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Multiple congenital anomalies associated with weekly low-dose methotrexate treatment of the mother.

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ARTHRITIS & RHEUMATISM
Val. 40, No. 5, May 1997, pp 971-973
0 1997, American College of Rheumatology
97 1
MULTIPLE CONGENITAL ANOMALIES ASSOCIATED WITH
WEEKLY LOW-DOSE METHOTREXATE
TREATMENT OF THE MOTHER
LENORE M. BUCKLEY, CHARLES A. BULLABOY, LAWRENCE LEICHTMAN, and
MARIELLA MARQUEZ
This report describes an infant with multiple
congenital anomalies born to a 20-year-old mother with
juvenile rheumatoid arthritis who had been taking
weekly low-dose methotrexate (MTX) during the first
trimester of pregnancy. The abnormalities found were
consistent with those associated with maternal ingestion
of MTX at dosage levels used to induce abortions, i.e.,
the group of abnormalities referred to as the “aminopterin syndrome.” Although weekly low-dose MTX has
been associated with spontaneous abortions, this is, to
our knowledge, the first case report describing multiple
congenital abnormalities consistent with MTX embryopathy secondary to weekly low-dose MTX treatment.
Methotrexate (MTX), a folic acid antagonist, is
commonly used in the treatment of rheumatoid arthritis
(RA) and severe juvenile rheumatoid arthritis (JRA), as
well as other rheumatic conditions. MTX and aminopterin, another folic acid metabolism antagonist, have
been used to induce abortions and are teratogenic (1).
However, there have been no reports of congenital
abnormalities associated with low-dose weekly MTX
used in the treatment of arthritis in the mother. We
report herein the case of a baby with multiple congenital
abnormalities born to a mother with JRA who had taken
low-dose MTX during the first trimester of pregnancy.
CASE REPORT
The mother was a 20-year-old woman who had
been diagnosed as having polyarticular JRA at the age of
Lenore M. Buckley, MD, MPH, Mariella Marquez: Medical
College of Virginia, Virginia Commonwealth University, Richmond;
Charles A. Bullaboy, MD, Lawrence Leichtman, MD: Eastern Virginia
Medical School, Norfolk.
Address reprint requests to Lenore M. Buckley, MD, MPH,
Medical College of Virginia, Virginia Commonwealth University, 1200
East Broad Street, Box 980102 MCV Station, Richmond, VA 23298.
Submitted for publication August 7, 1996; accepted in revised
form November 19, 1996.
12. She was initially treated with nonsteroidal antiinflammatory drugs (NSAIDs) and injectable gold.
MTX treatment was started at age 15, at doses between
10 mg and 12.5 mg per week with supplemental folic acid
(1 mg per day).
At age 20, the patient had an unplanned pregnancy, and stopped both MTX and naproxen after the
second missed menses. It was estimated that the fetus
was exposed to a total MTX dose of -100 mg over a
period of 8 weeks. Although folic acid was one of the
medications that the mother was listed as taking during
this time, her level of compliance with folic acid supplementation treatment was unclear. She first saw an
obstetrician when she was 4 months pregnant. The
possible teratogenic effects of MTX were discussed by
the obstetrician, a geneticist, and her rheumatologist,
but the patient decided not to terminate the pregnancy.
She received regular prenatal care during the remainder
of the pregnancy. Amniocentesis was performed at 16
weeks gestation, and the karyotype was consistent with a
chromosomally normal female (46,XX). Fetal echocardiography at 20 weeks gestation revealed a ventricular
septa1 defect, probable double-outlet right ventricle, and
suspected pulmonary artery stenosis since the great
vessels were disproportionate in caliber.
The patient gave birth to a 1.79-kg girl by vaginal
delivery at 35 weeks gestation. Examination of the infant
at birth revealed intrauterine growth retardation, skeletal abnormalities, and a heart murmur. Evaluation by
the geneticist when the infant was 1 day old revealed
brachycephaly, a one-half-cm anterior fontanelle, coronal ridging, shallow orbits with hypertelorism, and retrognathia. The left ear had a bifid lobule, an overfolded
helix, and a prominent antihelix, and the ear canal was
closed. The right ear had a notched lobule and a
prominent antihelix, and the ear canal was stenotic. The
palate had a posterior groove and a bifid uvula. There
was a small umbilical hernia. The spine had a dorsal
972
BUCKLEY ET AL
age. At 4 months of age, developmental milestones were
consistent with an age of 2 months, giving a developmental quotient of 50%. At 6 months of age, the infant
was admitted to the hospital with respiratory distress,
carbon dioxide retention, and progressive hypoxemia.
Respiratory syncytial virus bronchiolitis was diagnosed.
Attempts at resuscitation were unsuccessful. An autopsy
was not performed.
DISCUSSION
Figure 1. Angiogram obtained when the infant was 2 weeks of age
(dye injected in left ventricle), revealing a ventricular septal defect
(VSD), transposed great arteries, and pulmonary stenosis. Ao = aorta;
PA = pulmonary artery; RV = right ventricle; LV = left ventricle.
kyphosis, with L5 and S1 hemivertebrae. The right
thumb was deformed, and there was a reduction of the
radial ray on the right side. There were bilateral simian
creases. There was syndactyly of the fourth and fifth toes
of the right foot, and the fifth metatarsal bone was
absent. The nails were hypoplastic. The cardiac examination revealed a grade 11-IIINI harsh blowing systolic
murmur along the left sternal border. Results of an
ultrasound examination of the head were normal. MTX
embryopathy was diagnosed.
Cardiac catheterization, performed due to progressive cyanosis when the baby was 2 weeks of age,
revealed a double-outlet righit ventricle, a doubly committed ventricular septal defect with transposed great
arteries, pulmonary stenosis, a restrictive atrial septal
defect, a small patent ductus arteriosus, and an aberrant
right subclavian artery (Figure 1). An atrial balloon
septostomy was performed. Neonatal growth was adequate, and the infant did well except for viral infections.
Because of episodes of cyanosis with oxygen saturations
dropping to 50%, a 4-mm gortex shunt was placed from
the aorta to the right pulmonary artery (modified
Blalock-Taussig shunt) when the child was 3 months of
Dietary deficiency of folic acid or ingestion of
folate antagonists during pregnancy is teratogenic. Folic
acid is necessary for replication of nucleic acids by
tetrahydrofolate-mediated 1-carbon transfers. Exposure
of embryonic tissues in culture to MTX reduces dihydrofolate reductase activity and inhibits cell division (2).
In chick embryos, it has been shown that exposure to
MTX did not prevent cells from entering mitosis, but
caused them to arrest in metaphase (3). This was
associated with developmental abnormalities which included cleft palate, osteoporosis, and skull and limb
dysplasia. Exposure of the rabbit embryo to aminopterin
causes enlarged intercellular spaces in limb bud mesenchyme, and the associated multiple limb abnormalities.
Replacement of l-carbon transfer activity with a functional analog decreases developmental abnormalities
(4). Schmid described multiple organ system abnormalities in the rat embryo after exposure to MTX, including
congenital abnormalities of the brain, caudal trunk, heart,
and forelimb as well as the otic and optic systems (5).
The malformations described in humans are similar to those described in animals. MTX and aminopterin have been used to induce abortions, and many of
the case reports of congenital abnormalities resulted
from unsuccessful treatment of pregnant women to
Table 1. Features of the aminopterin syndrome
Central nervous system abnormalities
Spina bifida
Mental retardation
Hydrocephaly
Anencephaly
Skeletal abnormalities
Synostosis of the lambdoid sutures
Partial or absent ossification of bones
Micrognathia
High or cleft palate
Short extremities
Syndactyly of fingers
Absent digits
Clubfoot
Large fontanelles
Wide nasal bridge
Wide-set eyes
Cardiac abnormality: dextrocardia
CONGENITAL ANOMALIES AND LOW-DOSE MTX
induce abortion (6-1 1). The group of abnormalities has
been referred to as the “aminopterin syndrome” (Table
1) (12). Central nervous system abnormalities include
spina bifida ( l l ) , mental retardation (8), and hydrocephaly and anencephaly (9,lO). Multiple skeletal abnormalities have been described, including synostosis of the
lambdoid sutures, partial or absent ossification of bones,
micrognathia, high arched palate, short extremities, syndactyly of the fingers, absent digits, clubfoot, large
anterior and posterior fontanelles, wide depressed
bridge of the nose, and wide-set eyes. Cardiac abnormalities such as dextrocardia have been reported (6).
Although spontaneous abortions have been described in association with low-dose weekly MTX treatment, there have been no case reports of congenital
abnormalities. Powell and Ekert described an infant with
multiple congenital abnormalities after treatment of the
mother with MTX ( 5 mgday) for psoriasis until the
eighth week of pregnancy (12). Kozlowski and colleagues described 10 pregnancies in 8 women who
received low-dose weekly MTX for RA, JRA, and vasculitis, during an average of 7.5 weeks of pregnancy (13).
Although there were 3 spontaneous abortions and 2 elective abortions after MTX exposure, 5 pregnancies progressed to term with no congenital abnormalities found.
The mean age at followup of this group of infants was 11.5
years, and no intellectual or physical abnormalities were
noted. The authors commented that the lack of congenital
abnormalities seen in this group of patients may have been
related to the low doses of MTX taken, the once-a-week
dosing schedule, and the use of folic acid supplementation.
Feldkamp and Carey have suggested that exposure to MTX is not associated with congenital abnormalities unless the dosage exceeds 10 mg/week between
week 6 and week 8 of gestation (14). Ossification of the
parietal bone occurs from 2 nuclei that appear at about
the seventh gestational week. A crucial period of external ear ascent and development also occurs at this time
(7). The infant described herein was exposed to -25 mg
of MTX from week 6 to week 8, and did have significant
abnormalities of ear development.
We report the first case of multiple congenital
abnormalities after maternal ingestion of low-dose
weekly MTX for arthritis. However, similar abnormalities have been described after use of as little as 6-12 mg
of aminopterin given over a period of 2-5 days to induce
abortion (9,lO). The congenital abnormalities described
are typical of those seen with exposure to an antifolate
and include facial (otic and ophthalmologic), skeletal,
and cardiac abnormalities. Such abnormalities have not
been described in association with the use of NSAIDs,
the only other medication the mother was taking.
973
This case illustrates that there is a significant risk
of severe congenital abnormalities with maternal use of
MTX even when given in low doses on a once-weekly
schedule, although the frequency of such abnormalities
is difficult to quantitate. Therefore, contraception counseling is important for teenage girls and women who are
treated with low-dose MTX, and counseling should be
reinforced periodically, especially with younger patients
whose needs and preferences for contraception may
change over time. Patients should be informed that past
MTX use does not predispose to congenital abnormalities, but that MTX use must be terminated prior to
attempts to become pregnant. Breastfeeding is not recommended if the MTX treatment is reinstituted after
delivery. Information about the types of malformations
caused by MTX can aid the clinician in the counseling of
women who become pregnant during treatment with
weekly low-dose MTX.
REFERENCES
1. Ostensen M: Treatment with immunosuppressive and disease
modifying drugs during pregnancy and lactation. Am J Reprod
Immunol 28:148-152, 1992
2. DePaola DP, Mandella RD: Folate deficiency in vitro pathogenesis. 11. Effects of methotrexate on rabbit palate fusion, folate
pools, and dihydrofolate reductase activity. J Craniofac Genet Dev
Biol 4:321-327, 1984
3 . Brewton RG, MacCabe J A Studies of methotrexate-induced limb
dysplasias utilizing a 51chromiumrelease assay. Teratology 41:211221, 1990
4. DeSesso JM, Goeringer GC: Methotrexate-induced developmental toxicity in rabbits is ameliorated by 1-(p-tosyl)-3,4,4- trimethylimidazolidine, a functional analog for tetrahydrofolate-mediated
one-carbon transfer. Teratology 45:271-283, 1992
5. Schmid BP: Monitoring of organ formation in rat embryos after in
vitro exposure to azathioprine, mercaptopurine, methotrexate or
cyclosporin A. Toxicology 31:9-21, 1984
6. Milunsky A, Graef JW, Gaynor MF: Methotrexate-induced congenital malformations. J Pediatr 72:790-795, 1968
7. Emerson DJ: Congenital malformation due to attempted abortion
with aminopterin. Am J Obstet Gynecol 84:356-357, 1962
8. Shaw EB, Steinbach HL. Aminopterin-induced fetal malformation. A m J Dis Child 115:477-482, 1968
9. Thiersch JB: Therapeutic abortions with a folk acid antagonist,
4-aminopteroyglutamic acid (4-amino P.G.A.) administered by the
oral route. Am J Obstet Gynecol 63:1298-1304, 1952
10. Thiersch JB: The control of reproduction in rats with the aid of
antimetabolites and early experiences with antimetabolites as
abortifacient agents in man. Acta Endocrinol Suppl28:37-45,1956
11. Van den Hof MC, Nicolaides KH, Campbell J, Campbell S:
Evaluation of the lemon and banana signs in one hundred and
thirty fetuses with open spina bifida. Am J Obstet Gynecol
162:322-327, 1990
12. Powell H, Ekert H: Methotrexate-induced congenital malformations. Med J Aust 2:1076-7077, 1971
13. Kozlowski RD, Steinbrunner JV, MacKenzie AH, Clough JD,
Wilke WS, Segal AM: Outcome of first-trimester exposure to
low-dose methotrexate in eight patients with rheumatic disease.
Am J Med 88589-592, 1990
14. Feldkamp M, Carey JC: Clinical teratology counseling and consultation case report: low dose methotrexate exposure in the early
weeks of pregnancy. Teratology 47:533-539, 1993
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