Preterm Birth and Antidepressant Medication Use during Pregnancy: A Systematic Review and Meta-Analysis

Introduction: Preterm birth is a major contributor to neonatal morbidity and mortality and its rate has been increasing over the past two decades. Antidepressant medication use during pregnancy has also been rising, with rates up to 7.5% in the US. The objective was to systematically review the literature to determine the strength of the available evidence relating to a possible association between antidepressant use during pregnancy and preterm birth. Methods: We conducted a computerized search in PUBMED, MEDLINE and PsycINFO through September 2012, supplemented with a manual search of reference lists, to identify original published research on preterm birth rates in women taking antidepressants during pregnancy. Data were independently extracted by two reviewers, and absolute and relative risks abstracted or calculated. Our a priori design was to group studies by level of confounding adjustment and by timing of antidepressant use during pregnancy; we used random-effects models to calculate summary measures of effect. Results: Forty-one studies met inclusion criteria. Pooled adjusted odds ratios (95% CI) were 1.53 (1.40–1.66) for antidepressant use at any time and 1.96 (1.62–2.38) for 3rd trimester use. Controlling for a diagnosis of depression did not eliminate the effect. There was no increased risk [1.16 (0.92–1.45)] in studies that identified patients based on 1st trimester exposure. Sensitivity analyses demonstrated unmeasured confounding would have to be strong to account for the observed association. Discussion Published evidence is consistent with an increased risk of preterm birth in women taking antidepressants during the 2nd and 3rd trimesters, although the possibility of residual confounding cannot be completely ruled out

Sensitivity analysis of residual confounding (Rule-out approach).

<p>Example for estimated OR = 1.61 (depression adjusted point estimate) and OR = 1.26 (lower 95% bound of depression adjusted estimate) for different levels of confounder prevalence (▪ P_c = 0.05, OR = 1.61; •P_c = 0.25, OR = 1.61; □ P_c = 0.05, OR = 1.26; ○P_c = 0.25, OR = 1.26). Each line splits the area into two. The upper right area represents all combinations of OR_EC and RR_CD that would create confounding by an unmeasured factor strong enough to move the point estimate of OR to the null (OR = 1) or beyond. The area to the lower left represents all parameter combinations that would not be able to move the estimated OR to the null.</p

Funnel plot with pseudo 95% confidence limits.

<p>Funnel plot with pseudo 95% confidence limits.</p

Effect of antidepressant medication use during pregnancy on preterm birth: meta-analysis results.

(1)<p>Typically 1st trimester; some women continued during pregnancy, others discontinued.</p>(2)<p>Typically 3^rd trimester.</p>(3)<p>Factors varied between studies, but typically included maternal age, smoking, alcohol use, parity, and history of prematurity or miscarriage.</p>(4)<p>Values of I² are percentages (% of variance explained). 95% uncertainty intervals are calculated as proposed by Higgins and Thompson <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0092778#pone.0092778-Higgins1" target="_blank">[89]</a>.</p

Study-specific and pooled odds ratio estimates for antidepressant medication during pregnancy and preterm birth.

<p>Studies that did not adjust for other risk factors.</p

Characteristics of 41 studies evaluating the association between antidepressant medication use during pregnancy and preterm birth.

<p>Abbreviations: Prosp = Prospective cohort; Retro = Retrospective cohort; depr = depression; AD = antidepressant; SRI = serotonin reuptake inhibitor; TCA = tricyclic antidepressant; NaSSA = Noradrenergic and specific serotonergic antidepressants; SNRI = Serotonin–norepinephrine reuptake inhibitors; NRI = noradrenaline reuptake inhibitors; T = trimester; exp = exposed; TIS = Teratogen Information Service.</p

Adjusted study-specific and pooled odds ratio estimates for antidepressant medication during pregnancy and preterm birth.

<p>Subset of studies that account for the underlying psychiatric illness.</p

Study selection flowchart.

<p>Study selection flowchart.</p