Indian Pediatrics - Editorial

Letters to the Editor

Indian Pediatrics 2004; 41:963-964

Phenobarbital Toxic Levels in a Nursing Neonate

Antiepilepsy drugs have revolutionised the management of epilepsy however their use in pregnant and nursing mothers needs careful monitoring(1). Drugs like pheno-barbitone, primidone and ethosuximide accumulate in nursing neonates to levels approaching or even exceeding those of their mothers(2).The use of phenobarbital while breastfeed is controversial due to its slow elimination by the nursing infant (3).We report a case of phenobarbital toxicity in a newborn.

A 26-year-old mother with epilepsy (secondary to tuberculous meningitis) who was moderately controlled on 90 mg of phenobarbitone delivered a male baby at term weighing 2.75 kg .On day one of life baby had an absent suck and became progressively lethargic by the third day. Initially the infant was on when intravenous fluids and later as sensorium improved, baby was breastfed. The anticonvulsant concentrations measured in mother’s plasma, breast milk and baby’s blood on day 6 showed an increased levels of phenobarbital in the baby’s plasma which reached toxic levels by day19 (Table I). To avoid cumulative dose effect of phenobarbitone (PB), breast- milk was gradually withdrawn and the baby monitored for withdrawal reactions. A decision was made to reinstitute human milk, once maternal PB was replaced by another antiepileptic drug.

Table I

Phenobarbital levels (in µg/mL) in Mother, Baby and Breastmilk.

	Maternal plasma	Baby’s plasma	Breast Milk
Day 6
Pre-PB dose	36.2	12.06	4.34
Post 2½ hrs of dose	32.0	28.34	5.01
Day 19
Pre-PB dose	32.18	15.36	4.34
2½ hrs post PB dose	28.21	54.71	5.47

Little data till date is available on transplacental transfer of anticonvulsants. What is known, is that potentially reactive metabolites are formed by the fetal liver leading to variable accumulation in the organs. In utero the fetus receives a larger dose of anti epilepsy drugs (AED) via the placenta (80-108%) than the breastfed neonate (20-50%)(4). In fact most neonatal AED concentration at delivery approach maternal serum levels. Neonatal sedation, seizures, methemoglobinemia, reduced weight gain are the uncommon effects of maternal PB intake. Anti epileptics are usually protein bound but in late pregnancy due to low albumin levels, increased free drug levels are found. Therefore, one should be cautious against measuring the total plasm concentration and should aim to test both the protein bound and free drug levels(5).

We recommend regular antenatal monitoring of both free and bound pheno-barbital levels, and also that the lowest effective dose be given or else use another safer AED(6).Newborns exposed prenatally to phenobarbital should have serum drug levels monitored as also for withdrawal symptoms for at least 2-6 weeks of life.

Mona Pote,
Renuka Kulkarni,
Manish Agarwal,
Neonatal Unit,Department of Pediatrics and
Clinical Pharmacology,
T.N.Medical College and B.L.Nair Hospital,
A.L.Nair Road, Mumbai- 400 008, India.
E-mail: [email protected]

References

1. American Academy of Pediatrics Committee on Drugs. The transfer of drugs and other chemicals into human milk. Pediatrics 2001; 108: 776-789.

2. Nau H, Kuhnz W, Egger HJ, Rating D, HelgeH. Anticonvulsants during pregnancy and lactation. Transplacental, maternal and neonatal pharmacokinetics. Clin Pharmaco-kinet 1982; 7: 508-543.

3. Bar-Oz B, Nulman I, Koren G, Ito S. Anticonvulsants and breastfeeding: A critical review. Pediatr Drugs 2000; 2: 113-126.

4. Meyer FP, Quednow B, Potrafki A, Walther H. Pharmacokinetics of anticonvulsants in the perinatal period. Zentralbl Gynakol 1988; 110: 1195 -1205.

5. Caltz CS, Giacoia GP. Drugs and Breast Milk. Pediatr Clin N Am. 1972; 19: 151-166.

6. Hagg S, Spigset O. Anticonvulsant use during lactation. Drug Saf 2000; 22: 425-440.