The present rapid review analyzed eight papers published between 2020 and 2022, selected from more than 2500 studies identified in five databases. Although it seems few, it is important to consider that the COVID-19 pandemic was officially recognized in March 2020 [44]. Furthermore, the main outcome analyzed – development and behavior of infants exposed to SARS-CoV-2 during gestation – is time-consuming, considering the pregnancy duration and the time needed for developmental and behavioral disorders to emerge. It is noteworthy that only one of the studies collected data from low and middle-income countries (LMIC). The others were predominantly from China, which may not reflect the phenomena worldwide.
The longest follow-up was 12 months, which may be a very short period considering that most developmental delays emerge only when children are older [45]. Only three studies compared the exposed infants to a control group. The lack of a comparison group made it difficult to single out the effect of gestational exposure from other possible contextual and cultural risk factors. Moreover, the children’s development was mostly assessed using parents’-informed screening questionnaires. Thus, this implies that more information will be necessary to confirm or confirm the causal relation of gestational exposure to SARS-CoV-2 with developmental and behavioral disorders. Notably, only two studies included behavioral assessment, and only one had a comparison group.
Buonsenso et al. [43] was the only study that did not use screening questionnaires. The neurodevelopmental assessment in this paper was based on postural milestones and auditory and visual function evaluation [43]. The other two studies included an audiological assessment of exposed infants [40, 42]. Sensory integration is primordial to optimal development [46], and the experience with the TORCH’s infections (toxoplasmosis,“other”infections, rubella, cytomegalovirus, and herpes simplex virus) reinforce the importance of neurosensorial approaches for children exposed to gestational infections [47].
None of the three papers that included a comparison group demonstrated an association between SARS-CoV-2 gestational exposure and developmental or socio-emotional delays [33–35]. Of note, two studies investigated the same sample [34, 41]. The 57 exposed infants described by Wang et al. [41] were compared with non-exposed infants in Wu et al.’s [34] study. Wang et al. [41] found a considerable proportion of children at risk of delay, especially at the socio-emotional domain (86.4%). Nevertheless, when compared to the non-exposed sample, there were no differences in the proportions of children with delay between the groups in any of the domains. Thus, considering these results, it is not possible to conclude about the association between SARS-CoV-2 gestational exposure and developmental delay.
Considering the screening test cutoffs, no differences between exposed and non-exposed children were demonstrated regarding the risk of developmental delays. Nevertheless, the meta-analysis showed that exposed infants had a lower fine motor and problem-solving scores than non-exposed infants. Individually, the papers reported divergent results. Wu et al. [34] found that 3-month old exposed infants had lower scores in gross motor, fine motor, problem-solving, and personal social skills than the non-exposed infants. Shuffrey et al. [35] assessed the infants at six months old and did not find the same tendency. Cheng et al. [33] assessed the infants between eight to ten months old, and, at this age, exposed infants had lower scores than non-exposed infants only in the fine motor subdomain. Although the studies included in the meta-analysis [33–35] used the same instrument and design, the heterogeneity between them was moderate to high. This could be related to differences in the sample sizes and/or age range at the time of the assessment [38]. Populational studies demonstrate that the prevalence of developmental delay increases with children’s age [48]; thus, these initial results highlight the need for long-term follow-up studies to clarify the present research question.
The timing of infection and the severity of maternal disease are important factors that may be associated with the offspring outcomes in gestational infections [49–51]. Most mothers in the included studies were infected in the third gestational trimester, were asymptomatic, or had mild COVID-19 symptoms. Neither symptom severity nor the timing of infection was associated with the developmental outcomes reported by Shuffrey et al. [35]. However, Ayed et al. (2022) found that infections occurring in the first and second trimesters of pregnancy were associated with a higher risk of developmental delay than infections in the last trimester [39]. The immunological and inflammatory events related to SARS-CoV-2 infection during pregnancy are complex and not completely understood [8]. Many factors, such as the placenta maturity, the developmental stage of the fetus’s central nervous system at the moment of maternal infection, the viral load and variants, and the COVID-19 clinical presentation, would theoretically modify the developmental outcomes [8, 49, 52, 53]. Unfortunately, most studies included in the present review did not explore many of these factors, limiting their conclusions.
Beyond SARS-CoV 2’s direct effect on the mothers and infants, it is crucial to recognize the potential impact of the pandemic scenario on the children’s development and behavior [16, 20, 22]. Shuffrey et al.’s (2022) primary analysis showed no association of SARS-CoV-2 infection, timing, or disease severity with the ASQ-3 scores [35]. Nevertheless, when the pooled healthy infants born during the pandemic cohort were compared to a historical cohort, the authors observed significant differences between the groups in gross motor, fine motor, and personal social domains. These findings agree with Huang et al.’s (2021) results, which used the ASQ-3 to compare children born during the pandemic to a historical cohort [54]. In this paper, 12-month-old children from the pandemic cohort had lower scores in fine motor and communication domains than the historical cohort, implying that the “pandemic context” cannot be neglected. Thus, special attention of mother-child mental health and socioeconomic disparities must be universally assured, through integral and nurturing care, aiming to mitigate the long-term effects of the pandemic on humanity.
Finally, Chinese studies analyzed the impact of mother-newborn separation on child outcomes [34, 41]. It is noteworthy that early in the pandemic, international protocols recommended that SARS-CoV-2-infected mothers be kept apart from their newborns right after birth [7]. Wang et al. (2020) and Wu et al. (2022) demonstrated that the negative developmental outcomes of children exposed to SARS-Cov-2 during pregnancy were moderated by the duration of the mother-child separation, confirming that this protocol was more deleterious than helpful for many child outcomes [34, 41].
Concerning sensorial assessments, the studies showed that referral and confirmed auditory disorder rates among exposed infants were similar to the overall global incidence [40, 42, 43, 55]. This tendency was similarly reported by Ghiselli et al. (2022), although previous studies documented a high rate of infants exposed to SARS-Cov-2 during gestation who were referred for a retest [56, 57]. The retinal vascular problems identified by Buonsenso et al. [43] in a small sample of children exposed to SARS-CoV-2 during gestation were also described by Pereira Kiappe et al. (2021) [58]. Despite being incipient, those preliminary results highlight the need for neurosensorial assessments and multidisciplinary follow-up in prenatally exposed infants.
To the best of our knowledge, this is the first paper to review the potential impact of gestational exposure to SARS-CoV-2 on child development and behavior. Although we followed the recommended and updated protocols to conduct the present review and performed a meta-analysis, some limitations should be considered. We aimed to perform a rapid review; thus, we searched a limited number of databases and did not include preprint papers, so there is a chance that some studies were missed. The meta-analysis results of communication and personal-social domains should be interpreted cautiously as the overall effect test was higher than the recommended cutoffs.
Future research would investigate the impact of gestational exposure in other contexts, mainly in low and middle-income countries, where the pandemic deepened the social inequalities and raised many environmental stressors. Furthermore, the use of observational techniques to assess child development with longer follow-up, as well as considering the maternal infection clinical features, would bring more evidence on the impact of SARS-CoV-2 gestational exposure.
The present systematic review did not find evidence confirming the association between SARS-CoV-2 gestational exposure and neurodevelopmental delays. However, the meta-analysis indicated that gestational exposure negatively affected fine motor and problem-solving skills. Robust evidence on the topic is still incipient, and the available studies present methodological inconsistencies that limit the drawing of clear-cut conclusions.