In this retrospective cross-sectional study using data collected from IMaN network, we have included 4015 neonates with suspected/confirmed SARS-CoV-2 infection in one year from Feb 2020 to Feb 2021 and it is one of the largest reported studies in neonates. As the infection is still spreading worldwide, this study can provide physicians and policy makers with useful information about different aspects of SARS-CoV-2 infection in neonates.
Iran has reported its first confirmed cases of infections in Qom on 19 February 2019 . The number of new cases exceeded suddenly and since the beginning of SARS-COV-2 until Jan 2021 there have been 4 peaks; Nowruz peak (March-April), after Nowruz (April- May), Resurgence (May- June), and the new peak (June – July).
According to the Figure 1, we have a coordination between neonatal covid-19 peaks in comparison to peaks in the whole country and most of our cases have been admitted in Oct and Nov 2020.
The diagnosis of SARS-CoV-2 infection in neonates depends on history of contact with a known case of infection (mostly mothers) [18, 19] or other care- givers and laboratory and clinical findings. The current gold standard to diagnose SARS-CoV-2 infection is RT-PCR on respiratory specimens . Diagnosis via serological testing in neonates is particularly challenging given the transplacental transmission of maternal IgG, and that IgM assays are prone to false-positives and false-negatives, they are not the gold standard for diagnosis of congenital infections .
Twenty and a half percent of neonates had positive PCR test in our study which is lower than reported in another case study from Iran with 56% positive swab test , but higher than a Chinese study that reported 8.1% positive test in 1391 children younger than 16 years of age . In a literature review, Trippella, et al. showed 92% of tests in neonates were negative , however, among the negative neonates, some authors reported clinical symptoms [8, 23]. Multiple causes have been found for a negative swab test such as low virus titers, inappropriate swabbing sites, or variability on laboratory test performance .
There was no significant difference between genders of neonates in our study as was shown in other reports [14, 24, 25]. In those neonates with positive PCR, most of them were born at term gestation which is in line with other studies [25, 26, 27] and in Trippella`s study with 72% term infants .
Most of the neonates with PCR positive tests had normal weight (> 2500 g) and a minority of neonates had very low birth weight (< 1500 grams) as was seen in the study by Christine M Salvatore, et al., with 87% of neonates with weight ≥ 2500 gram, 12% between 1500 to 2500 grams and 1%< 1000 gram . In another study from Iran, no significant relation between COVID-19 infection and neonatal and maternal outcomes including preterm birth and low birth weight was reported but cesarean delivery and the need for ICU were higher in mothers with Covid-19 .
Different signs and symptoms were reported in neonatal period ranging from asymptomatic carriage to critical illness, and in this study the most frequently described symptoms showed a significant correlation to the time of admission. In our study, the most frequent symptoms were respiratory distress, sepsis like syndrome, cyanosis, sepsis like syndrome and fever. In other reports among symptomatic neonates, the most common clinical presentation was respiratory distress (40%), with fever (32%) and feeding intolerance (24%) . In an Iranian review article the most common symptoms were shortness of breath, tachypnea, cough, apnea, temperature instability and tachycardia . Respiratory changes are therefore the most common finding in studies in infected neonates.
The laboratory findings in our study, in order of prevalence, were as follows: elevated white blood cell count, elevated creatine phosphokinase (CPK), abnormal liver enzymes, and elevated C-reactive protein and/or procalcitonin. In an Iranian review article leukopenia, lymphopenia, thrombocytopenia in, elevated CPK, elevated CRP in, elevated procalcitonin and abnormality in liver test was seen in infected infants, in order of prevalence . In the published article by Al-Matary A, et al. most neonates had normal laboratory results and the most abnormal result was hyperbilirubinemia seen in 40% of neonates .
Different types of respiratory support were needed in neonates with COVID-19 diseases. About 58% of our admitted neonates needed some kinds of respiratory support and it was more prevalent in those infants who died before discharge that showed a significant difference between dead and alive infants. There is a difference between our study and a study by Belén Fernández Colomer, et al. from Spain in needing some kind of respiratory support . As in their study most of the neonates showed community-acquired infection, in 85.7% of admitted neonates there was no need for any respiratory support and in another article with Al-Matary A, et al., although 43% of neonates born to infected mothers were admitted to NICU, only 7% needed respiratory support .
However, the need for respiratory support might have been related to other conditions, such as prematurity, rather than SARS-CoV-2 infection. Among all types of respiratory support; invasive ventilation was the most prevalent way of support in preterm infants ≤ 32 weeks (59.8%) vs 11.8% in those ≥ 37 weeks (p value<0.01) and oxygen therapy was the most prevalent way of support in infants ≥ 37 gestational weeks (Table 4).
According to the time of admission after birth, 3372 (83%) of cases were admitted in the first week of life and 16% were admitted after the first week. In a study by Ronchi A., et al., from 62 infants born to 61 mothers with confirmed COVID-19 infection, only 1 infant (1.6%) was diagnosed as having SARS-CoV-2 infection at 7 days of life . A cohort study done by Pierce-Williams R., et al, indicates that about 63.6% of neonates born to infected mothers were transferred to the NICU .
About 4015 suspected COVID-19 neonates were admitted to the hospital, among which 7 percent died with a positive PCR in third of them. About half of positive PCR departed neonates were term and about one third of them were less than 32 weeks. Gestational age less than 32 weeks was related with newborn death as the 34% of them died in comparison to 6% death among neonates between 32 to 36 weeks and 5% death among neonates >=37 week (95% CI= 1.35-4.10 and p value <0.01). Death rate was not different in preterm infants with or without positive PCR test.
Also a birth weight of <1500 grams was connected with neonatal death. As 36% of newborns with birth weight of <1500 grams died while this ratio was 8% in neonates between 1500 to 2499 grams and 5% in neonates >= 2000 grams. (aOR=1.96; 95% CI=1.96-6.17) (p value <0.01), (Table 5).
Laboratory factors such as a positive PCR test, elevated CRP and leukocytosis were not significantly associated with neonatal death. (Table 5).
Among all neonates who were admitted to the hospital and required respiratory support (2331 from 4015; 58%), there is a significant association between death and respiratory support with OR= 18.17 and 95% CI 9.24-35.69 and p value<0.01. This difference could partially be due to more severe respiratory problem from the time of admission in those neonates who required respiratory care and died and as respiratory failure was the most common cause of death, but it could be related to other lung pathologies such as respiratory distress syndrome and pneumonia at the time of admission (Table 5).
About 58% of all neonates who were admitted to the hospital, required respiratory support which was a predictive factor for neonatal death (OR= 18.17 and 95% CI 9.24-35.69 and p value<0.01). Among those neonates who required respiratory care and died, the severity of respiratory problem at the admission was determinative. Respiratory failure was the most common cause of death along with other possible etiologies such as respiratory distress syndrome and pneumonia at the time of admission (Table 5).
There were several limitations in our study; although we had a large number of neonates with COVID-19 diseases, we were unable to screen the virus in amniotic fluid, umbilical cord or vagina to study vertical transmission. We did not have required facilities in our country to detect the virus in urine, stool or blood samples to confirm the disease in suspected cases with negative PCR test. Furthermore, we used PCR test to diagnose COVID 19 which has a notable false negative rate, as only 22% of our cases showed positive test and 77% of suspected cases had negative PCR.