Association Between Methylphenidate and Amphetamine Use in Pregnancy and Risk of Congenital Malformations: A Cohort Study From the International Pregnancy Safety Study Consortium
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Importance: Given the rapidly increasing use of stimulant medications during pregnancy and among women of reproductive age who may become pregnant inadvertently, there is a need to better understand their safety. Objective: To examine the risk of congenital malformations associated with intrauterine exposure to stimulants. Design, Setting, and Participants: Cohort study of the Medicaid-insured population in the United States nested in the 2000-2013 US Medicaid Analytic eXtract, with follow-up of safety signals detected in the Medicaid Analytic eXtract data using the Nordic Health registries (2003-2013) (Denmark, Finland, Iceland, Norway, and Sweden). A total of 1 813 894 publicly insured pregnancies in the United States and 2 560 069 singleton pregnancies in the 5 Nordic countries ending in live births were included. Relative risks were estimated accounting for underlying psychiatric disorders and other potential confounders. Relative risk estimates for the US and Nordic data were pooled using a fixed-effects meta-analytic approach. The study was conducted from July 1, 2015, to March 31, 2017. Exposures: Methylphenidate and amphetamines dispensed during the first trimester. Main Outcomes and Measures: Major congenital malformations and subgroup of cardiac malformations. Results: In the US data, of the 1 813 894 pregnancies evaluated, 35.0 per 1000 infants not exposed to stimulants were diagnosed as having congenital malformations, compared with 45.9 per 1000 infants for methylphenidate and 45.4 for amphetamines. For cardiac malformations, the risks were 12.7 (95% CI, 12.6-12.9), 18.8 (95% CI, 13.8-25.6), and 15.4 (95% CI, 12.5-19.0) per 1000 infants, respectively. The adjusted relative risks for methylphenidate were 1.11 (95% CI, 0.91-1.35) for any malformation and 1.28 (95% CI, 0.94-1.74) for cardiac malformations. No increased risks were observed for amphetamines: 1.05 (95% CI, 0.93-1.19) for any malformations and 0.96 (95% CI, 0.78-1.19) for cardiac malformations. Findings were confirmed in sensitivity analyses accounting for proxies of unmeasured confounders and increasing the specificity of the exposure and outcome definitions. Replication of the analyses for methylphenidate using the Nordic data including 2 560 069 pregnancies yielded a relative risk of 1.28 (95% CI, 0.83-1.97) for cardiac malformations, resulting in a pooled estimate of 1.28 (95% CI, 1.00-1.64). Conclusions and Relevance: These findings suggest a small increase in the risk of cardiac malformations associated with intrauterine exposure to methylphenidate but not to amphetamines. This information is important when weighing the risks and benefits of alternative treatment strategies for attention-deficit/hyperactivity disorder in women of reproductive age and during early pregnancy.
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Methylphenidate use during pregnancy was associated with a higher risk of cardiac malformations, increasing from 12.9 to 16.5 per 1,000 infants.
“A cohort study of over 1.8 million pregnancies in the United States and over 2.5 million pregnancies in the health registries of Denmark, Finland, Sweden, Norway, and Iceland reported that use of methylphenidate (but not amphetamines) by pregnant woman was associated with a higher risk for cardiac malformations from 12.9 per thousand infants to 16.5 per thousand infants (Huybrechts et al., 2018).”
From The World Federation of ADHD International Consensus Statement: 208 Evidence-based conclusions about the disorder (2021) · cites this paper as Huybrechts et al., 2018
The Discussion and Validation Analyses (page not supplied) report a small increased risk of cardiac malformations with first-trimester methylphenidate exposure, but not amphetamine exposure. The stated change from 12.9 to 16.5 per 1,000 is not reported: Table 3 gives 12.7 per 1,000 unexposed infants versus 18.8 per 1,000 methylphenidate-exposed infants in the US cohort; the Nordic figures are 13.3 versus 17.1. (LLM, conf=0.90)
Experimental — accuracy not yet measuredAmphetamine use during pregnancy was not associated with a higher risk of cardiac malformations.
“A cohort study of over 1.8 million pregnancies in the United States and over 2.5 million pregnancies in the health registries of Denmark, Finland, Sweden, Norway, and Iceland reported that use of methylphenidate (but not amphetamines) by pregnant woman was associated with a higher risk for cardiac malformations from 12.9 per thousand infants to 16.5 per thousand infants (Huybrechts et al., 2018).”
From The World Federation of ADHD International Consensus Statement: 208 Evidence-based conclusions about the disorder (2021) · cites this paper as Huybrechts et al., 2018
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Cites
Diagnostic and Statistical Manual of Mental Disorders(DSM)
Leong, F. T. L. (2008) · Sage eBooks · doi:10.4135/9781412963978.n182 · Cited by 10,858 · see citing works
Polanczyk, G. V., Salum, G. A., Sugaya, L. S., Caye, A., & Rohde, L. A. (2015) · Journal of Child Psychology and Psychiatry · doi:10.1111/jcpp.12381 · Cited by 3,990 · see citing works
FARAONE, S. V., BIEDERMAN, J., & MICK, E. (2006) · Psychological Medicine · doi:10.1017/s003329170500471x · Cited by 2,267 · see citing works
Diagnostic and Statistical Manual of Mental Disorders (DSM)
Mullner, R. M. (2009) · Encyclopedia of Health Services Research · doi:10.4135/9781412971942.n109 · Cited by 1,359 · see citing works
Cross-national prevalence and correlates of adult attention-deficit hyperactivity disorder
Fayyad, J., De Graaf, R., Kessler, R., Alonso, J., Angermeyer, M., Demyttenaere, K., De Girolamo, G., Haro, J. M., Karam, E. G., Lara, C., et al. (2007) · British Journal of Psychiatry · doi:10.1192/bjp.bp.106.034389 · Cited by 1,321 · see citing works
Schneeweiss, S., Rassen, J. A., Glynn, R. J., Avorn, J., Mogun, H., & Brookhart, M. A. (2009) · Epidemiology · doi:10.1097/ede.0b013e3181a663cc · Cited by 1,128 · see citing works
Self-citationAttention deficit hyperactivity disorder
Thapar, A., & Cooper, M. (2015) · The Lancet · doi:10.1016/s0140-6736(15)00238-x · Cited by 1,081 · see citing works
Drugs in Pregnancy and Lactation. A Reference Guide to Fetal and Neonatal Risk.
(1983) · Annals of Internal Medicine · doi:10.7326/0003-4819-99-1-144_6 · Cited by 851 · see citing works
Basic methods for sensitivity analysis of biases.
Greenland, S. (1996) · International Journal of Epidemiology · doi:10.1093/ije/25.6.1107 · Cited by 605 · see citing works
Development of a Comorbidity Index for Use in Obstetric Patients
Bateman, B. T., Mhyre, J. M., Hernández–Dı́az, S., Huybrechts, K. F., Fischer, M. A., Creanga, A. A., Callaghan, W. M., & Gagne, J. J. (2013) · Obstetrics and Gynecology · doi:10.1097/aog.0b013e3182a603bb · Cited by 491 · see citing works
Self-citationDrugs in Pregnancy and Lactation: A Reference Guide to Fetal and Neonatal Risk
Gilbert‐Barness, E. (1996) · Archives of Pediatrics and Adolescent Medicine · doi:10.1001/archpedi.1996.02170300118039 · Cited by 466 · see citing works
Agnew-Blais, J. C., Polanczyk, G. V., Danese, A., Wertz, J., Moffitt, T. E., & Arseneault, L. (2016) · JAMA Psychiatry · doi:10.1001/jamapsychiatry.2016.0465 · Cited by 459 · see citing works
Antidepressant Use in Pregnancy and the Risk of Cardiac Defects
Huybrechts, K. F., Palmsten, K. K., Avorn, J., Cohen, L. S., Holmes, L. B., Franklin, J. M., Mogun, H., Levin, R., Kowal, M. K., Setoguchi, S., et al. (2014) · New England Journal of Medicine · doi:10.1056/nejmoa1312828 · Cited by 405 · see citing works
Self-citationKieler, H., Artama, M., Engeland, A., Ericsson, Ö., Furu, K., Gissler, M., Nielsen, M. G., Nørgaard, M., Stephansson, O., Valdimarsdóttir, U. A., et al. (2011) · BMJ · doi:10.1136/bmj.d8012 · Cited by 276 · see citing works
Self-citationDesai, R. J., Rothman, K. J., Bateman, B. T., Hernández–Dı́az, S., & Huybrechts, K. F. (2016) · Epidemiology · doi:10.1097/ede.0000000000000595 · Cited by 246 · see citing works
Self-citationTrends in Medication Treatment for ADHD
Castle, L., Aubert, R. E., Verbrugge, R. R., Khalid, M., & Epstein, R. S. (2007) · Journal of Attention Disorders · doi:10.1177/1087054707299597 · Cited by 244 · see citing works
Statins and congenital malformations: cohort study
Bateman, B. T., Hernandez-Diaz, S., Fischer, M. A., Seely, E. W., Ecker, J. L., Franklin, J. M., Desai, R. J., Allen-Coleman, C., Mogun, H., Avorn, J., et al. (2015) · BMJ · doi:10.1136/bmj.h1035 · Cited by 236 · see citing works
Self-citationValidation of an obstetric comorbidity index in an external population
Metcalfe, A., Lix, L., Johnson, J., Currie, G. R., Lyon, A., Bernier, F. P., & Tough, S. (2015) · BJOG An International Journal of Obstetrics & Gynaecology · doi:10.1111/1471-0528.13254 · Cited by 169 · see citing works
The Use of Central Nervous System Active Drugs During Pregnancy
Källén, B. A. J., Borg, N., & Reis, M. (2013) · Pharmaceuticals · doi:10.3390/ph6101221 · Cited by 161 · see citing works
Zetterqvist, J., Asherson, P., Halldner, L., Långström, N., & Larsson, H. (2013) · Acta Psychiatrica Scandinavica · doi:10.1111/acps.12004 · Cited by 155 · see citing works
Renoux, C., Shin, J., Dell'Aniello, S., Fergusson, E., & Suissa, S. (2016) · British Journal of Clinical Pharmacology · doi:10.1111/bcp.13000 · Cited by 132 · see citing works
Basic Methods for Sensitivity Analysis of Biases
Greenland, S. (1996) · International Journal of Epidemiology · doi:10.1093/ije/25.6.1107-a · Cited by 109 · see citing works
Furu, K., Kieler, H., Haglund, B., Engeland, A., Selmer, R., Stephansson, O., Valdimarsdóttir, U., Zoega, H., Artama, M., Gissler, M., et al. (2015) · British medical journal · doi:10.1136/bmj.h1798 · Cited by 102 · see citing works
Self-citationSelective Serotonin Reuptake Inhibitors During Pregnancy and Risk of Stillbirth and Infant Mortality
Stephansson, O., Kieler, H., Haglund, B., Artama, M., Engeland, A., Furu, K., Gissler, M., Nørgaard, M., Nielsen, R. B., Zoëga, H., et al. (2013) · JAMA · doi:10.1001/jama.2012.153812 · Cited by 100 · see citing works
Self-citationUse of ADHD medication during pregnancy from 1999 to 2010: a Danish register‐based study
Hærvig, K. K., Mortensen, L. H., Hansen, A. V., & Strandberg‐Larsen, K. (2014) · Pharmacoepidemiology and Drug Safety · doi:10.1002/pds.3600 · Cited by 81 · see citing works
HUMAN TERATOGENS, PRENATAL MORTALITY, AND SELECTION BIAS
Khoury, M. J., Flanders, W. D., James, L. M., & Erickson, J. D. (1989) · American Journal of Epidemiology · doi:10.1093/oxfordjournals.aje.a115342 · Cited by 70 · see citing works
Effects of antenatal exposure to anorectic drugs
Milkovich, L., & van den Berg, B. J. (1977) · American Journal of Obstetrics and Gynecology · doi:10.1016/0002-9378(77)90645-7 · Cited by 65 · see citing works
First-Trimester Exposure to Methylphenidate
Pottegård, A., Hallas, J., Andersen, J. T., Løkkegaard, E., Dideriksen, D., Aagaard, L., & Damkier, P. (2014) · The Journal of Clinical Psychiatry · doi:10.4088/jcp.13m08708 · Cited by 64 · see citing works
Methylphenidate use in pregnancy and lactation: a systematic review of evidence
Bolea-Alamanac, B. M., Green, A. C., Verma, G., Maxwell, P., & Davies, S. (2013) · British Journal of Clinical Pharmacology · doi:10.1111/bcp.12138 · Cited by 54 · see citing works
MALFORMATIONS IN MICE INDUCED BY DEXAMPHETAMINE SULPHATE
Nora, J., Trasler, D. G., & Fraser, F. C. (1965) · The Lancet · doi:10.1016/s0140-6736(65)92892-8 · Cited by 52 · see citing works
Karlstad, Ø., Zoega, H., Furu, K., Bahmanyar, S., Martikainen, J., Kieler, H., & Pottegård, A. (2016) · European Journal of Clinical Pharmacology · doi:10.1007/s00228-016-2125-y · Cited by 51 · see citing works
Self-citationDiav‐Citrin, O., Shechtman, S., Arnon, J., Wajnberg, R. S., Borisch, C., Beck, E., Richardson, J. L., Bozzo, P., Nulman, I., & Ornoy, A. (2016) · The Journal of Clinical Psychiatry · doi:10.4088/jcp.15m10083 · Cited by 47 · see citing works
Increasing use of ADHD medications in pregnancy
Louik, C., Kerr, S., Kelley, K. E., & Mitchell, A. A. (2015) · Pharmacoepidemiology and Drug Safety · doi:10.1002/pds.3742 · Cited by 42 · see citing works
D ‐methylphenidate and D , L ‐methylphenidate are not developmental toxicants in rats and rabbits
Teo, S. K., Stirling, D., Hoberman, A. M., Christian, M. S., Thomas, S. D., & Khetani, V. D. (2003) · Birth Defects Research Part B Developmental and Reproductive Toxicology · doi:10.1002/bdrb.10018 · Cited by 32 · see citing works
Developmental toxicity assessment of d,l‐Methylphenidate and d‐Methylphenidate in rats and rabbits
Beckman, D. A., Schneider, M., Youreneff, M., & Tse, F. L. S. (2008) · Birth Defects Research Part B Developmental and Reproductive Toxicology · doi:10.1002/bdrb.20168 · Cited by 21 · see citing works
Attention Deficit Hyperactivity Disorder
Muñoz‐Solomando, A., & Thapar, A. (2017) · doi:10.1002/9781119170235.ch24 · Cited by 10 · see citing works
Selective Serotonin Reuptake Inhibitors During Pregnancy and Risk of Stillbirth and Infant Mortality
Stephansson, O., Kieler, H., Haglund, B., Artama, M., Engeland, A., Furu, K., Gissler, M., Nørgaard, M., Nielsen, R. B., Zoëga, H., et al. (2013) · Survey of Anesthesiology · doi:10.1097/sa.0b013e3182a4929c · Cited by 7 · see citing works
Self-citation
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Cited by
Sorted by citations
Faraone, S. V., Banaschewski, T., Coghill, D., Zheng, Y., Biederman, J., Bellgrove, M. A., Newcorn, J. H., Gignac, M., Al Saud, N. M., Manor, I., et al. (2021) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2021.01.022 · Cited by 1,545 · see citing works
“…in the health registries of Denmark, Finland, Sweden, Norway, and Iceland reported that use of methylphenidate (but not amphetamines) by pregnant women was associated with a higher risk for cardiac malformations from 12.9 per thousand infants to 16.5 per thousand infants (Huybrechts et al., 2018).”
InfluentialUpdated European Consensus Statement on diagnosis and treatment of adult ADHD
Kooij, J. J. S., Bijlenga, D., Salerno, L., Jaeschke, R., Bitter, I., Balázs, J., Thome, J., Dom, G., Kasper, S., Nunes Filipe, C., et al. (2019) · European Psychiatry · doi:10.1016/j.eurpsy.2018.11.001 · Cited by 686 · see citing works
Fetal safety of methylphenidate-A scoping review and meta analysis
Koren, G., Barer, Y., & Ornoy, A. (2020) · Reproductive Toxicology · doi:10.1016/j.reprotox.2020.03.003 · Cited by 26 · see citing works
- Authors
- Huybrechts, K. F., Bröms, G., Christensen, L. B., Einarsdóttir, K., Engeland, A., Furu, K., Gissler, M., Hernandez-Diaz, S., Karlsson, P., Karlstad, Ø., Kieler, H., Lahesmaa-Korpinen, A.-M., Mogun, H., Nørgaard, M., Reutfors, J., Sørensen, H. T., Zoega, H., & Bateman, B. T.
- Affiliations
- Brigham and Women's Hospital (US)
- Karolinska University Hospital (SE)
- Aarhus University Hospital (DK)
- University of Iceland (IS)
- Norwegian Institute of Public Health (NO)
- University of Turku (FI)
- Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, Massachusetts
- Information Services Department, National Institute for Health and Welfare, Helsinki, Finland
- Centre of Public Health Sciences, Faculty of Medicine, University of Iceland, Reykjavik, Iceland
- Corresponding author
- Huybrechts, Krista F.
- ORCID
- Venue
- JAMA Psychiatry
- Publisher
- American Medical Association (AMA)
- Published
- 2018-02-01
- Volume
- 75
- Issue
- 2
- Pages
- 167
- ISSN
- 2168-622X (ISSN-L)
- PMC
- PMC5838573
- OpenAlex
- W2773972383
- Semantic Scholar
- fc22c3dbf8ce9ab97baddf144912f5a640c4b6e4
- Cited by
- 142
- References
- 37
- Citations by year
- 2026: 10 · 2025: 20 · 2024: 15 · 2023: 17 · 2022: 10 · 2021: 20 · 2020: 15 · 2019: 12 · 2018: 20 · 2017: 2 · 2013: 1
- FWCI
- 12.56
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- JAMA Psychiatry (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Mental Health (K01MH099141)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (K08HD075831, R21HD092879)
- 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 › Pediatrics, Perinatology and Child Health › Pharmacological Effects and Toxicity Studies
- Keywords
- methylphenidate, amphetamine, stimulant medication, prenatal drug exposure, congenital malformations, cardiac anomalies, pregnancy, maternal medication use, ADHD medication, drug safety in pregnancy, fixed-effects meta-analysis, relative risk, psychiatric disorders in pregnancy, live birth, miscarriage, stillbirth
- MeSH terms
- Abnormalities, Drug-Induced, Adolescent, Adult, Amphetamine, Attention Deficit Disorder with Hyperactivity, Child, Female, Follow-Up Studies, Heart Defects, Congenital, Humans, Infant, Newborn, Methylphenidate, Middle Aged, Pregnancy, Pregnancy Complications, Pregnancy Outcome, Pregnancy Trimester, First, Risk, Scandinavian and Nordic Countries, United States, Cohort Studies, Risk Assessment, Young Adult
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