Sertraline concentrations in pregnant women are steady and the drug transfer to their infants is low

Abstract

Purpose Sertraline, a selective serotonin reuptake inhibitor (SSRI), is one of the most commonly used antidepressant during pregnancy. Plasma sertraline concentrations vary markedly between individuals, partly explained by variability in hepatic drug metabolizing cytochrome P450-enzyme activity. Our purpose was to study the variability in the plasma concentrations in pregnant women and the passage to their infants. Method Pregnant women with moderate untreated depression were recruited in 2016–2019 in Stockholm Region and randomized to treatment with sertraline or placebo. All received Internet-based cognitive behavior therapy as non-medical treatment. Sertraline plasma concentrations were measured around pregnancy weeks 21 and 30, at delivery, 1-month postpartum, in cord blood and at 48 h of age in the infant. The clinical course of the infants was followed. Results Nine mothers and 7 infants were included in the analysis. Median dose-adjusted sertraline concentration in second trimester was 0.15(ng/mL) /(mg/day), in third trimester and at delivery 0.19 and 1-month postpartum 0.25, with a 67% relative difference between second trimester and postpartum. The interindividual variation was 10-fold. Median concentrations in the infants were 33% and 25% of their mothers’, measured in cord blood, and infant plasma, respectively. Only mild and transient adverse effects were seen on the infants. Conclusion Placental passage of sertraline to the infant is low. However, the interindividual variation in maternal concentrations during pregnancy is huge, why therapeutic drug monitoring might assist in finding the poor metabolizers at risk for adversity and increase the safety of the treatment. Trial registration The trial was registered at clinicaltrials.gov July 9, 2014 with TRN: NCT02185547.

Neonatal outcome and adaption after in utero exposure to antidepressants: A systematic review and meta‐analysis

“…lowest concentration for sertraline and high interindividual variability. 18 Two previous meta-analyses assessed evidence on exposure to antidepressants in pregnancy and effects on neonates. 19,20 These publications point toward a significant effect of SSRIs on obstetric outcome and neonatal adaption as well as postpartum admission to a specialized setting such as a special care nursery or intensive care unit (ICU).…”

Studying the Liver Function in Male Neonates of Rats Born to Sertraline-Treated Mothers

“…Sertraline is generally a weak compound that binds to two plasma proteins, Albumin, and more to alpha 1-acid-glycoprotein. Plasma levels of Albumin and alpha-1-acid-glycoprotein decrease during pregnancy so they can affect the plasma concentration of Sertraline (Heinonen et al 2021). At birth, however, plasma Albumin concentrations in infants are usually higher than in mothers, while the plasma concentration of alpha 1-acid-glycoprotein is one third of the maternal plasma concentration (Ewing et al 2015).…”

Effect of Low and High Doses of Two Selective Serotonin Reuptake Inhibitors on Pregnancy Outcomes and Neonatal Mortality

“…However, fluoxetine, but not sertraline, decreases the capacity of OCT3 to transport serotonin from fetal circulation into the placenta in an in situ model [47]. Therefore, added to the decreased placental transfer of sertraline [23,24] resulting in lower concentrations of the drug in the fetal circulation, it seems likely that the similar effects of the two drugs on neonatal outcomes are mediated by their common capacity to inhibit SERT on the maternal side of the placenta [47]. This likely leads to increased serotonin signaling with a consequent compromise of placental vascular perfusion and function [11,15].…”

“…Interestingly, rodents exposed to SSRI perinatally have altered cardiac morphology [43,46] and dilated cardiomyopathy [23]. Because both drugs promote comparable neonatal mortality and increase serotonin concentrations in the maternal side of the placenta altering placental homeostasis [18,47] but have distinct placental transfer (70% fluoxetine [23] vs. 25% sertraline [24]), placental insufficiency is likely to be the underlying mechanism of SSRI-related pup mortality rather than a direct toxic effect of SSRI on fetal development. Nevertheless, these results do not exclude a direct role of fluoxetine (highest placental transfer) on fetal organogenesis.…”

“…Furthermore, fluoxetine metabolism produces an active metabolite, norfluoxetine, which has a longer half-life than fluoxetine itself (8-15 days) while sertraline's metabolites are essentially inactive. Lastly, placental transfer of fluoxetine is greater compared to sertraline (70% vs. 25%) [23,24]. It is unclear whether these two popular SSRI with distinct kinetics similarly affect pregnancy outcomes and neonatal morbidity/mortality, particularly given their distinct placental transfer.…”