| Fetal warfarin syndrome | |
|---|---|
 | |
| Warfarin | |
| Specialty | Teratology |
| Usual onset | Embryo |
| Causes | Maternalwarfarin administration |
| Diagnostic method | Observation of key symptoms |
| Prevention | Avoid administration of warfarin during pregnancy |
| Treatment | Administer Vitamin K and plasma with clotting factors. Surgical correction |
Fetal warfarin syndrome is adisorder of the embryo which occurs in a child whose mother took the medicationwarfarin (brand name:Coumadin) duringpregnancy. Resulting abnormalities includelow birth weight,slower growth,intellectual disability,deafness,small head size, and malformedbones,cartilage, andjoints.[1]
Warfarin is an oralanticoagulant drug (blood thinner) used to reduceblood clots,deep vein thrombosis, andembolism in people withprosthetic heart valves,atrial fibrillation, or those who have hadischemic stroke.[2] Warfarin blocks the action ofvitamin K, causing an inhibition of bloodclotting factors and the pro-bone-buildinghormoneosteocalcin.
Warfarin is ateratogen which can cross from the mother to the developingfetus. The inhibition of clotting factors can lead tointernal bleeding of the fetus while the inhibition of osteocalcin causes lower bone growth. As well as birth defects, warfarin can induce spontaneousabortion orstillbirth.[3] Because of this, warfarin iscontraindicated during pregnancy.
The keysymptoms, visible at birth, vary between individuals exposed to warfarinin utero. The severity and occurrence ofsymptoms is dose dependent with higher doses (>5 mg warfarin daily) more likely to cause immediately noticeable defects.[4]
The period of pregnancy in which warfarin is administered can affect the category of defects which develop. Warfarin taken in thefirst trimester of pregnancy is more likely to result inphysical abnormalities while warfarin taken in thesecond andthird trimester more commonly causes abnormalities of thecentral nervous system. The more extreme symptoms such as severe intellectual disability,blindness and deafness occur more often when warfarin is used throughout all three trimesters.[3]
Babies born with fetal warfarin syndrome may have a below-average birth weight and continue to grow at a reduced rate.[5]
Children with fetal warfarin syndrome show manyotolaryngological abnormalities consistent with abnormal bone and cartilage growth. Children may present withhypoplasia of the nasal ridge and a deep groove at the midline of the nose, thinned or absentnasal septum,choanal atresia,cleft lip andlaryngomalacia.[3][6] These facial defects and narrowing of the airways often lead torespiratory distress, noisy breathing and later,speech defects. Narrow airways often widen with age and allow for easier breathing.[3] Dental anomalies are also seen, such as abnormally large dental buds and late eruption ofdeciduous teeth.[6]
Development of the eyes is also affected by warfarin.Microphthalmia,telecanthus andstrabismus are common signs of fetal warfarin syndrome. The appearance of anectopiclacrimal duct, where the tear duct protrudes laterally onto the eye, has also been noted.[6]
Whole-body skeletal abnormalities are common in fetal warfarin syndrome. A generalized reduction in bone size causesrhizomelia,brachydactyly, shorter neck, shorttrunk,scoliosis andstippled epiphyses.[3][6] Abnormalities of the chest, typically eitherpectus carinatum orpectus excavatum, form an immediately recognizable sign of fetal warfarin syndrome.[3][6]
Congenital heart defects, such as a thinnedatrial septum,coarctation of the aorta andpatent ductus arteriosus, occur in 8% of fetal warfarin syndrome patients.Situs inversus totalis, the complete left-right mirroring of thoracic organs, has also been observed.
Defects of the central nervous system can lead to profound intellectual disabilities. Fetal warfarin syndrome can lead tomicrocephaly,hydrocephaly andagenesis of the corpus callosum. These defects contribute to the appearance of significant intellectual disability in 31% of fetal warfarin syndrome cases.[3]Hypotonia can appear innewborns with severe nervous deficits.Atrophy of theoptic nerve can also cause blindness in fetal warfarin syndrome.[7]
Inhibition of coagulation and resultant internal bleeding can causetoo few red blood cells to be present in the bloodstream andlow blood pressure in newborns with fetal warfarin syndrome.[5] Lowhemoglobin levels can lead to partial oxygen starvation, a high level oflactic acid in the bloodstream, andacidosis. Prolonged oozing of fluid from the stump of the cutumbilical cord is common.
Fetal warfarin syndrome appears in greater than 6% of children whose mothers took warfarin during pregnancy.[3] Warfarin has a lowmolecular weight so can pass from the maternal tofetal bloodstream through the tight filter-like junctions of theplacental barrier.
As the teratogenic effects of warfarin are well known, the medication is rarelyprescribed to pregnant women. However, for some patients, the risks associated with discontinuing warfarin use may outweigh the risk of embryopathy. Patients with prosthetic heart valves carry a particularly high risk of thrombus formation due to the inorganic surface andturbulent blood flow generated by a mechanical prosthesis. The risk of blood clotting is further increased by generalizedhypercoagulability as concentrations of clotting factors riseduring pregnancy.[8] This increased chance of blood clots leads to an increased risk of potentially fatal pulmonary or systemic emboli cutting off blood flow and oxygen to critical organs. Thus, some patients may continue taking warfarin throughout the pregnancy despite the risks to the developing child.
Warfarin's ability to cause fetal warfarin syndromein utero stems from its ability to limitvitamin K activation.[3] Warfarin binds to and blocks the enzymeVitamin K epoxide reductase which is usually responsible for activating vitamin K during vitamin K recycling. Vitamin K, once activated, is able to add acarboxylic acid group toglutamate residues of certainproteins which assists in correctprotein folding.[9] Without active vitamin K, a fetus exposed to warfarin is unable to produce large quantities ofclotting andbone growth factors.
Without vitamin K,clotting factors II, VII, IX and X are unable to be produced. Without these vital parts of thecoagulation cascade a durablefibrin plug cannot form to block fluid escaping from damaged or permeablevasculature.[2] Anemia is common in fetuses exposed to warfarin as blood constantly seeps into theinterstitial fluid oramniotic cavity.[5] High doses of warfarin and heavy bleeding lead to abortion and stillbirth.
Osteocalcin is another protein dependent on vitamin K for correct folding and function. Osteocalcin is normally secreted byosteoblast cells and plays a role in aiding correct bonemineralization and bone maturation.[10] In the presence of warfarin and subsequent absence of vitamin K and active osteocalcin, bone mineralization and growth are stunted.
Fetal warfarin syndrome is prevented by withholding prescription to pregnant women or those trying toconceive. As warfarin can remain in the mother's body for up to five days,[11] warfarin should not be administered in the days leading up to conception. Doctors must take care to ensure women of reproductive age are aware of the risks to the baby should they get pregnant, before prescribing warfarin.
For some women, such as those with prosthetic heart valves, anticoagulation medication cannot be suspended during pregnancy as the risk of thrombus and emboli is too high. In such cases an alternate anticoagulant, which cannot pass through the placental barrier to the fetus, is proscribed in place of warfarin.Heparin is one such anticoagulant medication, although its efficacy in patients with prosthetic heart valves is not well established.[12]
As well as the routine dose of vitamin K given to newborns after birth, babies born with fetal warfarin syndrome are given additional dosesintramuscularly to overcome any remaining warfarin in thecirculation and prevent further bleeding.Fresh frozen plasma is also administered to raise concentrations of active blood clotting factors. If the child is anemic from extensive bleedingin-utero,red blood cell concentrate is given to restore oxygen carrying capacity.[5]
Surgical interventions can be given to improve functionality and correct cosmetic abnormalities.Osteotomy (bone cutting) andzetaplasty surgeries are used to cut away abnormal tissue growths at thepiriform aperture around andpharynx to reduce airway obstruction.[6]Rhinoplasty surgery is used to restore normal appearance and function of the nose.[6]Heart surgery may also be required to close apatent ductus arteriosus.