# Antidepressant Use During Pregnancy and Birth Defects: What a Large Canadian Study Found A large Canadian study of nearly 18,500 pregnant women with depression or anxiety found that most antidepressants taken during the first trimester (the first 14 weeks of pregnancy) were not linked to a higher risk of major birth defects overall. However, specific medications did show increased risks for certain types of birth defects: citalopram was associated with a 36% higher risk of major malformations overall, paroxetine with heart defects, citalopram with musculoskeletal defects and a nearly fourfold higher risk of craniosynostosis, tricyclic antidepressants with eye/ear/digestive defects, and venlafaxine with respiratory defects. The study is important because it compared antidepressant users to depressed women who were not taking medication, helping separate the effects of the drugs from the effects of depression itself. # Antidepressant Use During Pregnancy and Birth Defects: What a Large Canadian Study Found ## Table of Contents - Key Points - Background: Why This Research Matters - Study Methods: How the Research Was Conducted - Key Findings: Detailed Results With All Numbers - Clinical Implications: What This Means for Patients - Limitations: What the Study Couldn't Prove - Recommendations: What Patients Should Consider - Frequently Asked Questions - Source Information ## Key Points - In a study of 18,487 pregnant women with depression or anxiety, most antidepressant classes were not linked to higher overall risk of major birth defects. - Citalopram showed a 36% higher odds of major malformations overall and a nearly fourfold increased risk of craniosynostosis. - Paroxetine was linked to heart defects, venlafaxine to respiratory defects, and tricyclic antidepressants to eye/ear and digestive defects. - Absolute risks remained small; about 2–3% of all babies have a major birth defect, so relative increases are modest. - Do not stop antidepressants suddenly; sudden stopping can cause withdrawal and depression relapse. Discuss all medication choices with your doctor. ## Background: Why This Research Matters Depression is common during pregnancy, and antidepressant use during pregnancy has been rising steadily over the past 20 years. The most widely used class of antidepressants during pregnancy is selective serotonin reuptake inhibitors (SSRIs), which include medications like paroxetine (Paxil), sertraline (Zoloft), citalopram (Celexa), fluoxetine (Prozac), and fluvoxamine (Luvox). However, use of other types — serotonin–norepinephrine reuptake inhibitors (SNRIs) like venlafaxine (Effexor), and tricyclic antidepressants (TCAs) like amitriptyline — has also increased. Why does this matter for the developing baby? Serotonin is essential for healthy fetal development during embryogenesis, the critical period when organs are forming in the first trimester. SSRIs cross the placental barrier and block serotonin reuptake transporter (SERT) sites. This can disturb the free movement of serotonin during this critical phase of development. SNRIs work similarly to SSRIs, and some TCAs, notably amitriptyline, also have serotonin-inhibiting effects. Previous human studies have shown that antidepressant exposure during gestation may increase the risk of various congenital malformations (birth defects), including cardiac (heart), musculoskeletal, respiratory, craniosynostosis (premature fusion of skull bones), and craniofacial (head and face) defects. However, results across studies have varied. Researchers have wondered whether underlying maternal depression itself — rather than the medication — might explain the increased risks. Other possible explanations include unaccounted confounders (other factors that could influence results), comparing class effects instead of individual drug effects, or simply lacking enough statistical power (a large enough sample) to detect true differences. This study was designed to address those concerns. The researchers specifically compared depressed women taking antidepressants to depressed women not taking antidepressants, which helps separate the medication's effect from the effect of depression itself. ## Study Methods: How the Research Was Conducted ### Setting and Data Sources The researchers conducted a register-based cohort study using data from the Quebec Pregnancy Cohort (QPC), a large, ongoing population-based database in Quebec, Canada. The QPC prospectively collected data on all pregnancies that occurred between January 1998 and December 2009, with follow-up of mothers and children for up to 11 years after the end of pregnancy. Data came from several linked provincial databases: - The medical service database (RAMQ) — diagnoses, medical procedures, and socioeconomic status of women and prescribers - The Quebec Public Prescription Drug Insurance Database — drug name, start date, dosage, and duration of prescriptions - The Hospitalisation Archive Database (MedEcho) — in-hospital diagnoses and procedures - The Quebec Statistics Database (ISQ) — patient socio-demographic information and birth weight ### Who Was Included From the 289,688 women in the Quebec Pregnancy Cohort, the researchers identified 18,487 pregnant women who met all inclusion criteria. To be eligible, pregnancies had to meet these requirements: 1. Continuous prescription drug insurance coverage for at least 12 months before the first day of gestation and during pregnancy 1. A diagnosis of depression and/or anxiety, OR exposure to antidepressants in the 12 months before pregnancy (with or without related disorders) 1. Ending in a live-born singleton birth (only one baby, not twins or multiples) Why did they limit it this way? Multiple births are associated with congenital malformations, so including only singletons reduces that complication. Requiring a depression/anxiety diagnosis or antidepressant treatment in the year before pregnancy helped ensure the women genuinely had depression. It also allowed the researchers to account for "maternal indication per design" — meaning they could compare women with similar depression severity, rather than comparing medicated depressed women to healthy unmedicated women. This design helped adjust for unmeasured confounders like alcohol consumption, smoking rates, and folic acid intake. The researchers excluded pregnancies exposed to known teratogens (substances that cause birth defects) during the first trimester, pregnancies with chromosomal abnormalities in the newborn, and those resulting only in minor malformations. They also excluded pregnancies where women used more than one type of antidepressant during the first trimester, since combining drugs may carry different risks. Very few pregnancies were excluded for this reason, because combination use or switching was rare. ### Defining Antidepressant Exposure Exposure was determined using the Quebec Public Prescription Drug Insurance Database, which records the dispensed date and duration of each prescription. The critical exposure window was the first trimester, defined as 0–14 weeks of gestation, confirmed by ultrasound. Pregnancies were considered "exposed" if a prescription was filled during the first trimester, or if a prescription filled before pregnancy overlapped with the first day of the last menstrual period. Primary analyses looked at four mutually exclusive antidepressant classes: - SSRI — citalopram, sertraline, paroxetine, fluoxetine, fluvoxamine - SNRI — venlafaxine - TCA — amitriptyline, desipramine, doxepin, imipramine, nortriptyline, trimipramine, clomipramine - Other antidepressants — L-tryptophan, trazodone, bupropion, moclobemide, buspirone, mirtazapine Secondary analyses examined eight mutually exclusive groups of individual drugs: paroxetine, sertraline, citalopram, fluoxetine, fluvoxamine, venlafaxine, TCA (as a group), and other antidepressants. For all analyses, the reference (comparison) group was depressed/anxious pregnant women who did not take any antidepressants during the first trimester — in other words, depressed but untreated with medication. ### How Birth Defects Were Identified Major congenital malformations diagnosed in the first year of life were identified from the RAMQ and MedEcho databases, using International Classification of Diseases (ICD)-9 and ICD-10 codes. All organ systems were considered, and defects were classified according to the European Registration of Congenital Anomalies and Twins (EUROCAT) Registry. The researchers included diagnoses made during the first year of life to allow for late detection and negative confirmatory diagnoses. The databases used in this study have been validated against patient charts. The prescription drug data had a positive predictive value (the chance that a recorded prescription was truly filled) of at least 87% (95% CI 70% to 100%) and a negative predictive value of at least 92% (95% CI 86% to 98%). For major congenital malformations, the positive predictive value was at least 80% and the negative predictive value 93%. Because these databases are prospectively collected, recall bias (where mothers might inaccurately remember medication use) was minimized. ### Statistical Methods The researchers used generalized estimating equation (GEE) models, which account for the fact that some women had multiple pregnancies during the follow-up period. They calculated crude and adjusted odds ratios (aOR) with 95% confidence intervals (CIs). They also calculated 99% CIs to test the robustness of their findings. Potential confounders included: - Socio-demographic variables: maternal age, marital status, welfare status, education level, place of residence - Maternal chronic conditions in the 12 months before pregnancy: hypertension, diabetes, asthma - Healthcare utilization: visits to psychiatrists, hospitalizations, emergency department visits, number of other medications (including benzodiazepines), and number of different prescribers They also performed probabilistic sensitivity analyses to quantify the likely effects of any misclassification of exposure or outcome. This is a sophisticated way of testing whether errors in recording drug use or birth defects could have changed the results. ## Key Findings: Detailed Results With All Numbers ### Study Population Of the 289,688 women in the Quebec Pregnancy Cohort, 18,487 pregnant women met all inclusion criteria and were included in the study. Before exclusions, the prevalence of maternal depression in the cohort was 7.3% (21,175 pregnancies). The main reasons for exclusion were: postnatal follow-up of less than 12 months for children (needed to assess malformations), use of more than one antidepressant during the first trimester, multiple birth, exposure to feto-toxic medications, and newborns with chromosomal abnormalities or minor malformations alone. In 4.6% of eligible pregnancies, mothers could not be linked to their newborns. Among the 18,487 women in the study population, 3,640 were exposed to antidepressants during the first trimester. Here is the breakdown of users: - **SSRIs: 2,327 women (63.9%)** — including 1,132 on paroxetine, 365 on sertraline, 584 on citalopram, 191 on fluoxetine, and 55 on fluvoxamine - **SNRIs: 738 women (20.3%)** — all were users of venlafaxine - **TCAs: 382 women (10.5%)** — of these, 318 were on amitriptyline (the most used TCA) - **Other antidepressants: 193 women (5.3%)** Antidepressant users were exposed for a mean duration of 47.0 days (SD = 17.0) during the first trimester. SSRI users averaged 51.0 days (SD = 27.3) of exposure, and non-SSRI users averaged 49.9 days (SD = 33.1). ### Trends Over Time Over the more than 10-year span of the study, the prevalence of antidepressant use during pregnancy **doubled** within the Quebec Pregnancy Cohort — from 21 per 1,000 pregnancies to 43 per 1,000 pregnancies (p<0.001). This coincided with a significant increase in the prevalence of maternal depression (p<0.05) and a significant increase in major congenital malformations (p<0.001) over the same period. ### Characteristics of Antidepressant Users vs. Non-Users Compared with non-users (n = 14,847), antidepressant users were generally older, more likely to live alone, and more likely to be welfare recipients. They also had more comorbidities (diabetes, hypertension, asthma) and used more health services. Notably, antidepressant users and non-users were comparable in terms of emergency department visits and hospitalizations, and SSRI and SNRI users were similar to non-users in the number of psychiatrist visits in the year before pregnancy. This similarity suggests that the mental health severity was comparable between the treated and untreated depressed women — an important point for interpreting the results. One difference stands out: antidepressant users had newborns with lower birth weights than non-users (p<0.001). The mean birth weights were: - Non-exposed: 3,309.7 g (SD = 562.7) - SSRI users: 3,252.1 g (SD = 567.4) - SNRI users: 3,226.2 g (SD = 566.0) - TCA users: 3,218.7 g (SD = 583.3) - Other antidepressant users: 3,247.5 g (SD = 620.7) Gestational age at birth was similar across groups (approximately 38.4–38.7 weeks, p = 0.10), indicating the lower birth weights were not simply due to earlier delivery. ### Overall Risk of Major Congenital Malformations **The most important overall finding:** after adjusting for confounders, using SSRIs, SNRIs, TCAs, or other antidepressants during the first trimester was **not** associated with an increased risk of major congenital malformations overall, compared with non-use in this population of depressed pregnant women. This held true when each class was compared individually against the non-exposed depressed group. However, the picture changed when individual antidepressant types were analyzed. Among the specific drugs, **only citalopram** was associated with a significantly increased risk of major congenital malformations overall, with an adjusted odds ratio (aOR) of 1.36 (95% CI 1.08 to 1.73), based on 88 exposed cases. This means citalopram users had a 36% higher odds of having a baby with any major birth defect compared with depressed women not taking antidepressants. There was also a trend toward increased risk for the most frequently used antidepressants, but these did not reach statistical significance. ### Organ-Specific Defects: Which Drugs, Which Defects When the researchers looked at organ-specific malformations, they found several important associations with antidepressants that have serotonin reuptake inhibition effects (SSRIs, SNRIs, and amitriptyline, the most commonly used TCA): - **Paroxetine and cardiac (heart) defects:** aOR 1.45 (95% CI 1.12 to 1.88). Paroxetine also increased the risk of ventricular/atrial septal defects (holes in the wall between the heart's chambers): aOR 1.39 (95% CI 1.00 to 1.93). - **Citalopram and musculoskeletal defects:** aOR 1.92 (95% CI 1.40 to 2.62) — nearly double the risk of defects affecting muscles and bones, such as clubfoot or limb abnormalities. - **Citalopram and craniosynostosis:** aOR 3.95 (95% CI 2.08 to 7.52) — a nearly fourfold increased risk of premature fusion of the skull bones, a condition that often requires surgery. - **TCAs and eye, ear, face, and neck defects:** aOR 2.45 (95% CI 1.05 to 5.72). - **TCAs and digestive defects:** aOR 2.55 (95% CI 1.40 to 4.66). - **Venlafaxine (SNRI) and respiratory defects:** aOR 2.17 (95% CI 1.07 to 4.38). The researchers noted that because many comparisons were made, chance could explain some of these findings. However, the 99% confidence intervals calculated to test robustness, along with the sensitivity analyses, suggested the main findings were reasonably stable. ## Clinical Implications: What This Means for Patients This study provides important reassurance and equally important cautions for women who take antidepressants during pregnancy. First, the reassurance: the study found **no overall increased risk of major birth defects** for most antidepressant classes when used in the first trimester. This is meaningful because the comparison group was depressed women not taking medication — not healthy women. That design helps rule out the possibility that the depression itself, rather than the medication, was driving the risk of birth defects. For the most commonly used class, SSRIs as a whole, and for SNRIs and TCAs as classes, the overall risk of major malformations was not significantly elevated. Second, the cautions: specific medications showed specific risks. The findings suggest these patterns: - **Citalopram** was the only drug linked to a higher risk of major malformations overall (aOR 1.36), and it was specifically associated with musculoskeletal defects (aOR 1.92) and craniosynostosis (aOR 3.95). - **Paroxetine** was linked to heart defects (aOR 1.45) and septal defects specifically (aOR 1.39). This confirms previous research that has flagged paroxetine's cardiac risk. - **TCAs** as a group were linked to eye/ear/face/neck defects (aOR 2.45) and digestive defects (aOR 2.55). - **Venlafaxine** was linked to respiratory defects (aOR 2.17). For women who are pregnant or planning pregnancy, these findings underscore the importance of a careful, individualized discussion with healthcare providers. The absolute risks remain relatively small for most individual defects. For example, the baseline risk of a major congenital malformation in the general population is roughly 2–3%. Even a doubling of risk for a specific defect translates to a relatively small absolute increase. The study did not assess the risks of untreated depression, which also has known consequences for both mother and baby. ## Limitations: What the Study Couldn't Prove Several limitations should be considered when interpreting these results: - **Observational design:** This is a cohort study, not a randomized controlled trial. While the researchers adjusted for many confounders, it is not possible to fully rule out residual confounding — unmeasured differences between women who take antidepressants and those who don't. - **Multiple comparisons:** The researchers made many statistical comparisons across drug classes, individual drugs, and organ systems. By chance alone, some findings could be false positives. The authors acknowledged this: "Owing to the number of comparisons made, chance could explain some of the findings." - **Statistical power:** For some of the less commonly used drugs (e.g., fluvoxamine with only 55 users), the sample sizes were small, limiting the ability to detect increased risks. The study was powered to detect moderate-to-large effects, but smaller risks might have been missed. - **Exposure measurement:** Exposure was based on filled prescriptions, not actual ingestion. Although the prescription data were validated (positive predictive value at least 87%), some women may not have taken the medication exactly as prescribed. - **Generalizability:** The study population was from Quebec, Canada, and included women with public prescription drug insurance. Results may not apply directly to other populations with different demographic characteristics or healthcare systems. - **Medication switching and combinations:** The study excluded women who used multiple antidepressants during the first trimester, so the risks of switching medications or combining them were not evaluated. - **Depression severity:** Although the study design helped match treated and untreated depressed women on some measures of severity, depression severity is complex and cannot be perfectly measured in administrative databases. ## Recommendations: What Patients Should Consider Based on this study and the broader body of evidence, here are key takeaways for women taking antidepressants who are pregnant or planning pregnancy: 1. **Do not stop antidepressants suddenly.** Suddenly stopping an antidepressant can trigger withdrawal symptoms and a relapse of depression, which carries its own risks for both mother and baby. Always talk to your doctor before making any changes. 1. **Have an early, honest conversation with your healthcare provider.** If you are pregnant or planning a pregnancy, discuss your medication options before conception if possible. The first trimester — the period studied here — is when the baby's organs are forming, so planning ahead matters. 1. **Ask about your specific medication.** This study found different risks for different drugs. Citalopram, paroxetine, venlafaxine, and TCAs showed specific organ-related risks, while other drugs like sertraline and fluoxetine did not show significant associations in this analysis. Your doctor can help weigh whether switching medications is appropriate for your situation. 1. **Understand the absolute risk, not just the relative risk.** A 36% higher risk sounds alarming, but if the baseline risk is small, the absolute increase is also small. About 2–3% of all babies are born with a major birth defect. Discuss what these numbers actually mean for you. 1. **Consider the risks of untreated depression.** Depression during pregnancy is itself associated with poor pregnancy outcomes, including lower birth weight, preterm birth, and difficulties with bonding and postpartum mental health. The right choice for many women is to continue treatment. 1. **Don't rely solely on this study.** This is one important piece of evidence, but not the final word. The scientific literature contains conflicting results across studies. Your doctor should integrate this information with your personal medical history, the severity of your depression, and your treatment history. The study's authors concluded: "Antidepressants with effects on serotonin reuptake during embryogenesis increased the risk of some organ-specific malformations in a cohort of pregnant women with depression." This means women taking these specific medications should have informed discussions with their doctors, but they should not panic. The overall risk of major malformations was not increased for most antidepressants, and even for the drugs with elevated risks, the absolute chances of any given birth defect remain relatively low. ## Frequently Asked Questions ### Did taking antidepressants during the first trimester raise the overall risk of major birth defects? In a study of 18,487 pregnant women with depression or anxiety, most antidepressant classes—SSRIs as a group, SNRIs, TCAs, and others—were not linked to a higher overall risk of major birth defects. However, citalopram specifically showed a 36% higher odds of major malformations overall compared with depressed women not taking antidepressants. ### Which antidepressant was associated with the highest risk for a specific birth defect? Citalopram was linked to a nearly fourfold increased risk of craniosynostosis, a condition where skull bones fuse prematurely and often requires surgery. The adjusted odds ratio was 3.95. Citalopram was also associated with musculoskeletal defects and with higher overall risk of major malformations. ### How did this study separate the effects of medication from the effects of depression itself? The researchers compared pregnant women with depression or anxiety who took antidepressants to depressed or anxious pregnant women who did not take any antidepressants during the first trimester. This design helps account for the possibility that depression itself, rather than medication, could be responsible for increased birth defect risks. ### Did all antidepressants show the same risks during pregnancy? No. Specific medications showed specific risks. Paroxetine was linked to heart defects, citalopram to musculoskeletal defects and craniosynostosis, tricyclic antidepressants to eye/ear/digestive defects, and venlafaxine to respiratory defects. Sertraline and fluoxetine did not show significant associations in this analysis. ### Should I stop taking my antidepressant suddenly if I find out I am pregnant? Do not stop suddenly. Stopping can trigger withdrawal symptoms and a relapse of depression, which carries risks for both mother and baby. Speak with your doctor first about your specific medication, risks, and whether switching is appropriate. Always discuss before making any medication changes. ### What were the main limitations of this birth defect study? The study was observational, not a randomized trial, so residual confounding is possible. Many statistical comparisons were made, so chance could explain some findings. Less commonly used drugs had small sample sizes, and exposure was based on filled prescriptions, not actual ingestion. Results may not apply to all populations. ## Source Information **Original article title:** Antidepressant use during pregnancy and the risk of major congenital malformations **Authors:** Anick Bérard, Jin-Ping Zhao, Odile Sheehy **Journal:** BMJ Open, 2017;7:e013372. doi:10.1136/bmjopen-2016-013372 **Affiliations:** Research Center, CHU Sainte-Justine, Montreal, Quebec, Canada; Faculty of Pharmacy, University of Montreal, Montreal, Quebec, Canada **Funding/sponsorship:** The research was presented in part at the 55th Annual Scientific Meeting of the Teratology Society, Montreal, Canada, June 27 to July 1, 2015. *This patient-friendly article is based on peer-reviewed research. It is intended for educational purposes and is not a substitute for individualized medical advice from your healthcare provider.* --- Publisher: Diagnostic Detectives Network (https://diagnosticdetectives.com) — independent multi-expert medical second opinions, worldwide, private-pay. Author byline: Anton Titov, MD, PhD. Contact: https://diagnosticdetectives.com/pages/contact Canonical page: https://diagnosticdetectives.com/products/antidepressant-use-during-pregnancy-and-birth-defects-what-a-large-canadian-study-found