There were 228,876 singleton pregnancies in women enrolled in the Tennessee Medicaid Program over the 13 study years, 1995–2007 (). Among the pregnancies that were studied, 13,593 women (5.9%) had a diagnosis of depression before pregnancy; 23,280 women (10.2%) filled at least 1 prescription of antidepressant medication before pregnancy, and 6340 women (2.8%) initiated antidepressant therapy during pregnancy, although they filled on average only 2 antidepressant prescriptions during pregnancy. Compared with women who were not depressed and never filled antidepressant prescriptions, women who were classified as depressed were older, more educated, and more likely to be white, suburban, or rural, to be married, to have a comorbid illness, and to have more children at home (P < .001; ).
Maternal characteristics by depression and antidepressant exposure status during pregnancy
Antidepressant medication use was inconsistent; only 8004 of 23,280 women (34%) who filled a prescription before LMP filled a prescription ≥4 times before and during pregnancy. Seventy-five percent of women who filled antidepressant prescriptions before pregnancy discontinued use before or during the first trimester. Only 2161 women (0.9%) consistently filled prescriptions before and throughout pregnancy (). Of the 13,593 women with diagnosed depression in the 180 days before LMP, 4874 (35%) did not fill any antidepressant prescriptions 180 days before LMP. Among all antidepressant users, women were 2.7 times more likely to fill prescriptions for SSRIs (n = 12,386) than for non-SSRIs (n = 4510).
Antidepressant medication prescription pattern before and during pregnancy
Antidepressant prescription filling was positively and significantly associated with lower birthweight in the univariate analysis (P < .001; ). However, this significant relationship between antidepressant use and birthweight disappeared after we controlled for confounders that included gestational age, maternal race, age, education, smoking during pregnancy, comorbidity, parity, previous depression diagnosis, anxiety disorder, bipolar disorder, obsessive compulsive disorder, schizophrenia, substance abuse, prepregnancy use of antidepressants, psychotropic polytherapy, infant sex, and birth year ().
Adverse pregnancy outcomes by maternal depression and antidepressant exposure status
Maternal antidepressant medication and pregnancy outcomes
In multivariable models, filling more antidepressant prescriptions by women in the second trimester was associated with progressively shorter gestational age after we controlled for confounders (P < .001; ). This strong, significant, relationship between duration of exposure to second trimester antidepressant prescription and shorter gestational age was also observed when odds ratios for gestational age <32 weeks and <37 weeks were considered (). The relationship between antidepressant use and early preterm labor and results were consistent (). Because previous preterm delivery is a strong risk factor for preterm birth, we conducted a subanalysis of gestational age and preterm labor in 68,007 nulliparous women. The significant relationship between second trimester antidepressant prescription filling and shorter gestational age persisted; filling 1, 2, and ≥3 antidepressant prescriptions during the second trimester was associated with gestational age that was shorter by 2.6 (95% confidence interval [CI], 1.3–3.9), 5.8 (95% CI, 3.9 –7.8), and 6.6 (95% CI, 4.6–8.6) days, respectively. Both SSRI and non-SSRI prescriptions in the second trimester were similarly and independently associated with shorter gestational age (P < .0001 for both SSRIs and non-SSRIs).
Conversely, filling antidepressant prescriptions in the third trimester was associated positively with longer gestational age after we controlled for confounders; gestational age was 0.9 (95% CI, 0.3–1.6), 1.8 (95% CI, 0.9–2.7), and 6.4 (95% CI, 5.5–7.3) days longer, respectively, when women filled 1, 2, or ≥3 antidepressant prescriptions during the third trimester (). Similar trends were observed between third-trimester antidepressant use and longer gestational age in proportional odds regression analysis () and between third trimester antidepressant use and early preterm labor ().
There were also significant associations between any antidepressant use and infant respiratory distress parallel to the association with preterm labor (). Respiratory distress was 1.1 (95% CI, 0.9 –1.3), 1.4 (95% CI, 1.1–1.8), and 1.6 (95% CI, 1.2–2.0) times more common among infants who were born to women who filled 1, 2, and ≥3 prescriptions during the second trimester and 0.9 (95% CI, 0.7–1.1), 0.8 (95% CI, 0.6 –1.0), and 0.6 (95% CI, 0.5– 0.8) times as common among antidepressant users in the third trimester.
The relationships between gestational age and several potential important confounders were also estimated in the multivariable regression model. After we controlled for maternal race, age, education, smoking during pregnancy, parity, substance abuse, anxiety disorder, infant sex, and birth year, diagnosed maternal depression increased gestation by 0.8 days (95% CI, 0.5–1.1; P < .001). Previous antidepressant use (P = .87), maternal anxiety (P = .91), and psychiatric polytherapy (P = .57) had no independent effect on gestational age. Maternal substance abuse decreased gestation by 1.4 days (95% CI, 1.2–1.6; P < .001) and maternal comorbid psychiatric diagnosis (bipolar disorder, obsessive compulsive disorder, or schizophrenia) decreased gestation by 4.3 days (95% CI; 3.8–4.7; P < .001). Ever antidepressant use, cumulative pregnancy count of antidepressant prescriptions, and first-trimester use of antidepressants were also not associated with preterm delivery.
SSRI use, but not non-SSRI use in the third trimester, was associated positively with convulsions in the infant, with a strong relationship between risk of convulsions and duration of SSRI use (); the model presented included terms for SSRI and non-SSRI medication use by a count of prescriptions filled and trimester. The odds ratios for filling 1, 2, and ≥3 SSRI prescriptions in the third trimester were 1.4 (95% CI, 0.7–2.8), 2.8 (95% CI, 1.4 –5.5), and 4.9 (95% CI, 2.6 –9.5), respectively.
Maternal selective- and non-SSRI medication and infant convulsion