The fetal warfarin syndrome, also known as warfarin embryopathy or di Sala syndrome is caused by fetal exposure to warfarin, an anti-vitamin K anticoagulant used for thromboembolic disorders treatment and prophylaxis, leading to a series of complex malformations, as well as neurological and mental impairment. The disease is more severe if exposure occurs during the first trimester of pregnancy.
Presentation
The presentation of the fetal warfarin syndrome depends on the quantity of the drug that the mother has ingested, the teratogenicity being dose dependent [1] and the duration of the fetal exposure to warfarin. The greatest risk is encountered during the sixth and the ninth week of gestation [2] [3]. The drug has a low molecular weight and crosses the placenta, causing vitamin K deficiency in the embryo or fetus. The mother can present for spontaneous abortion or the pregnancy can be carried to term, but the child may be born dead or die during the neonatal period [4]. When the child survives, he or she has a series of congenital abnormalities [5] [6]. The facial traits of a fetal warfarin syndrome-affected child include nasal hypoplasia, nose bridge depression, the presence of a groove between the tip of the nose and the alae nasi. Small nostrils resulting from these abnormalities may impair air flow and cause neonatal respiratory distress, that may be severe enough to require intervention. Osseous stippling occurs in the axial skeleton and femurs [7]. It may be accompanied by scoliosis and hypoplasia of the extremities, ranging from rhizomelia to dystrophic nails. Central nervous system and eye malformations occur more frequently when the fetus has been exposed to warfarin during the second and third trimesters of pregnancy. Abnormalities consist of hydrocephalus, microcephaly, corpus callosum agenesis, microphthalmia and optic atrophy. Blindness, deafness, and seizures, as well as severe bleeding at birth, not predictable from the maternal international normalized ratio, may also be seen [8] [9]. Other teratogenic effects of warfarin include cardiac and laryngeal abnormalities, aortic coarctation, situs inversus totalis, ventral midline dysplasia, bilobed lungs, congenital cataract, short neck, cleft palate and/or lip [10], mental retardation, feeding difficulties, widely spaced nipples and the Dandy-Walker malformation. Hypotonia or muscular spasticity may be encountered. These children usually fail to thrive.
Entire Body System
- Feeding Difficulties
Symptoms and Signs Symptoms include low birth weight, seizures, reduced muscle tone, deafness, feeding difficulty, shortened fingers, widely spaced nipples, and failure to thrive. Warfarin ingestion may also be chronic or acute. [dianamossop.com]
difficulty * Failure to thrive Causes - Fetal warfarin syndrome Not supplied. [checkorphan.org]
difficulties, widely spaced nipples and the Dandy-Walker malformation. [symptoma.com]
[…] groove between nostril and nasal tip, Stippling of uncalcified epiphyses during first year, Mild hypoplasia of nails, Shortened fingers, Low birth weight, Significant mental retardation, Seizures, Reduced muscle tone, Widely spaced nipples, Deafness, Feeding [definitions.net]
Symptoms & Signs Symptoms include low birth weight, seizures, reduced muscle tone, deafness, feeding difficulty, shortened fingers, widely spaced nipples & failure to thrive. Warfarin ingestion may also be chronic or acute. [signssymptoms.org]
- Inflammation
Septic arthritis is caused by joint infection, gouty arthritis is caused by deposition of uric acid crystals in the joint that results in subsequent inflammation. [wikivisually.com]
Increased pressure within the muscle compartment causes loss of blood supply and nerve inflammation. This causes significant pain and numbness or paresthesia. (para=abnormal + ethesia=feeling). [medicinenet.com]
In these patients, ischemic lesions of fingers or toes are caused by arteriolar inflammation and the thrombosis of microvessels that appear as a consequence. The syndrome of cholesterol embolism is often a multiorgan disorder. [escardio.org]
Although the eruption usually resolves during infancy, older children may subsequently develop inflammation and wasting (atrophy) of follicles (follicular atrophoderma), causing pores to appear unusually large. [rarediseases.org]
In these cases, thrombosis must be present without evidence of inflammation of the vessel wall. Women who experience fetal loss greater than or equal to 10 weeks gestation should have confirmation that the fetus was morphologically normal. [clinicaladvisor.com]
- Asymptomatic
Patients may experience syncope, pre-syncope, palpitations, or dizziness; however, they often are asymptomatic or have subtle or nonspecific symptoms. [aafp.org]
Many patients with May-Thurner anatomy remain entirely asymptomatic throughout their adult life. [vasculardiseasemanagement.com]
As a result, one or more of the parent’s children may inherit the gene mutation, potentially leading to manifestation of the disorder, while the parent may have no apparent symptoms (asymptomatic carrier). [rarediseases.org]
This is because you are asymptomatic (you have no symptoms). [patient.info]
If aPL are identified in asymptomatic patients, any factor predisposing for thrombosis (e.g., defects in coagulation factors, platelet defects, hyperviscosity, oral contraceptives, estrogen replacement therapy, nephrotic syndrome, smoking, or surgery) [uspharmacist.com]
- Developmental Delay
A smaller population will have growth problems and developmental delay, or intellectual disability. Methemoglobinemia is a rarely seen side effect. Heart defects and cleft lip [3] may also be featured. [en.wikipedia.org]
Postnatal developmental delay has been observed following in utero exposure to warfarin, but when reported was mainly in children with FWS. [medicinesinpregnancy.org]
The most common anomalies include developmental delay, neurological complications (usually hydrocephalus and occasional agenesis of the corpus callosum and meningoencephalocele), midfacial hypoplasia, and various ocular, skeletal, and other defects. [icd10data.com]
A positive family history in a proband with developmental delay should prompt consideration of genetic testing of the FMR1 gene. [obfocus.com]
- Epilepsy
Dilantin is the brand name of the drug phenytoin sodium in the United States, commonly used in the treatment of epilepsy. [en.wikipedia.org]
Polycystic (congenital) (disease) 759.89 degeneration, kidney - see Polycystic, kidney Pseudo-Turner's syndrome 759.89 Rubinstein-Taybi's syndrome (brachydactylia, short stature and intellectual disabilities) 759.89 Rud's syndrome (mental deficiency, epilepsy [icd9data.com]
Other teratogenic effects in fetuses exposed to warfarin after second or third trimester include optic atrophy, blindness, corneal opacity, deafness, microcephaly, hydrocephalus, epilepsy, Dandy-Walker malformation and mental retardation. [jemds.com]
Respiratoric
- Saddle Nose
FETAL WARFARIN SYNDROME • Saddle nose • Retarded growth • Defects of limbs, eyes and central nervous system 28. Tetracycline- Teeth and bone damage • Yellow staining • Enamel hypoplasia • Caries and pigmentation of permanent teeth 29. [slideshare.net]
Gastrointestinal
- Failure to Thrive
Symptoms and Signs Symptoms include low birth weight, seizures, reduced muscle tone, deafness, feeding difficulty, shortened fingers, widely spaced nipples, and failure to thrive. Warfarin ingestion may also be chronic or acute. [dianamossop.com]
[…] to thrive Causes - Fetal warfarin syndrome Not supplied. [checkorphan.org]
[…] to thrive Numerology Chaldean Numerology The numerical value of fetal warfarin syndrome in Chaldean Numerology is: 6 Pythagorean Numerology The numerical value of fetal warfarin syndrome in Pythagorean Numerology is: 4 Images & Illustrations of fetal [definitions.net]
Symptoms & Signs Symptoms include low birth weight, seizures, reduced muscle tone, deafness, feeding difficulty, shortened fingers, widely spaced nipples & failure to thrive. Warfarin ingestion may also be chronic or acute. [signssymptoms.org]
Additionally, warfarin can cause birth defects such as abnormal development of the spine, changes to bones in the face (especially the nose), intellectual disability, and failure to thrive. [diseaseinfosearch.org]
Skin
- Skin Ulcer
Patients with APS may suffer from other problems including low number of platelets, mottled purplish discoloration of the skin (livedo reticularis), and skin ulcerations. [rheumatology.org]
During the 10‐year period study on 1000 patients across 13 European countries (Euro‐Phospholipid project), thrombosis was the most frequent manifestation (28.1%) with 5.3% stroke, 4.7% TIA, 4.3% DVT, 3.5% PE, 8.1% livedo reticularis and 3.1% skin ulcer [cochranelibrary.com]
Musculoskeletal
- Brachydactyly
He also had short limbs, brachydactyly, nail hypoplasia, and calcifications in the epiphyseal regions of humeri, femora and vertebrae radiographically. The patient eventually died from respiratory failure at 6 months of age. [ncbi.nlm.nih.gov]
Reported clinical features include: facial anomalies nasal bone hypoplasia nasal bridge depression skeletal anomalies stippled non calcified epiphyses shortened fingers : brachydactyly nail hypoplasia scoliosis central nervous system mental retardation [radiopaedia.org]
Affected children also have a hypoplastic nose, eye abnormalities, mental retardation, brachydactyly, and scoliosis. [aippg.net]
[…] are anticoagulant drugs that provide efficient thromboprophylaxis and that can cross the placenta. 5-12 % of infants exposed to warfarin between 6-9 weeks gestation present nasal hypoplasia and skeletal abnormalities, including short limbs and digits (brachydactyly [rarediseases.info.nih.gov]
Ears
- Hearing Impairment
Less often, affected individuals exhibit hearing impairment, incomplete closure of the roof of the mouth (cleft palate), misalignment of the eyes (strabismus), structural malformations of the heart (congenital heart defects), mild intellectual disability [rarediseases.org]
Breast
- Widely Spaced Nipples
Symptoms and Signs Symptoms include low birth weight, seizures, reduced muscle tone, deafness, feeding difficulty, shortened fingers, widely spaced nipples, and failure to thrive. Warfarin ingestion may also be chronic or acute. [dianamossop.com]
spaced nipples * Deafness * Feeding difficulty * Failure to thrive Causes - Fetal warfarin syndrome Not supplied. [checkorphan.org]
spaced nipples and the Dandy-Walker malformation. [symptoma.com]
spaced nipples, Deafness, Feeding difficulty, Failure to thrive Numerology Chaldean Numerology The numerical value of fetal warfarin syndrome in Chaldean Numerology is: 6 Pythagorean Numerology The numerical value of fetal warfarin syndrome in Pythagorean [definitions.net]
Symptoms & Signs Symptoms include low birth weight, seizures, reduced muscle tone, deafness, feeding difficulty, shortened fingers, widely spaced nipples & failure to thrive. Warfarin ingestion may also be chronic or acute. [signssymptoms.org]
Face, Head & Neck
- Depressed Nasal Bridge
The baby was well, except for facial dysmorphism in the form of depressed nasal bridge, narrow nares and suspected left choanal atresia. [ncbi.nlm.nih.gov]
Symptoms - Fetal warfarin syndrome * Nasal hypoplasia * Depressed nasal bridge * Deep groove between nostril and nasal tip * Stippling of uncalcified epiphyses during first year * Mild hypoplasia of nails * Shortened fingers * Low birth weight * Significant [checkorphan.org]
GENERAL FEATURES Facial Anomalies: Depressed nasal bridge and nasal hypoplasia. Skeletal Anomalies: Stippling of non calcified epiphyses. Shortened fingers and hypoplasia of the nails. [fetalultrasound.com]
The symptoms are Nasal hypoplasia, Depressed nasal bridge, Deep groove between nostril and nasal tip, Stippling of uncalcified epiphyses during first year, Mild hypoplasia of nails, Shortened fingers, Low birth weight, Significant mental retardation, [definitions.net]
Following Prenatal Exposure from 6 to 9 Weeks Anomalies in the face seen are nasal hypoplasia and depressed nasal bridge, often with a deep groove between the alae nasi and nasal tip. [jemds.com]
Neurologic
- Seizure
Reported clinical features include: facial anomalies nasal bone hypoplasia nasal bridge depression skeletal anomalies stippled non calcified epiphyses shortened fingers : brachydactyly nail hypoplasia scoliosis central nervous system mental retardation seizures [radiopaedia.org]
Symptoms and Signs Symptoms include low birth weight, seizures, reduced muscle tone, deafness, feeding difficulty, shortened fingers, widely spaced nipples, and failure to thrive. Warfarin ingestion may also be chronic or acute. [dianamossop.com]
[…] syndrome * Nasal hypoplasia * Depressed nasal bridge * Deep groove between nostril and nasal tip * Stippling of uncalcified epiphyses during first year * Mild hypoplasia of nails * Shortened fingers * Low birth weight * Significant mental retardation * Seizures [checkorphan.org]
Blindness, deafness, and seizures, as well as severe bleeding at birth, not predictable from the maternal international normalized ratio, may also be seen. [symptoma.com]
- Neurologic Manifestation
[…] the warfarin embryopathy has skeletal and neurological manifestations. while the skeletal involvement can occur only in the first trimester, the neurological involvement can happen anytime during pregnancy. the incidence of warfarin embryopathy is about [medicalfundas.blogspot.com]
neurologic manifestations, and livedo reticularis, a lattice-like pattern of superficial veins most often found on the thighs, shins, and hands. [uspharmacist.com]
View Article PubMed Google Scholar Brey RL: Management of the neurological manifestations of APS – what do the trials tell us?. Thromb Research. 2004, 114: 489-99. 10.1016/j.thromres.2004.06.018. [jautoimdis.biomedcentral.com]
- Convulsions
Lancet 2:680 CrossRef PubMed CAS Google Scholar Cowe L, Lloyd D, Dawling S (1982) Neonatal convulsions caused by with drawal from maternal clomipramine. [link.springer.com]
Workup
Fetal warfarin syndrome diagnosis is mostly based on pregnancy history and clinical examination. However, skeleton radiographs can provide additional information, such as the epiphyseal stippling of vertebrae, long bones, and sacrum. These findings are transient and disappear as the child grows older [11]. Scoliosis, as well as short limbs and digits, can also be noticed on radiological films [12]. Epiphyses can be found to be non calcified. These findings are present in 5-12% of infants who were exposed to warfarin between the sixth and the ninth week of gestation.
Treatment
Treatment : How to Treat "Fetal warfarin syndrome"? Teartment for fetal warfarin syndrome includes general avoidance to drugs that are known to enhance bleeding as well as increase metabolism of the anticoagulant drug. [signssymptoms.org]
Treatment may require the coordinated efforts of a team of specialists. [en.wikipedia.org]
CLOSE Medical Disclaimer The medical information on this site is provided as an information resource only, and is not to be used or relied on for any diagnostic or treatment purposes. [diseaseinfosearch.org]
Prepare for clinical challenges and save time in addressing them thanks to expert advice on treatment options from international contributors. [books.google.com]
Standard Therapies Treatment The treatment of Binder syndrome is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. [rarediseases.org]
Prognosis
Ovulation Tests o Home Fertility Tests o Home Rhesus/RH Blood Type Tests o Home Fetal Tests * Fertility-related Home Testing: o Home Ovulation Tests o Home Fertility Tests * Male Fertility Tests o Home Sperm Tests o Sperm Count Tests o Sperm Motility Tests Prognosis [checkorphan.org]
Mild forms of the disease have a good prognosis and subside without sequelae. However, diffuse multisystemic forms have a very poor prognosis. The kidney is the organ that is most often affected (in approximataly 50 % of cases). [escardio.org]
[…] boys than in girls, but occurs in less than 15% of patients. 6 The overall prognosis should be good. [nature.com]
What is the prognosis for compartment syndrome? Acute compartment syndrome is a potentially devastating condition. [medicinenet.com]
Etiology
Introduction Binder syndrome is a rare congenital anomaly with multiple etiologies and multiple associated disorders which are poorly understood because of rarity. [casereports.in]
[…] microphthalmia: a suspected warfarin embryopathy. ( 19702715 ) Downie A.C....Vote B.J. 2009 9 Fetal warfarin syndrome. ( 16856447 ) Sathienkijkanchai A....Wasant P. 2005 10 Fetal warfarin syndrome. ( 15605910 ) Hou J.W. 2004 11 Common phenotype and etiology [malacards.org]
CDP is etiologically heterogeneous. [dovepress.com]
Epidemiology
Our knowledge of potential risks to the fetus and newborn, therefore, is based on case reports, epidemiologic surveys of exposed individuals, and animal studies. [pedsinreview.aappublications.org]
[…] nerve dysfunction in a child following low-dose maternal warfarin exposure. 61 Khan AO 17896319 2007 45 Neurological sequelae of intrauterine warfarin exposure. 61 Raghav S...Reutens D 17107801 2007 46 Rheumatic and nonrheumatic valvular heart disease: epidemiology [malacards.org]
Epidemiologic measures of the course and outcome of pregnancy. Epidemiol Rev 2002; 24: 91-101. DOI:10.1093/epirev/mxf006 Garcia-Enguidanos A, Calle ME, Valero J, et al. Risk factors in miscarriage: a review. [th.schattauer.de]
(See Etiology and Epidemiology.) [3] Additionally, although warfarin is no longer used primarily as a rodenticide, several long-acting coumarin derivatives (the so-called superwarfarin anticoagulants, such as brodifacoum, diphenadione, chlorophacinone [emedicine.medscape.com]
Douketis, C.K.) and Clinical Epidemiology and Biostatistics (J.J., L.C., W.Y., M.G.), McMaster University, Hamilton, Ont.; the Department of Medicine (C.L., P.F., W.G.) and the Undergraduate Medical Program (S.W.), University of Toronto, Toronto; the [nejm.org]
Pathophysiology
The pathophysiological mechanisms resulting in thrombosis in APS is incompletely understood. [clinicaladvisor.com]
with or without anti-La, rather than the type of maternal autoimmune disease, is the risk factor for the development of the disease.33 We do believe that in the cases of CPD, the maternal antibodies that cross the placenta have a major role in the pathophysiology [dovepress.com]
Prevention
Updated health promotion content includes Health Promotion boxes focusing on preventive strategies for achieving prenatal wellness, health during pregnancy, postnatal health, and pediatric illness prevention and wellness -- including the complete immunization [books.google.com]
Aspirin Aspirin (acetyl salicylic acid) is an antiplatelet agent which is commonly used to prevent thrombosis. [cochranelibrary.com]
Prevention[edit] Fetal warfarin syndrome is prevented by withholding prescription to pregnant women or those trying to conceive. [en.wikipedia.org]
References
- Vitale N, De Feo M, De Santo LS, et al. Dose-dependent fetal complications of warfarin in pregnant women with mechanical heart valves. J Am Coll Cardiol 1999;33:1637–41.
- Van Driel D, Wesseling J, Rosendaal FR, et al. Growth until puberty after in utero exposure to coumarins. Am J Med Genet. 2000;95:438-43.
- Walfisch A, Koren G. The ‘warfarin window’ in pregnancy: the importance of half-life. JOGC. 2010;32:988–9.
- Hall JG, Pauli RM, Wilson K. Maternal and fetal sequelae of anticoagulant during pregnancy. Am J Med 1980;68:122-40.
- Chan Ky, Gilbert-Barness E, Tiller G. Warfarin embryopathy. Pediatr Pathol Mol Med. 2003; 22:277-83.
- Bony C, Zyka F, Tiran-Rajaofera I, et al. Warfarin fetopathy. Arch Pediatr 2002;9:705-8.
- Menger H, Lin AE, Toriello HV, et al. Vitamin K deficiency embryopathy: a phenocopy of the warfarin embryopathy due to a disorder of embryonic vitamin K metabolism. Am J Med Genet. 1997;72:129-34.
- Lee HC, Cho SY, Lee HJ, et al. Warfarin-associated fetal intracranial hemorrhage: A case report. J Korean Med Sci. 2003;18:764-7.
- Masamoto H, Uehara H, Mekaru K, et al. Warfarin-associated fetal intracranial hemorrhage in woman with mitral valve replacements: a case report. Am J Perinatol. 2009;26:597–600.
- Chan WS, Anand S, Ginsberg JS. Anticoagulation of pregnant women with mechanical heart valves: a systematic review of the literature. Arch Intern Med. 2000;160:191–6.
- Mason JD, Jardine A, Gibbin KP. Foetal warfarin syndrome — a complex airway problem: Case report and review of the literature. J Laryngol Otol. 1992;106:1098-9.
- Sathienkijkanchai A, Wasant P. Fetal Warfarin syndrome. J Med Assoc Thai. 2005;88(Suppl 8):S246–50.