Transfer of Zolpidem to Cord Blood and Breast Milk: A Case Series Evaluating Zolpidem Serum Levels and Outcomes in Birth and Suckling Infants

Abstract

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

Insomnia is common in late pregnancy and postpartum¹ and is recognized as a major risk factor for stressors and mental health problems in parents and newborns.² Although women frequently require treatment with hypnotics,^3,4 the level of fetal and infant exposure to hypnotics administered by the mother, and the toxic effects of these agents is not well studied.⁵

Zolpidem is used for insomnia during pregnancy and lactation. Zolpidem crosses the placenta.^6,7 Previous case reports have shown that mothers treated with zolpidem during pregnancy are at increased risk for adverse pregnancy events such as preterm delivery, low birth weight, and neonatal respiratory depression, and that exposed neonates should be monitored for excessive sedation, hypotension, and respiratory depression.⁸ Zolpidem also passes into breast milk.^7,8 Zolpidem concentrations in breast milk are low and are not expected to adversely affect breastfed infants. Some expert opinions recommend the use of zolpidem during breastfeeding; however, these were based on a limited number of case reports. Additionally, there is still no information on zolpidem levels in infants breastfed by mothers taking zolpidem.

In this case series, we recruited pregnant women who were treated zolpidem during pregnancy and lactation, and assessed the concentration of zolpidem in maternal serum, cord blood, breast milk, and infant serum. We also evaluated the birth outcomes and infant developmental abnormalities during lactation.

Methods

This is a single-center prospective observational study on evaluation of placental transfer and breast milk secretion of maternal exposed drugs, and outcomes of childbirth and breastfed infants. After obtaining the informed consent from the pregnant women at the first visit to the Division of Infant and Toddler Mental Health, Department of Psychosocial Medicine, National Center for Child Health and Development, detailed information regarding drug exposures, maternal demographics, medical history, obstetric anamnesis, and demographics of childbirth outcomes were obtained and recorded during pregnancy and lactation. Maternal and infants' serum, cord blood, and breast milk were collected to evaluate the zolpidem levels in each sample. All mothers were informed that their records could be used for scientific purposes, provided their identities remain hidden.

Childbirth outcomes were evaluated based on the World Health Organization's definitions⁹ and the Surveillance of Congenital Anomalies (EUROCAT) definitions.¹⁰

Zolpidem detection

Zolpidem in serum and breast milk samples was determined using an improved version of a previously validated method based on liquid chromatography–tandem mass spectrometry.¹¹ In brief, chromatography was performed on a 3000 Ultimate LC system interfaced with a TSQ Vantage mass spectrometer (Thermo Fisher Scientific, Tokyo, Japan) interfaced with a 3000 Ultimate nano-LC system. Compounds were eluted from a Unison UK-C18 column (3 μm reversed phase, 3.0 × 50 mm; Imtakt, Kyoto, Japan). Zolpidem and zolpidem-d3 (internal standard for zolpidem) were 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 Milli-Q system (Millipore Waters, Tokyo, Japan). The method has good accuracy and precision in the concentration range of 0.10–500.0 ng/mL of zolpidem. The lower limit of quantification and detection of zolpidem in breast milk and serum was 0.05 ng/mL.

Sample collection and preparation

Maternal and infants' serum samples, cord blood, and breast milk samples were collected after maternal zolpidem dosing. Serum samples were immediately separated by ultracentrifugation. All collected samples were stored below −80°C until analysis. The timing of sample collection after zolpidem dosing is presented in Table 1.

Table 1.

Information on Pregnant and Lactating Mothers and Childbirth Outcomes

Case no.	Demographic information on pregnant and lactating mothers						Childbirth outcomes				Maternal serum ZOL conc.^a	Cord blood ZOL conc.^a	Breast milk ZOL conc.^a	RID calculated from maximum breast milk concentration^b	Infant serum ZOL conc.^a	Breastfeeding frequency (postpartum date, volume, times per day)
Case no.	Maternal age (year)	Reason for zolpidem use	Maternal ZOL dose (mg/dose, interval)	ZOL dosing periods (frequency)	Concomitant antipsychotics use, (dosage, dosing periods)	Concomitant use, others	Birthweight, gestational weeks	APGAR score (1/5 minute), medical intervention	Childbirth outcome (Finnegan score, FS)	1-month infant health checkup results	Maternal serum ZOL conc.^a	Cord blood ZOL conc.^a	Breast milk ZOL conc.^a	RID calculated from maximum breast milk concentration^b	Infant serum ZOL conc.^a
1	30	Insomnia	5 mg/dose, once daily	GA 34 − 37 weeks (once daily), postpartum day 5 (single dose)	None	Soluble ferric pyrophosphate (GA 35 to present)	3,091 g 38 weeks 5 days Vaginal delivery	8/9, No medical intervention	No abnormality FS = 0 (day 1–7)	No abnormality (1-month)	LLOD (GA 37 w, 288 hours) 57 ng/mL (postpartum day 6, 1.1 hours)	LLOD (GA 37 w, 299 hours)	10.1 ng/mL (postpartum day 6, 6.5 hour)	1.77%	LLOD (postpartum day 6, 7.5 hour)	Day 1: 10 mL × 5 Day 2: 20 mL × 8 Day 3: 30 mL × 7 Day 4: 40 mL × 7 Day 5: 50–70 mL × 6 Day 6: 50 mL × 6
2	33	Panic disorder	5 mg/dose, once daily	Postpartum day 1–2	Alprazolam (0.4 mg q8 hours, GA 16 weeks 5 days to present), Escitalopram (10 mg q24 hours, GA 18 weeks 5 days to 18 weeks 6 days) Risperidone (0.5 mg q12 hours, postpartum day 1–11), Sulpiride (100 mg, q8 hours, 19 weeks 4 days to present)	Potassium iodide (GA 9 w to present)	3,193 g 39 weeks 0 days Cesarean section	8/9, No medical intervention	No abnormality FS = 2 (day 1)	No abnormality (1 month)	27.9 ng/mL (postpartum day 4, 0.6 hours) 71.3 ng/mL (postpartum day 4, 2.0 hours) 62.6 ng/mL (postpartum day 4, 2.5 hours)	N/A	3.5 ng/mL (postpartum day 1, 14.6 hours) 0.6 ng/mL (postpartum day 2, 18.1 hours) 4.8 ng/mL (postpartum day 3, 10.1 hours) 1.2 ng/mL (postpartum day 4, 16.7 hours)	0.89%	LLDO (postpartum day 1, 14.6 hours) LLOD (postpartum day 2, 18.1 hours) LLOD (postpartum day 3, 10.1 hours) LLOD (postpartum day 4, 16.7 hours)	Day 1: 5 mL × 5 Day 2: 10 mL × 8 Day 3: 25–30 mL × 6 Day 4: 30–40 mL × 6 Day 5: 40–50 mL × 6 Day 6: 50 mL × 6
3	35	Anxiety disorder	5 mg/dose, when anxiety symptoms are present	GA 38 weeks—postpartum day 2	None	Chinese herbal medicine (Postpartum day 5 to present)	2,559 g 39 weeks1 day Cesarean section	8/9, No medical intervention	Early-onset jaundice (day 0–12) Oxygen demand (−day 1) FS = 3 (day 1)	No abnormality (1 month)	3.4 ng/mL (postpartum day 1, 17.2 hours) LLOD (postpartum day 7, 105 hours)	4.21 ng/mL (GA 39 w, 16.1 hours)	LLOD (postpartum day 3, 9.5 hours) LLOD (postpartum day 3, 15.0 hours) LLOD (postpartum day 3, 18.4 hours) LLOD (postpartum day 3, 23.5 hours)	N/A	LLOD (postpartum day 2, 9.5 hours) LLOD (postpartum day 2, 15.0 hours) LLOD (postpartum day 3, 9.5 hours) LLOD (postpartum day 3, 15.0 hours) LLOD (postpartum day 5, 18.4 hours) LLOD (postpartum day 6, 23.5 hours)	Day 1: 15 mL × 2 Day 2: 15 mL × 3 Day 3: 15–20 mL × 4 Day 4: 20–30 mL × 5 Day 5: 20–30 mL × 6 Day 6: 40 mL × 6

Sample collection date and elapsed time after ZOL administration were shown in parentheses.

RID was calculated using the maximum milk concentration and maximum milk intake (150 mL/kg/day) as the numerator and the dose per body weight of the mother (mg/kg/day) as the denominator.

FS, Finnegan score; GA, gestational age; LLOD, lower limit of detection; N/A, not available; RID, relative infant dose; ZOL, zolpidem.

Ethics approval

This study was approved by the Ethics Committee of the National Center for Child Health and Development, and was conducted in line with the principles of the Declaration of Helsinki and Good Clinical Practices. The participants provided written informed consent. During the data analysis, patients were anonymized, and no data were shared with other parties except the researchers. The records regarding patients' identities were protected in compliance with the relevant national and international legislations and registrations.

Results

Three pregnant women were recruited between September 28, 2019 and April 5, 2022.

The zolpidem dose, duration of administration, concomitant medications, pregnancy outcomes, birth outcomes, zolpidem concentrations in cord blood, maternal blood, breast milk and infant serum, and breast milk intake for all three mothers in the study are shown in Table 1. Details of each case are presented below.

Case 1

A 30-year-old woman weighing 58.3 kg was pregnant with her first child. At 34 weeks gestational age (GA), she presented with insomnia and was prescribed 5 mg zolpidem. During pregnancy, once daily zolpidem was taken irregularly (only during insomnia). Because she was diagnosed with anemia, she was also treated with soluble ferric pyrophosphate syrup three times daily. Zolpidem was completely discontinued at 37 weeks GA. At 38 weeks GA, a male infant was born by vaginal delivery. The infant weighed 3,091 g at birth and had 1- and 5-minute Apgar scores of 8 and 9, respectively. The infant required no mechanical ventilation, circulatory support, or drug treatment and was discharged 6 days after birth. There were no congenital malformations, and the infant had a normal developmental course. Daily milk intake for infant was 50–300 mL for breast milk and 100–200 mL for artificial milk. On the fifth postpartum day, the patient had insomnia and was given only one dose of zolpidem 5 mg. No drug-related adverse effects were noted during hospitalization or at the 1-month postpartum checkup by the pediatrician.

Zolpidem was not detected in cord blood or maternal serum at 288 or 299 hours after the last maternal dose. On postpartum day 6 (1.1 hours after maternal dose), zolpidem was detected at 57.0 ng/mL in maternal serum. The breast milk zolpidem level 6.5 hours after the single maternal dose on postnatal day 6 was 10.1 ng/mL. No zolpidem was detected in the infant's serum despite the fact that the infant was breastfed.

Case 2

A 33-year-old woman weighing 62.0 kg was diagnosed with panic disorder at 32 years of age. Alprazolam was initiated at 16 weeks of gestation, and continued during pregnancy and lactation. Although 10 mg escitalopram was initiated due to frequent symptoms of panic disorder, escitalopram was immediately discontinued due to severe nausea. At 19 weeks of gestation, sulpiride was initiated and the daily dose was gradually increased from 150 to 300 mg. Until delivery, her symptoms of panic disorder were not worsened. She had also been taking 10 mg potassium iodide every other day since prepregnancy for treatment of Basedow's disease.

At 39 weeks of gestation, a healthy normal-birth-weight female (weight 3,193 g) was delivered by cesarean section. The Apgar scores at 1 and 5 minutes were 8 and 9, respectively. No congenital anomalies were observed. No respiratory distress was found. The total Neonatal Withdrawal Score on postpartum day 1 was 2, based on the Finnegan checklist. No medication or circulatory support was needed during admission. Until discharge on postpartum day 7, the infant received both breast milk and milk formula. Daily milk intake ranged from 25 to 300 mL for pumped breast milk and from 30 to 300 mL for milk formula. The mother initiated 5 mg once daily zolpidem and 0.5 mg risperidone immediately after delivery for her anxiety symptoms and insomnia. At postpartum day 5, zolpidem was discontinued. Risperidone was also discontinued at postpartum day 11 because her anxiety symptoms were worsened after risperidone initiation. At the 1-month postpartum health checkup, the infant had no detectable developmental anomalies.

The zolpidem level in each maternal serum sample collected at 0.6, 2.0, and 2.5 hours after fifth zolpidem dose was 27.9, 71.3, and 62.6 ng/mL, respectively. Zolpidem concentrations in breast milk ranged from 0.6 to 4.8 ng/mL between the first and fourth day postpartum. Even though the infant received breast milk, zolpidem was not detected from the infants' serum.

Case 3

A 35-year-old woman, weighing 58.5 kg, diagnosed with suspected Post-Traumatic Stress Disorder, neurosis, and anxiety disorder at age 29, presented for her second pregnancy. Her first child was delivered by cesarean section at term. She did not use any antipsychotic agents during her first pregnancy. At the time of delivery of her second child, insomnia persisted, and once daily 5 mg zolpidem was started at 37 weeks of gestation.

A healthy normal-birth-weight male (weight 2,559 g) was born by cesarean section at 39 weeks GA. One- and 5-minute Apgar scores were 8 and 9 points, and no congenital abnormalities were noted. At 5 minutes of age, because of residual trapped breathing in the supraclavicular fossa and rib vacation, the patient was started on oxygen. Oxygen saturation was maintained around 90%. The patient was admitted to the Growing Care Unit for respiratory management due to persistent mild respiratory depression. After admission, an elevated plasma bilirubin level was observed, and phototherapy was administered until the 12th postpartum day. Respiratory condition improved on the second postpartum day. After phototherapy, the plasma bilirubin level improved, and the infant was discharged on postpartum day 13. The maximum neonatal withdrawal score of 3 was based on the Finnegan checklist.

The infant consumed both breast milk and formula until discharge on the seventh postpartum day, with daily milk intake of 30–240 mL of pumped breast milk and 100–300 mL of formula. The mother took once daily 5 mg zolpidem on the second postpartum day, and then discontinued zolpidem treatment. At the 1-month postpartum checkup, no developmental problems were noted in the infant.

The zolpidem concentration in cord blood taken immediately after delivery (16.1 hours after the last dose) was 4.21 ng/mL, and in maternal serum (17.2 hours after the last dose) was 3.4 ng/mL. No zolpidem was detected in breast milk collected over time on the third postpartum day (9.5–23.5 hours after the last dose). Zolpidem was also not detected in infant serum collected on postpartum days 2–6 (9.5–23.5 hours after maternal administration).

Discussion

For enabling safe and adequate treatment of mothers and their infants, information on transfer of drugs across the placenta and breast milk, and clarifying the amount of exposure to the infant is important. In this study, we report three pregnant and lactating women with zolpidem. This study presents postpartum infants' outcomes for three cases: one exposed in utero, one exposed just before delivery, and all three exposed during lactation. Zolpidem passed from the mother's blood into the placenta and breast milk, but had no serious adverse effects on the infant.

In case 3 who was given zolpidem just before delivery, zolpidem was detected in the cord blood that was in a concentration, which was in line with the previous report.⁸ In our case, zolpidem transferred into the infant through placenta was cleared from the infant's blood at least within 2 days. Fetal risk such as small for GA and preterm delivery has been reported after administration of zolpidem to mothers,^12–16 but no severe adverse events were observed in infants after delivery. All three infants had optimal birth weights relative to GA and Apgar scores of 8 or higher. Although, one infant (case 3) developed jaundice of prematurity requiring phototherapy, and was hospitalized due to oxygen administration, this case was not severe. In all three cases, including case 3, no abnormalities were found at the 1-month postdischarge health checkup.

In cases 1, and 2, and 4, zolpidem was transferred into breast milk, in concentrations that were in line with the previous studies.^7,8 The infants of all three cases were breastfed, however, zolpidem was not detected in infants' serum. In cases 1 and 2, the estimated maximum exposures by feeding were 0.72 and 1.52 μg/kg/day (calculated at a maximum intake of 150 mL/kg), respectively, which are about 1.77% and 0.89% of the maternal dose per body weight.

As limitations of this study, this report is limited to three cases and does not include cases of premature infants. Further study in a larger population is required. Additionally, the follow-up period was short (1 month), and a longer-term safety study may be warranted.

Conclusions

This case series study confirmed that zolpidem passed from the mother's blood into the placenta and breast milk, but caused no serious adverse effects on the infant. Our data may be useful to supplement existing information on the safety of zolpidem in pregnant and lactating mothers. Further studies are needed to assess the adverse effects of exposure to zolpidem in utero and during lactation.

Footnotes

Acknowledgments

The authors would like to thank Ms. Mariko Takagai for her expert research assistance. They are also grateful to the lactating mother for donating her precious breast milk.

Disclosure Statement

A.M. received a research grant from Chugai Pharmaceutical, Co., Ltd. and speaking fees from Chugai Pharmaceutical Co., Ltd., Astellas Pharma, Inc., and UCB Japan Co., Ltd. All other authors declare no conflicts of interest. Each author has confirmed compliance with the journal's requirements for authorship.

Funding Information

This work was supported by the National Center for Child Health and Development (NCCHD2021C-5) awarded to J.S. The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

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