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Background: Zolpidem is used for insomnia in pregnant and lactating women. Although zolpidem has been shown to cross the placenta and to be secreted into breast milk, it would not be expected to cause any adverse effects in newborn and breastfed infants. However, there is no relevant information on serum zolpidem levels in the newborn and breastfed infant from zolpidem-treated mother. This study aimed to present the outcomes of zolpidem exposure into infant who was delivered or breastfed by a zolpidem-treated mother. Methods: In this case series, zolpidem-treated pregnant women were recruited between September 2019 and April 2022, and maternal serum, cord blood, breast milk, and infants' serum were collected, and the zolpidem concentration in each sample was evaluated. Childbirth outcomes, including 1-month health care checkup, were also evaluated. Results: Three cases were recruited during investigation period. No spontaneous abortion or preterm live deliveries occurred. Oxygen intervention was required in one term infant, but the findings resolved on postpartum day 1. No medical intervention was required in other three infants. Zolpidem was not detected in infants' serum even after breastfeeding. There are no abnormal developmental findings in any of the infants in their 1-month health checkups. Conclusions: Zolpidem transferred into fetal circulation in utero and breast milk, however no harmful findings existed in infants during pregnancy and lactation. Exposure doses through breastfeeding is small, which may be a cause of rare detection from the infants' serum. Due to the limited number of cases, larger studies and integrated review are needed.

Background: Hypnotics are frequently used for insomnia in pregnant and lactating women. This case study assessed zolpidem concentrations in the cord blood and breast milk and ramelteon concentrations in the breast milk of a woman who was treated with zolpidem and ramelteon for insomnia. Materials and Methods: Zolpidem concentrations were measured in maternal serum, breast milk, and cord blood. Concentrations of ramelteon and M-II, an active ramelteon metabolite, were measured in maternal serum and breast milk. Case Report: A 46-year-old female patient diagnosed with insomnia received 5-10 mg/day zolpidem during pregnancy and lactation and 8 mg/day ramelteon during lactation. A male infant weighing 3,329 g was born at 38 weeks' gestation, with no congenital abnormalities found during pregnancy or at birth. The infant was normal at the 1-month postpartum checkup. The maternal/placental ratio of zolpidem concentrations was 0.1 at 7.4 hours after maternal dosing, similar to that reported in previous studies. The calculated relative infant dose through breast milk based on the maximum drug concentration in breast milk at 2.2 hours after maternal dosing was 2.7% for zolpidem and 0.2% for ramelteon. Ramelteon and its metabolite (M-II) concentrations in the breast milk were equivalent to those in the maternal serum, although the infant exposure of these drugs was low for an oral dose. Conclusions: In the current case, zolpidem transferred into the placenta and breast milk, and ramelteon transferred into the breast milk. Further studies should assess the safety of zolpidem and ramelteon in fetus and breastfed infants.

Background: Trazodone is used to treat anxiety disorder, insomnia, and sleep disorders, which occur in ∼15% of pregnant and lactating women. However, pharmacokinetic information on the transfer of trazodone and its active metabolite, 1- m -chlorophenylpiperazine (mCPP), across the placenta or into breast milk is limited. In this study, we describe the pharmacokinetic profile of trazodone and mCPP concentrations in maternal and neonatal blood and breast milk. Case Presentation: A 44-year-old female received oral trazodone 50 mg once daily during pregnancy (28-38 gestational weeks) and lactation, along with etizolam for anxiety disorder with depressive syndrome. A male infant weighing 2,918 g was born at 38 weeks of gestation. Because of persistent respiratory disturbance, oxygenation was initiated immediately after birth, and the infant was admitted in the neonatal intensive care unit for 5 days. No pulmonary dysfunction or birth defects were detected, and no medication and circulatory support were needed during admission. Trazodone and mCPP concentrations in cord blood at 7.4 hours after maternal dosing were 267.6 and 22.8 ng/mL, respectively, which were comparable with maternal serum levels. The trazodone and mCPP concentrations in breast milk collected 7.2 hours after maternal dosing were 50.2 and 3.2 ng/mL, respectively. The infant developed normally, with no drug-related adverse effects at the 1-, 3-, and 6-month postpartum checkups. Conclusion: Trazodone and its active metabolite were transferred into placenta and breast milk. However, their effects in utero could not be clarified. Further studies are warranted to assess the safety of trazodone in fetuses and breastfed infants.

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.

Background: Emedastine difumarate is a second-generation antihistamine that is more effective for nasal congestion than first-generation antihistamines. The oral form of emedastine is used for the treatment of allergic rhinitis (AR). However, data characterizing emedastine transfer across the placenta and excretion into breast milk are limited. In this case report, we assessed emedastine concentrations in maternal and neonatal blood, cord blood, and breast milk. Materials and Methods: After the patient provided informed consent, emedastine concentrations in maternal serum, breast milk, cord blood, and neonatal serum were measured while the mother was taking oral emedastine 2 mg once daily. Case Report: A 39-year-old woman with AR received emedastine during pregnancy and lactation. Her female infant was born at 37 weeks of gestation with a birth weight of 2,820 g. Emedastine concentrations in maternal serum at 11.5 and 19.0 hours after maternal dosing were 0.39 and 0.22 ng/mL, respectively. The emedastine concentration in cord blood (19.6 hours after maternal dosing) was 0.18 ng/mL. At 24 hours after delivery (44 hours after maternal dosing), emedastine was under the lower limit of quantification (<0.05 ng/mL) in the infant's serum. Emedastine concentrations in breast milk ranged from 0.06 to 0.44 ng/mL. Calculated infant doses through breast milk were much lower than the clinical dose of emedastine. The infant had normal developmental progress and no detectable drug-related adverse effects. Conclusions: Rates of emedastine transfer into placenta and breast milk were low. Further study is required to assess the safety of emedastine in fetuses and breastfed infants.

Background: Esomeprazole is the S -isomer of omeprazole and is used to treat stomach acid-related diseases. Most data regarding the safety of esomeprazole during pregnancy are derived from studies on omeprazole, and the data characterizing esomeprazole transfer across the placenta and excretion into breast milk are limited. In this report, we discuss the safety of esomeprazole with reference to drug concentrations in maternal and neonatal blood and breast milk. Materials and Methods: After the patient provided informed consent, esomeprazole concentrations in maternal serum, breast milk, cord blood, and infant's serum were measured after 10 mg of maternal oral esomeprazole administration. Case Report: A 34-year-old female diagnosed with rheumatoid arthritis received esomeprazole before and during pregnancy and lactation. The esomeprazole concentration in cord blood was 40% of the level in maternal serum. At 12 hours after delivery (23.2 hours after dose), omeprazole was not detected in the infant's serum. In breast milk, esomeprazole concentrations at 0.7, 4.0, and 8.2 hours after the last dose were 10.5, 19.6, and 3.0 ng/mL, respectively, and esomeprazole was not detected at 10 hours after maternal administration. The calculated daily infant dose of esomeprazole through breast milk was 0.003 mg/[kg·day]. The infant demonstrated normal developmental progress and no detectable drug-related adverse effects. Discussion and Conclusions: Exposure to esomeprazole through placenta and breast milk was not clinically relevant in the infant. Further studies are needed to evaluate any harmful effects after exposure to esomeprazole in utero or during breastfeeding after esomeprazole treatment.

Background: Belimumab is a recombinant human immunoglobulin G1 lambda monoclonal antibody that binds soluble B lymphocyte stimulator protein with high affinity and inhibits its biological activity. Belimumab is not recommended for breastfeeding women due to insufficient data about its excretion into breast milk. In this study, we measured belimumab concentrations in the breast milk of one nursing mother diagnosed with mixed connective tissue disease (MCTD) and evaluated the health of her breastfed infant. Materials and Methods: Maternal serum and breast milk belimumab concentrations were collected three times (2 weeks after the first dose, the day after the second dose, and 7 weeks after the second dose) after ethical approval and informed consent. An enzyme-linked immunosorbent assay was used to detect belimumab in serum and breast milk samples. Case Report: A 39-year-old para 4 female was diagnosed with MCTD. The serum concentrations at three times were 29.45, 76.82, and 33.95 mcg/mL. The concentrations in breast milk were 0.12, 0.17, and 0.12 mcg/mL. The milk-to-serum concentration ratios at each sampling point were 0.0041, 0.0022, and 0.0035, respectively. Her infant experienced no health problems. Routine vaccinations were administered without any adverse effects such as infection or immunoreaction. Discussion and Conclusions: Breast milk levels of belimumab ranged from 1/200 to 1/500 of those in serum, and no harmful effect occurred in her infant. This is the first study reporting belimumab concentrations in human breast milk. Further studies are needed to elucidate the impact of exposure on breastfeeding infants.

Background: Oral direct factor Xa inhibitors, collectively referred to as direct oral anticoagulants, are not recommended for breastfeeding women due to insufficient data about the transfer of these drugs into breast milk. In this study, we serially measured rivaroxaban concentrations in the breast milk of one nursing mother who was at high risk of deep vein thrombosis and evaluated the health of her breastfed infant. Materials and Methods: Breast milk rivaroxaban concentrations were measured 3 months after delivery by a validated liquid chromatography-tandem mass spectrometry method. Breast milk samples were collected sequentially after 15 mg of oral rivaroxaban administration after ethical approval and informed consent. Case report: A 38-year-old female diagnosed with the antiphospholipid syndrome had received rivaroxaban after delivery. The infant was partially breastfed until the age of 18 months. The mean minimum and maximum rivaroxaban concentrations in breast milk were 9.73 ng/mL before each dose and 53.9 ng/mL at 6 hours after each dose, respectively. The mean daily infant dose was 0.0034 mg/kg and the mean relative infant dose (RID) via breast milk was 1.79%. Discussion and Conclusion: The RIDs of rivaroxaban did not exceed 10% of the maternal dose, suggesting that exposure of rivaroxaban via breastfed is seldom clinically relevant for the infant. A pediatric assessment of the infant found no detectable drug-related adverse effects. Further studies are needed to elucidate how breastfeeding infants are impacted by exposure to rivaroxaban.

Breast milk is the optimum for all infants, but hospitalization in the neonatal intensive care unit can cause separation of mothers and infants, which often interferes with milk secretion. Some reports show that domperidone is effective in promoting milk secretion. However, the Food and Drug Administration in the United States cautioned to not use domperidone for increasing milk volume because domperidone carries some risk of cardiac events, including QT prolongation, cardiac arrest, and sudden death. In contrast, it is used in Canada, Australia, and the United Kingdom with safety. The pharmacodynamics and pharmacokinetics of drugs may vary by race or ethnic origin, and it is not known whether domperidone is effective or safe for Japanese. In this study we report the effects of domperidone for Japanese mothers with insufficient lactation. Ten mothers were enrolled in a pilot study. After confirming that there were no abnormal findings on the electrocardiogram, the mothers were administered domperidone. Seven of 10 who took domperidone increased their milking volume. Prolactin was increased in 9 of 10 mothers. Adverse events were observed in two mothers, one headache and one abdominal pain; all symptoms were mild and improved promptly; and there were no adverse cardiac events. These results are consistent with reports from other countries. Domperidone may tentatively be considered effective for increasing milk secretion in Japanese mothers as in other populations. Our preliminary study of 10 cases indicates the need for further studies with larger sample sizes to assess the efficacy and safety of domperidone.