Maternal Phenytoin Ingestion Congenital Abnormalities:
Report
and
of a Case
The first
reported association of congenital malformations and anticonvulsant drugs was published in 1968.1 Cleft lip and cleft palate were reported in six infants born to mothers who had been taking anticonvulsants during pregnancy. Monson et al2 compared the frequency of malformations in infants exposed in utero to antiepileptic medication with that in infants not so exposed. In their study, the malformation rate among children exposed to phenytoin
(formerly diphenylhydantoin)
sodium
continuously during embryonic and early fetal development was 61 in 1,000 live births. This rate is higher than the 25 in 1,000 live births in chil-
dren born to normal control women. The possibility of having a malformed child appears to be two to three times greater in epileptic women who received phenytoin continuously early in pregnancy than in normal women. This frequency of malformations has been confirmed by other studies.3,4 In most reports, cleft lip and palate proved to be the most frequently as¬ sociated malformation,5 followed by congenital heart disease, skeletal ab¬ normalities, and abnormalities of the central nervous system. Gastrointes¬ tinal tract abnormalities include dia¬ phragmatic hernia, whereas genito¬ urinary tract malformations include hydronephrosis and hypospadias. Our case verifies a combination of
gastrointestinal tract, genitourinary tract, and dermatologie abnormalities not previously associated with use of phenytoin during pregnancy.
Report of a Case.-A 3,700-gm (8.2-lb) boy was born at term to a 28-year-old, gravida 2, para 1 woman. Her first preg¬ nancy had resulted in a normal girl 15 months earlier. The mother has had grand
mal seizures since she was 16 years of age. She has taken phenytoin sodium (100 mg three times daily) for the last three years, including the period of this pregnancy; three years before this delivery she had taken phénobarbital for one year. Her last seizure occurred three years before the
second pregnancy. The only other medica¬ tions have been an occasional aspirin and chlorothiazide diuretics during the last weeks of gestation. The infant had Apgar scores of 5 and 7 and was noted to have the following malformations: (1) complete exstrophy of the bladder, (2) omphalocele, (3) imperforate anus, (4) rectourethral fis¬ tula, (5) solitary kidney (right), and (6) cutis marmorata telangiectatica6 of the
right leg. The penis is normal. The child under¬ went successful repair of the omphalocele. A colostomy was performed and primary closure of the bladder was attempted within the first week of life. However, the wound later separated, and definitive re¬ pair of the bladder and the imperforate anus is planned.
Comment.—Exstrophy of the blad¬ der occurs in one of 30,000 to 50,000 births. It has been associated with imperforate anus and omphalocele. Epispadias is considered part of the complex of complete exstrophy.7 Its absence in our patient is noteworthy. This single case does not prove that maternal ingestion of phenytoin throughout pregnancy caused the anomalies noted. However, we wish to call attention to the possible associ¬ ation of yet another set of malforma¬ tions with prenatal exposure to phenytoin.
MOSHE HIRSCHBERGER, MD FREDRIC KLEINBERG, MD Mayo Clinic and Mayo Foundation 200 First St SW Rochester, MN 55901 1. Meadow SR: Anticonvulsant drugs and congenital abnormalities. Lancet 2:1296, 1968. 2. Monson RR, Rosenberg L, Hartz SC, et al: Malformations. N Engl J Med 289:1049-1052,
1973. 3. Lowe CR: Congenital malformations among infants born to epileptic women. Lancet 1:9-10, 1973. 4. Fedrick J: Epilepsy and pregnancy: A report from the Oxford record linkage study. Br Med J 2:442-448, 1973. 5. Hill RM, Verniaud WM, Horning MG, et al: Infants exposed in utero to antiepileptic drugs: A prospective study. Am J Dis Child 127:645-653, 1974. 6. Way HB, Hermann J, Gilbert EF, et al: Cutis marmorata telangiectatica congenita. J Cutaneous Pathol 1:10-25, 1974. 7. Uson AC, Lattimer JK, Melicow MM: Types of exstrophy of urinary bladder and concomitant malformations: A report based on 82 cases. Pediatrics 23:927-934, 1959.
Idiopathic Acute Pancreatitis in Children Sir.\p=m-\Morenset al of
reported two cases Reye syndrome with acute pancre-
Downloaded From: http://archpedi.jamanetwork.com/ by a University of Manitoba User on 06/17/2015
atitis in the September issue of the Journal (128:401, 1974). They stated that ". . pancreatitis has not been described previously in association with this syndrome. ." It should be brought to the attention of the readers that Glick et al found pancreatitis in four of 46 necropsies of children with Reye syndrome.1 Review of English literature disclosed ten additional cases with clinical and pathologic features of Reye syndrome in which acute pancreatitis was found at necropsy.2-6 The fact that at least 16 patients have been described so far implies that pancreatitis may be a more common feature of Reye syndrome than previously considered. NISAN GILBOA, MD Department of Pediatrics University of Oregon Health Sciences Center Portland, OR 97201 .
.
.
1. Glick TH, Likosky WH, Levitt LP, et al: Reye's syndrome: An epidemiologic approach.
Pediatrics 46:371-377, 1970. 2. Sherman FE, Michaels RH, Kenny FM: Acute encephalopathy (encephalitis) complicating rubella. JAMA 192:675-681, 1965. 3. Laraya-Cuasay LR, Wolfe R, Hughes WT: Acute pancreatitis and hypoglycemia. Clin Pediatr 7:525-528, 1968. 4. Norman MG: Encephalopathy and fatty degeneration of the viscera in childhood: I. Review of cases at the Hospital for Sick Children, Toronto (1954-1966). Can Med Assoc J 99:522-526, 1968. 5. Eiben RM: Acute brain swelling (toxic encephalopathy). Pediatr Clin North Am 14:797\x=req-\ 808, 1967. 6. Stover SL, Wanglee P, Kennedy C: Acute hemorrhagic pancreatitis and other visceral changes associated with acute encephalopathy. J Pediatr 73:235-241, 1968.
In
Reply.\p=m-\Thankyou for allowing me on Dr. Gilboa's thoughtful
to comment
letter, in which he cites several refer-
presumably describing cases of Reye syndrome with pancreatitis. Since it has only been in the past
ences
several years that suitable criteria for the diagnosis of Reye synrdome have begun to emerge, there are, regrettably, inherent problems in evaluating reports in the older literature. As has been adequately documented, even in one of Dr. Gilboa's cited references1 (vide supra), what first appears to be Reye syndrome may prove to be something entirely different on closer examination. On the basis of this, we entitled our article, "Idio-
Report
and
of a Case
The first
reported association of congenital malformations and anticonvulsant drugs was published in 1968.1 Cleft lip and cleft palate were reported in six infants born to mothers who had been taking anticonvulsants during pregnancy. Monson et al2 compared the frequency of malformations in infants exposed in utero to antiepileptic medication with that in infants not so exposed. In their study, the malformation rate among children exposed to phenytoin
(formerly diphenylhydantoin)
sodium
continuously during embryonic and early fetal development was 61 in 1,000 live births. This rate is higher than the 25 in 1,000 live births in chil-
dren born to normal control women. The possibility of having a malformed child appears to be two to three times greater in epileptic women who received phenytoin continuously early in pregnancy than in normal women. This frequency of malformations has been confirmed by other studies.3,4 In most reports, cleft lip and palate proved to be the most frequently as¬ sociated malformation,5 followed by congenital heart disease, skeletal ab¬ normalities, and abnormalities of the central nervous system. Gastrointes¬ tinal tract abnormalities include dia¬ phragmatic hernia, whereas genito¬ urinary tract malformations include hydronephrosis and hypospadias. Our case verifies a combination of
gastrointestinal tract, genitourinary tract, and dermatologie abnormalities not previously associated with use of phenytoin during pregnancy.
Report of a Case.-A 3,700-gm (8.2-lb) boy was born at term to a 28-year-old, gravida 2, para 1 woman. Her first preg¬ nancy had resulted in a normal girl 15 months earlier. The mother has had grand
mal seizures since she was 16 years of age. She has taken phenytoin sodium (100 mg three times daily) for the last three years, including the period of this pregnancy; three years before this delivery she had taken phénobarbital for one year. Her last seizure occurred three years before the
second pregnancy. The only other medica¬ tions have been an occasional aspirin and chlorothiazide diuretics during the last weeks of gestation. The infant had Apgar scores of 5 and 7 and was noted to have the following malformations: (1) complete exstrophy of the bladder, (2) omphalocele, (3) imperforate anus, (4) rectourethral fis¬ tula, (5) solitary kidney (right), and (6) cutis marmorata telangiectatica6 of the
right leg. The penis is normal. The child under¬ went successful repair of the omphalocele. A colostomy was performed and primary closure of the bladder was attempted within the first week of life. However, the wound later separated, and definitive re¬ pair of the bladder and the imperforate anus is planned.
Comment.—Exstrophy of the blad¬ der occurs in one of 30,000 to 50,000 births. It has been associated with imperforate anus and omphalocele. Epispadias is considered part of the complex of complete exstrophy.7 Its absence in our patient is noteworthy. This single case does not prove that maternal ingestion of phenytoin throughout pregnancy caused the anomalies noted. However, we wish to call attention to the possible associ¬ ation of yet another set of malforma¬ tions with prenatal exposure to phenytoin.
MOSHE HIRSCHBERGER, MD FREDRIC KLEINBERG, MD Mayo Clinic and Mayo Foundation 200 First St SW Rochester, MN 55901 1. Meadow SR: Anticonvulsant drugs and congenital abnormalities. Lancet 2:1296, 1968. 2. Monson RR, Rosenberg L, Hartz SC, et al: Malformations. N Engl J Med 289:1049-1052,
1973. 3. Lowe CR: Congenital malformations among infants born to epileptic women. Lancet 1:9-10, 1973. 4. Fedrick J: Epilepsy and pregnancy: A report from the Oxford record linkage study. Br Med J 2:442-448, 1973. 5. Hill RM, Verniaud WM, Horning MG, et al: Infants exposed in utero to antiepileptic drugs: A prospective study. Am J Dis Child 127:645-653, 1974. 6. Way HB, Hermann J, Gilbert EF, et al: Cutis marmorata telangiectatica congenita. J Cutaneous Pathol 1:10-25, 1974. 7. Uson AC, Lattimer JK, Melicow MM: Types of exstrophy of urinary bladder and concomitant malformations: A report based on 82 cases. Pediatrics 23:927-934, 1959.
Idiopathic Acute Pancreatitis in Children Sir.\p=m-\Morenset al of
reported two cases Reye syndrome with acute pancre-
Downloaded From: http://archpedi.jamanetwork.com/ by a University of Manitoba User on 06/17/2015
atitis in the September issue of the Journal (128:401, 1974). They stated that ". . pancreatitis has not been described previously in association with this syndrome. ." It should be brought to the attention of the readers that Glick et al found pancreatitis in four of 46 necropsies of children with Reye syndrome.1 Review of English literature disclosed ten additional cases with clinical and pathologic features of Reye syndrome in which acute pancreatitis was found at necropsy.2-6 The fact that at least 16 patients have been described so far implies that pancreatitis may be a more common feature of Reye syndrome than previously considered. NISAN GILBOA, MD Department of Pediatrics University of Oregon Health Sciences Center Portland, OR 97201 .
.
.
1. Glick TH, Likosky WH, Levitt LP, et al: Reye's syndrome: An epidemiologic approach.
Pediatrics 46:371-377, 1970. 2. Sherman FE, Michaels RH, Kenny FM: Acute encephalopathy (encephalitis) complicating rubella. JAMA 192:675-681, 1965. 3. Laraya-Cuasay LR, Wolfe R, Hughes WT: Acute pancreatitis and hypoglycemia. Clin Pediatr 7:525-528, 1968. 4. Norman MG: Encephalopathy and fatty degeneration of the viscera in childhood: I. Review of cases at the Hospital for Sick Children, Toronto (1954-1966). Can Med Assoc J 99:522-526, 1968. 5. Eiben RM: Acute brain swelling (toxic encephalopathy). Pediatr Clin North Am 14:797\x=req-\ 808, 1967. 6. Stover SL, Wanglee P, Kennedy C: Acute hemorrhagic pancreatitis and other visceral changes associated with acute encephalopathy. J Pediatr 73:235-241, 1968.
In
Reply.\p=m-\Thankyou for allowing me on Dr. Gilboa's thoughtful
to comment
letter, in which he cites several refer-
presumably describing cases of Reye syndrome with pancreatitis. Since it has only been in the past
ences
several years that suitable criteria for the diagnosis of Reye synrdome have begun to emerge, there are, regrettably, inherent problems in evaluating reports in the older literature. As has been adequately documented, even in one of Dr. Gilboa's cited references1 (vide supra), what first appears to be Reye syndrome may prove to be something entirely different on closer examination. On the basis of this, we entitled our article, "Idio-
