Maternal Carbamazepine Therapy and Unusual Adverse Effects in a Breastfed Infant

Introduction

Breastfeeding is known for its beneficial effects. ¹ However, in epileptic mothers under long-term therapy with anticonvulsants, the decision to encourage breastfeeding should be taken after a careful evaluation of the possible side-effects on the infant.

Usually, no adverse effects are observed in breastfed infants whose mothers are treated with the anti-epileptic carbamazepine. However, some transient adverse reactions such as poor sucking and sedation,^2,3 hepatic dysfunction ⁴ and cholestasis ⁵ have been reported. Therefore, it is recommended to monitor serum carbamazepine levels, blood cell count, and liver enzymes in breastfed neonates and infants during maternal treatment with this medication. ⁶

In this article, we describe unusual adverse effects observed in a young infant after exposure to carbamazepine during pregnancy and lactation, and we discuss this case in the light of the literature.

Case Report

A 40-day-old female infant, born at term with a birth weight of 3,190 g, was admitted to the Pediatric Clinic at University of Sassari, Italy, for recurrent regurgitations and vomiting. She was exclusively breastfed since birth, and her mother was under chronic anti-epileptic monotherapy with carbamazepine. The dosage of the medication, 800 mg/day divided into two doses, was increased to 1,200 mg/day (600 mg twice daily) at the 36th week of gestation after a partial epileptic seizure, and this dosage was continued after delivery and during breastfeeding.

The history of the present illness revealed that the infant manifested poor weight gain, poor sucking, and vomiting from the earliest days of life, whereas neurological assessment and laboratory tests were normal.

Gastroesophageal reflux was initially suspected; therefore, postural therapy and oral ranitidine (15 mg/day in two divided doses) were applied, but without any benefit. High levels of carbamazepine were detected in infant serum (1.3 mcg/mL) and in maternal breast milk at three different time points within a six-hour interval (3.5, 4.4, 3.1 mcg/mL) (Table 1). The presence of relevant concentrations of carbamazepine in both biofluids suggested a possible correlation between the infant's symptoms and the drug ingestion through breast milk. Initially, an attempt to combine breastfeeding with formula feeding was made during a two-week period, but it was unsuccessful despite a decrease in infant serum carbamazepine levels (0.6 mcg/mL). Therefore, the switch to exclusive formula feeding was made, after which a rapid resolution of symptoms and a body weight increase were observed. A one-month follow-up confirmed a good weight gain and the absence of vomiting or regurgitation after discharge.

Discussion and Conclusions

The antiepileptic carbamazepine is considered relatively safe during pregnancy, and its use is compatible with breastfeeding. ⁷ Nevertheless, the safety of the maternal intake of this medication during pregnancy and breastfeeding, particularly as regards its potential side effects in newborns and infants, raises several questions and needs further evaluation.

Data available on these side effects are scant, dispersed in the scientific literature and in specialized databases, and, thus, not easily accessible to health professionals. Moreover, most of the data are referred to women under antiepileptic polytherapy, with possible interaction between drugs.

After exposure to maternal carbamazepine during lactation, some authors reported poor sucking and poor weight gain,^2,3 whereas other cases are referred, respectively, to transient hepatic dysfunction ⁴ and cholestatic hepatitis in breastfeeding infants. ⁵ In addition, seizures, ⁸ and refusal to feed, irritability, and drowsiness ² were reported when carbamazepine was taken with other medications.

More recently, some authors ⁹ documented no adverse effects on cognitive functions after exposure via breastfeeding to some antiepileptic drugs (carbamazepine, lamotrigine, phenytoin, and valproate) at age 6 years.

A report describing a suspected adverse drug reaction associated with carbamazepine exposure during pregnancy (maternal dose 200 mg/day) and lactation was obtained from the database of the Italian Pharmacovigilance Network (Rete Nazionale di Farmacovigilanza): the infant showed gastrointestinal symptoms (vomiting and diarrhea).

In our case, given the presence of symptoms from the earliest days of life, it is possible that the higher dose (1,200 mg/day) taken by the mother in the last weeks of gestation could have led to an increase in serum levels of carbamazepine in the neonate at birth, and that breastfeeding could have further contributed to prolonging the infant's exposure to the drug during the first few weeks of life. Maternal doses of carbamazepine taken during pregnancy and lactation were higher compared with those reported in other cases where side effects were observed in infants: 400 mg/day ⁵ or 600 mg/day. ⁸

Carbamazepine has a moderately high degree of plasma protein binding and may transfer into breast milk to some degree, with a milk/plasma ratio of 0.2–0.7. ¹⁰ This medication and its active epoxide metabolite are excreted into breast milk with concentrations variable from 0.34 to 6 mg/L, ¹¹ and serum levels in babies are usually low. ¹² In our case, carbamazepine concentration detected in the infant's serum (1.3 mcg/mL) was similar (1.1 mcg/mL) ⁴ or higher (0.5, 0.5, and 0.7 mcg/mL)^5,8,13 compared to those reported by other authors. Milk concentrations, measured at three different time points, were higher than those cited by a review on the use of carbamazepine and sodium valproate during breastfeeding. ¹⁴

Other factors such as prematurity or synergistic interactions with other medications were absent in our case.

The relationship between infant exposure to carbamazepine and clinical symptoms was demonstrated by the fact that the suspension of breastfeeding and the use of exclusive formula feeding were sufficient to obtain the complete clinical resolution: the use of the Naranjo probability scale (Table 2) also indicated a “probable” relationship between the observed symptoms and prenatal/transmammary exposure to carbamazepine. ¹⁵

As suggested by other authors, ¹⁴ carbamazepine may not be as benign as initially thought. If the mother has received, as in this case, the medication during the final weeks of pregnancy, a short “washout” period of few days for the neonate could be taken into consideration. However, the pros and cons of withholding colostrum from the newborn infant should be carefully weighed, considering the questionable advantages of this measure, as well as the benefits of colostrum.

In conclusion, when unexplained symptoms occur in breastfed infants whose mothers are treated with carbamazepine, it is indicated to measure drug levels in infant and mother serum, and to discontinue breastfeeding if necessary.

Consent for Publication

Written informed consent of the patient's parents has been obtained to publish this article.