Evaluation of the Safety of Taking Brexpiprazole During the Lactation Period

Plan sheets for lactation

In 2011, we started a systematic evaluation of the risk in infants whose mothers breastfed while taking psychotropic drugs at the Department of Obstetrics, Tohoku University Hospital. ¹¹ At 28 weeks of gestation, pregnant women were asked to provide information about their disease symptoms, drugs used, dosage regimen, and their desire to breastfeed after delivery using check sheets referred to as “plan sheets for lactation.” Based on these check sheets, midwives interviewed each pregnant woman about her background, noted her comments on the mother’s concerns and requirements regarding breastfeeding after delivery, and sent them to the Department of Pharmaceutical Sciences. Pharmacists collected information about the safety of taking the drugs stated in the plan sheets for lactation from sources such as Drugs in Pregnancy and Lactation and Medication and Mothers’ Milk^8,9 and provided that information along with their comments to the obstetricians. The obstetricians then discussed with pediatricians the risk of breastfeeding infants whose mothers were taking drugs during the lactation period. Eventually, the results of the evaluation were explained to the pregnant women by the medical staff.

Data collection

Pregnant women taking BPZ were evaluated for the risk using plan sheets for lactation from April 2018 to July 2023. We excluded the following cases from our examination: women who changed from BPZ to another psychotropic agent after delivery and women whose infants were exclusively formula-fed. The remaining participants were included in the study.

We collected data on the mothers’ and infants’ characteristics from medical records and lactation plan sheets. Maternal characteristics included age, body mass index (BMI), daily BPZ dose, purpose of taking BPZ, number of psychotropic classes of drugs administered (including BPZ), and gestational weeks at delivery. Infant characteristics, including sex, body weight at birth and at the 1-month checkup, weight gain from birth to the 1-month checkup, nutritional method (exclusive breastfeeding or mixed feeding), Isobe’s neonatal withdrawal syndrome (NWS) score, ¹² and the number of adverse events (AEs) from just after birth to 1 month after birth, were retrospectively collected from their medical records. The NWS is a modified version of Finnegan’s scoring system, ¹³ which is an assessment tool that is used for early treatment. The Isobe scoring system is based on a point-addition technique that evaluates symptoms related to the digestive, autonomic, and central nervous systems. According to the Isobe scoring system, medical treatment is often considered needed when the NWS score is 8 or more. ¹³ The medical staff routinely evaluated the infant’s symptoms at 2 hours, 1–7 days, 2 weeks, and 1 month after birth according to the scoring system and calculated the NWS score. The highest score from days 0 to 7 for each infant was considered the NWS score. Withdrawal symptoms were evaluated at the 1-month checkup after birth. We could not follow up after 1 month postpartum because the mother–infant pair is ordinarily followed up in community clinics or hospitals, and not in our hospital.

The study protocol was reviewed and approved by the Ethics Committee of the Tohoku University Graduate School of Medicine (2023-1-650).

Case 1

A woman aged 32 years at delivery, weighing 55 kg (BMI, 22.3 kg/m²) before pregnancy, was diagnosed with depression at 16 years of age. BPZ treatment (1 mg/day) was initiated at 29 years of age, discontinued at 31 years of age (1 month before conception), reinitiated with the same dose at 32 years of age (28 weeks of gestation), and continued during pregnancy and lactation. No concomitant use of other psychotropic agents was recorded.

At 40 weeks of gestation, a healthy, normal-birthweight female infant (weight 3,471 g) was delivered vaginally. The Apgar scores at 1 and 5 minutes were 8 and 9, respectively. No AEs were observed during the delivery. The maximum Isobe NWS score during postpartum days 0–7 was 0. No medication or circulatory support was required during the 5 days of admission.

At the postpartum day 16 visit, it was confirmed that the infant had recently been receiving both breast milk and formula. Daily milk intake ranged from 30 to 40 mL/feed × 2–3 feeds of pumped breast milk and 70–80 mL/feed × 7–8 feeds of formula. At the 1-month postpartum health check-up, the body weight of the infant was 4,772 g. Daily milk intake ranged from 10 to 40 mL/feed × 1–3 feeds of pumped breast milk and 60 to 100 mL/feed × 7–8 feeds of formula. The infant had no detectable developmental anomalies. Mild neonatal jaundice and acne were observed 16 days to 1 month after delivery.

Case 2

A woman aged 41 years at delivery, weighing 51 kg (BMI, 21.5 kg/m²) before pregnancy, was diagnosed with schizophrenia at 19 years of age. BPZ treatment (2 mg/day) was initiated at 39 years of age and continued during pregnancy and lactation. No concomitant use of other psychotropic agents was recorded.

At 39 weeks of gestation, a normal-birthweight male infant (weight, 3,817 g) was delivered vaginally. The Apgar scores at 1 and 5 minutes were 8 and 9, respectively. At birth, the infant was diagnosed with a cleft palate and jaundice, necessitating admission to the neonatal intensive care unit (NICU) for phototherapy within a day. The maximum Isobe NWS score during postpartum days 0–7 was 0. No medication or circulatory support was required for 7 days after admission.

At the postpartum day 19 visit, it was recorded that the infant had been receiving both breast milk and formula. Daily milk intake was approximately 100 mL/feed × 8 feeds of pumped breast milk and 100 mL/feed × 8 feeds of formula. At the 1-month postpartum health checkup, the infant’s body weight was 4,846 g. Daily milk intake was approximately 100 mL/feed × 1 feed of pumped breast milk and 120–130 mL/feed × 8 feeds of formula. The infant was unable to breastfeed effectively because of the cleft palate; however, this deficiency was compensated for by the use of formula. Mild neonatal jaundice and acne were observed at the 1-month visit.

Case 3

A woman aged 34 years at delivery, weighing 47 kg (BMI, 17.7 kg/m²) before pregnancy, was diagnosed with schizophrenia at 15 years of age. BPZ treatment (2 mg/day) was initiated at 31 years of age and continued during pregnancy and lactation. No concomitant use of other psychotropic agents was recorded.

At 39 weeks of gestation, a healthy, relatively low-birthweight female infant (weight 2,589 g) was delivered vaginally. The Apgar scores at 1 and 5 minutes were 8 and 8, respectively. No AEs were observed during the delivery. The maximum Isobe NWS score during postpartum days 0–7 was 0. No medication or circulatory support was required during the 5 days of admission.

At the postpartum day 19 visit, it was confirmed that the infant had been receiving both breast milk and formula. Daily milk intake ranged from 6 to 8 feeds of pumped breast milk (dose unknown) and 60 to 100 mL/feed × 6–8 feeds of formula. At the 1-month postpartum health checkup, the infant’s body weight was 3,484 g. Daily milk intake ranged from 6 to 10 feeds of pumped breast milk (amount unknown) and 60 to 100 mL/feed × 6–8 feeds of formula. The infant had no detectable developmental anomalies. Mild neonatal jaundice and acne were observed 19 days to 1 month after delivery.

Safety in infants

BPZ has a very long half-life of 91 hours. There are no safety data for infants whose mothers are treated with BPZ while breastfeeding, and there is no pediatric application for BPZ; therefore, its safety in children who are breastfed by mothers taking BPZ has not been established.^7–9 However, this study did not identify any signs of withdrawal syndrome or specific AEs related to breastfeeding with BPZ in the newborns and infants. BPZ has a molecular weight of 434 Da and a high protein-binding capacity of 99.8%, making it unlikely to transfer significantly into breast milk. Although the blood concentrations of BPZ in the newborns and infants were not measured, a potential explanation for the nonoccurrence of NWS or AEs related to breastfeeding may be the limited transfer of BPZ into breast milk. The mild neonatal jaundice and acne observed in all infants, as well as the jaundice requiring phototherapy and NICU admission observed in the infant in Case 2, were unlikely to be AEs resulting from BPZ transfer into breast milk. The cleft palate observed in Case 2 is one of the most common congenital abnormalities. ¹⁴ To date, there are no reports (including animal studies) of congenital abnormalities associated with BPZ administration during pregnancy. Therefore, it is difficult to determine whether this was influenced by the administration of BPZ during pregnancy.

Impact of BPZ administration on breast milk secretion

In this study, no medical records indicated any effect of BPZ on breast milk secretion. However, the amount of breast milk intake by the infants in this study was clearly lower than the typical volume of breast milk intake. Although we could not identify the rationale behind the low breast milk intake by the infants in this study because we were unable to measure prolactin levels in the mothers, previous studies have suggested that BPZ administration is associated with reduced breast milk production.^10,15 Berlin et al. reported that a woman with bipolar disorder who was taking 2 mg of BPZ daily from the third trimester of pregnancy could only pump 30 mL of milk per day. The patient then discontinued BPZ therapy and started treatment with metoclopramide. Within 10 days of discontinuing BPZ, her serum prolactin levels and milk supply increased. ¹⁰ Jiang et al. found 6 reports of “lactation disorder” and 10 cases of “breast discharge” linked to BPZ administration in the U.S. Food and Drug Administration’s Adverse Event Reporting System between 2015 and 2023. ¹⁵ BPZ may influence breast tissue and prolactin secretion via various mechanisms, resulting in lactation disorders and breast discharge.^16–18 Therefore, it cannot be ruled out that breast milk secretion was low in the study participants, and that supplementation with pasteurized banked human milk or formula may be necessary for infants whose mothers are taking BPZ.

Limitations and strengths

This study has several limitations. First, the study only included three mother–infant pairs. Therefore, further studies with larger sample sizes are needed. Second, the BPZ concentrations in breast milk and infant blood were not measured. Blood sampling is particularly invasive for infants, and it would have been unnecessary to measure BPZ blood concentrations, as none of the infants experienced severe AEs. Hence, we could not evaluate the relationship between BPZ concentrations and infant safety, which should be investigated in future studies. Third, it was not possible to consider the risk of high-concentration exposure due to immature metabolic enzymes, particularly CYP2D6, which metabolizes BPZ, because the blood concentrations of BPZ and the activity of CYP2D6 were not measured. Fourth, we could not evaluate long-term safety in infants. Therefore, the data presented herein must be carefully interpreted, and further safety studies with long-term follow-up are required. However, the present study is the first to evaluate the safety of BPZ use during lactation from the viewpoint of the NWS and AEs in infants.

Implications

The results of this study suggest that BPZ use is not a reason for breastfeeding abandonment and may serve as a resource for deciding whether to breastfeed.