Presence of Hypnotics in the Cord Blood and Breast Milk,with No Adverse Effects in the Infant: A Case Report

Introduction

Insomnia, which is highly prevalent in the last trimester of pregnancy and the postpartum period,^1,2 has been recognized as an important stressor and major risk factor for mental health issues in parents and newborns. ³ Women frequently require treatment with hypnotic agents,^4,5 and exposure of the fetus and infant to maternally administered hypnotic drugs as well as the potential toxic effects of these medications should be evaluated. ⁶

Ramelteon is a melatonin analog used as a hypnotic drug that exhibits higher affinity to the melatonin receptors MT1 and MT2 compared to melatonin. ⁷ The hypnotic effect of ramelteon is mediated by its potent, long-lasting agonism of the melatonin receptors, and it does not exhibit affinity for benzodiazepine, dopamine, and opiate receptors or ion channels. Ramelteon is approved by the U.S. Food and Drug Administration for the treatment of insomnia characterized by difficulty with sleep onset. ⁸ However, no study to date has reported information on the transfer of ramelteon to the breast milk.

In addition, no information on the effects of ramelteon in breastfed infants is available in the Drugs and Lactation Database, ⁹ and caution should be exercised during the administration of ramelteon to nursing women. ⁸

Zolpidem, which is also used for insomnia during pregnancy and lactation, crosses the placenta. ¹⁰ Studies previously demonstrated that the risk of adverse pregnancy outcomes, such as low-birth-weight, preterm delivery, small-for-gestational age infants, and neonatal respiratory depression, was higher in mothers who received zolpidem treatment during pregnancy, ¹¹ and that exposed neonates should be monitored for excess sedation, hypotonia, and respiratory depression.^12–14 Zolpidem is present in the breast milk of lactating women ¹⁵ ; however, information regarding the transfer of zolpidem to breast milk is limited, and no information is available on the safety of zolpidem in breastfed infants. ¹⁶

In the present case report of a woman who was administered zolpidem during pregnancy and lactation and ramelteon during lactation, we assessed the concentrations of zolpidem in cord blood and breast milk and the concentrations of ramelteon and its active metabolite M-II, which has a longer half-life and greater systemic exposure than ramelteon, in maternal serum and breast milk.

Materials and Methods

Case Report

A 46-year-old, gravida 2, para 1 woman weighing 67 kg, who was pregnant with her second child after intracytoplasmic sperm injection, was diagnosed with insomnia before the current pregnancy and prescribed zolpidem 7.5 mg once daily before the blastocyst transplantation. During her first pregnancy at 43 years of age, she was diagnosed with gestational diabetes mellitus (GDM) and followed with weight management for excessive weight gain, without the need for medical treatment. However, she was diagnosed with impaired glucose tolerance based on a blood glucose levels of 95, 207, and 159 mg/dL with a 3-point oral glucose tolerance test performed 26 weeks' gestational age during the second pregnancy.

The patient was initiated on insulin therapy with 4–10 U of insulin aspart (genetical recombination) that is a rapid-acting insulin administered three times a day and 2–6 U of insulin detemir (genetical recombination) that is a long-acting insulin administered once a day. The patient was also diagnosed with postpartum pre-eclampsia after her first delivery; therefore, during the second pregnancy she was initiated on once daily low-dose aspirin (81 mg/day) at 13 weeks' gestational age, which was continued until 34 weeks' gestational age. She also continued taking 5–10 mg zolpidem during the second pregnancy.

At 38 weeks' gestational age, a male infant was born by suction delivery. The infant weighed 3,329 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 5 days after birth. There were no congenital malformations, and the infant exhibited normal neurodevelopmental progress. He received both breast milk and milk formula. Daily milk intake at home ranged from 40 to 100 mL for pumped breast milk and from 100 to 220 mL for milk formula.

During lactation, the mother continued insomnia treatment with immediate-release 5–10 mg zolpidem (Myslee^® tablets), and 8 mg ramelteon (Rozerem^® tablets) was initiated due to continued insomnia. However, ramelteon was discontinued after 5 days due to the lack of improvement in insomnia. The patient was also initiated on 5 mg amlodipine twice daily for postpartum pre-eclampsia. No drug-related adverse effects were detected in the infant at the 1-month postpartum health checkup with the pediatric care physician. The symptoms of GDM, postpartum pre-eclampsia, and insomnia have been continuously followed in the outpatient department.

Discussion

Accurate information on the transfer of drugs to the infant across the placenta and breast milk is important for the safe and effective treatment of mothers and infants. We herein presented a patient with insomnia who was treated with zolpidem during pregnancy and lactation as well as with ramelteon during lactation. Zolpidem was detected in the cord blood and breast milk, in line with a previous study of five breastfeeding women who ingested a single oral dose of 20-mg immediate-release zolpidem. ¹⁵ In that study, the ratio of zolpidem concentrations in breast milk and plasma samples at 3 hours after the last dose was 0.13, in agreement with that detected in the current case, wherein the ratio at 2.2 hours was 0.10. The current infant did not exhibit any adverse effects after delivery although increased fetal risk has been reported after maternal zolpidem treatment.^11–14

We did not examine the milk-to-serum ratio of ramelteon or peak ramelteon concentrations in maternal serum and breast milk in the current patient; however, the reported mean peak ramelteon and M-II concentrations in serum samples of healthy subjects are 1.5 and 54.2 ng/mL at 1.1 hour after the administration of 8 mg ramelteon, ⁸ similar to the pharmacokinetic profile of the current case. The calculated relative infant ramelteon concentration at 2.2 hours after the last dose was 0.2% of the weight-adjusted maternal dose.

Concerning the safety of zolpidem during lactation, the breastfed infant of the current patient did not exhibit any adverse effects, in agreement with a previous study, ¹⁵ suggesting that zolpidem administration during lactation might outweigh the risk of adverse effects in infants caused by breastfeeding.

The current patient received ramelteon for a short duration, which was a limitation of this study, and infant outcomes after prolonged maternal ramelteon treatment could not be evaluated. In addition, the breast milk samples were not collected at the time of peak ramelteon and zolpidem levels in serum, and accurate exposure of these hypnotic drugs to the infant could not be evaluated.

Conclusions

In this case study, we demonstrated that zolpidem transferred from the maternal blood to the fetus across the placenta. We also found that zolpidem, ramelteon, and M-II transferred to the breast milk, although with no harmful effects on the infant. To the best of our knowledge, this is the first study reporting ramelteon and M-II concentrations in human breast milk. Although ramelteon was discontinued during lactation in the current case due to the lack of improvement in insomnia, these findings should be useful in extending the current information on ramelteon safety in lactating mothers. Further studies are needed to evaluate the potential harmful effects of hypnotic drugs following exposure in utero and during breastfeeding.