Trazodone Levels in Maternal Serum,Cord Blood,Breast Milk,and Neonatal Serum

Abstract

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.

Introduction

Anxiety and sleep disorders occur in up to 15% of pregnant women.^1–3 Many antidepressants usually prescribed for these disorders cross the placenta and blood–brain barrier. These drugs may affect fetal growth and development⁴ and have been associated with increased risks of preterm birth, low Apgar scores, neonatal intensive care unit admission, and neonatal respiratory distress syndrome.^5,6 These risks should be considered before administering anxiolytics to pregnant and lactating mothers. Evaluating infants' exposure levels to maternally administered drugs and the toxicological effects of these drugs is essential.⁷ In previous studies, side effects such as drowsiness and sedation have been identified in infants during breastfeeding.^8,9

Trazodone is a triazolopyridine antidepressant chemically unrelated to other classes of antidepressants. Even though trazodone is only approved by the Food and Drug Administration as a prescription drug used for depression,¹⁰ it is also used in patients with primary and secondary insomnia.¹¹

The safety of trazodone to pregnant mothers has been investigated in several prospective controlled studies and meta-analyses. In the prospective controlled study, no significant differences were observed in terms of spontaneous abortions, elective abortions, stillbirths, major malformations, gestational age at birth, or birth weights in 147 pregnancies exposed to trazodone in the first trimester compared with the group treated with other antidepressants or nonteratogens.¹² One meta-analysis of seven prospective comparative cohort studies involving 1,774 patients who were exposed to seven antidepressants including trazodone showed no statistically significant increase in the risk of major birth defects in the general population.¹³

Although trazodone treatment is considered safe as reported by previous studies, recent studies suggest that trazodone use during pregnancy is potentially a serious public health concern because trazodone interferes with sterol biosynthesis and might be a risk factor for in utero development of a neurodevelopmental disorder.^14,15

An observational study involving six healthy lactating women who were administered a single 50-mg oral dose of trazodone at 3 to 8 months postpartum found that the mean milk:plasma ratio based on the area under the time–concentration curve was 0.14, indicating that the infants would have received a trazodone dose of 0.005 mg/kg at the given maternal dose or 0.65% of the maternal weight-adjusted dosage.¹⁶ This study was unable to evaluate the potentially active metabolite 1-m-chlorophenylpiperazine (mCPP) in the analysis. In another case study wherein one woman received 75 mg trazodone, the milk level and estimated daily infant dose were 40 ng/mL and <0.01 mg/(kg·day), respectively. At any rate, the infant had a normal and healthy development.¹⁷ Although these previous studies suggested that trazodone is safe for pregnant and lactating women and breastfed infants, the information on trazodone transfer into fetal circulation is limited, and the elimination of transferred trazodone from the infant body was not investigated. Furthermore, the effects of mCPP as an active metabolite of trazodone has never been investigated.

In this case report, we assessed trazodone and mCPP concentrations in maternal and infant blood, cord blood, and breast milk during pregnancy and lactation. Infant behavior and development were also evaluated to determine the effects of the long-term use of trazodone. This case has previously been reported as a case study on etizolam use during pregnancy and lactation.¹⁸

Case

A 44-year-old woman weighing 63 kg became pregnant with her second child. She was diagnosed with early-onset pre-eclampsia during her first pregnancy, for which she underwent a cesarean section during gestational week (GW) 30 and delivered a female infant weighing 1,205 g. Thus, in her second pregnancy, 81 mg/day of low-dose aspirin was started at GW 11 to prevent pre-eclampsia. She was treated with 50 mg trazodone during GW 28 for anxiety disorder with depressive symptoms. Trazodone treatment was continued during pregnancy and tempolarity stopped after childbirth. Concomitantly, 0.5 to 1.0 mg/day of etizolam was also administered before her second pregnancy and continued during pregnancy. At GW 38, a healthy male infant weighing 2,918 g was delivered by cesarean section. Apgar scores at 1 and 5 minutes were 8 and 8, respectively. Owing to persistent respiratory disturbance, oxygenation was initiated immediately after birth. The infant remained tachypneic with an oxygen saturation in room air of 89%; therefore, continuous positive airway pressure was initiated with oxygen at 1 L/min, and he was admitted to the neonatal intensive care unit. His respiratory condition improved 4 days after delivery, and oxygenation was discontinued. No medication or circulatory support was needed during admission, and the infant was discharged on day 5. No congenital malformations were observed, and the infant exhibited normal developmental progress. During a 3-month lactation period, the infant was partially breastfed, with >50% of nutrition derived from breastfeeding. Although the mother resumed taking 50 mg/day of trazodone and 1.0 mg/day of etizolam in 3 days after childbirth and continued during lactation, the infant demonstrated no detectable drug-related adverse effects at the 1-, 3-, and 6-month postpartum health checkups. The score on the Denver Developmental Screening Test II, the most widely used tool for screening proper neonatal development, was normal at 6 months of age.

After approval by the ethics committee and obtaining the participant's written informed consent, trazodone and mCPP levels in maternal serum, umbilical cord blood, breast milk, and infant serum were evaluated.

Materials and Methods

Trazodone and mCPP detection

Trazodone and mCPP in serum and breast milk samples were determined using a modified version of a previously validated method based on liquid chromatography–tandem mass spectrometry.¹⁹ 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). Trazodone and mCPP were obtained from Fujifilm Wako Chemicals (Tokyo, Japan), and trazodone-d6 (an internal standard) 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). The method was fully validated for its sensitivity, selectivity, accuracy and precision, matrix effect, stability study, and dilution integrity.²⁰ A linear dynamic range of 2.0–1000.0 ng/mL for trazodone and 0.5–50.0 ng/mL for mCPP was evaluated with mean correlation coefficients of 0.9991 and 0.9992, respectively. The intrabatch and interbatch precision (%CV) across five validation runs were <7.4% for both analytes. The lower limit of quantification and the lower limit of detection (LLOD) for trazodone/mCPP were 2.0/0.5 and 0.7/0.2 ng/mL, respectively.

Sample collection and preparation

The mother took one 50 mg trazodone 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 five times between 6.4 and 77.0 hours after trazodone dosing. Breast milk samples were collected four times on days 5 and 6 postpartum, and infant serum samples were collected at 0, 2, 3, and 5 days after birth. The timing of sample collection after trazodone dosing is presented in Table 1.

Table 1.

Trazodone and m-Chlorophenylpiperazine Concentrations in Serum and Breast Milk Samples After Oral Administration of 50 mg Trazodone

Days postpartum	Maternal serum		Umbilical cord blood		Breast milk		Infant serum
Days postpartum	Time after maternal TRZ dose (hours)	TRZ/mCPP concentration (ng/mL)	Time after maternal TRZ dose (hours)	TRZ/mCPP concentration (ng/mL)	Time after maternal TRZ dose (hours)	TRZ/mCPP concentration (ng/mL)	Time after maternal TRZ dose (hours)	TRZ/mCPP concentration (ng/mL)
−1	6.4	256.1/20.1
0	30.5	23.5/1.3	7.0	255.3/19.8			14.2	156.6/9.8
2	77.0	<0.2/<0.2					41.6	7.0/0.6
3							83.0	4.0/<0.2
4	7.4	267.6/22.8
4	21.0	69.3/7.3
5					7.2	50.2/3.2	126.3	1.3/<0.2
					18.9	21.2/1.3
					20.4	18.2/0.9
6					29.0	8.0/<0.2

TRZ, trazodone; mCPP, 1-m-chlorophenylpiperazine.

Trazodone and mCPP concentrations in maternal serum and cord blood

The assays showed that the trazodone and mCPP concentrations in maternal serum were 256.1 and 20.1 ng/mL, respectively, at 6.4 hours after the last trazodone dose, whereas those in cord blood collected immediately after delivery (7.0 hours after the last dose) were 255.3 and 19.8 ng/mL, respectively, which are comparable with the maternal serum levels.

Trazodone and mCPP concentrations in breast milk

In breast milk, the trazodone and mCPP concentrations at 7.2 hours after the last dose on postpartum day 5 were 50.2 and 3.2 ng/mL, respectively (Table 1). The calculated daily infant dose of trazodone through breast milk, based on the largest detected trazodone concentration in breast milk (50.2 ng/mL) and the average breast milk intake (150 mL/kg/day), was 0.008 mg/(kg·day), which is low compared with that for the weight-adjusted therapeutic dose of trazodone for adults (∼1–3 mg/day) and agreed with previous findings.¹⁶ The infant dose through breast milk was 0.8% of the maternal daily dose, which was considered acceptable.²¹ The actual infant dose of trazodone through breast milk might be lower than this estimated value because the infant was not exclusively breastfeeding.

Trazodone and mCPP concentrations in infant serum

In infant serum, trazodone and mCPP concentrations at 7.2 hours after birth (14.2 hours after maternal administration) were 156.6 and 9.8 ng/mL, respectively. At 2 days after birth (41.6 hours after maternal administration), trazodone and mCPP decreased to 7.0 and 0.6 ng/mL, respectively, and mCPP could not be detected (under the LLOD) at 5 days after birth.

Discussion

Information on drug disposition in pregnant and lactating women is important for the safe and adequate treatment of mothers and their infants. In this case, the mother was treated with trazodone during pregnancy and lactation for depression and insomnia. The trazodone and mCPP concentrations detected in cord blood were equal to those in maternal serum, and the trazodone/mCPP ratio was equal to that of a previous report.²² The calculated breast milk intake was 0.008 mg/(kg·day) that is in agreement with a previous finding.¹⁶ Furthermore, although trazodone and mCPP were detected in infant serum at least 41.6 hours after maternal administration, trazodone decreased 5 days after birth, and mCPP concentration was below the detection limit (LLOD = 0.2 ng/mL) at 83.0 hours after maternal administration.

In our case, persistent respiratory disturbance was observed in the infant after delivery. Cohort studies found that in utero exposure to selective serotonin reuptake inhibitors affected one-third of neonates, with 3% to 13% demonstrating severe neonatal withdrawal or neonatal abstinence syndrome.^23,24 Polysubstance exposure was an independent predictor of neonatal withdrawals requiring pharmacological treatment.²⁵ Based on this background, respiratory disturbance in our case may have been caused by a combination of drugs. Since the relationship between respiratory disturbance and trazodone exposure in utero is unknown, a causal relationship between trazodone use during pregnancy and neonatal respiratory distress syndrome could not be ruled out in the present case.

Conclusions

Our findings show that trazodone and its active metabolite mCPP can cross the placental barrier and be excreted into breast milk. Although the infant had a healthy normal development, he underwent respiratory disturbance at delivery. Since the relationship between trazodone exposure in utero and respiratory disturbance at birth has not been elucidated, a causal relationship between these two events could not be ruled out.

To the best of our knowledge, this is the first report describing the pharmacokinetic profile of transferred trazodone and mCPP across the placenta and mCPP transfer into breast milk. Further studies are needed to evaluate potentially harmful effects after exposure to trazodone in utero and during breastfeeding.

Footnotes

Authors' Contributions

J.S., M.I., A.M., N.Y., H.K., Y.T., and A.M. were involved in study concept and design, data collection, and drafting and final approval of the article. T.S. and H.S. carried out drafting and final approval of the article. A.Y. was involved in study concept and design and critical revision and final approval of the article.

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.

Ethical approval

This study was approved by the ethics committee of the National Center for Child Health and Development (2021-007). The patient provided written informed consent.

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 have no conflicts of interest to declare.

Funding Information

This study was supported by the National Center for Child Health and Development (NCCHD-2021C-5) awarded to J.S.

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