Bar-Oz B, Einarson T, Einarson A, et al.. Paroxetine and congenital malformations: meta-analysis and consideration of potential confounding factors

Motherisk Program, The Hospital for Sick Children, Toronto, Ontario, Canada.
Clinical Therapeutics (Impact Factor: 2.73). 06/2007; 29(5):918-26. DOI: 10.1016/j.clinthera.2007.05.003
Source: PubMed


Antidepressants have been commonly used by women of childbearing age. Recent studies suggest that paroxetine, a selective serotonin reuptake inhibitor (SSRI), might specifically increase teratogenic risk.
The purpose of this study was to quantify first-trimester exposure to paroxetine and birth defects and examine potential sources of bias in the in utero or postnatal detection of more congenital malformations among women with depression. We also sought to examine whether paroxetine was used for the same indications as other SSRIs among pregnant women.
This meta-analysis was designed to quantify malformation rates associated with the use of paroxetine. A search of the literature from 1985 to 2006 (English language) found in MEDLINE, EMBASE, REPROTOX, Scopus, and Biological Abstracts was conducted using the following terms: pregnancy outcome, congenital or fetal AND anomalies, malformations, cardiac/heart defects, AND selective serotonin reuptake inhibitors, paroxetine, and Paxil. Administrative databases of medication and medical services use in the Province of Quebec, Canada, were used to calculate the rates of ultrasound and echocardiogram in pregnancy and infancy in women/infants exposed to SSRIs and to compare the indications for general SSRI use versus paroxetine use.
Based on the studies analyzed, first-trimester paroxetine exposure was associated with a significant increase in the risk for cardiac malformation (odds ratio [OR], 1.72; 95% CI, 1.22-2.42). Women using antidepressants in pregnancy had a 30% higher rate of utilization of ultrasound in pregnancy. Infants of women who received SSRIs underwent approximately twice as many echocardiograms in the first year of life compared with children of women who used nothing. Significantly more women receiving paroxetine used the drug for anxiety or panic than women receiving other SSRIs (OR, 4.11; 95% CI, 2.39-7.08).
Based on the results of this metaanalysis, first-trimester exposure to paroxetine appears to be associated with a significant increase in the risk for cardiac malformation. However, a detection bias cannot be ruled out as contributing to the apparent increased detection of cardiovascular malformation of children exposed in utero to paroxetine. A significantly greater number of women were using paroxetine for anxiety or panic when compared with women using other SSRIs.

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    • "The risk of congenital malformations associated with maternal use of antidepressants, especially selective serotonin reuptake inhibitors (SSRIs) as a group, appears to be small and mostly non-significant212223, however, meta analyses have found an association between specific SSRIs and birth defects. An increased risk for some heart defects was observed with paroxetine use (Category D)[8,24,25]as well as fluoxetine[8](currently Category C), while the evidence for sertraline (Category C) is conflicting[8,22,23]. Overall, sertraline was the most commonly dispensed of these three antidepressants . Fluoxetine had the highest rates of use in women below 20 years, and paroxetine was used by 1 % or less of women in each year of age, despite the availability of antidepressants with less risk potential. "
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    ABSTRACT: Background This study aimed to examine current utilisation of prescribed medicines amongst Australian women of child-bearing age, with a particular focus on the extent of use of medicines in Category D and X risk groups, which are moderate and high risk teratogens, respectively. The use of those medicines may pose risk of birth defects in pregnant women. Methods A retrospective cross-sectional study was undertaken involving all women of child-bearing age (15 to 44 years) who were dispensed medicines in 2013 using the 10 % random sample of dispensing data from the Australian Government Department of Human Services. Dispensing patterns were reported by medicine, therapeutic class, pregnancy risk category and women’s age. Results Over one-third of women aged 15 to 44 years received at least one prescribed medicine in 2013. Psychoanaleptics, antibiotics and analgesics were the top three classes. Around 9 % of all dispensings were for medicines from risk category D, with statins, agents acting on renin-angiotensin system, and some anti-epileptic agents being the most commonly used. Both statins and agents acting on renin-angiotensin system showed increasing use with age, estimated to be 35,600 women nationally for each group. Collectively between 2 % and 4 % of women used anti-epileptics from risk category D in each year of age, with overall use estimated to be 51,000 women nationally. Below 1 % of all dispensings were for category X medicines, mainly isotretinoin. Conclusions It is important for medical practitioners to offer counselling around pregnancy planning and the risk of birth defects when prescribing moderate or high risk teratogens to women in child-bearing age. For the antihypertensives and some anti-epileptics, alternative medicines with lower risk categorization are available.
    Full-text · Article · Dec 2015 · BMC pharmacology & toxicology
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    • "However , certain standard mood stabilizers (e.g., divalproex sodium) have teratogenic effects in the first trimester (Cohen 2007). Likewise, questions have been raised about the safety of selective serotonin reuptake inhibitors in women with MDD (Bar-Oz et al. 2007). Thus, preventative psychosocial treatments are as relevant in the preconception phase as in pregnancy or the postpartum phases, especially among women with mood disorders who seek alternatives to pharmacotherapy. "
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    ABSTRACT: The perinatal period is a high-risk time for mood deterioration among women vulnerable to depression. This study examined feasibility, acceptability, and improvement associated with mindfulness-based cognitive therapy (MBCT) in perinatal women with major depressive disorder (MDD) or bipolar spectrum disorder (BSD). Following a diagnostic evaluation, 39 perinatal women with a lifetime history of MDD (n = 27) or BSD (n = 12) enrolled in an 8-week program of MBCT classes (2 h each) that incorporated meditation, yoga, and mood regulation strategies. Participants were pregnant (n = 12), planning pregnancy (n = 11), or up to 1-year postpartum (n = 16). Participants were self-referred and most had subthreshold mood symptoms. Assessments of depression, (hypo)mania, and anxiety were obtained by interview and self-report at baseline, post-treatment and at 1- and 6-month post-treatment. Women with a history of MDD were more likely to complete the classes than women with BSD. Of 32 women who completed the classes, 7 (21.9 %) had a major depressive episode during the 6-month post-treatment follow-up. On average, participants with MDD reported improvements in depression from pre- to post-treatment. Mood improvement was not observed in the BSD group. In the full sample, improvements in depression symptoms across time points were associated with increasing mindful tendency scores. This study was limited by its uncontrolled design, heterogeneous sample, and questionnaire-based assessment of mindfulness skills. MBCT may be an important component of care for perinatal women with histories of major depression. Its applicability to perinatal women with BSD is unclear.
    Full-text · Article · Oct 2015 · Cognitive Therapy and Research
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    • "In a meta-analysis of seven studies, firsttrimester paroxetine exposure was associated with a significant increase in the risk of cardiac malformations (OR ¼ 1.72; 95% CI ¼ 1.22, 2.42) [38]. Women using antidepressants in pregnancy had a 30% higher rate of ultrasound examinations and their infants underwent echocardiography about twice as often in the first year of life. "
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    ABSTRACT: Observational studies of drug effects are often regarded as inadequate in providing evidence of benefits but accepted as evidence of harms. Important harms that have been suggested by observational studies include teratogenicity of selective serotonin reuptake inhibitors, suicide associated with isotretinoin, and asthma associated with paracetamol. However, in all these cases the evidence is highly variable, and factors such as confounding by indication or selection bias have not been adequately taken into account. Systematic reviews of studies that are subject to confounding are themselves similarly affected. Other examples of drug-event pairs highlighted by observational studies include glucocorticoids and atrial fibrillation, antipsychotic drugs and raised hemoglobin A1C, adverse reactions to proton pump inhibitors plus clopidogrel, psychoactive drugs and memory loss, and adverse reactions to methylphenidate. We should not jump to the conclusion that causation is implied when an event has been attributed to a medication in an observational study, unless the odds ratio is very high or the study has been designed so as to eliminate or at least reduce the likelihood of such factors as confounding and selection bias; whenever possible, studies of adverse drug reactions should be so designed from the start. Furthermore, when adverse reactions are listed in information sources, such as Summaries of Product Characteristics, the level of evidence on which they are based should be stated. If the evidence falls short of proof of an association, it may be appropriate to issue a precautionary warning, making it clear that the association has not been proven.
    Full-text · Chapter · Dec 2014
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