PEDIATRIC PHARMACOLOGY AND THERAPEUTICS Paul S. Lietman,Editor

Withdrawal symptoms in neonates from intrauterine exposure to diazepam Three infants are presented who had withdrawal symptoms after prolonged, intrauterine exposure to diazepam. Symptoms, clinical course, management, and laboratory findings are described Some physiologic aspects of diazepam in the fetus and neonate are discussed. One infant died at six weeks of age," death was attributed to the sudden infant death syndrome.

Jos6 Luis Rementeria, M.D.,*

B r o o k l y n N. Y.

and Kishor Bhatt, M.D.,

B r o n x , N . Y.

DIAZEPAM, commercially available since 1963, has become the most commonly prescribed medication in the United States' and perhaps in the world.'-' The wide use of diazepam in pregnancy and during labor has resulted in newborn infants with hypothermia? .~ hyperbilirubinemia,' poor sucking, hypotonia, asphyxia, and respiratory depression." ~' Newborn infants have been reported to have had withdrawal symptoms from such drugs as phenobarbital, v-'' desmethylimipramine, TM ethchlorvynol (Placidyl), 1~ pentazocine (Talwin), r-' and chlordiazepoxide (Librium).':' Recently, withdrawal symptoms have been reported in adults TM who had their average doses of diazepam discontinued after usage of four to six months. During 1973, three newborn infants in our nursery presented with symptoms resembling narcotic withdrawal. In the evaluation of these infants it was found that all three had prolonged, intrauterine exposure to diazepam. To our knowledge, these may be the first reported cases of withdrawal symptoms related to diazepam in neonates. CASE REPORTS Case 1. Infant boy V. was born to a 25-year-old gravida 5. para 2, abortions 2 mother. During the sixteenth week of pregnancy her physician prescribed phenobarbital 90 mg twice a day and diazepam 10 mg twice a day for ten days. For the remaining 17 weeks of her pregnancy therapy was continued with diazepam 10 'From the Department of Pediatrics, Fordham Hospital. *Reprint address: Department of Pediatrics, Brooklyn Hospital, 121 DeKalb Ave., Brooklyn. N.Y. 11201.

mg two times a day. The last dose of diazepam was approximately 48 hours prior to delivery. There was no history of narcotic intake. At birth, the infant weighed 2,098 gm. At 2~A hours of life a mild tremor was noted, which gradually increased in severity. Serum concentrations of glucose (59 mg/dl), calcium (9.1 mg/dl), magnesium (1.9 mg/dl), and electrolytes were normal. Because of the increasing tremors, the mother was suspected of being a possible narcotic abuser despite her denial. The infant was treated with phenobarbital, 8 mg/kg/day, and responded satisfactorily. Despite the medication, mild tremors persisted for a period of ten days. Urine evaluation for narcotics was done by thin layer chromatography, a method that can detect diazepam. There was no evidence of narcotics or diazepam, Case 2. Infant boy A., weighing 3,205 gin, was born (at another hospital) to a 21-year-old primigravida. At three hours of life a mild tremor was noted. Concentrations of glucose and calcium were reported as being normal and the infant was discharged on Day 4. At 12 days of age the infant was admitted to our hospital with a history of tremors (persisting from Day 3 of life), loose stools four to five per day) of two days' duration, vomiting (two times) on the day of admission, and poor weight gain (3,137 gm). The infant was mildly dehydrated and moderate tremors were noted. In addition, there were hyperactivity, irritability, hypertonicity, vigorous sucking, and tachypnea. The initial laboratory data included negative stool cultures, a serum concentration of glucose of 91 mg/dl, calcium of 9.1 mg/dl, magnesium of 2.2 mg/dl, and normal electrolyte values. No drugs were detected in the urine. The dehydrated state was corrected, but the tremors continued to increase in severity so that treatment was initiated with phenobarbital (10 mg/kg/day) on the fourth hospital day (Day 16 of life). Thereafter, the symptoms decreased in severity: the The Journal of P E D I A T R I C S Vol. 90, No. 1, pp. 123-126

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The Journal of Pediatrics January, 1977

Table I. Data on the three infants exposed to intrauterine diazepam

I Gestational age (wk) Apgar score Amniotic fluid Duration of maternal diazepam intake prior to delivery Last dose of diazepam prior to delivery Initial symptoms in infant Onset of symptoms postnatally Duration of tremors Symptoms

Phenobarbital dose needed to control symptoms Duration of phenobarbital therapy Clinical evaluation of phenobarbital effect

Infant V.

Infant A.

lnfant F.

33 8-10 Clear 4 mo

40 NK NK 5 mo

37 9-10 Clear 3 mo

48 hr

48 hr

2 wk

Tremors 2V~ hr

Tremors 3 hr

Tremors 6 hr

10 days Tremors, severe; irritability; hypertonicity; duskiness (2 occasions associated with feedings); sucking, vigorous,

5 wk Tremors. mild; irritability; abdominal fullness: vigorous sucking.

8 mg/kg/24 hr

6 wk Tremors, severe: hyperactive: hypertonicity; tachypnea: diarrhea; vomiting; dehydration; poor weight gain; vigorous sucking. 10 mg/kg/24 hr

13-days

16 days

28 days

Symptoms well controlled

Symptoms well controlled

5 mg/kg/24 hr

Symptoms well controlled

NK = Not known.

dosage of phenobarbital was gradually lowered and discontinued after 16 days. The maternal history indicated that the mother had been receiving diazepam during the last five months of her pregnancy: 5 mg twice a day for two months and 5 mg three times a day for the last months. The only other known medication taken during the pregnancy was the smoking of one marijuana cigarette in the fourth month of pregnancy. Case 3. Infant baby boy F. was born to a 26-year-old, multigravida, black woman; he weighed 3,010 gm. The maternal history indicated the use of diazepam, 5 mg three times a day, during the last three months of her pregnancy. The mother stated that she stopped taking diazepam two weeks prior to delivery. There is a negative history for any other medication during the pregnancy. The infant did well until six hours after birth when tremors were noted. Laboratory evaluations for serum concentrations were normal: glucose (110 mg/dl), calcium (8.0 mg/dl), magnesium (1.9 mg/dl)~ Evaluation of the urine for drugs was negative. The tremors gradually increased in severity and in the second day of life treatment with phenobarbital, 3 mg/kg/day, was started. Initially the infant did well on this dosage; however, two days later, owing to increasing irritability and tremors, the dose was increased to 5 mg/kg/day. Thereafter the phenobarbital dosage was gradually decreased and discontinued at 28 days. The infant still had a mild tremor that persisted for ten days after cessation of medication. The infant died at home prior to his first scheduled Well-Baby

Clinic visit. The medical examiners report indicated sudden infant death syndrome. DISCUSSION The clinical picture presented by these three infants could not be distinguished from that of infants undergoing narcotic withdrawal-tremors, irritability, hyperactivity, hypertonicity, tachypnea, vigorous sucking, and, in one case, poor weight gain, loose stools, and some vomiting. The initial symptoms (tremors) were noted quite early in the post natal life (2~h to 6 hours). One infant had such severe tremors in the first day of life that treatment was immediately initiated; the other two were treated with phenobarbital on Days 2 and 16 of life. respectively. In order to control the symptoms of withdrawal, 3 to 5 m g / k g / d a y of phenobarbital was initiated in divided (intramuscular) doses and then either increased or decreased, depending on the clinical status of the infant. The infants required phenobarbital in the range of 5 to 10 m g / k g / d a y for symptoms to be controlled. Phenobarbital was selected for use in these three cases, because it was being used in our nurseries for the treatment of narcotic withdrawal and the initial, clinical impression given by the three infants mimicked narcotic withdrawal. Phenobarbital therapy controlled the symptoms sufficiently so that the infants had only mild, occasional tremors, fed

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well, and gained weight. The mild tremors persisted for long periods of time in two infants-five and six weeks, respectively. The phenobarbital dosage was decreased every three to four days as long as the symptoms remained minimal, Although phenobarbital proved satisfactory in controlling the diazapam withdrawal, other medications may result in a better pharmacologic response. Intrauterine exposure to diazepam for long periods did not adversely affect the birth weight of the three infants as has been reported with heroin. 1..... Despite the readily obtained history of maternal therapy with diazepam, all three infants were still suspected of possibly experiencing narcotic withdrawal. Evaluation of the urine of the three infants for drugs, however, was negative. The perinatal period of two of the three infants appeared to be uneventful; there was no meconiumstained amniotic fluid, no fetal distress, and each had good Apgar scores (Table I). The death of the infant who died at home was attributed to the sudden infant death syndrome. An apparent increase in the incidence of the sudden infant death syndrome among infants of narcotic addicted women has been reported. ~ .... Diazepam is a small molecule and easily passes the placentas It has an affinity for lipids and is stored in adipose tissue. In some instances, diazepam levels in newborn infants have been reported to be double that of their mothers.'-'" Premature and term infants tend to accumulate diazepam in their adipose tissue and to bind it to serum proteins.-'" The half-life of diazepam is longer in infants than in older children. In children (age, three to seven years) the half-life is 18 hours; in preterm infants (age, eight to 81 days; gestational age, 28 to 34 weeks) the half-life is 54 hoursS' The process of demethylation and hydroxylation of diazepam appears to be diminished in term and preterm infants, so that they presumably have a limited ability to metabolize and excrete the drug. In the term infant the hydroxylated compound of diazepam may not begin to appear in the urine until two or three weeks after birth. This limited ability to metabolize and excrete diazepam may result in a longer persistence of the drug in the body and longer pharmacologic effectsS' The early withdrawal experienced by the three infants might have been due to the fact that in each case the mother had not taken any diazepam for a period of 48 hours or more prior to the birth of the infant. Most of the studies '~ -'..... in infants exposed to diazepam in utero have been limited to short periods of time: minutes to hours. If diazepam is used continuously by the mother, the tissue of the fetus, especially the liver, will

Withdrawal symptoms from diazepam

125

accumulate the drug. The higher diazepam concentrations in the tissues may not be reflected in the serum level of the infant at birth5 ~ The fetus that is exposed to long, persistent levels of diazepam may be in danger of manifesting postnatal withdrawal manifestations. The variability in the onset of symptoms, their severity, and duration can be the result of many factors-maternal dosage, fetal absorption and storage, postnatal tissue binding and release, serum half-life, metabolism, and excretion. Any infant, whose mother has been receiving diazepam during the last few months of her pregnancy, should be closely observed for the possibility of developing withdrawal manifestations. REFERENCES

1. Blackwell B: Psychotropic drugs in use today, JAMA 225:1637, 1973. 2. Altman LK: New York Times, May 19, 1974, p 1. 3. Owen JR, Irani SF, and Blair AW: Effort of diazepam administered to mothers during labor on temperature regulation of neonate, Arch Dis Child 47:107, 1972. 4. Cree JE, Meyer J, and Hailey DM: Diazepam in labor: Its metabolism and effect on the clinical condition and thermogenesis of the newborn, Br Med J 4:251, 1973. 5. Schiff D, Chan G, and Stern L: Fixed drug combination and the displacement of bilirubin from albumin, Pediatrics 48:139, 1971. 6. McCarthy GT, O'Connell B, and Robinson AE: Blood levels of diazepam in infants of two mothers given large doses of diazepam during labor, J Obstet Gynaecol Br Commonw 80:349, 1973. 7. Bleyer WA. and Marshall RE: Barbiturate withdrawal syndrome in a passively addicted infant, JAMA 221:185, 1972. 8. Schweigert BF: Neonatal barbiturate withdrawal, JAMA 221:1282, 1972. 9. Desmond MM, Schwanecke RP, Wilson GS, Yasunaga S. and Burgdorff I: Maternal barbiturate utilization and neonatal withdrawal symptomatology, J PEDIATR80:190, 1972. 10. Webster PAC: Withdrawal symptoms in neonates associated with maternal antidepressant therapy, Lancet 2:318, 1973. l l. Rumack BH, and Walravens PA: Neonatal withdrawal following maternal ingestion of ethchlorvynol (Placidyl), Pediatrics 52:714, 1973. 12. Goetz RL, and Bain RV: Neonatal withdrawal symptoms associated with maternal use of pentazocine, J PEDIATR 84:887. 1974. 13. Athinarayanan P, Pierog SH, Nigam SK, and Glass L: Chlordiazepoxide withdrawal in the neonate, Am J Obstet Gynecol 124:212. 1976. 14. Haskell D: Withdrawal of diazepam, JAMA 233:135, 1975. 15. Glass L: The neonate in withdrawal-identification, diagnosis and treatment, Pediatr Ann 4:384, 1975. 16. NaeyeRL, Blanc W, Leblanc W, and Khatamee MA: Fetal complications of maternal heroin addiction: Abnormal growth, infection, and episodes of stress, J PEDIATR83:1055, 1973.

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17. Pierson PS, Howard P, and Kleber HD: Sudden deaths in infants born to methadone maintained addicts, JAMA 220:1733, 1972. 18. Kandall SR: Delayed onset of neonatal drug withdrawal symptoms, Pediatr Ann 4:391. 1975. 19. Rementeria JL, Kerdman L, Marrero G, and Hollander M: Socio-medical study involving 135 drug addicted mothers and their infants, North American Congress on Alcoholism and Drug Abuse, San Francisco, Calif., December 13, 1974.

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Erkkola R, Kangas L, and Pekkarinen A: The transfer of diazepam across the placenta during labor, Acta Obstet Gynecol Scand 52:167, 1973. 21. Morselli PL, Principi N, Tagnani G, Reali E, Belvedere G, Standen SM, and Sereni F: Diazepam elimination in premature and full term, and children, J Perinat Med 1:133, 1973. 22. Erkkola R, Kanto J, and Sellman R: Perinatal metabolism of diazepam, Br Med J 3:472, 1974.

Withdrawal symptoms in neonates from intrauterine exposure to diazepam.

PEDIATRIC PHARMACOLOGY AND THERAPEUTICS Paul S. Lietman,Editor Withdrawal symptoms in neonates from intrauterine exposure to diazepam Three infants a...
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