Elsevier

The Lancet

Volume 365, Issue 9458, 5–11 February 2005, Pages 482-487
The Lancet

Articles
Selective serotonin reuptake inhibitors in pregnant women and neonatal withdrawal syndrome: a database analysis

https://doi.org/10.1016/S0140-6736(05)17865-9Get rights and content

Summary

Background

Selective serotonin reuptake inhibitors (SSRIs) have been associated with withdrawal symptoms. We investigated whether use of these drugs in pregnant women might cause neonatal withdrawal syndrome.

Methods

An association between paroxetine and neonatal convulsions was identified in December, 2001, by the data mining method routinely used to screen the WHO database of adverse drug reactions. An information component (IC) measure was used to screen for unexpected adverse reactions relative to the information in the database. We then assessed cases of neonatal convulsions and neonatal withdrawal syndrome associated with drugs included in the anatomical therapeutic chemical groups N06AB and N06AX.

Findings

By November, 2003, a total of 93 suspected cases of SSRI-induced neonatal withdrawal syndrome had been reported, and were regarded as enough information to confirm a possible causal relation. 64 of the cases were associated with paroxetine, 14 with fluoxetine, nine with sertraline, and seven with citalopram. The IC–2 SD for the group became greater than 0 in the first quarter of 1991, and the IC increased to 2·68 (IC–2 SD 0·32) by the second quarter of 2003. For each individual compound, the IC–2 SD was greater than 0.

Interpretation

SSRIs, especially paroxetine, should be cautiously managed in the treatment of pregnant women with a psychiatric disorder.

Introduction

Since 1990, the British National Formulary1 has included a warning of a possible withdrawal syndrome associated with antidepressants. Discontinuation of treatment with tricyclic antidepressants has been linked to withdrawal syndrome for almost 20 years.2 The main symptoms—influenza-like syndrome and sleep disturbances—are mostly in agreement with a cholinergic rebound as the underlying mechanism, with a connection with noradrenergic and dopaminergic pathways.2, 3, 4, 5

Since the introduction of selective serotonin reuptake inhibitors (SSRIs) in clinical practice in 1988, they have become the drugs of choice in the treatment of depression and are becoming the gold standard of treatment for a wide spectrum of other mood and behavioural disorders, such as obsessive-compulsive disorder, panic disorder, social phobia, post-traumatic stress disorder, premenstrual dysphoric disorder, and generalised anxiety disorder. SSRIs do not affect α adrenergic receptors so intensively, but withdrawal syndromes have been described with these compounds, and the presence of withdrawal reaction to SSRIs is now widely acknowledged.6 Neonatal withdrawal syndrome associated with SSRIs—characterised by convulsions, irritability, abnormal crying, and tremor—has been reported in several cases.7, 8, 9, 10 This database study was done to analyse a large series of reports of neonatal withdrawal syndrome associated with SSRIs and the possible differences between them.

Section snippets

Methods

Spontaneously reported cases of suspected adverse drug reactions (ADRs) are forwarded from national centres (appointed by national governments) in 72 countries (plus nine associated countries) to the WHO Collaborating Centre for International Drug Monitoring, Uppsala Monitoring Centre, Sweden. The case reports, recorded in a common format, are processed and stored in the ADR database. Over 3 000 000 case records are maintained by the centre, which provides a unique source of international ADR

Results

A total of 102 cases (reported up to the second quarter of 2003, from 11 different countries) of SSRI use associated with either neonatal convulsions or withdrawal syndrome were identified. Paroxetine was the most commonly reported SSRI with these ADRs. Cases were also reported for fluoxetine, sertraline, and citalopram, but not for any of the other drugs included in the N06AB group (table 1). Copies of the original reports were obtained from the national centres for 66 cases and, after careful

Discussion

Risks of neonatal convulsions and neonatal withdrawal syndrome seem to be increased with all SSRIs. Nearly two-thirds of reported cases of suspected SSRI-induced neonatal withdrawal syndrome were associated with paroxetine. The withdrawal syndrome is related to the mechanism of action of the compounds. With tricyclic antidepressants, withdrawal syndrome in the adult has been associated with the suspension of the effect on cholinergic muscarinic receptors, cholinergic rebound syndrome,

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      Poor neonatal adaptation, often termed neonatal adaptation syndrome (NAS), has been described in infants exposed to antidepressant medications in utero. This syndrome consists of a group of newborn signs including restlessness, rigidity, tremor, tachypnea, hypoglycemia, temperature instability, and irritability.56-59 NAS has been reported in up to 30% of infants exposed to SSRI during the third trimester55,56,60 and is more frequently observed in infants exposed to venlafaxine, paroxetine, and fluoxetine.61

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