Selective Serotonin Reuptake Inhibitor (SSRI) Use during Pregnancy and Effects on the Fetus and Newborn: A Meta-Analysis

Lattimore, Keri A.; Donn, Steven M.; Kaciroti, Niko; Kemper, Alex R.; Neal, Charles R.; Vázquez, Delia M.

doi:10.1038/sj.jp.7211352

Cited by 159 publications

(113 citation statements)

References 52 publications

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“…There is still controversy whether symptoms observed in neonates born to mothers to whom SSRI during pregnancy were administered, reflect neonatal withdrawal (enhanced clearance) or are the manifestation of persistent high SSRI concentrations with toxicity due to limited clearance (26). SSRIs undergo CYP2D6 dependent metabolic clearance.…”

Section: Discussionmentioning

confidence: 99%

Postmenstrual Age and CYP2D6 Polymorphisms Determine Tramadol O-demethylation in Critically Ill Neonates and Infants

Allegaert¹,

Schaik

Vermeersch³

et al. 2008

Pediatr Res

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ABSTRACT:To document determinants of O-demethylation in critically ill (pre)term neonates and infants, tramadol (M) and O-demethyl tramadol (M1) concentrations were quantified in eightysix 24 h urine collections and 168 plasma samples. A significant correlation of urine log M/M1 (0.98, SD 0.66) and plasma log M/M1 (0.78, SD 0.45) with postmenstrual age (PMA) (r ϭ Ϫ0.69 and Ϫ0.65) was observed. One-way analysis of variance documented a significant decrease in urine log and plasma log M/M1 with increasing CYP2D6 activity score (F value 11.6 and 22.55). PMA and CYP2D6 activity score determined the urine and plasma log M/M1 (R 2 0.59 and 0.64) in a forward multiple regression model. We therefore conclude that PMA and CYP2D6 polymorphisms determined O-demethylation activity in (pre)term neonates and young infants, illustrating the impact of pharmacogenetics on drug metabolism in neonates although a relevant part of the interindividual varaibility remained unexplained. Besides compound-specific relevance, CYP2D6 iso-enzyme specific data on in vivo ontogeny of O-demethylation can contribute to safer and more effective administration of drugs metabolized by the same route in this population. I nterindividual variability in drug metabolism is based on constitution, environment, and genetics, but mainly reflects ontogeny in early life. Although the total cytochrome (CYP) content in fetal liver is 30 to 60% of adult content, iso-enzyme specific ontogeny precludes generalization of a single developmental pattern, necessitating iso-enzyme specific assessment (1). Based on observations on in vivo dextrometorphan in healthy infants and tramadol metabolism in critically ill (pre)term neonates and young infants, phenotypic activity of N-demethylation (CYP3A) displays slower increase to adult activity compared with O-demethylation (CYP2D6) (2,3). In addition to ontogeny, co-morbidity, co-medication, or polymorphisms in drug metabolizing enzymes and transporters likely further contribute to the interindividual variability of drug disposition (1,4,5).Tramadol (M) hydrochloride is a 4-phenyl-piperidine analogue of codeine and is a racemic mixture of two enantiomers. O-demethylation of (ϩ)-tramadol to O-(ϩ)-demethyl tramadol (M1) is catalyzed by CYP2D6 and to a much lesser extent, by CYP2B6. Tramadol therefore provide us with a probe drug to assess phenotypic variability in O-demethylation activity. The logarithmic value of tramadol over O-demethyl tramadol (log M/M1) has been used to study in vivo CYP2D6 activity in adults, children, and neonates (6 -9). Based on urine log M/M1 values, the impact of postmenstrual age (PMA) on phenotypic O-demethylation activity in 29 neonates and young infants was described, but PMA only in part explained (R adj Ϫ0.51) the interindividual variability in O-demethylation activity (8). The purpose of this study was to estimate the impact of ontogeny [PMA, postnatal age (PNA), weight] and pharmacogenetics (quantified by the CYP2D6 activity score) on interindividual variability of O-demethylation in earl...

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Section: Discussionmentioning

confidence: 99%

Postmenstrual Age and CYP2D6 Polymorphisms Determine Tramadol O-demethylation in Critically Ill Neonates and Infants

Allegaert¹,

Schaik

Vermeersch³

et al. 2008

Pediatr Res

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“…According to the majority of studies, the use of SSRIs and TCAs in pregnancy imposes no increased risk for malformations (Altshuler et al 2001;Alwan et al 2007;Austin and Mitchell 1998;Emslie and Judge 2000;Ericson et al 1999;Hogberg and Wang 2005;Kallen and Otterblad Olausson 2007;Koren et al 2005;Lattimore et al 2005;Malm et al 2005;Misri et al 2000a;Misri et al 2000b;Nordeng and Spigset 2005;Ramos et al 2008), although some reports have raised concerns about fetal cardiac effects, newborn persistent pulmonary hypertension, respiratory distress and other effects (ACOG 2006;Oberlander et al 2008). However, it is recommended to avoid paroxetine use among pregnant women or women planning to become pregnant, if possible (ACOG 2006).…”

Section: Pregnancymentioning

confidence: 99%

World Federation of Societies of Biological Psychiatry (WFSBP) Guidelines for the Pharmacological Treatment of Anxiety, Obsessive-Compulsive and Post-Traumatic Stress Disorders – First Revision

Bandelow

Zohar

Hollander

et al. 2008

The World Journal of Biological Psychiatry

696

400

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In this report, which is an update of a guideline published in 2002 (Bandelow et al. 2002, recommendations for the pharmacological treatment of anxiety disorder, obsessive-compulsive disorder (OCD) and post-traumatic stress disorder (PTSD) are presented. Since the publication of the first version of this guideline, a substantial number of new randomized controlled studies of anxiolytics have been published. In particular, more relapse prevention studies are now available that show sustained efficacy of anxiolytic drugs. The recommendations, developed by the World Federation of Societies of Biological Psychiatry (WFSBP) Task Force for the Pharmacological Treatment of Anxiety, Obsessive-Compulsive and Post-Traumatic Stress Disorders, a consensus panel of 30 international experts, are now based on 510 published randomized, placebo-or comparator-controlled clinical studies (RCTs) and 130 open studies and case reports. First-line treatments for these disorders are selective serotonin reuptake inhibitors (SSRIs), serotonin-noradrenaline reuptake inhibitors (SNRIs) and the calcium channel modulator pregabalin. Tricyclic antidepressants (TCAs) are equally effective for some disorders, but many are less well tolerated than the SSRIs/ SNRIs. In treatment-resistant cases, benzodiazepines may be used when the patient does not have a history of substance abuse disorders. Potential treatment options for patients unresponsive to standard treatments are described in this overview. Although these guidelines focus on medications, non-pharmacological were also considered. Cognitive behavioural therapy (CBT) and other variants of behaviour therapy have been sufficiently investigated in controlled studies in patients with anxiety disorders, OCD, and PTSD to support them being recommended either alone or in combination with the above medicines.

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“…Several recent studies suggest that although individual SSRIs may confer an increased risk of some specific birth defects (as expressed by the odds ratios), there is only a slight effect on absolute risk (7)(8)(9). Others observed that third-trimester intake of SSRIs accounts for symptoms of poor neonatal adaptation (10 -14) and, consequently, higher-than-normal rates of admission to neonatal special care and intensive care units (10,15). According to a 2005 literature review, SSRI exposure is associated with an overall risk ratio of 3.0 (95% CI, 2.0 -4.4) for neonatal behavioral syndrome (12); one study also reported an alarming complication of persistent infantile pulmonary hypertension (16).…”

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confidence: 99%

Effect of Exposure to Selective Serotonin Reuptake Inhibitors In Utero on Fetal Growth: Potential Role for the IGF-I and HPA Axes

et al. 2009

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ABSTRACT:To investigate the possible effect of fetal exposure to selective serotonin reuptake inhibitors (SSRIs) on somatic growth and on hormones of the hypothalamic-pituitary-adrenal (HPA) and insulin-like growth factor (IGF)-I axes, we compared the anthropometric parameters and hormonal profile of 21 SSRI-exposed infants and 20 matched controls. The SSRI group was characterized by lower crown-heel length (p Ͻ 0.01), smaller head circumference (p ϭ 0.08), and higher percentage of infants with birth weight, birth length, and head circumference below the 10th percentile (p Ͻ 0.045, p ϭ 0.08, p Ͻ 0.04, respectively), in addition to a significantly lower cord blood level of cortisol (p Ͻ 0.03) and higher level of thyroidstimulating hormone (TSH) (p Ͻ 0.004). Infants exposed to citalopram had a lower cord blood IGF-I level than infants exposed to paroxetine (p Ͻ 0.001) and controls (p Ͻ 0.003). Placental IGF-I receptor (IGF-IR) expression was significantly higher in the SSRI group than in controls (p Ͻ 0.01). Urine 5-hydroxyindoleacetic acid T he reported prevalence of depression in women of childbearing age and during pregnancy ranges from 10 to 15% (1-3). Treatment usually consists of selective serotonin reuptake inhibitors (SSRIs), especially citalopram, fluoxetine, paroxetine, sertraline, and fluvoxamine. However, their safety for the fetus has not been fully established. Findings regarding major congenital malformations are conflicting (4 -6). Several recent studies suggest that although individual SSRIs may confer an increased risk of some specific birth defects (as expressed by the odds ratios), there is only a slight effect on absolute risk (7-9). Others observed that third-trimester intake of SSRIs accounts for symptoms of poor neonatal adaptation (10 -14) and, consequently, higher-than-normal rates of admission to neonatal special care and intensive care units (10,15). According to a 2005 literature review, SSRI exposure is associated with an overall risk ratio of 3.0 (95% CI, 2.0 -4.4) for neonatal behavioral syndrome (12); one study also reported an alarming complication of persistent infantile pulmonary hypertension (16). It remains unclear, however, if these symptoms are a manifestation of abrupt drug withdrawal at delivery or of serotonergic overstimulation during pregnancy. Studies have shown that maternal SSRI intake during pregnancy induced a significant reduction in cord blood levels of serotonin and 5-hydroxyindoleacetic acid (5-HIAA) (1,17). Laine et al.(1) reported that the cord blood 5-HIAA level was inversely and significantly correlated with the clinical serotonergic symptom score and attributed this finding to the increase in central nervous system (CNS) serotonin activity.The question of whether in utero exposure to SSRIs affects birth weight and/or length and head circumference is also unresolved. Some studies noted decreased values of these parameters (18 -21), whereas others did not (1,2,5). Growth attenuation accompanied by impaired growth hormone (GH) secretion was also reported in f...

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Selective Serotonin Reuptake Inhibitor (SSRI) Use during Pregnancy and Effects on the Fetus and Newborn: A Meta-Analysis

Cited by 159 publications

References 52 publications

Postmenstrual Age and CYP2D6 Polymorphisms Determine Tramadol O-demethylation in Critically Ill Neonates and Infants

Postmenstrual Age and CYP2D6 Polymorphisms Determine Tramadol O-demethylation in Critically Ill Neonates and Infants

World Federation of Societies of Biological Psychiatry (WFSBP) Guidelines for the Pharmacological Treatment of Anxiety, Obsessive-Compulsive and Post-Traumatic Stress Disorders – First Revision

Effect of Exposure to Selective Serotonin Reuptake Inhibitors In Utero on Fetal Growth: Potential Role for the IGF-I and HPA Axes

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