In this study, we investigated the risk factors associated with severe COVID-19 in neonates admitted to Neonatology and Neonatal Intensive Care Units of The Affiliated Children’s Hospital of Xi’an Jiaotong University, during the Omicron variant epidemic in China. To the best of our knowledge, this is the largest case series on neonatal COVID-19 in China. Among the 108 hospitalised neonates with COVID-19, 22.2% had a severe infection, which was lower than the proportion reported in a previous study (42%) [2]. Only 4 patients (3.7%) required respiratory support, and no patients were treated with invasive ventilation. The proportion of respiratory support was lower than that of other previous reports [2, 3, 9]. These differences may be related to different study populations and weak pathogenicity of the Omicron variant. In addition, the low proportion of premature neonates (6.5%) and the absence of early premature patients in our study may contribute to the differences. No patient was treated with antiviral drugs, immunoglobulins, or glucocorticoids, and there were no deaths, confirming that neonatal COVID-19 typically has a good prognosis [14].

Neonatal COVID-19 can affect multiple systems, resulting in respiratory, digestive, or neurological symptoms [15, 16]. These manifestations are similar to those of adults and older children diagnosed with COVID-19. Fever and cough were the most common symptoms of neonatal COVID-19 in our study. Trachyphonia (hoarseness), tachypnoea, apnoea, and pneumonia were among the least common findings. The incidence of respiratory symptoms was lower than previous studies [2, 3, 9]. The main reason for this difference may be that the Omicron variant does not replicate in the upper respiratory tract as robustly as other SARS-CoV-2 variants [12, 17]. There were no significant statistical differences in the various clinical manifestations of neonatal COVID-19 between the severe and non-severe groups, indicating that there were no specific symptoms that could identify a severe infection.

Compared to adults and older children, neonates are more susceptible to infection due to the immature development of their organs, and passive acquisition of antibodies from the mother is a key factor in establishing immunity. Breast milk contains various bioactive factors, such as different types of immunoglobulins, that can promote the development of immune function in neonates and prevent different infectious diseases [18,19,20]. In this study, 65.7% patients were breastfed after birth, which could provide some protection for the neonates. When a pregnant woman is infected with SARS-CoV-2, the maternal specific immunoglobulin G can be transferred to the foetus through the placenta. This would theoretically provide protection against COVID-19 in neonates. However, the maternal protection is uncertain due to multiple factors such as maternal antibody concentration, placental transfer rate, and time from infection to delivery [21,22,23]. A previous study showed that most neonates who tested positive for SARS-CoV-2 after birth were asymptomatic [24]. In this study, we were only able to confirm that a few mothers were infected with SARS-CoV-2 during pregnancy. Most mothers of neonates in this study, who received the swab test for virus detection, were not infected with SARS-CoV-2. Therefore, we hypothesize that protection from mothers against SARS-CoV-2 infection was negligible.

Pregnant women receiving the COVID-19 vaccine can have a strong immune response, and the specific antibodies produced after vaccination can be transferred to the foetus or neonate through the placenta or breast milk, providing effective protection for them in the first few months of life [25, 26]. Due to the unknown efficacy and safety of the COVID-19 vaccine at that time, pregnant women were excluded during the clinical trial phase of vaccine development in China. Therefore, all mothers of the neonates in our study were not vaccinated with the COVID-19 vaccine during pregnancy.

The severity of COVID-19 is also influenced by age, and COVID-19 in children is milder than in adults [27, 28]. Excessive immune response and secondary immunological injury can lead to severe COVID-19 in adults. In general, children have stronger immunologic tolerance to COVID-19 that results in a lower immune response and damage [29, 30]. Angiotensin-converting enzyme 2 (ACE2) and transmembrane protein serine 2 (TMPRSS2) are two important receptors for SARS-CoV-2 entry into host cells. Several studies have confirmed that the expression of ACE2 and TMPRSS2 in children is lower than in adults, which may be another potential factor for the decreased severity of the disease in such population [31,32,33]. The expression of ACE2 and TMPRSS2 in the nasal endothelium of neonates, whether at term or preterm, is lower than that of adults, which may explain the mildness of neonatal COVID-19 due to the Omicron variant [34].

The incidence of neurological complications in children with COVID-19 is approximately 7%, and is associated with an increase in disease severity [35]. Neonatal COVID-19 often has no or very few specific neurological symptoms [2, 3, 9]. The mechanisms of neurological complications in COVID-19 patients include the direct invasion of SARS-CoV-2, immune damage mediated by infection, and systemic diseases involving the nervous system [36]. In this study, 2 patients experienced seizures, and the electroencephalograms revealed mild abnormalities, although the role of comorbidities affecting the central nervous system (as for example incontinentia pigmenti suspected in one of them), could not be be excluded.

This study found that gestational age at birth, NEU, and LYM are independent risk factors for severe COVID-19 in neonates. Previous studies have shown that premature birth is one of the risk factors for severe COVID-19 in young children or infants [37, 38]. Premature infants are more susceptible to infection due the immature development of their organs [39]. In addition, the ability of T cells (which play an important role in viral infection) in premature neonates to produce C-X-C motif chemokine ligand 8 is insufficient, which may lead to serious complications and even adverse outcomes after infection [40]. It has been confirmed that intrauterine infection is related to low-birth weight and/or small for gestational age status [41]. In our study, maternal data were not available and only three cases were potentially infected by SARS-CoV-2 through vertical transmission, so it was still unclear whether COVID-19 infection will lead to high risk of intrauterine growth disorders.

The decrease of LYM in peripheral blood is associated with severe COVID-19 in our study, which is consistent with the results of other reports. This may be caused by T cell immune dysfunction [42, 43]. NEU is one of the indicators reflecting inflammation in the body, and its increase often indicates a strong inflammatory response, such as multisystem inflammation syndrome in children [44]. Currently, few reports have shown that COVID-19 in neonates or young infants can lead to a decrease in NEU levels [45]. Although the NEU level was decreased in neonates with severe COVID-19, the mechanism is not yet clear. We hypothesize that the temporary decrease in NEU levels is similar to the decrease in NEU during other viral infections. The decrease in NEU may also be associated with different immune responses in neonates or young infants after infection caused by the Omicron variant.

There were some limitations in this study. First, the study was a retrospective study. All neonates with COVID-19 were from a single centre, which was a children’s hospital located in northwestern China. Therefore, the results may not be applicable to all neonates with COVID-19. Second, the data were collected during a period when the Omicron variant was the only detected SARS-CoV-2 strain in China. Therefore, the results only reflect the clinical characteristics of neonatal COVID-19 caused by such variant and may not be applicable to other SARS-CoV-2 ones. Lastly, maternal data in relation to neonatal COVID-19 were lacking. For example, we were unable to obtain information on specific antibodies against SARS-CoV-2 in serum or breast milk. Further research investigating the protection of maternal antibodies on neonates infected with the Omicron variant is needed.