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TERIS agent: 1012   METHOTREXATE

TERIS Agent Number:1012Bibliographic Search Date:02/14
Agent Name:METHOTREXATERevision Date:02/14

Methotrexate is a folic acid antagonist. It is administered orally or parenterally in the treatment of neoplasia, rheumatic diseases, and psoriasis and is also given, usually in combination with misoprostil, for termination of pregnancy. The dose employed varies from about 35 mg to as much as 2500 mg/wk in neoplasia, from 7.5-25 mg/wk in rheumatic disease, from 10-30 mg/wk in psoriasis, and from 25-100 mg in a single or repeated dose for pregnancy termination.



Magnitude of Teratogenic Risk to Child Born After Exposure During Gestation:
 
MODERATE TO HIGH

Quality and Quantity of Data on Which Risk Estimate is Based:
 
FAIR TO GOOD

Comments:   

1) THE RISK OF EMBRYOPATHY OCCURRING AS A RESULT OF MATERNAL METHOTREXATE TREATMENT DURING THE FIRST TRIMESTER OF PREGNANCY IS GREATER WITH LARGER DOSES AND SMALLER WITH SMALL DOSES (SEE BELOW).

2) FEATURES OF METHOTREXATE EMBRYOPATHY HAVE OCCURRED IN INFANTS WHOSE MOTHERS TOOK AS LITTLE AS 7.5 MG/WK OF METHOTREXATE DURING THE FIRST TRIMESTER OF PREGNANCY (MARTIN ET AL., 2014).

3) THE EFFECT ON THE FETUS OF MATERNAL TREATMENT WITH METHOTREXATE DURING THE SECOND OR THIRD TRIMESTER OF PREGNANCY IS UNKNOWN.


Summary of Teratology Studies:

More than two dozen individuals with a very uncommon and characteristic pattern of congenital anomalies have been born to women treated with methotrexate during the first trimester, and usually between eight to ten weeks, of gestation (Feldkamp & Carey, 1993; Lloyd et al., 1999; Donoway et al., 2012; Hyoun et al., 2012; MacDonald et al., 2013; Martin et al., 2014). Typical features in these patients include fetal growth retardation, abnormal head shape, large fontanelles, craniosynostosis, ocular hypertelorism, and skeletal defects. Microcephaly, brain anomalies, and intellectual disability may also occur. The pattern of anomalies is strikingly similar to that seen in children born to women who took aminopterin, a closely-related agent, early in pregnancy (Warkany, 1978; Lloyd et al., 1999). A different pattern of anomalies with tetralogy of Fallot and renal and limb malformations predominating may occur with earlier exposure (Nurmohamed et al., 2011; Piggott et al., 2011; Poggi & Ghidini, 2011; Hyoun et al., 2012).

The frequency of malformations among infants of women treated with methotrexate during pregnancy does not appear to be extremely high and is probably dose-related (Lloyd et al., 1999; Martinez Lopez et al., 2009; Gromnica-Ihle & Kruger, 2010; Martin et al., 2014). None of 19 infants whose mothers were treated with low-dose methotrexate during the first trimester of pregnancy was noted to have a major malformation in one series; one of these children had nonspecific minor anomalies (Lewden et al., 2004). The weekly dose was 12.5 mg or less of methotrexate in all but one of these women, and most stopped taking the drug around the time of conception. Congenital anomalies may be especially common in pregnancies that continue after a failed attempt at medical abortion with higher-dose methotrexate with or without concomitant misoprostol administration (Hyoun et al., 2012).

Methotrexate is used clinically as an abortifacient and in the treatment of ectopic pregnancy (Hyoun et al., 2012). Not surprisingly, the rate of miscarriage is high among women who are treated with methotrexate for other reasons early in pregnancy (Martinez Lopez et al., 2009; Gromnica-Ihle & Kruger, 2010). Spontaneous abortions occurred in 42.5% (95% confidence interval 29.2-59.7%) of 188 pregnancies in women who were treated with low-dose methotrexate for rheumatic disease and called a teratogen information service during the first trimester of pregnancy, compared to 22.5% in a disease-matched comparison cohort (Weber-Schoendorfer et al., 2014).

Prenatal diagnosis of methotrexate embryopathy is sometimes possible by ultrasound examination in the second or third trimester of pregnancy (Chapa et al., 2003; Zand et al., 2003; Yedlinsky et al., 2005; Goffman et al., 2006; Seidahmed et al., 2006; Usta et al., 2007; Poggi & Ghidini, 2011). However, all prenatally-diagnosed cases have had major malformations and were associated with treatment early in pregnancy to induce abortion.

Fetal death occurs with increased frequency in pregnant mice, cats, rats, and rabbits treated with methotrexate in doses equivalent to or greater than those used in humans (Hyoun et al., 2012). Somewhat higher doses are required to produce this effect in pregnant rhesus monkeys (Wilson et al., 1979). Dose-dependent increases in the frequency of malformations were observed among the offspring of rats and rabbits treated during pregnancy with methotrexate in doses equivalent to those used in humans, but such defects were not found in rhesus monkeys at this or a five-fold greater dose or in mice until single doses were increased to at least 2-4 times the maximum weekly dose used to treat cancer in humans (Hyoun et al., 2012). Cleft palate and limb malformations were the anomalies observed most often, but neural tube defects were also frequent in mice (Zhao et al., 2013).

A child has been reported with developmental delay and a de novo cytogenetically balanced reciprocal translocation whose mother was being treated with methotrexate when she conceived (Delatycki, 2005). This observation is of concern because a higher-than-expected frequency of acquired chromosomal aberrations has been found in the somatic cells of adult humans, in cultured human cells, and in mouse spermatogonia, spermatocytes, and embryonic oogonia exposed to methotrexate (Voorhees et al., 1969; Hansmann, 1974; Jensen & Nyfors, 1979; Mondello et al., 1984; Palo & Choudhury, 2006; Padmanabhan et al., 2009). Various acquired cytogenetic abnormalities were also observed in lymphocytes of an infant whose mother was treated with methotrexate and other cytotoxic drugs during the second and third trimesters of pregnancy (Schleuning & Clemm, 1987).

No increase in the frequency of congenital anomalies was apparent in clinical series that included more than 1100 children whose mothers had been treated with methotrexate before becoming pregnant (Van Thiel et al., 1970; Rustin et al., 1984; Hsieh et al., 1985; Green et al., 1991, 1997; Woolas et al., 1998; Matsui et al., 2003; Braga et al., 2009; Svirsky et al., 2009).

Key References:
(Each paper is classified as a review [R], human case report [C], human epidemiological study [E], human clinical series [S], animal study [A], or other [O].)

Braga A, Maesta I, Michelin OC, Delmanto LRG, Consonni M, Rudge MVC, Belfort P: Maternal and perinatal outcomes of first pregnancy after chemotherapy for gestational trophoblastic neoplasia in Brazilian women. Gynecol Oncol 112(3):568-571, 2009. [E]

Chapa JB, Hibbard JU, Weber EM, Abramowicz JS, Verp MS: Prenatal diagnosis of methotrexate embryopathy. Obstet Gynecol 101(5 Pt 2):1104-1107, 2003. [C]

Delatycki MB: A de novo, apparently balanced reciprocal translocation in a child with developmental delay whose mother was being treated with low-dose methotrexate at the time of conception. Birth Defects Res A Clin Mol Teratol 73(4):253-254, 2005. [C]

Donoway T, Mandeville J, Gauer R: When a fetus survives methotrexate exposure. J Fam Pract 61(3):E1-E4, 2012. [C]

Feldkamp M, Carey JC: Clinical teratology counseling and consultation case report: low dose methotrexate exposure in early weeks of pregnancy. Teratology 47(6):533-539, 1993. [C]

Goffman D, Cole DS, Bobby P, Garry DJ: Failed methotrexate termination of pregnancy: a case report. J Perinatol 26(10):645-657, 2006. [C]

Green DM, Fiorello A, Zevon MA, Hall B, Seigelstein N: Birth defects and childhood cancer in offspring of survivors of childhood cancer. Arch Pediatr Adolesc Med 151(4):379-383, 1997. [S]

Green DM, Zevon MA, Lowrie G, Seigelstein N, Hall B: Congenital anomalies in children of patients who received chemotherapy for cancer in childhood and adolescence. N Engl J Med 325(3):141-146, 1991. [E]

Gromnica-Ihle E, Kruger K: Use of methotrexate in young patients with respect to the reproductive system. Clin Exp Rheumatol 28(5 Suppl 61):S80-S84, 2010. [R]

Hansmann I: Chromosome aberrations in metaphase II-oocytes stage sensitivity in the mouse oogenesis to amethopterin and cyclophosphamide. Mutat Res 22(2):175-191, 1974. [A]

Hsieh F-J, Chen T-CG, Cheng Y-T, Huang S-C, Hsieh C-Y, Ouyang P-C: The outcome of pregnancy after chemotherapy for gestational trophoblastic disease. Biol Res Pregnancy Perinatol 6(4):177-180, 1985. [S]

Hyoun SC, Obican SG, Scialli AR: Teratogen update: methotrexate. Birth Defects Res A Clin Mol Teratol 94(4):187-207, 2012. [R]

Jensen MK, Nyfors A: Cytogenetic effect of methotrexate on human cells in vivo. Comparison between results obtained by chromosome studies on bone-marrow cells and blood lymphocytes and by the micronucleus test. Mutat Res 64(5):339-343, 1979. [O]

Lewden B, Vial T, Elefant E, Nelva A, Carlier P, Descotes J; French Network of Regional Pharmacovigilance Centers: Low dose methotrexate in the first trimester of pregnancy: results of a French collaborative study. J Rheumatol 31(12):2360-2365, 2004. [S]

Lloyd ME, Carr M, McElhatton P, Hall GM, Hughes RA: The effects of methotrexate on pregnancy, fertility and lactation. QJM 92(10):551-563, 1999. [R]

MacDonald K, Norman WV, Popescu O: New anomalies due to methotrexate and misoprostol exposure in early pregnancy. Int J Gynaecol Obstet 122(3):267-268, 2013. [C]

Martin MC, Barbero P, Groisman B, Aguirre MA, Koren G: Methotrexate embryopathy after exposure to low weekly doses in early pregnancy. Reprod Toxicol 43:26-29, 2014. [E]

Martinez Lopez JA, Loza E, Carmona L: Systematic review on the safety of methotrexate in rheumatoid arthritis regarding the reproductive system (fertility, pregnancy, and breastfeeding). Clin Exp Rheumatol 27(4):678-684, 2009. [R]

Matsui H, Iitsuka Y, Suzuka K, Yamazawa K, Tanaka N, Seki K, Sekiya S: Risk of abnormal pregnancy completing chemotherapy for gestational trophoblastic tumor. Gynecol Oncol 88(2):104-107, 2003. [E]

Mondello C, Giorgi R, Nuzzo F: Chromosomal effects of methotrexate on cultured human lymphocytes. Mutat Res 139(2):67-70, 1984. [O]

Nurmohamed L, Moretti ME, Schechter T, Einarson A, Johnson D, Lavigne SV, Erebara A, Koren G, Finkelstein Y: Outcome following high-dose methotrexate in pregnancies misdiagnosed as ectopic. Am J Obstet Gynecol 205(6):533.e1-533.e3, 2011. [S]

Padmanabhan S, Tripathi DN, Vikram A, Ramarao P, Jena GB: Methotrexate-induced cytotoxicity and genotoxicity in germ cells of mice: intervention of folic and folinic acid. Mutat Res 673(1):43-52, 2009. [A]

Palo AK, Choudhury RC: Modulation of methotrexate-induced cytogenotoxicity in mouse spermatogonia and its transmission in the male germline by caffeine. Environ Toxicol Pharmacol 21(3):254-259, 2006. [A]

Piggott KD, Sorbello A, Riddle E, DeCampli W: Congenital cardiac defects: a possible association of aminopterin syndrome and in utero methotrexate exposure? Pediatr Cardiol 32(4):518-520, 2011. [C]

Poggi SH, Ghidini A: Importance of timing of gestational exposure to methotrexate for its teratogenic effects when used in setting of misdiagnosis of ectopic pregnancy. Fertil Steril 96(3):669-671, 2011. [C]

Rustin GJS, Booth M, Dent J, Salt S, Rustin F, Bagshawe KD: Pregnancy after cytotoxic chemotherapy for gestational trophoblastic tumours. Br Med J 288(6411):103-106, 1984. [E]

Schleuning M, Clemm C: Chromosomal aberrations in a newborn whose mother received cytotoxic treatment during pregnancy. N Engl J Med 317(26):1666-1667, 1987. [C]

Seidahmed MZ, Shaheed MM, Abdulbasit OB, Al Dohami H, Babiker M, Abdullah MA, Abomelha AM: A case of methotrexate embryopathy with holoprosencephaly, expanding the phenotype. Birth Defects Res A Clin Mol Teratol 76(2):138-142, 2006. [C]

Svirsky R, Rozovski U, Vaknin Z, Pansky M, Schneider D, Halperin R: The safety of conception occurring shortly after methotrexate treatment of an ectopic pregnancy. Reprod Toxicol 27(1):85-87, 2009. [E]

Usta IM, Nassar AH, Yunis KA, Abu-Musa AA: Methotrexate embryopathy after therapy for misdiagnosed ectopic pregnancy. Int J Gynaecol Obstet 99(3):253-255, 2007. [C]

Van Thiel DH, Ross GT, Lipsett MB: Pregnancies after chemotherapy of trophoblastic neoplasms. Science 169(952):1326-1327, 1970. [S]

Voorhees JJ, Janzen MK, Harrell ER, Chakrabarti SG: Cytogenetic evaluation of methotrexate-treated psoriatic patients. Arch Derm 100(3):269-274, 1969. [O]

Warkany J: Aminopterin and methotrexate: folic acid deficiency. Teratology 17(3):353-357, 1978. [R]

Weber-Schoendorfer C, Chambers C, Wacker E, Beghin D, Bernard N, Shechtman S, Johnson D, Cuppers-Maarschalkerweerd B, Pistelli A, Clementi M, Winterfeld U, Eleftheriou G, Pupco A, Kao K, Malm H, Elefant E, Koren G, Vial T, Ornoy A, Meister R, Schaefer C: Pregnancy outcome after rheumatologic methotrexate (MTX) treatment prior to or during early pregnancy: a prospective multicenter cohort study. Arthritis Rheumatol 2014 Jan 27 (Epub ahead of print). [E]

Wilson JG, Scott WJ, Ritter EJ, Fradkin R: Comparative distribution and embryotoxicity of methotrexate in pregnant rats and rhesus monkeys. Teratology 19(1):71-79, 1979. [A]

Woolas RP, Bower M, Newlands ES, Seckl M, Short D, Holden L: Influence of chemotherapy for gestational trophoblastic disease on subsequent pregnancy outcome. Br J Obstet Gynaecol 105(9):1032-1035, 1998. [E]

Yedlinsky NT, Morgan FC, Whitecar PW: Anomalies associated with failed methotrexate and misoprostol termination. Obstet Gynecol 105(5 Pt 2):1203-1205, 2005. [C]

Zand DJ, Blanco C, Coleman B, Huff D, Zackai E: In utero methotrexate exposure resulting in long bone aplasia. Am J Hum Genet 73(5 Suppl):591, 2003. [C]

Zhao J, Guan T, Wang J, Xiang Q, Wang M, Wang X, Guan Z, Xie Q, Niu B, Zhang T: Influence of the antifolate drug methotrexate on the development of murine neural tube defects and genomic instability. J Appl Toxicol 33(9):915-923, 2013. [A]

THE OTIS AUTOIMMUNE DISEASES IN PREGNANCY PROJECT

MotherToBaby, a service of the non-profit Organization of Teratology Information Services (OTIS), is conducting a nationwide, prospective study in an effort to gain additional information regarding autoimmune diseases, their treatment during pregnancy, and the potential effects of the treatment on the developing embryo or fetus.

Women within their first 19 weeks of pregnancy, living in the United States or Canada, who have an autoimmune disease, and who may or may not be using medication are eligible to enroll. All information collected will remain strictly confidential. Identity of the women and their children will not be used in any report or publication and all files are kept in a locked cabinet.

The coordinating center for the study is located at the University of California, San Diego Medical Center in the Department of Pediatrics. The medical director is Dr. Kenneth Lyons Jones, a pediatrician and specialist in birth defects. More information about the study can be found at the MotherToBaby website: http://www.pregnancystudies.org/ongoing-pregnancy-studies/autoimmune-studies/

Contact Information for Referrals: MotherToBaby (OTIS)
Phone: 1-877-311-8972 (toll-free)
Email: otisresearch@ucsd.edu