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The effects of methotrexate on pregnancy, fertility and lactation

M.E. Lloyd, M. Carr, P. Mcelhatton, G.M. Hall, R.A. Hughes
DOI: http://dx.doi.org/10.1093/qjmed/92.10.551 551-563 First published online: 1 October 1999

Introduction

Low-dose weekly methotrexate (MTX) is widely used in the treatment of rheumatoid arthritis1 and is now increasingly used in other rheumatic conditions, including systemic lupus erythematosus and juvenile arthritis. Because of its anti-metabolic and cytotoxic actions, questions of its safety in those of childbearing age are likely to become increasingly important. The aim of this review is to aid clinicians in the counselling and education of patients taking or about to start taking low-dose MTX. We examine the effects of MTX with respect to fertility, pregnancy and lactation, based upon information obtained using `Medline' search strategies from 1966 to 1997, hand search through the last ten years of the journal Teratology, source paper references and data from the UK National Teratology Information Service (NTIS) from 1992.

Background

MTX is a derivative of the folic acid analogues. The importance of folic acid, a B group vitamin, in haematopoiesis was realized in the early 1940s, and by 1946 it had been synthesized and given its chemical term, pteroylglutamic acid.2 By the following year, the synthesis, anti-bacterial and anti-metabolic actions of its 4-amino derivative, aminopterin, had been described.3 The megaloblastic appearance of marrow in some cases of leukaemia, similar to that seen in folic acid deficiency, led early researchers to speculate that folic acid analogues could be useful in treating this form of malignancy. Paradoxically, it was found that a folate-deficient diet could cause depletion of leukaemic cell lines, which led to the use of the competitive analogues in haematological malignancies.4

In 1951, aminopterin was used for the first time for patients with a connective tissue disease, with six out of seven patients with rheumatoid arthritis experiencing some benefit. The authors commented, `The toxic effects of aminopterin place practical limitations on its use as a therapeutic agent'.5

MTX (amethopterin) is a methyl-derivative of aminopterin and was first described in 1947.3 Work suggesting MTX had a wider therapeutic index than aminopterin when used in mice led to rapid ascendance over its predecessor.6 Like aminopterin, MTX is both a folate analogue and a folate antagonist. Because folates are used in the transfer of one-carbon units, they are crucial to the synthesis of purines, thymidine and amino acids. The enzyme dihydrofolate reductase (DHFR) is reversibly inhibited by MTX. DHFR reduces folic acid to tetrahydrofolic acid, and MTX therefore limits the availability of one-carbon fragments necessary for the synthesis of purines, and interferes with the conversion of deoxyuridylate to thymidylate in the synthesis of DNA and cell reproduction.7 MTX is further metabolized to MTX polyglutamases, long-lived metabolites which also inhibit other folate-dependent enzymes. It has been suggested that the efficacy of MTX may be related to these latter effects.8

The precise molecular mechanism by which MTX suppresses inflammation is unknown, but it has effects on endothelial cell growth, chemotaxis, polyamine synthesis, neovascularization and various cytokine activities, as well as suppressing the generation of inflammatory mediators, such as lipoxygenase products.9 On a cellular level, animal studies have shown that MTX causes cells to arrest in metaphase.10

Methotrexate in pregnancy

Folic acid deficiency in pregnancy

Folic acid is required for normal development, and its deficiency may be harmful in pregnancy. If the actions of MTX are mediated via inhibition of folic acid, then folic acid deficiency occurring in pregnancy may give clues to the effect of MTX on the fetus.

Animal studies

The importance of folic acid in embryonic development was soon realized. Initial work using rats showed that folate deficiency had a lethal effect on embryos; the number dying being directly related to the duration of deficiency prior to conception.11 Further rat studies showed that folic acid deficiency could also cause embryonic deformities, the most common being cleft palate and limb abnormalities. As would be expected, folate deficiency after the thirteenth day of a 21-day gestation (i.e. after the critical period of organogenesis) was associated with a marked reduction in the number of abnormalities.12 Closed neural tubes but poor brain development were seen in rat embryos cultured on folate-deficient serum,13 and neural tube defects have been demonstrated in embryos of folic-acid-deficient rats.14 The effect of folic acid deficiency on the fetus appears to be species-dependent. Mice fed varying amounts of folic acid showed an apparent threshold for fetal resorption without the development of abnormalities. This pattern of abortion rather than abnormality suggests either the presence of major fetal abnormalities leading to abortion, or a specific abortifacient effect.15

Human studies

It was not until the 1960s that a role for folic acid deficiency was suspected in human neural tube defects (NTD). These defects include anencephaly, meningocele, myelomeningocele, encephalocele and spina bifida cystica. In 1965, it was suggested that women with lower levels of folic acid had a higher incidence of fetal abnormalities, particularly those of the central nervous system.16 Later studies showed that levels of red-cell folate, directly measured, were lower in women who had given birth to babies with CNS defects.17

As a result of these studies, intervention trials were performed to look at the effect of folic acid supplementation in pregnancy. Initially these were inconclusive, with some showing a protective effect18,,19 and others not.20 The issue appeared to be resolved in 1991 when a landmark trial confirmed the value of folic acid supplementation in preventing NTD recurrence. Supplementation of 4 mg folic acid daily until the 12th week of pregnancy reduced the risk of a mother having a second child with NTD by 72%. There were 12 other observed abnormalities apart from NTD in pregnancies where women were not given folate supplementation. These included partial deletion of chromosome 18, Downs syndrome, bilateral talipes (two cases), pes equinovarus, hydropic fetus, complex cardiac malformation, Kleinfelter's syndrome, cervical hygroma and adrenal hamartoma.21

The protective effect of folic acid in the primary prevention of NTD has also been suggested by a large trial of 4156 women randomized to receive either a trace element tablet or vitamin mineral tablet containing 0.8 mg folic acid. There were no NTD in the vitamin mineral group and six in the control group.22 However, the trial design was such that the effect of folic acid alone could not be proven.

Although trial evidence strongly supports the role of folic acid supplementation in the prevention of NTD, it has been difficult to confirm that folic acid deficiency produces NTD in humans. Most studies have shown only small or no differences in RBC folate levels between women with affected and unaffected pregnancies and no difference in dietary folate in women with affected pregnancies. Although the UK has one of the highest rates of NTD in the world, the UK diet is not particularly low in folate, daily intake in UK women being similar to that in US women (0.4 mg/day), but more than in Canadian women.23 It is possible that the range of folic acid intake and levels in the population may be too small for differences to be detected in studies to date,24 or that the effect of folate deficiency in NTD is not direct. The influence of other factors has been suggested, in particular homocysteine, as high levels, possibly secondary to reduced methionine synthase activity, have been noted in women carrying a fetus with NTD.25 As a result of this body of evidence, folic acid supplementation is now routinely advised in the first trimester of pregnancy.

Folic acid antagonists in pregnancy: animal studies

Embryonic growth delay induced by folic acid antagonists was first described in chickens.26 Later work in this species suggested that the limb abnormalities seen were caused by transient inhibition of cell division, rather than by cell death.27 Further studies suggested species-specific effects, with embryotoxicity in cats, and embryotoxicity and teratogenicity in rats, mice and rabbits. The latter two species appeared relatively resistant.28,29,,30 MTX has been compared in rat and rhesus monkey pregnancy. Twenty-five monkeys were given MTX at different dosages and durations (gestation days 17–45). Only one showed evidence of embryotoxicity, with evidence of abnormal ossification of long bones and thoracic vertebrae. In the rats, malformations were `largely confined to caudal vertebrae' in up to 75% of fetuses following MTX exposure between day 9 and 11 of a (presumed) 21-day gestation.31 Work in rabbits showed that MTX administration on days 8 and 9 led to universal litter resorption, but that administration on days 10, 11 or 12 caused abnormalities, including hydrocephalus, microphthalmia, cleft lip and palate and dysplastic vertebrae. Administration from day 12 to day 15 caused mainly distal limb dysplasias.30

When rabbits were injected with MTX (19.2 mg/kg) on day 12 of gestation, 94% of fetuses were malformed, the commonest abnormalities being (in order) limb and digit abnormalities, micrognathia, cleft palate and hydrocephalus. Prior treatment with a compound capable of transferring one-carbon units led to some protection against abnormalities, suggesting that impaired one-carbon transfer may be the fundamental cause of the fetal abnormalities seen with MTX.32

Folic acid antagonists in pregnancy: humans

The aminopterin syndrome

The first suggestions that folic acid antagonists were teratogenic in humans were based on the reports of failed terminations in mothers given aminopterin in the first trimester (Table 1). All reports of abnormality include neural tube, skull or limb problems, with gestational ages at exposure ranging from four to 12 weeks.

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Table 1

Abnormal fetuses in pregnancies complicated by exposure to aminopterin

AuthorCaseAgeIndicationGestational age of exposureTotal exposure dosageGestation at birthAbnormalities
Thiersch 195277126Abortion7 weeks10 mg67 daysMeningoencephalocele
222Abortion5 weeks10 mg70 daysHydrocephalus
336Abortion7 weeks15 mg112 daysCleft palate and hare lip
Thiersch 1956784?Abortion4–6 weeks12 mgFull termAnencephaly
Melzer 195679525Abortion6–8 weeks20 mgFull termMalformed occipital bone with lacunar formation; synostosis lambdoid sutures; very wide posterior fontanelle; left talipes equinovarus
Warkanay 195980627Abortion10–12 weeks12 mgFull termAbsent ossification of parietal bones; rudimentary frontal and temporal bones, only partial ossification of frontal bones; synostosis of hands and feet; abnormal postures
Emerson 196281723Abortion6–8 weeks29 mg24 weeksAbsent parietal bones; rudimentary horn ossification of temporal and frontal bones; hydrocephalus and cerebral hypoplasia; right talipes equinovarus
Goetsch 1962828?Abortionc. 9 weeksc. 12 mgc. 15 weeksGross multiple abnormalities
Shaw 1968831128Abortion7–8 weeks?39 weeksIncomplete skull ossification, poorly developed orbital ridges, hypognathia, high arched palate, small low set ears, shortened and deformed radii and ulnae, low IQ, `back-combed' appearance to hair
Alvarez 1962 in Goetsch829????Full termHydrocephalus
10????Full termHydrocephalus
Reich 1978841329Abortion8–12 weeks?Full termHydrocephalus, ossification defects parietal region, hypertelorism, short philtrum, micrognathia, low set ears, syndactyly feet, hypoplastic toes, brachydactyly fingers
14?Abortion6–8 weeks?Full termCleft palate, hypertelorism, low set ears

The pattern of abnormalities seen in these case reports gave rise to the description `aminopterin syndrome'.33 Although widely mentioned in the literature, the only other full description of the `syndrome' is given by Buckley et al.34 (Table 2), using many of the features described by Powell.35 Dextrocardia, however, does not appear to be a common feature in the cases reported.

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Table 2 

The aminopterin syndrome

Description from reference 34.
CNS abnormalitiesSpina bifida
Mental retardation
Hydrocephaly
Anencephaly
Skeletal abnormalitiesSynostosis of lambdoid sutures
Partial or absent ossification of bones
Micrognathia
High or cleft palate
Short extremeties
Wide set eyes
Syndactyly of fingers
Absent digits
Club foot
Large fontanelles
Wide set nasal bridge
Cardiac abnormalitiesDextrocardia

Methotrexate in malignant conditions

MTX is a common constituent of multi-drug regimens in malignancies, in particular leukaemias and lymphomas. Table 3 includes all reports of MTX in pregnancy that we have been able to find. Included in the table are 47 cases of fetal exposure in malignant conditions, of which 19 occurred during the first trimester. Of these, two cases developed physical abnormalities. In the first case, treatment with MTX (50 mg weekly between 8 and 32 weeks gestation) for hydatidiform mole resulted in an abnormal fetus born at 34 weeks. The abnormalities were hydrocephalus, hypoplasia of frontal and orbital bones, micrognathia and hypertelorism.36 A recent report by Bawle et al. describes three patients with MTX-associated abnormalities. One of these was exposed to 5-fluorouracil and high-dose MTX (total 480 mg) from the seventh week of gestation, because of maternal breast cancer. A male child survived, with microcephaly, hypertelorism, low set ears and up sweep of the frontal hairline, but normal extremities.101 The NTIS has data on a patient treated with combined chemotherapy (MTX, chlorambucil, 5-fluorouracil, prednisolone) in the first trimester who gave birth at 28 weeks to a child with a normal karyotype but multiple abnormalities, including dysmorphic features, short proximal limbs, low set ears, small chin and mouth, mongoloid slant and a systolic heart murmur.

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Table 3 

All cases of methotrexate exposure during pregnancy with known fetal outcome

AuthorNumber of exposed fetusesTrimester of exposureNumber of affected fetusesIndication
Kozlowski375First0RA, juvenile RA, angiitis
Donenfield405First (4 cases), third0Breast carcinoma (1 case), RA (2 cases), infection (1 case), unknown (1 case)
Buckley341First1 (skull, hand, spine, cardiac, palate)RA
Powell351First1 (skull, hands)Psoriasis
Diniz361First1 (skull, including hydrocephalus)Hydatidiform mole
Feldkamp381First0RA
Milunsky391First1 (skull, hands, feet)Abortion
Sokal412Second, third0Leukaemia
Rubaltelli426Third2 (developmental)Cancer (2 cases), rhesus iso-immunization
Okun451 (intrathecal)First0Leukaemia
Lowenthal461 (intrathecal)Second0Lymphoma
Krueger471 (intrathecal)Third0Leukaemia
Schleuning591 (intrathecal)Second, third0Leukaemia
Aviles679First (8 cases), second (1 case)0Leukaemia
Aviles686First (4 cases), second (2 cases)0Leukaemia
Freedman852 (twins)Second0Choriocarcinoma
Turchi861Second0Leukaemia
Blatt871Third0Leukaemia
Awidi881Second0Leukaemia
Karp891 (intrathecal)Second0Leukaemia
Coopland901Second0Leukaemia
Berrebi911Third0Lymphoma
Dara921First0Leukaemia
Khurshid931Second0Leukaemia
Burnier941Second0Leukaemia
Doney951Third0Leukaemia
Feliu962First0Leukaemia
Frankel971Second0Leukaemia
Yahia981Second0Leukaemia
Spunberg991First0Brain tumour
Pizzuto1005First (4 cases), second (1 case)0Leukaemia
Bawle1013First3 (i) skull, (ii) skull, (iii) skull, hands, feetBreast cancer, termination
NTIS4First3 (i) skull, limbs, heart, (ii) RDS, ileal perforation, (iii) skull, limbChemotherapy, RA, psoriasis, scleroderma (normal child)

A further two cases of severe intellectual impairment following high-dose MTX treatment after the thirtieth week of pregnancy (for uterine cancer and sarcoma) are described below.

Low-dose methotrexate

There have been several reports of pregnancies complicated by the administration of MTX in the treatment of inflammatory conditions (Table 4).

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Table 4 

Fetal outcome in pregnancies complicated by the administration of low-dose methotrexate

AuthorCaseAgeIndicationAdditional folic acidDoseGestational duration of exposure Total doseOutcomeFetal abnormalities
Milunsky 196839123AbortionNo2.5 mg daily8–10 weeks (approx)12.5 mgLive birth 35 weeksAbsent coronal and lambdoid sutures, oxycephaly, wide posterior fontanelle, frontal bone absent, all toes but one absent, partial bilateral syndactyly
Powell 197135240Psoriasis?5 mg daily0–8 weeks300 mgLive birth at 39 weeksOxycephaly, large anterior fontanelle, fusion of coronal sutures, wide metopic suture, webbing between fingers
Koslowski 199037329?Yes7.5 mg weekly0–3 weeks22.5 mgFull-term live birthNone
433?No7.5 mg weekly0–12 weeks90 mgFull-term live birthNone
540?No7.5 mg weekly0–2 weeks15 mgFull-term live birthNone
624?Yes7.5 mg weekly0–2 weeks15 mgFull-term live birthNone
728?Yes7.5 mg weekly0–15 weeks112.5 mgFull-term live birthNone
829?Yes10 mg weekly0–9 weeks90 mgSpontaneous abortion
922?Yes7.5 mg weekly0–8 weeks60 mgSpontaneous abortion
1022?Yes7.5 mg weekly0–4 weeks30 mgSpontaneous abortion
Feldkamp 1993381139RANo7.5 mg weekly0–5 weeks (approx)37.5 mgFull-term live birthNone
Donnenfield 1994401235RA?Not known (5 tabs)3–5 weeksNot knownLive birth at 36 weeksNone
1338??7.5 mg weekly0–2 weeks15 mgFull-term live birthNone
1431RA?7.5 mg weekly0–3 weeks22.5 mgFull-term live birthNone
Buckley 1997341520RAPossibly10–12.5 mg weekly0–8100 mgLive birth at 35 weeksIUGR, brachycephaly, retrognathia, ear malformation, bifid uvula, dorsal kyphosis, two hemivertebrae, syndactyly, multiple cardiac abnormalities. Died at 6 months of chest infection
NTIS16?RA?No7.5 mg (single dose)4–7 weeks7.5Emergency LSCS at 28 weeks (placenta praevia)Positive sweat test for cystic fibrosis. Ileal perforation. Mild respiratory distress. Severe lung disease
17?SclerodermaNo10 mg twice weekly0–6 weeks (probable)120 mgNormal babyNone
18?PsoriasisNo20 mg weekly0–19 weeks380 mgTermination at 19 weeks(From fetal scan) Brachycephaly, depressed nasal bridge, short right femur

The cases described by Koslowski et al. include six patients with RA, one with juvenile RA and one with allergic angiitis.37

Feldkamp suggests that the threshold dose of MTX required to produce defects is 10 mg weekly, and that the vulnerable period of gestation is between 6 and 8 weeks. Using this concept, they successfully advised a patient to continue her pregnancy.38 The patient reported by Milunsky et al. had a `grossly irregular' menstrual cycle, but the gestational age of exposure was 8 to 10 weeks, rather than the 6 to 8 suggested by Feldkamp.39

Donnenfield used information from 63 centres participating in the prospective evaluation of fetal abnormalities, and felt that the data obtained supported the observations of Feldkamp in that the gestation period of 6 to 8 weeks was a critical period in methotrexate teratogenesis, and that a critical weekly dosage was >10 mg.40 These assumptions remain speculative.

Buckley et al. report the only case of fetal abnormality seen in a patient taking weekly low-dose MTX. Skull, limb, digit, vertebral and cardiac abnormalities were seen; the only other medication taken by the mother was a non-steroidal anti-inflammatory drug.34

The NTIS have been informed about five pregnancies involving exposure to low-dose (<20 mg/ week) MTX, all of which occurred in the first trimester. Three pregnancies were terminated: in two there is no data on fetuses or abortuses. In the third, an abnormal fetus (brachycephaly, depressed nasal bridge, short right femur) was aborted at 19 weeks. The mother had been treated with 20 mg MTX weekly for psoriasis. A woman received one dose of 7.5 mg MTX for rheumatoid arthritis sometime between 4 and 7 weeks gestation. An emergency caesarean section for placenta praevia was performed at 28 weeks, and the baby had a number of abnormalities: respiratory distress syndrome, positive sweat test for cystic fibrosis, and ileal perforation. One baby probably exposed to MTX 10 mg twice weekly between 0 and 6 weeks gestation in a mother with scleroderma was born normal.

Methotrexate in late pregnancy

Donnenfield reports a healthy baby born following exposure to 42 mg intravenous MTX at between 37 and 38 weeks gestation. No details of fetal blood counts are given, although the baby developed pneumonia at one month of age.40 There are a further two cases of MTX given in association with 6-mercaptopurine, one at 7.5 to 8.5 months gestation and one at 4 to 5 months gestation. No abnormalities were seen in the fetuses, who were followed up for over 1 year.41 Rubatelli reports two cases of severe psychological abnormality in fetuses exposed in the third trimester;42 this would be compatible with the known general effects of drugs in causing growth retardation and functional abnormalities in fetuses exposed in the later stages of pregnancy.

Other cases

Two other cases described by Bawle involved MTX exposure secondary to attempted termination. The first was exposed to MTX 100 mg bi-weekly from 11 to 17 weeks post conception, and 200 mg bi-weekly from 17 to 23 weeks. The living male child had a bulging forehead, bitemporal narrowing, low set ears, broad nasal tip and a high arched palate. Psychomotor development was normal. The second case was exposed to an unknown amount of MTX within 6 weeks post-conception. Abnormalities included hypertelorism, abnormalities of the bones at the base of the skull, low set ears, subluxed radial heads and syndactyly of the fingers. Psychomotor development was normal.101 In an ultrasonographic study of at-risk pregnancies, 2/14 fetuses exposed to `antifolate drugs' were found to have open spina bifida. No other details of the drugs involved are given.43

In a large review of drugs in pregnancy, Roubenoff et al.44 reference 13 apparent cases of fetal exposure to MTX,35,39,41,45–,48 including two resulting in abnormality.35,,39 However, the two cases described by Sokal41 are also included in the report by Nicholson.48 Elsewhere in the article, the authors estimate a fetal abnormality rate of 3.4% (95% CI 1.7–6.3), based on 10 abnormal births out of a total of 290 exposures. The source data for the latter figures is not clear.

In addition to the cases detailed above, the NTIS has been informed of three other cases of in utero MTX exposure which have been lost to follow-up.

The Medicines Control Agency has reports of three abnormal fetuses resulting from single-agent MTX exposure between 1963 and 1997. The abnormalities are described as hydrocephalus, nail disorder and multiple congenital abnormalities. No details regarding gestational age at exposure, background disease or dose are available.

Methotrexate exposure before conception

After administration, methotrexate is widely distributed in body tissues, the highest concentrations being in the kidneys, gallbladder, spleen, liver and skin. Its presence in the liver has been reported up to 116 days after exposure, although the amount of drug retained does not appear to be related to the dose received.7,,49 There is thus a theoretical risk of fetal exposure in babies of mothers who have taken the drug up to 4 months prior to conception. Table 5 summarizes the largest prospective study of pregnancy outcome in women on MTX prior to conception.40 It is also the only study where low-dose MTX was used within 1 year of pregnancy. A high rate of spontaneous abortion is seen (as mentioned above), but there were no abnormalities of surviving fetuses. However, the numbers (nine in total) are small. A study looked at 368 pregnancies in 210 women who had had single- and combined-agent chemotherapy for gestational trophoblastic tumours over a 20-year period. All patients were given MTX, followed in the majority by folinic acid. The mean duration between cessation of treatment and pregnancy was 2.7 years, the mean cumulative dose of MTX around 1.2 g, and the maximum dose over 6 g. Abnormalities included two anencephalic stillbirths, and one case each of spina bifida, tetralogy of Fallot, talipes equinovarus, collapsed lung and umbilical hernia. One child of a mother who had received MTX developed desquamative fibrosing alveolitis 1 month after birth. The mother later gave birth to a healthy child, but 3 years later, a further child suffered the same problem. In the study overall, there was a slightly higher but statistically insignificant incidence of stillbirth and congenital abnormality compared to the expected background rate.50 In an earlier report of a smaller number of patients, presumably from the same sample, the authors describe four cases of abnormality in 130 women who had received MTX alone. The abnormalities were: umbilical hernia, doliocephaly plus talipes, anencephaly and fibrosing alveolitis. Again, the fetal wastage rate was not raised.51 These authors, from an oncology unit, advise delaying conception for a year after the cessation of chemotherapy. This advice differs from manufacturer's recommended `washout period' before MTX cessation and conception, which varies between 3 and 6 months.52 In order to allow for the persistence of MTX in tissues and to avoid potential chromosomal damage to the dividing follicle, a minimum delay of 6 months would seem logical.

View this table:
Table 5 

Case reports of low-dose methotrexate treatment prior to conception

CaseAgeIndicationWeeklyTotal dosageExposure timeOutcome
Data from reference 40. RA, rheumatoid arthritis; LMP, last menstrual period; FT, full term; SA,spontaneous abortion; NK, not known.
128RA12.5 mg0.5 g10 months (up to 2 weeks prior to LMP)FT, healthy
226RANK3 doses: 34 days prior to LMP, 29 days prior to LMP, 21 days prior to LMPSA 11 weeks
334Psoriasis7.5 m2.3 g6 years up to 28 days prior to LMPSA 9 weeks
425RA7.5 mg0.39 g1 year, up to 28 days prior to LMPFT healthy
532RA7.5 mg0.39 g1 year, up to 16 weeks prior to LMPSA 12 weeks
627RA?up to 6 months prior to conceptionSA 5 weeks
729??6 months; up to 10 months prior to conceptionFT healthy
827??6 months, up to 11 months prior to conception?FT; healthy
928Carcinoma, breast?1 year prior to conceptionFT, cavernous haemangioma

There is a theoretical risk of sperm mutation in males treated with MTX. However, a study looking at men with rheumatoid arthritis on low-dose MTX found no significant chromosomal breakage.53 Green et al. report two children with birthmarks (no further details given) and one with a skin tag out of 35 children born to 25 males who had received single and multiple chemotherapy in childhood or adolescence. Two of the abnormal children were born to the 11 men who had received MTX (possibly among other agents).54 There is a case report of a 34-year-old man with Reiter's syndrome who had received intermittent MTX for 5 years, and continuous MTX for 5 months prior to conception, who fathered a normal child.55 As the duration of individual spermatogenesis is approximately 74 days, it would seem sensible to add this figure to the (minimum) 4 months needed for MTX excretion before attempting conception.

Summary of evidence for methotrexate as a possible teratogen

Teratology is a new science and its terminology is being refined. One definition of a teratogenic agent is `one that acts during prenatal life to produce a permanent physical or functional defect in the offspring' and the following criteria have been proposed to help establish the teratogenicity of a substance: (i) proven exposure to agent at critical time(s) in prenatal development; (ii) consistent findings by two or more epidemiological studies of high quality; (iii) careful delineation of the clinical cases, specific defect or syndrome; (iv) rare environmental exposure associated with rare defect, three or more cases probably required; (v) teratogenicity in experimental animals (important but not essential); (vi) the association should make biological sense; (vii) proof in an experimental system that the agent acts in an unaltered state. (i), (ii) and (iii) or (i), (iii) and (iv) are denoted as essential criteria.56 More recent definitions include the complex effects on growth, functional abnormalities, behavioural abnormalities and transplacental carcinogenesis that may result from fetal exposure.

Placental transport of maternal substances is established by the fifth week of embryonic life, and the first trimester of fetal life is the most vulnerable to teratogens. The neural tube closes at approximately day 29 of gestation, and weeks 4–7 are the most sensitive for arm and leg development.57,,58 Exposure to teratogens after the first trimester tends to cause abnormalities in growth and brain development.56 It is not necessary for drugs to cross the placenta in order to exert a teratogenic effect, although MTX is known to pass to the fetus, even after maternal intrathecal administration.59

Table 3 lists all cases of MTX exposure during pregnancy with known outcome found by our search strategy. There have been 71 exposed fetuses, 42 in the first trimester. Twelve cases of abnormality are reported, ten of which involved physical abnormalities. Of these twelve, nine involved skull abnormalities and six peripheral skeletal problems. All cases of definite physical abnormality occurred following first trimester exposure34,35,36,39,,101 (three NTIS cases). Four of the cases involved dosages of <20 mg/week or less, and in none was folic acid definitely co-prescribed. The classical NTD that one might expect to see associated with a folic acid antagonist have not been seen. It may be that the effects of MTX and aminopterin are consequences of general cytotoxicity, and that the abnormalities are in fact `non-specific'. Pregnancies exposed to cyclophosphamide have also resulted in craniofacial defects in monkeys and hand abnormalities in humans.44 However, the patterns of malformation are similar to those seen in fetuses exposed to aminopterin and are comparable to results from some animal models of MTX exposure, particularly in the rabbit. There is no obvious `safe' period of gestational exposure, as the timing of exposure in the four cases resulting in abnormal fetuses runs weeks. The dose effect of MTX appears unpredictable, with extremely large amounts within the first trimester being tolerated by some fetuses and an abnormal fetus being born after exposure to 7.5 mg (NTIS case). Genetic differences in placental and fetal response to toxins may partly explain this. A case is reported of non-identical twins exposed to aminopterin immediately before conception and to cyclophosphamide throughout pregnancy. One twin was born with multiple (including limb) abnormalities, the other healthy.60 Recently a folate receptor has been identified in placental tissue; MTX effects could conceivably be modified by allelic variations.61

Even allowing for the fact that the number of unaffected pregnancies complicated by MTX administration may be underestimated by this review, the fetal abnormality rate appears to be significantly higher than the background rate of 2–3.5%; a rate which rises to around 5% in childhood as less obvious abnormalities are detected.

Folic acid supplementation and methotrexate exposure

Folic acid supplementation at a dose of 400 μg daily (5 mg daily in those with a previous affected fetus) is now recommended to all women in the pre-conception period and during the first trimester.62 A recent review has suggested that women exposed to MTX should continue supplementation (dose not specified) throughout pregnancy.63 In support of this, none of the three cases that we have found in which folic acid supplementation was given with low-dose MTX resulted in fetal abnormality. However, because the affinity of DHFR for MTX is far greater than its affinity for folic acid, complete reversal of the anti-folate effects of MTX requires the administration of folinic acid. When given soon after MTX exposure in pregnant rabbits, leucovirin (a close structural analogue of folinic acid) virtually eliminates teratogenic effects.64 Use of this agent at the equivalent MTX dose (e.g. 7.5 mg weekly if prior exposure was 7.5 mg MTX weekly) may be more logical for at least 4 months following cessation of MTX administration in a woman wishing to continue the pregnancy.

Methotrexate and abortion

Folic acid antagonists are effective in the treatment of trophoblastic cancers in humans. As a result of this, MTX has been used as an abortifacient. A recent study showed that a single high dose of MTX (50 mg/m2) given before 8 weeks gestation causes abortion in over 95% of cases.65 It might therefore be expected that MTX exposure in pregnancy would lead to an increased abortion rate. There is some evidence for this. Out of eight cases of low-dose first-trimester MTX exposure, three cases of spontaneous abortion were reported.37 In a prospective study, there were three pregnancy losses (all first trimester) out of five cases of MTX exposure within 4 months prior to conception.40 Elsewhere in the literature, however, an increased abortion rate is not noticeable. Possible explanations for this are that: (a) early miscarriages are under-reported in this group of women, many of whom are likely to suffer from menstrual irregularities secondary to their underlying condition and treatment and (b) many of the cases of exposure will involve exposure after 8 weeks gestation.

Long-term effects of methotrexate treatment in pregnancy

There is a theoretical risk of chromosomal damage, and therefore cancer and second-generation abnormality risk, in fetuses exposed to cytotoxic agents. Chromosome gaps and a ring chromosome were seen in the child of a mother who received intrathecal MTX among a cocktail of anti-metabolite agents for acute lymphoblastic leukaemia.59 Breaks, gaps, fragments and extra chromosomes have been found in leucocyte cultures from patients on MTX.66 However, larger follow-up studies have not shown definite long-term effects on children, although the number of exposed fetuses is small. Koslowski followed up exposed babies for a mean of 11.5 years; no abnormalities developed other than a minor speech impediment which resolved with speech therapy.37 Cohen67 found no increased cytogenetic abnormality in seven children born to mothers who had received MTX and/or actinomycin D prior to pregnancy. Two studies looking at total of 59 children exposed in a range of trimesters (including 14 exposed to MTX) for up to 22 years showed no apparent adverse effects. Assessment included neurological and psychological testing (with comparison against a control group). Chromosomal analysis from marrow samples in the exposed children showed no abnormalities.68,,69 A large study looked at 2308 offspring of survivors of child and adolescent cancer, 25% of whom were treated with chemotherapy. Details of the type of chemotherapy are not given, but no increased risk of cancer was seen, although follow-up was limited to the second decade of life.70 Six cases of high-dose MTX given after the 28th week of gestation are reported. After a follow-up of 13 years, two children showed grossly disturbed psychological development, though normal physical development. In both of the affected cases the mothers had died shortly after birth from cancer. Four other children whose mothers had been treated with similar MTX regimens were unaffected.42

Although there is a theoretical risk of chromosomal aberration causing long-term effects in babies exposed to MTX in utero, the studies to date do not confirm the risk. However, follow-up time is limited. Most of the small amount of data comes from cases in which oncological doses of MTX were used; the risk with low-dose MTX (which has not been shown to be associated with an increased risk of neoplasia71) may be less.

Methotrexate and fertility

The risk of infertility appears low even after high-dose MTX. One review reports a 97% conception rate in women 1 year or more after cessation of MTX treatment.50 Oligospermia has been reported in association with MTX treatment,72 but a detailed study looking at a small number of men and women during and after high-dose MTX treatment (up to 400 g) for osteosarcoma showed no long-term effect on ovarian or testicular function.73 A further study reported 26 psoriatic males who had semen analysis before treatment and 70 days after MTX 25 mg weekly for 10 weeks. Five subjects also had testicular biopsies. There was no difference in sperm count, mobility or abnormal forms, and no abnormality was seen in the biopsies.74

On the basis of the limited data available, fertility after low-dose MTX would seem to be only marginally affected.

Methotrexate and breast feeding

MTX is excreted into breast milk in low concentrations; MTX concentrations in milk are less than 10% of those in plasma.75 It is not known whether these small amounts are potentially harmful to the developing child. In the absence of a clear evidence base, and because there is a danger of accumulation within fetal tissues, paediatric advice suggests avoidance of MTX during breast feeding.76 This advice seems logical.

Conclusions

MTX demonstrates significant teratogenicity. Skull and limb abnormalities are most frequent. The effects are unpredictable, making counselling difficult in individual cases. Depending on the condition being treated and the age of the mother the risk of abnormality and its consequences may be seen as acceptable.

Women wishing to continue with a pregnancy following exposure to MTX in the first trimester can be informed that there is a 10/42 chance of abnormality in the fetus on the basis of data from cases of MTX exposure. Four out of 13 cases of low-dose (<20 mg/week) exposure have resulted in abnormal fetuses. This incidence of abnormality is at least twice that seen following anti-convulsant exposure, where women are given an overall risk of malformation of around 10%.

In cases of MTX exposure, the drug should be stopped and women wishing to continue the pregnancy should, following counselling, be offered treatment with folinic acid for at least 5 months in order to minimize MTX effects on the fetus.

Women should be warned that there may be a small increased risk of spontaneous abortion early in pregnancy, and advised against taking MTX if they are considering conception. Those who choose to stop MTX and proceed to pregnancy should be advised against conception within 6 months of taking MTX. In the event of conception within this time, full counselling and close fetal monitoring should be offered.

MTX treatment is unlikely to have a major effect on short- or long-term fertility in men and women, but a washout period of 6 months cessation of treatment prior to conception is advisable to prevent the small chance of chromosomal abnormalities in offspring.

Breast feeding in mothers taking MTX will lead to infant MTX exposure and should be avoided.

With the increasing use of MTX in the rheumatic diseases and other inflammatory conditions, it is essential that all cases of MTX exposure in pregnancy are reported to central surveillance bodies to provide a complete picture of the teratogenicity of MTX. In the UK, this is the National Teratology Information Service, which also now monitors CSM reporting. Exposed children and their offspring should be monitored closely in the long term for the development of delayed neoplasms or second-generation congenital defects.

References