Anticoagulant
PREGNANCY RECOMMENDATION: Contraindicated—1st Trimester
BREASTFEEDING RECOMMENDATION: Compatible; Contraindicated (Phenindione)
PREGNANCY 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 6th–9th 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.
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 coworkers (2) reviewed this subject in 1980 (167 references). In the 3 years following this review, a number of other reports have appeared (3–12). The principal problems confronting the fetus and newborn are as follows:
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) (1–4). 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 as follows:
Birth weight <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 coworkers (2), seems to be the 6th–9th 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 were 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: (a) dorsal midline dysplasia characterized by agenesis of corpus callosum, Dandy-Walker malformations, and midline cerebellar atrophy (encephaloceles may be present); and (b) 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 (2–12):
1ST TRIMESTER EXPOSURE (263):
Normal infants—167 (63%)
Spontaneous abortions—41 (16%)
Stillborn/neonatal death—17 (6%)
FWS—27 (10%)
CNS/other defects—11 (4%)
2ND TRIMESTER EXPOSURE (208):
Normal infants—175 (84%)
Spontaneous abortions—4 (2%)
Stillborn/neonatal death—19 (9%)
CNS/other defects—10 (5%)
TOTAL INFANTS EXPOSED (471):
Normal infants—342 (73%)
Spontaneous abortions—45 (10%)
Stillborn/neonatal death—36 (8%)
FWS/CNS/other defects—48 (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 16,20,22).
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 (13–25). 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 I—68 pregnancies treated with acenocoumarol until the diagnosis of pregnancy was made, and then treated with dipyridamole or aspirin, or both; group II—128 pregnancies treated with acenocoumarol throughout gestation; group III—12 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 IV—15 pregnancies in women with biologic prostheses who were not treated with anticoagulant therapy. The fetal outcomes in the four groups were as follows: 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 I—23 pregnancies treated with acenocoumarol except for heparin from the 6th to 12th week of gestation; group II—12 pregnancies treated the same as group I except that heparin treatment was started after the 7th week; and group III—37 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 reports described the pregnancy outcomes in mothers with prosthetic heart valves and who were treated with anticoagulants (18–20). 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 as follows: spontaneous abortions 7 and 0, prematurity 14 and 2 (p <0.05), low birth weight 15 and 2 (p <0.05), stillbirth 1 and 0, neonatal mortality 5 and 0, and birth defects 4 and 0. The 4 infants from group 1 with birth defects included 3 with typical features of FWS (1 with low birth weight and upper airway obstruction) and 1 with left ventricular hypoplasia and aortic atresia (died in neonatal period). The other 4 neonatal deaths involved 3 from respiratory distress syndrome and 1 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 (20). Twenty women in group 1 either continued the warfarin throughout delivery (N = 12) or discontinued the drug (N = 8) 1–2 days before delivery. The pregnancy outcomes of the two groups were as follows: induced abortion 9 and 22, fetal loss before 20 weeks’ gestation 7 and 8, fetal loss after 20 weeks’ gestation 6 and 1 (p <0.01), total fetal loss 13 and 9 (p <0.05), and live births 34 and 64 (p <0.05). Two infants, both in group 1 had birth defects—a ventricular septal defect in 1 and a hypoplastic nose in the other (20).
Five reports have described single cases of exposure to warfarin during pregnancy (21–25). 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 (1–8 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 ninth 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-restricted (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 restricted (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 (F. 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 (8–10 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 1 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 (26).
In a 2013 report, a 19-year-old primigravid woman at 32 weeks’ gestation was admitted to the hospital with coagulopathy (27). She had spontaneous bleeding from the oral mucosa and from nicks on her legs from shaving and frank hematuria. Her international normalized ratio (INR) was >9. The fetus showed evidence of acidosis. Fresh-frozen plasma was given and bleeding stopped after about 1 hour. A 2180-g female infant was delivered by emergent cesarean section with Apgar scores of 0, 2, and 3 at 1, 5, and 10 minutes, respectively. The infant’s INR was >9. She died on day 4 of life. Further history was obtained from the mother and it was learned that she had ingested brodifacoum, a second-generation rodenticidal anticoagulant. The agent was identified in maternal serum and cord blood. Because brodifacoum is lipophilic and has a very long half-life (up to several months), the mother required IV vitamin K (35 mg over several days) and high oral doses (up to 60 mg/day). Thirty days after presentation, her INR had decreased to 1.8 (27).
BREASTFEEDING 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 (28–30). Doses ranged between 2 and 12 mg/day in 13 patients (7 nursing, 6 not nursing) with serum levels varying from 1.6 to 8.5 μmol/L (28,29). 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. In another report, the warfarin doses in two breastfeeding women were not specified nor were maternal plasma drug levels determined (30). 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.
Exposure to ethyl biscoumacetate in milk resulted in bleeding in 5 of 42 exposed infants in one report (31). 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 600–1200 mg/day (32). The drug was detected in only 13 samples with levels varying from 0.09 to 1.69 mcg/mL. No correlation could be found between the milk concentrations and the dosage or time of administration. Twenty-two infants were breastfed from these and other mothers receiving ethyl biscoumacetate. No adverse effects were observed in the infants, but coagulation tests were not conducted (32).
More than 1600 postpartum women were treated with dicumarol to prevent thromboembolic complications in a 1950 study (33). 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 breastfed infant shortly after a herniotomy was performed (34). 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 1 to 5 mcg/mL have been reported after 50- or 75-mg single doses of phenindione (35). When the dose was 25 mg, only 18 of 68 samples contained detectable amounts of the anticoagulant.
Maternal warfarin consumption apparently does not pose a significant risk to normal, full-term, breastfed infants. Other oral anticoagulants should be avoided by the lactating woman. The American Academy of Pediatrics classifies phenindione (which is not used in the United States) as contraindicated during breastfeeding because of the risk of hemorrhage in the infant (36). Both warfarin and dicumarol (bishydroxycoumarin) are classified by the Academy as compatible with breastfeeding.
References
1.DiSaia PJ. Pregnancy and delivery of a patient with a Starr-Edwards mitral valve prosthesis. Obstet Gynecol 1966;28:469–71.
2.Hall JG, Pauli RM, Wilson KM. Maternal and fetal sequelae of anticoagulation during pregnancy. Am J Med 1980;68:122–40.
3.Baillie M, Allen ED, Elkington AR. The congenital warfarin syndrome: a case report. Br J Ophthalmol 1980;64:633–5.
4.Harrod MJE, Sherrod PS. Warfarin embryopathy in siblings. Obstet Gynecol 1981;57:673–6.
5.Russo R, Bortolotti U, Schivazappa L, Girolami A. Warfarin treatment during pregnancy: a clinical note. Haemostasis 1979;8:96–8.
6.Biale Y, Cantor A, Lewenthal H, Gueron M. The course of pregnancy in patients with artificial heart valves treated with dipyridamole. Int J Gynaecol Obstet 1980;18:128–32.
7.Moe N. Anticoagulant therapy in the prevention of placental infarction and perinatal death. Obstet Gynecol 1982;59:481–3.
8.Kaplan LC, Anderson GG, Ring BA. Congenital hydrocephalus and Dandy-Walker malformation associated with warfarin use during pregnancy. Birth Defects 1982;18:79–83.
9.Chen WWC, Chan CS, Lee PK, Wang RYC, Wong VCW. Pregnancy in patients with prosthetic heart valves: an experience with 45 pregnancies. Q J Med 1982;51:358–65.
10.Vellenga E, Van Imhoff GW, Aarnoudse JG. Effective prophylaxis with oral anticoagulants and low-dose heparin during pregnancy in an antithrombin III deficient woman. Lancet 1983;2:224.
11.Michiels JJ, Stibbe J, Vellenga E, Van Vliet HHDM. Prophylaxis of thrombosis in antithrombin III-deficient women during pregnancy and delivery. Eur J Obstet Gynecol Reprod Biol 1984;18:149–53.
12.Oakley C. Pregnancy in patients with prosthetic heart valves. Br Med J 1983;286:1680–3.
13.Chong MKB, Harvey D, De Swiet M. Follow-up study of children whose mothers were treated with warfarin during pregnancy. Br J Obstet Gynaecol 1984;91:1070–3.
14.Salazar E, Zajarias A, Gutierrez N, Iturbe I. The problem of cardiac valve prostheses, anticoagulants, and pregnancy. Circulation 1984;70(Suppl 1):I169–77.
15.Iturbe-Alessio I, Fonseca MDC, Mutchinik O, Santos MA, Zajarias A, Salazar E. Risks of anticoagulant therapy in pregnant women with artificial heart valves. N Engl J Med 1986;315:1390–3.
16.Sheikhzadeh A, Ghabusi P, Hakim S, Wendler G, Sarram M, Tarbiat S. Congestive heart failure in valvular heart disease in pregnancies with and without valvular prostheses and anticoagulant therapy. Clin Cardiol 1983;6:465–70.
17.Lee P-K, Wang RYC, Chow JSF, Cheung K-L, Wong VCW, Chan T-K. Combined use of warfarin and adjusted subcutaneous heparin during pregnancy in patients with an artificial heart valve. J Am Coll Cardiol 1986;8:221–4.
18.Ayhan A, Yapar EG, Yuce K, Kisnisci HA, Nazli N, Ozmen F. Pregnancy and its complications after cardiac valve replacement. Int J Gynecol Obstet 1991;35:117–22.
19.Born D, Martinez EE, Almeida PAM, Santos DV, Carvalho ACC, Moron AF, Miyasaki CH, Moraes SD, Ambrose JA. Pregnancy in patients with prosthetic heart valves: the effects of anticoagulation on mother, fetus, and neonate. Am Heart J 1992;124:413–7.
20.Lee C-N, Wu C-C, Lin P-Y, Hsieh F-J, Chen H-Y. Pregnancy following cardiac prosthetic valve replacement. Obstet Gynecol 1994;83:353–60.
21.Cola LM, Lavin JP Jr. Pregnancy complicated by Marfan’s syndrome with aortic arch dissection, subsequent aortic arch replacement and triple coronary artery bypass grafts. J Reprod Med 1985;30:685–8.
22.Copplestone A, Oscier DG. Heparin-induced thrombocytopenia in pregnancy. Br J Haematol 1987;65:248.
23.Normann EK, Stray-Pedersen B. Warfarin-induced fetal diaphragmatic hernia: case report. Br J Obstet Gynaecol 1989;96:729–30.
24.Campbell JM, Tate G, Scott JS. The use of warfarin in pregnancy complicated by circulating lupus anticoagulant; a technique for monitoring. Eur J Obstet Gynecol Reprod Biol 1988;29:27–32.
25.Ruthnum P, Tolmie JL. Atypical malformations in an infant exposed to warfarin during the first trimester of pregnancy. Teratology 1987;36:299–301.
26.Olthof E, De Vries TW, Touwen BCL, Smrkovsky M, Geven-Boere LM, Heijmans HSA, Van der Veer E. Late neurological, cognitive and behavioural sequelae of prenatal exposure to coumarins: a pilot study. Ear Hum Develop 1994;38:97–109.
27.Mehlhaff KM, Baxter CC, Rudinsky K, McKenna DS. Lethal neonatal coagulopathy after maternal ingestion of a superwarfarin. Obstet Gynecol 2013;122:500–2.
28.Orme ML, Lewis PJ, De Swiet M, Serlin MJ, Sibeon R, Baty JD, Breckenridge AM. May mothers given warfarin breast-feed their infants? Br Med J 1977;1:1564–5.
29.De Swiet M, Lewis PJ. Excretion of anticoagulants in human milk. N Engl J Med 1977;297:1471.
30.McKenna R, Cole ER, Vasan U. Is warfarin sodium contraindicated in the lactating mother? J Pediatr 1983;103:325–7.
31.Gostof, Momolka, Zilenka. Les substances derivees du tromexane dans le lait maternal et leurs actions paradoxales sur la prothrombine. Schweiz Med Wochenschr 1952;30:764–5. As cited in Daily JW. Anticoagulant and cardiovascular drugs. In: Wilson JT, ed. Drugs in Breast Milk. Balgowlah, Australia: ADIS Press, 1981:63.
32.Illingworth RS, Finch E. Ethyl biscoumacetate (Tromexan) in human milk. J Obstet Gynaecol Br Commonw 1959;66:487–8.
33.Brambel CE, Hunter RE. Effect of dicumarol on the nursing infant. Am J Obstet Gynecol 1950;59:1153–9.
34.Eckstein HB, Jack B. Breast-feeding and anticoagulant therapy. Lancet 1970;1:672–3.
35.Goguel M, Noel G, Gillet JY. Therapeutique anticoagulante et allaitement: etude du passage de la phenyl-2-dioxo,1,3 indane dans le lait maternal. Rev Fr Gynecol Obstet 1970;65:409–12. As cited in Anderson PO. Drugs and breast feeding—a review. Drug Intell Clin Pharm 1977;11:208–23.
36.Committee on Drugs, American Academy of Pediatrics. The transfer of drugs and other chemicals into human milk. Pediatrics 2001;108:776–89.