In utero exposure to antidepressant drugs and risk of attention deficit hyperactivity disorder: a nationwide Danish cohort study
Open accessAbstract
Objective: To investigate whether in utero exposure to antidepressants is associated with increased risk of attention deficit hyperactivity disorder (ADHD). Design: Cohort study. Setting: Denmark. Participants: All Danish singletons born alive from 1996 to 2009 were included. Using national medical registries, we defined in utero exposure to antidepressants as redemption of an antidepressant prescription by the mother 30 days prior to or during pregnancy. We defined maternal former users of antidepressants as women, who had redeemed a prescription up to 30 days prior to pregnancy, and never users as women who had never redeemed a prescription. Main outcome measures: ADHD was defined as redemption of a prescription for ADHD medication or an ADHD hospital diagnosis. Children were followed through 2010, and we used proportional-hazards regression to compute adjusted HRs comparing children exposed in utero and children born to former antidepressant users with children born to never users. To adjust for confounding from family-related factors, we conducted a within-mother between-pregnancy analysis comparing exposed children with unexposed siblings using conditional logistic regression. Results: We identified a cohort of 877 778 children, of whom 1.7% were exposed in utero. The overall median follow-up time was 8 years; selective serotonin reuptake inhibitors were the most commonly used class of antidepressant during pregnancy (78% of users). The adjusted HR comparing children exposed to any antidepressant in utero with children born to never users was 1.2 (95% CI 1.1 to 1.4), and 1.6 (95% CI 1.5 to 1.8) comparing children born to former users to children born to never users of antidepressants. In the within-mother between-pregnancy analysis (n=867), the adjusted OR was 0.7 (95% CI 0.4 to 1.4). Conclusions: This study provides no evidence to support a causal association between in utero exposure to antidepressants and risk of ADHD.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Despite a similar pattern of confounding, some ADHD risk appears to persist.
“Third, they indicate that despite a similar pattern of confounding, some risk appears to persist for ADHD, consistent with effects observed in two prior studies, one using claims data, the other a national registry from Denmark12, 13.”
A larger cohort found an association between antidepressant exposure and either current or past antidepressant use.
“given that antidepressant exposure has also been associated with ADHD liability in one cohort12, while a larger one found association with either current or past antidepressant use13.”
A larger Danish registry-based study identified a more modest association with antidepressant exposure, also observed among offspring of mothers with prior, but not current, antidepressant treatment.
“A larger Danish registry-based study identified a more modest association with antidepressant exposure, which was also observed among offspring of mothers with prior, but not current, antidepressant treatment13.”
Adjustment for use of other medicines during pregnancy occurred in five studies assessing ASD and four studies assessing ADHD.
“Adjustment for use of other medicines during pregnancy occurred in five studies assessing ASD as the outcome and four studies assessing ADHD as the outcome [19, 25, 31, 34–37].”
The definition of exposure to other medicines during pregnancy focused on other psychotropic drugs, anxiolytics and sedatives, or nicotine products, with only one study accounting for all types of medications used.
“However, the definition of exposure to the use of other medicines during pregnancy focused on the use of other psychotropic drugs [35, 36, 38], use of anxiolytics and sedatives [19, 31, 37] or use of nicotine products [29], with only one study accounting for all types of medications used [25].”
A total of seven observational studies measuring ADHD as an outcome were identified.
“a total of seven observational studies measuring ADHD as an outcome [17, 18, 31, 34, 36–38] were identified”
For ADHD, three case-control studies involving 51,944 patients and 4,375 cases and four cohort studies involving 2,713,779 patients and 51,938 cases were included.
“For ADHD as the outcome, three case–control studies (involving 51,944 patients and 4,375 cases of ADHD) [17, 18, 36] and four cohort studies (involving 2,713,779 patients and 51,938 cases of ADHD) [31, 33, 37, 38] were included.”
Three observational studies reported results from sibling analyses for ADHD.
“Three observational studies reported results from sibling analyses [34, 37, 38]”
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Regression Models and Life-Tables
Cox, D. R. (1972) · Journal of the Royal Statistical Society Series B: Statistical Methodology · doi:10.1111/j.2517-6161.1972.tb00899.x · Cited by 39,793 · see citing works
The worldwide prevalence of ADHD: a systematic review and metaregression analysis
Polanczyk, G., de Lima, M. S., Horta, B. L., Biederman, J., & Rohde, L. A. (2007) · American Journal of Psychiatry · doi:10.1176/ajp.2007.164.6.942 · Cited by 5,346 · see citing works
The Danish Civil Registration System
Pedersen, C. (2011) · Scandinavian Journal of Public Health · doi:10.1177/1403494810387965 · Cited by 4,713 · see citing works
Kessler, R. C., Adler, L., Barkley, R., Biederman, J., Conners, C. K., Demler, O., Faraone, S. V., Greenhill, L. L., Howes, M. J., Secnik, K., et al. (2006) · American Journal of Psychiatry · doi:10.1176/ajp.2006.163.4.716 · Cited by 3,886 · see citing works
The Danish National Prescription Registry
Wallach‐Kildemoes, H., Sørensen, H. T., & Hallas, J. (2011) · Scandinavian Journal of Public Health · doi:10.1177/1403494810394717 · Cited by 2,470 · see citing works
Molecular genetics of attention-deficit/hyperactivity disorder
Faraone, S. V., Perlis, R. H., Doyle, A. E., Smoller, J. W., Goralnick, J. J., Holmgren, M. A., & Sklar, P. (2005) · Biological Psychiatry · doi:10.1016/j.biopsych.2004.11.024 · Cited by 2,357 · see citing works
The Danish National Hospital Register. A valuable source of data for modern health sciences.
Andersen, T. F., Madsen, M., Jørgensen, J. O. L., Mellemkjoer, L., & Olsen, J. H. (1999) · PubMed · Cited by 2,034 · see citing works
Grote, N. K., Bridge, J. A., Gavin, A. R., Melville, J. L., Iyengar, S., & Katon, W. J. (2010) · Archives of General Psychiatry · doi:10.1001/archgenpsychiatry.2010.111 · Cited by 1,882 · see citing works
Prevalence of Depression During Pregnancy: Systematic Review
Bennett, H. A., Einarson, A., Taddio, A., Koren, G., & Einarson, T. R. (2004) · Obstetrics & Gynecology · doi:10.1097/01.aog.0000116689.75396.5f · Cited by 1,725 · see citing works
The Danish Psychiatric Central Research Register
Mors, O., Perto, G. P., & Mortensen, P. B. (2011) · Scandinavian Journal of Public Health · doi:10.1177/1403494810395825 · Cited by 1,589 · see citing works
Genetics of attention deficit hyperactivity disorder
Faraone, S. V., & Larsson, H. (2019) · Molecular Psychiatry · doi:10.1038/s41380-018-0070-0 · Cited by 1,338 · see citing works
Selective Serotonin-Reuptake Inhibitors and Risk of Persistent Pulmonary Hypertension of the Newborn
Chambers, C., Hernández–Dı́az, S., Marter, L. J. V., Werler, M. M., Louik, C., Jones, K. L., & Mitchell, A. A. (2006) · New England Journal of Medicine · doi:10.1056/nejmoa052744 · Cited by 877 · see citing works
The Danish Medical Birth Registry.
Lb, K., & Olsen, J. (1998) · PubMed · Cited by 809 · see citing works
Linnet, K. M., Dalsgaard, S., Obel, C., Wisborg, K., Henriksen, T. B., Rodriguez, A., Kotimaa, A., Moilanen, I., Thomsen, P. H., Olsen, J., et al. (2003) · American Journal of Psychiatry · doi:10.1176/appi.ajp.160.6.1028 · Cited by 778 · see citing works
Birth Outcomes in Pregnant Women Taking Fluoxetine
Chambers, C., Johnson, K. A., Dick, L. M., Felix, R. J., & Jones, K. L. (1996) · New England Journal of Medicine · doi:10.1056/nejm199610033351402 · Cited by 735 · see citing works
Swanson, J. M., Kinsbourne, M., Nigg, J., Lanphear, B., Stefanatos, G. A., Volkow, N., Taylor, E., Casey, B. J., Castellanos, F. X., & Wadhwa, P. D. (2007) · Neuropsychology Review · doi:10.1007/s11065-007-9019-9 · Cited by 580 · see citing works
Sibling Comparison Designs: Bias From Non-Shared Confounders and Measurement Error
Frisell, T., Öberg, S., Kuja-Halkola, R., & Sjölander, A. (2012) · Epidemiology · doi:10.1097/ede.0b013e31825fa230 · Cited by 551 · see citing works
Depressive symptoms during pregnancy: Relationship to poor health behaviors
ZUCKERMAN, B. S., Amaro, H. D. L. A., Bauchner, H., & Cabral, H. (1989) · American Journal of Obstetrics and Gynecology · doi:10.1016/0002-9378(89)90170-1 · Cited by 521 · see citing works
Søgaard, K. K., Horváth–Puhó, E., Grønbæk, H., Jepsen, P., Vilstrup, H., & Sørensen, H. T. (2008) · The American Journal of Gastroenterology · doi:10.1038/ajg.2008.34 · Cited by 420 · see citing works
Molecular Genetics of Attention Deficit Hyperactivity Disorder
Faraone, S. V., & Mick, E. (2010) · Psychiatric Clinics of North America · doi:10.1016/j.psc.2009.12.004 · Cited by 411 · see citing works
Depression during Pregnancy: Overview of Clinical Factors
Bennett, H. A., Einarson, A., Taddio, A., Koren, G., & Einarson, T. R. (2004) · Clinical Drug Investigation · doi:10.2165/00044011-200424030-00004 · Cited by 317 · see citing works
Neonatal Antidepressant Exposure has Lasting Effects on Behavior and Serotonin Circuitry
Maciąg, D., Simpson, K. L., Coppinger, D., Lu, Y., Wang, Y., Lin, R. C. S., & Paul, I. A. (2005) · Neuropsychopharmacology · doi:10.1038/sj.npp.1300823 · Cited by 302 · see citing works
Pedersen, L. H., Henriksen, T., Vestergaard, M., Olsen, J., & Bech, B. H. (2009) · BMJ · doi:10.1136/bmj.b3569 · Cited by 296 · see citing works
New perspectives on the neurodevelopmental effects of SSRIs
Homberg, J. R., Schubert, D., & Gaspar, P. (2009) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2009.11.003 · Cited by 266 · see citing works
Selective serotonin reuptake inhibitors and adverse pregnancy outcomes
Wen, S. W., Yang, Q., Garner, P. R., Fraser, W. D., Olatunbosun, O. A., Nimrod, C. A., & WALKER, M. C. (2006) · American Journal of Obstetrics and Gynecology · doi:10.1016/j.ajog.2006.02.019 · Cited by 235 · see citing works
Antenatal depression, substance dependency and social support
Pajulo, M., Savonlahti, E., Sourander, A., Helenius, H. Y. M., & Piha, J. (2001) · Journal of Affective Disorders · doi:10.1016/s0165-0327(00)00265-2 · Cited by 212 · see citing works
Drug-Associated Acute Pancreatitis: Twenty-One Years of Spontaneous Reporting in The Netherlands
Eland, I. A., van Puijenbroek, E., Sturkenboom, M., et al. (1999) · The American Journal of Gastroenterology · doi:10.1111/j.1572-0241.1999.01367.x · Cited by 131 · see citing works
Figueroa, R. (2010) · Journal of Developmental & Behavioral Pediatrics · doi:10.1097/dbp.0b013e3181e5ac93 · Cited by 116 · see citing works
Adult ADHD and comorbid depression: A consensus-derived diagnostic algorithm for ADHD
Binder, C., McIntosh, Kutcher, S., Levitt, Rosenbluth, & Fallu (2009) · Neuropsychiatric Disease and Treatment · doi:10.2147/ndt.s4720 · Cited by 110 · see citing works
Polańska, K., Jurewicz, J., & Hanke, W. (2012) · International Journal of Occupational Medicine and Environmental Health · doi:10.2478/s13382-012-0048-0 · Cited by 65 · see citing works
Behavioral changes in developing mice after prenatal exposure to paroxetine (Paxil)
Coleman, F. H., Christensen, H. D., Gonzalez, C. L., & Rayburn, W. F. (1999) · American Journal of Obstetrics and Gynecology · doi:10.1016/s0002-9378(99)70102-x · Cited by 51 · see citing works
Use of glucocorticoids and risk of breast cancer: a Danish population-based case-control study
Sørensen, G. V., Cronin-Fenton, D. P., Sørensen, H. T., et al. (2012) · Breast Cancer Research · doi:10.1186/bcr3106 · Cited by 36 · see citing works
Chu, S., Tsai, M.-H., Hwang, F.-M., Hsu, J., Huang, H. R., & Huang, Y. (2012) · BMC Psychiatry · doi:10.1186/1471-244x-12-85 · Cited by 30 · see citing works
Platon, A. M., Erichsen, R., Christiansen, C. F., et al. (2014) · BMJ Open Respiratory Research · doi:10.1136/bmjresp-2014-000036 · Cited by 24 · see citing works
Strid, J. M. C., Gammelager, H., Johansen, M. B., Tønnesen, & Christiansen, C. F. (2013) · Clinical Epidemiology · doi:10.2147/clep.s47679 · Cited by 18 · see citing works
Use of medications and risk of revision after primary total hip arthroplasty
Thillemann, T. M. (2009) · Acta Orthopaedica · doi:10.3109/17453670903448240 · Cited by 4 · see citing works
Obesity, diabetes and hospitalization with pneumonia
Kornum, J. B. (2009) · Cited by 1 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Malm, H., Brown, A. S., Gissler, M., Gyllenberg, D., Hinkka-Yli-Salomäki, S., McKeague, I. W., Weissman, M., Wickramaratne, P., Artama, M., Gingrich, J. A., et al. (2016) · Journal of the American Academy of Child & Adolescent Psychiatry · doi:10.1016/j.jaac.2016.02.013 · Cited by 206 · see citing works
Clements, C. C., Castro, V. M., Blumenthal, S. R., Rosenfield, H. R., Murphy, S. N., Fava, M., Erb, J. L., Churchill, S. E., Kaimal, A. J., Doyle, A. E., et al. (2015) · Molecular Psychiatry · doi:10.1038/mp.2014.90 · Cited by 197 · see citing works
Man, K. K. C., Chan, E. W., Ip, P., Coghill, D., Simonoff, E., Chan, P. K. L., Lau, W. C. Y., Schuemie, M. J., Sturkenboom, M. C. J. M., & Wong, I. C. K. (2017) · BMJ · doi:10.1136/bmj.j2350 · Cited by 135 · see citing works
Morales, D. R., Slattery, J., Evans, S., & Kurz, X. (2018) · BMC Medicine · doi:10.1186/s12916-017-0993-3 · Cited by 118 · see citing works
Liu, X., Agerbo, E., Ingstrup, K. G., Musliner, K., Meltzer-Brody, S., Bergink, V., & Munk-Olsen, T. (2017) · BMJ · doi:10.1136/bmj.j3668 · Cited by 90 · see citing works
El Marroun, H., White, T., Verhulst, F. C., & Tiemeier, H. (2014) · European Child & Adolescent Psychiatry · doi:10.1007/s00787-014-0558-3 · Cited by 92 · see citing works
Man, K. K. C., Chan, E. W., Ip, P., Coghill, D., Simonoff, E., Chan, P. K. L., Lau, W. C. Y., Schuemie, M. J., Sturkenboom, M. C. J. M., & Wong, I. C. K. (2018) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2017.12.007 · Cited by 32 · see citing works
- Authors
- Laugesen, K., Olsen, M. S., Telén Andersen, A. B., Frøslev, T., & Toft Sørensen, H.
- Affiliations
- Aarhus University Hospital (DK)
- Corresponding author
- Laugesen, Kristina
- Venue
- BMJ Open
- Publisher
- BMJ
- Published
- 2013-09
- Volume
- 3
- Issue
- 9
- Pages
- e003507
- ISSN
- 2044-6055 (ISSN-L)
- PMC
- PMC3780335
- OpenAlex
- W2111674205
- Cited by
- 58
- References
- 40
- Citations by year
- 2026: 3 · 2025: 2 · 2024: 1 · 2023: 3 · 2022: 7 · 2021: 5 · 2020: 5 · 2019: 4 · 2018: 6 · 2017: 8 · 2016: 8 · 2015: 2 · 2014: 4
- FWCI
- 4.76
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by-nc
- Locations
- BMJ Open (publishedVersion, cc-by-nc)
- Europe PMC (PubMed Central) (publishedVersion, other-oa)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- Funders
- American Brain Tumor Association
- Aarhus Universitet
- Aarhus Universitetshospital
- Familien Hede Nielsens Fond
- Topics
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Pregnancy and Medication Impact
- Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Prenatal Substance Exposure Effects
- Health Sciences › Medicine › Psychiatry and Mental health › Attention Deficit Hyperactivity Disorder
- Keywords
- prenatal exposure, antidepressants, attention deficit hyperactivity disorder, maternal antidepressant use, pregnancy, selective serotonin reuptake inhibitors, prenatal drug exposure, ADHD risk, sibling comparison
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
