Objective
The purpose of this study was to describe antidepressant medication use patterns during pregnancy and pregnancy outcomes.
Study Design
We evaluated a cohort of 228,876 singleton pregnancies that were covered by Tennessee Medicaid, 1995-2007.
results
Of 23,280 pregnant women with antidepressant prescriptions before pregnancy, 75% of them filled none in the second or third trimesters of pregnancy, and 10.7% of them used antidepressants throughout pregnancy. Filling 1, 2, and ≥3 antidepressant prescriptions during the second trimester was associated with shortened gestational age by 1.7 (95% confidence interval [CI], 1.2–2.3), 3.7 (95% CI, 2.8–4.6), and 4.9 (95% CI, 3.9–5.8) days, when controlled for measured confounders. Third-trimester selective serotonin reuptake inhibitor use was associated with infant convulsions; adjusted odds ratios were 1.4 (95% CI, 0.7–2.8); 2.8 (95% CI, 1.9–5.5); and 4.9 (95% CI, 2.6–9.5) for filling 1, 2, and ≥3 prescriptions, respectively.
Conclusion
Most women discontinue antidepressant medications before or during the first trimester of pregnancy. Second-trimester antidepressant use is associated with preterm birth, and third-trimester selective serotonin reuptake inhibitor use is associated with infant convulsions.
Depression is very common among pregnant women, with a prevalence of 10-20% in various survey studies. The prevalence of medication therapy for depression during pregnancy has been reported recently to be 4-10% in the United States and Canada. Antidepressant use has increased nationally, and the prevalence of antidepressant use during pregnancy has increased from the 1990s through 2007. To date, most studies have found that exposure to selective serotonin reuptake inhibitors (SSRIs) during pregnancy may be associated with preterm birth, lower birthweight, heart defects, and a neurologic withdrawal syndrome among infants who have been exposed to SSRIs in the third trimester; more extreme cases may include neonatal convulsions. Some notable studies have failed to confirm associations with gestational age and birthweight after adjustment for gestational age. Several larger studies failed to confirm the association between SSRIs and heart defects. Thus, more information from large, population-based studies is needed. The objective of this study was to estimate the independent effects of antidepressant medications on pregnancy outcomes by trimester after adjustment for available depression covariates. This study draws on the strengths of administrative Medicaid data, including the very large size of the population, the ability to describe patterns of antidepressant medication use, the ascertainment of some depression covariates before and during pregnancy, and the classification of antidepressant exposure by trimester.
Materials and Methods
Study population
We conducted a retrospective cohort study of 228,876 singleton pregnancies among women aged 15-44 years who were enrolled in the Tennessee Medicaid program from 1995 to 2007, with 180 days of continuous enrollment before their last menstrual period (LMP) through 90 days after delivery. All the data were anonymized, and the protocol was approved to be exempt by the institutional review boards of Vanderbilt University and the Tennessee Department of Health.
Data were obtained from the Medicaid database and birth certificates, which were developed for studying medication use and pregnancy outcomes among pregnant women who are enrolled in the Tennessee Medicaid. Birth certificates include the date of the maternal LMP, which was used to estimate the week of pregnancy for 85.3% of subjects. When LMP was not available on the birth certificate, LMP was set to median gestational age in weeks for infants of the same race, birthweight, and birth year (14.6%) or assigned a gestation period of 273 days (0.2%). Trimesters of pregnancy were defined as LMP at 91 days, 92-182 days, and 183 days through the date of delivery.
Women were classified as depressed if (1) an International Classification of Diseases , 9th Revision, diagnosis code of 296.2, 296.3, 300.4, or 311 was recorded in any diagnostic field on an inpatient or outpatient professional claim from 180 days before LMP to LMP or (2) they filled a prescription for at least 1 antidepressant medication from 180 days before LMP to the date of delivery. Filled prescriptions of antidepressant medications ( Supplementary Table 1 ) were counted for the 180 days before LMP, during each trimester of pregnancy, and for the 90 days after delivery. Prescriptions are typically for a 30-day supply of medication. Mothers who met the definition of depression were further classified as depressed before pregnancy (before LMP), during pregnancy (from LMP to date of delivery), or both.
Infant sex, birthweight, and gestational age and maternal age, education, race, adequacy of prenatal care, parity, and smoking status were abstracted from birth certificates; the remaining maternal and infant adverse outcomes and potential confounders were determined with the use of International Classification of Diseases , 9th Revision diagnostic codes ( Supplementary Table 2 ). Common and serious maternal comorbidities were defined as inpatient or outpatient claims for asthma, chronic cardiac disease, chronic obstructive pulmonary disease, malignancy, diabetes mellitus, immunodeficiency, renal disease, mental retardation, anxiety disorder, bipolar disorder, obsessive compulsive disorder, schizophrenia, and substance abuse during 180 days before LMP to LMP. Markers of depression severity were defined as depression diagnosis before LMP, prepregnancy use of antidepressants, and psychotropic polytherapy.
Statistical analysis
Descriptive statistics were presented as number (percentage) and in mean (±SD), as appropriate. Multivariable linear or logistic regression models were performed for continuous or categoric pregnancy outcomes. The main exposure of interest was number of filled antidepressant prescriptions during each trimester and throughout pregnancy. SSRI prescriptions or both SSRI and non-SSRI prescription filling were further analyzed separately. The continuous outcomes included birthweight and gestational age in days. The categoric outcomes included infant respiratory distress, preterm labor, early preterm labor, and neonatal convulsions in the first 14 days. To better understand the relationship between antidepressant medication filling and gestational age, we further applied a proportional odds model with categoric gestational age as outcome (<32, 32-36, and ≥37 weeks). In this model, the odds ratios for having a gestational age <32 weeks or <37 weeks in women with a specific medication history is calculated with respect to women without this history. This model makes the proportional odds assumption that we assume the odds ratios for early gestational age that are associated with any risk factor are the same for a gestational age <32 weeks as for a gestational age <37 weeks. The proportional odds assumption was assessed graphically and by logistic regression to ensure the proportional odds model was reasonable. Because previous preterm delivery is the single biggest risk factor for preterm birth, we further conducted subgroup analyses of gestational age and preterm labor that included only nulliparous women. All multivariable models were adjusted for gestational age (unless gestational age, preterm labor, or early preterm labor were the outcome), maternal age, smoking during pregnancy, maternal race, education, comorbidity, adequacy of prenatal care, maternal parity (unless limited to primiparous women), infant sex, year of delivery, depression diagnosis before LMP, anxiety disorder, substance abuse diagnosis, filling antidepressant prescriptions before LMP, psychiatric medication polytherapy, and co-existing psychiatric diagnosis (bipolar disorder, obsessive compulsive disorder, or schizophrenia). All statistical tests were 2-tailed; the probability values of all tested models are presented. R-software (version 2.9.2; www.r-project.org ) and SAS software (version 9.1; SAS Institute Inc, Cary, NC) were used for data analyses.
Results
There were 228,876 singleton pregnancies in women enrolled in the Tennessee Medicaid Program over the 13 study years, 1995-2007 ( Table 1 ). 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; Table 1 ).
| Maternal characteristics | Entire cohort (n = 228,876) | Not classified as depressed (n = 195,079) | Depressed pregnant women | ||
|---|---|---|---|---|---|
| No prescription (n = 16,901) | 1-2 prescriptions (n = 10,700) | ≥3 prescriptions (n = 6196) | |||
| Age, y a | 23.2 ± 5.2 | 22.9 ± 5.1 | 23.8 ± 5.3 | 24.6 ± 5.5 | 26.5 ± 5.9 |
| Race, n (%) | |||||
| White | 127,592 (55.7) | 100,340 (51.4) | 13,317 (78.8) | 8552 (79.9) | 5383 (86.9) |
| Black | 95,503 (41.7) | 89,816 (46.0) | 3164 (18.7) | 1903 (17.8) | 620 (10.0) |
| Other | 5781 (2.5) | 4923 (2.5) | 420 (2.5) | 245 (2.3) | 193 (3.1) |
| Residence: 228,395 women, n (%) | |||||
| Urban | 113,890 (49.9) | 101,755 (52.3) | 5996 (35.6) | 3911 (36.6) | 2228 (36.0) |
| Standard metropolitan statistical area (suburban) | 51,316 (22.5) | 41,633 (21.4) | 4835 (28.7) | 3020 (28.3) | 1828 (29.6) |
| Rural | 63,189 (27.7) | 51,283 (26.3) | 6032 (35.8) | 3745 (35.1) | 2129 (34.4) |
| Education: 228,350 women, n (%) | |||||
| <12 | 96,170 (42.1) | 82,577 (42.4) | 7258 (43.1) | 4206 (39.4) | 2129 (34.5) |
| 12 | 98,224 (43.0) | 83,896 (43.1) | 6997 (41.5) | 4676 (43.8) | 2655 (43.0) |
| >12 | 33,956 (14.9) | 28,174 (14.5) | 2597 (15.4) | 1792 (16.8) | 1393 (22.6) |
| Smoking in pregnancy: 228,490 women, n (%) | 64,248 (29.9) | 52,513 (27.0) | 7528 (44.6) | 5044 (47.2) | 3163 (51.1) |
| Parity: 228,365 women, n (%) | |||||
| Primiparous | 67,265 (29.5) | 58,116 (29.9) | 5067 (30.1) | 2711 (25.4) | 1371 (22.2) |
| 1 | 79,742 (34.9) | 68,162 (35.0) | 5765 (34.2) | 3661 (34.3) | 2154 (34.9) |
| 2 | 45,813 (20.1) | 38,328 (19.7) | 3551 (21.1) | 2463 (23.1) | 1471 (23.8) |
| ≥3 | 35,545 (15.6) | 30,051 (15.4) | 2471 (14.7) | 1843 (17.3) | 1180 (19.1) |
| Married: 228,775 women, n (%) | 74,805 (32.7) | 60,876 (31.2) | 6751 (40.0) | 4331 (40.5) | 2847 (46.0) |
| Any comorbidity, n (%) b | 21,232 (9.3) | 15,366 (7.9) | 2691 (15.9) | 1926 (18.0) | 1249 (20.2) |
| Diagnosed depression before pregnancy, n (%) | 13,593 (5.9) | 0 | 8397 (49.7) | 2901 (27.1) | 2295 (37.0) |
| Substance abuse, n (%) | 34,353 (15.0) | 23,592 (12.1) | 4934 (29.2) | 3516 (32.9) | 2311 (37.3) |
| Anxiety disorder, n (%) | 17,958 (7.8) | 7064 (3.6) | 4897 (29.0) | 3313 (31.0) | 2684 (43.3) |
| Bipolar disorder diagnosis, n (%) | 4897 (2.1) | 2937 (1.5) | 845 (5.0) | 602 (5.6) | 513 (8.3) |
| Schizophrenia diagnosis, n (%) | 638 (0.3) | 214 (0.1) | 162 (1.0) | 122 (1.1) | 140 (2.3) |
| Personality disorder, n (%) | 1369 (0.6) | 331 (0.2) | 414 (2.4) | 299 (2.8) | 325 (5.2) |
| Antipsychotic in pregnancy, n (%) | 2756 (1.2) | 603 (0.3) | 365 (2.2) | 855 (8.0) | 933 (15.1) |
| Anxiolytic in pregnancy, n (%) | 13,966 (6.1) | 7073 (3.6) | 2010 (11.9) | 2590 (24.2) | 2293 (37.0) |
| Sedative in pregnancy, n (%) | 3172 (1.4) | 1608 (0.8) | 422 (2.5) | 569 (5.3) | 573 (9.2) |
| Narcotic in pregnancy, n (%) | 65,504 (28.6) | 49,491 (25.4) | 7183 (42.5) | 5464 (51.1) | 3366 (54.3) |
| Using antidepressants 180 days before last menstrual period through last menstrual period, n (%) | 23,280 (10.2) | 0 | 12,724 (75.3) | 5859 (54.8) | 4697 (75.8) |
| Used antidepressants on the date of delivery through date of delivery + 90 days, n (%) | 17,773 (7.8) | 7340 (3.8) | 2782 (16.5) | 3389 (31.7) | 4262 (68.8) |
a Data are given as mean ± SD;
b Includes asthma, chronic cardiac disease, malignancy, diabetes mellitus, immunodeficiency, renal disease, mental retardation, and chronic obstructive pulmonary disease.
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 ( Figure 1 ). 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 prescription filling was positively and significantly associated with lower birthweight in the univariate analysis ( P < .001; Table 2 ). 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 ( Figure 2 , A).
| Pregnancy outcome | Entire cohort (n = 228,876) | Not classified as depressed (n = 195,079) | Depressed pregnant women | ||
|---|---|---|---|---|---|
| 0 prescriptions (n = 16,901) | 1-2 prescriptions (n = 10,700) | ≥3 prescriptions (n = 6196) | |||
| Birthweight: 228,813 babies, g a | 3163 ± 587.2 | 3165 ± 587.5 | 3159 ± 577.9 | 3136 ± 588.2 | 3139 ± 598.7 |
| Gestation age, d a | 270.7 ± 17.5 | 270.8 ± 17.7 | 270.5 ± 16.5 | 270.6 ± 16.3 | 269.7 ± 16.2 |
| <32 wk, n (%) | 5491 (2.4) | 4843 (2.5) | 340 (2.0) | 190 (1.8) | 118 (1.9) |
| 32 to <37 wk, n (%) | 25,481 (11.2) | 21,524 (11.1) | 1939 (11.5) | 1231 (11.5) | 787 (12.7) |
| ≥37 wk, n (%) | 197,519 (84.4) | 168,377 (86.5) | 14,595 (86.5) | 9271 (86.7) | 5276 (85.4) |
| Preterm labor: 224,362 women, n (%) | 59,606 (26.6) | 50,094 (26.2) | 4682 (28.1) | 3064 (29.1) | 1766 (29.0) |
| Early preterm labor: 224,362 women, n (%) | 2975 (1.3) | 2542 (1.3) | 209 (1.3) | 129 (1.2) | 95 (1.6) |
| Delivery method: 228,821 deliveries, n (%) | |||||
| Normal, spontaneous vaginal delivery | 160,171 (70.0) | 138,009 (70.8) | 11,211 (66.3) | 7027 (65.7) | 3924 (63.3) |
| Cesarean section delivery | 53,407 (23.3) | 43,951 (22.5) | 4490 (26.6) | 3065 (28.7) | 1901 (30.7) |
| Assisted | 15,243 (6.7) | 13,070 (6.7) | 1199 (7.1) | 603 (5.7) | 371 (5.9) |
| Respiratory distress n (%) | 9981 (4.4) | 8358 (4.3) | 774 (4.6) | 516 (4.8) | 333 (5.4) |
| Convulsions n (%) | 548 (0.2) | 429 (0.2) | 47 (0.3) | 31 (0.3) | 41 (0.7) |
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