First‐Trimester Pregnancy Exposure to Venlafaxine or Duloxetine and Risk of Major Congenital Malformations: A Systematic Review

Abstract

Major depressive disorder is common among women in child-bearing age, and medical treatment is subject to substantial discussions and controversies. For Selective Serotonin reuptake inhibitors, SSRIs, a vast amount of data are available. For the newer antidepressant group of serotonin and noradrenaline reuptake inhibitors, SNRIs, significantly less data are available. Following the PRISMA guideline for systematic reviews, we performed a systematic search on the risk of major congenital malformations after first trimester in utero exposure to venlafaxine or duloxetine. We identified eight cohort studies reporting on the outcome upon in utero exposure to venlafaxine or duloxetine during the first trimester. The cumulated data for venlafaxine were 3186 exposed infants and 107 major malformations, resulting in a relative risk estimate and 95% confidence interval of 1.12 (0.92-1.35). The corresponding data for duloxetine were 668 infants and 16 major malformations, resulting in a relative risk estimate and 95% confidence interval of 0.80 (0.46-1.29). First-trimester in utero exposure to venlafaxine is not associated with an increased risk of major congenital malformations. The amount of data for duloxetine are significantly smaller but does not suggest a clinically important increased risk.Depression is common among women of child-bearing age. Approximately 20% of all women of child-bearing age will experience a depression during their life time, and 1% to 8% will use an antidepressant drug during pregnancy [1]. Untreated depression during pregnancy carries risk of severe consequences to the pregnant mother and her unborn child such as: epidural analgesia, caesarean section, intensive ward admission, preterm delivery, low birthweight, and disturbances in the child's neurocognitive and socio-emotional development [2]. Untreated depression during pregnancy increases the risk of post-partum depression 6-fold [3,4].The controversy of possible untoward foetal effects after in utero exposure to selective serotonin receptor inhibitors (SSRIs) has been ongoing for more than a decade. Data on more than 50,000 first-trimester SSRI-exposed newborn have accumulated, and it is accepted that first-trimester exposure to any antidepressant does not result in an overall increased risk of congenital malformations. The risk of cardiovascular malformations is still somewhat unclear, but if true, absolute risks are minor and may pertain to specific SSRIs, especially paroxetine and fluoxetine [5][6][7][8][9][10]. Comparatively, pregnancy data on the newer combined serotonin/noradrenaline receptor inhibitors (SNRI), venlafaxine and duloxetine, are scarce. A recent large Scandinavian study did not suggest an increased risk associated with venlafaxine [10], and a recent commentary concluded that the amount of information for duloxetine was too little [11].Current guidelines are vague and offer little decision support. The NICE guideline does not distinguish between the various types of antidepressants and offers no direct suggestio...

Review of Post-Marketing Safety Data on Tapentadol, a Centrally Acting Analgesic

“…First trimester pregnancy exposure to serotonin–noradrenaline reuptake inhibitors (SNRIs) such as venlafaxine and duloxetine which—like tapentadol—include the NRI mechanism of action have been reviewed for major congenital malformations [30]; there was no increased risk with venlafaxine treatment and no clinically important risk with duloxetine. Venlafaxine was also judged as relatively safe during pregnancy (relating to major malformations) but the authors could not draw a definite conclusion regarding breastfeeding [31].…”

Medication Use and Pain Management in Pregnancy: A Critical Review

“…Serotonin has an important role in embryonic development, particularly of the neural tube and the heart . There are now data on more than 50,000 newborns exposed to SSRIs in utero, which collectively does not suggest an overall increased risk for congenital malformations . There is ongoing debate about the risk for cardiovascular malformations with first‐trimester use of SSRIs, but any increase in absolute risk is likely clinically insignificant and may be associated with particular SSRIs such as paroxetine .…”

“…A small number of studies have evaluated outcomes following SNRI (venlafaxine or duloxetine) use in pregnancy and have found no major teratogenic effects . Two recent systematic reviews found no association between first trimester exposure to venlafaxine and an increased risk for major congenital malformations . Conversely, studies have found a possible association with an increased risk for some perinatal complications, including a withdrawal syndrome with venlafaxine use in the third trimester .…”

Prenatal exposure to antidepressants and risk of epilepsy in childhood

“…Exposure in utero to selective serotonin reuptake inhibitors (SSRIs) and other antidepressants has been associated with birth defects, prematurity, small for gestational age, low birth weight, poor neonatal adaptation syndrome, gestational hypertension, and preeclampsia, although not all studies support these findings . Antidepressant medication during pregnancy may affect early brain development in humans as it has been seen in animals .…”

“…Exposure in utero to selective serotonin reuptake inhibitors (SSRIs) and other antidepressants has been associated with birth defects, 4,5 prematurity, 6 small for gestational age, 7 low birth weight, 8 poor neonatal adaptation syndrome, 9 gestational hypertension, 10 and preeclampsia, 11 although not all studies support these findings. [12][13][14][15] Antidepressant medication during pregnancy may affect early brain development in humans 16,17 as it has been seen in animals. [18][19][20] Disturbances in fetal brain development by antidepressant use in pregnancy could lead to an increased susceptibility to autism and attention deficit disorders in children.…”