Abstract
Background:
Brotizolam is a sedative-hypnotic thienotriazolodiazepine that is a benzodiazepine analog used for debilitating insomnia. Anxiety, depression, and sleep disorders occur in about 15% of pregnant and lactating women; however, no studies have examined brotizolam transfer across the placenta or its excretion into breast milk. In this case report, we assessed brotizolam concentrations in maternal and neonatal blood, cord blood, and breast milk.
Materials and Methods:
Brotizolam concentrations in maternal serum, breast milk, cord blood, and neonatal serum were measured while the mother was taking oral brotizolam 0.25 mg once daily.
Case Report:
A 28-year-old woman diagnosed with bipolar II disorder received brotizolam during pregnancy (28–40 weeks' gestational age) and lactation, along with sertraline, alprazolam, and trazodone. A male infant weighing 3,412 g was born at 40 weeks of gestation. Neonatal abstinence syndrome manifested as fever, limb tremor, and central cyanosis, requiring oxygenation and intravenous phenobarbital administration for 4 days. No pulmonary dysfunction or birth defects were detected. Brotizolam concentrations in maternal serum at 7.0 and 14.0 hours after maternal dosing were 0.51 and 0.22 ng/mL, respectively. Brotizolam was not detected in cord blood or infant serum 9.2 hours after maternal dosing. The brotizolam concentration in breast milk collected 7.1 hours after maternal dosing was 0.12 ng/mL. The infant developed normally, with no drug-related adverse effects at the 1-, 3-, or 6-month postpartum checkups.
Conclusion:
Brotizolam transfer into placenta and breast milk was negligible. Further studies should assess the safety of brotizolam in fetuses and breastfed infants.
Introduction
Anxiety and sleep disorders occur in up to 15% of pregnant women.1–3 Anxiety disorders may require pharmacological treatment, and it has been estimated that 10–26% of pregnant women with these disorders are prescribed benzodiazepines or benzodiazepine-like hypnotic drugs.4,5 These medications cross the placenta and blood–brain barrier, may affect fetal growth and development,6,7 and have been associated with increased risks of preterm birth, low Apgar scores, neonatal intensive care unit (NICU) admission, and neonatal respiratory distress syndrome.8,9 These risks should be considered before administering anxiolytics to lactating mothers. Women also frequently experience sleep problems during the postpartum period, and some require treatment with hypnotic agents.10,11 It is essential to evaluate infants' exposure levels to maternally administered drugs, as well as these drugs' toxicological effects. 12
Although breastfed infants exposed to medications for depression and insomnia are unlikely to be exposed to high drug levels, 13 several side effects, such as drowsiness and sedation, have been identified in infants during breastfeeding.14,15
Brotizolam is a sedative-hypnotic thienotriazolodiazepine drug that is a benzodiazepine analog. It possesses anxiolytic, anticonvulsant, hypnotic, sedative, and skeletal muscle relaxant properties, and is similar in effect to short-acting benzodiazepines such as triazolam. 16 It is used in the short-term treatment of severe or debilitating insomnia. Brotizolam has been approved for sale in the Netherlands, Germany, Spain, Belgium, Luxembourg, Austria, Portugal, Israel, Italy, Taiwan, and Japan, but not in the United Kingdom, the United States, or Canada. Owing to the limited distribution and use of brotizolam worldwide, only one report from Japan published the information on brotizolam transfer into breast milk. 17 Furthermore, the information on brotizolam transfer into the fetal circulation is limited.
In this case report, we assessed brotizolam concentrations in maternal and infant blood, cord blood, and breast milk.
Materials and Methods
Brotizolam detection
Brotizolam in serum and breast milk samples were determined using a modified version of a previously validated method based on liquid chromatography–tandem mass spectrometry. 18 In brief, chromatography was performed on a 3000 Ultimate nano-LC system interfaced with a TSQ Vantage mass spectrometer (Thermo Fisher Scientific, Tokyo, Japan). Compounds were eluted from a Unison UK-C18 column (3 μm reversed phase, 3.0 × 150 mm; Imtakt, Kyoto, Japan). Brotizolam was obtained from Fujifilm-Wako Chemicals (Tokyo, Japan), and diazepam (an internal standard for brotizolam) was obtained from Toronto Research Chemicals (Toronto, Canada). Acetonitrile, ammonium acetate, ethyl acetate, formic acid, and methanol were obtained from Thermo Fisher Scientific. Water was purified using a Milli-Q system (Millipore Waters, Tokyo, Japan). This method has good precision and accuracy over the concentration range of 0.10–30.0 ng/mL. The lower limits of quantification and detection for brotizolam in both breast milk and serum were 0.10 and 0.05 ng/mL, respectively.
Sample collection and preparation
The mother took one 0.25 mg brotizolam tablet orally per day at bedtime. Umbilical cord blood was collected after delivery. All serum samples were immediately separated by ultracentrifugation and stored below −80°C until analysis. Maternal serum samples were collected at 7.0 and 14.0 hours after brotizolam dosing. Infant serum samples were collected at 0, 2, 3, and 4 days after birth. The timing of sample collection after brotizolam dosing is presented in Table 1.
Brotizolam Concentrations in Serum and Breast Milk Samples After Oral Administration of 0.25 mg Brotizolam
BRZ, brotizolam.
Ethics approval
This study was approved by the ethics committee of the National Center for Child Health and Development (Registration number: 1782). The participant provided written informed consent.
Results
Case
A 28-year-old woman diagnosed with bipolar II disorder and weighing 73 kg was pregnant with her first child (G1P0). Because she had symptoms of depression and insomnia, zolpidem 10 mg once daily (QD) was prescribed beginning at 7 weeks' gestational age (GA). Before her pregnancy, duloxetine 60 mg QD, brexpiprazole 1 mg QD, zolpidem 10 mg QD, and lorazepam 0.5–1 mg three times daily were used to treat depression and insomnia. Duloxetine 20 mg QD and zolpidem 5 mg QD were resumed at 20 weeks' GA. In addition, brotizolam 0.25 mg QD, sertraline 25 mg QD, alprazolam 0.4 mg QD, and trazodone 50 mg QD were initiated at 24 weeks' GA. Both duloxetine and zolpidem were ineffective, so they were discontinued at 24 weeks' GA; brotizolam, alprazolam, and trazodone were continued at the same dose until childbirth. The dosage of sertraline was gradually increased to 100 mg twice daily (BID) and was also continued until childbirth. At 40 weeks' GA, a male infant was born by suction delivery. The infant weighed 3,412 g at birth. Apgar scores at 1 and 5 minutes were 7 and 9, respectively. Because the infant developed neonatal abstinence syndrome (NAS) with symptoms of fever, limb tremor, and central cyanosis, oxygenation and intravenous phenobarbital were initiated. By 4 days after delivery the limb tremor resolved, and both oxygenation and phenobarbital treatment were discontinued. The infant required no mechanical ventilation or circulatory support while in the NICU. There were no congenital malformations and the infant exhibited normal developmental progress. During the NICU hospitalization, pumped breast milk was administrated to the infant. Daily milk intake in NICU ranged from 40 to 100 mL for pumped breast milk and from 100 to 220 mL for milk formula. After NICU discharge on day 8, the infant was breastfed exclusively up to 3 months. During lactation, the mother received brotizolam 0.25 mg QD, sertraline 50 mg BID, alprazolam 0.4 mg QD, and zolpidem 10 mg QD. No drug-related adverse effects were detected at the 1-, 3-, or 6-month postpartum health checkups with the pediatric care physician.
Brotizolam concentrations in maternal serum, umbilical cord blood, and neonatal serum
The brotizolam concentration in maternal serum was 0.22 ng/mL at 24 hours before delivery (14.0 hours after the last brotizolam dose). Four days after childbirth, the concentrations in maternal serum at 7.0 and 14.0 hours after the last dose were 0.51 and 0.22 ng/mL, respectively. No brotizolam was detected in cord blood collected immediately after delivery (9.2 hours after the last dose). The brotizolam concentration in the infant's serum was also below the lower limit of detection (0.05 ng/mL).
Brotizolam concentrations in breast milk
To assess the degree of brotizolam transfer to breast milk, brotizolam concentrations in breast milk were measured several times after birth. The concentration was 0.12 ng/mL at 7.1 hours after dosing, but brotizolam was undetectable in breast milk after that point (Table 1).
Discussion
Information on drug disposition in pregnant and lactating women is important for enabling safe and adequate treatment of mothers and their infants. In this study, we report a case in which depression and insomnia were treated with brotizolam during pregnancy and lactation. Brotizolam was not detected in either umbilical cord blood or infant serum at 9.2 hours after maternal administration.
Although neither the milk-to-serum ratio nor the peak brotizolam levels in maternal serum and breast milk were clearly identified in this study, the peak brotizolam level in maternal serum was reported to range from 3 to 10 ng/mL after administration of 0.25 mg brotizolam.19–22 Reported protein binding and elimination half-life of brotizolam are 92% and 5 hours. 21 From these facts, the low milk levels at 7 hours after a dose might be expected. Although the mother also received alprazolam and trazodone, these drugs have not been reported to cause side effects such as drowsiness and sedation in infants exposed through breast milk.14,15
Regarding NAS, cohort studies found that one-third of neonates were affected after in utero exposure to selective serotonin reuptake inhibitors, with 3–13% demonstrating severe NAS.23–25 NAS after in utero benzodiazepine exposure was also reported, and polysubstance exposure was an independent predictor of NAS requiring pharmacological treatment.26,27 Based on this background, the NAS in our case may have been caused by sertraline, alprazolam, or a combination of drugs, and the causal relationship between NAS and brotizolam exposure in utero is unknown.
Information on the excretion of various psychotropic drugs into breast milk was reported previously.12,28 Our results in this single case cannot be evaluated in light of these previous studies, but brotizolam was excreted into breast milk and rapidly eliminated.
Conclusions
In this case study, we could not confirm the placental transfer of brotizolam from maternal blood to the fetus. Brotizolam was transferred to breast milk, but it had no harmful effects on the infant. Although brotizolam is available in a limited number of countries, our data may be useful in complementing the existing information on brotizolam safety in pregnant and lactating women. Further studies are needed to evaluate the potentially harmful effects of exposure to brotizolam in utero and during breastfeeding.
Footnotes
Acknowledgments
We thank Ms. Mariko Takagai for her expert research assistance. We are also grateful to the lactating mothers for donating their precious breast milk.
Disclosure Statement
A.M. has received research grants from Astellas Pharma Inc., and Chugai Pharmaceutical Co. Ltd., and lecture fees from Astellas Pharma Inc., Chugai Pharmaceutical Co. Ltd., and Bristol-Myers KK. All other authors declare no conflicts of interest.
J.S., M.I., Y.M., H.K., N.Y., Y.T., and A.M. were in charge of study concept and design, data collection, and drafting and final approval of the article. A.S., T.S., and H.S. were responsible for drafting and final approval of the article. A.Y. was in charge of study concept and design, critical revision, and final approval of the article.
Funding Information
This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.