title: Disturbed development of the enteric nervous system after in utero exposure of selective serotonin re-uptake inhibitors and tricyclic antidepressants. Part 2: Testing the hypotheses.
abstract: OBJECTIVE
  Antidepressant use has increased in the last decade. Several studies have suggested a possible association between maternal antidepressant use and teratogenic effects.
  
  
  METHODS
  The pharmacy prescription database IADB.nl was used for a cohort study in which laxative and antidiarrhoeal medication use in children after in utero exposure to antidepressants (TCA, SSRI, fluoxetine or paroxetine exposed) was compared with no antidepressant exposure. Laxatives and antidiarrhoeal medication use were applied as a proxy for constipation and diarrhoea respectively, which may be associated with disturbed enteric nervous system (ENS) development.
  
  
  RESULTS
  Children exposed in utero to SSRIs (mainly fluoxetine and paroxetine) in the second and third trimester or to TCAs in the first trimester, more often received laxatives. Combined exposure to TCAs and SSRIs in pregnancy was associated with a 10-fold increase in laxative use. In utero exposure to SSRIs is not associated with antidiarrhoeal medication use compared with non-exposed children. In contrast, antidiarrhoeal medication use was significantly higher in children exposed to TCAs anytime in pregnancy.
  
  
  CONCLUSIONS
  The increased laxative use after second and third trimester exposure to SSRIs might be explained through the inhibitory effect of the serotonin re-uptake transporter (SERT) and because of selectivity for the 5-HT(2B) receptor which affects the ENS. TCA exposure during the first trimester leads to increased laxative use probably through inhibition of the norepinephrine transporter (NET). Exposure of TCAs anytime in pregnancy leads to increase diarrhoeal use possibly through down-regulation of α₂-adrenoceptors or up-regulation of the pore forming α(1c) subunit.
authors.affiliation: Department of Pharmaco-epidemiology and Pharmaco-economy, University of Groningen, Groningen, The Netherlands.
authors.forename: Cynthia M
authors.initials: CM
authors.lastname: Nijenhuis
authors.forename: Peter G J
authors.initials: PG
authors.lastname: ter Horst
authors.forename: Nienke
authors.initials: N
authors.lastname: van Rein
authors.forename: Bob
authors.initials: B
authors.lastname: Wilffert
authors.forename: Lolkje T W
authors.initials: LT
authors.lastname: de Jong-van den Berg
mesh_terms: D000014:Abnormalities, Drug-Induced / Q000209:etiology; D000929:Antidepressive Agents, Tricyclic / Q000009:adverse effects*; D015331:Cohort Studies; D003866:Depressive Disorder / Q000188:drug therapy*; D017615:Enteric Nervous System / Q000187:drug effects*; D005260:Female; D006801:Humans; D050484:Norepinephrine Plasma Membrane Transport Proteins / Q000187:drug effects; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000139:chemically induced*; D017367:Selective Serotonin Reuptake Inhibitors / Q000009:adverse effects*; D013997:Time Factors
chemical_list: D000929:Antidepressive Agents, Tricyclic; D050484:Norepinephrine Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors