Abstract
Background:
Information about influences of vortioxetine on pregnant women and neonates during perinatal period is almost unknown.
Case Presentation:
The case was a 28-year-old Japanese woman in her first pregnancy, treated for depression with vortioxetine (20 mg daily) among other medications. At 36 weeks of gestation, she was admitted for premature rupture of the membranes and delivered a girl with no apparent congenital anomalies. Immediately after birth, the neonate required brief respiratory support due to her dyspnea and poor muscle tone. Her respiratory condition improved in 6 days after delivery, and she demonstrated normal developmental progress afterward. Maternal plasma and breast milk samples, collected 4 days postpartum, revealed vortioxetine concentrations of 11.4 ng/mL and 9.3 ng/mL, respectively. The calculated relative infant dose (RID) was estimated at 0.32%. After discharge from hospital, the infant presented no detectable drug-related adverse effects, with over 50% of nutrition derived from breastfeeding.
Conclusion:
This case showed minimal transfer of vortioxetine into breast milk, reflected in a low RID. The findings suggest limited neonatal exposure to the drug, with no adverse developmental effects observed in the infant. However, the case also indicated the potential for vortioxetine use during pregnancy to contribute to the onset of severe neonatal asphyxia. Further research is needed for a comprehensive understanding of its impact on neonatal health.
Background
Vortioxetine is a multimodal antidepressant with two different types of pharmacologic targets: serotonin receptors and transporters. In vitro, vortioxetine acts as a 5-HT1A receptor agonist, 5-HT3, 5-HT7, and 5-HT1D receptor antagonist, 5-HT1B receptor partial agonist, and inhibitor of the 5-HT transporter (SERT). 1 This drug was licensed in Japan in 2019 and approved for the treatment of major depressive disorder.
In general, the antidepressants cross the placenta, have been associated with increased risks of preterm birth, low Apgar score, neonatal intensive care unit admission, and neonatal respiratory distress syndrome. 2 However, information about influences of vortioxetine on pregnant women and neonates during perinatal period is almost unknown. To date only one case series by Marshall et al. has addressed the safety and efficacy of vortioxetine use during pregnancy and lactation. 3
In this case report, we describe the clinical course of a patient who was administered vortioxetine during pregnancy and lactation and report drug levels in maternal plasma and breast milk.
Case Presentation
The patient was a 28-year-old Japanese woman in her first pregnancy. She had been diagnosed with depression and a sleep disorder three years before her pregnancy. Her depression was treated with a daily oral dose of vortioxetine 20 mg, zolpidem 10 mg, duloxetine 20 mg, triazolam 0.125 mg, Kami-kihi-tou (Asian herbal medicine composed of 14 medical plants, which is considered to have antidepressant-like and antianxiety effects 4 ) 2.5 g, and rebamipide (a gastrointestinal agent that enhances mucosal defense, protects the stomach lining, and promotes the healing of ulcers, which is sold mainly in Asia. It was prescribed by the mother’s health care provider for chronic gastritis.) 100 mg. She was admitted due to the risk of premature delivery and remained hospitalized from 29 weeks to 34 weeks of gestation. She stopped triazolam at 30 weeks of gestation. She had no other comorbidity or treatment apart from folic acid that was started before pregnancy.
At 36 weeks of gestation, she was admitted to our hospital for premature rupture of the membranes (PROM). Due to uterine inertia, her labor was induced with oxytocin. She gave birth at 36 weeks of gestation to a girl weighing 2,129 grams (13.1% tile) and measuring 45 cm (19.0% tile), with no apparent congenital anomalies. Apgar scores at 1, 5, 10, and 15 minutes were 1, 5, 6, and 6, respectively. Immediately after birth, due to the absence of spontaneous breathing and poor muscle tone, the neonate needed respiratory support using a mask and bag for one minute. Spontaneous breathing and muscle tone improved after 1.5 minutes of respiratory support, the neonate remained tachypneic with an oxygen saturation in room air of 90%, and therefore continuous positive airway pressure with 8.8 L/min of oxygen was initiated, and the neonate was admitted to the neonatal intensive care unit. Her respiratory condition improved at 6 days after delivery, and oxygen was discontinued. Thereafter no medication or circulatory support was needed during admission. No congenital malformations were observed, and the infant exhibited normal developmental progress.
Although the mother was physically well after giving birth, she experienced maternity blues three days after delivery. The dysphoric mood was transient. A follow-up examination a month after delivery showed both the mother and the infant to be in good health. The infant’s follow-up has since continued at our hospital. During a 3-month lactation period, the infant was partially breastfed, with over 50% of nutrition derived from breastfeeding. The infant demonstrated no detectable drug-related adverse effects at the 1-, 3-, 5-, 7-, and 9-month postpartum health checkups.
Ethics Statement
The mother gave written informed consent for obtaining blood and milk samples and for the publication. Ethics approval was obtained from the Ethics Committee of KKR Tachikawa Hospital. The procedures used in this study adhered to the tenets of the Declaration of Helsinki.
Methods
Samples
Breast milk was collected manually. We used 5 mL of foremilk as the sample. The plasma was collected by centrifugal separation (at 1000 ×g for 10 minutes) of total blood.
Sample preparation and analyses
For sample preparation, 100 μL of plasma or breast milk was added to a 1.5-mL polypropylene tube, followed by 900 μL of 4% formic acid in water, 100 μL of IS solution, and the mixture was vortexed. The prepared samples were extracted by Oasis® MCX (1 mL/30 mg, 30 μm, Waters® Corporation) SPE cartridges. The cartridge was conditioned and equilibrated with 1 mL of methanol and ultrapure water. After 1 mL of sample was loaded, the cartridge was washed with 1 mL of 2% formic acid in water, followed by 1 mL of 100% methanol. Then, the sample was eluted with 1 mL of 1.25% ammonium hydroxide diluted with 100% methanol. The eluates were collected in 1.5-mL polypropylene tubes and evaporated at 60°C and 300 ×g for 60 minutes. The dried samples were dissolved in 100 μL of mobile phase (see later) and injected 1 μL into a followed analytical system.
The concentration of vortioxetine in plasma and breast milk was determined using an Acquity H-class ultra-performance liquid chromatography (UPLC) system coupled to a QDa mass detector (Waters® Corporation). UPLC analysis was carried out under isocratic condition with the mobile phase composed of acetonitrile and 10 mM ammonium formate with 0.1% formic acid in ultrapure water (50/50, v/v) at a flow rate of 0.3 mL/min. We selected diazepam as the internal standard (IS). The separation of vortioxetine and diazepam was carried out on an ACQUITY UPLC BEH C18 Column (2.1 × 100 mm, 1.7 μm) and an ACQUITY UPLC BEH C18 VanGuard Pre-column (2.1 × 5 mm, 1.7 μm) (Waters® Corporation). The column and sample temperatures were set to 40°C and 10°C, respectively. Electrospray ionization was used in positive ion mode for quantification using [M + H]+ ions at m/z 299.14 for vortioxetine and m/z 285.10 for diazepam.
This UPLC analysis method was validated referring to the U.S. Food and Drug Administration and the European Medicines Agency guidelines for the validation of bioanalytical methods.5,6 A validated linear range of vortioxetine in plasma and breast milk was 2.5–400 ng/mL with a coefficient of determination (R2) of at least 0.9970 using weighted (1/x) linear least-squares regression. The accuracy (%) and precision (% coefficient of variation) range of within-batch for plasma were −0.44–3.43% and 3.05–12.52%, for breast milk were −6.72–4.55% and 2.19–6.59%, and between-batch for plasma were 2.55–14.05% and 3.45–6.95%, for breast milk were −1.39–2.51% and 0.91–5.00%. Both precision of matrix effect for plasma and breast milk were within 3%. No matrix substances were detected in either plasma or breast milk that interfered with the quantification of vortioxetine and diazepam. Both the blank plasma and breast milk samples did not show any peaks from the preceding samples that interfered with quantitation; these results indicate no carryover.
Calculations
To assess the neonate’s exposure to vortioxetine, we calculated the theoretical infant dose (TID) and the relative infant dose (RID). The equations used to estimate the RID and the TID of vortioxetine are as follows:
Mother’s weight adjusted dose (μg/kg/day) = drug dose (mg/day) ÷ mother’s weight (kg) × 1000 (μg/mg)
TID (μg/kg/day) = 0.15 (L/kg/day) × drug concentration in milk (μg/L)
RID (%) = TID ÷ mother’s weight-adjusted dose × 100
Results
The mother’s height and weight at 5 days after delivery were 155 cm and 46 kg, respectively, resulting in a body surface area of 1.44 m2. The sampling was conducted 4 days after birth. While on a daily regimen of 20 mg vortioxetine, milk and blood samples were collected 2 hours postdose.
As a result of the assays, the vortioxetine concentration in maternal plasma and breast milk was 11.4 ng/mL and 9.3 ng/mL, respectively. Therefore, the calculated RID was estimated to be 0.32%.
Discussion
This is the first report of negative effects in a neonate after birth to a mother receiving vortioxetine during pregnancy, although these negative effects were short term and transient. Moreover, this report presented the transfer of vortioxetine in human milk based on concentrations of the drug in maternal blood and human milk sample. To our knowledge, this study is the first to provide a quantitative description of vortioxetine’s transfer into breast milk in an Asian woman.
In our study, we evaluated the transfer of vortioxetine into breast milk using the relative infant dose (RID) and its concentration in plasma and breast milk two hours after the last dose. Previous studies reported a low RID for vortioxetine,3,7 but there were no data on the concentration in both plasma and breast milk. We found that the vortioxetine concentration in breast milk was lower than its concentration in plasma. Although the accurate milk-to-plasma ratio, where a value below 1.0 is generally preferred during lactation, 8 cannot be calculated in a single point, the result implied limited transfer to breast milk. Additionally, the RID at sampling point was calculated at only 0.32%, significantly below the 10% threshold considered safe, 9 suggesting minimal exposure for the breastfed infant. The oral bioavailability of vortioxetine is 75%, and it is approximately 99% bound to plasma proteins, which could explain its low concentration in breast milk. 1
These results were consistent with previous studies in demonstrating that the transfer rate of vortioxetine into breast milk was sufficiently low to be considered safe for infants.3,7 However, RID and breast milk concentration in our study were approximately one-quarter of those reported in these studies. This discrepancy could be attributed to differences in the peak plasma concentrations or the timing of sample collection postdose. The maximal plasma concentration of vortioxetine after multiple dosing is typically reached within 7–11 hours postdose,1,10 and our sample was collected approximately 2 hours after dose. Although the timing might have been before peak blood levels were reached, it is unlikely that the blood concentration would significantly increase. Another potential factor to consider is that our sample was foremilk. Foremilk, the milk produced at the beginning of a feeding, typically has a lower fat content, which could result in lower concentrations of lipophilic drugs compared with hindmilk. 11 In fact, vortioxetine is a highly lipid-soluble drug with a log p value of 4.44. 12 Furthermore, race or ethnicity might account for some of these differences. It has been shown that there are variations in breast milk lipid composition and the expression of cytochrome P450 enzymes involved in drug metabolism between Asian and Caucasian populations.13,14
In our case, neonatal asphyxia and sequential hypotonia with dyspnea developed after birth. Exposure to SNRIs and SSRIs (SRIs) in the second half of pregnancy has been associated with developmental toxicity in infants, including low birth weight, prematurity, neonatal serotonin syndrome, neonatal withdrawal, possibly sustained abnormal neurobehavior beyond the neonatal period, respiratory distress, and persistent pulmonary hypertension. 2 In fact, a study in rats showed that prenatal exposure to vortioxetine induced a delayed response in neonatal muscular reflexes. 15 Although the possibility that vortioxetine could induce these conditions, similar to other depressants, is not negligible, no cases of poor neonatal adaptation syndrome have been reported with vortioxetine to date. Understandably, the effect of combination drugs such as duloxetine or zolpidem on these clinical conditions should also be considered. 8
The hypotonia and dyspnea were transient. Additionally, there were no apparent signs of developmental toxicity or other forms of toxicity in the infant during the first three months of breastfeeding following recovery. However, long-term follow-up has not been conducted in exposed infants and the possibility of functional/neurobehavioral deficits appearing later in life cannot be excluded.
Further cases and studies are needed to evaluate potentially harmful effects after exposure to vortioxetine in utero and during breastfeeding.
Conclusion
We presented a case of Asian woman who raised a possibility that vortioxetine during pregnancy induces PROM and neonatal asphyxia. Furthermore, the case showed low plasma to milk transfer of vortioxetine. Assessment of safety by amassed data is required.
Footnotes
Authors’ Contributions
M.K. and T.S. substantially contributed to the study conceptualization and drafted the original article. M.T., M.I., R.W., K.I., S.N., and A.K. significantly contributed to develop the quantification method of vortioxetine, data analysis, and interpretation. All authors critically reviewed and revised the article draft and approved the final version for submission.
Author Disclosure Statement
None of the authors has any conflict of interest to disclose.
Funding Information
No funding was received for this article.