Taking Venlafaxine or Duloxetine During Early Pregnancy: What the Research Says About Birth Defect Risk

Table of Contents

• Key Points
• Background: Why This Research Matters
• Study Methods: How the Research Was Conducted
• Key Findings: Venlafaxine
• Key Findings: Duloxetine
• Discussion: Putting the Numbers in Context
• Clinical Implications: What This Means for Patients
• Study Limitations: What This Research Couldn't Prove
• Recommendations: What This Means for Women and Their Doctors
• Why This Research Is Important
• Frequently Asked Questions
• Source Information

Key Points

• Among 3,186 first-trimester exposures, venlafaxine showed no statistically significant increase in major birth defects.
• Duloxetine data from 668 exposed infants found no clinically important increased malformation risk, but more data are needed.
• Untreated depression in pregnancy carries risks, including preterm delivery, low birth weight, and a six-fold higher risk of postpartum depression.
• Women stable on venlafaxine or duloxetine can continue treatment, as switching risks relapse and poor response.
• This review did not assess miscarriage, stillbirth, preterm birth, poor newborn adaptation, or long-term neurodevelopment.

Background: Why This Research Matters

Depression is a common and serious condition among women of childbearing age. Approximately 20% of all women in this age group will experience depression at some point in their lifetime, and between 1% and 8% will use an antidepressant drug during pregnancy.

Untreated depression during pregnancy carries serious risks for both the mother and her unborn child. These include:

• A higher likelihood of needing epidural analgesia (pain relief during labour)
• Increased risk of caesarean section
• Higher rates of intensive care ward admission
• Preterm delivery (birth before 37 weeks)
• Low birth weight
• Disturbances in the child's neurocognitive (thinking and learning) and socio-emotional development

Perhaps most concerning, untreated depression during pregnancy increases the risk of postpartum depression 6-fold — an important fact for any expectant mother weighing the risks and benefits of medication.

For more than a decade, researchers and doctors have debated whether antidepressant use during pregnancy — particularly in the first trimester, when the baby's organs are forming — is safe. The older class of antidepressants, called selective serotonin reuptake inhibitors (SSRIs), has been studied extensively. Data from more than 50,000 first-trimester SSRI-exposed newborns have now accumulated, and it is widely accepted that first-trimester exposure to SSRIs does not result in an overall increased risk of congenital malformations (birth defects). The risk of cardiovascular (heart) malformations is still somewhat unclear, but if a true risk exists, the absolute risks are minor and may pertain mainly to specific SSRIs, especially paroxetine (Paxil) and fluoxetine (Prozac).

Comparatively, pregnancy data on the newer combined serotonin/noradrenaline receptor inhibitors (SNRIs) — venlafaxine and duloxetine — are scarce. A recent large Scandinavian study did not suggest an increased risk associated with venlafaxine, and a recent commentary concluded that the amount of information for duloxetine was too little.

Current guidelines are vague and offer little decision support. The NICE guideline (used in the UK) does not distinguish between the various types of antidepressants and offers no direct suggestion about which drug is preferred during pregnancy. The British Association for Psychopharmacology does not mention antidepressant use during pregnancy in their guideline at all, and the World Federation of Societies of Biological Psychiatry has no recommendations for treatment during pregnancy. This lack of guidance leaves women and their doctors with difficult decisions. The goal of this systematic review was to gather all available data on venlafaxine and duloxetine exposure during the first trimester and estimate the risk of major congenital malformations.

Study Methods: How the Research Was Conducted

The researchers followed the PRISMA guidelines (Preferred Reporting Items for Systematic Reviews and Meta-Analyses), the internationally recognized standards for conducting and reporting systematic reviews. The literature search was conducted by a research librarian and three clinical pharmacologists (physicians specializing in how drugs affect the body), all of whom are involved in evidence-based counselling of healthcare professionals on the use of drugs during pregnancy.

Two separate literature searches were performed — one for venlafaxine and one for duloxetine — using the medical databases PubMed (Medline) and EMBASE (Excerpta Medica Database, via Ovid). Two search strings were created, combining terms for the drugs with "Pregnancy" and "Congenital Abnormalities." The databases were searched from their inception through the end of April 2015. Only studies involving humans and written in English were included.

To be eligible for inclusion, studies had to be case reports or cohort studies reporting original data on first-trimester exposure to venlafaxine and/or duloxetine that resulted in live births with a known outcome. The researchers allocated exposure data to venlafaxine or duloxetine regardless of whether the woman was also taking other medications (concomitant drug use) — an important consideration, since many women with depression take more than one medication.

Excluded from the review were:

• Abstracts and conference proceedings
• Unpublished work
• Case–control studies (a different study design that compares affected and unaffected infants)
• Papers without original data on the specific drugs
• Papers without information on first-trimester exposure or pregnancy outcomes

Extracted articles were cross-referenced to find additional original publications. When more than one study or updated data were available from the same cohort of patients, the study holding the most comprehensive or transparent data was selected. To calculate the relative risk of major malformations, the researchers used a population reference value of 3% for major congenital malformations in the general population — meaning that in any pregnancy, there is about a 3% background chance of a major birth defect. The relative risk tells us how much the drug exposure increases or decreases that baseline risk.

Key Findings: Venlafaxine

The initial literature search returned 3,231 articles. Sixty-five papers reported data on either venlafaxine or duloxetine. After excluding 11 duplicates and 48 papers without original data, the researchers were left with 11 cohort studies and 6 case reports/series. For venlafaxine, four cohort studies were identified:

1. Nordic countries (Denmark, Sweden, Finland, Iceland and Norway), 1996–2010: A population-based cohort study including 2,763 first-trimester exposed pregnancies — by far the largest source of data, representing 87% of all venlafaxine-exposed infants in this review. Among these, 95 major malformations were identified, giving an adjusted odds ratio of 1.06 (95% CI 0.86–1.32). Notably, an additional sibling-controlled analysis (comparing outcomes among siblings born to the same mother) reduced the odds ratio even further.
2. Czech Republic, 2002–2009: A small cohort study with 10 exposed infants, of whom 1 had a major malformation.
3. Canada, 1997–2002: A study using data from the Motherisk Program (a counselling service for pregnant women with drug-exposure concerns), with 288 exposed infants and 9 major malformations.
4. Canada, year not available: Another Motherisk-based study with 125 exposed infants and 2 major malformations.

Combined, this gave a total of 3,186 venlafaxine-exposed infants and 107 major malformations, resulting in a malformation rate of 3.36%. The relative risk estimate was 1.12 (95% CI 0.92–1.35). Because the 95% confidence interval includes 1.0, this increase is not statistically significant — meaning the observed difference could easily be due to chance.

The researchers also examined the risk of cardiac (heart) malformations specifically. Among the 2,763 venlafaxine-exposed children in the Nordic study, the odds ratio for cardiac malformations was 1.14 (95% CI 0.82–1.57) — again not reaching statistical significance.

Key Findings: Duloxetine

For duloxetine, four cohort studies were identified:

1. Canada, 2010–2012: Data from national teratogen information services (specialized counselling services for pregnant women) in Canada, France, Israel, England, Italy, Australia, Switzerland and Finland. This study included 165 exposed infants, with 3 major malformations.
2. USA, 2011: A study conducted by the manufacturer, using data from the Lilly Safety System and the FDA Adverse Events Database. The researchers initially identified 400 exposed pregnancies with known outcomes — 233 reported prospectively and 167 retrospectively. The retrospective data were excluded from the analysis because the exact number of live-born infants was unknown. Among the 189 prospective exposed pregnancies with known outcomes, there were 6 major malformations. (The prospective group also included 3 ectopic pregnancies and 41 abortions, where congenital anomalies were presumably undetected.)
3. USA, year not available: An analysis of data from eight placebo-controlled clinical trials. Only women using contraception were eligible for these trials — yet 28 pregnancies still occurred, all without congenital anomalies.
4. Sweden, 1996–2011: Data from the Swedish Birth Registry, including 286 live-born infants exposed to duloxetine in the first trimester, with 7 malformations.

Combined, this gave a total of 668 duloxetine-exposed infants and 16 major malformations, resulting in a malformation rate of 2.40%. The relative risk estimate was 0.80 (95% CI 0.46–1.29) — meaning the observed rate was actually slightly lower than the population background rate. This difference is not statistically significant, and the confidence interval is wide, reflecting the smaller amount of data available for this drug.

Discussion: Putting the Numbers in Context

The researchers emphasized that the Nordic countries' unique system of personal identification numbers allows for exceptionally high-quality pharmacoepidemiological research. Every person living in the five Nordic countries has a personal identification number that can link prescription records, birth registries and illness databases across the entire population. This makes it possible to conduct large, cross-national studies with validated data that are difficult to match anywhere else in the world.

One issue the researchers addressed was the possibility of overlapping data between studies. Two Scandinavian cohort studies were excluded because of possible overlap with the large Nordic study. Similarly, two Canadian studies using the data from the Motherisk Program were suspected of reporting overlapping data — the exact same two malformations appeared in both studies. The researchers selected the earlier, more transparent 2001 study, which was a multi-centre study with centres in Toronto (Canada), the USA, Italy and Brazil, while the 2009 study included only data from Toronto.

For the population reference risk, the researchers noted that recent large, validated and complete population-based data from the Nordic countries — based on about 2.3 million births — suggest an incidence of major malformations of 3.15%. The reference incidence used in this review was 3.0%. The authors noted that using different background estimates would only yield minor changes in the risk estimates.

The researchers also noted some differences in how malformations were recorded across countries. Risk estimates from specific studies in Sweden and Denmark lacked complete alignment, but the odds-ratio point estimates from Swedish data (1.05) were similar to the pooled Nordic data (1.13), suggesting these differences are unlikely to affect the overall conclusions.

This review identified significantly more data than previously available. A new review on venlafaxine reported about 900 exposures, while this review found 3,186 — more than three times as much data. For duloxetine, the data here are about twice the amount discussed in a recent commentary.

Clinical Implications: What This Means for Patients

The findings of this review are reassuring for women who need treatment with venlafaxine or duloxetine during pregnancy. Specifically:

• First-trimester exposure to venlafaxine is not associated with an increased risk of major congenital malformations, based on a substantial body of data (over 3,000 exposed infants).
• The available data on duloxetine, while much smaller (668 exposed infants), do not suggest a clinically important increased risk of major malformations.
• The European Medicines Agency (EMA) safety guidelines typically require data on more than 1,000 exposed pregnancies without signs of increased risk of malformations before a drug can be labelled as safe during pregnancy. The venlafaxine data clearly meet this threshold.

The researchers noted that current Summaries of Product Characteristics (SPCs) — the official prescribing information for medications in Europe — 'disregard the evidence at hand.' This means that doctors and patients may see warnings that do not reflect the current state of scientific knowledge.

However, the review also has limits on what it can tell us. It does not address other potential unwanted effects on the foetus, such as stillbirth, miscarriage, preterm birth, small-for-gestational-age (babies born smaller than expected for the number of weeks of pregnancy), poor neonatal adaptation (problems in the newborn period, such as difficulty feeding or irritability), or long-term neurobehavioural development.

Study Limitations: What This Research Couldn't Prove

No scientific study is perfect, and the authors were transparent about the limitations of this review:

Lack of control groups. Most of the included studies did not have a control group of unexposed pregnant women. This means the data offer little or no control for "confounders" — other factors that could influence the outcome.

Unaccounted factors. Important variables such as maternal age, parity (how many previous pregnancies a woman has had), body mass index (BMI), smoking, alcohol consumption, social status, and use of other medications were not accounted for in most of the underlying studies.

Confounding by indication. This is a major challenge in pregnancy drug-safety research. Depression itself can affect pregnancy outcomes, making it difficult to separate the effect of the drug from the effect of the disease. A study of SSRIs and congenital malformations found evidence of bias against the null (i.e., towards finding a risk) from confounding by indication. No such data are yet available for SNRIs, but this bias could also lead to over-estimating the risk for these drugs.

Publication bias. Cases or series that present malformations or complications possibly related to drug exposure are more likely to be published than cases or series without problems. This means the true risk could be even lower than reported here.

Small duloxetine sample. The duloxetine data are based on only 668 exposed infants, and the confidence interval (0.46–1.29) is wide. A larger body of evidence is needed to confidently rule out a small increased risk.

Specific malformations. While the overall risk of major malformations can be assessed, this review does not allow precise estimation of the risk of minor or specific types of malformations.

Nordic study nuances. Even in the large Nordic study, some data sets indicated differences in how malformations were recorded and confirmed between countries, though the authors concluded this was unlikely to affect the overall estimates.

Retrospective data excluded. For the manufacturer's duloxetine surveillance study, only prospectively collected data (data gathered before the outcome was known) were used, because retrospective data are more susceptible to bias. This is a strength, not a weakness, but it means that some data were not used.

Recommendations: What This Means for Women and Their Doctors

The authors concluded that the available data justify an update to the Summary of Product Characteristics for these medications, and that these findings should be considered in available guidelines on pharmacological antidepressant treatment in pregnant women.

The key recommendations from this review are:

1. For women starting antidepressant treatment during pregnancy: The large amount of data on SSRIs supports these as the drugs of choice when medication is being initiated during pregnancy.
2. For women already taking venlafaxine or duloxetine who become pregnant: Women who are well treated with venlafaxine or duloxetine before conception should continue their medication and can be reassured about safety during pregnancy with respect to major malformations.
3. For healthcare providers: The decision about whether to change medications should be made on a case-by-case basis, weighing the risks of untreated depression (including the 6-fold increased risk of postpartum depression and the risks of preterm delivery, low birth weight and developmental concerns) against the reassuring malformation data for these SNRIs.

The authors' core message is one of reassurance. Switching from a well-tolerated, effective antidepressant to a different drug carries its own risks — of relapse, of poor response, and of exposure to a medication that may also be unfamiliar during pregnancy. The evidence presented in this review suggests that, at least with respect to major birth defects, women who are stable on venlafaxine or duloxetine can continue therapy with confidence.

Why This Research Is Important

Every year, thousands of women face the difficult decision of whether to continue antidepressant treatment during pregnancy. Being pregnant with depression is a complex situation where the risks and benefits of treatment must be carefully weighed. More than 50,000 cases of SSRI exposure in early pregnancy have been documented, but far fewer data existed for the SNRIs — a significant gap, given that venlafaxine and duloxetine are widely prescribed.

This systematic review helps close that gap. By pooling data from all available studies, it provides the most comprehensive assessment to date of whether these two drugs increase the risk of major malformations. The finding that venlafaxine does not appear to increase this risk — based on a large Nordic dataset that accounts for important confounders like maternal smoking, diabetes and concurrent drug use — offers women and their doctors better information for making informed decisions.

This is especially valuable because current guidelines have been vague. When official guidelines say little, women may be forced to make decisions based on incomplete information or unnecessary fear. Systematic reviews like this one are a critical tool for translating available evidence into practical guidance.

Frequently Asked Questions

If I took venlafaxine in the first trimester, does it increase the risk of major birth defects?

A pooled analysis of 3,186 infants exposed to venlafaxine in the first trimester found a relative risk of 1.12 for major congenital malformations. This was not statistically significant because the confidence interval included 1.0. The malformation rate was 3.36%, similar to the 3% background risk. This is reassuring information to discuss with your doctor.

If I took duloxetine in early pregnancy, does it raise the risk of birth defects?

Data from 668 infants exposed to duloxetine in the first trimester showed a relative risk of 0.80 for major malformations, meaning the observed rate was lower than the population background risk. This difference was not statistically significant, and the confidence interval was wide. The available evidence does not suggest a clinically important increased risk.

I am stable on venlafaxine or duloxetine and just found out I am pregnant. Should I stop my medication?

The researchers concluded that women who are well treated with venlafaxine or duloxetine before conception should continue their medication, with reassurance regarding the risk of major malformations. Switching antidepressants carries risks of relapse and poor response. Any change should be decided individually with your healthcare provider.

What are the risks of untreated depression during pregnancy?

Untreated depression during pregnancy is associated with higher rates of epidural analgesia, caesarean section, intensive care unit admission, preterm delivery, low birth weight, and disturbances in the child's neurocognitive and socio-emotional development. It also increases the risk of postpartum depression six-fold, which is important when weighing medication risks.

How much safety data is available for venlafaxine versus duloxetine in pregnancy?

The review found 3,186 venlafaxine-exposed infants and 668 duloxetine-exposed infants. The venlafaxine data exceed the European Medicines Agency threshold of more than 1,000 exposed pregnancies without increased malformation risk. The duloxetine data are much smaller, so a larger body of evidence is still needed to rule out a small risk.

I'm pregnant and taking venlafaxine for depression — should I seek a second opinion about switching or continuing my antidepressant?

Deciding whether to continue venlafaxine during pregnancy is a common dilemma. In pooled data from over 3,000 first-trimester exposures, venlafaxine was not linked to a statistically significant increase in major birth defects (relative risk 1.12; 95% CI 0.92–1.35). Duloxetine data, though fewer, also showed no increased risk. Because untreated depression carries serious risks—including a 6-fold higher risk of postpartum depression—women who are stable on these medications may continue with reassurance. A second opinion can help you weigh these factors individually. Diagnostic Detectives Network provides independent expert second opinions.

Source Information

Original article title: Venlafaxine orDuloxetine and Risk of Major Congenital Malformations

Authors: Dorte Lassen, Zandra Nymand Ennis, and Per Damkier

Journal: Basic & Clinical Pharmacology & Toxicology, 2016, Volume 118, pages 32–36

DOI: 10.1111/bcpt.12497

Affiliations: Department of Clinical Chemistry and Pharmacology, Odense University Hospital, Odense, Denmark; and Department of Public Health, Clinical Pharmacology, University of Southern Denmark, Odense, Denmark

Received: 7 July 2015; Accepted: 28 September 2015

This patient-friendly article is based on peer-reviewed research published in the above journal. The original article is available for those who wish to read the full scientific text. This summary is intended for informational purposes only and should not replace professional medical advice. Always discuss your medications with your healthcare provider before making any changes during pregnancy.