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.
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 uncomplilind (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
Volume 127 Number 2
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
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.
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 uncomplilind (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
Volume 127 Number 2
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
