Coumarin Derivatives in Pregnancy and Breastfeeding
Fetal Risk Summary
Coumarin derivatives (dicumarol, ethyl biscoumacetate, and warfarin) are oral anticoagulants, as are the indandione derivatives (anisindione and phenindione). Use of any of these agents during pregnancy may result in significant problems for the fetus and newborn. Since the first case of fetal coumarin embryopathy described by DiSaia in 1966 (1), a large volume of literature has accumulated. Hall and co-workers (2) reviewed this subject in 1980 (167 References). In the 3 years following this review, a number of other reports have appeared (3,4,5,6,7,8,9,10,11 and 12) . The principal problems confronting the fetus and newborn are: Embryopathy (fetal warfarin syndrome) Central nervous system defects Spontaneous abortion Stillbirth Prematurity Hemorrhage First trimester use of coumarin derivatives may result in the fetal warfarin syndrome (FWS) (1,2,3 and 4). The common characteristics of the FWS are nasal hypoplasia because of failure of development of the nasal septum and stippled epiphyses. The bridge of the nose is depressed, resulting in a flattened, upturned appearance. Neonatal respiratory distress occurs frequently because of upper airway obstruction. Other features that may be present are: Birth weight less than 10th percentile for gestational age Eye defects (blindness, optic atrophy, microphthalmia) when drug also used in 2nd and 3rd trimesters Hypoplasia of the extremities (ranging from severe rhizomelic dwarfing to dystrophic nails and shortened fingers) Developmental retardation Seizures Scoliosis Deafness/hearing loss Congenital heart disease Death The critical period of exposure, based on the work of Hall and co-workers (2), seems to be the 6th9th weeks of gestation. All of the known cases of FWS were exposed during at least a portion of these weeks. Exposure after the 1st trimester carries the risk of central nervous system (CNS) defects. No constant grouping of abnormalities was observed, nor was there an apparent correlation between time of exposure and the defects, except that all fetuses were exposed in the 2nd and/or 3rd trimesters. After elimination of those cases that were probably caused by late fetal or neonatal hemorrhage, the CNS defects in 13 infants were thought to represent deformations that occurred as a result of abnormal growth arising from an earlier fetal hemorrhage and subsequent scarring (2). Two patterns were recognized: Dorsal midline dysplasia characterized by agenesis of corpus callosum, Dandy-Walker malformations, and midline cerebellar atrophy; encephaloceles may be present Ventral midline dysplasia characterized by optic atrophy (eye anomalies) Other features of CNS damage in the 13 infants were (number of infants shown in parenthesis): Mental retardation (13) Blindness (7) Spasticity (4) Seizures (3) Deafness (1) Scoliosis (1) Growth failure (1) Death (3) Long-term effects in the children with CNS defects were more significant and debilitating than those from the fetal warfarin syndrome (2).
Fetal outcomes for the 471 cases of in utero exposure to coumarin derivatives reported through 1983 are summarized below (2,3,4,5,6,7,8,9,10,11 and 12): 1ST TRIMESTER EXPOSURE (263) Normal infants167 (63%) Spontaneous abortions41 (16%) Stillborn/neonatal death17 (6%) FWS27 (10%) CNS/other defects11 (4%) 2ND TRIMESTER EXPOSURE (208) Normal infants175 (84%) Spontaneous abortions4 (2%) Stillborn/neonatal death19 (9%) CNS/other defects10 (5%) TOTAL INFANTS EXPOSED (471) Normal infants342 (73%) Spontaneous abortions45 (10%) Stillborn/neonatal death36 (8%) FWS/CNS/other defects48 (10%) Hemorrhage was observed in 11 (3%) of the normal newborns (premature and term). Two of the patients in the 2nd and 3rd trimester groups were treated with the coumarin derivatives phenprocoumon and nicoumalone. Both infants were normal.
Congenital abnormalities that did not fit the pattern of the FWS or CNS defects were reported in 10 infants (2,9). These were thought to be incidental malformations that were probably not related to the use of coumarin derivatives (see also three other cases, in which the relationship to coumarin derivatives is unknown, described in the text below, References 16, 20 and 22) .
Asplenia, two-chambered heart, agenesis of pulmonary artery Anencephaly, spina bifida, congenital absence of clavicles Congenital heart disease, death Fetal distress, focal motor seizures Bilateral polydactyly Congenital corneal leukoma Nonspecified multiple defects Asplenia, congenital heart disease, incomplete rotation of gut, short broad phalanges, hypoplastic nails Single kidney, toe defects, other anomalies, death Cleft palate A 1984 study examined 22 children, with a mean age of 4.0 years, who were exposed in utero to warfarin (13). Physical and mental development of the children was comparable to that of matched controls.
Since publication of the above data, a number of additional reports and studies have appeared describing the outcomes of pregnancies treated at various times with coumarin derivatives (14,15,16,17,18,19,20,21,22,23,24 and 25). The largest series involved 156 women with cardiac valve prostheses who had 223 pregnancies (14). During a period of 19 years, the women were grouped based on evolving treatment regimens: group I68 pregnancies treated with acenocoumarol until the diagnosis of pregnancy was made, and then treated with dipyridamole or aspirin, or both; group II128 pregnancies treated with acenocoumarol throughout gestation; group III12 pregnancies treated with acenocoumarol, except when heparin was substituted from pregnancy diagnosis to the 13th week of gestation, and again from the 38th week until delivery; and group IV15 pregnancies in women with biologic prostheses who were not treated with anticoagulant therapy. The fetal outcomes in the four groups were: spontaneous abortions 10.3% vs. 28.1% vs. 0% vs. 0% (p<0.0005); stillbirths 7.4% vs. 7.1% vs. 0% vs. 6.7%; and neonatal deaths 0% vs. 2.3% vs. 0% vs. 0%. (See Reference for maternal outcomes in the various groups.) Of the 38 children examined in group II, 3 (7.9%) had features of the FWS.
In a subsequent report from these investigators, the outcomes of 72 pregnancies studied prospectively were described in 1986 (15). The pregnancies were categorized into three groups according to the anticoagulant therapy: group I23 pregnancies treated with acenocoumarol except for heparin from the 6th12th weeks of gestation; group II12 pregnancies treated the same as group I except that heparin treatment was started after the 7th week; and group III37 pregnancies treated with acenocoumarol throughout gestation (pregnancies in this group were not detected until after the 1st trimester). In most patients, heparin was substituted for the coumarin derivative after the 38th week of gestation. The fetal outcomes in the three groups were: spontaneous abortions 8.7% vs. 25% vs. 16.2%; and stillbirths 0% vs. 8.3% vs. 0%. Not all of the infants born to the mothers were examined, but of those that were, the FWS was observed in 0% of group I (0 of 19), 25.0% of group II (2 of 8), and 29.6% of group III (8 of 27). Thus, 10 (28.6%) of the 35 infants examined who were exposed at least during the first 7 weeks of gestation had warfarin embryopathy.
A 1983 report described 14 pregnancies in 13 women with a prosthetic heart valve who were treated throughout pregnancy with warfarin (16). Two patients had spontaneous abortions, two delivered premature stillborn infants (one infant had anencephaly), and two newborns died during the neonatal period. The total fetal and neonatal mortality in this series was 43%. Other defects noted were corneal changes in two, bradydactyly and dysplastic nails in two, and nasal hypoplasia in one.
In 18 pregnancies of 16 women with an artificial heart valve, heparin was substituted for warfarin when pregnancy was diagnosed (between 6 and 8 weeks after the last menstrual period) and continued until the 13th week of gestation (17). Nine of the 18 pregnancies aborted, but none of the nine liveborn infants had congenital anomalies or other complications.
Three recent reports have described the pregnancy outcomes in mothers with prosthetic heart valves and who were treated with anticoagulants (18,19 and 20). A study published in 1991 described the outcomes of 64 pregnancies in 40 women with cardiac valve replacement, 34 of whom had mechanical valves (18). Warfarin was used in 47 pregnancies (23 women), heparin in 11 pregnancies (11 women), and no anticoagulation was given in 6 pregnancies (6 women). Fetal wastage (spontaneous abortions, neonatal death after preterm delivery, and stillbirths) occurred in 25 (53%) of the warfarin group, 4 (36%) of those treated with heparin, and 1 (17%) of those not treated. Two infants, both exposed to warfarin, had congenital malformations: single kidney and toe, and finger defects in one; cleft lip and palate in the other.
Two groups of pregnant patients with prosthetic heart valves were compared in a study published in 1992 (19). In Group 1 (N=40), all treated with coumarin-like drugs until near term when therapy was changed to heparin, 34 (85%) had mechanical valves, whereas none of those in Group 2 (N=20) were treated with anticoagulation and all had biological valves. The pregnancy outcomes of the two groups were: spontaneous abortions 7 vs. 0, prematurity 14 vs. 2 (p<0.05), low birth weight 15 vs. 2 (p<0.05), stillbirth 1 vs. 0, neonatal mortality 5 vs. 0, and birth defects 4 vs. 0, respectively. The four infants from Group 1 with birth defects included three with typical features of the Fetal Warfarin Syndrome (one with low birth weight and upper airway obstruction) and one with left ventricular hypoplasia and aortic atresia (died in neonatal period). The other four neonatal deaths involved three from respiratory distress syndrome and one from a cerebral hemorrhage.
A 1994 Reference compared retrospectively two groups of pregnant women: Group 1 (56 pregnancies in 31 women) with mechanical valve replacements, all of whom were treated with warfarin; and Group 2 (95 pregnancies in 57 women) with porcine tissue valves, none of whom received anticoagulation. Twenty women in Group 1 either continued the warfarin throughout delivery (N=12) or discontinued the drug (N=8) 12 days before delivery. The pregnancy outcomes of the two groups were: induced abortion 9 vs. 22, fetal loss before 20 weeks' gestation 7 vs. 8, fetal loss after 20 weeks' 6 vs. 1 (p<0.01), total fetal loss 13 vs. 9 (p<0.05), and live births 34 vs. 64 (p<0.05). Two infants, both in Group 1 had birth defects, a ventricular septal defect in one and a hypoplastic nose in the other.
Five reports have described single cases of exposure to warfarin during pregnancy (21,22,23,24 and 25). A woman with Marfan's syndrome had replacement of her aortic arch and valve combined with coronary artery bypass performed during the 1st week of her pregnancy (18 days after conception) (21). She was treated with warfarin throughout gestation. A normal female infant was delivered by elective cesarean section at 34 weeks' gestation. Warfarin was used to treat a deep vein thrombosis during the 3rd trimester in a 34-year-old woman because of heparin-induced maternal thrombocytopenia (22). A normal infant was delivered at term. In another case involving a woman with a deep vein thrombosis that had occurred before the present pregnancy, warfarin therapy was continued through the first 14 weeks of gestation (23). At term, a 3660-g infant was delivered who did not breathe and who died after 35 minutes. At autopsy, an almost total agenesis of the left diaphragm and hypoplasia of both lungs were noted. The relationship between warfarin and the defect is unknown.
The use of warfarin to treat a deep vein thrombosis associated with circulating lupus anticoagulant during pregnancy has been described (24). Therapy was started after the 9th week of gestation. Because of severe pregnancy-induced hypertension, a 1830-g female infant was delivered by cesarean section at 31 weeks. No information was provided about the condition of the infant.
A woman with a mitral valve replacement 8 months before pregnancy was treated continuously with warfarin until 6 weeks after her last menstrual period (25). Warfarin was then stopped and except for cigarette smoking, no other drugs were taken during the pregnancy. A growth-retarded (2340 g, 3rd percentile; 50 cm length, 50th percentile; 35 cm head circumference, 50th percentile) female infant was delivered at term. Congenital abnormalities noted in the infant were triangular face with broad forehead, micrognathia, microglossia, hypoplastic fingernails and toenails, and hypoplasia of the distal phalanges. No epiphyseal stippling was seen on a skeletal survey. A normal female karyotype, 46,XX was found on chromosomal analysis. Psychomotor development was normal at 1 year of age but physical growth remained retarded (3rd percentile). The authors concluded that the pattern of defects represented the earliest teratogenic effects of warfarin, but they could not exclude a chance association with the drug.
In a surveillance study of Michigan Medicaid recipients involving 229,101 completed pregnancies conducted between 1985 and 1992, 22 newborns had been exposed to warfarin during the 1st trimester (Franz Rosa, personal communication, FDA, 1993). One (4.5%) major birth defect was observed (one expected), a cardiovascular defect (0.2 expected).
A report published in 1994 assessed the neurological, cognitive and behavioral development of 21 children (8 to 10 years of age) who had been exposed in utero to coumarin derivatives (26). A control group of 17 children was used for comparison. Following examination, 32 of the children were classified as normal (18 exposed and 14 control children), 5 had minor neurological dysfunction (2 exposed and 3 control children), and one child had severe neurological abnormalities which were thought to be due to oral anticoagulants. Although no significant differences were measured between the groups, the children with the lowest neurological assessments and the lowest IQ-scores had been exposed to coumarin derivatives.
In summary, the use of coumarin derivatives during the 1st trimester carries with it a significant risk to the fetus. For all cases, only about 70% of pregnancies are expected to result in a normal infant. Exposure in the 6th9th weeks of gestation may produce a pattern of defects termed the fetal warfarin syndrome with an incidence up to 25% or greater in some series. Infants exposed before and after this period have had other congenital anomalies, but the relationship between warfarin and these defects is unknown. Infrequent central nervous system defects, which have greater clinical significance to the infant than the defects of the fetal warfarin syndrome, may be deformations related to hemorrhage and scarring with subsequent impaired growth of brain tissue. Spontaneous abortions, stillbirths, and neonatal deaths may also occur. If the mother's condition requires anticoagulation, the use of heparin from the start of the 6th gestational week through the end of the 12th gestational week, and again at term, may lessen the risk to the fetus of adverse outcome.
[* Risk Factor X according to manufacturerDuPont Pharma, 2000.]
Breast Feeding Summary
Excretion of coumarin (dicumarol, ethyl biscoumacetate, and warfarin) and indandione (anisindione and phenindione) derivatives into breast milk is dependent on the agent used. Three reports on warfarin have been located totaling 15 lactating women (27,28 and 29). Doses ranged between 2 and 12 mg/day in 13 patients (7 nursing, 6 not nursing) with serum levels varying from 1.68.5 mol/L (27,28). Warfarin was not detected in the milk of any of the 13 patients or in the plasma of the 7 nursing infants. No anticoagulant effect was found in the plasma of the three infants tested (27,28). In another report, the warfarin doses in two breast feeding women were not specified nor were maternal plasma drug levels determined (29). However, no spectrophotometric evidence for the drug was found in the milk of one mother and no anticoagulant effect was measured in either nursing infant (29).
Exposure to ethyl biscoumacetate in milk resulted in bleeding in 5 of 42 exposed infants in one report (30). The maternal dosage was not given. An unidentified metabolite was found in the milk that may have led to the high complication rate. A 1959 study measured ethyl biscoumacetate levels in 38 milk specimens obtained from four women taking 6001200 mg/day (31). The drug was detected in only 13 samples with levels varying from 0.091.69 g/mL. No correlation could be found between the milk concentrations and the dosage or time of administration. A total of 22 infants were breast-fed from these and other mothers receiving ethyl biscoumacetate. No adverse effects were observed in the infants, but coagulation tests were not conducted.
More than 1,600 postpartum women were treated with dicumarol to prevent thromboembolic complications in a 1950 study (32). Doses were titrated to adjust the prothrombin clotting time to 40%50% of normal. No adverse effects or any change in prothrombin times were noted in any of the nursing infants.
Phenindione use in a lactating woman resulted in a massive scrotal hematoma and wound oozing in a 1.5-month-old breast-fed infant shortly after a herniotomy was performed (33). The mother was taking 50 mg every morning and alternating between 50 and 25 mg every night for suspected pulmonary embolism that developed postpartum. Milk levels varying from 15 g/mL have been reported after 50- or 75-mg single doses of phenindione (34). When the dose was 25 mg, only 18 of 68 samples contained detectable amounts of the anticoagulant.
In summary, maternal warfarin consumption apparently does not pose a significant risk to normal, full-term, breast-fed infants. Other oral anticoagulants should be avoided by the lactating woman. The American Academy of Pediatrics considers phenindione (which is not used in the United States) to be contraindicated during breast feeding because of the risk of hemorrhage in the infant (35). Both warfarin and dicumarol (bishydroxycoumarin) are classified by the Academy to be compatible with breast feeding (35).
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