As early as the 1950s malformations were being described resulting from treatment with aminopterin, a substance related to methotrexate (Warkany 1959, Meltzer 1956, Thiersch 1952). There are reports about failed terminations of pregnancies using aminopterin, in which malformations such as the following have been described: CNS anomalies (meningo-encephaiocele, hydrocephalus, brachy-cephaly, anencephaly); anomalies of the facial cranium (micrognathia, cheiloschisis, and cleft palate, craniostenosis, low-set cars, hypertelorism); malformations of the limbs; growth retardation; and mental retardation (see review by Briggs 2005). There are also some publications containing case reports with normal pregnancy outcome after exposure during the first trimester.
Methotrexate (a methyl derivative of aminopterin, which is also called amethopterin) has a half-life of 12-24 hours, but approximately 5-35% is stored for several months as polyglutamate derivative in hepatocytes and erythrocytes (Hendcl 1984). It is used for a wide range of indications - for example, to terminate ectopic or unwanted pregnancies, and for the treatment of autoimmune diseases, chronic inflammatory diseases, and neoplasias. Methotrexate carries a teratogenic risk, with a similar pattern of malformations to aminopterin (see above), so that sometimes reference is made to an aminopterin/methotrexate syndrome (Bawle 1998). However, in view of the close correspondence between the various malformations described for methotrexate, cyclophosphamide, and cytarabine (see section 2.13.6), the term aminopterin/methotrexate embryopathy does not seem justified. It is not clear whether these drugs have a common embryotoxic mechanism of action, as Vaux (2003) assumes. At present, it is not possible to say whether other antimetabolites cause similar malformations.
In children with characteristic malformations (skull ossification defects, facial dysmorphism, CNS anomalies with lower intelligence, and defects of the extremities) and intrauterine growth restriction, the fatter seems to persist during postnatal development, resulting in short stature. During subsequent development, both normal intellectual development and mental retardation were observed.
In more than 30 published articles, there are over 200 cases of pregnant women treated during the first trimester. Since these were, in general, retrospective case reports and not a prospective study, statistical calculation of the malformation rate is not valid. Moreover, some of these publications do not contain details about dose and indication. For example, McElhatton (2000) describes 82 exposed fetuses, including 53 exposed during the first trimester; 12 (for which no exposure period is given) showed anomalies, including nine cranial anomalies and six other malformations of the skeleton. In the following paragraphs, only the more detailed case reports are presented.
Ten articles describe pregnant women who had received methotrexate as part of cancer therapy during the first trimester. It is notewor thy that 16 healthy children were bom in this high-risk group (Zemlickis 1992, Aviles 1991, Feliu 1988, Dara 1981, Pizzuto 1980); 1 child had inguinal hernia (Giannakopoulou 2000), there was 1 spontaneous miscarriage (Giacalone 1999), and 1 stillbirth without malformations (Peres 2001). Only 1 child had characteristic malformations (Bawlc 1998) ; this child's mother had been treated for breast cancer with a weekly dose of 80 mg MTX from weeks 8-29. Moreover, she had received irradiation treatment from weeks 16-25, with the fetal dose estimated at 14 rad.
When administered during the second and third trimesters, methotrexate may - like other cytostatic drugs - produce intrauterine growth restriction, myclosuppression in the fetus, and (albeit rarely) fetal death.
Eight publications contain case reports of unsuccessfully attempted terminations of pregnancy. All 11 children showed the malformations characteristic for MTX (see, for example, Seidahmed 2006, Milunsky
1968). The total dose was between 10 and 100 nig methotrexate. In seven of these pregnancies (eight children), misoprostol was administered additionally several days after methotrexate (Ycdlinski 2005, Adam 2003, Wheeler 2002). In one instance, curettage had been performed beforehand but without success (Bawle 1998). Other reports discuss the anomalies of exposed fetuses which were diagnosed prenatally and led to termination of the pregnancy (Chapa 2003, Krahenmann 2002).
Ten publications listing more than 110 pregnancies with exposure during the first trimester refer to the so-called "low-dose" therapy for rheumatic diseases. However, with the exception of a recently published small prospective study from France (Lewden 2004) and our own unpublished data, all listed cases represent retrospective reports or, at best, small prospective case studies describing a maximum of four pregnancies (Ostensen 2000, Donnenfeld 1994).
There were a total of four children with characteristic malformations. Two of the mothers (Del Campo 1999, Powell 1971) had taken more MTX (one took 3 x 2.5 mg per week until week 10, and the other took 5 mg per day until week 8) than is usual for a "low-dose" therapy (i.e. maximally 25 mg per week). Another mother received 7.5 mg per day for 2 days in week 6 (Nguyen 2002), and the fourth woman received 12.5 mg per week until week 10 in combination with a daily dose of 1 mg folic acid (Buckley 1997).
In contrast to these publications, there are case reports of 14 healthy children whose mothers had a dosage of between 7.5 and 15 mg per week (Ostensen 2000, Donnenfeld 1994, Feldkamp 1993, Kozlowski 1990), 4 spontaneous miscarriages (Ostensen 2000, Kozlowski 1990), and 2 induced abortions without embryo-pathic background. Chakravarty (2003) describes 38 retrospective ascertained pregnancies with "low-dose" MTX therapy without giving details regarding the period of administration and the dose;
21 children were born healthy, 3 had malformations (no details given), there were 7 spontaneous miscarriages, and 8 pregnancies were electively terminated. A prospective French study (Lewden 2004) with 28 cases and a weekly median dose of 10.5 mg MTX reports 4 spontaneous miscarriages, 5 induced abortions, and 19 live births, none of which was a MTX embryopathy.
These findings are in agreement with those of the TIS Berlin: of the
22 prospectively ascertained pregnancies with exposure during the first trimester (with a weekly dose of 10-25 mg MTX), 3 pregnancies were terminated despite Inconspicuous ultrasound findings, 5 resulted in spontaneous miscarriages, and 13 healthy children were born (1 premature infant at 36 weeks). One child whose mother additionally took phenprocoumon and other drugs weighed 1600 g at birth and was growth restricted, had an inguinal hernia, and was highly irritable for 14 days.
The dose ranges of M IX administered in combination chemotherapy, attempted abortions, and for rheumatic indications ("low-dose" treatment) overlap. Therefore, the conclusion is inadmissible that Lhcrc arc safe and risky indications for MTX. However, since there has been only one case with suspicious symptoms following 10 mg MTX per week, the hypothesis proposed by Feldkamp (1993) seems plausible: that MTX is teratogenic only at a weekly dose in excess of 10 mg. In addition, the author postulates a sensitive phase between weeks 8 and 10. However, the data available do not permit a definitive conclusion in this respect.
Recommendation. Developmental anomalies resulting from treatment with the teratogenic drug methotrexate have been observed in a number of pregnancies, essentially comprising growth restriction beginning at a prenatal stage, severe ossification defects of the calvaria, facial dysmorphisms, CNS anomalies with or without diminishing of Intelligence, and defects of the extremities. A safe dose cannot be defined; however, at present there are no indications for teratogen ic effects to occur below a weekly dose of 10 mg. Antirheumatic " low-dose" therapy which had been continued (inadvertently) during the first trimester seems to be associated at most with a slightly increased risk of malformations, In general, exposure during the first trimester does not necessarily lead to malformations, even when used to treat malignant diseases.
Although antirheumatic MTX treatment should be stopped before planning a pregnancy, the data available at present do not justify the advice to postpone pregnancy for at least 3 months after stopping methotrexate therapy. Pregnant women who have been (inadvertently) exposed to MTX during the first trimester should be offered a detailed ultrasound scan to obtain confirmation of the normal development of the fetus.
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