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RFLP analysis and clinical characterization of a de novo trisomy
and mapping by fluorescence in situ hybridization. Genomics
Kozma C, Meck JM. 1994. Familial 10p trisomy resulting from a
Van Buggenhout G, Decock P, Fryns JP. 1996. A distinct phenotype
maternal pericentric inversion. Am J Med Genet 49: 281–287.
associated with partial trisomy 10q due to proximal direct
Lee FK, Cheung MC, Chung S. 1994. The human sorbitol
duplication 10q11pq223? Genet Couns 7: 53–59.
dehydrogenase gene: cDNA cloning, sequence determination,
In utero first trimester exposure to low-dose methotrexate with increased fetalnuchal translucency and associated malformations
We report on a 32-year-old Caucasian woman, gravida
and inflammatory rheumatic diseases. A ‘low-dose
3 para 1, suffering from rheumatoid arthritis treated
exposure’ to methotrexate is not well defined, but
with two single intramuscular injections of 10 mg
there is a common agreement that it should not exceed
methotrexate at 4+6 weeks’ and at 5+6 weeks’
the maximal dose of 20 mg/week (Østensen et al.,
gestation. She took a daily oral dose of 1 mg folic
2000). In their overview of 24 patients with rheumatic
acid irregularly. She was referred at 12+3 weeks’
disease and low-dose methotrexate treatment in early
gestation for evaluation of increased nuchal translu-
pregnancy there was only one case with a so-called
cency (3.9 mm). In addition, using color Doppler, a
aminopterin syndrome. A late first trimester ultra-
complete atrioventricular septal defect (AVSD) was
sound scan is often offered to patients after drug
suspected. Chorionic villus sampling (CVS) revealed
exposure in early pregnancy to rule out major fetal
normal karyotype (46,XX), no microdeletion 22q11
anomalies. The present case shows that increased
and no tetrasomy 12p (Pallister-Killian). Diabetes
nuchal translucency thickness between 10 and 14
mellitus was excluded. Ultrasound was repeated at
weeks’ gestation can also be used for detection of
14+1 weeks’ gestation: The heart, having a complete
fetuses at high risk for malformations after teratogenic
AVSD, was seen in the left chest and the stomach was
drug exposure in early pregnancy. Furthermore, the
normally situated in the abdomen. No skeletal mal-
present case confirms that increased nuchal translu-
formations or malformations of the central nervous
cency in chromosomally normal fetuses is associated
system were found. Ultrasound at 18 weeks’ gestation
with heart defects and other anomalies such as
confirmed the cardiac defect but it was surprising to
diaphragmatic hernia. It also confirms the observation
find, in addition, a left-sided posterolateral diaphrag-matic hernia with herniation of stomach and bowelshifting of heart into the right thoracic cavity(Figure 1). The patient opted for termination ofpregnancy. The female fetus (170 g in weight, 19 cmin length) showed no external signs of malformationsand the autopsy confirmed the complete AVSD, theleft-sided diaphragmatic hernia with herniation ofstomach, spleen and left part of the liver into thethoracic cavity associated with hypoplastic lungs. Noneural tube defect, no signs of abnormal cranialossification, and no defect of the palate were found,and the X-ray showed normal findings correspond-ing to the gestational week with absence of boneabnormalities.
Methotrexate is a dihydrofolate reductase inhibitor
and hence a folic acid antagonist like aminopterin.
Both substances are known to be teratogenic agents.
After exposure to methotrexate or aminopterin,surviving children have an increased risk of havingmalformations of the skull, cerebral anomalies (includ-ing meningomyelocele), skeletal malformations, limbdefects,
disorders, also called the ‘aminopterin syndrome’.
Methotrexate is a widely used drug, not only as a
Figure 1—Transverse scan of the thorax at 18+4 weeks’ gestation.
chemotherapeutic agent, but also for treatment of
The stomach (st) is in the left thoracic cavity, and the heart is shifted
ectopic pregnancies, psoriasis, various liver disorders
into the right hemithorax. AVSD, Atrioventricular septal defect
Copyright # 2002 John Wiley & Sons, Ltd.
of Bronshtein and co-workers on the in utero evolution
of congenital diaphragmatic hernia (Bronshtein et al.,
ether) (Losty et al., 1999). The cardiovascular mal-
1995). The authors reported on 15 fetuses with
formations also included AVSD. Fetal exposure to
congenital diaphragmatic hernia: seven of them were
detected between 14 and 16 weeks’ gestation but the
increase cardiovascular defects. Recently Wenstrom
remaining eight were first detected between 21 and 28
et al. (2001) published a paper on the association
weeks’ gestation after having had a normal ultrasound
between C677T methylenetetrahydrofolate reductase
scan in the early second trimester. In the present case,
mutation and isolated cardiac defects. Hence, the
at 12 and 14 weeks’ gestation the stomach was found
question can be raised whether folic acid deficiency is
in the upper abdomen and the heart in the left thoracic
partly responsible for the pathogenesis of congenital
cavity. The stomach herniation occurred between 14
heart defects under non-drug exposure conditions.
and 18 weeks’ gestation leading to major cardiac
There are no reports on increased incidence of
displacement and lung hypoplasia. In this case, we
know exactly the time of drug exposure (on the 20th
In conclusion, we believe a detailed fetal ultrasound
and on the 27th day after conception) without any
scan is important after maternal administration of
concomitant drug intake. Other common causes for
the malformations have been excluded. So, a causalrelationship between exposure to methotrexate and themalformations may be suspected. Low-dose metho-
F. Kra¨henmann1*, M. Østensen2, Th. Stallmach3,
trexate also possibly induces other malformations
apart from the known aminopterin syndrome. Most
Division of Obstetrics, University Hospital Zurich,
abnormalities reported in the literature refer to
Frauenklinikstrasse10, CH-8091 Zurich, Switzerland.
postnatal findings, but in the present case pregnancy
2Division of Rheumatology, University Hospital, Bern,
was terminated at 19 weeks and we do not know
whether some other signs of the aminopterin syndrome
3Division of Pathology, University Hospital, Zurich,
have a later onset in pregnancy (intrauterine growth
retardation, skull ossification, skeletal abnormalities).
4Division of Obstetrics, Charite´, Berlin, Germany
Apart from methotrexate and aminopterin there are
other folic acid antagonists. Hernandez-Diaz reporteda relative risk of 2.2 for fetal cardiovascular defectsafter maternal intake of anti-epileptic drugs (such ascarbamazepine, phenytoin, primidone and pheno-
barbital) with folic acid antagonist effect and a rela-
Bronshtein M, Lewit N, Sujov PO, Makhoul IR, Blazer S. 1995.
tive risk of 3.4 after maternal intake of folic acid
Prenatal diagnosis of congenital diaphragmatic hernia: Timing of
antagonists such as trimethoprim, triamterene and
visceral herniation and outcome. Prenat Diagn 15: 695–698.
sulfasalazine (consisting of the group of dihydrofolate
Hernandez-Diaz S, Werler MM, Walker AM, Mitchell AA. 2000.
reductase inhibitors) (Hernandez-Diaz et al., 2000).
Folic acid antagonists during pregnancy and the risk of birth
The methotrexate exposure in the present case
defects. N Engl J Med 343: 1608–1614.
Losty PD, Connel MG, Freese R, et al. 1999. Cardiovascular
occurred at a time when neither the embryological
malformations in experimental congenital diaphragmatic hernia.
septum atrioventriculare nor the diaphragm were
Migliazza L, Otten C, Huimin X, Rodriguez JI, Diez-Pardo JA,
AVSD occurs in 7% of all heart defects and congenital
Tovar JA. 1999. Cardiovascular malformations in congenitaldiaphragmatic hernia: human and experimental studies. J Pediatr
diaphragmatic hernia in 1 : 4000 livebirths. The com-
bination of these two malformations is not unknown:
Østensen M, Hartmann H, Salvesen K. 2000. Low dose weekly
In a series of autopsies the combination of a congenital
methotrexate in early pregnancy. A case series and review of the
diaphragmatic hernia and non-chromosomally caused
literature. J Rheumatol 27: 1872–1875.
AVSD was reported by Migliazza et al. (1999).
Wenstrom KD, Johanning GL, Johnston KE, DuBard M. 2001.
Association of the C677T methylenetetrahydrofolate reductase
Moreover, this combination of malformations was
mutation and elevated homocysteine levels with congenital
induced in rat fetuses by the maternal administration
cardiac malformations. Am J Obstet Gynecol 184: 806–817.
Brain anomalies associated with 47,XYY karyotypes detected on a prenatal scan
47,XYY is one of the most common chromosomal
disclosed coincidentally as an unexpected karyotype
rearrangements with a frequency of 1 : 1000 males
result carried out for another indication (Sagi et al.,
(Abramsky et al., 2001). Most 47,XYY fetuses are
Copyright # 2002 John Wiley & Sons, Ltd.
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