Date Published: July 14, 2017
Publisher: Public Library of Science
Author(s): Andreas Austgulen Westin, Malin Brekke, Espen Molden, Eirik Skogvoll, Olav Spigset, Judith Homberg.
Pregnancy may cause changes in drug disposition. The clinical consequences may be profound and even counterintuitive; in some cases pregnant women may need more than twice their usual drug dose in order to maintain therapeutic drug levels. For antidepressants, evidence on drug disposition in pregnancy is scarce. The aim of this study was to determine the effects of pregnancy on serum levels of selective serotonin reuptake inhibitors (SSRIs) and venlafaxine in a large and naturalistic patient material, in order to provide tentative dose recommendations for pregnant women.
Using patient data from two routine therapeutic drug monitoring (TDM) services in Norway with linkage to the national birth registry, dose-adjusted serum drug concentrations of SSRIs and venlafaxine during pregnancy were compared to the women’s own baseline (non-pregnant) values, using a linear mixed model.
Overall, the TDM databases contained 196,726 serum concentration measurements from 54,393 women. After data linkage and drug selection (SSRIs or venlafaxine only), we identified 367 analyses obtained from a total of 290 pregnancies in 281 women, and 420 baseline observations from the same women. Serum concentrations in the third trimester were significantly lower than baseline for paroxetine (–51%; 95% confidence interval [CI], –66%, –30%; p<0.001), fluvoxamine (–56%; CI, –75%, –23%; p = 0.004) and citalopram (–24%; CI, –38%, –7%; p = 0,007), and higher than baseline for sertraline (+68%; CI, +37%, +106%; p<0.001). For escitalopram, fluoxetine and venlafaxine concentrations did not change significantly. For paroxetine and fluvoxamine the pronounced decline in maternal drug serum concentrations in pregnancy may necessitate a dose increase of about 100% during the third trimester in order to maintain stable concentrations. For fluoxetine, venlafaxine, citalopram, escitalopram and sertraline, the present study indicates that dose adjustments are generally not necessary during pregnancy.
Depression in pregnancy is a serious and often overlooked condition. It is estimated to impact 14–23% of pregnant women, which makes it more prevalent in pregnancy than conditions like gestational diabetes (18%) and preeclampsia (3–5%) . Maternal depression may cause a vast range of consequences for the mother and fetus, such as substance abuse, preterm delivery, neonatal intensive care unit admissions, poor bonding between mother and baby, adverse effects on the growth and neurodevelopment of the offspring, and even increased risk of maternal suicide [1, 2]. Therefore, in cases of severe or relapsing depression, the use antidepressants is considered favorable compared to exposing mother and child to untreated depressive illness [1–3].
Table 1 and Fig 1 provide an overview of all analyses and pregnancies included in the study. The model estimates for the loge-transformed serum concentrations across pregnancy are given in the S1 Table. Table 2 shows the estimated serum concentrations at baseline and by trimester during pregnancy, as well as the relative changes from baseline in percent. For paroxetine, fluvoxamine and citalopram concentrations in mid third trimester (gestational week 34) were 51%, 56% and 24% lower than baseline values, respectively. For venlafaxine, fluoxetine and escitalopram the concentration declines were smaller and not statistically significant. For sertraline, there was a 68% increase in mid third trimester concentrations compared to baseline (Table 2).
The present study, including SSRI and venlafaxine serum concentration data from 290 pregnancies, is by far the largest study to date investigating the disposition of antidepressants during pregnancy. The main finding is that the serum concentrations of paroxetine and fluvoxamine drop to about 50% of pre-pregnancy levels, whereas sertraline concentrations increase by approximately 60–70% (Table 2). Venlafaxine, fluoxetine, citalopram and escitalopram concentrations remain largely unchanged.