Newborns with microcephaly in Brazil and potential vertical transmission of Oropouche virus: a case series

Background Oropouche fever, an orthobunyavirus disease endemic in Brazilian Amazon, has caused many febrile epidemics. In 2024, an epidemic of Oropouche fever spread in Brazil, with more than 7930 cases reported between Jan 1 and Aug 31. Infections in pregnant people have suggested the possibility of negative fetal consequences, therefore we tested newborns with microcephaly for known congenital pathogens and Oropouche virus (OROV). Methods In this case series, we assessed historical cases of infants born with microcephaly, arthrogryposis, and other congenital malformations without a confirmed cause and their mothers for potential OROV congenital infections. The study population consisted of infants born in Brazil with samples from 2015-21 and 2024. Serum and cerebrospinal fluid (CSF) from this case series were analysed for: syphilis, toxoplasmosis, rubella, cytomegalovirus, herpes simplex, HIV, Zika, dengue, and chikungunya. Individuals that were negative for these pathogens were then tested for OROV. Pathogen testing included ELISA and haemagglutination inhibition testing for antibodies and RT-PCR for virus RNA. Findings We tested 68 samples from 65 historical cases of congential malformations and three cases from 2024. All cases were from ten states in Brazil. Three historical cases tested positive for OROV and 62 historical cases tested negative. The three cases from 2024 all tested positive for OROV. Of the positive cases, five were female and one was male. Not all pathogens were tested for each case, and some did not have maternal samples available. One of the newborns (case 6) died aged 47 days and tissue samples were tested by real-time RT-PCR, histopathology, and immunohistochemistry assays. One other newborn died in 2016 but no post-mortem samples were available. OROV IgM was detected in five of five newborn CSF samples, and five of five newborn serum samples. Four of five maternal serum samples were positive for OROV IgM. One of four newborn CSF samples (case 6 at age 44 days) was OROV positive by real-time RT-quantitative PCR and 0 of four newborn serum samples were positive, as were 0 of three maternal serum samples. Case 6 had major tissue changes of the brain macroscopically and microscopically, including necrotic and apoptotic changes of neurons, microglia and astrocytes, vacuolisation, and tissue atrophy. OROV RNA was detected in brain, lungs, kidney, CSF, and pleural fluid; OROV antigens were found in CNS, liver, kidney, heart, and lung, mainly in neurons and microglia and also in endothelial cells, suggesting vasculitis. Interpretation We detected OROV IgM in six of 68 newborns with microcephaly of unknown cause. One infant who died had OROV RNA and antigen in several tissues, including the brain. The possibility of OROV vertical transmission and potential fetal harm must be investigated with urgency. The evidence presented here does not completely confirm vertical transmission or congenital malformations due to OROV, but thorough case finding and detailed investigation of maternal or fetal OROV infection is a priority.