Overall, 300 women (10.7%) used a psychotropic medication during pregnancy. describes medications used. Of the women who were taking psychotropic medications, 235 (78%) took only one medication, 51 (17%) used two medications, and 14 (5%) used three or more medications. The characteristics of the study population and the incidence of adverse outcomes by categories of psychotropic medications used during pregnancy are depicted in . Women who used any medication differed from those who did not use medications in years of education, pre-pregnancy BMI, and rate of multiple pregnancy. Women who used SSRIs, selective norepinephrine receptor inhibitors (SNRI), or BZD were more likely to be multiparous than their counterparts who did not use psychotropic medications during pregnancy.
Distribution of psychotropic medications used by the Omega cohort members.
Characteristics of the study population according to psychotropic medications used during pregnancy.
Medications and Preterm Delivery
Among women who used any psychotropic medication, 23.3% (n=70) had a preterm delivery, compared with 9.4% of women who did not use psychotropic medications (). Compared with non-users, women who used any psychotropic medication during pregnancy had an increased risk of preterm delivery (unadjusted OR=2.94; 95% CI: 2.18–3.96). Adjustments for maternal age, race, marital status, education, smoking, parity, preeclampsia and singleton pregnancy, resulted in an attenuation of the association (adjusted OR=2.08; 95% CI: 1.46–2.96), though the association remained statistically significant. As shown in , there was evidence of an increasing trend of preterm delivery risk with the number of medications taken during pregnancy.
The Odds Ratio (ORs) and 95% Confidence Intervals (CI) for preterm delivery by type of treatment according to the logistic regression models.
Maternal use of any SSRI or SNRI was associated with a small non-significant increased risk of preterm delivery (adjusted OR=1.34, 95% CI: 0.76–2.36). There was a suggestion for differential risk of preterm delivery when specific medications within this class of therapeutic agents were evaluated. For example, maternal use of the SSRI, Paroxetine was associated with an adjusted OR of 2.30 for preterm delivery, though the association did not reach statistical significance (95% CI: 0.90–5.83; p=0.081). Maternal use of Venlafaxine, an SNRI, was associated with an adjusted OR of 3.78, though again this association did not reach statistical significance (95% CI: 0.81–17.6; p=0.091).
Information regarding the time of initiation of medication use was available for 121 (91.7%) of women who were taking SSRIs. Most (83%) mothers who have used SSRIs started treatment either before pregnancy or during the first trimester (i.e., before completion of 14 weeks) of pregnancy. Mothers who initiated use of SSRIs in second or third trimester tended to report use of multiple drugs compared with mothers who initiated medication use in early pregnancy, with additional medications in 47.6% vs. 18.8% of women who were taking SSRIs, respectively. An increased risk of preterm delivery was found only among mothers who began taking SSRIs in the second or third trimester with an adjusted OR of 4.79 (1.66–13.9; p=0.004), whereas no association was found among mothers who started using SSRIs before or during the first trimester (OR=0.88, 95% CI: 0.42–1.85; p=0.739) ().
Maternal use of BZD during pregnancy was associated with an adjusted OR of 6.79 for preterm delivery (95% CI=4.01–11.5; p<0.001). Among women who took BZD, those who used one medication had an adjusted OR of 5.56 for preterm delivery (95% CI: 2.71–11.4); those who used multiple BZD formulations or use used BZD in combination with another psychotropic medication had an OR of 8.48 for preterm delivery (95% CI: 4.03–17.8; p for trend<0.001). Lorazepam, the most frequently used BZD in the cohort, was associated with an OR of 7.94 for preterm delivery (95% CI: 4.47–14.1; p<0.001). Information regarding the onset of BZD use was available for 93% (n=80) of patients who used BZD. Of those, 11 started treatment either before pregnancy (n=4) or during first trimester (n=7), 19 had started treatment during the second trimester, and 50 had started treatment during the third trimester. Initiations of treatment before or during the first trimester, in second, or in third trimester of pregnancy were associated with adjusted ORs of 5.15 (95% CI: 1.34–19.8; p=0.017), 7.39 (95% CI: 2.35–23.2; p=0.001), and 10.1 (95% CI: 4.84–21.1; p<0.001), respectively.
We next sought to assess whether there was a differential association between maternal use of BZD and preterm delivery by the documented obstetric precursors of preterm delivery. Maternal use of BZD was associated with an adjusted OR of 5.40 for medically induced preterm delivery (95% CI: 2.18–13.3), and with an OR of 7.32 (95% CI: 4.11–13.0; p<0.001) for non-medically induced preterm delivery (either preterm premature rupture of the membranes (PPROM), or spontaneous preterm labor (SPTL) with intact membranes) (data not shown).
We further conducted a sensitivity analysis of the multivariate association between BZD and preterm delivery by the time interval from onset of BZD use to delivery (). With the exclusion of women who started treatment within a week, two weeks, and three weeks before delivery, the association weakened, however, it remained highly significant when only women who started treatment more than four weeks before delivery were included (OR=3.57, 95% CI: 1.71–7.47; p=0.001).
Figure 1 Sensitivity analysis of the association between benzodiazepines (BZD) and preterm delivery (PTD), according to the interval between initiation of BZD treatment and delivery (weeks). Odds ratios (AOR) and 95% confidence intervals (95% CIs) are adjusted (more ...)
Overall, hydroxyzine use during pregnancy appeared to be associated with an increased risk of preterm delivery (adjusted OR=2.45, 95% CI: 1.44–4.15; p=0.001). However, further analyses revealed that women who used hydroxyzine alone (n=76) had no substantially increased risk for preterm delivery (adjusted OR=1.19; 95% CI: 0.57–2.50) ().
LBW, SGA, low Apgar score, NICU admissions, and RDS
Maternal use of any psychotropic medication during pregnancy was associated with an increased risk of delivering LBW newborns (OR=2.12, 95%CI 1.37–3.27; p=0.001). Maternal use of any psychotropic medication was associated with low 5-minute Apgar scores (OR=2.46, 95% CI: 1.26–4.78), increased risk of admission to NICU, and increased risk of RDS (). Medication use was not associated with delivery of small for gestational age newborns (OR=1.36, 0.72–2.57). Associations of each perinatal outcomes with specific classes of psychotropic medications are shown in the bottom panels of .
Table 4 The association between treatment with psychoactive medications and adverse outcomes of birth associated with prematurity in a multivariate logistic regressions model after adjusted for age, race, marital status, education, smoking during pregnancy, preeclampsia, (more ...)
Overall, SSRIs were not associated with LBW, SGA, or low Apgar score (), neither were they associated with NICU admissions (OR=1.36, 95% CI: 0.70–2.67; p=0.369) or RDS (95% CI: 1.39, 0.56–3.44; p=0.480). However, an association for SSRIs with LBW was shown among women who started treatment with SSRIs in second or third trimester (OR=5.01, 95% CI: 1.37–18.4; p=0.015). No association was found with timing of treatment and SGA, low Apgar score, NICU admissions or RDS (data not shown). The SNRI, Venlafaxine, was associated with low 5-minute Apgar score (OR=11.6, 95% CI: 1.85–72.6; p=0.009), and there was a suggested association with NICU admissions (3.68, 0.76–17.8; p=0.104), and with RDS (5.23, 0.91–30.2; p=0.064). BZD were associated with increased risk of low birth weight (adjusted OR=7.43, 95% CI: 4.15–13.3; p<0.001), but not with SGA. BZD were associated with low 5-minutes Apgar score (OR=3.87, 95% CI: 1.53–9.76; p=0.004), with admission to NICU, (OR=4.33, 95% CI: 2.45–7.63; p<0.001), and with a diagnosis of RDS (OR=3.74, 95% CI: 1.86–7.54; p<0.001). There were too few subjects taking hydroxizine as a single treatment to complete similar analyses.