Viral Infections in Pregnancy and Impact on Offspring Neurodevelopment: Mechanisms and Lessons Learned

Abstract

Pregnant individuals with viral illness may experience significant morbidity and have higher rates of pregnancy and neonatal complications. With the growing number of viral infections and new viral pandemics, it is important to examine the effects of infection during pregnancy on both the gestational parent and the offspring. Febrile illness and inflammation during pregnancy are correlated with risk for autism, attention deficit/hyperactivity disorder, and developmental delay in the offspring in human and animal models. Historical viral epidemics had limited follow-up of the offspring of affected pregnancies. Infants exposed to seasonal influenza and the 2009 H1N1 influenza virus experienced increased risks of congenital malformations and neuropsychiatric conditions. Zika virus exposure in utero can lead to a spectrum of abnormalities, ranging from severe microcephaly to neurodevelopmental delays which may appear later in childhood and in the absence of Zika-related birth defects. Vertical infection with severe acute respiratory syndrome coronavirus-2 has occurred rarely, but there appears to be a risk for developmental delays in the infants with antenatal exposure. Determining how illness from infection during pregnancy and specific viral pathogens can affect pregnancy and neurodevelopmental outcomes of offspring can better prepare the community to care for these children as they grow.

INTRODUCTION

When a new viral infection emerges, it is important to include pregnant people and children in research since the impact of the infection may be different in these groups. In pregnancy, there are dynamic immunological adaptations to tolerate gestation of a genetically foreign fetus while also protecting the pregnant person from infection.^1,2 These immunologic changes may alter susceptibility to and severity of infections, and thus the pregnant person’s altered response to infectious diseases should be considered when planning for emerging infectious disease threats.³ Pregnant individuals have had poorer outcomes from past viral epidemics and pandemics and the offspring of affected pregnancies have not always been studied longitudinally. It is known that the developing brain is vulnerable to the effects of viral exposures throughout the fetal period and in early life. Historically, pathogens known to cause direct damage to the developing fetus have been described using the “TORCH” acronym, however the list of pathogens is now too large to fit the acronym.⁴ In other, less well-studied infections, or even in common febrile viral illnesses, it is difficult to distinguish whether the teratogenic effect is caused by the pathogen itself, or if the febrile and inflammatory state caused by systemic illness during pregnancy may have its own detrimental effects on the intrauterine environment and therefore fetal development.⁵

Since the newest iteration of the coronavirus pandemic has taken hold, and millions of pregnant individuals worldwide have been infected and given birth, it remains to be seen how this virus will affect the neurodevelopmental outcomes of children. Transplacental or vertical transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been reported, though rare.^6–8 Some reports found IgM against SARS-CoV-2 in neonatal blood shortly after birth, which suggests possible congenital infection or severe placental pathology.^7,9,10 However, of greater concern is the potential impact of the heightened maternal immune response to SARS-CoV-2 and the possible cytokine storm which may occur in some individuals.

There is evidence from previous epidemiologic, animal, and birth cohort studies that maternal immune activation (MIA) and the fever response itself can affect offspring neurodevelopment.^4,11–19 If that is the case, then will there be differences in neurodevelopment between children born to symptomatic parents vs. asymptomatic parents following antenatal SARS-CoV-2 infection? Will the effects in offspring differ based on the degree of symptoms and gestational age at exposure to infection? A look into pregnancy outcomes in previous viral epidemics may provide insight into what is to come following the births of infants to parents infected with SARS-CoV-2 during pregnancy.

This objective of this review is to describe maternal symptoms during pregnancy from viral infections and their potential impacts on offspring, to review outcomes from historical and seasonal viral infections, and to describe some of the more recent well-known viral infections and what is known regarding impact on offspring neurodevelopment (Figure 1). In this review, we aim to examine how illness from infection during pregnancy in addition to the specific viral pathogen affects pregnancy and neurodevelopmental outcomes of the offspring.

Figure 1: Viral exposures in pregnancy impact offspring neurodevelopment.

A graphical summary of how gestational exposure to multiple factors, including viral infections, fever, and immune activation in the gestational parent or the fetus may influence offspring neurodevelopment.

FEVER AS A MODULATOR OF NEURODEVELOPMENT

A hallmark of coronavirus disease 2019 (COVID-19) and of many other viral infections is fever. It is possible that the febrile state itself is teratogenic. Hyperthermia and fever during pregnancy have been suggested to cause a wide range of functional and neural tube defects and could act as a nidus for the development of neurological disorders including autism spectrum disorders (ASD), schizophrenia, and cerebral palsy.^5,20 In their meta-analysis, Dreier et. al. noted an increased risk of adverse offspring health in association with fever during pregnancy, between 1.5- and 3.0-fold increased risk for neural tube defects, congenital heart defects, and oral clefts when pregnant individuals were febrile in the first trimester, as well as an increased risk for ASD and developmental delay in offspring.²¹ Zerbo et. al. confirmed these findings, with both ASD and developmental delay associated with exposure to fever during pregnancy.²² In agreement, Croen et. al. found that infection during the second trimester with accompanying fever elevated the risk of ASD twofold.²³ Another study also found association between fever during pregnancy and developmental coordination disorders at age seven years.²⁴ A large cohort study of fever in pregnancy and ASD was performed in Denmark and included 96,736 children aged 8–14 years born between 1997 and 2003 from the Danish National Birth Cohort. The group obtained the diagnoses of ASD and infantile autism from the Danish Psychiatric Central Register; 976 (1%) children from the cohort had a diagnosis of ASD. They found that mild, common infections and short febrile episodes during pregnancy were not associated with ASD/infantile autism, but that there was a two- and three-fold increased risk of infantile autism with prenatal exposure to influenza infections and prolonged episodes of fever, respectively.^11,12 These child outcomes correlated with a more severe illness and increased inflammatory response in pregnancy. There is also evidence that antipyretic medications may offer a protective effect against neurodevelopmental disorders when used during a febrile illness in the gestational parent.^{21,22,25–27} However, some studies did not find a protective effect to antipyretic use.²³

The mechanism of this disruption to offspring development is not clearly known, but several mechanisms have been proposed. When there is an infection in pregnancy, the maternal immune system is activated, and there are changing concentrations of cytokines within the fetal environment. Some pyogenic cytokines, such as interleukin-1 (IL-1), interleukin-6 (IL-6), and tumor necrosis factor alpha (TNF-a) cause the hypothalamus to raise the set point of body temperature.²⁸ This elevated body temperature is hypothesized to effect protein synthesis, folding, and enzyme production, which results in altered or dysfunctional cellular processes (i.e., proliferation, migration, differentiation, apoptosis).^20,28 As a result of the fever, a heat shock response ensues.²⁹ Heat shock proteins help stabilize these processes against thermal stress.²⁸ However, the heat shock response is prioritized over other cellular activities, which can inhibit further protein synthesis and cell proliferation.²⁰ If a fever occurs during certain windows of vulnerability during fetal neurodevelopment, it is thought that these processes can be disrupted.

Studies have shown that ASD may be associated with prenatal exposure to a wide range of infectious agents.^{11,15,22,23,30} The diversity of potential infectious triggers begs the question of whether host factors, such as the fever response or activation of the maternal immune system may have a role in the development of these neurodevelopmental consequences.³¹ Some studies have found higher levels of inflammatory cytokines in amniotic fluid³² or parental mid-gestational serum³³ during the gestations of offspring with ASD compared to offspring without ASD. Parental immune responses to infection, including the timeline of febrile episodes relative to vulnerable periods in fetal brain development, may influence risk of ASD in offspring. Hornig et. al. performed a prospective cohort study in Norway to assess for an association between prenatal fever and ASD risk.²⁶ They found that ASD risk is increased for those with fever in pregnancy, particularly when it occurs in the second trimester, and the risk is magnified with exposure to three or more fevers during the second trimester.²⁶

Attention deficit/hyperactivity disorder (ADHD) has also been hypothesized to potentially be related to fever during pregnancy. Gustavson et. al. aimed to characterize the link between fever during pregnancy and ADHD diagnosis in offspring by age eight years through a prospective cohort study.³⁴ They found that fever during pregnancy, especially during the first trimester, carried two and a half times higher odds of the diagnosis of ADHD in offspring compared to children unexposed to fever in utero, and these children also had the highest inattention symptoms.³⁴ Another Danish cohort study found no overall association between exposure to fever or infection in pregnancy and ADHD occurrence in the offspring but did find higher rates of ADHD in the offspring when the exposure was considered during specific gestational periods. Specifically, genitourinary infections were associated with ADHD in offspring even after adjusting for fever, suggesting that the increase may be more associated with the local inflammatory response or treatment used to treat the infection rather than the symptom of fever alone.³⁵ Others have wondered whether prenatal fever can also affect the offspring’s academic performance. Dreier et. al. found no association between prenatal fever and prenatal exposure to common infections and academic performance in second through eighth grade.³⁶ In the absence of a viral pandemic, twenty percent of people report one or more episodes of fever during their pregnancy³⁷, and this percentage is likely to be higher since the onset of widespread SARS-CoV-2 infections during the COVID-19 pandemic. It is possible that SARS-CoV-2 infections with symptoms (including fever) may be associated with higher rates of abnormal neurodevelopment, given the correlation between fever in pregnancy and neuropsychiatric disorders in the offspring.

INFLAMMATION DURING GESTATION

While fever and inflammation often co-occur in infections, inflammation can occur without a fever; thus, it is important to distinguish the two when considering causative agents for fetal neurodevelopmental impacts during pregnancy. It is hypothesized that pregnant individuals in their first and third trimester are in a pro-inflammatory state, and an infection could lead to even more severe inflammation when occurring during these more vulnerable periods of pregnancy.^1,2 Inflammation in the gestational parent has also been associated with changes in fetal brain development.^5,38,39 Cytokines, a cornerstone of inflammation, are regulators of neuronal migration, proliferation, and neuronal cellular differentiation during brain development.⁴⁰ Proinflammatory cytokines, however, are known to cause neurotoxicity and may cause direct damage to oligodendrocytes and neurons through activation of microglia which can lead to subsequent neurobehavioral abnormalities from antenatal exposure to inflammation.^41,42 Jones et. al. sought to measure levels of cytokines in the maternal serum for children who had ASD with and without intellectual disability and compared them to control counterparts. The study found significantly increased levels of proinflammatory cytokines in gestational parents of children with ASD with intellectual disability, but not in gestational parents of children with ASD alone or gestational parents of control children.⁴³ These findings contrast with a study with a smaller sample size, which found that increased levels of proinflammatory cytokines in mid-gestational parental serum were associated with parents of children with ASD vs. without.³³ Another study reported a possible link between immune activation in the gestational parent and offspring intelligence and executive function.⁴⁴

C-reactive protein (CRP) is an acute phase reactant often associated with low-grade inflammation in both infectious and non-infectious states and is activated by IL-6.⁴⁵ From the Finnish National Birth Registry, Brown et. al. studied the stored serum of the pregnant parent drawn in the first and early second trimesters from over one million births.⁴⁶ They found that gestational parents with CRP levels in the highest quintile compared to the lowest quintile, had a 43% elevated risk of ASD in the offspring. This finding suggests that CRP elevation in the first or early second trimesters may be an early biomarker for ASD, and that inflammation may have a significant role in the subsequent development of ASD for some individuals.⁴⁶ Inflammatory exposure of the fetal brain during gestation may thus be an important factor in affecting offspring neurodevelopmental outcomes.

PREVIOUS CORONAVIRUS EPIDEMICS AND PANDEMICS: PREGNANCY AND NEONATAL OUTCOMES

Viruses have been affecting the maternal-placental-fetal triad for centuries with impacts on pregnancy and offspring outcomes (Figure 1). During the worldwide outbreak of Severe Acute Respiratory Syndrome (SARS) in 2003, the number of cases in pregnant individuals was too small to draw definite conclusions as to whether SARS was more severe in pregnancy than otherwise, but some editorials from hospitals with high numbers of cases of pregnant SARS patients described adverse fetal effects and increased risk for critical illness in the gestational parent.⁴⁷ The largest case series of pregnant people from the 2003 SARS outbreak was from Hong Kong, where twelve pregnant people with SARS were admitted to five public hospitals; three of them died, giving a case-fatality rate of 25%.⁴⁸ In a case-control study conducted in the same region, pregnant patients with SARS had more severe disease and increased risk of admission to intensive care units (ICU) than nonpregnant patients.⁴⁹ Live-born infants did not acquire the infection through vertical transmission, although some fetuses had severe intrauterine growth restriction and preterm neonates sometimes developed necrotizing enterocolitis.^50,51

In a systematic review of studies including 79 hospitalized pregnant patients with coronavirus infections (41 with COVID-19, 12 with [Middle Eastern Respiratory Syndrome] MERS, and 26 with SARS), greater than 90% of whom also had pneumonia, preterm birth was the most common pregnancy complication.⁵² Preeclampsia and cesarean delivery were also more common than in the general population.⁵² In this study, the most common adverse neonatal outcome was fetal distress, with more than half of all newborns admitted to the neonatal intensive care unit (NICU).⁵² Fortunately, there were no cases of death from COVID-19 among the gestational parents in this study, however in pregnant patients with MERS and SARS infections the mortality pooled proportion in pregnant patients ranged from 25%−30%.⁵² Very few pregnancy-associated cases of MERS coronavirus infection have been documented (n=11), but according to Alfaraj et. al., 91% of them had adverse clinical outcomes. Six pregnant patients required intensive care and three died.⁵³ The infant death rate was 27%, and the maternal death rate was 27%, similar to the overall case fatality rate of MERS in the general population.⁵³ Overall, there is strong epidemiologic evidence that pregnant patients are at higher risk of severe illness and mortality from viral infections, most notably during pandemics including influenza (discussed later in this review).^54–56 High symptomatology in gestational parents has potential risk to offspring neurodevelopment as described, however, conclusions have not been made in studies of prior coronavirus epidemics and pandemics.

INFLUENZA: SEASONAL AND PANDEMIC

Pregnant patients are at elevated risk for severe illness and complications from influenza during seasonal influenza^3,54–57 and pandemics.^56,58–61 Although proper control groups were not used for comparison, mortality rates among pregnant patients in the influenza pandemics of 1918 and 1957 appeared to be abnormally high.^59,61 Among 1,350 reported cases of influenza among pregnant individuals in Maryland, USA during the pandemic of 1918, the proportion of deaths was reportedly 27%, with a rate of 45% deaths among 86 pregnant individuals in Chicago, USA.⁵⁹ In Minnesota, USA during the 1957 pandemic, influenza was the leading cause of death in pregnant individuals, accounting for nearly 20% of deaths in pregnant individuals during the pandemic period. Half of the individuals of childbearing age who died from influenza in Minnesota during this period were pregnant.⁶¹ A systematic review examining the effects of pandemic influenza A (H1N1 2009), found H1N1 caused significantly more disease of higher severity in pregnant patients compared with age-matched nonpregnant controls, including pneumonia and subsequent acute respiratory distress syndrome (ARDS) requiring mechanical ventilation.⁵⁸ Pregnancy was associated with increased risk of hospital and ICU admission, and of death.⁶² Preterm and emergency cesarean-section deliveries were frequently reported.⁶³ In a United Kingdom cohort study, neonatal mortality rate was higher in infants born to infected patients (39 per 1,000 total births) than in infants of uninfected patients (7 per 1,000 total births). This could be explained by the increase in rates of stillbirth and preterm births.⁶⁴ In terms of neurodevelopmental outcomes, there has been limited long-term follow-up of children born to parents who had H1N1 2009 infections. In one study, early prenatal exposure to pandemic H1N1 influenza in gestational weeks 0–8 was modestly associated with delayed development and higher temperamental scores compared to non-exposed infants at age 6 months. Similar effects were not noted in infants exposed after the 9^th gestational week.⁶⁵

Even in non-pandemic influenza, pregnant individuals are at higher risk of adverse effects compared to non-pregnant individuals of similar age. In a study of over 4,000 patients of childbearing age during nineteen influenza seasons, pregnant patients were compared to postpartum patients (a group considered to be most similar to pregnant patients in demographics and health status) and were found to be significantly more likely to be hospitalized for a cardiopulmonary event during influenza season.⁵⁷

In addition, some studies suggest an increased risk for other adverse outcomes among infants born to gestational parents with influenza infections during pregnancy, including neural tube defects, cleft lip and palate, cardiovascular malformations, and neuropsychiatric conditions identified during childhood.^27,38,66 A population-based cohort study reported almost a twofold increased risk of ASD after self-reported influenza infection during pregnancy.¹² Deykin and MacMahon determined that the offspring of nearly 8% of pregnant patients who had influenza or exposure to influenza during their pregnancy later developed ASD.⁶⁷ Animal and birth cohort studies have linked development of schizophrenia in offspring to influenza infection of the pregnant parent during pregnancy.^17–19 However, Zerbo et. al. found that influenza infection was not associated with increased risk of ASD or developmental disorders, but fever was associated, as described above.²² Other studies have reported that influenza infection at any time during pregnancy was not associated with increased risk of development of ASD or developmental delay in offspring.^68,69 It seems that a diverse selection of respiratory viruses, including seasonal and pandemic influenza viruses, have the potential to contribute to poorer pregnancy outcomes and may alter the gestational environment.

ANIMAL MODELS

Animal studies have served as helpful models for maternal immune activation (MIA), especially the polyinosinic:polycytidylic acid (poly(I:C)) model, which uses a synthetic analog of double stranded RNA to mimic a viral infection in the host.⁷⁰ In a study using this model, pregnant mice were injected with poly(I:C), producing offspring that exhibit autistic features of increased repetitive and stereotyped behaviors and deficient social and communitive behaviors.⁷¹ This concurs with another study using the poly(I:C) model which noted highly abnormal behavior including deficits in prepulse inhibition in the acoustic startle response of animals exposed to early inflammation.⁷² Other studies have shown abnormalities in communication, altered social behavior, repetitive behaviors, impaired learning and memory in mice exposed to inflammation during gestation.⁷³ The extent and type of abnormality has been associated with the timing and severity of inflammatory response during pregnancy.⁴¹

The inflammatory cytokine IL-6 has been identified as a key intermediary in the neurobehavioral development of offspring following maternal inflammation. Smith et. al. reported that a single maternal injection of IL-6 during mid-gestation of mouse pregnancy causes altered behavior in offspring resembling ASD and schizophrenia, such as decreased prepulse inhibition and latent inhibition defects.⁷⁴ However, these behavior changes were prevented with the administration of anti-IL-6 antibody in the poly(I:C) model and were not seen with maternal immune activation in IL-6 knockout mice.⁷⁴ A recent prospective longitudinal study found that maternal IL-6 was inversely associated with human offspring cognitive development at 12 months of age.⁷⁵ This study noted changes in fronto-limbic white matter (important structure in socioemotional and cognitive development) detected on brain magnetic resonance imaging scans that were associated with maternal IL-6 concentrations during pregnancy.⁷⁵ Another study noted sustained alterations in patterns of microglial process motility and behavioral deficits in the brains of embryonic mice in the setting of MIA induced in the early second trimester.⁷⁶ Other studies found that interleukin-17a and Th17 cells are critical drivers in inducing ASD-like phenotypes in offspring of rodent mothers subjected to immune activation during pregnancy.^39,77 Pregnant rhesus monkeys given poly(I:C) produced offspring with abnormal repetitive behaviors, altered communication, and atypical social interactions, all behaviors resembling ASD and schizophrenia.⁷⁸ These findings strengthen the concern that MIA can adversely affect the intrauterine environment, which may in turn have neurodevelopmental consequences on offspring.^1,2,5

Similar behavioral changes have been seen in animal models with influenza infection during pregnancy. Prenatal influenza infection in the mouse has been associated with histopathologic changes in the brain⁷⁹ and behavioral alterations in offspring resembling ASD and schizophrenia.¹⁷ Respiratory infection of pregnant mice with human influenza virus yields offspring that exhibit highly abnormal behavior, including deficits in pre-pulse inhibition in the acoustic startle response, deficiency in exploratory behavior, and deficiency in social interaction.⁷² Although influenza viral RNA has not been found in the fetal brain in mice, these changes suggest that fetal effects could be secondary to MIA, rather than the result of a direct viral effect.¹⁶ These findings have also been seen in the rhesus monkey. Short and Lubach noted significant reductions in gray matter throughout most of the cortex and decreased white matter in the parietal cortex in the offspring of rhesus mothers inoculated with moderately virulent H3N2 influenza in the early third trimester; these changes were still present at the monkey-equivalent of early childhood, so it is suspected that these changes were permanent.⁸⁰ Despite these brain structural differences, early behavioral functioning and stress response were similar to rhesus control subjects. One of the few differences the group noted was that the flu-exposed offspring were quicker to develop autonomy from the mother by four months of age, which is an effect that can be seen in other psychologically stressed pregnancies.⁸⁰

Critical cellular pathways and neuronal function/connectivity are altered when exposed to MIA in mice, including derangements in neurotransmitter systems. Glutamatergic, GABAergic, dopaminergic, serotonergic, and cholinergic systems seem to be particularly vulnerable to MIA.⁸¹ Expression of genes coding for proteins involved in these systems are affected by epigenetic changes such as DNA methylation, which have been associated with MIA.^82–85 In particular, inflammation can NMDA receptor signaling and the developmental excitatory-inhibitory switch in GABAergic pathways.^81,83,86 Previously discussed animal model studies indicate a number of ways in which exposure to inflammation during the fetal period can affect various processes in the developing brain, and lead to behavioral changes resembling neuropsychiatric disorders in offspring.

FETAL BRAIN DYSGENESIS

Within the maternal-placental-fetal triad, interactions between genetic and epigenetic factors can damage sensitive parts of the developing brain that contain early neuronal and glial cell lineages. Some populations of progenitor cells seem to be affected by MIA depending on the timing of exposure. Microglial motility, migration, and function have been noted as abnormal when exposed to inflammation during gestation, with earlier exposure in the first half of pregnancy leading to abnormal differentiation pathways that adversely affect signaling, synapse formation, and neuronal connectivity in the second half of pregnancy.^76,87,88 Imbalances in cell positioning and connectivity affect the development and interactions between various types of neurons and glial cells, which in turn disrupts their proper differentiation. Interneurons participate in signaling in very early fetal brain development, and with injury, these excitatory and inhibitory properties can malfunction and affect mature brain function which are later expressed as a range of neurodevelopmental disorders including intellectual disability, ASD, and epilepsy.^89,90

During the second half of pregnancy, abnormal migration, dendritic arborization, synaptogenesis, and myelination contribute to early brain dysgenesis that originated during the first half of pregnancy.⁹¹ Para et al. describes two forms of fetal inflammatory response syndrome (FIRS) that may differentiate earlier vs. later effects on the brain based on distinct pathologic processes.⁹² FIRS Type I has been described with intra-amniotic infections from ascending lower genital tract infections and FIRS type II has been associated with chronic inflammatory lesions of the placenta.^93–95 In a study using RNA sequencing of human cord blood samples from preterm infants diagnosed with FIRS type I or FIRS type II, FIRS Type I was found to be characterized by an upregulation of host immune responses, including neutrophil and monocyte functions, together with a proinflammatory cytokine storm and a downregulation of T cell processes, indicating involvement of the innate limb of immunity consistent with host defense. In contrast, FIRS type II comprised a mild chronic inflammatory response involving perturbation of HLA transcripts, suggestive of fetal semiallograft rejection.⁹² During critical periods of brain development during the fetal period, exposure to MIA or FIRS may disrupt populations of progenitor cells, ultimately leading to compounding effects on cell communication, differentiation, myelination, and connectivity. These changes could lead to visible changes in offspring behavior.

COVID-19 (SARS-CoV-2) PANDEMIC

Between January 20, 2020 and July 25, 2022, there were 225,656 cases of COVID-19 in pregnant individuals reported to the U.S. Centers for Disease Control and Prevention (CDC) and 306 deaths.⁹⁶ Based on data from previous pandemics, pregnant individuals are at higher risk of acquiring infection and dying compared to nonpregnant counterparts.^59,61,97 Owing to differences in physiology during pregnancy, pregnancy represents a vulnerable state that may be associated with worse outcomes in COVID-19.^98,99 Pregnant and recently pregnant patients with COVID-19 admitted to hospitals for any reason were more likely to be admitted to the ICU or need invasive ventilation than non-pregnant patients of a similar age group, and risks were even higher in pregnant Hispanic and non-Hispanic Black patients.^100–103 In analysis of COVID-19 surveillance data from January to June 2020, the CDC found that more than 2,500 (31.5%) pregnant people with COVID-19 required hospitalization, much higher than non-pregnant cohorts (5.8%).^100,103 A systematic review and meta-analysis demonstrated that a high proportion of pregnant people with COVID-19 had preterm birth (22%) and cesarean delivery (48%).^{99,100,104,105} Their babies are more likely to be admitted to the NICU.⁹⁸ SARS-CoV-2 can cause placentitis from direct infection of the placenta and can lead to stillbirth and neonatal death due to poor perfusion and placental insufficiency.¹⁰⁶ The Delta variant was associated with more severe outcomes than pre-Delta for pregnancy: five times higher risk of admission to ICU, 76% higher risk of invasive ventilation or needing extracorporeal membrane oxygenation (ECMO), 1.3 times higher risk of death than that of nonpregnant people.¹⁰⁷ The Omicron variant spread rapidly but appeared to cause less severe disease than the Delta variant.¹⁰⁸ A study in Scotland found that 77.4% of nearly 5,000 COVID-19 cases, 90.9% of COVID-associated hospital admissions, and 98% of COVID-associated critical care admissions as well as all infant deaths occurred in pregnant people who were unvaccinated at the time of COVID-19 diagnosis (compared to fully vaccinated pregnant people). Vaccine uptake had been poor among pregnant people in Scotland, with only 32.3% of pregnant people giving birth in October 2021 having had two doses of vaccine compared to 77.4% in all people of childbearing age.¹⁰⁹ In both variants, most early neonatal SARS-CoV-2 infections occurred among unvaccinated pregnant patients with non-severe COVID-19.¹¹⁰ Pregnant individuals are a particularly vulnerable group with regard to COVID-19 severity, and the risks of poor neonatal outcomes are elevated with severe COVID-19. Some of the differences in neurodevelopment we may see in offspring exposed to SARS-CoV-2 may be related to the adverse effects of severe illness including need for maternal intensive care, preterm delivery, cesarean delivery, and need for higher levels of neonatal care.

COVID-19 AND NEURODEVELOPMENT: CURRENT KNOWLEDGE

The COVID-19 pandemic sparked significant interest in potential adverse effects of viral-triggered hyperinflammatory states on pregnancy and offspring. It has been suspected that vagal nerve suppression of proinflammatory cytokine release in the cholinergic anti-inflammatory pathway (CAP) can play a role in the severity of SARS-CoV-2 infection. It is possible that disruption of either the maternal or fetal CAP could exacerbate the severity of gestational hyperinflammation and lead to increased risk for neurodevelopmental disorders in the offspring.¹¹¹ Another possible mechanism that could potentially contribute to increased risk of neurodevelopmental disorders is alteration in DNA methylation patterns. Viral infection during pregnancy is thought to affect neurodevelopment through epigenetic mechanisms, and a recent study out of Victoria, Australia has found changes in DNA methylation in genes involved in pathways that play a role in neurodevelopment in human infants exposed to SARS-CoV-2 infection during gestation.⁸⁵ SARS-CoV-2 is known to infect the placenta and can lead to preeclampsia, preterm birth, and intrauterine growth restriction, which on their own can lead to adverse neurodevelopmental outcomes.¹¹² Disruption of the maternal-fetal interface could lead to more inflammatory cytokines crossing the placenta into the newborn, causing developmental delay.^112,113 Fetal brain injury may also be possible but has been infrequently reported. A case report from Germany reported a pregnant individual with only mild symptoms of COVID-19 in the second trimester who presented in preterm labor with elevated serum inflammatory markers. The infant was delivered prematurely and had bilateral intracranial bleeds which the group suspects were caused by a post-COVID systemic inflammatory response produced coagulopathy affecting fetal circulation.¹¹⁴

Because of the rather small collective level of knowledge and heterogeneity of COVID-19 infections, such as strain variability, symptoms, gestational age, vaccination status, and co-morbidities of the gestational parent, it is difficult to define a congenital viral syndrome for SARS-CoV-2. Clinical and epidemiologic data show a myriad of possible neurodevelopmental disabilities following prenatal viral infection. It is critical to understand these possible outcomes, especially in a disease as prevalent as COVID-19. There is evidence that antenatal and early neonatal exposure to SARS-CoV-2 with symptomatic infection of the gestational parent is associated with lower scores on developmental screening tools in the first six months of age.¹¹⁵ Edlow et. al. found that infants prenatally exposed to SARS-CoV-2 were more likely to be diagnosed with a neurodevelopmental disorder than those unexposed, even after accounting for preterm births.¹¹⁶

Other studies have not been able to verify this link, and instead associate being born during a pandemic (without exposure to prenatal SARS-CoV-2 infection) as the risk factor for developing a neurodevelopmental disorder.^117,118 A study from Kuwait found no increase in the rate of developmental delay in infants exposed to SARS-CoV-2 infection during gestation compared to a historical control of infants born before the COVID-19 pandemic.¹¹⁹ Longitudinal studies of child neurodevelopmental outcomes are needed for infants born with antenatal exposure to SARS-CoV-2, as changes in neurodevelopment may not appear until later childhood or adolescence.¹²⁰

It cannot be understated that being pregnant and becoming a new parent can be stressful experiences – to do this during a global pandemic with social isolation is undoubtedly more stressful, even if one does not become ill.^121,122 Critical clinical protocols were put in place to protect and care for newborns early in the pandemic, but these efforts had a negative effect on mental health in pregnancy.¹²³ On top of the isolation and fear of COVID-19 unknowns, the stress of becoming significantly ill with a virus can impact the developing fetus. Pregnant patients during the pandemic had higher levels of stress, anxiety, and depression compared to pre-pandemic pregnant controls.¹²⁴ In a quantitative fetal brain magnetic resonance imaging study, fetal brain volumes were decreased and fetal cortical gyration was delayed in pregnancies during the COVID-19 pandemic compared to pre-pandemic pregnancies.¹²⁴ It is known that postnatal bonding has important implications for infant brain development, and the consequences of maternal mental health conditions on offspring may not be evident for years to come.¹²¹ Thus, neurodevelopmental effects on offspring of the pandemic may relate to a number of factors, including viral exposure in utero, changes in gestational environment, maternal mental health both prenatally and postnatally, and underlying structural brain differences.

CONCLUSION AND FUTURE DIRECTIONS

Pregnancy has always been a vulnerable state, as highlighted by the poorer outcomes experienced by this population in the current COVID-19 pandemic as well as during prior viral epidemics and seasonal virus infections over the last century. The emergence of Zika virus (ZIKV) as a viral teratogen in 2015 emphasized the need to consider viral epidemics in pregnancy. When infected pregnant individuals, with only mild or no symptoms, began to give birth, the devastating effects of congenital Zika infection became glaringly clear.^125,126 Infants were born with eye abnormalities and hearing loss, seizures, hypertonia, contractures, decreased brain tissue with subcortical calcifications, and severe microcephaly with partial skull collapse.^127–130 However, it is important to note that not every Zika-exposed child had birth defects and severe symptoms, and that many children appeared normal at birth and only displayed differences in the development as they grew older. Studies have shown below average scores on developmental testing or development of abnormalities in hearing or vision in children exposed to ZIKV in utero.^131–136 These findings stress the importance of continued follow-up of exposed infants and children, even when their initial evaluations do not suggest neurologic changes. In fact, the CDC recommends long-term follow-up of all infants exposed to ZIKV in utero, not just those with manifestations of congenital Zika syndrome at birth.^130,134 Once effects of SARS-CoV-2 infection in pregnancy are known, it is likely that offspring from these pregnancies will need similar longitudinal neurodevelopmental follow-up.

The “exposome”, a term coined in 2005 by Wild, is an evolving concept of the totality of nonheritable factors affecting the genome, and the neural exposome would encompass those factors affecting the genome responsible for neurologic processes and plasticity.¹³⁷ It includes endogenous factors (genes/epigenetics, pre-existing conditions, metabolism, microbiome, xenobiotics), exogenous factors (environmental toxicants, light and noise, climate, ecosystems, economics/education) and behavioral factors (psychosocial effects, drugs/alcohol/tobacco, lifestyle, sleep, stress).¹³⁸ Exposure to inflammation in utero would be included in the exposome. Since the exposome includes all lifetime exposures, it seems that individuals are at the greatest risk for damage if insults occur during particularly critical periods of development (such as the embryonic/fetal/neonatal period).^88,139 Developmental origins and life-course theories stress the relevance of fetal and neonatal development when considering the diagnosis and treatment of adult-onset cerebrovascular, cognitive, and neurodegenerative disorders.^88,140 Disruption of brain development in the fetal or neonatal period often precedes childhood to adulthood disease expression by months to years.¹³⁹ With an event as widespread as COVID-19, it is important to establish rigorous studies and follow offspring outcomes, so we may have an opportunity to identify the delayed onset of diseases that may be associated with SARS-CoV-2 exposure in utero.

Fetal exposure to fever, inflammation, and immune activation in the pregnant parent during gestation at certain developmental windows are likely very important ways in which viral infection in pregnancy impacts offspring neurodevelopment. In the absence of direct teratogenic effects from the virus, this exposure risk seems true regardless of the identity of the viral pathogen. For SARS-CoV-2, the scientific community is still relatively early in its study of the effects on pregnancy, birth outcomes, and infant and child neurodevelopment. However, compared to past viral epidemics and pandemics, more studies seem to be underway that will address the vulnerable populations of pregnant individuals and children and answer important questions on the risk to offspring neurodevelopment.

Future research should aim to provide serial longitudinal data linking viral infections in pregnancy to long-term outcomes in offspring. It is likely that many viral exposures in pregnancy affect offspring in similar ways and so lessons learned from one antenatal viral exposure may be applicable to other viral exposures in pregnancy or the next worldwide pandemic. Further delineation of effects on neurodevelopment, such as strain variability, symptomatology, fevers, antipyretic or anti-inflammatory use, and effects of vaccination in preventing developmental delay in children are needed. Characterization of developmental delays in children associated with congenital or early-in-life exposure to viral infections can help inform recommendations for early interventions, therapies, and treatments to help improve developmental trajectories. Clinicians caring for young children should inquire about exposure to infection during pregnancy and when present, screen for signs of developmental delay or behavioral disorders. Viral infections in pregnancy will continue, therefore it is critical that we understand the mechanisms by which they can impact offspring neurodevelopment so we can develop ways to protect and better support the developing brain.

Impact.

• Viral infections have impacted pregnant people and their offspring throughout history.

• Antenatal exposure to maternal fever and inflammation may increase risk of developmental and neurobehavioral disorders in infants and children.

• The recent SARS-CoV-2 pandemic stresses the importance of longitudinal studies to follow pregnancies and offspring neurodevelopment.