Abstract
Background:
Little is known about antidepressant medication use patterns during pregnancy among periconception (before and immediately following conception) users. Additionally, the associations between these patterns and birth outcomes is unclear, after taking into account underlying depression severity.
Objective:
This study describes patterns of antidepressant use among periconception users and examines associations between usage patterns and birth outcomes.
Study Design:
This retrospective cohort study included pregnant Kaiser Permanente Northern California (KPNC) members with a live birth between 2014–2017 and an antidepressant medication fill that overlapped the 8th week of pregnancy. Outcomes were preterm birth and neonatal intensive care unit (NICU) admission. Data were extracted from KPNC’s electronic health records. Modified Poisson regression was conducted.
Results:
Of the 3,637 pregnancies meeting inclusion criteria, 33% (n=1204) continued antidepressant use throughout the pregnancy (refilled throughout pregnancy), 47% (n=1721) discontinued use (no refills), and 20% (n=712) stopped and reinitiated use (refill after 30+ day gap in supply). Women who continued use had 1.86 (95% confidence interval (CI) 1.53, 2.27) times the risk of preterm birth and 1.76 (95% CI: 1.42, 2.19) times the risk of NICU admission, compared to women who discontinued use during pregnancy. Similarly, women with continued use had 1.66 (95% CI: 1.27, 2.18) times the risk of preterm birth and 1.85 (95% CI: 1.39, 2.46) times the risk of NICU admission, compared to women who stopped and reinitiated use. This relationship held when examining continuous exposure; the relationship between continuous exposure and preterm delivery was stronger in later trimesters.
Conclusions:
Periconception antidepressant users who continue use during pregnancy, particularly into the second and third trimesters, may be at higher risk of adverse birth outcomes. This evidence should be considered alongside the risks associated with depression relapse.
Keywords: perinatal depression, antidepressant medication, pregnancy, anxiety, mood disorders
Introduction
Prenatal depression and anxiety are prevalent mental health disorders affecting up to 20% of pregnant individuals. [1–3] Prenatal depression and anxiety can affect diet, sleep, and other behaviors that are key to maintaining personal health and wellness during pregnancy.[4] Further, they are associated with negative outcomes for both mother and child, including preterm birth, low birth weight, decreased breastfeeding initiation, lower maternal-infant bonding, and cognitive and emotional delays in children.[5–7] Treatment of depression and anxiety during pregnancy with psychotherapy or medication as appropriate is currently recommended by several professional organizations,[8–11] and many women choose medication as treatment for these conditions during pregnancy.
Between 2011 and 2014, 9.8% of women in the United States between the ages of 20 to 39 years were taking antidepressant medications.[12–14] For women who discontinue antidepressants during pregnancy, depression and anxiety relapse rates are high, and left untreated they are associated with increases in the risk of adverse events such as poor antenatal care attendance, poor nutrition, and even suicide.[15–19] During pregnancy, however, there is concern that medication use may adversely impact fetal development and birth outcomes. Some antidepressant medications have been shown to be associated with preterm birth.[20–24] Studies have also shown associations between some antidepressant medications and neonatal intensive care unit (NICU) admission, birth defects, small for gestational age birthweight, or childhood developmental delays.[7,20,25–29] Particularly for women with depression that is effectively being treated by antidepressants at the start of pregnancy, they face a challenging decision upon becoming pregnant of whether to continue antidepressant use during the sensitive period of gestation.
For those who continue antidepressant use during pregnancy, some studies have found adverse outcomes to be dependent on dose and/or duration of exposure—though there is considerable heterogeneity on how exposure is measured and classified across studies.[30–33] Timing of antidepressant use may also be important. A previous study reported antidepressant use in late pregnancy, but not early pregnancy, was associated with preterm birth, [21] but many studies fail to consider timing within the pregnancy period. Examining antidepressant use patterns allows for consideration of timing and duration of antidepressant use across pregnancy; however, previous studies using this approach rarely include information on depression severity—a key factor in the decision of whether to continue medication use during pregnancy.[33]
To address these gaps, this study utilizes a large retrospective cohort of pregnant individuals who were taking antidepressants at the beginning of pregnancy to: (i) examine patterns of antidepressant use across pregnancy; and (ii) examine the associations of antidepressant use patterns with birth outcomes, adjusting for demographic characteristics and depression severity. This study focused on two important pregnancy outcomes, preterm birth and NICU admission, associated with potential severe parental psychological distress such as post-traumatic stress disorder (PTSD), adverse long-term child developmental outcomes, as well as extreme health care costs.[34–36]
Materials and Methods
Setting
This study was conducted in Kaiser Permanente Northern California (KPNC), a large integrated health care delivery system providing medical care to over 4.5 million members. All 15 regional service centers (with 48 associated office facilities) have Obstetrics and Gynecology and Behavioral Medicine/Psychiatry Departments. KPNC members are covered by employee-sponsored insurance plans, the insurance exchange, Medicare, and Medicaid. Coverage is provided for approximately 30% of the northern California population and characteristics of members are similar to those of the population living in the northern California geographic area. Information on diagnoses, hospitalizations, outpatient visits, and prescribed medications are maintained within administrative and electronic health records (EHR).
Study Design and Population
We conducted a secondary analysis using data from a retrospective cohort study of live births at a KPNC facility between September 2014 and September 2017. We included deliveries in individuals who were at least 15 years of age, who were continuously enrolled in the Kaiser Permanente Health Plan throughout pregnancy, and had an antidepressant prescription fill that overlapped with the 8th gestational week. The study programmer/analyst extracted all data from KPNC’s EHR (collected during routine clinical care).
This study was approved by the KPNC Institutional Review Board. The requirement of informed consent was waived.
Measures
Outcomes
We examined preterm birth and NICU admission as our outcomes. Preterm birth was defined as birth that occurred before 37 weeks of gestation.[37] NICU admission was defined as infant admission to the NICU during the delivery hospitalization, and was identified in the EHR through linkage of parental and infant medical record numbers.
Exposure: Antidepressant use
Exposures were examined from 8 weeks of gestation until 37 weeks of gestation for preterm birth and until delivery for NICU admission. For each outcome, antidepressant (see Appendix for a list of antidepressants) dispensing data was extracted from the EHR and used to define three patterns of exposure: i) continued use, ii) discontinued use, and iii) stopped and reinitiated. Continued use was defined as a pattern of continuous antidepressant fills without any gaps in medication supply greater than 30 days across the exposure period. Discontinued use was defined as a pattern of antidepressant fills with a medication supply gap greater than 30 days with no subsequent antidepressant fills for the rest of the exposure period. Stopped and reinitiated use was defined as a pattern of antidepressant fills with a medication supply gap greater than 30 days with one or more subsequent antidepressant fills after the medication supply gap during the exposure period.
Covariates
Covariates included maternal age, self-reported race and ethnicity, Medicaid insurance during pregnancy, nulliparity, alcohol use during pregnancy, tobacco use during pregnancy, other drug use during pregnancy, and maximum Patient Health Questionnaire (PHQ-9) depression screener score during pregnancy. Self-report alcohol, tobacco, and other drug use during pregnancy were captured as part of universal prenatal substance use screening upon entry into prenatal care.
Statistical Analysis
We graphed the proportion of pregnant individuals with antidepressant medication use for each gestational week by antidepressant medication pattern separately for patterns until 37 weeks (used for preterm birth analyses) and patterns until delivery (used for NICU analyses). We used modified Poisson regression models[38] to estimate relative risks and 95% confidence intervals (95% CI) for continuous use (with each of the other two antidepressant use patterns as the reference category) with birth outcomes (preterm birth and NICU admission). In all models, we adjusted for maternal age (in years), race and ethnicity (non-Hispanic white, Hispanic, Asian, non-Hispanic Black, other), education (high school graduate or less, some college, college graduate or more), Medicaid insurance during pregnancy (yes/no), nulliparity (yes/no), alcohol use during pregnancy (yes/no), tobacco use during pregnancy (yes/no), other drug use during pregnancy (yes/no), and maximum PHQ-9 depression screener score during pregnancy. To address the possibility that associations of antidepressant use patterns with birth outcomes may be different for those with varying depression severity (effect modification by PHQ-9 score), we considered a model additionally adjusting for the interaction between exposure category and PHQ-9 score (significance defined as α=0.10 for the interaction term). In all other analyses, a significance level of α=0.05 was used. All regression parameters were estimated using generalized estimating equations to account for potential correlation within individuals since some individuals (n=137) had two pregnancies during the study period.
For pregnancies with missing data for maternal education (18%), nulliparity (6%), and PHQ-9 score (27%), we used multiple imputation using the Markov Chain Monte Carlo method [39–41] under the assumption of multivariate normality with 100 imputations to impute education category, nulliparity, and maximum PHQ-9 score, allowing these observations to remain in our analyses (rather than being excluded and introducing potential bias). The imputation model included covariates from all models, all outcomes, and additional variables related to missing variables [most recent PHQ-9 score prior to birth (continuous), parity (continuous)]. Regression models were run using each of the 100 imputed datasets and results were combined using Rubin’s rules[39].
Sensitivity analyses
To address important aspects of antidepressant use not captured by antidepressant use patterns, we conducted several sensitivity analyses. To examine the association between the duration of prenatal antidepressant medication use and birth outcomes, we calculated the medication possession ratio. The medication possession ratio was defined as the days supply of the medication dispensed over the total number of gestational days elapsed during the entire pregnancy and during each trimester (days supplied/days elapsed). We used modified Poisson regression models with the same covariates as described above to estimate associations of medication possession ratio (across pregnancy and for each trimester) with birth outcomes. To explore potential differences in medication patterns by drug class, we examined antidepressant use patterns by the drug classes outlined by the United States Food and Drug Administration and used as part of the American College of Obstetrics and Gynecologists (ACOG) Guidelines for Psychiatric Medication Use During Pregnancy and Lactation[42]. Classes included the following categories: class B, no evidence of risk in humans; class C, risk cannot be ruled out; and class D, positive evidence of risk. To account for non-medication treatment of depression and anxiety during pregnancy, we additionally adjusted models for psychotherapy during pregnancy.
All analyses were conducted in SAS 9.4, and graphs were creating using the ggplot2 package in R version 4.0.3.[43]
Results
Of the 3,637 pregnancies in our study (among 3,500 women), 33% (n=1204) continued antidepressant use throughout the pregnancy, 47% discontinued use (n=1721), and 20% (n=712) stopped and reinitiated use later in pregnancy (Table 1). Women who continued antidepressant use were more likely to be non-Hispanic white, attend college, and not have Medicaid insurance. There were no large differences between PHQ-9 score during pregnancy among the exposure categories, though a slightly greater proportion of individuals who stopped and reinitiated antidepressant medication had at least moderate severity PHQ-9 scores compared with those who continued antidepressant medication. Antidepressant discontinuation was most common in the late first or early second trimester (Figure 1). Those who stopped and reinitiated use generally reinitiated in the late second or early third trimester (Figure 1). Among the continued use group, 16% (n=193) resulted in a preterm birth and 15% (n=178) in a NICU admission. For both the discontinued use and stopped and reinitiated use groups, preterm birth or NICU admission rates were between 8–9% (Table 1).
Table 1.
Characteristics of 3,637 pregnancies (among 3,500 individuals) with antidepressant use during pregnancy overall and by antidepressant use pattern
| Total (N=3,637) | Continued Use (N=1,204) | Discontinued Use (N=1,721) | Stopped and Reinitiated (N=712) | |
|---|---|---|---|---|
| Sociodemographic characteristics | ||||
| Maternal age (years), mean (SD) | 32 (5) | 32 (5) | 31 (6) | 32 (5) |
| Maternal race/ethnicity, n (%) | ||||
| Asian | 232 (6) | 65 (5) | 132 (8) | 35 (5) |
| Non-Hispanic Black | 154 (4) | 30 (2) | 99 (6) | 25 (4) |
| Hispanic | 691 (19) | 162 (13) | 408 (24) | 121 (17) |
| Non-Hispanic white | 2418 (66) | 912 (76) | 1005 (58) | 501 (70) |
| Other | 142 (4) | 35 (3) | 77 (4) | 30 (4) |
| Maternal education, n (%) | ||||
| High school graduate or less | 330 (11) | 78 (8) | 190 (14) | 62 (11) |
| Some college | 1050 (35) | 290 (29) | 564 (41) | 196 (34) |
| College graduate or more | 1591 (54) | 644 (64) | 634 (46) | 313 (55) |
| Missing | 666 | 192 | 333 | 141 |
| Medicaid insurance during pregnancy, n (%) | 336 (9) | 78 (6) | 185 (11) | 73 (10) |
| Pregnancy characteristics | ||||
| Prenatal care initiation (weeks), mean (SD) | 7.0 (2.3) | 6.9 (2.1) | 7.1 (2.4) | 6.9 (2.4) |
| Nulliparous, n (%) | 1309 (38) | 484 (43) | 590 (37) | 235 (35) |
| Missing | 220 | 70 | 109 | 41 |
| Alcohol use during pregnancy, n (%) | 363 (10) | 110 (9) | 178 (10) | 75 (11) |
| Tobacco use during pregnancy, n (%) | 187 (5) | 49 (4) | 94 (5) | 44 (6) |
| Other drug use during pregnancy, n (%) | 109 (3) | 38 (3) | 52 (3) | 19 (3) |
| Psychotherapy during pregnancy, n (%) | 872 (24) | 295 (25) | 374 (22) | 203 (29) |
| Maximum PHQ-9 score during pregnancy category, n (%) | ||||
| None (0–4) | 1053 (40) | 388 (43) | 482 (40) | 183 (34) |
| Mild (5–9) | 797 (30) | 271 (30) | 364 (30) | 162 (30) |
| Moderate (10–14) | 401 (15) | 131 (14) | 180 (15) | 90 (17) |
| Moderately severe (15–19) | 249 (9) | 71 (8) | 117 (10) | 61 (11) |
| Severe (20–27) | 163 (6) | 52 (6) | 72 (6) | 39 (7) |
| Missing | 974 | 291 | 506 | 177 |
| Depression or anxiety diagnosis | 2857 (79) | 1039 (86) | 1219 (71) | 599 (84) |
| Pregnancy outcomes | ||||
| Preterm birth, n (%) | 419 (12) | 193 (16) | 162 (9) | 64 (9) |
| NICU admission, n (%) | 375 (10) | 178 (15) | 141 (8) | 56 (8) |
Note: NICU, neonatal intensive care unit; PHQ-9, Patient Health Questionnaire (PHQ-9); SD, standard deviation.
Figure 1.
Antidepressant medication use by gestational week for each pattern for a) preterm birth and b) NICU admission.
Note: The color scale represents the proportion of pregnant women with antidepressant medication use. The number in each box is the denominator for the proportion. Ns are only labeled when there is a change in denominator value. NICU, neonatal intensive care unit
After adjusting for covariates, continued antidepressant use was associated with an 86% higher risk of preterm birth (adjusted Relative Risk [aRR]: 1.86, 95% CI: 1.53, 2.27) compared to individuals who discontinued antidepressant use and with a 66% higher risk of preterm birth (aRR 1.66, 95% CI: 1.27, 2.18; Table 2) compared to those who stopped and reinitiated antidepressant.
Table 2.
Associations of antidepressant use patterns during pregnancy with birth outcomes
| Adjusted Relative Risk† (95% CI) | ||
|---|---|---|
| Continued use vs discontinued use | Continued use vs stopped and reinitiated | |
| Preterm birth | 1.86 (1.53, 2.27) | 1.66 (1.27, 2.18) |
| NICU admission | 1.76 (1.42, 2.19) | 1.85 (1.39, 2.46) |
Model is adjusted for maternal age (years), race/ethnicity (Asian, non-Hispanic Black, Hispanic, non-Hispanic White, other), education (high school graduate or less, some college, college graduate or more), Medicaid during pregnancy (Y/N), nulliparity (Y/N), alcohol use during pregnancy (Y/N), tobacco use during pregnancy (Y/N), other drug use during pregnancy (Y/N), and maximum Patient Health Questionnaire (PHQ-9) score during pregnancy
Note: NICU, neonatal intensive care unit. Additional adjustment for an interaction term between exposure category and Patient Health Questionnaire (PHQ-9) score was not significant at the α=0.1
0 level (not shown)
Similarly, continued antidepressant use was associated with 76% higher risk of NICU admission (aRR: 1.76, 95% CI: 1.42, 2.19) compared to antidepressant discontinuation and with an 85% higher risk of NICU admission (aRR: 1.85, 95% CI: 1.39, 2.46; Table 2) compared to individuals who stopped and reinitiated antidepressant use. .
When the interaction term for the exposure category and PHQ-9 score was included in the model, it was not statistically significant (p>0.10).
Sensitivity Analyses
Results were similar when antidepressant use was examined as a continuous medication possession ratio; for every 0.1 unit increase in medication possession ratio (days supplied/days elapsed), there was a 14% higher risk of preterm birth (95% CI: 1.10, 1.18) and 9% higher risk of NICU admission (95% CI: 1.06, 1.12; Supplemental Table 1). Stronger associations between medication possession ratio (proportion of medication coverage) and preterm birth were observed in the second and third trimester compared to the first trimester; NICU results were similar across trimesters.
Most (>90%) antidepressant use in our population of interest was classified as class C medication use per ACOG guidelines (meaning risk cannot be ruled out; Supplemental Figure 1). Results restricting to class C medications were consistent with the main results (Supplemental Table 2; models for classes B and D not included due to small sample sizes). Results after additional adjustment for depression diagnoses (Supplemental Table 3) and psychotherapy during pregnancy were similar to main results (Supplemental Table 4).
Discussion
Comment
Principal Findings
In this study evaluating relationships between patterns of antidepressant exposure during pregnancy and birth outcomes among periconception (use before and immediately following conception) antidepressant users, we found that nearly half of periconception users discontinued medication during pregnancy. Most of the women who discontinued did so in the first or early second trimester. Those with continued use of antidepressants during pregnancy had a higher risk of preterm birth and NICU admission compared to individuals who discontinued antidepressants or stopped and reinitiated use, accounting for depression symptom severity. We found an exposure-response relationship between increases in antidepressant medication exposure during pregnancy and both preterm birth and NICU admission risk; the risk for preterm birth was higher when antidepressant exposure continued into the second and third trimesters. Of importance, these results took into consideration underlying depression symptom severity through inclusion of PHQ-9 scores. These findings have implications for patients and clinicians making treatment decisions at the beginning of pregnancy regarding continuation of antidepressant use.
Results in the Context of What is Known
Our results are consistent with previous research documenting a relationship between prenatal antidepressant use and a higher risk of preterm birth [21–24] as well as NICU admission.[20] This study expands the literature that explores patterns of antidepressant use [44] by focusing specifically on patterns among periconception users. We also found that the relationship between medication possession ratio and preterm birth was stronger in the second and third trimesters for preterm birth risk, suggesting the timing of exposure may also be important.[21]
Clinical Implications
Although some studies documented antidepressant use patterns in pregnancy,[44] this study is among the first investigations of these patterns among individuals taking antidepressants periconception. The greater risk of preterm birth and NICU admission associated with continued prenatal antidepressant use relative to discontinued or stopped and reinitiated use highlights the need to closely monitor women prescribed antidepressants during pregnancy, particularly later in gestation. The decision to continue or discontinue antidepressants during pregnancy should consider a woman’s individual needs, the risks and consequences of depression and/or anxiety relapse, in tandem with risks of antidepressant use.
Research Implications
Future research should include antidepressant dosage data to understand specific dose-response relationships between prenatal antidepressant use and birth outcomes. There may be more nuanced dosage categories among the “continued” users, for example. Additionally, as prenatal depression and anxiety are the strongest risk factors for postpartum depression and anxiety, which in turn can increase the risk of suicide (a leading cause of postpartum mortality), future research needs to assess the relationship between the antidepressant use patterns and depression or anxiety relapse or postpartum depression or anxiety risk. Understanding the risks and benefits of continued antidepressant use during pregnancy is important for patient and provider clinical decision making. In future work there may also be merit in utilizing data-adaptive approaches, including unsupervised machine learning, which would meaningfully group data to delineate specific patterns of use that may not be captured through a priori-specified categories.[45]
Strengths and Limitations
Though we controlled for key covariates in this analysis, including controlling for depression symptom severity, this study is potentially subject to unmeasured confounding. We used the maximum PHQ-9 score to measure depression severity during pregnancy, which reflects both underlying severity as well as control of depression symptoms through treatment. Although individuals who stopped and reinitiated antidepressant medication had higher PHQ-9 scores than those who continued antidepressant medication use, we are unable to temporally link the stopping of use with an elevated PHQ score in the current dataset. Further, we did not have anxiety symptom screening data. This may result in some residual confounding by depression and/or anxiety severity. Although more than 96% of prescriptions are filled within KPNC pharmacies,[46] prescriptions filled outside of the health plan would not be captured, which could result in underreporting of medication use and subsequent measurement error of the exposure of interest. Additionally, we did not have dose data which limited our ability to assess dose-response associations, nor did we assess the effects of polypharmacy. Future research should ascertain dose data by medication class to investigate the risk of adverse pregnancy outcomes associated with continuing antidepressant use but of a different class and/or at a lower dose. Finally, we included individuals with an antidepressant medication fill that overlapped with the 8th week of gestation to capture those who were taking antidepressant medication before knowledge of their current pregnancy and would need to decide whether to continue antidepressant use during pregnancy. Additional research on antidepressant use patterns for individuals who initiate antidepressant use during pregnancy is also warranted.
A key strength of this study is the use of an expansive, diverse, and representative sample of periconception antidepressant users. KPNC’s universal perinatal depression screening program, implemented in 2012, allows for the capture and inclusion of depression severity during pregnancy as a covariate. Though severity is a key confounder that affects both depression treatment and patient outcomes, it is rarely routinely captured and therefore is often missing from datasets. These women are a key population to engage early in pregnancy, as they are most vulnerable to a depression and anxiety relapse which carries risks that must be weighed in any treatment decision.[18]
Conclusions
The present study found a higher risk of preterm delivery and NICU admissions with a pattern of continued antidepressant use throughout pregnancy in a population of periconception antidepressant users. Further, there was an association between duration of prenatal antidepressant use and risk of preterm birth. These results suggest the need for increased monitoring of periconception antidepressant users who decide to continue antidepressant use through pregnancy, particularly during the 2nd and 3rd trimesters.
Supplementary Material
Acknowledgments:
This work was supported by Community Health, Kaiser Permanente Northern California, and the National Institute of Health R01HD101483. S.E.B was funded by the Postdoctoral Training Program in Women’s and Children’s Health supported in part by Community Health, Kaiser Permanente Northern California. S.E.B was additionally funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (K99HD100585). K.R time was supported by The Permanente Medical Group’s Physician Researcher Program. Dr. Badon and Ms. Nance conducted the data analysis for this study. Dr. Avalos had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
APPENDIX
Appendix.
Antidepressant medications included in the analysis.
| Class | Generic medication |
|---|---|
| SSRIs | Citalopram |
| Escitalopram | |
| Fluoxetine | |
| Fluvoxamine | |
| Paroxetine | |
| Sertraline | |
| TCAs | Amitriptyline |
| Clomipramine | |
| Desipramine | |
| Nortriptyline | |
| Doxepin | |
| Imipramine | |
| Protriptyline | |
| Trimipramine | |
| SNRIs | Desvenlafaxine |
| Duloxetine | |
| Milnacipran | |
| Venlafaxine | |
| Others | Monoamine oxidase inhibitors (phenelzine and tranylcypromine) |
| Trazodone | |
| Bupropion | |
| Atomoxetine | |
| Mirtazapine | |
| Nefazodone | |
| Vilazodone |
SNRI, serotonin and norepinephrine; SSRI, selective serotonin reuptake inhibitor; TCA, tricyclic antidepressant
Footnotes
Conflict of Interest: The authors declare no conflicts of interest.
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