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WARFARIN
SUMMARY
 Warfarin is classified as FDA pregnancy category X. Warfarin passes through the
placental barrier and there is the potential for fatal hemorrhage to the fetus in utero.
The use of warfarin during pregnancy has been associated with teratogenic effects.
TERATOGENICITY
 SKELETAL MALFORMATION
 Characteristic skeletal anomalies (warfarin embryopathy) have been commonly
associated with warfarin use during the first trimester and central nervous system
defects when given later in pregnancy (Kaplan, 1985; Schardein, 1985).
 CONGENITAL ANOMALY
 FIRST TRIMESTER - The use of coumarin derivatives during the first trimester of
pregnancy has resulted in characteristic anomalies (fetal warfarin syndrome),
including nasal hypoplasia with or without choanal atresia, secondary respiratory
deficiency, dextrocardia, abdominal situs inversus, calcified stippled epiphyses,
reduced birth weight, rhizomelia (short proximal limbs), scoliosis, short phalanges,
and growth or mental retardation (Prod Info COUMADIN(R) oral tablets, IV
injection, 2007; Hall et al, 1980; Mason et al, 1992; Wong et al, 1993; Barker et al,
1994; Wellesley et al, 1998).
 2ND & 3RD TRIMESTER - Second- and third-trimester exposure have been
associated with central nervous system (CNS) defects, although not
characteristically grouped (Hall et al, 1980; Iturbe-Alessio et al, 1986; Pauli, 1988;
Pati & Helmbrecht, 1994). CNS defects include mental retardation, optic atrophy,
spasticity, and seizures. Fetal death, neonatal hemorrhage, and increased risk of
maternal hemorrhage are also potential complications of second- or third-trimester
anticoagulant therapy (Prod Info COUMADIN(R) oral tablets, IV injection, 2007;
Abadi et al, 2002). (Wong et al, 1993).
 Asplenia and delayed psychomotor development have also been reported (Cox,
1977; Holzgreve, 1976). Craniofacial (including nose and tongue),
musculoskeletal, skin, gastrointestinal, and cardiovascular developmental
abnormalities have been observed in humans (Lewis, 1996).
 CONGENITAL OPHTHALMIC ABNORMALITIES - The offspring of women taking
therapeutic warfarin during pregnancy have had a variety of ophthalmic disorders
including optic atrophy, large eyes, microphthalmos, and opacified lenses (Grant,
1993).

 EXCESSIVE DOSES - Some of these complications have been associated with
excessive doses and failure to stop warfarin for a sufficient time prior to delivery
(Witter et al, 1981; Lamontagne et al, 1984; Hall et al, 1980; Kort & Cassel, 1981)
 DOSE-DEPENDENCE - In a retrospective review of 43 women with mechanical
heart valves and 58 pregnancies over a 10-year period, investigators observed a
dose-dependent effect of warfarin on fetal complications. The patients received
warfarin throughout pregnancy to maintain the international normalized ratio (INR)
between 2.5 and 3.5, and underwent planned caesarian section at 38 weeks, 2
days after temporary warfarin discontinuation. The 58 pregnancies resulted in 31
healthy infants and 27 fetal complications. Among 33 pregnancies in women on a
warfarin dose of 5 mg/day or less, there were 28 healthy infants (27 full-term and
1 premature) and 5 fetal complications (4 miscarriages and 1 growth retardation).
Among 25 pregnancies in women on a warfarin dose above 5 mg/day, there were
3 full-term healthy infants and 22 fetal complications (18 miscarriages, 2 warfarin
embryopathies of cartilage maldevelopment, 1 stillbirth, and 1 ventricular septal
defect). The difference in fetal complications between the two warfarin dose
groups was statistically significant (p=0.0001). Maternal complications included
two cases of valve thrombosis, with no bleeding events (Vitale et al, 1999).

Long term anticoagulant therapy is often indicated in patients with heart valves or
thromboembolic disease, and the teratogenic potential of these therapeutic agents
may contraindicate pregnancy. However, high-risk pregnancies may be inherent
in this patient population, regardless of drug treatment (Hall et al, 1980a; Nageotte
et al, 1981; Born et al, 1992).
 ANIMAL STUDIES
 In rodent studies, post-implantation mortality, fetotoxicity, musculoskeletal and
craniofacial developmental abnormalities, biochemical and metabolic changes,
fetal death, extra-embryonic structures, fertility changes and still births have
been observed ((RTECS, 1998)).
 LACK OF EFFECT
 In one case, serial fetal blood samples showed adequate clotting status between
33 and 38 weeks of gestation when a pregnant woman was treated with warfarin
1 mg/day for antithrombin III deficiency that could not be managed with heparin
(Porreco et al, 1993). It cannot, however, be concluded from this single case that
this dose of warfarin is safe for the unborn, because the child would require longterm follow-up evaluation to exclude latent developmental effects.
PREGNANCY EFFECTS
 PREGNANCY DISORDER
 Because warfarin passes through the placental barrier, fatal hemorrhage to the
fetus in utero may occur (Prod Info COUMADIN(R) oral tablets, IV injection,
2007).
 An increased risk of spontaneous abortion with no congenital abnormalities has
been associated with warfarin therapy received during weeks 13 through 37 of
pregnancy (Lee, 1986).
 In one study, nearly 29% of pregnancies in 115 women receiving coumarin
derivatives resulted in malformations, including structural defects (13.9%), in utero
fetal death (13%), and neonatal hemorrhage (1.8%) (Guillot, 1979). . In another
study of 418 pregnancies exposed to warfarin, 2 out of 3 had normal outcomes, 1
of 6 had malformations, and 1 of 6 resulted in abortion or stillbirth (Hall et al,
1980).
 In a study of 40 patients with heart disease who received warfarin therapy during
pregnancy, fetal mortality was 12.5%, but no cases of congenital epiphyseal
stippling were detected. Maternal postpartum bleeding, however, was frequent
(Kort & Cassel, 1981).
 In a study of 52 patients with mechanical valve prostheses who had a total of 71
pregnancies (52 first pregnancies and 19 subsequent pregnancies) and who were
on long-term warfarin therapy for the duration of their pregnancies, spontaneous
abortions occurred in 23 of the pregnancies, stillbirths occurred in 5 of the
pregnancies, and embryopathies occurred in 2 of the pregnancies. Poor
pregnancy outcome appeared to be directly related to the warfarin dose. A
warfarin daily dose of greater than 5 mg was associated with a poor pregnancy
outcome in 27 of 30 pregnancies as compared with a warfarin daily dose of 5 mg
or less that was associated with a poor pregnancy outcome in 3 of 30 pregnancies
(Cotrufo et al, 2002).
 HEMORRHAGE
 FETAL INTRAVENTRICULAR HEMORRHAGE - detected in the third trimester of
pregnancy, developed following maternal ingestion of warfarin. The infants died at
29 and 33 weeks gestation (Ville et al, 1993).
 PREGNANCY CATEGORY
 The manufacturer has classified warfarin as FDA pregnancy category X (Prod Info
COUMADIN(R) oral tablets, IV injection, 2007).
 PLACENTAL BARRIER
 Warfarin freely crosses the placenta and results in hemorrhagic complications in
the fetus. Warfarin (administered as sodium warfarin) was found to bind less
tightly to fetal albumin in comparison to albumin in both pregnant and non-
pregnant women. Levels of free warfarin were higher in the fetus (Bajoria et al,
1996). This implies that the fetus would be exposed to higher effective
concentrations of warfarin than the mother.
 ABORTION
 A high incidence of spontaneous abortion (9 of 18 pregnancies) in the absence of
congenital malformations occurred when warfarin was given between the 13th
and 37th weeks of pregnancy (Lee, 1986a).
BREAST FEEDING
 BREAST MILK
 LACK OF EFFECT
 Based on limited data, warfarin is not present in the breast milk of nursing
mothers treated with warfarin. There are no reports of the effect of concomitant
breast-feeding and warfarin use on a premature nursing infant (Prod Info
COUMADIN(R) oral tablets, IV injection, 2007). Breast milk assays from a total
of 28 mothers receiving 2 to 12 mg/day of warfarin exhibited nearly
undetectable levels, and none of the infants had detectable plasma warfarin
levels (Orme et al, 1977; DeSwiet & Lewis, 1977; McKenna et al, 1983)
 BREAST MILK
 Prolonged prothrombin times have been reported in some breast-fed infants of
mothers treated with warfarin; however, the prothrombin time in the mother is
more prolonged.(Prod Info COUMADIN(R) oral tablets, IV injection, 2007).
Warfarin is considered compatible with breast-feeding by The American
Academy of Pediatrics and the World Health Organization (WHO) (McKenna et
al, 1983a; Anon, 2002; Anon, 2001).
FERTILITY EFFECTS
SUMMARY
 LACK OF INFORMATION
 No information about possible male reproductive effects was found in
available references at the time of this review.
MALE


LACK OF INFORMATION
No information about possible male reproductive effects was found in
available references at the time of this review.
COUMARIN DERIVATIVES
Reprotox
®
Summaries on the effects of medications, chemicals, infections, and physical agents
on pregnancy, reproduction, and development
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Quick take: Use of warfarin and related anticoagulants during pregnancy increases the risk of structural
malformations and other adverse pregnancy outcome. It is possible that low-dose warfarin is associated
with less risk, but substitution of heparin during pregnancy may be a useful alternative.
***
Coumarin derivatives (warfarin, dicumarol, phenindione, acenocoumarol, diphenadione, phenprocoumon,
anisindione) are orally active anticoagulants. Warfarin (Coumadin) is by far the most widely used agent. The
other members of this group are generally more toxic and difficult to use safely. Phenindione has been
associated with such severe side effects that specific recommendations against its clinical use have been
made (1). No phenindione product is marketed in the United States, although phenindione is still listed in
the USP (37). The American College of Obstetricians and Gynecologists recommends use of heparin #1261
(especially low molecular weight heparins) instead of coumarins during pregnancy, except possibly for
women with valve prostheses due to their greater susceptibility to thrombosis (52).
The coumarin anticoagulants were at one time considered unique among agents that cause birth defects in
humans because of the lack of an animal model (2,3). A rat model (4) has been described, however, and
will be discussed below. The major anomalies associated with first trimester human exposures to warfarin
(the fetal warfarin syndrome) are skeletal defects, which include nasal hypoplasia and stippled epiphyses
(5,6). The stippling of the epiphyses is a radiologic finding that apparently resolves as the epiphyses calcify;
however, limb hypoplasia, primarily involving the distal digits, may be seen in up to one-third of children with
the warfarin embryopathy (7). The nasal hypoplasia may be severe, and if associated with choanal atresia
may require intubation for ventilatory support. Other abnormalities that have been associated with the
warfarin embryopathy are central nervous system and ophthalmic anomalies, hearing loss, intrauterine
growth retardation, and, in a small number of cases, congenital heart disease (7,24,39) and one report of
hepatopathy (40).
A proposed mechanism by which the coumarin anticoagulants induce bone and cartilage abnormalities
involves the inhibition of vitamin K epoxide reductase by these agents (16). A rat model of maxillonasal
hypoplasia and other skeletal anomalies induced by warfarin demonstrates that the anomalies are not
prevented by co-administration of vitamin K (4). The authors suggested that the anomalies were most likely
associated with extrahepatic vitamin K deficiency, which prevents the normal formation of bone matrix
proteins. Additional case reports suggest that coumarin exposures during the first trimester may induce
malformations of the central nervous system, eye, and jaw without causing the other stigmata of warfarin
embryopathy (17,18). Two case reports associating first trimester warfarin exposure and fetal diaphragmatic
hernia have appeared (19,20). Another case report has suggested that kidney abnormalities and
malformations of the urinary tract may also be associated with maternal warfarin exposure (17). Case
reports do not establish causation.
A teratology information service study (51) reported pregnancy outcomes for 666 pregnancies exposed to
one or more vitamin K antagonists including phenprocoumon (n=280), acenocoumarol (n=226), fluindione
(n=99), warfarin (n=63), and phenindione (n=2). Outcomes were assessed by structured questionnaires or
telephone interviews with the mother and/or involved physicians. There is concern about outcome
information collected from different sources, including non-physician mothers and physicians with different
levels of training; however, according to the lead author of this study, data are routinely checked for
plausibility and completeness of the pediatric findings. In case of doubts the pediatrician and/or additional
physicians are contacted to complete the data set (C. Schaefer, personal communication). The authors
reported a statistically significant increased risk of miscarriage, odds ratio 3.78 (95% CI 2.77-5.18), preterm
birth, odds ratio 2.61 (95% CI 1.76-3.86), and major congenital malformation, odds ratio 4.02 (95%
confidence interval 1.96-8.24), for these drugs considered together. The greatest increase in congenital
malformations occurred with warfarin; however, this analysis was based on only 5 affected children who had
diverse abnormalities (one child each with renal dysplasia, pyloric stenosis, enlarged cerebral ventricles,
diaphragmatic hernia, clubfoot). The lead author commented that although a significantly increased rate of
major birth defects with first trimester exposure to vitamin K antagonists was found (4.8% vs. 1.4%; OR
3.86; 95% CI 1.86-8.00), there were only two coumarin embryopathies observed among 356 live births
(0.6%). Apart from two children with diaphragmatic hernias - one was exposed beyond the sensitive period,
and this defect was therefore unrelated to the VKA exposure - the majority of birth defects were
heterogeneous and not indicative of coumarin embryopathy. Therefore, the study suggests that vitamin K
antagonists do not represent a major teratogenic risk in early pregnancy. Similar to earlier published case
reports, this study found no indication of coumarin embryopathy in cases where exposure was exclusively
before week 8 menstrual weeks gestation.
Women with a history of thromboembolic disease or artificial heart valves often require long-term
anticoagulant therapy. This patient population may experience pregnancy complications no matter which
class of anticoagulant is prescribed (8-10, 30, 45). Some reports suggest that obstetric risks may be less
when heparin (#1261) is used (9), while others suggest low dose warfarin (<5 mg) is more effective as an
anticoagulant (41,44). In addition to increased pregnancy risks in women receiving anticoagulants, normal
ovulation is more likely to induce a corpus luteum hemorrhage, and some clinicians recommend the
suppression of ovulation to avoid this possibility (11). The frequency of adverse pregnancy outcome in this
population includes 12 to 15% stillbirths, a prematurity rate as high as 20%, and an incidence of normal
births of only 60 to 70%. Although there is general agreement that heparin, and perhaps dextran 70, are the
anticoagulants of choice for pregnant women with thromboembolic disease (12,13), these agents may not
be as effective in controlling thrombotic complications in patients with prosthetic heart valves (14). Thus, for
such patients, the use of coumarin anticoagulants has been recommended by some authors, except during
the 6th through 12th week of gestation, when warfarin teratogenicity is most likely (8,14,15,46-50). It should
be recognized, however, that developmental toxicity associated with second and third trimester exposure
has been described (46-48).
Fetal coumarin exposure after the first trimester increases the risk of central nervous system defects,
probably caused by microhemorrhages in neuronal tissues (8,14,16,24,28,34). Five case reports have
described massive intracranial hemorrhages that sometimes proved fatal to the fetuses (21,46-48). The
authors of one of these case reports suggested that the fetus is uniquely susceptible to warfarin induced
hemorrhage because of low stores of vitamin K and physiologically low levels of vitamin-K-dependent
procoagulant factors (21).
Because of possible developmental toxicity of coumarin anticoagulants during all stages of pregnancy,
some clinicians consider the use of the coumarin anticoagulants contraindicated during pregnancy (12).
There is, however, a single case report of "mini-dose" warfarin (1 mg/d) used from 32 weeks of pregnancy
until term, in which fetal blood showed no evidence of an anticoagulant effect (22). In a series of 71 births in
women with mechanical heart valves, only four of the infants had signs of warfarin embryopathy (23,33).
The authors found the probability of poor outcomes was highly correlated with daily doses of warfarin over 5
mg (33). In another report that compared the pregnancy outcomes of 33 women who used < 5mg/d doses
of warfarin with 25 women who used doses >5mg/d, the lower dose group had significantly fewer fetal
complications (38).
A population-based cohort study was conducted on 307 coumarin-exposed children and 267 non-exposed
controls aged 8 to 15 years (32). The mean height and overall growth of exposed children did not differ from
those of the unexposed children. One of two children in the exposed population, born with signs of
coumarin embryopathy, displayed a deficit in height at school age. Overall, long-term growth was not
affected by a high cumulative dose or exposure after the first trimester. These authors concluded that, when
exposure during the first trimester was avoided, coumarin therapy during pregnancy had no demonstrable
risk for a child's skeletal development (32). To avoid perinatal bleeding complications, various authors have
also recommended the substitution of heparin for warfarin anticoagulants in the last 2-4 weeks of pregnancy
(32,38).
Guidelines for anticoagulant use in pregnancy were published by the Pregnancy and Thrombosis Working
Group in 2007 (42). In 2008, detailed guidelines were also published by the American College of Chest
Physicians (43). These guidelines include recommendations on the choice of anticoagulant and timing for
use in a variety of pregnant subpopulations, including women with mechanical heart valves.
Phenindione is the only member this group of anticoagulants that has been associated with adverse effects
in infants when used during breastfeeding (35). The American Academy of Pediatrics classified phenindione
among "drugs that have been associated with significant effects on some nursing infants and should be
given to nursing mothers with caution" (36). There has also been a suspected problem with bleeding in
babies exposed to ethyl biscoumacetate in breast milk (25). Phenindione and a metabolite of ethyl
biscoumacetate are secreted in milk in an active form that can impair blood coagulation in the newborn
(19,20,35). Warfarin levels in the milk of women on therapy were undetectable (26,27). One estimate of
daily phenprocoumon intake from maternal milk was 6 to 8 mcg/kg (29). This amount is much less than the
average maintenance requirement for anticoagulation with phenprocoumon in children (about 50 mcg/kg/d).
The American College of Obstetricians and Gynecologists considers warfarin therapy compatible with
breastfeeding (52).
Selected References
1. O'Reilly R: Anticoagulant, antithrombotic, and thrombolytic drugs. in: Gilman AG et al. (eds), The
Pharmacological Basis of Therapeutics, 6th ed. MacMillan Publ Co, New York, 1980. p.1359.
2. Kronick J et al: Effects of sodium warfarin administered during pregnancy in mice. Am J Obstet Gynecol
118: 819-823, 1974.
3. Grote W, Weinmann J: [Uberprufung der Wirkstoffe cumarin und Rutin im tertatologischen Versuch an
Kaninchen]. Arzneim-Forsch 23:1319-1320, 1973.
4. Howe AM, Webster WS. The warfarin embryopathy: a rat model showing maxillonasal hypoplasia and
other skeletal disturbances. Teratology 1992;46:379-390.
5. Harrod MJE, Sherrod PS: Warfarin embryopathy in siblings. Obstet Gynecol 57:673-6, 1981.
6. Holzgreve W et al: Warfarin-induced fetal abnormalities. Lancet 2:914-5, 1976.
7. Pauli RM, Haun J. Intrauterine effects of coumarin derivatives. Dev Brain Dysfunc 1993;6:229-247.
8. Hall JG et al: Maternal and fetal sequelae of anticoagulation during pregnancy. Am J Med 68:122-40,
1980.
9. Nageotte MP et al: Anticoagulation in pregnancy. Am J Obstet Gynecol 141:472, 1981.
10. Born D, Martinez EE, Almeida PA, et al: Pregnancy in patients with prosthetic heart valves: the effects
of anticoagulation on mother, fetus, and neonate. Am Heart J 124: 413-7, 1992.
11. Bogers JW, Huikeshoven FJ, Lotgering FK: Complications of anticoagulant therapy in ovulatory women.
[letter] Lancet 337:618-9, 1991.
12. Berkowitz RL et al: Handbook for Prescribing Medications During Pregnancy 2nd ed. 1986 Little, Brown
& Co. Boston/Toronto pp. 91 & 144.
13. Weiner CP: Diagnosis and management of thromboembolic disease during pregnancy. Clin Obstet
Gynecol 28:107-118, 1985.
14. Iturbe-Alessio I et al: Risks of anticoagulant therapy in pregnant women with artificial heart valves. N
Engl J Med 315:1390-3, 1986.
15. Pillans PI, Coetzee EJ: Anticoagulants during pregnancy. S Afr Med J 69:469, 1986.
16. Pauli RM: Mechanism of bone and cartilage maldevelopment in the warfarin embryopathy. Pathol
Immunopathol Res 7:107-12, 1988.
17. Hall BD: Warfarin embryopathy and urinary tract anomalies: possible new association (letter). Am J Med
Genet 34:292-3, 1989.
18. Oakley C: Pregnancy in patients with prosthetic heart valves. Br Med J 286:1680-3, 1983.
19. Czeizel A, Kovacs M: A family study of congenital diaphragmatic defects. Am J Med Genet 21, 105-115,
1985.
20. Normann EK, Stray-Pedersen B: Warfarin-induced diaphragmatic hernia. Case report. Br J Obstet
Gynecol 96:729-730, 1989.
21. Ville Y, Jenkins E, Shearer MJ et al: Fetal intraventricular haemorrhagia and maternal warfarin. Lancet
341:1211, 1993.
22. Porreco RP, McDuffie RS Jr, Peck SD. Fixed mini-dose warfarin for prophylaxis of thromboembolic
disease in pregnancy: a safe alternative for the fetus? Obstet Gynecol 1993;81:806-807.
23. Cotrufo M, de Luca TSL, Calabro R, et al.: Coumarin anticoagulation during pregnancy in patients with
mechanical valve prostheses. Eur J Cardiothroac Surg 5:300-305, 1991.
24. Kaplan LC: Congenital Dandy Walker malformation associated with first trimester warfarin: a case report
and literature review. Teratology 32:333-337, 1985.
25. Ruthnum P, Tolmie JL: Atypical malformations in an infant exposed to warfarin during the first trimester
of pregnancy. Teratology 36:299-301, 1987.
26. Orme M'L, 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.
27. de Swiet M, Lewis PJ: Excretion of anticoagulants in human milk [letter]: N Engl J Med 1977;297:1471.
28. Pati S, Helmbrecht GD: Congenital schizencephaly associated with in utero warfarin exposure. Reprod
Toxicol 8:115-20, 1994.
29. von-Kries R, Nocker D, Schmitz-Kummer E, de-Vries JX: [Transfer of phenprocoumon in breast milk. Is
oral anticoagulation with phenprocoumon a contraindication for breastfeeding?] Monatsschr Kinderheilkd
1993; 141: 505-7.
30. Shannon MS, Edwards MB, Long F et al: Anticoagulant management of pregnancy following heart valve
replacement in the United Kingdom, 1986-2002. J Heart Valve Dis. 2008, Sep; 17(5):526-32.
32. van Driel D, Wesseling J, Sauer PJ et al: In utero exposure to coumarins and cognition at 8 to 14 years
old. Pediatrics 2001;107:123-9.
33. Cotrufo M, DeFeo M, DeSanto LS et al: Risk of warfarin during pregnancy with mechanical valve
prostheses. Obstet Gynecol 99:35-40, 2002.
34. van Driel D, Wesseling J, Sauer PJ et al: Teratogen update: Fetal effects after in utero exposure to
coumarins overview of cases, follow-up findings, and pathogenesis. Teratology 66:127-140, 2002.
35. Eckstein HB, Jack B: Breast-feeding and anticoagulant therapy. Lancet 1970;1:672-3.
36. Committee on Drugs, American Academy of Pediatrics. The transfer of drugs and other chemicals into
human breast milk. Pediatrics 108:776-89,2001.
37. United States Pharmacopeia and National Formulary. 2004/5 ed., Washington, DC.
38. N Vitale, M De Feo, LS De Santo, A Pollice, N Tedesco, M Cotrufo: Dose-dependent fetal complications
of warfarin in pregnant women with mechanical heart valves. J Am Coll Cardiol 33;1637-1641, 1999.
39. Raghav S, Reutens D. Neurological sequelae of intrauterine warfarin exposure. J Clin Neurosci. 2007;
14(2):99-103.
40. Hetzel PG, Glanzmann R, et al: Courmarin embryopathy in an extremely low birth weight infant
associated with neonatal hepatitis and ocular malformations. Eur J Pediart. 2006; 165(6): 358-60.
41. Khamooshi AJ, Kashfi F, Hoseini S, et al: Anticoagulation for prosthetic heart valves in pregnancy. Is
there and answer? Asian Cardiovasc Thorac Ann. 2007; 15(6): 493-6.
42. Duhl AJ, Paidas MJ, Ural SH, et al: Antithrombotic therapy and pregnancy: consensus report and
recommendations for prevention and treatment of venous thromboembolism and adverse pregnancy
outcomes. Am J Obstet Gynecol. 2007, Nov; 197(5):457.e1-21.
43. Bates SM, Greer IA, Pabinger I, Sofaer S, Hirsh J: Venous thromboembolism, thrombophilia,
antithrombotic therapy, and pregnancy: American College of Chest Physicians Evidence-Based Clinical
Practice Guidelines (8th Edition). Chest 133(6 Suppl):844S 886S, 2008.
44. De Santo LS, Romano G, Della Corte A, Tizzano F, Petraio A, Amarelli C, De Feo M, Dialetto G,
Scardone M, Cotrufo M: Mitral mechanical replacement in young rheumatic women: analysis of long-term
survival, valve-related complications, and pregnancy outcomes over a 3707 patient-year follow-up. J Thorac
Cardiovasc Surg 130(1):13-19, 2005.
45. Nassar AH, Hobeika EM, Abd Essamad HM, Taher A, Khalil AM, Usta IM: Pregnancy outcome in
women with prosthetic heart valves. Am J Obstet Gynecol 191(3):1009-1013, 2004.
46. Simonazzi G, Pilu G, Palareti G, Bernardi B, Rizzo N: Foetal cerebral hemispheric atrophy and
porencephaly after intrauterine exposure to maternal warfarin for mechanical prosthetic heart valve. Prenat
Diagn 28(2):157-159, 2008.
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with mitral valve replacements: a case report. Am J Perinatol. 2009, Sep; 26(8):597-600.
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© 2013 Reproductive Toxicology Center
WARFARIN
TERIS
Information designed to assist physicians or other healthcare professionals in assessing
the risks of possible teratogenic exposures in pregnant women
Top of Page
Agent Number: 1078 Bibliographic Search Date: 01/09
Agent Name: WARFARIN Review Date: 02/09
Summary of Teratology Studies:
Warfarin is an anticoagulant that depresses synthesis of vitamin K dependent clotting factors. It is used in
treatment of a variety of thrombo-embolic disorders. Warfarin is also employed as a rodenticide.
=========================
MAGNITUDE OF TERATOGENIC
RISK TO CHILD BORN AFTER
EXPOSURE DURING GESTATION
=========================
SMALL TO MODERATE
===============================
QUALITY AND QUANTITY OF DATA
ON WHICH RISK ESTIMATE IS BASED
===============================
GOOD
========
COMMENTS
========
1) THIS RATING IS FOR CHRONIC USE OF WARFARIN IN THERAPEUTIC DOSES.
2) WOMEN WHO REQUIRE WARFARIN THERAPY MAY PUT THEIR OWN HEALTH AT SUBSTANTIAL
RISK IF THEY STOP OR INAPPROPRIATELY MODIFY THEIR TREATMENT BECAUSE OF
PREGNANCY. ANTICOAGULANT THERAPY FOR PREGNANT WOMEN IS CONTROVERSIAL AND
REQUIRES EXPERT MANAGEMENT (DANIK & FUSTER, 2004; ELKAYAM ET AL., 2004; DUHL ET AL.,
2007; BATES ET AL., 2008).
A very uncommon but strikingly similar pattern of congenital anomalies has been repeatedly observed
among children born to women treated with warfarin during pregnancy (Chan et al., 2000; van Driel et al.,
2002; Hung & Rahimtoola, 2003). Frequent features of this pattern of anomalies, which is called the
warfarin embryopathy or fetal warfarin syndrome, include nasal hypoplasia, stippled epiphyses on
radiographs, and growth retardation. More serious skeletal abnormalities may also occur (van Driel et al.,
2002).
The greatest period of susceptibility to the skeletal features of fetal warfarin syndrome is the latter half of the
first trimester of pregnancy. In one series in which physical examinations were performed to look for
features of warfarin embryopathy, one (3%) of 38 children born to women treated with warfarin throughout
pregnancy had typical features of warfarin embryopathy, and two others (5%) had mild manifestations of
this condition (Salazar et al., 1984). In a review of seven series in women with prosthetic heart valves who
had been treated with warfarin during pregnancy, Blickstein & Blickstein (2002) calculated that warfarin
embryopathy was recognized in eight (2.4%) of 333 fetuses or infants. Other more recent reviews that
included these data as well as cases that were exposed to other coumarins during pregnancy estimated
that 6-8% of liveborn infants whose mothers had taken an oral anticoagulant of this class during pregnancy
had warfarin embryopathy (Hung & Rahimtoola, 2003).
The embryopathy is more frequent in children of women who took more than 5 mg/d of warfarin early in
pregnancy than in children whose mothers were treated with smaller daily doses (Cotrufo et al., 1991, 2002;
Vitale et al., 1999, 2002; De Santo et al., 2005). In a prospective series of pregnancies in women treated
with warfarin because of cardiac valve replacement, embryopathy was observed in one (3%) of 38 fetuses
or infants born to women treated with 5 mg/d or less of warfarin and in three (9%) of 33 fetuses or infants
born to women treated with larger doses (Vitale et al., 1999; Cotrufo et al., 2002). Warfarin embryopathy
appears to be less frequent in pregnancies in which the mother was changed from warfarin or a related to
coumarin-derived oral anticoagulant to heparin or a heparin-derived agent before the beginning of the
eighth week of pregnancy (Schaefer et al., 2006).
Central nervous system (CNS) and eye anomalies occur unusually often among the children of mothers
who were treated with warfarin during pregnancy (Chan et al., 2000; van Driel et al., 2002). Reported
abnormalities include microcephaly, cerebral atrophy, hydrocephalus, agenesis of the corpus callosum,
schizencephaly, Dandy-Walker malformation, and optic atrophy. Mental retardation or hearing loss may also
occur. In a review of previously reported studies, CNS anomalies were observed in four (0.7%) and eye
anomalies in one (0.2%) of 615 infants born to women who were treated after the sixth week of pregnancy
with warfarin or another coumarin-derived oral anticoagulant (Chan et al., 2000). Among 49 cases of
warfarin embryopathy summarized in one review, 19 had major CNS or eye anomalies (van Driel et al.,
2002). These abnormalities may also occur in otherwise unaffected infants whose mothers took warfarin
during pregnancy or with maternal use of warfarin after the first trimester of pregnancy. Long-term outcome
is variable in children who have warfarin-associated CNS abnormalities noted at birth (van Driel et al.,
2002).
Three infants with fatal diaphragmatic hernia who were born to women treated with warfarin during
pregnancy have been described (O'Donnell et al., 1985; Normann & Stray-Pedersen, 1989; Schaefer et al.,
2006). None of these children was noted to have features of warfarin embryopathy, but the clinical
descriptions are quite limited.
Major malformations were more frequent than expected among 63 pregnancies in women who were treated
with warfarin in a study performed through 12 European teratogen informative services (odds ratio=8.8,
95% confidence interval 3.0-25.5) (Schaefer et al., 2006). None of the affected infants was recognized to
have warfarin embryopathy. Major congenital anomalies were reported in one (4.5%) of 22 infants born to
women who had been given prescriptions for warfarin during the first trimester of pregnancy in a study of
Michigan Medicaid recipients (Rosa, 1993); the expected rate was the same as that observed. However, it
is unlikely that most of the features of warfarin embryopathy would have been detected in this study.
The frequency of stillbirth appears to be substantially increased in the pregnancies of warfarin-treated
women, and spontaneous abortion is also more common than expected (Ashour et al., 2000; Chan et al.,
2000; Sadler et al., 2000; Cotrufo et al., 2002; Blickstein & Blickstein, 2002; Nassar et al., 2004; Schaefer et
al., 2006). Both the warfarin treatment and the mother's underlying disease probably contribute to these
risks (Frewin & Chisholm, 1998; Sadler et al., 2000). Fetal death is more frequent in women whose daily
dose of warfarin is greater than 5 mg than in those treated with smaller daily doses (Vitale et al., 1999,
2002; Cotrufo et al., 2002).
Maternal warfarin treatment late in pregnancy has been associated with fetal, placental, and neonatal
hemorrhage (Oakley, 1995; Lee et al., 2003; Matsuda et al., 2003). Such hemorrhage may result from the
pharmacologic action of warfarin.
Fetal CNS anomalies, nasal hypoplasia, limb shortening, and epiphyseal and vertebral stippling have been
demonstrated by ultrasound examination during the second or third trimester in women who took warfarin
while pregnant (Sherer et al., 1998; Wellesley et al., 1998; Tongsong et al., 1999; Huisman et al., 2002;
Chan et al., 2003; Oswal & Agarwal, 2008; Simonazzi et al., 2008).
A dose-dependent increased frequency of fetal death has been reported among the offspring of mice
treated during pregnancy with warfarin in doses 1-4 times those used in humans (Kronick et al., 1974). An
increased frequency of minor skeletal anomalies was also observed in this study, but the effect was not
clearly related to dose. No increase in the frequency of major malformations was observed among the
offspring of pregnant rabbits treated with 10-100 times the usual human dose of warfarin (Grote &
Weinmann, 1973). Increased frequencies of fetal death and of hemorrhages of the brain, face, eyes, ears,
and occasionally limbs were seen among the offspring of rats treated during pregnancy with warfarin in
doses <1-500 times those used in humans (Mirkova & Antov, 1983; Howe & Webster, 1990). Club feet were
also seen among the offspring in one of these studies (Mirkova & Antov, 1983). No skeletal anomalies were
seen in affected fetuses in the other study, but similar treatment of the pups postnatally produced marked
maxillonasal hypoplasia (Howe & Webster, 1992). Much of the skeletal maturation that occurs prenatally in
humans does not occur until after birth in rats.
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