Pregnancy outcome in women exposed to leflunomide before or during pregnancy.

OBJECTIVE: Findings from animal studies have suggested that leflunomide may be a human teratogen. In the only human cohort study published to date, an increase in adverse outcomes in pregnancies after exposure to leflunomide was not detected. The aim of the present analysis was to expand on the previously published data with a description of birth outcomes among women who did not meet the previous cohort study criteria but who were exposed to leflunomide either during pregnancy or prior to conception. METHODS: Data on pregnancy exposures and outcomes were collected from 45 pregnant women who had contacted counseling services of the Organization of Teratology Information Specialists in the US or Canada between 1999 and 2009. Sixteen women were exposed to leflunomide during the first trimester of pregnancy and 29 women were exposed preconception. RESULTS: All 16 of the pregnancies with leflunomide exposure during pregnancy and 27 (93%) of the pregnancies with exposure prior to conception resulted in liveborn infants. There were 2 infants with major malformations from mothers who were exposed during pregnancy, and no malformations reported in the preconception group. There was a potential known alternative etiology for at least some of the defects observed. CONCLUSION: These data provide additional reassurance to women who inadvertently become pregnant while taking leflunomide and who undergo the washout procedure, as well as women who discontinue the medication prior to conception but have no prepregnancy documentation of drug clearance. However, until more conclusive data become available, women receiving leflunomide should be advised to use contraceptive methods and avoid pregnancy.

Chondrodysplasia Punctata: A Case Report of Fetal Warfarin Syndrome.

Chondrodysplasia punctata is abnormal calcification in the cartilage of developing bones and has been seen in association with deranged vitamin K metabolism. Warfarin, an oral anticoagulant acting on vitamin K dependent clotting factors is known to cause chondrodysplasia punctata. Despite the knowledge of the condition the management of patients with prosthetic heart valves might require use of the drug for anticoagulation. Here, we present a case of a fetal warfarin syndrome in a second born child of a 27 year lady under warfarin for prosthetic heart valve. The pregnancy was complicated by polyhydramnios in third trimester and terminated at term by normal vaginal delivery. The baby was well, except for facial dysmorphism in the form of depressed nasal bridge, narrow nares and suspected left choanal atresia. Radiograph revealed stippled ephiphysis of vertebra, femora and humera supporting diagnosis of fetal warfarin syndrome. The baby did not develop any perinatal complication and was discharged home.

Maternal and fetal sequelae of anticoagulation during pregnancy.

Review of published cases of pregnancies in which coumarin derivatives or heparin were administered demonstrates that use of either class of anticoagulant carries substantial risks. Of 418 reported pregnancies in which coumarin derivatives were used, one-sixth resulted in abnormal liveborn infants, one-sixth in abortion or stillbirth and, at most, two-thirds in apparently normal infants. In addition to the expected hemorrhagic complications, fetal effects of coumarin derivative administration include a specific embryopathy and central nervous system abnormalities. All available cases (including unpublished ones) of warfarin embryopathy and central nervous system abnormalities following gestational exposure to coumarin derivatives are reviewed, various complications are tabulated, critical periods of teratogenesis are discussed and possible mechanisms proposed. The use of heparin during gestation does not result in a significantly better outcome of pregnancy. In 135 published cases, the infants in one-eighth were stillborn, in one-fifth premature (a third of whom died) and, again at most, in two-thirds apparently normal. Because of the substantial risks of both clases of anticoagulants, and the inherent risks of pregnancy complicated by the indications for anticoagulation, prevention of pregnancy is usually indicated. If pregnancy occurs, a relatively normal outcome can be anticipated in about two-thirds of the pregnancies regardless of the anticoagulant used. Heparin does not appear to be a clearly superior alternative to coumarin derivatives.

Prenatal exposure to phenytoin, facial development, and a possible role for vitamin K.

Ten patients with maxillonasal hypoplasia (Binder "syndrome"), who were prenatally exposed to phenytoin (usually in combination with other anticonvulsants), were identified retrospectively. In addition to their facial anomalies, 6 of the patients were radiographed neonatally and showed punctate calcification, characteristic of chondrodysplasia punctata. Evidence is presented that the facial abnormalities seen in these children are due to anticonvulsant-induced vitamin K deficiency, causing abnormal development of the cartilaginous nasal septum. We propose that early vitamin K supplementation of at-risk pregnancies may prevent the development of maxillonasal hypoplasia, which in some patients is severely disfiguring and causes great emotional distress. Correction of this facial defect requires surgical and dental treatment over a long period of time.

Warfarin embryopathy in siblings.

Two siblings were noted to have the physical stigmata of the fetal warfarin syndrome. Their mother had received warfarin sodium for thrombophlebitis during both pregnancies but not during that of an unaffected sibling. Teratogens may produce syndromes that mimic genetic disease in both phenotype and familial aggregation.

[Symptomatic calcification in the newborn. Phenocopies of chondrodysplasia punctata]. / Symptomatische Verkalkungen beim Neugeborenen. Phänokopien der Chondrodysplasia punctata.

Stippled epiphyses occur in the new-born and young infant in the different hereditary forms of chondrodysplasia punctata. Symptomatic stippling has been described also in association with chromosomal anomalies, gangliosidosis and drug induced embryopathies. We present patients with Cumarin-embryopathy (2), fetal alcohol syndrome (1), Zellweger-syndrome (2) and chromosomal anomaly 16 (1) and discuss the typical roentgenographic features, distribution and differential diagnosis of epiphyseal stippling.

[Warfarin fetopathy]. / Foetopathie coumarinique.

UNLABELLED: We report a case of warfarin embryopathy. This disease affects more than 6% of fetuses exposed in utero to a vitamin K antagonist. OBSERVATION: A child whose mother was treated with acenocoumarol because of a mechanical heart valve presented with signs of warfarin embryopathy. He showed chondrodysplasia punctata with telebrachydactyly, facial dysmorphism with nasal hypoplasia, a cataract, and a bilateral pyeloureteral junction syndrome. COMMENTS: Characteristics of this drug induced embryopathy are reminded, while bearing in mind the conflict of interests between the mother and the fetus. The mechanisms of this embryopathy are debated in light of the recent knowledge concerning fetal metabolism of vitamin K.

Warfarin embryopathy: fetal manifestations.

During the period 1991-2007, autopsy was undertaken in 13 fetuses with warfarin embryopathy. Pregnancy data and radiographic babygrams were available in each instance. Gestational age ranged from 17 to 37 weeks. Eleven of the fetuses had the characteristic nasal hypoplasia, but only three had radiological epiphyseal stippling. Cerebral hemorrhage was a major feature of autopsy in 8 of the fetuses, and it is evident that bleeding is a significant factor in the pathogenesis of warfarin embryopathy. A wide variety of additional visceral manifestations which were observed at autopsy have been tabulated. There was no obvious correlation between maternal or gestational age and the presence and severity of any specific embryopathic feature. No information was available concerning the dose and timing of warfarin administration in this series.

Chondrodysplasia punctata after warfarin in early pregnancy. Case report and summary of the literature.

A third case of chondrodysplasia punctata after exposure to warfarin alone in early pregnancy is described. The clinical course of the child during the first 18 months is outlined. The use of warfarin in early pregnancy must be avoided because of its established teratogenic effects in causing this syndrome, in addition to an overall increase in perinatal mortality.

Warfarin as a possible teratogen.

A case of congenital stippled epiphyses is presented, and attention is drawn to the possibility that this condition was caused by maternal ingestion of warfarin during early pregnancy.

[Coumarin-induced fetal abnormalities and stippled epiphyses]. / Embryo-foetopathie coumarinique et maladie des épiphyses ponctuees.

The ability of most anticoagulants (except heparin) to cross the placenta and the consequent hemorrhage in the fetus has been recognized for some time (3). A teratogenic effect specifically attributed to warfarin sodium is a more recent finding (7, 9, 10). The following is a case report of a newborn with clinical and roentgenographic features similar to the cases reported previously.

Chondrodysplasia punctata in an adult recognized as vitamin K antagonist embryopathy.

A 32-year-old man with disproportionate short stature and striking facial dysmorphism came to genetic counseling as his wife was expecting their first child. In early infancy he had been diagnosed as having chondrodysplasia punctata, later regarded to be the autosomal dominant hereditary form. The expectant father was therefore convinced of a high risk of recurrence and vacillated between thoughts of taking his own life and of having his wife's pregnancy terminated. When his history revealed recurrent thromboses in his mother, treated with anticoagulants during pregnancy, her medical records of 1953 were located, and they disclosed that she had been treated with phenprocoumon (Marcoumar) from the 8th to the 12th and from the 13th to the 15th weeks of pregnancy. The patient has since become the father of a healthy son.

Chondrodysplasia punctata after warfarin. Case report with 18-month follow-up.

Administration of warfarin during pregnancy may cause a rare syndrome characterized by nasal hypoplasia, usually associated with stippled epiphyseal and extraepiphyseal calcifications resembling chondrodysplasia punctata. A case of chondrodysplasia punctata after warfarin with 18 months follow-up is reported.

Warfarin embryopathy--a case report.

This is a case report of an infant born with nasal hypoplasia, stippling of epiphyses, and toe deformities. This embryopathy is due to maternal ingestion of Warfarin during pregnancy. Other defects including ophthalmologic and neurologic abnormalities also occur, but the nasal malformation is the only constant clinical feature.

[Coumarin embryopathy]. / Coumarin-Embryopathie.

Anticoagulant therapy using coumarin derivatives (vitamin K antagonists) during early pregnancy may result in a characteristic embryopathy appearing as a phaenocopy of chondrodysplasia punctata (Conradi-Hünermann's disease). This has been suggested in advance by observations made in newborns of mothers who had been treated previously with warfarin or acenocoumon. Similar observations made in a newborn after the mother's treatment with phencoumon in early pregnancy are described in this paper. Coumarin embryopathy is proposed as a common term.

Warfarin therapy initiated during pregnancy and phenotypic chondrodysplasia punctata.

An infant is described who has clinical manifestations and roentgenographic features consistent with the diagnosis of chondrodysplasia punctata. The mother of this infant received warfarin during pregnancy. Eight cases demonstrating an association between warfarin therapy during pregnancy and chondrodysplasia punctata in the child have been reported; in the present case therapy was initiated following conception (see following case report). Warfarin may be teratogenic, producing a phencopy of the heritable forms of chondrodysplasia punctata. Because of the evident association we suggest (1) warfarin is contraindicated in pregnancy and alternative anticoagulants should be used; (2) products of at-risk pregnancies should be screened for the characteristic radiologic findings; and (3) preconceptual counselling and antenatal diagnosis of the disease may be beneficial.

Fetal risks due to warfarin therapy during pregnancy.

Two mothers with heart valve prosthesis were treated with warfarin during pregnancy. In the first case a caesarean section was done one week after replacement of warfarin with heparin. The baby died of cerebral and pulmonary hemorrhage. The second mother had a male infant by caesarean section. The baby showed warfarin-induced embryopathy with nasal hypoplasia and stippled epiphyses (chondrodysplasia punctata). Nasal hypoplasia with or without stippled epiphyses has now been reported in 11 infants born to mothers treated with warfarin during the first trimester, and a causal association is probable. In view of the risks to both mother and fetus in women with prosthetic cardiac valves it is recommended that therapeutic abortion be advised as the first alternative.

Hazards of oral anticoagulants during pregnancy.

Prenatal exposure to oral anticoagulants during pregnancy may result in defective fetal development or life-threatening hemorrhage. Fetal exposure during the first eight weeks of pregnancy may cause abnormal development of the facial structures, hypoplastic digits, strippled epiphyses, and mental retardation. Midtrimester exposure may result in optic atrophy, faulty brain growth, and developmental retardation. Third-trimester exposure may produce fetal anticoagulation, predisposing the infant to life-threatening hemorrhage in the perinatal period. Anticoagulation with heparin sodium does not provide a clearly safe alternative, since this therapy has been associated with excessive fetal loss.