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Peer-reviewedCC BY-NC 4.0RMD Open

First trimester exposure to hydroxychloroquine during pregnancy and major congenital malformations: a systematic review and meta-analysis

  • Estelle Cournand1
  • Alexandre Teboul2
  • Nathalie Costedoat-Chalumeau3,4,5
  • François Chasset2
  • Bruno Fautrel6
  • Elisabeth Elefant7
  • Florence Tubach8
  • Agnès Dechartres8
  • Bénédicte Coulm1,9
  • Benoît Marin1
9 affiliations
  1. 1Sorbonne Université, INSERM, Institut Pierre Louis d’Epidémiologie et de Santé Publique, Équipe PEPITES, AP-HP, Hôpital Pitié-Salpêtrière, Département de Santé Publique, Centre de Référence sur les Agents Tératogènes (CRAT), Paris, France
  2. 2Sorbonne Université, INSERM, Institut Pierre Louis d’Epidémiologie et de Santé Publique, Équipe PEPITES, AP-HP, Hôpital Tenon, Service de dermatologie et Allergologie, Paris, France
  3. 3Equipe ECAMO, CRESS (UMR 1153), Université Paris Cité, Paris, France
  4. 4Service de Médecine Interne, Centre de référence des maladies auto-immunes et auto-inflammatoires systémiques rares d'Ile-de-France, de l’Est et de l’Ouest, Hôpital Cochin, Paris, France
  5. 5Assistance PubliqueHôpitaux de Paris (AP-HP), Université Paris Cité, Paris, France
  6. 6Sorbonne Université, INSERM, Institut Pierre Louis d’Epidémiologie et de Santé Publique, Équipe PEPITES, AP-HP, Hôpital Pitié Salpêtrière, Rheumatology department, CEREMAIA rare disease center, Paris, France
  7. 7Département de Santé Publique, Centre de Référence sur les Agents Tératogènes (CRAT), AP-HP, Hôpital Pitié-Salpêtrière, Paris, France
  8. 8Sorbonne Université, INSERM, Institut Pierre Louis d’Epidémiologie et de Santé Publique, Équipe PEPITES, AP-HP, Hôpital Pitié-Salpêtrière, Département de Santé Publique, Centre de Pharmacoépidémiologie (CEPHEPI), Paris, France
  9. 9Département Universitaire de Maïeutique, Sorbonne Université, Paris, France
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Abstract

Objective: To assess the association between hydroxychloroquine (HCQ) use during the first trimester of pregnancy and the risk of major congenital malformations (MCMs).

Methods: In this systematic review and meta-analysis, we searched MEDLINE, EMBASE, CENTRAL, clinical trials registers and specialised databases from inception to 9 July 2025. We included randomised controlled trials (RCTs) and comparative observational studies. Study selection and data extraction were performed independently by two reviewers. Risk of bias was assessed using Risk of Bias in Non-Randomised Studies of Interventions or Risk of Bias 2. Primary outcome was any MCM. Meta-analyses used fixed-effects and random-effects models (REM) based on adjusted or crude ORs.

Results: From 4311 records, we included 20 studies (18 cohorts, 1 case-control and 1 RCT) including 4260 HCQ-exposed and 361 802 unexposed-pregnancies. The risk of bias was serious (n=4), critical (n=15) and ‘some concern’ (n=1, RCT). A significant association was found between HCQ and any MCM (OR=1.27, 95% CI (1.11 to 1.45) for REM, I2=0.0%, Tau2=0, n=19 studies). The pooled association based on adjusted OR was also statistically significant (aOR 1.29, 95% CI (1.09 to 1.53) for REM, I²=0.0%, Tau2=0, n=8). The certainty of evidence was low.

Conclusion: A slight association between HCQ exposure and MCM was observed, with low certainty of evidence. Given the well-established maternal/fetal benefits of HCQ in systemic lupus erythematosus, these results do not support changes in current clinical practice regarding its use during pregnancy. For other indications where alternatives exist, its use during pregnancy should be considered on a case-by-case basis.

PROSPERO registration number: CRD420250609725.

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Cite

BibTeXRIS
BibTeX
@article{cournand2026first,
  title = {{First trimester exposure to hydroxychloroquine during pregnancy and major congenital malformations: a systematic review and meta-analysis}},
  author = {Estelle Cournand and Alexandre Teboul and Nathalie Costedoat-Chalumeau and François Chasset and Bruno Fautrel and Elisabeth Elefant and Florence Tubach and Agnès Dechartres and Bénédicte Coulm and Benoît Marin},
  journal = {RMD Open},
  year = {2026},
  month = oct,
  doi = {10.1136/rmdopen-2026-007015},
  url = {https://doi.org/10.1136/rmdopen-2026-007015},
  note = {CC BY-NC 4.0},
}
RIS
TY  - JOUR
TI  - First trimester exposure to hydroxychloroquine during pregnancy and major congenital malformations: a systematic review and meta-analysis
AU  - Estelle Cournand
AU  - Alexandre Teboul
AU  - Nathalie Costedoat-Chalumeau
AU  - François Chasset
AU  - Bruno Fautrel
AU  - Elisabeth Elefant
AU  - Florence Tubach
AU  - Agnès Dechartres
AU  - Bénédicte Coulm
AU  - Benoît Marin
PY  - 2026
DA  - 2026/10/26
JO  - RMD Open
DO  - 10.1136/rmdopen-2026-007015
UR  - https://doi.org/10.1136/rmdopen-2026-007015
AB  - Objective: To assess the association between hydroxychloroquine (HCQ) use during the first trimester of pregnancy and the risk of major congenital malformations (MCMs).  Methods: In this systematic review and meta-analysis, we searched MEDLINE, EMBASE, CENTRAL, clinical trials registers and specialised databases from inception to 9 July 2025. We included randomised controlled trials (RCTs) and comparative observational studies. Study selection and data extraction were performed independently by two reviewers. Risk of bias was assessed using Risk of Bias in Non-Randomised Studies of Interventions or Risk of Bias 2. Primary outcome was any MCM. Meta-analyses used fixed-effects and random-effects models (REM) based on adjusted or crude ORs.  Results: From 4311 records, we included 20 studies (18 cohorts, 1 case-control and 1 RCT) including 4260 HCQ-exposed and 361 802 unexposed-pregnancies. The risk of bias was serious (n=4), critical (n=15) and ‘some concern’ (n=1, RCT). A significant association was found between HCQ and any MCM (OR=1.27, 95% CI (1.11 to 1.45) for REM, I2=0.0%, Tau2=0, n=19 studies). The pooled association based on adjusted OR was also statistically significant (aOR 1.29, 95% CI (1.09 to 1.53) for REM, I²=0.0%, Tau2=0, n=8). The certainty of evidence was low.  Conclusion: A slight association between HCQ exposure and MCM was observed, with low certainty of evidence. Given the well-established maternal/fetal benefits of HCQ in systemic lupus erythematosus, these results do not support changes in current clinical practice regarding its use during pregnancy. For other indications where alternatives exist, its use during pregnancy should be considered on a case-by-case basis.  PROSPERO registration number: CRD420250609725.
SN  - 2056-5933
ER  -