UNDP/UNFPA/WHO/World Bank Special Programme of Research, Development and Research Training in Human Reproduction A review of the toxicology ofmethotrexate combined with misoprostol for termination of early pregnancy found that: (1) methotrexate is teratogenic in both animals and humans, and 12) some data suggest thatmisoprostol maybe a human teratogen. The combined regimen ofmethotrexate and misoprostol fails to interruptpregnancy in about fourper cent of cases. Sen’ous congenital abnormalities have been observed in several of these continuingpregnancies. Because of possible risks to the woman’s health and the potential birth ofinfants with severe congenital abnormalities if treatment fails and thepregnancyis carried to term, the use ofmethotrexate as a non-surgical method for first trimester termination ofpregnancy cannot be recommended. This paper summarises the review and the Panel’s comments. ETHOTREXATE is a folic acid antago- nist and an anti-metabolite, and is the methyl derivative of aminopterin. It is used mainly in the treatment of certain cancers, severe psoriasis and adult rheumatoid arthritis. Experimental teratology began with the obser- vations that maternal vitamin A and riboflavin deficient diets resulted in ocular and skeletal malformations in pigs and rats1 Subsequent research demonstrated that folate deficient diets supplemented with antibiotics or anti-metabolites resulted in congenital malformations.z,3 In the early 195Os, fetal death and absorption in rats and mice were reported following the administration of small doses of aminopterin, a folic acid antagonist, in early pregnancy.4 This led to the use of aminopterin for the induction of abortion in women with advanced tuberculosis or malignant disease. After several variations of administration and of drugs, Thiersch concluded that the folic acid antagonists were too uncertain to induce abortion unless in case of failed use surgical intervention could be carried out’ .5 However, aminopterin continued to be used as an abortifacient, including unsupervised use. Between 1956 and 1972, there were a number of publications on fetal malformations associated with the use of aminopterin.6-12 There were striking similarities between the nature of the malformations described, which led to their compilation as the fetal aminopterin syndrome. This consists of cranial dysplasia, broad nasal bridge, low-set ears, and limb anomalies. Methotrexate has been used since 1962 for the induction of abortion,13 and recently has been combined with the prostaglandin analogue misoprostol for this purpose. Pharmacological aspects Methotrexate interferes with DNA synthesis, repair and cellular replication. Actively prolifer- ating tissues such as malignant cells, bone marrow, fetal and trophoblastic cells, buccal and intestinal mucosa and cells of the urinary bladder are in general most sensitive to this effect of methotrexate. Details of the clinical pharmacology, pharma- cokinetics, metabolism, half-life and excretion of metbotrexate are contained in references.1417 Small amounts of methotrexate may remain in tissues for extended periods. The retention and prolonged drug action of these active meta- bolites vary among different cells, tissues and tumours. Human teratology Not all anti-folate compounds seem to have the same toxicity; therefore reports of malforma- tions with aminopterin cannot be directly extrapolated to methotrexate (Berry 1996, personal communication). 162
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UNDP/UNFPA/WHO/World Bank Special Programme of Research, Development and Research Training in Human Reproduction
A review of the toxicology ofmethotrexate combined with misoprostol for termination of early pregnancy found that: (1) methotrexate is teratogenic in both animals and humans, and 12) some data suggest thatmisoprostol maybe a human teratogen. The combined regimen ofmethotrexate and misoprostol fails to interruptpregnancy in about fourper cent of cases. Sen’ous congenital abnormalities have been observed in several of these continuingpregnancies. Because of possible risks to the woman’s health and the potential birth ofinfants with severe congenital abnormalities if treatment fails and thepregnancyis carried to term, the use ofmethotrexate as a non-surgical method for first trimester termination ofpregnancy cannot be recommended. This paper summarises the review and the Panel’s comments.
ETHOTREXATE is a folic acid antago- nist and an anti-metabolite, and is the methyl derivative of aminopterin. It is used mainly in the treatment of
certain cancers, severe psoriasis and adult rheumatoid arthritis.
Experimental teratology began with the obser- vations that maternal vitamin A and riboflavin deficient diets resulted in ocular and skeletal malformations in pigs and rats1 Subsequent research demonstrated that folate deficient diets supplemented with antibiotics or anti-metabolites resulted in congenital malformations.z,3
In the early 195Os, fetal death and absorption in rats and mice were reported following the administration of small doses of aminopterin, a folic acid antagonist, in early pregnancy.4 This led to the use of aminopterin for the induction of abortion in women with advanced tuberculosis or malignant disease. After several variations of administration and of drugs, Thiersch concluded that the folic acid antagonists were too uncertain to induce abortion unless in case of failed use surgical intervention could be carried out’.5 However, aminopterin continued to be used as an abortifacient, including unsupervised use. Between 1956 and 1972, there were a number of publications on fetal malformations associated with the use of aminopterin.6-12 There were striking similarities between the nature of the malformations described, which led to their
compilation as the fetal aminopterin syndrome. This consists of cranial dysplasia, broad nasal bridge, low-set ears, and limb anomalies.
Methotrexate has been used since 1962 for the induction of abortion,13 and recently has been combined with the prostaglandin analogue misoprostol for this purpose.
Pharmacological aspects Methotrexate interferes with DNA synthesis, repair and cellular replication. Actively prolifer- ating tissues such as malignant cells, bone marrow, fetal and trophoblastic cells, buccal and intestinal mucosa and cells of the urinary bladder are in general most sensitive to this effect of methotrexate.
Details of the clinical pharmacology, pharma- cokinetics, metabolism, half-life and excretion of metbotrexate are contained in references.1417 Small amounts of methotrexate may remain in tissues for extended periods. The retention and prolonged drug action of these active meta- bolites vary among different cells, tissues and tumours.
Human teratology Not all anti-folate compounds seem to have the same toxicity; therefore reports of malforma- tions with aminopterin cannot be directly extrapolated to methotrexate (Berry 1996, personal communication).
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In 1968, a case report cited congenital abnor- malities associated with the use of methotrexate between the eighth and tenth week of pregnancy at a dose of 2.5 mg daily for five days in an unsuccessful attempt to self-induce an abortion.13 The infant was born with flattened facies, broad nasal bridge, prominent eyeballs and under- developed supraorbital ridges. She had bilateral epicanthic folds, hypertelorism, micrognathia, high arched palate and marked oxycephaly. There was a deficient frontal bone and an irregularly grooved occipital bone together with absent coronal and lambdoid sutures. The ears were low- set and abnormally shaped. The neck was short with multiple skin folds and a low posterior hair line. Simian creases were present on both hands and the thumbs were short. There was partial bilateral syndactyly of the third and fourth fingers, no digits on the right foot and only one toe on the left. These findings are very similar to those described as the fetal aminopterin syndrome.
In 1971, Powell and Ekert described a case in which a woman with psoriasis received 35 mg of methotrexate weekly between O-8 weeks of gestation. The infant, delivered at 39 weeks, had oxycephaly, fused coronal sutures, facial abnor- malities and webbed digits.‘*
Diniz et al reported a case of resistant hydatidiform mole that was inadvertently treated from 8-32 weeks of gestation with 50 mg weekly of methotrexate. The infant, delivered at 34 weeks’ gestation, had hydrocephalus, hypo- plastic frontal and orbital bones, micrognathia, hypertelorism and short limbs.1g
Although Warkany says: ’ . . . it can be stated that folic acid antagonists aminopterin and metho- trexate administered in early pregnancy have been clearly established as teratogens in human be- irIgs,’ this has been questioned by some authors. A number of authors have reported on metho- trexate given in early pregnancy with a healthy normal infant being born subsequently.21-23
These normal pregnancy outcomes occurred in subjects where the methotrexate exposure was before the proposed critical timing for the development of the aminopterin syndrome or the methotrexate equivalent (6-8 weeks post conception).21 In addition, in two of the preg- nancies reported by Donnerfeld et al where the exposure dosages were available, the dose received was less than the ‘proposed critical level of 10 mg/week’.*’ The critical period of
6-8 weeks post-conception is borne out by data from the publications on aminopterin- associated malformations. The majority of the women with failed abortion attempts delivered infants with aminopterin syndrome and most of the maternal exposure included the sixth to eighth week post-conception.21
It is worth noting that methotrexate is retained for several weeks in the kidney and for several months in the liverI and that the effects of methotrexate exposure prior to conception are not well established. In five pregnancies where exposure ceased 2-16 weeks prior to the onset of the last menstrual period, there were three spontaneous abortions at 9, 11 and 12 weeks and two full-term normal infants.‘*
Methotrexate in the management of ectopic pregnancy Methotrexate administered directly into the gestational sac has been used in the conservative treatment of intra-tubal pregnancy for the past ten years or SO.*~-*~ In other reports, the methotrexate was given by intramuscular injection. Folic acid was given on the first day of each course or at the end of the treatment. Elevated liver enzymes have been reported,27-34 as well as stomatitis,27,28,31-36 gastroenteritis,2g nausea,2g dermatitis 2g myelo- I suppression30 and pleuritis.28 These side effects were seen in up to 11 per cent of subjects but were much less common with single dose regimens3’ It should be noted that idiosyncratic side effects such as pneumonitis can occur following local administration of a methotrexate dose as low a 12.5 mg.38 For details of doses and routes of administration of methotrexate in the manage- ment of ectopic pregnancy, see 1391.
Two cases of life-threatening neutropenia following methotrexate treatment of ectopic pregnancy have been documented.40 In both cases pretreatment laboratory values, including white cell count, were within normal limits. Both subjects were admitted to hospital with stoma- titis, pyrexia and life-threatening neutropenia.
Methotrexate for termination of intrauterine pregnancy In 1992, methotrexate was used to induce an abortion in a patient with multiple uterine leiomyomata. 41 In this case, a total of 50 mg of methotrexate was injected directly into the amniotic fluid and into the placenta. In 1993. data
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from ten subjects given methotrexate and oral mlsoprostol were published.42 Since this publi- cation, there have been reports of seven more series of subjects (total 529 pregnancies) who received this treatment regimen.43-4g
Pregnancy duration at induction of abortion was variously ~42 days43, ~56 days,4Z,4547,4g ~63 days‘@, or 57-63 days.% In almost all cases, misoprostol was given 3 to 8 days after metho- trexate, and repeat doses of misoprostol given from 1 to 5 days after the first dose if no abor- tion had occurred.44-4g Surgical abortion was available at the woman’s request in all studies.
In one of the larger of these series (100 women), there was 1 incomplete abortion, 7 continuing pregnancies. Only 48 abortions were complete by day 5, 84 by day 28 and 89 by day 44.4g In another of similar size (101 women), there was 1 incomplete abortion, 1 continuing preg- nancy, and 98 complete abortions by day 14.47
In the largest of the series (178 women) there were no continuing pregnancies,48 while in a smaller series (46 women) 9 per cent were continuing.46 In the 529 total pregnancies the overall rate of continuing pregnancies was 3.6 per cent. In 3 of the 13 cases of incomplete abortion, surgical intervention was required for heavy vaginal bleeding. Other adverse side effects reported following methotrexate included nausea, stomatitis, vomiting, diarrhoea, head- ache, dizziness and mild abdominal cramping. Side effects were not stated for two studies.
Human teratogenicity In one of the series mentioned above, the pregnancies were less than 8 weeks’ duration and the women were given 50 mg/m2 of methotrexate.4g At subsequent surgical aspira- tion of the 7 continuing pregnancies, it was possible to examine the products of conception of three women. In all three cases, ‘limb defects’ (unspecified) were observed.
In a further series, 13 of the surgical aspira- tions for continuing pregnancies were delayed and resulted in a fetus of at least ten weeks’ gestation. Six of these were examined and all were found to have limb defects, including missing and abnormally shaped digits and short limbs. There were also unspecified skull and facial abnormalities (Wiebe 1996, personal communication).
Misoprostol teratogenicity In Brazil, where misoprostol is marketed for the treatment of gastric ulcers, the drug is increa- singly misused as an illegal, self-administered abortifacient.5o There have been two reports, possibly including overlapping subjects, on congenital malformations observed in infants exposed to misoprostol in utero. Both reports (totalling 8 cases) describe a localised frontal and/or temporal abnormality consisting of an asymmetrical, well-circumscribed defect of the cranium and overlying scalp, exposing dura mater through which the cerebrum could be seen.51,52 The national teratogenic information system based in Port0 Alegre, Brazil, reported on 29 women who contacted the centre having attempted abortion induction using misoprostol. Seventeen live births were traced; there were no congenital abnormalities seen.53
Conclusions ?? Methotrexate is teratogenic in both animals
and humans. ?? There are some data suggesting that miso-
prostol may be a human teratogen.
Toxicology Panel review The background documentation was circulated to three members of the Toxicology Panel of the Special Programme of Research, Development and Research Training in Human Reproduction. The replies are abstracted below:
Reviewer 1: The teratogenic potential of methotrexate has been established beyond doubt in the human. This is a sufficient reason to respond in the negative.. whether WHO could say that metho- trexate is a safe and acceptable agent for pregnancy termination from the toxicological viewpoint.
, . . . unless a surgical evacuation is performed [in cases of continuingpregnancy] there is substan- tial risk of teratogenic fetal exposure.. . in utero. ’
‘The proportion of cases that have been lost to follow-up after methotrexate is far from negli- gible. One would expect a much largerproportion of such cases if the drug is allowed to be used for pregnancy termination routinely.’
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This reviewer also drew attention to additional potential hazards, including methotrexate- induced lung disease which may occur acutely at any time during therapy, which is not always reversible and has been reported in doses as low as 7.5 mglweek. Methotrexate is an immuno- suppressive agent and its administration to women already immunologically compromised, eg. with AIDS, could have serious repercussions. Methotrexate is excreted in breastmilk and its use is contra-indicated in breastfeeding women.
Reviewer 2: The evidence from experimental teratology is clear that such chemicals [includingmethotrexate] can be potent teratogens (when) administered during the first trimester.. . causing serious malformation. ’
‘It is obvious that the crucial issue with this drug as an abortifacient is that of the failed abortion cases.’
‘It is my opinion that the use of methotrexate as an agent for aboriion is not a safe and acceptable procedure and does not deserve further study when safer alternatives are available.’
Reviewer 3: ‘As for the position of WHO, it seems to me that this is really more of a policy issue than a toxicological issue since the data in animals and humans are fairly convincing that failed abortions carry a risk of fetal malformations. ‘
‘. . . it would be difficult to consider this treatment safe and acceptable even if surgical abortion was not available.’
References Warkany 3,1978. Aminopterin and methotrexate: folic acid de- ficiency. Teratology. 17:353-58. 4 Evans HM, Wright HV, Ashllng CW et al, 1953. Congenital skeletal anomalies resulting from transitory maternal folic acid deficiency. Anatomical Record. 5 115: 303-06. Giroud A, Leftbvres-Boisselot, 1995. Anomalies provoqukes chez le foetus en l’absence d’acide folique. Archives
Concluding statement Methotrexate has recently received attention in the scientific literature for its use in combination with the prostaglandin analogue misoprostol as a non-surgical method for the termination of early first trimester pregnancy. Methotrexate is approved for the treatment of certain malig- nancies including choriocarcinoma and osteo- genic sarcoma, severe psoriasis and adult rheumatoid arthritis. It acts to block cell division and DNA synthesis and repair. Methotrexate has been shown to be teratogenic in animals and in humans and its use in the human can be associated with potentially serious side effects including bone marrow suppression and irreversible lung disease; these effects appear to be dose-related. From the reports published to date it appears that the combination regimen of methotrexate and misoprostol fails to interrupt pregnancy in about 4 per cent of women; fetal abnormalities have been observed in several of these continuing pregnancies. Because of the possible risks to the woman’s health and the potential for the birth of infants with severe congenital abnormalities if treatment fails and the continuing pregnancy is not interrupted surgically, the use of methotrexate as a non- surgical method for first trimester termination of pregnancy cannot be recommended.
Correspondence Special Programme of Research, Development and Research Training in Human Reproduction, WHO, 1211 Geneva 27, Switzerland. Fax 41-22. 791-4171.
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Brandner M and Nusslk D, 1969. Foetopathie due g I’aminoptkrine avec stenose congknitale de l’espace mkdullaire des OS tubulaires longs. Annales de Radiologie. 12:703-10. Emerson DJ, 1962. Congenital malformations due to attempted abortion with aminopterin. American Journal of Obstetric > and Gynecology. 84:356-57. Goetsch C, 1962. An evaluation
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10. Mehzer HJ, 1956. Congenital anomalies due to attempted abortion with 4- aminoptero- glutamic acid. Journal of American Medical Association. 161:1253.
11. Shaw EB and Steinbach HL, 1968. Aminopterin-induced fetal malformation: survival of infant after attempted abortion. American Journal of Diseases in Children. 115:477-82.
12. Shaw EB, 1972. Fetal damage due to maternal aminopterin ingestion. American Journal of Diseases in Children. 124:93-94.
14. Methotrexate. Physicians' Desk Reference. Medical Economics Company, Montvale, NJ, 1996:1275-79.
15. Schiff E, Shalev E, Bustan M et al, 1992. Pharmacokinetics of methotrexate after local tubal injection for conservative treatment of ectopic pregnancy. Fertility and Sterility. 57:688-90.
16. Fernandez H, Bourget P, Ville Y et al, 1994. Treatment of unruptured tubal pregnancy with methotrexate: pharmaco- kinetic analysis of local versus intramuscular administration. Fertility and Sterility. 62:943-47.
17. Bourget P, Fernandez H, Lesne A et al, 1991. Pharmacocinetique du methotrexate et reponse clinique associee dans le traitement medical des grossesses extra-uterines. Thkrapie. 46:399-403.
19. Diniz EM, Corradini HB, Ramos JL et al, 1978. Efietos sobre o concept0 do methotrexate (ametopterine) administrado a mat. Apresentacao de case. Revista do Hospital das Clinicas; Faculdade de Medicine a Universidade de Sao Paulo. 33286-90.
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I methotrexate in eight patients with rheumatic disease. American Journal ofMedicine. 88:589-92.
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25. Stangel JJ, 1986. Recent techniques for the conservative management of tubal pregnan- cy: surgery, laparoscopy and medicine. Journal of Repro- ductive Medicine. 31:98-101.
26. Fernandez H, De Ziegler D, Bourget P, 1991. The place of methotrexate in the management of interstitial pregnancy. Human Reproduction. 6:302-06.
27. Stovall TG, Ling FW, Gray LA et al, 1991. Methotrexate treatment of unruptured ectopic pregnan- cy: a report of 100 cases. Obste- tn’cs and Gynecology. 77:749-53.
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R6sum6 Une revue des Etudes toxicologiques sur le du mkthotrexate utilisk comme abortif en dCbut de grossesse a montr6 que 1) le produit est tCratog&ne chez l’animal et chez l’homme, et 2) certaines indications donnent B penser que le misoprostol pourrait Ctre tCratog&ne chez l’homme. 11 ressort des rapports publiCs ?I cette date que l’administration combirke de m&ho- trexate et de misoprostol pour interrompre une grossesse est un Bchec chez 4% des femmes environ; des anomalies foetales ont Btk constaGes dans plusieurs des grossesses qui se sont ainsi poursuivies. Compte tenu des risques Lwentuels pour la santC de la femme et des possibilitks de graves anomalies congknitales de l’enfant en cas d’kchec du traitement mhdical, si la grossesse n’est pas alors interrompue chirurgicalement, il n’est pas possible de recommander le mkthotrexate comme mbthode non chirurgicale d’interruption d’une grossesse au premier trimestre.
Resumen Este ensayo examina la toxicologia de1 metotrexato combinado con el misoprostol cuando se utiliza para la realizacidn de abortos en las primeras semanas de embarazo, y concluye que: (1) el metotrexato es teratogknico tanto en 10s animales corn0 en 10s seres humanos, y (2) existen datos que sugieren la posibilidad de que el misoprostol sea un terat6geno humano. El ensayo se basa en una serie de informes publicados hasta la fecha, para concluir que el r&men combinado de meto- trexato y misoprostol no consigue interrumpir embarazos en un cuatro por ciento de mujeres. En varios de estos embarazos se han observado malformaciones fetales. El uso de metotrexato coma m&odo no quir6rgico de terminacibn de1 embarazo durante el primer trimestre no es recomendable. Esto es debido a 10s posibles riesgos para la salud de la mujer y el potential de bebks nacidos con serias malformaciones congknitas, si falla el tratamiento y el embarazo no es interrumpido quirdrgicamente.
