Pnd77465-3 489.490

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.
E-mail: franziska.kraehenmann@fhk.usz.ch 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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