A new study has found that children born during the first year of the COVID-19 pandemic, including those exposed to the virus in utero, were no more likely to test positive for autism than pre-pandemic children. Surprisingly, children whose mothers had COVID during pregnancy were less likely to test positive for autism.
A wealth of data from epidemiological studies over the years has demonstrated that maternal infection during pregnancy, including viral infection due to influenza, is associated with adverse neurodevelopmental outcomes in offspring.
Risks for a wide range of disorders (autism spectrum disorder, schizophrenia, cerebral palsy, cognitive dysfunction, bipolar disorder, anxiety, and depression) are thought to be elevated to varying degrees, depending on several variables, including the severity of the infection and possible comorbid health conditions in the mother.
While most of these disorders take years to become evident in a young person, some, including several types of cognitive dysfunction, can be detected in the first few years of life.
Although the 12-month milestone is often too early to detect, for example, autism spectrum disorders, some consider early developmental signs to indicate increased risk in a child.
The link between maternal infection during pregnancy and increased risk of neurodevelopmental disorders in the child is thought to be traceable to inflammation caused by the mother’s infection. Fetal brain development may be impacted by the mother’s immune response to inflammation that can be communicated through the placenta.
A preliminary study, conducted in 2022 and published in the journal JAMA Network Open, of thousands of children born during the pandemic found that those whose mothers tested positive for COVID-19 during pregnancy had an increased risk of being diagnosed with a developmental disorder during the first 12 months of life.
The team led by Roy H. Perlis, a young investigator at Massachusetts General Hospital, used electronic medical records covering births at six Massachusetts hospitals between March 2020 (shortly after the pandemic began) and September 2020.
The records captured 7,772 live births to 7,466 women, 222 of whom received a positive PCR test for COVID-19 during pregnancy.
Among the findings of the current study, it was clear that COVID infection during pregnancy was more likely to increase the risk of a child’s neurodevelopmental disorder when the infection occurred in the third trimester of pregnancy; and that mothers with COVID infection were significantly more likely to have given birth prematurely (14.4% vs. 8.7%).
Because all babies born prematurely, taken together, are at higher risk than babies born at term, it was important for the team to quantify the elevated neurodevelopmental risk in children of infected mothers who were born on schedule.
After accounting for preterm birth, the odds of a neurodevelopmental diagnosis were still 86% higher in children of infected mothers, suggesting that the relationship between COVID-19 infection during pregnancy and neurodevelopmental risk in the child is not merely a reflection of more preterm births.
Dr. Perlis’ team, as well as a reviewer in the journal where the study appeared, JAMA Network Open, noted that the results of this study were not designed to demonstrate a causal connection between maternal COVID infection and neurodevelopmental risk in the child, only an association.
This is one reason for the team's call to the research community to conduct larger, longer-lasting follow-up studies investigating the impact of COVID-19 infection during pregnancy on mothers and their children.
Dr. Perlis’s team’s requests were heeded, and another study, now conducted in 2024, has been published. The study, published in JAMA Network Open, is the first report on autism risk among children in the pandemic era. The study was led by Dani Dumitriu, an associate professor of pediatrics and psychiatry at Columbia University and the study’s senior author.
Dumitriu’s team has been studying the potential effects of COVID-19 pandemic-related maternal stress and maternal infection on children’s neurodevelopment at different points since birth through the COVID-19 Mother Baby Outcomes (COMBO) Initiative.
Children who were in the womb during the early stages of the pandemic are now reaching the age at which early indicators of autism risk may emerge.
The current study looked at nearly 2,000 children born at Morgan Stanley Children’s Hospital and Allen Hospital at NewYork-Presbyterian between January 2018 and September 2021.
Autism risk was calculated based on responses to a neurodevelopmental screening questionnaire that pediatricians give to parents to assess their children’s behavior. It’s important to note, Dumitriu adds, that the study did not look at autism diagnoses, only the risk of developing autism, as measured by a screening questionnaire completed by the child’s parents.
There has been a lot of speculation about how the COVID-19 generation is developing, and this study gives us the first glimpse of an answer regarding autism risk.
Scores were compared for children born during and before the pandemic and for children with and without in-utero exposure to COVID-19. All children were screened between 16 and 30 months of age.
The results were reassuring, with researchers finding no difference in positive autism screenings between children born before the pandemic and those born during the pandemic.
Surprisingly, the study also found that fewer children exposed to COVID-19 in utero tested positive for autism compared to children whose mothers did not have COVID-19.
The researchers suspect that having COVID-19 during pregnancy may have influenced parents’ assessments of their child’s behavior. Since parents who did not have COVID-19 may have experienced more stress, due to constant worry about getting sick and vigilance around infection prevention, they may have been more likely to report concerning behaviors in their child.
As the children get older, researchers will continue to monitor them for autism diagnoses. But based on the current results, Dumitriu thinks it’s unlikely that there will be a spike in COVID-related autism.
It is also well known that autism is influenced by the prenatal environment. Several studies of babies who were in the womb during previous pandemics, natural disasters, famines, and wartime have shown that other neurodevelopmental conditions, potentially triggered by the stressful environment, can emerge in adolescence and even early adulthood.
We need to recognize the unique experiences and environments of children born during the pandemic, including parental stress and social isolation, and continue to monitor them for potential developmental or psychiatric differences.
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Study 1:
Neurodevelopmental Outcomes at 1 Year in Infants of Mothers Who Tested Positive for SARS-CoV-2 During Pregnancy
Andrea G. Edlow, MD, MSc; Victor M. Castro, MS; Lydia L. Shook, M1; et al
JAMA Netw Open. 2022;5(6):e2215787. doi:10.1001/jamanetworkopen.2022.15787
Abstract:
Importance Epidemiologic studies suggest maternal immune activation during pregnancy may be associated with neurodevelopmental effects in offspring.
Objective To evaluate whether in-utero exposure to SARS-CoV-2 is associated with risk for neurodevelopmental disorders in the first 12 months after birth.
Design, Setting, and Participants This retrospective cohort study examined live offspring of all mothers who delivered between March and September 2020 at any of 6 Massachusetts hospitals across 2 health systems. Statistical analysis was performed from October to December 2021. Exposures Maternal SARS-CoV-2 infection confirmed by a polymerase chain reaction test during pregnancy. Main Outcomes and Measures Neurodevelopmental disorders determined from International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10) diagnostic codes over the first 12 months of life; sociodemographic and clinical features of mothers and offspring; all drawn from the electronic health record.
Results The cohort included 7772 live births (7466 pregnancies, 96% singleton, 222 births to SARS-CoV-2 positive mothers), with mean (SD) maternal age of 32.9 (5.0) years; offspring were 9.9% Asian (772), 8.4% Black (656), and 69.0% White (5363); 15.1% (1134) were of Hispanic ethnicity. Preterm delivery was more likely among exposed mothers: 14.4% (32) vs 8.7% (654) (P = .003). Maternal SARS-CoV-2 positivity during pregnancy was associated with greater rate of neurodevelopmental diagnoses in unadjusted models (odds ratio [OR], 2.17 [95% CI, 1.24-3.79]; P = .006) as well as those adjusted for race, ethnicity, insurance status, offspring sex, maternal age, and preterm status (adjusted OR, 1.86 [95% CI, 1.03-3.36]; P = .04). Third-trimester infection was associated with effects of larger magnitude (adjusted OR, 2.34 [95% CI, 1.23-4.44]; P = .01).
Conclusions and Relevance This cohort study of SARS-CoV-2 exposure in utero found preliminary evidence that maternal SARS-CoV-2 may be associated with neurodevelopmental sequelae in some offspring. Prospective studies with longer follow-up duration will be required to exclude confounding and confirm these associations.
Study 2:
Positive Autism Screening Rates in Toddlers Born During the COVID-19 Pandemic
Firestein M; Manessis A.; Warmingham JM; Dumitriu D; et al.
JAMA Netw Open. 2024;7(9):e2435005. doi:10.1001/jamanetworkopen.2024.35005
Abstract:
Importance
Stress and viral illness during pregnancy are associated with neurodevelopmental conditions in offspring. Autism screening positivity for children born during the pandemic remains unknown.
Objective To examine associations between prenatal exposure to the pandemic milieu and maternal SARS-CoV-2 infection with rates of positive Modified Checklist for Autism in Toddlers, Revised (M-CHAT-R) screenings.
Design, Setting, and Participants Data for this cohort study were drawn from the COVID-19 Mother Baby Outcomes (COMBO) Initiative. M-CHAT-R scores obtained from children aged 16 to 30 months during routine clinical care at Columbia University Irving Medical Center in New York City were abstracted from electronic health records (EHRs) for children born between January 2018 and September 2021 (COMBO-EHR cohort). Separately, the M-CHAT-R was administered at 18 months for children born between February 2020 and September 2021 through a prospective longitudinal study (COMBO-RSCH cohort). Prenatal pandemic exposure (birth after March 1, 2020) and maternal SARS-CoV-2 status during pregnancy was determined through EHRs. Data were analyzed from March 2022 to June 2024.
Exposures Prenatal exposures to the pandemic milieu and maternal SARS-CoV-2 infection.
Main Outcomes and Measures The primary outcome was rate of positive M-CHAT-R screenings. For all primary analyses, unadjusted χ2 tests and adjusted logistic regression models were performed.
Results The COMBO-EHR cohort included 1664 children (442 born before the pandemic and 1222 born during the pandemic; 997 SARS-CoV-2 unexposed, 130 SARS-CoV-2 exposed, and 95 with unknown SARS-CoV-2 exposure status), of whom 266 (16.0%) were Black, 991 (59.6%) were Hispanic, 400 (24.0%) were White, 1245 (74.8%) were insured through Medicaid, 880 (52.9%) were male, and 204 (12.3%) were born prematurely. The COMBO-RSCH cohort included 385 children (74 born before the pandemic and 311 born during the pandemic; 201 SARS-CoV-2 unexposed, 101 SARS-CoV-2 exposed, and 9 with unknown SARS-CoV-2 exposure status), of whom 39 (10.1%) were Black, 168 (43.6%) were Hispanic, 157 (40.8%) were White, 161 (41.8%) were insured through Medicaid, 222 (57.7%) were male, and 38 (9.9%) were born prematurely. Prenatal pandemic exposure was not associated with a higher positive M-CHAT-R screening rate in either the COMBO-EHR or COMBO-RSCH cohort. Prenatal exposure to maternal SARS-CoV-2 infection was associated with a lower rate of M-CHAT-R positivity in the COMBO-EHR cohort (12.3% [16 children] vs 24.0% [239 children]; adjusted odds ratio, 0.40; 95% CI, 0.22-0.68; P = .001), but no association was found in the COMBO-RSCH cohort (12.9% [13 children] vs 19.9% [40 children]; adjusted odds ratio, 0.51; 95% CI, 0.24-1.04; P = .07).
Conclusions and Relevance In this cohort study of 2 groups of children with prenatal pandemic exposure and/or exposure to maternal SARS-CoV-2 infection, neither exposure was associated with greater M-CHAT-R positivity.
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