Summary

Crimean-Congo hemorrhagic fever (CCHF) is a serious viral disease. There are limited data on the clinical course of the disease during pregnancy. Here, we report two pregnant women with CCHF and literature review. Tick bite history, thrombocytopenia, leukopenia, and elevated liver enzymes were noted in both cases. The diagnosis was confirmed via CCHF virus-polymerase chain reaction (PCR) or IgM positivity. Supportive therapy was given to the patients, but ribavirin was not administered. Blood product was not required in one of the patients, and three apheresis thrombocyte suspensions were given to the other one. Both patients were treated successfully and improved. Pregnancy was terminated in one and continued without any problem in the other patient and a healthy baby was born. Overall there were 42 CCHF diagnosed pregnants reported in the literature and 15 of these were from Turkey (including our cases). Maternal and fetal mortality rates were found to be 6.6% (1/15) and 40% (6/15), respectively in Turkish patients. Fetal loss was observed in 3/4 in the first trimester, 2/7 in the second trimester, and 1/4 in the third trimester. There was hemorrhage in 8 of 15 pregnants (53.3%). Maternal mortality was recorded in 1/8 (12.5%) patients with bleeding, and there was fetal loss in 6/6 (100%). CCHF during pregnancy is a rare but an important clinical problem. Clinical severity is of great importance for mother survival, and both gestational week and mother"s clinical condition seem to be important for fetus health. The virus may be transmitted by the vertical mode and fetal infection may cause intrauterine death. CCHF should be considered in women with vaginal bleeding in endemic areas.

Keywords:

Crimean-Congo hemorrhagic fever, tick, pregnancy, maternal mortality, fetal mortality

Introduction

We have limited knowledge about the clinical course of CCHF in pregnancy. Here, we report two pregnant patients and a review of the literature about the clinical course of CCHF in pregnancy.

Case Report

Case 2
A pregnant with a history of tick bite was admitted with the complaints of fever, myalgia, nausea, and vomiting. On physical examination, facial hyperemia (butterfly rash), hepatosplenomegaly, and fever were noted (Figure 1). Obstetric US showed a 5-week fetal pole. There was no vaginal bleeding. Thrombocytopenia (23.000 mm3/dL), leukopenia (1200 mm³/dL), and elevated liver and muscle enzymes (ALT: 350 U/L, AST: 480 U/L, LDH: 450 U/L, CK: 350 U/L) were recorded. The diagnosis was was confirmed by CCHFV-PCR positivity. Supportive therapy was given to the patient without ribavirin. Three units of apheresis thrombocyte were given. During hospitalization, obstetric US was repeated several times and was found to be normal. The mother was treated successfully. After one week, the patient completely recovered, and was discharged. Pregnancy continued without any problem. At follow-up three months after discharge, a live-fetus was observed by means of US. The baby was born without any complication. Since the patient's husband did not have any complaint, he was not tested for CCHF.

Figure 1: Butterfly rush on face of the patient with Crimean- Congo hemorrhagic fever

Review of the Literature
Web of Science, PubMed, and Google Scholar database were scanned for pregnancies with CCHF. Articles published between February 1979 and January 2018 were included. Keywords were as follows: "Pregnancy", "Crimean-Congo hemorrhagic fever", "fetus", and "newborn". There were a total of 43 reported cases and 15 of these were from Turkey[7-13]. One case was excluded due to duplication. Cases reported from Turkey are shown in Table 1.

Table 1: Clinical course of Crimean-Congo hemorrhagic fever in pregnancy from Turkey

Ergonul at al.[7] reported the first three cases of CCHF in pregnancy from Turkey. The first case was a pregnant at the 38^th week of gestation and was prediagnosed with HELLP syndrome. Delivery was via cesarean section. CCHF was diagnosed by PCR and ribavirin treatment was commenced. On the fifth postoperative day, the patient was re-operated because of intraabdominal hemorrhage. After intensive fresh frozen plasma and platelet infusion, the patient was discharged with full recovery, however, the baby died due to massive hemorrhage. The second case was a pregnant woman at the 19th week of gestation who was infected with CCHF. Ribavirin was not used in this case. The fetus was lost at the 22^th gestational week. The third case was a pregnant woman at the 28^th week of gestation who was diagnosed with CCHF. She died with the fetus[7]. Dizbay et al.[8] reported a case of CCHF infection in a 36-week pregnant woman who received ribavirin treatment resulting in survival of the mother and the baby. They did not find any clinical and laboratory findings related to CCHF. In our cases, only supportive therapy was administered and ribavirin was not used.

Gozel at al.[9] reported five pregnant women with CCHF infection. In only one case, CCHF infection was acquired during the first trimester resulting in abortion. The others had no complication and reached a healthy full-term gestation and delivered healthy babies. Duygu et al.[10] reported two pregnant women with CCHF, one in the 17^th week and the other in the 20^th week of pregnancy. Both delivered healthy babies. Our first pregnant had to undergo an abortion in the 9th week of pregnancy. The other patient delivered a full-term healthy baby without any complication.

In their systematic review and case series from Russia, Kazakhstan and Turkey, Pschenichnaya et al.[12] analyzed a total of 42 pregnant with CCHF. Maternal and fetal mortality rates were reported to be 34% (14/41) and 58.5% (24/41), respectively. In addition, they found no significant difference in maternal and fetal/neonatal mortality between the first 20 weeks of pregnancy and 20-40 weeks. They reported that hemorrhage was associated with maternal and fetal/neonatal death. Dedkov et al.[13] reported that CCHFV easily penetrated the placental barrier without significant selection of viral populations. They concluded that the risk of CCHFV-induced death of the fetus was extremely high in pregnant women with CCHF.

Up to now, overall 15 pregnant CCHF cases have been reported in the literature from Turkey including our cases[7-11]. Only one mother died due to intracerebral hemorrhage. Maternal and fetal/ neonatal mortality rates were found to be 6.6% (1/15) and 40% (6/15), respectively in Turkish cases (Table 1). Fetal mortality was found in 3/4 in the first trimester, 4/8 in the first 20 weeks, and 2/7 in the second 20 weeks. Unlike what Pschenichnaya et al.[12] reported, fetal mortality was found to be different in terms of pregnancy period in our study. Hemorrhage was found in 8 of 15 pregnant women (53.3%). Mortality was recorded in 1/8 mothers without bleeding and in 6/6 fetuses of whose mothers were with bleeding. Therefore, hemorrhage that determines the severity of the disease affects both maternal and fetal mortality rates.

Discussion

There is limited experience about the clinical course of CCHF during pregnancy. Transmission of CCHF infection may be intrauterine and/or perinatal during pregnancy. It may lead to abortion as a neonatal complication and death of the baby. The cause for abortion may be vaginal bleeding and/or intrauterine infection. Perinatal results vary according to the severity of maternal infection and gestational weeks[7, 13].

There is no specific antiviral treatment for CCHF. Ribavirin, which is effective against RNA viruses, has been shown to prevent replication of viruses in in vitro experiments, but the use of ribavirin is controversial in CCHF[2-6]. Ribavirin is embryolethal and teratogenic. It is a Federal Drug Administration Pregnancy Category X product and contraindicated in pregnant women[14]. Tatar et al.[15, 16] showed genotoxic effect of ribavirin in patients with CCHF. Roberts at al. reported six outcomes with birth defects (torticollis, hypospadias, polydactyly and a neonatal tooth, glucose-6-phosphate dehydrogenase deficiency, ventricular septal defect and cyst of 4th ventricle of the brain) in 49 live births with ribavirin direct exposure and 69 live births following indirect ribavirin exposure. Ribavirin is contraindicated also in men whose partners may become pregnant. Additionally, females and female partners of males using ribavirin must avoid pregnancy during treatment and for six months after ribavirin treatment has stopped[17].

Ribavirin was not given in our patients, and in all but two cases reported from Turkey. Aydemir et al.[11] have reported an infant born at the 37^th week of gestation to a mother with CCHF. Ribavirin was not used in this case. PCR test was negative and the baby, who was born small for gestational age, did not develop any signs or symptoms of CCHF during one-week observation.

Maternal and fetal mortality rates are lower in Turkish cases than in others reported by Pshenichnaya et al.[12]. In that report, some cases occurred between 1979 and 2016 and CCHF was not widely recognised at this period. The Ministry of Health of Turkey established well organized healthcare centers and provided education for doctors for early diagnosis and treatment of patients with CCHF. Additionally, general health insurance system has provided Turkish people early healthcare services including air medical services. Algorithms for diagnosis and treatment of CCHF are determined and all healthcare professionals working in endemic areas have been informed accordingly. All these measures might have reduced the rates of CCHF associated mortality in Turkey.

Limitation of this study was its retrospective form. However, the study included valuable global data related with CCHF in pregnancy. Comparison of Turkish and other cases was important to provide information on national mortality rates and future strategies.

Conclusion

Ethics
Informed Consent: Informed consent was received from the presented cases.

Peer-review: Externally and internally peer-reviewed.

Authorship Contributions
Surgical and Medical Practices: Z.K., Z.Ö., Concept: E.Ç.T., Design: Z.Ö., Data Collection or Processing: E.P., B.G.K., Analysis or Interpretation: Z.Ö., Literature Search: İ.B.D., B.G.K., Z.K., Writing: E.Ç.T., Z.Ö.

Conflict of Interest: No conflict of interest was declared by the authors.

Financial Disclosure: The authors declared that this study received no financial support.

References

Leblebicioglu H. Crimean-Congo haemorrhagic fever in Eurasia. Int J Antimicrob Agents. 2010;36(Suppl 1):43-6.

Ozkurt Z, Kiki I, Erol S, Erdem F, Yilmaz N, Parlak M, Gundogdu M, Tasyaran MA. Crimean-Congo hemorrhagic fever in Eastern Turkey: clinical features, risk factors and efficacy of ribavirin therapy. J Infect. 2006;52:207-15.

Leblebicioglu H, Bodur H, Dokuzoguz B, Elaldi N, Guner R, Koksal I, Kurt H, Senturk GC. Case management and supportive treatment for patients with Crimean-Congo hemorrhagic fever. Vector Borne Zoonotic Dis. 2012;12:805-11.

Elaldi N, Bodur H, Ascioglu S, Celikbas A, Ozkurt Z, Vahaboglu H, Leblebicioglu H, Yilmaz N, Engin A, Sencan M, Aydin K, Dokmetas I, Cevik MA, Dokuzoguz B, Tasyaran MA, Ozturk R, Bakir M, Uzun R. Efficacy of oral ribavirin treatment in Crimean-Congo haemorrhagic fever: a quasiexperimental study from Turkey. J Infect. 2009;58:238-44.

Duygu F, Kaya T, Baysan P. Re-evaluation of 400 Crimean-Congo hemorrhagic fever cases in an endemic area: is ribavirin treatment suitable? Vector Borne Zoonotic Dis. 2012;12:812-6.

Ozkurt Z, Ozden K, Kiki I, Usanmaz M. Prognostic significance of antithrombin activity in patients with Crimean-Congo Hemorrhagic Fever. Eurasian J Med. 2011;43:83-6.

Ergonul O, Celikbas A, Yildirim U, Zenciroglu A, Erdogan D, Ziraman I, Saracoglu F, Demirel N, Cakmak O, Dokuzoguz B. Pregnancy and Crimean- Congo haemorrhagic fever. Clin Microbiol Infect. 2010;16:647-50.

Dizbay M, Aktas F, Gaygisiz U, Ozger HS, Ozdemir K. Crimean-Congo hemorrhagic fever treated with ribavirin in a pregnant woman. J Infect. 2009;59:281-3.

Gozel MG, Elaldi N, Engin A, Akkar OB, Bolat F, Celik C. Favorable outcomes for both mother and baby are possible in pregnant women with Crimean- Congo hemorrhagic fever disease: a case series and literature review. Gynecol Obstet Invest. 2014;77:266-71.

Duygu F, Cicek AC, Kaya T. Crimean-Congo hemorrhagic fever and pregnancy: Two cases. Journal of Microbiology and Infectious Diseases. 2015;5:29-31.

Aydemir O, Erdeve O, Oguz SS, Dilmen U. A healthy newborn born to a mother with Crimean-Congo hemorrhagic fever: is there protection from transplacental transmission? Int J Infect Dis. 2010;14:450.

Pshenichnaya NY, Leblebicioglu H, Bozkurt I, Sannikova IV, Abuova GN, Zhuravlev AS, Barut S, Shermetova MB, Fletcher TE. Crimean Congo hemorrhagic fever in pregnancy: A systematic review and case series from Russia, Kazakhstan and Turkey. Int J Infect Dis. 2017;58:58-64.

Dedkov VG, Shchelkanov MY, Bushkieva BT, Rudenko TA, Kurdyukova OV, Galkina IV, Sapotsky MV, Blinova EA, Dzhambinov SD, Shipulin GA. A neonatal death associated with Crimean Congo hemorrhagic fever (Republic of Kalmykia, Russia, June 2016). Antiviral Res. 2017;146:146-8.

http://www.accessdata.fda.gov/drugsatfda_docs/label/2002/21511_ Copegus_lbl.pdf

Tatar A, Ozkurt Z, Kiki I. Genotoxic effect of ribavirin in patients with Crimean-Congo hemorrhagic fever. Jpn J Infect Dis. 2005;58:313-5.

Tatar A, Ozkurt Z, Hacimuftuoglu A, Yesilyurt A, Vancelik S. Evaluation of Ribavirin Genotoxicity with Sister Chromatid Exchange and Micronuclei Assays in Humans. Turk J Med Sci. 2009:39:241-6.

Roberts SS, Miller RK, Jones JK, Lindsay KL, Greene MF, Maddrey WC, Williams IT, Liu J, Spiegel RJ. The Ribavirin Pregnancy Registry: Findings after 5 years of enrollment, 2003-2009. Birth Defects Res A Clin Mol Teratol. 2010;88:551-9.