No increase in the rate of congenital anomalies, increased risk for overall and cardiac malformations in the high-dose (>25 mg/d) group (Ad OR 3.07 (95% CI 1.00–9.42))
Prescription study, calculation of average daily dose affected by duration in the first trimester
SSRIs 2.4% of cases 2.1% of controls, (sertraline 0.8%, fluoxetine 0.7%, paroxetine 0.5% citalopram 0.2%)
Associations between any SSRI and craniosynostosis, paroxetine/sertraline and anencephaly, paroxetine and right ventricular outflow tract obstruction defects, omphalocele and gastroschisis—small absolute risks
Small numbers of exposed infants for individual anomalies, multiple comparisons, data on dosage unavailable, potential recall and selection biases
SSRIs: 2.7% of infants without malformations, 1.6–4.8% of infants with various malformations
Association between paroxetine and right ventricular outflow tract obstruction defects, clubfoot, undescended testes and NTDs, sertraline and omphalocele and septal defects—small absolute risks
Small number of exposed infants for individual anomalies, multiple comparisons, data on dosage unavailable, potential recall and selection biases
Increased Cr OR for cardiovascular anomalies after paroxetine 3.47 (95% CI 1.13–10.58) Ad OR 2.66 (95% CI 0.80–8.90), Cr OR 4.81 (95% CI 1.56–14.71) Ad OR 4.47 (95% CI 1.31–15.27) after fluoxetine
After adjustment for potential confounders OR significant only for fluoxetine and cigarette smoking of 10 or more/day, septal defects considered major anomalies even when spontaneously closed, large confidence intervals
Increased risk of cardiovascular (CV) defects after combined exposure to SRI and BZ, increased risk for an ASD after SRI monotherapy, major anomalies after fluoxetine and BZ
Clinical significance of the anomaly not verified, many septal defects minor and spontaneously resolve, attempt to control for confounders
Increased prevalence of septal defects with sertraline (OR 3.25 (95% CI 1.21–8.75)) and citalopram (OR 2.52 (95% CI 1.04–6.10))
Prescription study, potential selection bias, underlying condition potential confounder, information on malformation from hospital registry (more sensitive to severe and visible malformations)
3/808 (0.4%) had congenital heart disease after exposure to SSRIs compared with 2.05/24,406 (0.8%) without exposure to SSRIs ()
No review of SSRI exposure timing, of demographic or clinical information including use of other drugs, smoking, or alcohol use, data from physician prescription records. Small VSDs may be undetected soon after birth.
Non syndromic heart defects (mild) identified by echocardiography among infants with murmur on 2nd-3rd day of life RR 2.17 (95% CI 1.07–4.39)
Small sample size of exposed group, lack of data on potential confounders, ascertainment of SSRI use based on maternal report, no detection bias; all newborns with murmur examined by a pediatric cardiologist including echocardiography.
SSRI use associated with increased risk of overall malformations (Ad OR 1.3 (95% CI 1.1–1.6)) and cardiac (Ad OR 1.7 (95% CI 1.1–2.5)), for specific SSRIs increased risk for septal defects with sertraline (Ad OR 3.3 (95% CI 1.5–7.5))
Prescription study, potential selection bias, underlying condition potential confounder, information on malformation from hospital registry (more sensitive to severe and visible malformations)
Population-based case- control study, the Netherlands
with heart defects 615 controls
Paroxetine
No significantly increased risk for heart defects overall (AOR 1.5 (95% CI 0.5–4.0)) increased risk for ASD with paroxetine in T1 (AOR 5.7 (95% CI 1.4–23.7))
Small number of exposed infants for individual anomalies
Increased risk for cystic kidney () with SSRIs (OR 2.39 (95% CI 1.09–4.54)), for relatively severe malformation (OR 1.29 (95% CI 1.00–1.67)) with fluoxetine, for any cardiovascular defect (OR 1.66 (95% CI 1.09–2.53) 12/24 septal defects) and for hypospadias () (OR 2.45 (1.12–4.64)) with paroxetine
Prospective exposure information, largest dataset available. Incomplete drug reporting, potential detection bias, multiple comparisons, possible confounding by the underlying psychiatric condition, smoking, obesity, alcohol, folic acid, association with preexisting diabetes and hypertension
Increased risk for isolated VSDs with fluoxetine () (Adj OR 2.03 (95% CI 1.28–3.21)) (0.5% absolute risk increase), for right ventricular outflow tract defects with paroxetine () (Adj OR 4.68 (95% CI 1.48–14.74)) (0.2% absolute risk increase), for NTDs with citalopram () (Adj OR 2.46 (95% CI 1.20–5.07))
Large dataset, attempt to control for confounders (i.e., maternal age, parity, year of pregnancy, marital status, smoking, purchase of other psychiatric drugs, maternal prepregnancy diabetes). Large number of comparisons, some associations based on small numbers, drug compliance and timing of exposure in pregnancy not confirmed, septal defects considered major anomalies even when spontaneously closed
aFrom the same database of the Swedish Medical Birth Register, b from the same database of the Finnish registries, c from the same database of the Danish registries.