decrease in ossification of the calvarium; hypoplastic supraorbital ridges; small, low-set ears; micrognathia; limb abnormalities; and occasional mental retardation (1). Exposure in the 2nd and 3rd trimesters may be associated with fetal toxicity and mortality. Although methotrexate may persist in tissues for long periods, pregnancies occurring after treatment with methotrexate do not appear to be at a risk any different from that of an unexposed population. If methotrexate is used in pregnancy for the treatment of rheumatoid arthritis, health care professionals are encouraged to call the toll-free number 877-311-8972 for information about patient enrollment in the Organization of Teratology Information Specialists (OTIS) Rheumatoid Arthritis study.
FETAL RISK SUMMARY
Methotrexate is a folic acid antagonist. It is in the same antineoplastic subclass as aminopterin, pemetrexed, and pralatrexate.
A number of references describing the use of this antineoplastic agent in pregnancy have been located (1–28). Methotrexate-induced congenital defects (also known as the aminopterin-methotrexate syndrome) are similar to those produced by another folic acid antagonist, aminopterin (see also Aminopterin) (7). 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 restriction, very wide posterior fontanelle, hypoplastic mandible, multiple anomalous ribs (3); and oxycephaly caused by absent coronal sutures, large anterior fontanelle, depressed and wide nasal bridge, low-set ears, long webbed fingers, wide-set eyes (4).
A 1990 report described the pregnancy outcomes of eight women who were treated with low-dose oral methotrexate for rheumatic disease during 10 pregnancies (18). The outcomes included two elective abortions (EABs) (no details given for these cases), three spontaneous abortions (SABs), and five normal full-term live births. In the eight pregnancies (six women) with details, the methotrexate weekly dose (usually given as a single dose) was 7.5 mg in seven and 10 mg in one. In the live birth group, the mean methotrexate exposure was 6.8 weeks postconception (range 2–15 weeks), whereas in the SAB group the mean exposure was 7 weeks (range 4–9 weeks). The mean cumulative methotrexate dose prior to conception was 1384 mg (range 165–3545 mg) (live births) and 333 mg (range 45–775 mg) (SAB). Other drugs taken by the women included aspirin, nonsteroidal anti-inflammatory agents, prednisone (<10 mg/day), and hydroxychloroquine. Folate supplements had been taken in three of the five pregnancies ending in live births and in all three of the SAB cases. No obvious differences were apparent between the live birth and SAB groups in terms of smoking, use of alcohol, or the use of other drugs. Information on the long-term development of the five live births was obtained by telephone interview at a mean age of 11.5 years (range 3.7–16.7 years). All of the children were healthy and had experienced normal physical and mental development (one child had a minor speech impediment that had resolved with speech therapy) (18).
A 1993 case report and review described the pregnancy outcome of a 39-year-old woman with severe rheumatoid arthritis who was exposed to methotrexate and other drugs shortly after conception (19). For about 6 months before conception she had been taking methotrexate (7.5 mg once weekly), ibuprofen (6.4 g/day), misoprostol (0.4 mg/day), and cimetidine (600 mg) or sucralfate (3 g) per day. All medications were stopped within 10 days of the last menstrual period (as determined by ultrasound at 5–6 weeks’ gestation). A healthy full-term, 3962-g male infant was delivered by cesarean section (breech presentation) with Apgar scores of 8 and 9 at 1 and 5 minutes, respectively. Examination by a dysmorphologist at 12 weeks of age revealed a healthy, normal infant with no evidence of embryopathy (19).
A 25-year-old woman at 30 weeks’ gestation was diagnosed with metastatic choriocarcinoma of the vagina and lungs (20). The woman was treated with IV methotrexate 20 mg/day for 5 days. Five days later, she delivered a preterm male infant with an Apgar of 10 (no other details given). The mother and infant were alive and well at 12 months’ follow-up (20).
In a 1994 reference, data relating to methotrexate use before or during pregnancy were gathered from programs participating in the Organization of Teratology Information Services (OTIS) and the European Network of Teratology Information Services (ENTIS) (21). The survey resulted in data for 21 prospectively ascertained cases. Seven exposures occurred more than 1 year before conception and they were excluded from the analysis. In the remaining 14 cases, 9 were exposed within 1 year of conception and 5 were exposed during pregnancy. Four of the five pregnancy exposures occurred within the first 6 weeks of gestation with a duration of exposure of 1–3 weeks and one single dose exposure occurred at 37–38 weeks’ gestation. Doses ranged from 7.5 mg/week (one woman had been taking this dose for 3 years) to a single 42 mg IV dose. All of these outcomes resulted in healthy infants without birth defects (one delivered at 36 weeks’). In the women exposed within 1 year of pregnancy, the duration of exposures ranged from a few weeks to 6 years. The doses were known in four cases (7.5 mg/week in three, 12.5 mg/week in one). The outcomes of these nine cases were four SABs, four healthy infants, and one infant born at term with a cavernous hemangioma. The authors concluded that the limited data confirmed that the critical time for methotrexate-induced defects was 6–8 weeks postconception and the critical dose was ≥10 mg/week (21).
A 1997 case report described an adverse pregnancy outcome in a 20-year-old woman with polyarticular rheumatoid arthritis who had been treated with oral doses of methotrexate (10–12.5 mg/week) for about 5–6 years (22). Folic acid (1 mg/day) was also prescribed but her compliance was unclear. The woman discontinued treatment at about 8 weeks’ gestation (estimated dose during gestation about 100 mg). At 35 weeks’ she gave birth to a 1.79-kg female (normal 46,XX karyotype) infant with IUGR and multiple congenital anomalies. The defects included brachycephaly, 0.5-cm anterior fontanelle, coronal ridging, shallow orbits with hypertelorism, retrognathia, malformed ears, palate with a posterior groove and a bifid uvula, umbilical hernia, spinal defects (dorsal kyphosis with L5 and S1 hemivertebrae), deformed thumb, bilateral simian creases, hypoplastic nails, reduction of radial ray on right side, syndactyly of fourth and fifth toes, absent fifth metatarsal bone, and cardiovascular defects (double-outlet right ventricle, doubly committed ventricular septal defect, transposed great vessels, restrictive atrial septal defect, pulmonary stenosis, and an aberrant right subclavian artery). The infant died at 6 months of age. The authors concluded that the anomalies were consistent with methotrexate-induced embryopathy (22).
A 26-year-old man with fetal methotrexate syndrome and two children with mild manifestations of the syndrome were described in 1998 (23). In the adult’s case, his mother (who gave him up for adoption) had attempted to terminate the pregnancy at 6–8 weeks’ gestation with an unknown amount of methotrexate. His malformations included hypertelorism, ptosis of the eyelids, short palpebral fissures, sparse eyebrows, prominent nose, low-set ears, a widow’s peak at the frontal hairline, flexion contractures of the metacarpophalangeal joints of both thumbs and syndactyly of all fingers (all repaired surgically), four metacarpals, and a single fused hypoplastic nub of tissue at the forefoot (corrected surgically with reconstruction of all toes). His physical growth was restricted, but his psychomotor development was normal, as is his intelligence. The first child, a 9-year-old male, was exposed to 80 mg/week of methotrexate for 6 doses at 7.5–28.5 weeks’ gestation. His mother, with an undetected pregnancy, had been treated for breast cancer with methotrexate, fluorouracil (1200 mg/week × 10 doses), and radiation (total dose estimated to be 14 rads). He was born at 29 weeks with a birth weight of 820 g (small for gestational age) and he remains growth restricted. Malformations included hypertelorism, a frontal hair whorl, upsweep of the frontal hairline, microcephaly, low-set ears, micrognathia, right palmar simian crease, and borderline mental retardation (composite IQ of 70). The second child is a 3.5-year-old male infant who was born at 29 weeks’ gestation with a normal weight (1160 g; 50th percentile). His mother had undergone a failed EAB (dilatation, suction, and curettage; 11 weeks after the last menstrual period [LMP]) and then, because of large uterine myomas, had chosen to have a medical abortion with methotrexate. She received 100 mg bi-weekly from about 13 to 19 weeks’ and 200 mg bi-weekly from 19 to 25 weeks’, but this abortion attempt also failed. Birth defects noted were a bulging forehead, bitemporal narrowing, upward slanting palpebral fissures, sparse hair on the temporal areas, low-set ears, broad nasal tip, and a high arched palate. He has had chronic diarrhea since 9 months of age. An intestinal biopsy revealed villous atrophy. His psychomotor development has been normal. At 34 months, his weight and length were restricted, but his head circumference was normal (75th percentile) (23).
A 1999 report described the outcomes of pregnancies in 20 women with breast cancer who were treated with antineoplastic agents (24). (See also Fluorouracil.) Methotrexate (25 mg/m2), in combination with epirubicin and vincristine, was administered to one woman at 6 weeks’ gestation. The pregnancy ended in an SAB (24).
Another 1999 reference reported the outcome of a male infant (normal karyotype 46,XY) whose mother had been treated for chronic severe psoriasis with 12.5 mg methotrexate 3 times weekly during the first 8 weeks postconception (1). He was delivered at 40 weeks’ gestation with Apgar scores of 2, 5, and 6 at 1, 5, and 10 minutes, respectively. Birth weight, length, and head circumference were severely restricted (<3rd percentile). Malformations included widely separated sutures and large fontanels; bilateral epicanthal folds and sparse eyebrows laterally with hypoplastic supraorbital ridges; broad nasal bridge; anteverted nares; smooth long philtrum; hypoplastic nipples; small umbilical hernia; diastasis recti; a shawl scrotum; decreased extension of the elbows; short bilateral proximal phalanges of the third, fourth, and fifth fingers; and mildly hypoplastic fingernails. The only neurologic abnormality noted was mild hypotonia. At 20 months, he was still growth restricted. He had a triangular face (trigonocephaly) with a prominent metopic suture and the open anterior fontanel finally closed at age 30 months. Generalized tonic-clonic seizures associated with fever were noted at 1 and 2 years (both of his older sisters had a similar episode during the first 2 years of life). Developmental testing revealed mental retardation with significant early motor and cognitive delays (1).
A 23-year-old woman underwent an attempted EAB at 8 weeks’ gestation with IM methotrexate 100 mg followed by misoprostol 800 mcg 4 days later (25). Four weeks later she still had a viable pregnancy but could not afford hospitalization for surgical termination. She eventually delivered a 2050-g female infant at term with Apgar scores of 4 and 8 at 1 and 5 minutes, respectively. The infant was hypotonic. All growth parameters (weight, height, and head circumference) were severely growth restricted. Multiple malformations were noted including a disproportionately long head (dolichocephaly), a prominent broad nose, hypertelorism, short palpebral fissure, small mouth, micrognathia, fifth-finger clinodactyly, extra flexion creases on the thumbs, mild syndactyly of the second and third toes with fourth and fifth toe clinodactyly, and hypoplastic toenails. Severe growth restriction was evident at the 12- and 18-month examinations. The mother declined developmental testing of the child, but stated that the usual developmental milestones were normal (25).
A 2002 case report described the pregnancy outcome of a woman who was treated for psoriasis with two doses of methotrexate 7.5 mg/day at 3.5 weeks postconception (26). She also was taking sertraline and smoked cigarettes. An ultrasound examination at 18 weeks’ gestation revealed multiple anomalies and the pregnancy was terminated 2 weeks later. The male fetus (normal 46,XY karyotype) had a wide anterior fontanelle, sloping forehead, under mineralization of the skull, low-set and poorly formed ears, absent auditory canals, flat nose, micrognathia, multiple skeletal abnormalities (absent and slender ribs, a hemivertebrae, and fusion of the third through fifth lumbar vertebral bodies), limb defects (absent left radius, hypoplastic right radius, bilaterally short forearms, hypoplastic left thumb, and clinodactyly of the fifth digit bilaterally), tracheal atresia, markedly hypoplastic lungs, cardiovascular defects (left ventricle mildly hypoplastic, ventricular septal defect, persistent right subclavian artery with an arterial ring, and absent left and right pulmonary arteries), malrotated intestines, duodenal atresia, a Meckel’s diverticulum, multiple accessory spleens, enlarged left liver lobe, and a two-vessel umbilical cord (26).
A 2003 case reported a failed pregnancy termination attempt at 6 weeks’ gestation with IM methotrexate 75 mg and oral misoprostol 400 mcg (27). The pregnancy was terminated at 27 weeks’ secondary to ultrasound diagnosis of methotrexate embryopathy. Autopsy revealed a 918-g female (normal karyotype) fetus with upper extremities that were asymmetric in length, bilateral shortening of the radii and ulnae, asymmetric in length lower extremities with bilateral absent fibulae, polydactyly of the right foot, small head, prominent eyes, low-set ears, micrognathia, and a two-vessel umbilical cord (27).
A survey of 600 members of the American College of Rheumatology, partially conducted to determine the outcomes of pregnancies exposed to disease-modifying antirheumatic drugs (etanercept, infliximab, leflunomide, and methotrexate), was published in 2003 (28). From the 175 responders, the outcomes of 39 pregnancies exposed to methotrexate were 21 full-term healthy infants, 7 spontaneous abortions (1 with a congenital malformation), 8 elective abortions, 1 woman still pregnant, and 2 liveborn infants with birth defects. No information was available on the three cases with malformations or if they were thought to have resulted from methotrexate exposure (28).
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 (29). 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 [41]). 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 (30). However, conception occurred 3 months after discontinuance of therapy in one case (31), after 6 months in a second (14), and after 7 months in a third (32). 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 (5). The second infant, delivered at 31 weeks’ gestation, was exposed to methotrexate only during the 12th week of pregnancy (10). 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 (2). 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 (32–34). Several studies, however, have followed individual infants for periods ranging from 2 to 84 months and have not discovered any problems (10–14,16,17).
Methotrexate crosses the placenta to the fetus (15). 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 26–29 weeks’ gestation; the dose was then increased to 20 mg/m2 weekly until delivery at 40 weeks’ gestation. Methotrexate levels in cord serum and red cells were 1.86 × 10–9 mol/L, and 2.6 × 10–9 mol/g of hemoglobin, respectively, with 29% as the polyglutamate metabolite (15).
In the case described above, chromosomal analysis of the newborn revealed a normal karyotype (46,XX), but with gaps and a ring chromosome (15). 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 (15).
Successful pregnancies have followed the use of methotrexate before conception (14,29,31,32,35–41). Apparently, ovarian and testicular dysfunction are reversible (34,42–45). 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 (41,46).
In 438 long-term survivors treated with chemotherapy between 1958 and 1978, 436 received methotrexate either alone or in combination with other antineoplastic agents (41). This report was a continuation of a brief 1979 correspondence that discussed some of the same patients (29). 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 SABs, and 6 EABs. 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 (41).
The 1988 report described the reproductive results of 265 women who had been treated from 1959 to 1980 for gestational trophoblastic disease (46). 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 (47). 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 (48). 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).
BREASTFEEDING SUMMARY
Methotrexate is excreted into breast milk in low concentrations (49). After a dose of 22.5 mg/day, milk concentrations of 0.26 mcg/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, breastfeeding is contraindicated. The American Academy of Pediatrics classifies methotrexate as a cytotoxic drug that may interfere with cellular metabolism of the nursing infant (50).
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