Multiple congenital anomalies associated with oral anticoagulants

Multiple congenital anomalies associated with oral anticoagulants WILLIAM L. SHAUL, M.D. JUDITH G. HALL, M.D.

Seattl.e, Washington

The administration of oral anticoagulants during the latter part of pregnancy is known to cause fetal or placental hemorrhage. In addition, there is increasing evidence that the administration of oral vitamin K antagonists or warfarin-related compounds during the first 8 weeks of gestation may result in congenital malformations. The most consistent malformations include nasal hypoplasia, stippling of bones, ophthalmologic abnormalities, intrauterine growth retardation, and developmental delay. Whether the malformations are a result of microhemorrhages in embryonic cartilage, the result of an unknown, more widespread teratogenic effect, or a manifestation of fetal vitamin K deficiency remains to br clarified. Women for whom anticoagulation during pregnancy is mandatory should probably be maintained on heparin during the first 12 weeks of gestation. If oral anticoagulants are necessary or have been given during the first trimester, the mothers should be warned about the possible congenital malformations. (AM. J. 0BSTET. GYNECOL. 127: 191, 1977.) IN 1966 DiSaia 1 reported the case of a child with multiple congenital anomalies born to a mother who had been on Coumadin (sodium warfarin) throughout her pregnancy. Since then, another nine similarly affected infants whose mothers had taken Coumadin during the first trimester have been recognized 2 - 7 (see Table I). In addition, an eleventh infant 7 has been reported whose mother was on phenindione, another vitamin K antagonist closely related to warfarin. The purpose of this report is to review the clinical features of these 11 infants, to alert physicians who might be prescribing these drugs to women of child-bearing age, and to speculate about the pathogenesis of this problem.

tion was a hypoplastic nose. In all ll cases underdeveloped nasal cartilage gave the nose a flattened, upturned appearance (Fig. 1). The nose may actually appear sunken into the face and, in Case 5, was tender to touch until l ye~r of age. The nasal cartilage may appear stippled on roentgenogram. The nares were usually small with narrowed passages. Although choana! stenosis was described in only two cases (Cases 2 and 5), respiratory difficulties were significant enough in five cases (Cases 2, 5, 7, 8, and 11) that oral airways were required to maintain ventilation. As the infants have grown, their noses have remained relatively small but have cosmetically and functionally improved in most cases. The second most common feature has been bone abnormalities, the most striking of which is the stippling seen on roentgenograms of newborn infants. The vertebral column has been the area to show stippling most frequently (nine of the 10 cases examined), particularly the lumbosacral (Fig. 2A) and cervical areas. The proximal long bones and ankles have been the next most commonly involved; the trocanteric area of the femurs (Fig. 2B) and the calcaneus (Fig. 2C) being most consistently affected. With growth the stippled areas have either been reabsorbed or become incorporated into the normally developing bone. Some areas of stippling, such as the sacrum, may be late to ossify. Asymmetric growth of the long bones has generally not occurred, although asymmetry of the vertebral column

Case material Table I summarizes the clinical features of affected infants. The most consistent feature noted on examinaFrom the Departm.ents of Pediatrics and MediciTUJ, University of Washington School of Medicine and Children's Orthopedic Hospital and Medical Center. Supported by National Foundation-March of Dimes Grant CA-90, National Institutes of Health Grant 5SO! RR05655-07, and National Institutes of Health Grant POI GM15253-08. Received for publication February 23, 1976. Accepted February 24, 1976. Reprint address: Judith G. Halt, M.D., Division of Medical Genetics, Children's Orthopedic Hospital and Afedical Center, 4800 Sand Point Way, N.E., Seattle, Washington 98105. 191

192 Shaul and Hall

January l.'i, l977 Am . .J. Obstet. Cmc< ol

Table I. Case summaries Case No. and Ref

VitaminK antagonist

Daily dose

Rx lmgth

(mg.)

(wk.)

Indication

0-26 28-30

Rheumatic mitral valve replacement

39 wk./midforceps/ small and infarcted

0-32

Rheumatic mitral valve replacement

Hirthl-

Vngth ofpreg/Umcy!

Hzrth

delit'er~l

length

placenta

( (fll,)

((;Ill,)

t7

~.:27!)

I'

39 wk./low forceps/ normal

\UWl

\I

:2,950

F

ul.

I

Sr.\

].1.5

Coumadin

2.2.3,*

Coumadin

3.<

Coumadin

5-10

0-35

Rheumatic mitral valve replacement

36 wk./transverse lie: cesarean section/ normal

4.5

Coumadin

7.5

0-35

Rheumatic aortic valve replacement

35 wk./breech

23.5 C/R

1,:>70

\I

5.6

Coumadin

2.5-5

0-35

Rheumatic mitral stenosis

%wk./slow fetal pulse: cesarean section/normal

43

1.800

\I

6.t

Coumadin

0-15

Class III organic heart

15 wk./saline-induced abortion eccentric insertion of cord

183

l()l)

F

7. Case F

Phenindione

0-41

Rheumatic aortic valve replacement

42 wk.

:~.:200

M

8. Case 2 7

Coumadin

5-7.5

0-38

Rheumatic mitral valve replacement

38 wk./low forceps

2.:":i00

\!

9. Case 3

Coumadin

7.5-10

0-38

Rheumatic valvotomy

41 wk.

3,300

F

10. Holmes:j:

Coumadin

7.5-10

0-8

Thrombophlebitis

Term uncompli<.:ated

47.5

2,438

II. Pauli§

Coumadin

7.5-10

6-32

Thrombophlebitis with pulmonary embolism

32 wk./uncomplicated single artery

44

1.720

7.5

*Wilroy, R. S., and Summitt, R. L.: Personal communication. tBurdi, A. R.: Personal communication. To be published. :j:Holmes, L.: Personal communication. To be published. §Pauli, R. M., et al.:]. Pediatr. 88: 506, 1976.

Volume !27 Number 2

Nose

Flat nose, absent septum, small nares, ectopic lacrimal duct Marked hypoplasia. choana! stenosis, severely sunken into face Hypoplastic nasal cartilage

Hypoplastic nasal bridge, severely sunken into face Hypoplastic bridge and alae nasa, choana! stenosis Broad base of nose, flattened upturned nose

Congenital anomalies and oral anticoagulants

Bones

Develop" ment

Other

Bilateral optic atrophy; blind bilaterally

Nasal obstruction

MildMR

No abnormality noted

Respiratory distress

Moderate MR

Occasional seizures, deafness

Occipital bone abnormality

Microophtha!mia; probably blind

Severe MR

Stippling of vertebrae, sacrum, and long bones; severely shortened, mildly asymmetric long bones; short broad fingers Prominant occiput; stippling of cervical vertebrae; sacrum, trochanters. and calcaneus Vertebrae not examined; small distal phalanges

Opacity left lens

Died

Lowest ears; high arched palate; per" sistent ductus arteriosis; occipital meningomyelocele; h ydrocephaius post meningitis Poorly developed ears; contractu res of right elbow and wrist

Short neck; stippling of vertebrae, sacrum, and carpals; hypoplastic distal phalanges with radial deformity of index fingers

Severely hypoplastic nose, narrow nasal passage

Third fontanelle; stippling of vertebrae, sacrum, cuboid, carpal bones, terminal phalanges, and calcaneus; terminal phalanges small in hands and feet No stippling noted on x-ray

Severely hypoplastic nose, hypoplastic alae nasi

Breathing problems

Prominant occiput; stippling in cervical vertebrae. sacrum and femurs; kyphoscoliosis Short limbs, dubbed digits and broad fingers, short, stubby hands; scoliosis

Nasal hypoplasia

Slightly underdeveloped nose. has gotten worse with age Hypoplastic nose

Eye

193

Vertebrae not stippled; stippiing of femoral trochanters and distal phalanges; deft or posterior cervical vertebrae; short distal phalanges Stippling of vertebrae, particularly cervical and lumbar, also costal cartilage, trochanter, calceneus. femurs. and patella; scoliosis

Normal exam

Large. prominem eyes; eyelids small; h yperterlorism Right optic atrophy; left pale direct; blind right eye; hyperterlorism Normal exam

No abnormality noted

Respiratory distress; required 0-P tube

Normal

Hypotonic

Aborted

Large, broad tongue

Moderate distress

Mild MR

Crinky ears; large tongue; short neck; sparse hair in frontal area; small fingernails

Apnea at birth; needs 0-Ptube

Normal

Small fingernails

No respiratory problems

Normal

Normal exam

Normal exam

Normal

Stridor and apnea

Normal

Hypotonic; moderately hypertrophied clitoris, subluxable hips

194 Shaul and Hall Am

J.

January 15. 1977 Obstet. Cvn eml.

Fig. 1. Case 5. Note small nose with hvpo plastic bridge giving ap pearance of being sunken into rhe face.

Fig. 2A. Case 5. Note stippling in lumbosacral area and cervical areas.

was present in Case I , and the long bones of Case 4 were very short and mildly asymmetric. Kyphoscoliosis developed in Cases I , 2, and 11 . Broad, short hands and fingers have been described in six cases (Cases 2, 4. 6, 7, 8, and IO). The distal phalanges were noted to be short in four cases (Cases 6, 7, 8, and 10). In one of these, the mother was on Dilantin during th e pregnancy (Case 7). Abnormalities of the skull hav e been noted in three cases (Cases I , 3, and 8). Five of the cases were noted to have ophthalmologic abnormalities (Cases I. 3, 4, 6, and 7). Specific problems included optic atrophy (Case I and 7). cataract (Case 4), microophthalmia (Case 3), hypertelorism

(Cases 6 and 7), and, in the aborted case, prominent eyes with small eyelids (Case 6). Three of the five patients are living and are reported to be partially or lOtally l>lind (Cases I , 3, and 7). Although most of the surviving patients are still quite young, four of them are developmentally retarded (Cases 1-3 and 7). Worth noting, however, is that all o f them have additional problems. Three of the four cases are also blind and one of these has an occipital meningomyelocele, h ydrocephalus. a nd a history of me ningitis (Case 3). The fourth patient with developmental delay is deaf and bas seizures (Case 2). Miscella neo us other abn orma li ties which were no1ed

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Congenital anomalies and oral anticoagulants

195

Fig. 2B. Case 5. Note stippling of trochamers of femurs.

include mild transient hypotonia (Cases 5 and 11) , poorly developed ears (Cases 3. 4, and 7), seizures (Case 2), occipital meningomyelocele with hydrocephalus (Case 3). posterior cleft of cervical vertebrae (Case 10), short neck (Case 7), persistent truncus arteriosus (Case 3). deafness (Case 2), severely short and curved bones with contractures of one elbow (Case 4), large tongue (Cases 6 and 7), hypertrophied clitoris (Case II). and single umbilical artery (Case 11 ). Two cases have had multiple severe anomalies (Cases 3 and 4). Several cases have had abnormalities in the neck area (Cases 3. 7, and 10). Three of the affected newborns were at or below the third percentile for their gestational age (Cases I, 5, and 10). The mothers all had cardiovascular complications requiring anticoagulant therapy. Six had cardiac valve prostheses (Cases l-4, 7, and 8). one had rheumatic mitral stenosis (Case 5). two had thrombophlebitis (Cases I 0 and 11 ), and two had pulmonary embolism (Cases l and ll). Eight of the e leve n mothers were on Coumadin at the time of conception and , in general, took it cominuously until a tew weeks prior to delivery when heparin was substituted (or in the case of one patient (Case 6) until therapeutic abortion at 1.5 weeks of gestation) . One mother was on Coumadin at the time of conception and discontinued it at approximately 8 weeks after her last menstrual period (Case l 0). One mother did not begin taking Coumadin until the second month of her pregnancy (Case 11). One mother took phenindione throughout all three trimes-

Fig. 2C. Case 5. Note stippling of calcaneus.

ters (Case 7). Dosages of warfarin ranged from 2.5 to 10 mg. per day in order to maintain the prothrombin time within therapeutic range . Most of the women were taking other medications during their pregnancies, but no other medication was taken by all the mothers and no correlation between the additional drugs and severity of abnormalities could be made. It was noted that digitalis and thiazide preparations were the most frequently prescribed additional medications. The mothers ranged from 21 to 36 years of age (average 26.9 years) at the time of their pregnancy. The pregnancies were all somewhat complicated. Cases 5 and 7 h ad polyhydramnios. Cases 1 and 11 had pulmonary emboli. and Cases 4, 5, and 11 had premature labor. Case 4 was a breech presentation and two deliveries were by cesarean section (one for transverse lie-Case 3-and one for slow fetal heart rate-Case 5). Placentas were considered normal except for two cases; in Case I the placenta appeared small and infarcted and in Case 6 there was an ecce ntric insertion of the cord. Five females and five males were born. The one induced abortion was of a female fetus. The average weight was within normal limits but at about the

196 Shaul and Hall

January 15, 1977 Am

twenty-fifth percentile for gestational age; the average height was at the thirty-fifth percentile for gestational age. Pathologic studies were available in only Cases 4 and 6. Case 6, which was aborted at 15 weeks. had shortened long bones, particularly the middle and distal phalanges. The epiphyseal area of the long bones lacked linear arrangement of cartilage cells. The cartilage cells were normal in appearance but were arranged in clumps rather than columns. A few free-floating red blood cells were also seen. The postmortem examination of Case 4, after spontaneous breech delivery, showed that the focal areas of calcification in epiphyseal areas corresponding to areas of stippling. Histologically, the areas were either welldelineated foci of atypical cartilage or acellular areas. The chondrocytes in these areas were proliferating in association with calcification of the matrix. The zone of enchondral ossification looked normal, but there were areas of focal penetration of the epiphyses by periosteal fibrovascular tissue. The acellular areas showed myxomatous material and numerous thinwalled, vascular chambers.

Comment The features described in these ll cases strongly suggest that vitamin K antagonist anticoagulants have a teratogenic effect in some embryos and on some embryonic tissues. There may be a period during the first 8 weeks, more specifically the fourth and eighth week of gestation (since Case 11 did not begin Cournadin until about 6 weeks after conception and Case 10 stopped at 8 weeks) during which time developing tissues are particularly susceptible. Different tissues may be susceptible at different times (Case 10 in which Coumadin was not taken after 8 weeks had no stippling of the vertebrae, while the vertebrae were involved in most of the other cases). When vitamin K antagonists are taken for anticoagulation after the first trimester, and only during the second and third trimester, there may be serious fetal and placental hemorrhage. 8 - 11 Stillbirth is a frequent result but malformations have been infrequently reported and are generally not similar to those described here. The incidence of malformations, the presence of different abnormalities in relation to time of ingestion, and the variability of severity are difficult to determine since so few cases are known and some features have not always been reported. In reviewing reported cases of maternal use of vitamin K antagonists during the first trimester we were able to find 25 cases in which the infants were reported as normal; 8- 13 however, the nose~ were not commented on, x-rays were not done,

J.

Obstet. Gynecol.

and little or no follow-up was available. Only eight o! these reports indicate that therapeutic levels of warfitrin were definitely used throughout the first rimester,'· 9 11 We assume that there are other unreported cases of · both affected and unaffected infants, and that more details may be available on reported cases. However. it is clear that there is a substamial risk of a congenital abnormality in the infants of women taking vitamin K antagonists in therapeutic doses during the first trimester. The actual magnitude of this risk is unkno\' 11. Whether the risk is increased when the drugs are tak,n all three trimesters is not known either. Hopefully. data giving accurate incidence will soon be available. In the meantime, we would guess that the risk of m
Volume 127 Number 2

not dear and a teratogenic effect of vitamin K defi(iency has not been described to our knowledge. Animal studies of vitamin K antagonists during pregnancv have not shown consistent teratogenic effects in offspring. 1"- 17 Perhaps by studying the affected human infants in more detail or by use of an experimental model more insight into the role which vitamin K normally plavs in human embryogenesis will be\obtained. We fed there is compelling evidence that oral anticoagulant therapy during the first trimester of pregnancY can cause congenital malformations. For this reason the indications for anticoagulation of any woman who is. or plans to become. pregnant must be carefully reviewed. If anticoagulation is determined to be essential. we would recommend that with the cessation of birth control measures. anticoagulation with heparin be established prior to conception and throughout the first trimester of pregnancy. Limiting the use of oral anticoagulants to the second and early third trimester would appear to protect the fetus from the teratogenic effects described above. Since heparin does not cross the placenta, tR its use in the latter part of the third trimester might protect the fetus from the hemorrhagic complications seen when oral anticoagulants are used. In addition. we feel that women who become pregnant and are taking oral anticoagulants during the first trimester should be informed of the possible congenital defects which may result.* Finally, because the risk of malformation is substantial, we recommend that women who have received vitamin K antagonists during the first trimester he offered the option of termination of the pregnancy. As more information is gathered concerning the incidence of this problem, the calculated risks for the fetus, and the possibility of prenatal diagnosis, decisions regarding termination or continuation ofthe individual's pregnancy will hopefully be more rationaL

Summary The dinical features of ll cases of vitamin K antagonist embryopathy are presented and discussed. The most typical abnormalities include nasal hypoplasia, stippled epiphyses, eye anomalies, and developmental retardation. All of the women whose pregnancies were reviewed had taken a vitamin K antagonist during the first 8 weeks of gestation. The mechanism whereby these warfarin-related compounds disrupt chondrogenesis and cause develop*Endo Laboratories, the producers of Coumadin, have recently sent a letter of warning to all physicians in the United States and have changed the package inserts to warn about the possibility of congenital malformations in the fetus of women using this drug during pregnancy.

Congenital anomalies and oral anticoagulants

197

mental abnormalities is not clear. The lack of clotting factors normally during the first trimester suggests that anticoagulation alone is probably not responsible. A separate, more widespread insult is likely, but has yet to be defined. General recommendations are outlined for the management of women requiring anticoagulation during the first trimester of pregnancy. The authors wish to express appreciation for advice and information on patients to Drs. Lewis B. Holmes, Alphonse R. Burdi, Melvin H. Becker, Thomas Shepard, Arno Motulsky, M. Michael Cohen, RobertS. Wilroy, Jr., Robert Summitt, Richard M. Pauli, Laurence Karp, and Josef Warkany; and for the technical and secretarial assistance of Ellen Helseth.

Addendum Since submitting this manuscript, we have become aware of three additional cases of affected newl:x)rn infants whose mothers received warfarin during the first trimester of pregnancy. Fourie and Hay 19 reported a woman who ingested sodium warfarin (5 mg.) daily throughout her pregnancy, which was complicated by mild hydramnios. Heparin therapy was instituted one week prior to delivery of a healthy 2,840 gram female infant whose length was 48 em. and whose occipitofrontal circumference was 34.5 em. The infant had a hypoplastic, upturned nose, mild choana! stenosis, short fingers, and dystrophic nails. There was no evidence of central nervous system or ophthalmologic abnormalities in the newborn period. Roentgenograms revealed stippled epiphyses in the cuboids, proximal femora, sacrum, and vertebral column. Richman and Lahman 20 reported a case of a 5 pound, 14 ounce neonate born to a 19-year-old woman who received warfarin throughout her pregnancy. Polyhydramnios was noted in the third trimester. The infant was physically normal at birth except for a hypoplastic nasal bridge and slight choana! narrowing. Stippled epiphyses were present only in the calcanei. We are aware of a third infant 21 born to a mother who received warfarin beginning at approximately six weeks' gestation. The infant had the characteristic nasal deformity and stippling of the bones. However, further details are not yet available. Two recent reports 22 ' 23 of women who took warfarin only during the second and third trimesters raise the question of the safety of warfarin use during this period of gestation. These cases raise the possibility that mental retardation, ophthalmologic abnormalities, and more generalized central nervous system anomalies (in addition to the already known fetal deaths and stillbirths 10 ' 18) may result from the use of oral anticoagulants during the second and third trimesters. However, it seems dear that the characteristic hypoplastic nose and stippled epiphyses of warfarin

198 Shaul and Hall

January 15, 1977

Am.

embryopathy occur only with use during the first trimester. The maintenance of anticoagulation therapy during pregnancy has become complicated by a number of factors. When anticoagulation is dearly indicated for the mother's health and when she strongly desires to maintain the pregnancy, the following should he considered to minimize risks to the fetus. During the first trimester, warfarin therapy appears to be associated with embryopathy in 25 to 50 per cent of known cases. Therefore, heparin appears to be the drug of choice for the first trimester. 24 However, heparin therapy is not without complications. The dangers of hemorrhage and hypersensitivity reaction are well known. tH The frequency of adverse reactions such as osteoporosis and painful nodules appears to increase with use of heparin for longer than six months. tH Although heparin dues not cross the placenta, its longterm use may deplete the mother of nutrients required by the fetus. The impracticality of heparin use throughout the pregnancy further complicates the therapeutic plan. Heparin therapy can be maintained into the second trimester but becomes increasingly complicated. Alternatively, during the second and early third trimesters, the patient may be managed with a combination of

I. DiSaia, P. ].: Pregnancy and delivery of a patient with a

2. 3.

4. 5. 6. 7. 8. 9. 10. II. 12.

Obstet. Gyoecol.

warfarin, dipyndamole, and aspirin. Ibarra-Percz and associates 25 recently followed 25 pregnancies in patients who re(·eived oral anticoagulants for prosthetit valves. Twenty-two of the women received dipvndamole or dipyridamole and aspirin in addition to warfarin-related compounds. There were apparently no congenital anomalies in the offspring of these women, but in two instances there 11-ere maternal emboli' complications when the women were receiving only dipyridamole and aspirin for anticoagulation. Whether or not warfarin is used alone or in combination 1\'ith dipyridamole and aspirin, care should be taken t<' maintain the prothrombin time in the therapeuti<. range. During the last trimester. it is unclear when heparin therapy should be reinstituted. Until further studies clarif)' this issue, heparin should definitely be started at least two 11eeks prior ro delivery, with all oral anticoagulants discontinued at the same time. These recommendations are offered with the awareness that prospective studies with large numbers of patients need to be done to clarify: (I) the risks of warfarin use during the second and third trimesters. (2) the risks of dipyridamole and aspirin throughout pregnancy, and (3) the incidence and nature of complications of long-term heparin use in pregnancy.

REFERENCES Starr-Edwards mitral valve prosthesis, Obstet. Gynecol. 28: 469, 1966. Kerber, I. J., Warr, 0. S., and Richardson, C.: Pregnancy in a patient with a prosthetic mitral valve, J. A. M.A. 203: 223, 1968. Holmes, B., Moser, H. W., Halldorsson, S., eta!.: Mental Retardation; An Atlas of Disease With Associated Physical Abnormalities, !'lew York, 1972, The Macmillan Company, pp. 136-137. Tejani, N .: Anticoagulant therapy with cardiac valve prosthesis during pregnancy, Obstet. Gynecol. 42: 785, 1973. Becker, M. H., Genieser, N. B., Finegold, M., et al.: Chondrodysplasia punctata. Is maternal warfarin therapy a factor? Am. J. Dis. Child. 129: 356, 1975. Shaul, W. L., Emery, H., and Hall, J. G.: Chondrodysplasia punctata and maternal warfarin use during pregnancy, Am. J. Dis. Child. 129: 360, 1975. Petti for, J. M., and Benson, R.: Congenital malformations associated with the administration of oral anticoagulants during pregnancy, J. Pediatr. 86: 459, 1975. Buxbaum, A., Aygen, M. M., Shahin, W., et al.; Pregnancy in patients with prosthetic heart valves, Chest 59: 639, 1971. Jenkins, B. S., and Braimbridge, M. V.: Management of anticoagulant therapy during pregnancy in patients with prosthetic heart valves, Thorax 26: 206, 1971. Hirsh, J., Case, J. F., O'Sullivan, E. F.: Clinical experience with anticoagulant therapy during pregnancy, Br. Med. J. I: 270, 1970. Fillmore, S. J., and McDevitt, E.; Effects of coumarin compounds on the fetus, Ann. Intern. Med. 73: 731, 1970. Bemiller, C. R., Forker. A. D., and Morgan, J. R.: Com-

J.

13. 14. 15. 16. 17. 18.

19. 20. 21. 22. 23. 24. 25.

plete heart block, prosthetic aortic valve and successfu! pregnancy.]. A.M. A. 214: 91!1. 1970. Reid, J. M., and Barclay, R. D.: Pregnancy and mitral valve prosthesis, Br. Med. J. 1: 326, 1971. Bleyer, W. A., Hakami, N., and Shepard. T. H.: The development of hemostasis in the human fetus and newborn infant, J. Pediatr. 79: 838, 1971. Quenneville, G., Barton, B., McDevitt, E., et al.; The use of anticoagulants for thrombophlebitis during pregnancy, AM. j. 0BSTET. GYNECOL. 77: 1135, 1959. Hirsh, J., Cade, J. F., and Gallus, A. S.: Fetal effects of Coumadin administered during pregnancy, Blood 36: 623, 1970. Kronick,J., Phelps, N. E., McCallion D.]., et al.: Effects of sodium warfarin administered during pregnancy in mice, AM. J. OssTET. GYNECOL. 118: 819, 1974. Flessa, H. C., Glueck, H. I., and Dritschilo, A.: Thromboembolic disorders in pregnancy: Pathophysiology, diagnosis and treatment with emphasis on heparin. Clin. Obstet. Gynecol. 17: 195, 1974. Fourie, D. T., and Hay, I. T.: Warfarin as a possible teratogen, S. A. Med. J., November 22, 1975, pp. 20812083. Richman, E. M., and Lahman, J. E.: Fetal anomalies associated with warfarin therapy initiated shortly prior to conception, J. Pediatr. 88: 509, 1976. O'Connor, N.: Personal communication. Sherman, S., and Hall, B. D.: Warfarin and fetal abnormality, Lancet 1: 692, 1976. Carson. M., and Reid, M.: Warfarin and fetal abnormality, Lancet 1: 1356, 1976. Editorial: Venous thromboembolism and anticoagulants in pregnancy, Br. Med.J. 4:421, 1975. Ibarra-Perez, C., et al.: The course of pregnancy in patients with artificial heart valves, Am. J. Med. 61: 504, 1976