# Venlafaxine Use During Pregnancy: What a Large UK Study Found About Safety for Mother and Baby This prospective observational study followed 281 pregnancies exposed to venlafaxine (an antidepressant) and compared them with 1,405 pregnancies not exposed to any antidepressant and 843 pregnancies exposed to SSRIs (another class of antidepressants). Researchers adjusted for differences in when pregnancies were reported and for competing risks. After adjusting, researchers found no statistically significant increase in the risk of spontaneous abortion (miscarriage), stillbirth, preterm delivery, low birth weight, or congenital malformations following venlafaxine use. The overall rate of major congenital malformations was 1.42% in the venlafaxine group, 1.36% in the unexposed group, and 1.67% in the SSRI group — differences that were not statistically significant. The authors conclude that this study provides no conclusive evidence that venlafaxine increases the risk of adverse pregnancy or fetal outcomes. # Venlafaxine Use During Pregnancy: What a Large UK Study Found About Safety for Mother and Baby ## Table of Contents - Key Points - Background: Why This Research Matters - How the Study Was Conducted - Who Was Included in the Study - Characteristics of the Mothers - Key Findings: Pregnancy and Fetal Outcomes - Spontaneous Abortion (Miscarriage) Risks - Congenital Malformations (Birth Defects) - Results After Adjusting for Other Factors - What These Findings Mean - How This Compares to Previous Research - Limitations of the Study - Clinical Implications for Patients - Recommendations - Frequently Asked Questions - Source Information ## Key Points - In a study of 281 venlafaxine-exposed pregnancies, no statistically significant increase was found in miscarriage, stillbirth, preterm delivery, low birth weight, or congenital malformations after adjustment. - The overall rate of major congenital malformations was 1.42% in the venlafaxine group, 1.36% in the unexposed group, and 1.67% in the SSRI group; differences were not statistically significant. - An initial higher crude miscarriage rate compared with unexposed pregnancies disappeared when venlafaxine was compared with SSRI-exposed pregnancies, suggesting depression itself may explain some difference. - Do not stop venlafaxine suddenly if pregnant or planning pregnancy; consult your healthcare provider first, as untreated depression can harm both mother and baby. - This observational study cannot prove safety; it only shows no evidence of harm, and rare risks may not be detected even in studies of this size. ## Background: Why This Research Matters Depression during pregnancy is common. Published estimates suggest that between 4% and 20% of pregnant women experience maternal depression. As a result, the use of antidepressant medications during pregnancy has increased in recent decades across Europe and the United States. Treating depression adequately during pregnancy matters. Poorly controlled depression may increase the risk of adverse outcomes for the mother, the fetus, and the child's later development. This makes it essential that reliable safety data are available. Patients and healthcare professionals need this information to have informed discussions about medication use during pregnancy. **Venlafaxine** is a serotonin-norepinephrine reuptake inhibitor (SNRI). It is licensed to treat and prevent major depressive episodes. It is also used to treat generalized anxiety disorder, social anxiety disorder, and panic disorder with or without agoraphobia. Considerable human pregnancy data on venlafaxine already exist. Together, these data do not provide evidence that venlafaxine increases the overall rate of congenital malformations (birth defects). However, less information is available about specific risks. These include spontaneous abortion (miscarriage), intrauterine fetal death or stillbirth, preterm delivery (birth before 37 weeks), and low birth weight. The primary aim of this study was to increase the amount of published data on the risk of spontaneous abortion following venlafaxine exposure in pregnancy. Secondary aims were to investigate risks of intrauterine fetal death or stillbirth, preterm delivery, fetal growth restriction, and congenital malformation. ## How the Study Was Conducted This was a prospective observational comparative cohort study. In simple terms, researchers followed groups of pregnant women forward in time and compared outcomes between those exposed to venlafaxine and those who were not. The study used data collected by the UK Teratology Information Service (UKTIS). UKTIS is a national service that collects information about medication and chemical exposures during pregnancy. Healthcare professionals across the UK contact UKTIS to discuss the potential effects of maternal exposures on the fetus. When a healthcare professional contacts UKTIS, the service collects relevant clinical, obstetric, and demographic information. This allows an accurate assessment of fetal risk. All enquiries involving maternal exposures in pregnancy are then included in a prospective surveillance system. This surveillance system uses postal questionnaires. These questionnaires are sent shortly after the estimated date of delivery (EDD). They collect pregnancy and fetal outcome data from the healthcare professional who originally contacted the service. ## Who Was Included in the Study The study sample consisted of non-duplicate pregnancy and fetal outcomes. These were collected following reports of maternal exposures between September 1995 and August 2018. Researchers excluded several types of pregnancies from the analysis: - Pregnancies where maternal age details were unavailable - Multiple pregnancies (twins or triplets) - Pregnancies involving maternal poisonings or overdoses - Pregnancies with exposure to known or suspected human teratogens (agents that cause birth defects) or fetotoxic agents (agents that harm the fetus) The excluded teratogens and fetotoxic agents included any retinoid, cytotoxic medication, antiepileptic medication, lithium, methotrexate, mycophenolate mofetil, thalidomide, warfarin, or coumarin derivatives. Alcohol and tobacco were exceptions and were not grounds for exclusion. The exposed study group included pregnancies in which mothers had used venlafaxine at any stage of pregnancy. Researchers compared this group with two comparator groups. Both comparator groups were matched to the venlafaxine-exposed pregnancies by calendar year and maternal age (within 2 years) at the time of UKTIS referral. The primary matched comparator group consisted of pregnancies not exposed to any antidepressant medications. The matching ratio was 5 to 1. These pregnancies were typically reported to UKTIS to discuss exposure to agents not known to be teratogenic. Examples include vitamin supplements, dental x-rays, and mild analgesics such as paracetamol or acetylsalicylic acid. A second, disease-matched comparator group was included. This group consisted of pregnancies exposed to SSRI antidepressants, matched at a ratio of 3 to 1. This group was included to control for confounding variables common to women with gestational depression. These comparators were selected by SSRI exposure status and the health professional's reported exposure indication only. No information was available to UKTIS regarding disease type or severity. In total, 7,897 pregnancies did not meet any of the study exclusion criteria. From these, researchers identified 281 venlafaxine-exposed pregnancies. These were matched to 1,405 antidepressant-unexposed pregnancies and 843 SSRI-exposed pregnancies. Gestational venlafaxine exposure occurred in at least the first trimester for the majority of the venlafaxine-exposed group (270 out of 281 pregnancies, or 96.1%). Treatment was initiated before the 24th gestational week in all but four pregnancies. Details about the exact gestational age when venlafaxine treatment started were available for 196 pregnancies. Of these, the majority were exposed from before conception (167 out of 196, or 85.2%). For the 29 pregnancies where venlafaxine was started during pregnancy, therapy began at a median of 6 weeks (interquartile range: 5 to 10 weeks; range: 3 to 21 weeks). A total of 174 pregnancies had information about the stage of pregnancy when venlafaxine was both started and ended. These data describe a median therapeutic exposure period spanning 7 gestational weeks (interquartile range: 5 to 11 weeks; range: 1 to 40 weeks). Concomitant psychiatric medication use was common among the venlafaxine-exposed pregnancies. Co-exposure to other antidepressants, antipsychotics, benzodiazepines, or hypnotic benzodiazepine receptor antagonists was reported for 94 of 281 women in this group (33.5%). In the SSRI-exposed comparator group, 79 women used more than one SSRI. The majority were exposed to fluoxetine (33.0%), citalopram (31.2%), or sertraline (21.4%). Fewer were exposed to paroxetine (16.6%), escitalopram (3.08%), and fluvoxamine (0.237%). ## Characteristics of the Mothers The matching process limited statistically significant differences between the exposed and comparator groups for both calendar year of pregnancy and maternal age. The median enrollment year was 2006 for the venlafaxine group, 2007 for the antidepressant-unexposed group, and 2007 for the SSRI group. The median maternal age was 31 years in all three groups. However, some differences emerged between the venlafaxine group and the antidepressant-unexposed group: - Venlafaxine-exposed pregnancies were reported to UKTIS at a significantly earlier stage of pregnancy. The median was 7 weeks post-LMP (last menstrual period) compared with 10 weeks for the unexposed group (p<0.001). - The median body mass index (BMI) was significantly higher in the venlafaxine group: 28.0 kg/m² compared with 25.0 kg/m² (p=0.0334). - A significantly higher proportion reported gestational tobacco use: 51.0% versus 38.7% (p=0.0295). - A significantly higher proportion were of white ethnicity: 93.4% versus 83.1% (p=0.0213). In contrast, comparisons with the SSRI-exposed control group did not identify any statistically significant differences in these characteristics. Other characteristics were similar across groups. Multi-gravida (having been pregnant before) was reported for 69.1% of the venlafaxine group, 65.0% of the unexposed group, and 69.1% of the SSRI group. A history of spontaneous abortion among multi-gravida women was reported for 16.0%, 14.4%, and 11.0% respectively. Folate use during pregnancy was high across all groups: 93.6% in the venlafaxine group, 94.8% in the unexposed group, and 92.7% in the SSRI group. ## Key Findings: Pregnancy and Fetal Outcomes There were limited differences in adverse pregnancy and fetal outcomes among the three groups. However, some comparisons reached statistical significance. In comparison with the antidepressant-unexposed controls, the crude rate of live birth was significantly decreased following venlafaxine exposure. Live birth occurred in 75.1% of the venlafaxine group versus 81.9% of the unexposed group (p=0.0111). This observation appeared mainly driven by a statistically significant increase in the crude spontaneous abortion rate. However, when comparisons were made with the disease-matched SSRI-exposed group, no statistically significant differences were observed for any of the outcomes analyzed. Here is a summary of the crude outcome rates: - **Elective termination of pregnancy:** 7.47% in the venlafaxine group, 7.33% in the unexposed group, and 8.42% in the SSRI group. These differences were not statistically significant. - **Spontaneous abortion:** 21.0% in the venlafaxine group, 14.5% in the unexposed group (p=0.0225), and 20.1% in the SSRI group (not significant). - **Intrauterine fetal death or stillbirth:** 1.40% in the venlafaxine group, 1.03% in the unexposed group, and 1.06% in the SSRI group. These differences were not statistically significant. - **Live birth:** 75.1% in the venlafaxine group, 81.9% in the unexposed group (p=0.0111), and 77.2% in the SSRI group (not significant). - **Preterm delivery:** 16.7% in the venlafaxine group, 11.6% in the unexposed group, and 13.2% in the SSRI group. These differences were not statistically significant. - **Term low birth weight:** 2.86% in the venlafaxine group, 3.56% in the unexposed group, and 4.78% in the SSRI group. These differences were not statistically significant. - **Small for gestational age:** 9.02% in the venlafaxine group, 9.00% in the unexposed group, and 12.6% in the SSRI group. These differences were not statistically significant. ## Spontaneous Abortion (Miscarriage) Risks To assess the risk of spontaneous abortion while controlling for variation in the stage of pregnancy at reporting and rates of competing risks, researchers performed an event-history analysis. This analysis used a restricted dataset of 208 venlafaxine-exposed pregnancies, 912 antidepressant-unexposed pregnancies, and 550 SSRI-exposed pregnancies. Crude analysis of this restricted dataset produced similar risk estimates to the full dataset. However, a lower rate of elective termination was observed following venlafaxine exposure compared with the antidepressant-unexposed group. The event-history analysis adjusted spontaneous abortion cumulative incidences were as follows: - Venlafaxine-exposed pregnancies: 24.5% (95% confidence interval: 17.0% to 34.6%) - Antidepressant-unexposed pregnancies: 20.3% (95% confidence interval: 16.2% to 25.1%) - SSRI-exposed pregnancies: 28.2% (95% confidence interval: 21.4% to 36.7%) After adjustment for variation in gestational age at enrollment and competing risks, no statistically significant differences remained. The Z-test p-values were 0.198 for the comparison with the antidepressant-unexposed group and 0.264 for the comparison with the SSRI-exposed group. Unadjusted time-dependent Cox proportional hazards models also provided no evidence of an association. The hazard ratio (HR) for spontaneous abortion was 1.28 (95% confidence interval: 0.85 to 1.94) when comparing venlafaxine-exposed with antidepressant-unexposed pregnancies. The hazard ratio was 1.03 (95% confidence interval: 0.681 to 1.57) when comparing venlafaxine-exposed with SSRI-exposed pregnancies. In plain language, a hazard ratio of 1.28 means the venlafaxine group had a 28% higher relative hazard of miscarriage than the unexposed group. However, the confidence interval crossed 1.0, meaning this result was not statistically significant. The absolute rate of miscarriage was 24.5% in the venlafaxine group compared with 20.3% in the unexposed group — roughly 1 in 4 pregnancies versus 1 in 5. ## Congenital Malformations (Birth Defects) Seven venlafaxine-exposed infants were reported to have congenital malformations. Four infants had major malformations: - Tetralogy of Fallot (a heart defect) - Fixed bilateral talipes equinovarus (clubfoot affecting both feet) - Hypospadias (a condition where the opening of the urethra is on the underside of the penis) - Meningoencephalocele (a birth defect where brain tissue protrudes through an opening in the skull), diagnosed via ultrasound scans with subsequent elective termination Each of these major malformations affected a single infant exposed in the first trimester. Three minor malformations were reported: - One infant with unilateral mild talipes equinovarus and a capillary haemangioma (a type of birthmark) - One infant with a funnel chest - One male infant with unilateral cryptorchidism (undescended testicle) There were no statistically significant differences in major malformation rates following exposure at any time in pregnancy or following exposure in the first trimester only. The overall rate of major congenital malformation was 1.42% in the venlafaxine-exposed group. This compared with 1.36% in the antidepressant-unexposed group and 1.67% in the SSRI-exposed group. These differences were not statistically significant. For any congenital malformation (major or minor), the rates were 2.49% in the venlafaxine group, 3.36% in the unexposed group, and 3.94% in the SSRI group. Again, these differences were not statistically significant. ## Results After Adjusting for Other Factors Researchers added co-variable estimates to the cause-specific Cox proportional hazards models. These co-variables included tobacco use, alcohol use, recreational drug use, and folic acid use. This adjustment did not have a substantial effect on the risk estimate or the statistical significance for the hazard of spontaneous abortion following venlafaxine exposure. The adjusted hazard ratio was 1.26 (95% confidence interval: 0.829 to 1.91) when comparing venlafaxine-exposed with antidepressant-unexposed pregnancies. The adjusted hazard ratio was 1.00 (95% confidence interval: 0.655 to 1.53) when comparing venlafaxine-exposed with SSRI-exposed pregnancies. Similarly, consideration of co-variable estimates did not alter the statistical significance for the risk of preterm delivery. Consideration of co-variable estimates also did not alter the statistical significance for the risk of term low birth weight. Consideration of co-variable estimates also did not alter the statistical significance for the risk of small for gestational age. Consideration of co-variable estimates also did not alter the statistical significance for the risk of any or major congenital malformation. This held true even when the analysis was restricted to first-trimester exposed pregnancies. For example, the adjusted odds ratio for preterm delivery was 1.51 (95% confidence interval: 0.979 to 2.27) compared with the unexposed group and 1.32 (95% confidence interval: 0.844 to 2.06) compared with the SSRI group. The adjusted odds ratio for major congenital malformation was 1.06 (95% confidence interval: 0.305 to 2.87) compared with the unexposed group and 0.864 (95% confidence interval: 0.243 to 2.44) compared with the SSRI group. ## What These Findings Mean Comparisons between the venlafaxine-exposed group and the antidepressant-unexposed group identified a statistically significant increased crude rate of spontaneous abortion. However, this finding was not observed when the comparison was made with a disease-matched control group of SSRI-exposed pregnancies. Furthermore, two types of adjustment attenuated the statistically significant difference. First, event-history analysis adjusted for variation in gestational age at enrollment and rates of competing risks. Second, inclusion of the data in a time-dependent Cox proportional hazards model also accounted for these factors. No statistically significant differences in preterm birth or fetal growth parameters were observed. The overall rate of major congenital malformation among the venlafaxine-exposed group (1.42%) was not significantly different from the antidepressant-unexposed group (1.36%) or the SSRI-exposed group (1.67%). As such, the findings of this study provide no conclusive evidence that venlafaxine is a major human teratogen (an agent that causes birth defects). The findings also provide no conclusive evidence that venlafaxine is a fetotoxic agent (an agent that harms the fetus). ## How This Compares to Previous Research Controlled studies investigating the risk of adverse pregnancy or fetal outcomes following maternal venlafaxine use in human pregnancy consist of eight prospective cohort studies. Controlled studies also consist of four case-control studies and a systematic review. Together, these studies report the outcomes of at least 4,000 unique exposed pregnancies. None of these studies have identified statistically significant increased risks of any congenital malformation overall. However, some conflicting results have been provided for other adverse pregnancy and fetal outcomes. Two studies suggested possible associations with spontaneous abortion, while one did not. Two case-control studies that used an overlapping dataset also suggested possible associations with cardiac malformation. However, other large studies have not confirmed these findings. The authors note that the predominant limitation of the UKTIS surveillance method relates to the potential for adverse outcome detection heterogeneity. Because UKTIS collects outcome information from numerous healthcare professionals, responder clinical knowledge and experience is not standardized. This could theoretically lead to variation in the rate of outcome reporting. Additionally, outcome data are requested shortly following the estimated delivery date, but these outcome data may be provided up to six months post-delivery. ## Limitations of the Study This study has several important limitations that patients and healthcare professionals should consider: - **Detection heterogeneity:** Outcome information comes from many different healthcare professionals with varying clinical knowledge and experience. This lack of standardization could lead to variation in how outcomes are reported. - **Timing of outcome reporting:** Outcome data are requested shortly after the estimated delivery date but may be provided up to six months after delivery. - **No information on disease severity:** UKTIS had no information about the type or severity of depression in the women studied. - **Limited data on some outcomes:** Some analyses were based on restricted datasets, which reduces statistical power. - **Observational design:** As an observational study, it cannot prove cause and effect. It can only identify associations. - **No multiple comparison corrections:** The researchers did not perform multiple comparison corrections, which means some statistically significant findings could be due to chance. The authors also note that the study population was predominantly of white ethnicity (93.4% in the venlafaxine group where data were available). This may limit how well the findings apply to other populations. ## Clinical Implications for Patients This study provides reassuring data for pregnant women who are taking venlafaxine or who may need to take it during pregnancy. The findings suggest that venlafaxine does not substantially increase the risk of major birth defects, miscarriage, stillbirth, preterm delivery, or fetal growth restriction. The initial finding of an increased crude rate of spontaneous abortion compared with antidepressant-unexposed pregnancies is important to understand. This finding disappeared when researchers compared venlafaxine with SSRIs — another antidepressant group. This suggests that the underlying depression, rather than the specific medication, may explain some of the difference. Women with depression who become pregnant face a difficult decision. Untreated depression can harm both mother and baby. The authors emphasize that adequate treatment is important because poorly controlled gestational depression may increase the risk of adverse maternal, fetal, and childhood developmental outcomes. The overall rate of major congenital malformations in the venlafaxine group was 1.42%. This means that approximately 1 in 70 infants exposed to venlafaxine in this study had a major birth defect. This rate was not significantly different from the rates in the comparison groups. ## Recommendations Based on this study and the broader body of research, here are key points for patients and healthcare professionals: 1. **Do not stop taking venlafaxine suddenly if you are pregnant or planning pregnancy.** Abrupt discontinuation can cause withdrawal symptoms and may worsen depression. Always consult your healthcare provider first. 1. **Discuss the risks and benefits of treatment with your healthcare team.** This study provides data to support informed discussions about medication safety during pregnancy. 1. **Consider the risks of untreated depression.** Poorly controlled depression during pregnancy may increase risks for both mother and baby. 1. **Report your pregnancy to a teratology information service if available in your country.** Services like UKTIS collect data that help improve safety information for future patients. 1. **Take folic acid as recommended.** In this study, over 90% of women in all groups reported taking folic acid during pregnancy. 1. **Be aware that this study cannot prove safety — it can only show no evidence of harm.** Rare risks may not be detected even in studies of this size. The authors conclude that no conclusive evidence is provided from this study that venlafaxine increases the risk of adverse pregnancy or fetal outcomes. However, they note that continued surveillance and research are important to monitor safety as more data become available. ## Frequently Asked Questions ### Should I stop taking venlafaxine if I am pregnant or planning pregnancy? Do not stop taking venlafaxine suddenly if you are pregnant or planning pregnancy. Abrupt discontinuation can cause withdrawal symptoms and may worsen depression. Always consult your healthcare provider first. Discuss the risks and benefits of treatment with your healthcare team, because poorly controlled depression during pregnancy may increase risks for both mother and baby. ### Why did the study compare venlafaxine with SSRIs as well as unexposed pregnancies? The SSRI-exposed group was included to control for confounding variables common to women with gestational depression. When venlafaxine was compared with SSRIs, no statistically significant differences were observed for any outcome analyzed. This suggests that the underlying depression, rather than the specific medication, may explain some of the difference seen in the initial comparison with unexposed pregnancies. ### What are the limitations of this study that I should know about? This was an observational study, so it cannot prove cause and effect. Outcome information came from many different healthcare professionals with varying experience, which could lead to variation in reporting. Data may be provided up to six months after delivery. The study had no information on depression severity, and the population was predominantly of white ethnicity, which may limit how well findings apply to others. ### I'm pregnant and taking venlafaxine for depression — when should I get a second opinion about whether it's safe to keep taking it? Seek a second opinion when you need help weighing venlafaxine against untreated depression in pregnancy. This study of 281 exposed pregnancies found no statistically significant increase in miscarriage, stillbirth, preterm delivery, low birth weight, or congenital malformations after adjustment; major malformation rates were 1.42% with venlafaxine, 1.36% unexposed, and 1.67% with SSRIs. An initial higher crude miscarriage rate disappeared when compared with SSRI-exposed pregnancies, suggesting depression itself may explain some difference. Do not stop venlafaxine suddenly; consult your healthcare provider first. Diagnostic Detectives Network provides independent expert second opinions. ## Source Information **Original article title:** Pregnancy outcomes following maternal venlafaxine use **Authors:** J.L. Richardson, F. Martin, H. Dunstan, A. Greenall, S. Stephens, L.M. Yates, S.H.L. Thomas **Author affiliations:** UK Teratology Information Service, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle, UK; Institute of Cellular Medicine, Newcastle University, Newcastle, UK; Institute of Genetic Medicine, Newcastle University, Newcastle, UK; Northern Genetics Service, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle, UK **Journal:** Reproductive Toxicology, Volume 84, 2019, pages 108–113 **Publication details:** Received 13 September 2018; Received in revised form 13 December 2018; Accepted 9 January 2019; Available online 11 January 2019 **DOI:** https://doi.org/10.1016/j.reprotox.2019.01.003 *This patient-friendly article is based on peer-reviewed research. It is intended for educational purposes and should not replace personalized medical advice. Always consult your healthcare provider about your specific situation and treatment options during pregnancy.* --- 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/venlafaxine-use-during-pregnancy-what-a-large-uk-study-found-about-safety-for-mother-and-baby