FETAL WARFARIN SYNDROME

Warfarin is a low molecular weight anticoagulant that readily crosses the placenta and may cause spontaneous abortion, stillbirth, neonatal death as well as a wide variety of congenital anomalies (warfarin embryopathy or syndrome) (1,2). Warfarin depresses synthesis of Vitamin K-dependent clotting factors (II, Vii, Ix, X). It crosses the placenta readily due to its low molecular weight, resulting in anticoagulation in both the mother and fetus.

The critical period of exposure is between weeks 6 and 9, however controversy does exist regarding exposure in the second and third trimester.

Previous studies have suggested that central nervous system abnormalities are due to exposure to warfarin in the second or third trimester (secondary to hemorrhage and infarction). However, a case report on exposure between 8 and 12 weeks of gestation that resulted in CNS abnormalities suggest that it may have a direct teratogenic effect on the developing CNS. The teratogenic effect may occur from exposure in both the embryonic and fetal period probably secondary to destruction of structures from hemorrhage into the organs secondary to vitamin K deficiency that is induced by warfarin (3).

Risk of developing fetal warfarin syndrome:

• Two thirds will have a normal outcome.
• One third will have either fetal warfarin syndrome or spontaneous abortion.

GENERAL FEATURES

• Facial Anomalies:
• Depressed nasal bridge and nasal hypoplasia.
• Skeletal Anomalies:
• Stippling of non calcified epiphyses.
• Shortened fingers and hypoplasia of the nails.
• Mental retardation and seizures
• Less commonly:
• Microcephaly, hydrocephaly, Dandy-Walker malformation, callosal agenesis microphthalmia and cataracts.
• Scoliosis and congenital heart defects.
• Associations:
• The similarity between this syndrome and recessive chondrodysplasia punctata (CDPX) has suggested a common pathogenesis for these two disorders.
  Recent evidence that warfarin appears to inhibit arylsulphatase E, a genetically determined deficiency that is responsible for CDPX, provides support for this theory (3).

REFERENCES

1. Pettifor JM, Benson R. Congenital malformations associated with the administration of oral anticoagulants during pregnancy. J Pediatr 1975;86:459.
2. Hall JG, Pauli RM, Wilson KM. Maternal and fetal sequelae of anticoagulation during pregnancy. Am J Med 1980;6:122.
3. Francho B, Meroni G, Parenti G et.al. A cluster of sulfatase genes on Xp22.3: Mutations in chondrodysplasia punctata (CDPX) and implications for warfarin embryopathy. Cell 1995;81:15.
4. Iturbe-Alessio I et.al. Risk of anticoagulant therapy in women with artificial heart valves. N Engl J Med 1986;315:1390.
5. Jones KL. Smith's Recognizable patterns of human malformations (5th edition). WB Saunders, Philadelphia 1997;568-569.
6. Tongsong T, Wanapirak C, Piyamongkol W et.al. Prenatal ultrasonographic findings consistent with Fetal Warfarin Syndrome. J Ultrasound Med 1999;18:577-580.