The fetal inflammatory response (FIRS) due to maternal SARS-CoV-2 infection can contribute to severe neonatal morbidity, which includes stillbirth, neonatal death, preterm birth, low birth weight, fetal distress, and neonatal asphyxia [19–21]. This is perhaps the first study reporting neurological assessments of neonates born to mothers from West Asia with SARS-CoV-2-positive RT-PCR test results during pregnancy using the ASQ-3. The findings of this study indicate that infants born to mothers who test positive for SARS-CoV-2 infection during pregnancy need to be assessed for neurodevelopmental delays.
To assess the developmental attainment of infants born to mothers with SARS-CoV-2-positive test results during pregnancy, this study employed the ASQ-3, a screening tool used for assessing the developmental attainment of infants and young children [18]. This screening tool is used widely in assessing development in children aged 1–66 months at a low cost, with cutoff scores identifying developmental delays. In the current study, an Arabic version of the ASQ-3 was used for parents who were well versed in Arabic. Since the study cohort included diverse as well as immigrant parents, questionnaires were sent to parents, and fortunately, the majority of them consented to respond.
The study data revealed that the majority (91.6%) of the pregnant women had SARS-CoV-2 infection during their third trimester, whereas 6.7% had SARS-CoV-2 infection in their second trimester. This finding is in agreement with those of other studies that have also reported that most SARS-CoV-2 infections in pregnant women occur in their third trimester [22, 23]. In the current study, only a relatively small number of women were infected during the first trimester. However, first-trimester infections are important as the principal stages of brain development, such as primary neurulation (weeks 3–4), prosencephalic development (months 2–3), and neuronal proliferation (months 3–4), occur during the early stages of pregnancy [24]. In fact, infections with some common pathogens, such as cytomegalovirus (CMV), Zika virus, Rubella virus, Mycobacterium tuberculosis (TB), and Toxoplasma gondii, during the first and early second trimesters increase the risk of symptomatic infants, with up to 32% being associated with neurological manifestations [25]. Owing to the relatively recent emergence of COVID-19, information related to pregnancy outcomes among women with SARS-CoV-2 infection and the consequences of infant exposure to the virus is very scarce. As more women become infected during their first and second trimesters progress in their pregnancy and as newborns with SARS-CoV-2 infection develop, a better understanding of the neurological effects of this novel virus will emerge. In brief, various types of evidence support the theory that maternal infection and/or inflammation occurring during critical periods of fetal development could alter brain structure and function in a time-sensitive manner.
Nevertheless, SARS-CoV-2 infection increases the chances of fetal distress, leading to high incidences of admission to the neonatal intensive care unit (NICU) [23]. Similar to other reported studies, in the current study, 76 out of 298 (25.5%) neonates born to mothers with SARS-CoV-2-infection during pregnancy required NICU admission [26–29]. On the other hand, a systematic review reported that approximately 95% of neonates born to mothers with SARS-CoV-2 infection during pregnancy were born in good condition [1].
Recent evidence suggests that vertical transmission of SARS-CoV-2 either antenatally or intrapartum can occur, but it is uncommon. In this study, only 2 (0.7%) neonates tested positive for SARS-CoV-2 infection, and notwithstanding some seemingly perinatal complications, the majority of neonates (296 out 298) born were negative for SARS-CoV-2 infection. Our observation is in agreement with those of other studies [30–32], which implies that the consequences of SARS-CoV-2 infection on neurodevelopment were largely due to in utero effects rather than direct effects on the fetus. The reason for the low vertical transmission rate is that the placenta has low expression of the canonical receptors necessary for viral entry, which may explain the rarity of vertical transmission of SARS-CoV-2 [32]. Importantly, teratogenic effects of SARS-CoV-2 on the fetus were not observed, which is in contrast to other viral infections, such as Middle East respiratory syndrome coronavirus, CMV, herpes virus, Zika virus, and Rubella virus infections [33–37].
In this study, we evaluated the infant’s neurobehavioral development 10-12 months post discharge, perhaps the adequate duration for effects to appear. In this study, overall, 69.1% of neonates at the end of 10-12 months showed normal developmental attainment, and only 10.1% (n=30) showed developmental delays. The PregCOV-19 living systematic review [1] found that approximately 95% of neonates born to SARS-CoV-2-positive mothers were reported to be born in good condition. However, it is not clear whether this systematic review included evaluations of neurodevelopmental delays in neonates. A study from the UK, in which information about educational and behavioral problems was collected from 177 children, found that 25% required support from a nonteaching assistant, 4% required a statement of special educational needs, and 3% were in a special school [38]. Many investigators have studied the effects of various viral infections, albeit not SARS-CoV-2, on pregnancy and fetal/neonatal outcomes and have reported that maternal influenza, hepatitis C, varicella-zoster, and other viruses produce distinct fetal brain structure and anatomy clinical pathology of varying severity [39–42].
Of note, the role of cytokine storms, particularly the role of IL-6 in the pathogenesis of neurodevelopmental disorders, is not fully elucidated; however, in a longitudinal study, alterations in brain architecture, executive function, and working memory abilities were reported in 2-year-old neonates exposed to increased IL-6 levels during pregnancy [43]. An analysis of 214 patients with SARS-CoV-2 infection revealed that 36% had neurological symptoms [44]. Many case-control studies have demonstrated that elevated maternal cytokine levels affect the fetal brain, causing neurological disease [45–47]. The FIRS, due to increased IL-6 following maternal SARS-CoV-2 infection [13], may induce a wide range of adverse neurodevelopmental sequelae, such as autism, psychosis, and neurosensory deficits, later in life [48], similar to certain bacterial infections [49]. However, long-term longitudinal studies are required to validate these associations.
Moreover, the risk of neurological effects on neonates differs by the trimester when SARS-CoV-2 infection occurred [50]. In this study, developmental delays were relatively more prevalent when infection occurred in the first and second trimesters than when infection occurred in the third trimester (P<0.001). Neonatal characteristics were similar between the groups. Moreover, infants born at less than 31 weeks gestation were more likely to have developmental delays than those born at more than 31 weeks gestation (10% versus 0.8%; P=0.002).
The findings of the study may be considered reliable, as the cohort of parents who participated in the study was well educated, and women were young (median age: 31 years). Three-fourths of women were devoid of pregnancy-induced hypertension or gestational diabetes.