Developmental Outcomes Linked to COVID-19 Exposure During Pregnancy

COVID-19 and Pregnancy

According to the CDC, pregnant individuals are statistically more likely to get sick from a SARS-CoV-2 infection. Unlike healthy, non-pregnant individuals who may be asymptomatic, pregnant people often experience more severe illness, including a higher risk of hospitalization, intensive care unit (ICU) admission, ventilator reliance, and mortality.

Data from multiple studies have hypothesized that physiological changes during pregnancy can compromise a patient’s immune response, preventing them from effectively fighting off infection. Within the pregnant patient population, there are additional risk factors that push patients into an even higher risk category, including the following:

• Underlying medical conditions or morbidities
• Pregnancy over 25
• COVID-19 prevalence and low vaccination rates in the surrounding environment
• Race and ethnicity, with disparities impacting minority groups more heavily

COVID-19 and Pregnancy Outcomes

Although researchers may not fully understand the impact of COVID-19 on pregnancy outcomes, the epidemiology revealing a high incidence rate has caused clinicians to investigate further. Repetitive research has identified a correlation between COVID-19 infection during pregnancy and pregnancy complications. Beyond complications with pregnancy, there have also been adverse birth outcomes and post-natal complications.

Data from the CDC revealed that between January 1, 2020, and December 25, 2021, pregnant individuals between 15 and 44 who got COVID were five times more likely to be admitted into the ICU than non-pregnant individuals. Additionally, they are 76% more likely to require ventilation or ECMO.

“At the pandemic’s peak, pregnant women in the second and third trimesters showed a higher risk of hospitalization requiring oxygen support, ventilation, and ICU Care,” said David R. Little, MD, MS, Director of clinical informatics at Epic Research in an interview with LifeSciencesIntelligence.

During the Delta period, between June 27, 2021, and December 25, 2021, pregnant individuals had an even higher risk of adverse outcomes and extreme disease severity than during the pre-Delta period, between January 1, 2020, and June 26, 2021.

For example, the risk of ICU admission was 41% higher in the Delta period. Additionally, pregnant individuals infected during the Delta period were 83% more likely to require invasive ventilation than those in the pre-Delta period.

A 2021 meta-analysis published in the Canadian Medical Association Journal (CAMJ) analyzed the impact of maternal SARS-CoV-2 infection during pregnancy on delivery and maternal outcomes. Among the 438,548 pregnant people across 42 studies, COVID-19 cases yielded worse or higher risk outcomes.

The risk of preterm birth in pregnant individuals with COVID-19 was 82% higher than in pregnant individuals who did not have COVID-19. “Early in the pandemic, we observed minimal differences in preterm delivery, low birth weight, or congenital heart defects in babies born to COVID-positive mothers compared to babies born to mothers who were COVID-negative or untested,” began Little.

However, he noted, “A follow-up study in May 2021 did show an increased rate of preterm birth in COVID-positive or untested pregnant women compared to women who tested negative.”

According to the March of Dimes, preterm birth, also known as premature birth, is delivery before 37 weeks gestation. Additionally, the Cleveland Clinic notes that early delivery is linked to higher anxiety levels and postpartum depression. Beyond a higher risk of adverse pregnancy outcomes, babies delivered prematurely may also be impacted.

Premature birth is linked to multiple unfavorable infant outcomes, including anemia, breathing problems, jaundice, infections, and more.

Further investigation revealed that unvaccinated pregnant individuals were more likely to have pre-term deliveries and babies with low birth weight.

Additional insights revealed a 33% higher risk of preeclampsia, with severe COVID-19 being over four times more likely to be linked to preeclampsia than mild COVID. According to an article published in UpToDate, severe hypertension is preeclampsia's most common clinical characteristic. Preeclampsia has been linked to placental abruption, fetal growth restriction, and other adverse outcomes.

In addition to these potentially fatal pregnancy and delivery conditions, the risk of stillbirth was more than double in pregnant patients with COVID-19 than in healthy pregnant people.

Severe COVID-19 infection was also linked to a two-fold increase in gestational diabetes and an 89% increased risk of low birth weight.

In Utero COVID-19 and Childhood Development

While a significant amount of research has been available on the pregnancy impacts of COVID-19 infection, there has been minimal data on the child and infant development outcomes for babies born to COVID-19-positive mothers. To collect more data on the developmental impacts of neonatal COVID-19 infection, Epic Research conducted a study using information from medical records entered into Cosmos to evaluate developmental outcomes.

“This is the first study from Epic Research focused specifically on childhood development outcomes,” noted Little.

Using information from the Cosmos database, the researchers collected information from April 1, 2020, to June 1, 2021. Insights on 17,110 babies whose pregnant parents had a positive COVID-19 diagnosis during pregnancy were analyzed and compared to 68,440 babies born to parents who did not have COVID-19 exposure. An ICD-10 code, the results of a polymerase chain reaction (PCR) SARS-CoV-2 test, or another lab test identified the diagnosis.

Throughout the first year of the child’s infancy, researchers analyzed data on length, weight, head circumference, and length-to-weight ratio. Beyond external physical growth, the investigators also extrapolated data on 46 congenital or developmental disorders.

“The study design was developed by two independent teams of clinical experts and data scientists working independently.  Methods reconciled between teams were used to achieve the final methodology,” revealed Little. “The methodology and findings were subsequently reviewed and validated by an independent review by clinical and data science experts.”

According to Little, the study identified associations between COVID-19, congenital cardiovascular defects, heart rhythm abnormalities, metabolic disorders, and perinatal respiratory disorders.

“In all four of the associated syndromes we identified, the risk was significantly higher for babies born to mothers infected in the second trimester,” he added. “Given the correlations identified in this population-based analysis, further research by clinical researchers is needed to understand the overall impact.”

In addition to the data collected in the Epic Research study, a 2023 retrospective cohort study published in JAMA Network Open analyzed the neurodevelopmental outcomes of babies with mothers who had SARS-CoV-2 positive test results during pregnancy. That research noted that male babies exposed to COVID in utero had a higher risk of neurodevelopmental disorders than males who were not exposed; however, female babies showed no significant change in risk.

Future Directions

While both studies have provided insight into the connection between infectious disease and infant or neonatal outcomes, additional studies with a larger sample size and a broader patient demographic are required to make confident conclusions.

“Epic Research studies identify correlations between factors and outcomes, but data of this nature does not establish causation,” Little told LifeSciencesIntelligence. “Understanding why these correlations are identified will require further study by clinical research experts in the academic community (rather than the population-based analyses performed in Cosmos).”

As researchers continue investigating these links, pregnant and breastfeeding individuals should get their COVID-19 vaccine and booster if eligible. Vaccination significantly minimizes the risk of infection, severe illness, hospitalization, ICU admission, and death.

Beyond that, new parents are urged to keep all their vaccinations current, follow good public health practices, consult with their child’s physician on prevention protocols, and get their child vaccinated as directed by the CDC, American Academy of Pediatrics, and their baby’s provider.