In this meta-analysis integrating published and previously unpublished cases, we applied a patient-level analytical framework to examine CCHF during pregnancy. By harmonizing clinical manifestations, laboratory parameters, gestational timing, treatment exposure, and maternal and fetal outcomes at the patient level, we were able to explore trimester-specific risk patterns and treatment associations. Our findings suggest that CCHF in pregnancy is associated with substantial maternal mortality rates and high rates of fetal loss, highlighting pregnancy as a clinically relevant modifier of disease course and outcome.

The overall maternal CFR of 28.8% observed in our cohort exceeds that reported in most contemporary nonpregnant CCHF cohorts, where the fatality rate typically ranges from 5% to 20% (7). Of note, the patient-level approach enabled stratification by gestational age, revealing a clear increase in maternal mortality rates with advancing pregnancy. We observed no maternal deaths for first-trimester infection, whereas mortality rates rose substantially in the second and third trimesters (Table 1). That gestational gradient might reflect the cumulative physiologic burden of pregnancy, including increasing plasma volume, progressive cardiopulmonary demands, and heightened vulnerability to hemorrhage in late gestation (14,15). In contrast, fetal loss was most pronounced for first-trimester infection; >80% of CCHFV infections during early pregnancies resulted in fetal demise. That finding is biologically plausible because early gestation is characterized by rapid placental development and heightened susceptibility to systemic inflammation and maternal viremia (16,17).

In sensitivity analyses restricted to laboratory-confirmed cases, rates of both maternal death and fetal loss were lower. However, trimester-specific patterns of maternal and fetal outcomes remained similar. The observed reduction in absolute maternal mortality rates likely reflects differences in case ascertainment, including exclusion of postmortem diagnoses and cases without confirmed testing, as well as variability in clinical management and supportive care. The persistence of trimester-specific trends supports the robustness of the observed gestational risk gradient.

Consistent with prior reports (10), the most frequent clinical features included fever, mucosal bleeding, myalgia, and headache (Table 1). Vaginal bleeding was observed in nearly one quarter of cases, underscoring the dual obstetric and infectious risk profile of CCHF in pregnancy. Laboratory evaluation demonstrated profound thrombocytopenia, leukopenia, transaminase elevation, and coagulation abnormalities (Table 2), which are hallmarks of severe CCHF. Pregnancy-associated hemostatic changes likely amplify those imbalances, contributing to the high incidence of hemorrhagic complications observed. The association between maternal death and laboratory abnormalities could not be performed because so few cases were available.

The relatively high frequency of vaginal bleeding in our cohort demonstrates a crucial bedside challenge. In pregnant patients, hemorrhagic manifestations of CCHF can overlap with obstetric emergencies, such as placental abruption, placenta previa, miscarriage, or postpartum hemorrhage. Placental abruption is particularly relevant in the second half of pregnancy, where vaginal bleeding, abdominal pain, uterine tenderness, and fetal distress can dominate the clinical presentation (18). However, those findings might be difficult to distinguish from systemic viral hemorrhage in patients with CCHF, where thrombocytopenia, coagulopathy, and endothelial dysfunction are prominent features (1). As a result, vaginal bleeding in endemic settings should prompt consideration of both obstetric and infectious etiologies, particularly when accompanied by systemic symptoms, such as fever and myalgia.

Beyond obstetric causes of bleeding, HELLP (hemolysis, elevated liver enzymes, and low platelets) syndrome represents a key diagnostic mimic. Thrombocytopenia and elevated liver enzymes are central features of both HELLP syndrome and severe CCHF. Hemolysis can further complicate laboratory interpretation, particularly in patients receiving ribavirin, which is known to induce hemolytic anemia (19). In that context, distinguishing between pregnancy-specific disorders and viral hemorrhagic disease can be challenging. Therefore, in patients with thrombocytopenia, transaminase elevation, and bleeding, especially in endemic regions or with relevant exposure history, CCHF should be considered alongside HELLP syndrome and other hypertensive disorders of pregnancy (20). Early multidisciplinary assessment is essential because delays in recognizing either condition could adversely affect maternal and fetal outcomes.

Pregnancy is characterized by complex, stage-dependent immunologic adaptations aimed at maintaining fetal tolerance while preserving antimicrobial defense (21). Those changes include modulation of innate immune responses, shifts in T-cell polarization, altered interferon signaling, and dynamic cytokine regulation (21,22). Although such adaptations are physiologically essential, they could impair effective antiviral immunity and permit higher or more sustained viral replication during infections like CCHF (23). The placenta plays a central role in that interaction. Increasing evidence from viral hemorrhagic fevers suggests that the placenta might serve as a site of viral persistence, immune activation, and endothelial injury (24). Placental infection can result in local inflammation, microvascular damage, and disruption of the maternal–fetal barrier, predisposing to fetal hypoxia, intrauterine fetal demise, and preterm labor (25). In advanced gestation, the highly vascularized placental bed could also act as a source of ongoing viral replication and hemorrhage, potentially exacerbating maternal disease severity.

Vertical transmission of CCHF virus has been reported in several cases, but its true incidence remains unknown because of inconsistent neonatal testing and follow-up (12,26). Potential routes include transplacental transmission during maternal viremia, exposure to infected maternal blood during delivery, and postnatal contact with infectious bodily fluids. Of note, we found 4 PCR-positive and 1 IgG-positive cases reported in the literature (Table 1). In our dataset, neonatal outcomes were inconsistently documented, reflecting a critical gap in the literature and highlighting the need for standardized neonatal evaluation in future cases.

Although direct evidence for CCHFV transmission through breast milk is limited (27), viral RNA has been detected in blood and body fluids during acute infection, as well as in the convalescent phase (28). In 1 reported case, breast milk was CCHFV IgM-positive despite being PCR-negative (29). Therefore, temporary avoidance of breastfeeding during the viremic phase is prudent, particularly in cases of maternal bleeding or severe disease.

Ribavirin remains the most widely used antiviral agent for CCHF. Recent observational studies have suggested a potential positive role in reducing risk for death, particularly when initiated early in the disease course (30,31). However, its clinical application in obstetric populations is complicated by its classification as a category X drug. That designation stems from its potent teratogenic and embryocidal effects documented across multiple animal models, where even low-dose exposure resulted in substantial craniofacial, skeletal, and ocular malformations (19,32). In our meta-analysis, no patients infected during the first trimester received ribavirin, reflecting prevailing concerns regarding fetal toxicity and the absence of safety data in early pregnancy. Of note, ribavirin use was associated with lower observed maternal mortality rates, particularly in the third trimester, during which no deaths occurred among treated patients, and we observed a statistically significant difference in maternal deaths compared with untreated patients (Table 3). However, the number of patients who received ribavirin in the third trimester was limited. Thus, those findings must be interpreted cautiously and considered hypothesis-generating. Because treatment decisions were made across diverse clinical settings, differences in disease severity, timing of clinical manifestations, and overall clinical management might have influenced outcomes. Nevertheless, the lower maternal mortality observed among ribavirin-treated patients in later gestational periods aligns with clinical practice in several endemic regions, where maternal survival is prioritized once fetal organogenesis is complete.

The major strength of this study lies in its patient-level design, which enabled standardized variable definitions, gestational age–specific analyses, and direct comparison of treated and untreated patients. The inclusion of unpublished cases further enhances representativeness and mitigates publication bias toward unusually severe CCHF manifestations. Limitations include the retrospective nature of included data, incomplete reporting of outcomes, and heterogeneity in diagnostic and treatment practices across regions and decades. Variations in supportive care, including transfusion strategies, management of hemorrhagic manifestations, and access to intensive care, might have contributed to outcome variability. Laboratory confirmation was unavailable for some historical cases, and detailed timing of ribavirin initiation was missing for nearly all cases.

In conclusion, CCHF during pregnancy represents a critical clinical challenge characterized by a high maternal CFR and devastating neonatal outcomes. The unique immunologic environment of pregnancy, together with the placenta’s role as a potential viral reservoir, exacerbates disease severity and creates a substantial risk for vertical transmission. Our findings suggest that although CCHFV infection during the first trimester is associated with the highest rates of fetal loss, advanced gestation carries a higher risk for maternal hemodynamic collapse and catastrophic hemorrhage. Despite its known teratogenic risks, ribavirin could be considered in selected cases as part of life-saving maternal management. The small number of laboratory-confirmed neonatal CCHFV infections and inconsistent reporting of outcomes limit our understanding; further research into the long-term outcomes of survivors is needed to address the current gaps in obstetric and pediatric CCHF care. Ultimately, the high mortality rates observed in this cohort underscore the urgent need for standardized clinical protocols and for more structured CCHF surveillance and follow-up strategies in endemic regions.