506
March 1976 The Journal o f P E D I A T R I C S
Warfarin therapy initiated during pregnancy and phenotypic chondrodysplasia punctata An infant is described who hasclinical manifestations and roentgenographic features consistent with the diagnosis of chondrodysplasia punctata. The mother of this infant received warfarin during pregnancy. Eight cases demonstrating an association between warfarin therapy during pregnancy and chondrodysplasia punctata in the child have been reported," in the present case therapy was initiated following conception (see following case report). Warfarin may be teratogenic, producing a phenocopy of the heritable forms of chondrodysplasia punctata. Because of the evident association we suggest (1) warfarin is contraindicated in pregnancy and alternative anticoagulants should be used," (2) products of at-risk pregnancies should be screened for the characteristic radiologic findings," and (3) preconceptual counselling and antenatal diagnosis of the disease may be beneficial.
Richard M. Pauli, M.D., Ph.D., John D. Madden, M.D.,* K. Jeffery Kranzler, M.D., W a l t e r C u l p e p p e r , M . D . , a n d R o n a l d P o r t , M . D . , Chicago, IlL
RECENTLY Becker a n d associates 1 a n d Shaul a n d associates ~ have reported n e o n a t e s with r o e n t g e n o g r a p h i c a n d clinical features of c h o n d r o d y s p l a s i a p u n c t a t a in association with m a t e r n a l warfarin therapy. It is the p u r p o s e o f this report to describe a n infant with nearly identical findings b o r n to a m o t h e r in w h o m warfarin t h e r a p y h a d b e e n initiated in the second m o n t h of pregnancy.
CASE REPORT A 1,600 gm white female was born at 32 weeks' gestation to a 33-year-old gravida 8, para 5, abortus 3 woman. Each abortion had occurred in the second trimester. No abnormalities were noted in these fetuses. There was no history of congenital anomalies. During this pregnancy thrombophlebitis developed. Pulmonary embolization occurred early in the second month. Treatment included heparin, digoxin, cephalexin, meperidine, and acetaminophen. Warfarin therapy was continued throughout pregnancy at a dose of 7.5 mg daily and increased to 10 mg every third day. Hydroxyprogesterone was given during the fifth month; other therapy included ampicillin and doxycycline.
From the Pritzker School of Medicine of The University of Chicago and the Departments of Pediatrics and Radiology of The University of Chicago Hospitals and Clinics, Wyler Children's Hospital. *Reprint address: The University of Chicago, Department of Pediatrics, 950 E. 59th St., Chicago, lll. 60637. Vol. 88, No. 3, pp. 506-508
At 32 weeks labor began spontaneously. Oxytocin stimulation was given; the duration of labor was eight hours. At birth the infant required resuscitation. The Apgar scores were 3 at one minute and 2 at five minutes. The infant had a single umbilical artery and a hypoplastic nose. Punctate skeletal lesions were seen roentgenographically.
See related article, p. 509. Continued respiratory difficulty and a systolic murmur prompted transfer to The University of Chicago Intensive Care Nursery at three weeks of age. On admission the infant was moderately hypotonic and pale and had intermittent cyanosis, stridor, and substernal retractions. Length was 44 cm; weight was 1,720 gm. The face was broad with apparent hypoplasia of the midportion, markedly depressed nasal bridge, and hypoplastic alae nasi (Fig. 1). The tongue fell back against an intact palate. A systolic ejection murmur was heard best at the second and third left intercostal spaces. Ophthalmoscopic examination was negative. The clitoris was moderately hypertrophied. Both hips were subluxed. There was no evident asymmetry. Cyanosis and stridor improved after placement of an oral airway. The infant was briefly placed in oxygen (Frog = 30-40%); following transfusion with 20 ml of packed red blood ceils the infant appeared to be improved and the intensity of the murmur decreased. Results of laboratory data included hemoglobin 8.7 gm/dl, hematocrit 24% (42% following transfusion), reticulocyte count 2.6%, white blood count 2,600/ram:'; electrocardiogram, border-
Warfarin therapy and chondrodysfllasia punctata
Volume 88 Number 3
507
Table I. S u m m a r y o f d r u g e x p o s u r e d u r i n g first a n d s e c o n d t r i m e s t e r
Case No. (reference) Drug Warfarin Heparin Cardiac glycoside Sulfa Erythromycin Pencillins-cephalosporins Doxycycline Progesterone Diazepam Meperidine Alcohol Diphenylhydantoin Primidone Furosemide Thiazide Acetoaminophen
1"
2~" ~~
31
X
X X X X X
X
X
I
42
53
X
X
X
8* X X X
X
X X
X X X
X
X X X X
X X X X
*This report. T a b l e II. S u m m a r y o f positive findings in cases o f c h o n d r o d y s p l a s i a p u n c t a t a associated w i t h w a r f a r i n a d m i n i s t r a t i o n
Case No. (reference) Finding
111
]
21 . 1o
3~
4 o-
675
225-450
+ +
+ + +
53
63
73
8*
--
--
450
+ +
+
+ + +
R
Estimated warfarin dose (mg) in first trimester Low birth weight Nasal hypoplasia-abnormal facies Upper airway obstruction Cataracts Optic atrophy External ear anomaly Rhizomelia Asymmetric limbs Contractures Congenital hip dislocation Scoliosis Hypotonia Mental retardation Seizures Stippled calcification Calcification of thyroid-trachealarynx
675 _+ + +
+ + +
+ +
+
§ + + +
+ +
+ + +
+
+ _+
§
+
*This report. + Indicates presence of findings. _+Indicates borderline findings. line biventricular hypertrophy; total T~ 7.8%, free thyroxine index 7.0; chromosome analysis, normal 46 XY karyotype. Roentgenographic examination (Fig. 2) demonstrated multifocal punctate calcifications in central and posterior portions of the vertebrae, most noticeable in the cervical and lumbar regions. Punctate calcifications were also seen in some anterior costal cartilages, the proximal femoral epiphyses, the triradiate cartilages, trochlear epiphysis, calcanei, and right patella. There was a
calcific focus in a subglottic ring. The right hip appeared dislocated. DISCUSSION C h o n d r o d y s p l a s i a p u n c t a t a ~-~ is p r e s u m a b l y a h e r i t a b l e disease; it is c h a r a c t e r i z e d b y e p i p h y s e a l a n d e x t r a e p i p h y seal calcifications2 F r e q u e n t findings i n c l u d e f l a t t e n e d ,
508
Pauli et al
The Journal of Pediatrics March 1976
Fig. 2. REFERENCES
Fig. 1. hypoplastic nose, high-arched or cleft palate, cataracts, optic atrophy, skin lesions, rhizomelia, limb asymmetry, flexion contractures, hip dislocation, and foot deformities2 -s Attempts have been m a d e to divide the syndrome according to clinical findings and patterns o f inheritances. Spranger and associates s used the designation ConradiHtinermann for the milder form, which is apparently inherited as an autosomal dominant. A rhizomelic type with recessive inheritance, rhizomelic limb shortening, metaphyseal changes, and a much greater incidence of developmental retardation, eye involvement, and early death was also described. To our knowledge our patient is the eighth published case* describing a n association of chondrodysplasia p unctata with a maternal administration of warfarin. ~-~' ~~ ~i As in the case described below, warfarin therapy was begun following conception, implying a teratogenic rather than a germ cell mutational mechanism, the nature of which remains unknown. *See followingcase report.
1. Becker MH, Genieser NB, Finegold M, et al: Chondrodysplasia punctata-is maternal warfarin therapy a factor? Am J Dis Child 129:356, 1975. 2. Shaul WL, Emery H, and Hall JG: Chondrodysplasia punctata and maternal warfarin use during pregnancy, Am J Dis Child 129:360, 1975. 3. Pettifor JM, and Benson M: Congenital malformations associated with administration of oral anticoagulants during pregnancy, J P~DIATR86:459, 1975. 4. Conradi E: Vorzeitiges Auftreten von Knochen-und eigenartigen Verkalkungs Kernen bei Chondrod3fstrophia fotalis hypoplastica. Histologische und R6ntgenuntersuchungen, Jahrb Kinderheilkd 80:86, 1914. 5. H~nermann C: Chondrodystrophia calcificans congenita als abortive Form der Chondrodystrophie, Z Kinderheilkd 51:1, 1931. 6. Mosekilde E: "Stippled epiphyses" in the newborn and in infants, Acta Radiol 37:291, 1952. 7. Josephson BM, and Oriatti MD: Chondrodystrophia calcificans congenita: Report of a case and review of the literature, Pediatrics 28:425, 1961. 8. Melnick JC: Chondrodystrophia calcificans congenita, Am J I~is Child 110:218, 1965. 9. Spranger JW, Opitz JM, and Bidder U: Heterogeneity of chondrodysplasia punctata, Humangenetik 11:190, 1971. 10. DiSaia PJ: Pregnancy. and delivery of a patient with a startEdwards mitral valve prosthesis, Obstet Gynecol 28:469, 1966. 11. Kerber J, Warr OS III, and Richardson C: Pregnancy in a patient with a prosthetic mitral valve; associated with a fetal anomaly attributed to warfarin sodium, JAMA 203:223, 1968.
March 1976 The Journal o f P E D I A T R I C S
Warfarin therapy initiated during pregnancy and phenotypic chondrodysplasia punctata An infant is described who hasclinical manifestations and roentgenographic features consistent with the diagnosis of chondrodysplasia punctata. The mother of this infant received warfarin during pregnancy. Eight cases demonstrating an association between warfarin therapy during pregnancy and chondrodysplasia punctata in the child have been reported," in the present case therapy was initiated following conception (see following case report). Warfarin may be teratogenic, producing a phenocopy of the heritable forms of chondrodysplasia punctata. Because of the evident association we suggest (1) warfarin is contraindicated in pregnancy and alternative anticoagulants should be used," (2) products of at-risk pregnancies should be screened for the characteristic radiologic findings," and (3) preconceptual counselling and antenatal diagnosis of the disease may be beneficial.
Richard M. Pauli, M.D., Ph.D., John D. Madden, M.D.,* K. Jeffery Kranzler, M.D., W a l t e r C u l p e p p e r , M . D . , a n d R o n a l d P o r t , M . D . , Chicago, IlL
RECENTLY Becker a n d associates 1 a n d Shaul a n d associates ~ have reported n e o n a t e s with r o e n t g e n o g r a p h i c a n d clinical features of c h o n d r o d y s p l a s i a p u n c t a t a in association with m a t e r n a l warfarin therapy. It is the p u r p o s e o f this report to describe a n infant with nearly identical findings b o r n to a m o t h e r in w h o m warfarin t h e r a p y h a d b e e n initiated in the second m o n t h of pregnancy.
CASE REPORT A 1,600 gm white female was born at 32 weeks' gestation to a 33-year-old gravida 8, para 5, abortus 3 woman. Each abortion had occurred in the second trimester. No abnormalities were noted in these fetuses. There was no history of congenital anomalies. During this pregnancy thrombophlebitis developed. Pulmonary embolization occurred early in the second month. Treatment included heparin, digoxin, cephalexin, meperidine, and acetaminophen. Warfarin therapy was continued throughout pregnancy at a dose of 7.5 mg daily and increased to 10 mg every third day. Hydroxyprogesterone was given during the fifth month; other therapy included ampicillin and doxycycline.
From the Pritzker School of Medicine of The University of Chicago and the Departments of Pediatrics and Radiology of The University of Chicago Hospitals and Clinics, Wyler Children's Hospital. *Reprint address: The University of Chicago, Department of Pediatrics, 950 E. 59th St., Chicago, lll. 60637. Vol. 88, No. 3, pp. 506-508
At 32 weeks labor began spontaneously. Oxytocin stimulation was given; the duration of labor was eight hours. At birth the infant required resuscitation. The Apgar scores were 3 at one minute and 2 at five minutes. The infant had a single umbilical artery and a hypoplastic nose. Punctate skeletal lesions were seen roentgenographically.
See related article, p. 509. Continued respiratory difficulty and a systolic murmur prompted transfer to The University of Chicago Intensive Care Nursery at three weeks of age. On admission the infant was moderately hypotonic and pale and had intermittent cyanosis, stridor, and substernal retractions. Length was 44 cm; weight was 1,720 gm. The face was broad with apparent hypoplasia of the midportion, markedly depressed nasal bridge, and hypoplastic alae nasi (Fig. 1). The tongue fell back against an intact palate. A systolic ejection murmur was heard best at the second and third left intercostal spaces. Ophthalmoscopic examination was negative. The clitoris was moderately hypertrophied. Both hips were subluxed. There was no evident asymmetry. Cyanosis and stridor improved after placement of an oral airway. The infant was briefly placed in oxygen (Frog = 30-40%); following transfusion with 20 ml of packed red blood ceils the infant appeared to be improved and the intensity of the murmur decreased. Results of laboratory data included hemoglobin 8.7 gm/dl, hematocrit 24% (42% following transfusion), reticulocyte count 2.6%, white blood count 2,600/ram:'; electrocardiogram, border-
Warfarin therapy and chondrodysfllasia punctata
Volume 88 Number 3
507
Table I. S u m m a r y o f d r u g e x p o s u r e d u r i n g first a n d s e c o n d t r i m e s t e r
Case No. (reference) Drug Warfarin Heparin Cardiac glycoside Sulfa Erythromycin Pencillins-cephalosporins Doxycycline Progesterone Diazepam Meperidine Alcohol Diphenylhydantoin Primidone Furosemide Thiazide Acetoaminophen
1"
2~" ~~
31
X
X X X X X
X
X
I
42
53
X
X
X
8* X X X
X
X X
X X X
X
X X X X
X X X X
*This report. T a b l e II. S u m m a r y o f positive findings in cases o f c h o n d r o d y s p l a s i a p u n c t a t a associated w i t h w a r f a r i n a d m i n i s t r a t i o n
Case No. (reference) Finding
111
]
21 . 1o
3~
4 o-
675
225-450
+ +
+ + +
53
63
73
8*
--
--
450
+ +
+
+ + +
R
Estimated warfarin dose (mg) in first trimester Low birth weight Nasal hypoplasia-abnormal facies Upper airway obstruction Cataracts Optic atrophy External ear anomaly Rhizomelia Asymmetric limbs Contractures Congenital hip dislocation Scoliosis Hypotonia Mental retardation Seizures Stippled calcification Calcification of thyroid-trachealarynx
675 _+ + +
+ + +
+ +
+
§ + + +
+ +
+ + +
+
+ _+
§
+
*This report. + Indicates presence of findings. _+Indicates borderline findings. line biventricular hypertrophy; total T~ 7.8%, free thyroxine index 7.0; chromosome analysis, normal 46 XY karyotype. Roentgenographic examination (Fig. 2) demonstrated multifocal punctate calcifications in central and posterior portions of the vertebrae, most noticeable in the cervical and lumbar regions. Punctate calcifications were also seen in some anterior costal cartilages, the proximal femoral epiphyses, the triradiate cartilages, trochlear epiphysis, calcanei, and right patella. There was a
calcific focus in a subglottic ring. The right hip appeared dislocated. DISCUSSION C h o n d r o d y s p l a s i a p u n c t a t a ~-~ is p r e s u m a b l y a h e r i t a b l e disease; it is c h a r a c t e r i z e d b y e p i p h y s e a l a n d e x t r a e p i p h y seal calcifications2 F r e q u e n t findings i n c l u d e f l a t t e n e d ,
508
Pauli et al
The Journal of Pediatrics March 1976
Fig. 2. REFERENCES
Fig. 1. hypoplastic nose, high-arched or cleft palate, cataracts, optic atrophy, skin lesions, rhizomelia, limb asymmetry, flexion contractures, hip dislocation, and foot deformities2 -s Attempts have been m a d e to divide the syndrome according to clinical findings and patterns o f inheritances. Spranger and associates s used the designation ConradiHtinermann for the milder form, which is apparently inherited as an autosomal dominant. A rhizomelic type with recessive inheritance, rhizomelic limb shortening, metaphyseal changes, and a much greater incidence of developmental retardation, eye involvement, and early death was also described. To our knowledge our patient is the eighth published case* describing a n association of chondrodysplasia p unctata with a maternal administration of warfarin. ~-~' ~~ ~i As in the case described below, warfarin therapy was begun following conception, implying a teratogenic rather than a germ cell mutational mechanism, the nature of which remains unknown. *See followingcase report.
1. Becker MH, Genieser NB, Finegold M, et al: Chondrodysplasia punctata-is maternal warfarin therapy a factor? Am J Dis Child 129:356, 1975. 2. Shaul WL, Emery H, and Hall JG: Chondrodysplasia punctata and maternal warfarin use during pregnancy, Am J Dis Child 129:360, 1975. 3. Pettifor JM, and Benson M: Congenital malformations associated with administration of oral anticoagulants during pregnancy, J P~DIATR86:459, 1975. 4. Conradi E: Vorzeitiges Auftreten von Knochen-und eigenartigen Verkalkungs Kernen bei Chondrod3fstrophia fotalis hypoplastica. Histologische und R6ntgenuntersuchungen, Jahrb Kinderheilkd 80:86, 1914. 5. H~nermann C: Chondrodystrophia calcificans congenita als abortive Form der Chondrodystrophie, Z Kinderheilkd 51:1, 1931. 6. Mosekilde E: "Stippled epiphyses" in the newborn and in infants, Acta Radiol 37:291, 1952. 7. Josephson BM, and Oriatti MD: Chondrodystrophia calcificans congenita: Report of a case and review of the literature, Pediatrics 28:425, 1961. 8. Melnick JC: Chondrodystrophia calcificans congenita, Am J I~is Child 110:218, 1965. 9. Spranger JW, Opitz JM, and Bidder U: Heterogeneity of chondrodysplasia punctata, Humangenetik 11:190, 1971. 10. DiSaia PJ: Pregnancy. and delivery of a patient with a startEdwards mitral valve prosthesis, Obstet Gynecol 28:469, 1966. 11. Kerber J, Warr OS III, and Richardson C: Pregnancy in a patient with a prosthetic mitral valve; associated with a fetal anomaly attributed to warfarin sodium, JAMA 203:223, 1968.
