Benzodiazepine Concentrations in the Breast Milk and Plasma of Nursing Mothers: Estimation of Relative Infant Dose

Abstract

Benzodiazepines are common therapies for mental illness and insomnia and are used during pregnancy and lactation. Although benzodiazepines have been shown to be transferred into breast milk, the amount transferred is small and compatible with breastfeeding. However, information is not available for all drugs. Therefore, we aimed to determine the milk to plasma (M/P) ratio and relative infant dose (RID), which are used as indicators of drug transfer to breast milk, to determine the safety of such drugs for lactating women and breastfeeding infants. The study comprised 11 pregnant women who visited the obstetrics department of Hokkaido University Hospital and Tenshi Hospital for childbirth. The samples were analyzed using liquid chromatography-tandem mass spectrometry, and the M/P ratio and RID were calculated. The condition of the mother and baby at 1 month after delivery was determined from the clinical information. The target benzodiazepines were alprazolam, brotizolam, clonazepam, clotiazepam, etizolam, ethyl loflazepate, flunitrazepam, and lorazepam. For all drugs, the M/P ratios were <1 and remained constant over time. For drugs other than ethyl loflazepate, the RID values were less than 10%, which are considered safe; however, even with ethyl loflazepate, it was only slightly over 10%. No abnormalities were found in breastfeeding infants whose mothers were receiving these medications. The RID results of this study suggest that drug exposure through breast milk is small; thus, maternal drug treatment and breastfeeding are compatible. Good Good Clonazepam Flunitrazepam 1 No change Breast milk & formula milk Breast milk Good Good Etizolam 1 1.5 Breast milk Breast milk Good Worsening Lorazepam 0.5 No change Breast milk & formula milk Breast milk & formula milk Good Worsening Lorazepam Ethyl loflazepate 0.5 No change Breast milk Breast milk & formula milk Good Good Flunitrazepam 1 No change Breast milk Breast milk Good Good 10 Lorazepam 0.5 No change Breast milk & formula milk Breast milk & formula milk Good Good 11 Brotizolam 0.25 0.125 Breast milk & formula milk Formula milk (main) Good Good

Benzodiazepines Remain Important Therapeutic Options in Psychiatric Practice

“…Benzodiazepines are excreted in breast milk. A Japanese study of 11 nursing mothers and their 1-month-old infants taking benzodiazepines, including alprazolam, brotizolam, clonazepam, flunitrazepam, and lorazepam, among others, found that the ratio of breast milk to maternal plasma benzodiazepine level was consistently less than 1, and the relative infant dose was always less than 10% of the maternal dose except for ethyl loflazepate, which was only slightly greater than 10% [168]. No abnormalities were noted in the infants.…”

Clinical pharmacology of lorazepam in infants and children

“…Lorazepam was administered intravenously at a dose of 2.5 mg to pregnant mothers before surgical induction of labour or at the beginning of the second stage of labour. Lorazepam serum concentrations in newborns are similar to those in the maternal serum and rarely exceed the maternal concentrations [40].…”

“…Intranasal lorazepam has more favourable pharmacokinetics than buccal lorazepam in termination seizures in children [38]. Lorazepam freely crosses the human placenta [39,40], and lorazepam poorly migrates into the breast-milk [41][42][43][44].…”

Beyond the ‘normal’ worries: detection and treatment of perinatal anxiety and anxiety disorders

“…Benzodiazepines are excreted only in small amounts in breast milk, so their use could be compatible with breastfeeding. If treatment is beginning postpartum, lorazepam, alprazolam or clonazepam are suggested (Nishimura 2021).…”