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Association of Rift Valley fever virus infection with miscarriage in Sudanese women: a cross-sectional study
Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology. (Magnus Evander)ORCID iD: 0000-0002-1269-4770
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2016 (English)In: The Lancet Global Health, ISSN 2352-3026, E-ISSN 2214-109XArticle in journal (Refereed) Epub ahead of print
Abstract [en]

BACKGROUND: Rift Valley fever virus is an emerging mosquito-borne virus that causes infections in animals and human beings in Africa and the Arabian Peninsula. Outbreaks of Rift Valley fever lead to mass abortions in livestock, but such abortions have not been identified in human bezings. Our aim was to investigate the cause of miscarriages in febrile pregnant women in an area endemic for Rift Valley fever.

METHODS: Pregnant women with fever of unknown origin who attended the governmental hospital of Port Sudan, Sudan, between June 30, 2011, and Nov 17, 2012, were sampled at admission and included in this cross-sectional study. Medical records were retrieved and haematological tests were done on patient samples. Presence of viral RNA as well as antibodies against a variety of viruses were analysed. Any association of viral infections, symptoms, and laboratory parameters to pregnancy outcome was investigated using Pearson's χ(2) test.

FINDINGS: Of 130 pregnant women with febrile disease, 28 were infected with Rift Valley fever virus and 31 with chikungunya virus, with typical clinical and laboratory findings for the infection in question. 15 (54%) of 28 women with an acute Rift Valley fever virus infection had miscarriages compared with 12 (12%) of 102 women negative for Rift Valley fever virus (p<0·0001). In a multiple logistic regression analysis, adjusting for age, haemorrhagic disease, and chikungunya virus infection, an acute Rift Valley fever virus infection was an independent predictor of having a miscarriage (odds ratio 7·4, 95% CI 2·7-20·1; p<0·0001).

INTERPRETATION: This study is the first to show an association between infection with Rift Valley fever virus and miscarriage in pregnant women. Further studies are warranted to investigate the possible mechanisms. Our findings have implications for implementation of preventive measures, and evidence-based information to the public in endemic countries should be strongly recommended during Rift Valley fever outbreaks.

FUNDING: Schlumberger Faculty for the Future, CRDF Global (31141), the Swedish International Development Cooperation Agency, the County Council of Västerbotten, and the Faculty of Medicine, Umeå University.

Place, publisher, year, edition, pages
Keyword [en]
Rift Valley fever, Rift Valley fever virus, infectious diseases, virology, miscarriage, Sudan, maternal health
National Category
Infectious Medicine
Research subject
Infectious Diseases; Medical Virology; Obstetrics and Gynaecology
URN: urn:nbn:se:umu:diva-126472DOI: 10.1016/S2214-109X(16)30176-0PubMedID: 27692776OAI: diva2:1033555
Available from: 2016-10-07 Created: 2016-10-07 Last updated: 2016-10-12
In thesis
1. Rift Valley fever: consequences of virus-host interactions
Open this publication in new window or tab >>Rift Valley fever: consequences of virus-host interactions
2016 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Rift Valley fever virus (RVFV) is a mosquito-borne virus which has the ability to infect a large variety of animals including humans in Africa and Arabian Peninsula. The abortion rate among these animals are close to 100%, and young animals develop severe disease which often are lethal.

In humans, Rift Valley fever (RVF) presents in most cases as a mild illness with influenza-like symptoms. However, in about 8% of the cases it progresses into a more severe disease with a high case fatality rate. Since there is such a high abortion rate among infected animals, a link between human miscarriage and RVFV has been suggested, but never proven.

We could in paper I for the first time show an association between acute RVFV infection and miscarriage in humans. We observed an increase in pregnant women arriving at the Port Sudan Hospital with fever of unknown origin, and several of the patients experienced miscarriage. When we analysed their blood samples for several viral diseases we found that many had an acute RVFV infection and of these, 54% experienced a miscarriage. The odds of having a miscarriage was 7 times higher for RVFV patients compared to the RVFV negative women of which only 12% miscarried. These results indicated that RVFV infection could be a contributing factor to miscarriage.

RVFV is an enveloped virus containing the viral glycoproteins n and c (Gn and Gc respectively), where Gn most likely is responsible for the initial cellular contact. The protein DC-SIGN on dendritic cells and the glycosaminoglycan heparan sulfate has been suggested as cellular receptors for RVFV, however other mechanisms are probably also involved in binding and entry. Charge is a driving force for molecular interaction and has been shown to be important for cellular attachment of several viruses, and in paper II we could show that when the charge around the cells was altered, the infection was affected. We also showed that Gn most likely has a positive charge at a physiological pH.

When we added negatively charged molecules to the viral particles before infection, we observed a decreased infection efficiency, which we also observed after removal of carbohydrate structures from the cell surface.

Our results suggested that the cellular interaction partner for initial attachment is a negatively charged carbohydrate. Further investigations into the mechanisms of RVFV cellular interactions has to be undertaken in order to understand, and ultimately prevent, infection and disease.

There is currently no vaccine approved for human use and no specific treatments for RVF, so there is a great need for developing safe effective drugs targeting this virus. We designed a whole-cell based high-throughput screen (HTS) assay which we used to screen libraries of small molecular compounds for anti-RVFV properties. After dose-response and toxicity analysis of the initial hits, we identified six safe and effective inhibitors of RVFV infection that with further testing could become drug candidates for treatment of RVF. This study demonstrated the application of HTS using a whole-cell virus replication reporter gene assay as an effective method to identify novel compounds with potential antiviral activity against RVFV.

Place, publisher, year, edition, pages
Umeå: Umeå universitet, 2016. 58 p.
Umeå University medical dissertations, ISSN 0346-6612 ; 1843
Rift Valley fever, Rift Valley fever virus, viral haemorrhagic fever, miscarriage, entry, charge, carbohydrates, high-throughput screening, antiviral, cell-based assay
National Category
Infectious Medicine Microbiology in the medical area
Research subject
Medical Virology
urn:nbn:se:umu:diva-126602 (URN)978-91-7601-558-2 (ISBN)
Public defence
2016-11-04, Hörsal D, Unod T9, 9 trappor, Norrlands universitetssjukhus, Umeå, 09:00 (English)
Available from: 2016-10-14 Created: 2016-10-12 Last updated: 2016-10-12Bibliographically approved

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