Maternal SARS-CoV-2 positivity is associate with neurodevelopmental diagnoses at 12 months among male offspring

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Harvard Study Finds That Babies Born To Mothers Exposed To SARS-CoV-2 Likely To Develop Neurodevelopmental Disorders.

In this cohort study of offspring with SARS-CoV-2 exposure in utero, such exposure was associated with greater magnitude of risk for neurodevelopmental diagnoses among male offspring at 12 months following birth. As with prior studies of maternal infection, substantially larger cohorts and longer follow-up will be required to reliably estimate or refute risk.

The study findings were published in the peer reviewed journal: JAMA network Open.
https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2802745

Among a cohort of 18 355 infants born during the COVID-19 pandemic with 12 months of follow-up data, we identified a statistically significant elevation in risk among male but not female offspring, detectable using 2 complementary approaches to address potential confounding variables.

These effects were not attributable to preterm delivery, which was significantly more common among SARS-CoV-2–exposed offspring. Restriction of the cohort to offspring with 12-month follow-up visits within our hospital system yielded results of similar magnitude, suggesting they are less likely to be a consequence of differential follow-up among exposed offspring.

In the smaller subset of offspring for whom 18 months have elapsed since birth, we observed a similar pattern, with likelihood of a neurodevelopmental diagnosis numerically greater among SARS-CoV-2–exposed male offspring, although the 95% CI for this association included 1.00.

The similar pattern of increased neurodevelopmental risk among the 18-month cohort but the 95% CI spanning 1.00 suggests the importance of assembling larger cohorts that can be followed up over longer periods of time to determine whether the increased risk noted at 12 months persists.

As all deliveries occurred during the COVID-19 pandemic period, these effects cannot be attributed primarily to nonspecific effects of pandemic-era stress, given that both SARS-CoV-2–positive and uninfected mothers were exposed to such stress. While further work is needed to understand the mechanism by which maternal infection associates with sex-specific risk, differential impact of maternal infection and immune activation on male vs female immune and inflammatory signaling has been noted in prior work.31-34

Our findings are consistent with abundant evidence that the developing male brain is more vulnerable to in utero environmental effects,35,36 including maternal immune activation.37 In the case of SARS-CoV-2 infection in pregnancy, prior work identified robust immune activation at the maternal-fetal interface, even in the absence of placental infection and vertical transmission.15,38,39

Moreover, this work demonstrated sexually dimorphic effects of maternal SARS-CoV-2 positivity on placental immune response, with significant upregulation of types I, II, and III interferon signaling pathways in male placentas and downregulation in female placentas.15

Consistent with these findings in human SARS-CoV-2 infection, in murine models, upregulation of maternal type I interferon signaling in pregnancy was noted to be associated with a type I interferon signature in the embryonic yolk sac, a preplacental structure that serves as the origin of fetal brain microglia, and reduced microglial proliferation in offspring.40

These changes, in turn, were associated with a sex-specific impact on offspring behavior, with exposed male offspring demonstrating increased anxiety relative to female offspring.40

Thus, our finding that neurodevelopment in male offspring may be more adversely impacted than in female offspring in the setting of maternal SARS-CoV-2 infection is biologically plausible and consistent with prior studies that have demonstrated sex-specific impact of maternal types I, II, and III interferon signaling on the developing placenta and fetal brain.15,40

We did detect an increase in the risk for neurodevelopmental diagnoses, more modest in magnitude and similar among male and female offspring, associated with pandemic-era deliveries compared with 2018 (a prepandemic cohort with all offspring having 12-month follow-up prior to the COVID-19 pandemic) and 2019 (a prepandemic-born cohort with all offspring having at least some follow-up during the COVID-19 pandemic).

The increased odds of any neurodevelopmental diagnosis at 12 months in pandemic-born children was statistically significant in a pooled analysis of both sexes, in comparison with the prepandemic 2019 cohort. These comparisons with historical controls suggest that any secular trends (reflecting birth during the pandemic itself) are likely to have a more modest impact on observed neurodevelopmental risk in offspring than does maternal SARS-CoV-2 infection itself.

Overall, our results are consistent with abundant evidence that exposure to infection during pregnancy—including viral infections such as influenza—is associated with an increased risk for neurodevelopmental morbidity in offspring.5,41-45 Such risk was initially detected as an increase in schizophrenia and autism spectrum disorder diagnoses following influenza and rubella pandemics,1-3 was recapitulated in animal models,8,46,47 and was more recently directly tested in large registry studies.4,5

Risk of behavioral dysfunction in offspring after maternal prenatal exposures also has been reported to be greater in male offspring in rodent models.32,48 Because the neurodevelopmental risk in offspring is thought to be mediated in large part through maternal and placental immune activation6-8 and has been observed in other viral infections that, similar to SARS-CoV-2, are not thought to directly infect fetal brain tissue,6 it is biologically plausible that SARS-CoV-2 infection in pregnancy could impact offspring risk for neurodevelopmental disorders.

Prior investigations of neurodevelopment among SARS-CoV-2-exposed offspring yielded mixed results. A recent meta-analysis19 included 11 438 infants screened with the Ages and Stages Questionnaire–3 (ASQ-3)49 up to 12 months of age, of whom 691 had documented SARS-CoV-2 exposure. Of note, time to follow-up was not uniform among the included studies, and studies were included that assessed infants once at ages ranging from 3 to 12 months.

That analysis found no significant difference in overall rate of a composite neurodevelopmental impairment score combining all ASQ-3 domains among SARS-CoV-2–exposed offspring (12% among SARS-CoV-2–exposed vs 9% in contemporaneous SARS-CoV-2–unexposed offspring; OR, 1.38 [95% CI, 0.80-2.37]; P = .24). However, the meta-analysis did identify significantly greater rates of fine motor impairment in offspring exposed to maternal SARS-CoV-2 in utero (OR, 3.46 [95% CI, 1.43-8.38]; P = .006).

Some individual studies, including an early 3-month longitudinal study of mothers in China20 and a 10- to 12-month prospective study in Kuwait,21 have been limited by the absence of a contemporaneous noninfected control group. An early study of 57 SARS-CoV-2–exposed offspring in China that did include controls did not identify adverse outcomes at 3 months.50

Such a control group may be particularly important in light of another small 6-month study,22 including 114 SARS-CoV-2–exposed offspring, that failed to identify risk associated with exposure per se. That study did identify elevated scores among pandemic-era vs prepandemic offspring,22 suggesting a secular trend that was posited to reflect greater stress among parents during the COVID-19 pandemic, although the study did not assess parental stress.

Conversely, a preliminary report in a subset of the present cohort, including a noninfected contemporary control group, suggested that SARS-CoV-2 was associated with increased risk for neurodevelopmental diagnosis at 12 months of age,23 but did not yet have sufficient neurodevelopmental diagnoses to examine the impact of fetal sex, as we have now been able to examine in this substantially larger cohort.

As such, the present study does not refute our prior work,23 but suggests the previously observed effect was either driven by a sex-specific increase in neurodevelopmental risk, and/or that there is greater heterogeneity of effect among female offspring. This observation may still represent type I error, and further study will be required to more precisely understand the magnitude of risk that exists, if any.

We detected a more modest elevation in risk associated with birth during the COVID-19 pandemic period. We emphasize that such an effect cannot explain the SARS-CoV-2 associations we observe, as primary analyses are limited to the pandemic period. There are instead a wealth of potential explanations for such a secular trend, many unrelated to biology.

While greater maternal stress could represent one such explanation, as posited by a recent small study,22 absent direct measures of stress, this conclusion is purely speculative. Other potential explanations for this finding that are unrelated to maternal biology could include ascertainment bias (eg, clinicians being more likely to diagnose neurodevelopmental disorders in children born during the pandemic), changes in social environment for offspring during the pandemic, or even changes in billing as health systems adapt to remote assessment. These alternate explanations merit investigation in future studies.

Another study suggests that…

Maternal immune activation during pregnancy may be associated with neurodevelopmental effects in offspring. This is the conclusion reached by a growing body of research examining the impact of a mother’s immune system on her developing child.

The idea that a mother’s immune system could influence her child’s brain development has been around for decades. In the 1960s, researchers found that babies born to mothers who had been exposed to the flu during pregnancy were more likely to develop schizophrenia later in life. This led to a wave of research examining the impact of prenatal infections on offspring.

More recently, researchers have been investigating the impact of maternal immune activation (MIA) on brain development. MIA refers to an inflammatory response in the mother’s body triggered by infection or exposure to other immune system triggers. The inflammatory response can result in the release of cytokines, which can cross the placenta and affect the developing fetus.

A 2017 review of the literature on MIA and neurodevelopmental disorders found that MIA was associated with an increased risk of autism spectrum disorder (ASD), schizophrenia, and attention deficit hyperactivity disorder (ADHD) in offspring. The review included studies on both animal models and human populations.

One study included in the review found that pregnant women who experienced an infection requiring hospitalization during the second trimester had a higher risk of having a child with ASD or intellectual disability. Another study found that children born to mothers who had the flu during pregnancy had a higher risk of developing bipolar disorder.

Animal studies have also shown that MIA can have lasting effects on offspring. For example, a study published in the journal Brain, Behavior, and Immunity in 2015 found that pregnant mice exposed to a bacterial toxin had offspring that exhibited behaviors associated with autism, such as repetitive behaviors and decreased social interactions.

Researchers are still working to understand the mechanisms by which MIA affects brain development. One possibility is that cytokines released during MIA interfere with the normal development of neural circuits. Another possibility is that MIA alters the composition of the microbiome, the community of microorganisms that live in and on the body, which can in turn affect brain development.

There are also questions about the timing and severity of MIA and its impact on offspring. Some studies suggest that MIA during early pregnancy may have a greater impact on brain development than MIA during later stages of pregnancy. Other studies suggest that the severity of MIA, rather than its timing, is the key factor in determining its impact on offspring.

Despite the many questions that remain, the research on MIA and neurodevelopmental disorders has important implications for public health. If MIA is found to be a significant risk factor for conditions like ASD and schizophrenia, it may be possible to develop interventions to reduce the risk of these conditions in offspring.

For example, pregnant women who are at high risk of MIA could be advised to take steps to reduce their risk of infection, such as avoiding crowded spaces during flu season or practicing good hygiene. In addition, researchers are exploring the possibility of developing drugs that can block the effects of cytokines on the developing brain.

In conclusion, the research on maternal immune activation during pregnancy and its potential impact on neurodevelopmental disorders is an exciting and rapidly evolving field. While there are still many questions to be answered, the findings so far suggest that MIA is a significant risk factor for a range of conditions, including ASD, schizophrenia, and ADHD. Further research in this area may lead to new interventions to reduce the risk of these conditions in offspring, improving the health and well-being of future generations.

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