Miscarriage and stillbirth following maternal Zika virus infection in nonhuman primates

Abstract

Zika virus (ZIKV) infection is associated with congenital defects and pregnancy loss. Here, we found that 26% of nonhuman primates infected with Asian/American ZIKV in early gestation experienced fetal demise later in pregnancy despite showing few clinical signs of infection. Pregnancy loss due to asymptomatic ZIKV infection may therefore be a common but under-recognized adverse outcome related to maternal ZIKV infection.

Fig. 1: Kaplan–Meier curves comparing survival rates among macaques exposed to ZIKV under different conditions.

References

  1. 1.

    Schaub, B. et al. Eur. J. Obstet. Gynecol. Reprod. Biol. 207, 240–241 (2016).

    Article  Google Scholar 

  2. 2.

    Brasil, P. et al. N. Engl. J. Med. 375, 2321–2334 (2016).

    Article  Google Scholar 

  3. 3.

    Subissi, L. et al. Int J. Infect. Dis. 65, 116–118 (2017).

    Article  Google Scholar 

  4. 4.

    van der Eijk, A. A. et al. N. Engl. J. Med. 375, 1002–1004 (2016).

    Article  Google Scholar 

  5. 5.

    Esposito, D. L. et al. Am. J. Trop. Med. Hyg. 97 (Suppl. 5), 1959 (2017).

    Google Scholar 

  6. 6.

    Hoen, B. et al. N. Engl. J. Med. 378, 985–994 (2018).

    Article  Google Scholar 

  7. 7.

    Pouliot, S. H. et al. Obstet. Gynecol. Surv. 65, 107–118 (2010).

    PubMed  Google Scholar 

  8. 8.

    Carter, A. M. et al. Best. Pract. Res Clin. Obstet. Gynaecol. 25, 249–257 (2011).

    Article  Google Scholar 

  9. 9.

    Dudley, D. M. et al. Nat. Commun. 7, 12204 (2016).

    CAS  Article  Google Scholar 

  10. 10.

    Nguyen, S. M. et al. PLoS Pathog. 13, e1006378 (2017).

    Article  Google Scholar 

  11. 11.

    Adams Waldorf, K. M. et al. Nat. Med. 22, 1256–1259 (2016).

    CAS  Article  Google Scholar 

  12. 12.

    Adams Waldorf, K. M. et al. Nat. Med. 24, 368–374 (2018).

    Article  Google Scholar 

  13. 13.

    Mohr, E. L. et al. PLoS One 13, e0190617 (2018).

    Article  Google Scholar 

  14. 14.

    Hirsch, A. J. et al. Nat. Commun. 9, 263 (2018).

    Article  Google Scholar 

  15. 15.

    Seferovic, M. et al. Sci. Rep. 8, 6851 (2018).

    Article  Google Scholar 

  16. 16.

    Wilcox, A. J. et al. N. Engl. J. Med .319, 189–194 (1988).

    CAS  Article  Google Scholar 

  17. 17.

    Ammon Avalos, L. et al. Birth Defects Res A Clin. Mol. Teratol. 94, 417–423 (2012).

    CAS  Article  Google Scholar 

  18. 18.

    Hirsch, A. J. et al. PLoS Pathog. 13, e1006219 (2017).

    Article  Google Scholar 

  19. 19.

    van der Linden, V. et al. MMWR 65, 1343–1348 (2016).

    PubMed  Google Scholar 

  20. 20.

    Martinot, A. J. et al. Cell 173, 1111–1122.e10 (2018).

    CAS  Article  Google Scholar 

  21. 21.

    Noronha, L. et al. Mem. Inst. Oswaldo Cruz 111, 287–293 (2016).

    Article  Google Scholar 

  22. 22.

    Martines, R. B. et al. MMWR Morb. Mortal. Wkly Rep. 65, 159–160 (2016).

    Article  Google Scholar 

  23. 23.

    Mlakar, J. et al. N. Engl. J. Med 374, 951–958 (2016).

    CAS  Article  Google Scholar 

  24. 24.

    Heger, W. et al. in Non-Human Primates: Developmental Biology and Toxicology (Ueberreuter Wissenschaft, Berlin and Vienna,1988).

  25. 25.

    Coffey, L. L. et al. PLoS One 12, e0171148 (2017).

    Article  Google Scholar 

  26. 26.

    Golub, M. S. et al. Lab Anim. Sci. 38, 435–438 (1988).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank the Veterinary Services, Colony Management, Scientific Protocol Implementation, and Pathology Services staff at the WNPRC for their contribution to this study. We thank M. Harke, K. Brunner, T. Frost, M. Schotzko, W. Newton, K. Antony, S. Kohn, C. Newman, L. Stewart, M. Koenig, M. Breitbach, and M. Mohns for technical assistance and for monitoring the ZIKV-infected pregnant animals at WNPRC. We thank J. Eickhoff for help with statistical analysis. We thank T. Morgan for help with interpreting pathology. Studies at WNPRC were supported by DHHS/PHS/NIH R01Al116382-01A1 to D.H.O. and by the Pediatric Infectious Diseases Society to E.L.M. We thank E. Kallas for providing information on 2016 live-birth rates in Brazil. This work was also supported in part by the Office of Research Infrastructure Programs/OD grant (P51OD011106) awarded to WNPRC, Madison–Wisconsin. This research was conducted in part at a facility constructed with support from Research Facilities Improvement Program grants RR15459-01 and RR020141-01. The studies at CNPRC were supported by a CNPRC pilot research grant, 1R21AI129479-01 (K.K.V.R.), the Office of Research Infrastructure Programs/OD (P51OD011107) (CNPRC), FDA contract HHSF223201610542P (L.L.C.) and start-up funds from the Pathology, Microbiology and Immunology Department to L.L.C. We thank V. Bakula, I. Cazares, M. Christensen, C. Cruzen, A. Gibbons, D. Lemos, A. Singapuri, J. Usachenko, W. von Morgenland, J. Watanabe, J. Yee, A. Murphy, and the staff of Clinical Labs, Veterinary and Colony Research Services for technical assistance. Work at the ONPRC was supported by the National Institutes of Health Office of Research Infrastructure Programs grant (P51OD011092) to ONPRC and R21HD091032 to D.N.S. We thank L. Drew Martin, B. Dozier and N. Sternberger for their veterinary expertise, and the dedicated staff in the ONPRC Department of Comparative Medicine for assistance with animal care. The studies at Tulane National Primate Research Center (TNPRC) were supported by NIH grant R01 AI099795-05 to X.W. and by the National Institutes of Health Office of Research Infrastructure Program grant (P51OD011104) to TNPRC. We thank F. Schiro, R. Blair, and P. Aye for technical assistance. At WaNPRC, the work was primarily supported by generous private philanthropic gifts, including those from five donors from Florida who wish to remain anonymous. Further support was obtained from the University of Washington Department of Obstetrics & Gynecology, the Seattle Children’s Research Institute, and National Institutes of Health grants R01AI100989 (L.R. and K.A.W.), AI083019 (M.G.), and AI104002 (M.G.). The National Institutes of Health Office of Research Infrastructure Programs (P51 OD010425) also supported this project. We thank J. Ogle, W. Lee, and J. Thiel for technical assistance in monitoring the animals. Work at SNPRC was supported by NIH grants R01HL105704 and R21AI129455 (C.Y.C.), National Institutes of Health Office of Research Infrastructure Programs grant P51 ODOD011133 to SNPRC, and the Texas Biomedical Research Institute. We thank D. Layne-Colon for marmoset pregnancy management, ultrasonography, and collection and processing of placental and fetal material. We also thank S. Davis for technical support; M. Suter for guidance in the placental studies and analysis; and X. de Lamballerie (European Virus Archive) and B. Russell (CDC) for providing ZIKV strains.

Author information

Affiliations

Authors

Contributions

D.M.D., D.H.O., T.C.F., E.L.M., K.K.V.R., L.L.C., P.L.G., D.N.S., A.J.H., J.L.P., S.T., M.S., K.M.A., C.Y.C., X.W., R.S.V., K.M.A.W., M.G., L.R., N.J.M., A.T.P., M.H.G., and R.P.B. designed experiments. D.M.D., K.K.V.R., L.L.C., A.A., P.L.G., R.J.S., D.N.S., A.J.H., J.L.P., M.T., M.S., K.M.A., C.S.-S.M., C.Y.C., X.W., K.M.A.W., M.G., L.R., R.S.V., N.J.M., A.T.P., A.M., and H.A.S. analyzed data. D.M.D., E.L.M., T.G.G., T.C.F., S.V.C., K.K.V.R., L.L.C., R.J.S., M.S., S.T., K.M.A., C.Y.C., K.M.A.W., M.G., and A.T.P. drafted the manuscript. S.V.C., R.P.M., T.H., M.H.G., and R.P.B. were part of the veterinary staff who monitored the nonhuman primates. S.V.C., T.H., and C.E.H. collected data from breeding-colony records. R.I.K., H.L.P., L.M.C., E.B.-M., H.A.S., and A.M. provided pathology assistance. E.L.M., A.A., and R.J.S. managed projects. There is one representative corresponding author per NPRC involved in this article. The publication’s contents are solely the responsibility of the authors and do not necessarily represent the official views of NCRR or NIH.

Corresponding authors

Correspondence to Koen K. Van Rompay or Daniel N. Streblow or Suzette Tardif or Antonito T. Panganiban or Kristina M. Adams Waldorf or David H. O’Connor.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Supplementary Text and Figures

Supplementary Figure 1 and Supplementary Tables 1, 2, 4 and 5

Reporting Summary

Supplementary Table 3

Per-animal data collected from each primate research center used in data analysis for this study

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Dudley, D.M., Van Rompay, K.K., Coffey, L.L. et al. Miscarriage and stillbirth following maternal Zika virus infection in nonhuman primates. Nat Med 24, 1104–1107 (2018). https://doi.org/10.1038/s41591-018-0088-5

Download citation

Further reading

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing