TCA and pregnancy

• if an antidepressant is prescribed during pregnancy the the choice of drug will take into account the safety of the drug in pregnancy, in addition to its effectiveness, tolerability and adverse effects
• tricyclic antidepressants (TCAs) have been used for many years during pregnancy. The most studied of the selective serotonin re-uptake inhibitors (SSRIs) appears to be fluoxetine (1). Fluoxetine is the only SSRI licensed for use in pregnancy (2). It has been stated that neither fluoxetine nor TCAs have been shown to cause neurobehavioural effects in children or congenital abnormalities if the child was exposed to these antidepressants in utero (3)
  • however a more recent literature review concerning the use of SSRIs in the last trimester reported (4)
    • available evidence indicates that in utero exposure to SSRIs during the last trimester through delivery may result in a self-limited neonatal behavioral syndrome that can be managed with supportive care
      • a severe syndrome that consists of seizures, dehydration, excessive weight loss, hyperpyrexia, or intubation is rare in term infants (1/313 quantifiable cases). There have been no reported neonatal deaths attributable to neonatal SSRI exposure
  • with respect to TCAs, the BNF advises that muscle spasms, tachycardia and irritability in the neonate has been reported with the use of imipramine during pregnancy (5)

NICE state (6):

• if a woman taking paroxetine is planning a pregnancy or has an unplanned pregnancy, she should be advised to stop taking the drug
• when choosing an antidepressant for pregnant or breastfeeding women, prescribers should, while bearing in mind that the safety of these drugs is not well understood, take into account that:
  • tricyclic antidepressants, such as amitriptyline, imipramine and nortriptyline, have lower known risks during pregnancy than other antidepressants
  • most tricyclic antidepressants have a higher fatal toxicity index than SSRIs
  • fluoxetine is the SSRI with the lowest known risk during pregnancy
  • imipramine, nortriptyline and sertraline are present in breast milk at relatively low levels
  • citalopram and fluoxetine are present in breast milk at relatively high levels
  • SSRIs taken after 20 weeks' gestation may be associated with an increased risk of persistent pulmonary hypertension in the neonate
  • paroxetine taken in the first trimester may be associated with fetal heart defects
  • venlafaxine may be associated with increased risk of high blood pressure at high doses, higher toxicity in overdose than SSRIs and some tricyclic antidepressants, and increased difficulty in withdrawal
  • all antidepressants carry the risk of withdrawal or toxicity in neonates; in most cases the effects are mild and self-limiting

Antidepressants in pregnancy and development of neurodevelopment disorders in children (10)

• results of a cohort study suggest that antidepressant use in pregnancy itself does not increase the risk of neurodevelopmental disorders in children

Notes:

• there has been data to support an association between the maternal use of SSRIs in late pregnancy and persistent pulmonary hypertension of the newborn in the offspring (7)
  • MHRA advice suggests that
    • epidemiological data suggest that the use of SSRIs in pregnancy, particularly in the later stages, may increase the risk of persistent pulmonary hypertension in the newborn. Healthcare professionals are encouraged to enquire about the use of SSRIs and SNRIs, particularly in women in the later stages of pregnancy. Close observation of neonates exposed to SSRIs or SNRIs for signs of PPHN is recommended after birth (8)
• a retrospective epidemiological study has suggested that the use of paroxetine during the first trimester of pregnancy may be associated with an increased incidence of birth abnormalities compared to use of other antidepressants (9). The types of abnormalities seen were reflective of those seen in the general population. The most common birth abnormalities seen were cardiovascular (of which the most common were ventral septal defects)
• women on antidepressant treatment prior to pregnancy
  • study evidence suggests that for women with severe mental illnesses and currently receiving stable treatment, continuing antidepressant treatment during pregnancy may be beneficial (11)

The respective summary of product characteristics must be consulted before prescribing an antidepressant during pregnancy.

Reference:

• 1) Cohen LS, Rosenbaum JF (1998). Psychotropic drug use during pregnancy: weighing the risks. J Clin Psychiatry, 58 (suppl 2), 18-28.
• 2) Pulse (2002), 62 (29), 60.
• 3) Nulman I, Rovet J, Stewart DE et al (1997). Neurodevelopment of children exposed in utero to antidepressant drugs. NEJM, 336, 258-62.
• 4) Moses-Kolko EL et al. Neonatal signs after late in utero exposure to serotonin reuptake inhibitors: literature review and implications for clinical applications. JAMA 2005;293:2372-83.
• 5) BNF (Appendix 4: Pregnancy)
• 6) NICE (February 2007). Antenatal and postnatal mental health.
• 7) Chambers CD et al. Selective serotonin-reuptake inhibitors and risk of persistent pulmonary hypertension of the newborn. N Engl J Med. 2006 Feb 9;354(6):579-87
• 8) MHRA.Drug Safety Update. May 2010;3(10):7-8
• 9) GSK (December 2005). Paroxetine - Important Prescribing Information
• 10) Suarez EA, Bateman BT, Hernandez-Díaz S, et al. Association of Antidepressant Use During Pregnancy With Risk of Neurodevelopmental Disorders in Children. JAMA Intern Med. Published online October 03, 2022. doi:10.1001/jamainternmed.2022.4268
• 11) Trinh NTH, Munk-Olsen T, Wray NR, et al. Timing of Antidepressant Discontinuation During Pregnancy and Postpartum Psychiatric Outcomes in Denmark and Norway. JAMA Psychiatry. Published online March 08, 2023. doi:10.1001/jamapsychiatry.2023.0041