Infant Exposure to Antituberculosis Drugs via Breast Milk and Assessment of Potential Adverse Effects in Breastfed Infants: Critical Review of Data

Abstract

Infants of mothers treated for tuberculosis might be exposed to drugs via breast milk. The existing information on the exposure of breastfed infants lacks a critical review of the published data. We aimed to evaluate the quality of the existing data on antituberculosis (anti-TB) drug concentrations in the plasma and milk as a methodologically sound basis for the potential risk of breastfeeding under therapy. We performed a systematic search in PubMed for bedaquiline, clofazimine, cycloserine/terizidone, levofloxacin, linezolid, pretomanid/pa824, pyrazinamide, streptomycin, ethambutol, rifampicin and isoniazid, supplemented with update references found in LactMed®. We calculated the external infant exposure (EID) for each drug and compared it with the recommended WHO dose for infants (relative external infant dose) and assessed their potential to elicit adverse effects in the breastfed infant. Breast milk concentration data were mainly not satisfactory to properly estimate the EID. Most of the studies suffer from limitations in the sample collection, quantity, timing and study design. Infant plasma concentrations are extremely scarce and very little data exist documenting the clinical outcome in exposed infants. Concerns for potential adverse effects in breastfed infants could be ruled out for bedaquiline, cycloserine/terizidone, linezolid and pyrazinamide. Adequate studies should be performed covering the scenario in treated mothers, breast milk and infants.

Pharmacokinetics and Safety of Group A and B Anti-Tuberculosis Drugs Used in Treatment of Rifampicin-Resistant Tuberculosis during Pregnancy and Post-Partum: A Narrative Review

“…No maternal blood was taken to calculate the milk-plasma concentration ratio; however, an earlier study of older-generation quinolone exposure in pregnant and lactating women indicated high concentrations in breastmilk (>75% relative to maternal plasma concentrations even two hours after dosing) [14]. The clinical implications of fluoroquinolone exposure in breastmilk have not been widely reported; however, based on available data, the risks to the breastfeeding infant are considered to be negligible given the extremely low estimated dose delivered to the infant through breastmilk in this case [8].…”

“…Low linezolid levels in breastmilk are unlikely to be harmful to nursing infants but concerns for adverse effects cannot be ruled out [8]. No routine monitoring is currently recommended, but assessment of full blood count and differential in the infant might be clinically indicated.…”

“…Although linezolid has been detected in breastmilk, pharmacokinetic data from three case reports suggest that systemic exposure in the infant is minimal [8]; the risk of subtherapeutic doses in the context of neonatal M. tuberculosis infection is a potential but unvalidated concern.…”

“…A few other case reports of clofazimine exposure among women successfully treated for leprosy or tuberculosis during pregnancy indicate that clofazimine crosses the placenta (as evidenced by infant skin discolouration), but no teratogenic effects have been documented [46][47][48]; neonatal pharmacokinetic parameters for clofazimine have not been reported [8].…”

“…After birth, infants can be assessed clinically for adverse events possibly related to exposure to specific drugs, in utero and through breastfeeding, and the co-ordinated pharmacokinetic sampling of foetal blood, umbilical cord blood, maternal blood and/or breastmilk can provide estimates of the extent of foetal exposure to such drugs [7]. A recent systematic literature review found that published data on maternal plasma and breastmilk concentrations and infant exposures to most second-line antituberculosis drugs are extremely scarce [8].…”