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Nirmatrelvir/ritonavir use in pregnant women with SARS-CoV-2 Omicron infection: a target trial emulation

Nature Medicine volume 30, pages 112–116 (2024)Cite this article

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Abstract

To date, there is a lack of randomized trial data examining the use of the antiviral nirmatrelvir/ritonavir in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected pregnant persons. This target trial emulation study aimed to address this gap by evaluating the use of nirmatrelvir/ritonavir in nonhospitalized pregnant women with symptomatic SARS-CoV-2 Omicron variant infection. Among patients diagnosed between 16 March 2022 and 5 February 2023, exposure was defined as outpatient nirmatrelvir/ritonavir treatment within 5 days of symptom onset or coronavirus disease 2019 (COVID-19) diagnosis. Primary outcomes were maternal morbidity and mortality index (MMMI), all-cause maternal death and COVID-19-related hospitalization, while secondary outcomes were individual components of MMMI, preterm birth, stillbirth, neonatal death and cesarean section. One-to-ten propensity-score matching was conducted between nirmatrelvir/ritonavir users and nonusers, followed by cloning, censoring and weighting. Overall, 211 pregnant women on nirmatrelvir/ritonavir and 1,998 nonusers were included. Nirmatrelvir/ritonavir treatment was associated with reduced 28-day MMMI risk (absolute risk reduction (ARR) = 1.47%, 95% confidence interval (CI) = 0.21–2.34%) but not 28-days COVID-19-related hospitalization (ARR = −0.09%, 95% CI = −1.08% to 0.71%). Nirmatrelvir/ritonavir treatment was also associated with reduced risks of cesarean section (ARR = 1.58%, 95% CI = 0.85–2.39%) and preterm birth (ARR = 2.70%, 95% CI = 0.98–5.31%). No events of maternal or neonatal death or stillbirth were recorded. The findings suggest that nirmatrelvir/ritonavir is an effective treatment in symptomatic pregnant women with SARS-CoV-2 Omicron variant infection.

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Fig. 1: Flowchart of inclusion and exclusion of pregnant women with symptomatic SARS-CoV-2 infection who had received outpatient nirmatrelvir/ritonavir and those who had not.

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Data availability

The clinical outcome data and vaccination records were extracted from the Hospital Authority database in Hong Kong, and data on confirmed cases of SARS-CoV-2 infection were extracted from the eSARS data provided by the Center for Health Protection (Department of Health, the Government of the Hong Kong Special Administrative Region). The data custodians (the Hospital Authority and the Department of Health) provided the underlying individual patient data to the University of Hong Kong to perform scientific research for the study. Restrictions apply to the availability of these data, which were used under the license of the Hospital Authority and the Department of Health for this study. The authors cannot transmit or release the data, in whole or in part in whatever form or media, or to any other parties or place outside Hong Kong. The authors fully comply with the duties under the laws of Hong Kong relating to the protection of personal data including those under the Personal Data (Privacy) Ordinance and its principles in all aspects.

Code availability

The code used for this study is publicly available on GitHub (https://github.com/MSH-Chung/COVID-19-pregnant-oral_antiviral).

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Acknowledgements

This work was supported by the Health and Medical Research Fund (reference: COVID190210 to C.K.H.W.); Health Bureau, Government of Hong Kong Special Administrative Region, China; AIR@InnoHK administered by Innovation and Technology Commission, Government of Hong Kong Special Administrative Region, China. The funding source had no involvement in the study design, in the collection, analysis and interpretation of data, in the writing of the report or in the decision to submit the article for publication.

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Author notes

  1. These authors contributed equally: Carlos K. H. Wong, Kristy T. K. Lau, Matthew S. H. Chung, Ivan C. H. Au.

Authors and Affiliations

  1. Laboratory of Data Discovery for Health (D24H), Hong Kong SAR, China

    Carlos K. H. Wong, Eric H. Y. Lau, Benjamin J. Cowling & Gabriel M. Leung

  2. Department of Family Medicine and Primary Care, School of Clinical Medicine, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China

    Carlos K. H. Wong

  3. Department of Pharmacology and Pharmacy, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China

    Carlos K. H. Wong, Kristy T. K. Lau, Matthew S. H. Chung, Ivan C. H. Au & Yasmin Daoud

  4. Vaccine Confidence Project, Department of Infectious Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, UK

    Carlos K. H. Wong

  5. Department of Medicine, School of Clinical Medicine, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China

    Matthew S. H. Chung

  6. School of Public Health, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China

    Ivan C. H. Au

  7. Department of Obstetrics and Gynaecology, School of Clinical Medicine, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China

    Ka Wang Cheung

  8. WHO Collaborating Centre for Infectious Disease Epidemiology and Control, School of Public Health, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China

    Eric H. Y. Lau, Benjamin J. Cowling & Gabriel M. Leung

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Contributions

C.K.H.W. designed the study, wrote the manuscript, contributed to the interpretation of the analysis and attests that all listed authors meet authorship criteria and that no others meeting the criteria have been omitted. C.K.H.W. and K.T.K.L. reviewed the literature and wrote the manuscript. Y.D. reviewed the literature and manuscript. M.S.H.C. and I.C.H.A conducted analysis and revised the manuscript. K.W.C. contributed to the interpretation of the analysis. C.K.H.W., M.S.H.C., I.C.H.A., and E.H.Y.L. accessed and verified the underlying data. E.H.Y.L, B.J.C. and G.M.L. reviewed and revised the manuscript.

Corresponding author

Correspondence to Carlos K. H. Wong.

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Competing interests

C.K.H.W. reports the receipt of the General Research Fund, Research Grant Council, Government of Hong Kong SAR; EuroQol Research Foundation; AstraZeneca and Boehringer Ingelheim, all outside the submitted work. B.J.C. reports honoraria from AstraZeneca, Fosun Pharma, GlaxoSmithKline, Haleon, Moderna, Pfizer, Roche and Sanofi Pasteur and has provided scientific advice to Pfizer and AstraZeneca on issues related to disease burden and vaccine effectiveness. He has not provided scientific advice to either company related to COVID-19 antiviral effectiveness, and he has not received any funding from Pfizer or AstraZeneca for any research on antiviral effectiveness including the current work. All other authors declare no competing interests.

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Nature Medicine thanks Kelly Gebo, Laurie Tomlinson, and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Primary Handling Editor: Alison Farrell, in collaboration with the Nature Medicine team.

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Wong, C.K.H., Lau, K.T.K., Chung, M.S.H. et al. Nirmatrelvir/ritonavir use in pregnant women with SARS-CoV-2 Omicron infection: a target trial emulation. Nat Med 30, 112–116 (2024). https://doi.org/10.1038/s41591-023-02674-0

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