In a recent study published in the journal PNAS, researchers investigated the pregnancy outcomes of COVID-19 and the effects of vaccination on these outcomes. They used linked population-level data from birthing facilities between 2014 and 2023 and found that COVID-19 caused infected pregnant women to deliver preterm. Preterm births are associated with significant lifelong health and socioeconomic consequences. In contrast, early vaccine adopters were safeguarded from these effects and delivered normally. These findings revealed that vaccine availability and the choice to vaccinate may have drastically altered the health landscape for the next generation, especially in the US, where this study was carried out.
Study: Vaccination, immunity, and the changing impact of COVID-19 on infant health. Image Credit: Unai Huizi Photography / Shutterstock
COVID-19 and pregnancy risks
The coronavirus disease 2019 (COVID-19) remains one of the worst pandemics in human history, with the World Health Organization reporting over 772 million cases and almost 7 million deaths since the beginning of the outbreak in late 2019. The impacts of the disease extend beyond just morbidity and mortality, however, with outcomes including widespread socioeconomic loss and severe, population-level mental health declines.
Survivors of the disease were left with potentially lifelong cardiovascular and neural comorbidities, with recent research suggesting the increasing prevalence of 'long COVID', a condition characterized by the persistence of COVID-19 symptoms (and, in some cases, the emergence of novel symptoms) months or even years following recovery from the original infection. While most COVID-19 response efforts targeted older adults due to their higher mortality risk, emerging evidence suggests that children and infants have been significantly affected by the condition.
Studies on younger individuals have revealed that infection by the severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2) is associated with harmful cardiovascular, cognitive, reproductive, and physical health outcomes. In the fall of 2020, researchers identified negative connections between COVID-19 and pregnancy, with the former resulting in preterm births and a higher probability of newborns requiring neonatal intensive care unit (NICU) hospitalization. This is especially alarming given that they suggest that COVID-19 impacts cross generational boundaries and is thought to comprise the most enduring legacy of the pandemic.
Painting a holistic picture of the long-term health impacts of COVID-19 on pregnancies faces three major hurdles – 1. Infection risk is selective, with socioeconomically deprived individuals at higher risk than their more affluent counterparts, 2. Measures and diagnosis of infection vary temporally, and 3. SARS-CoV-2 is a rapidly evolving virus. These hurdles, especially 2. and 3., are temporal and require long-term monitoring data to draw actionable conclusions adequately. Unfortunately, research of this kind remains lacking.
About the study
In the present study, researchers used nine years' worth of data comparing siblings' neonatal health outcomes before and during the pandemic to investigate the impacts of mothers' COVID-19 infections on their infants' health. They utilized linked administrative vaccination and natality data to overcome the three hurdles mentioned above: selective infection risk, irregular testing, and the consequences of a constantly evolving pathogen.
The dataset comprised restricted-access natality data from all births in the state of California between January 2014 and February 2023. Collected data included date of birth, the infant's anthropometrics (height, weight, gestational age), and the mother's demographics and anthropometrics (age, race/ethnicity, residential zip code, education level, economic status). In order to avoid confounds associated with multiple birth pregnancies, analyses were restricted to single infant births.
California presents an ideal data source due to a government mandate that requires all pregnancies during and after June 2020 to undergo COVID-19 screening mandatorily. Consequently, data from January 2020 to June 2020 was discarded from the dataset unless COVID-19 status was mentioned in the birth certificate due to voluntary or clinically necessitated diagnosis. Furthermore, if COVID-19 status was not mentioned in the birth certificate, the corresponding data point was removed from analyses unless hospital archives contained the information.
Statistical analyses used regression models adjusted for maternal and infant anthropometric and demographic variables.
"Model 1 captures the association between maternal COVID-19 infection and preterm birth using a linear probability model adjusting only for birth facility fixed effects and month fixed effects. Model 2 adds controls for a large set of potential confounders including mother's sociodemographic characteristics (age, educational attainment, race/ethnicity, SES disadvantage of zip code of residence, and parity) and the leading risk factors for preterm birth (maternal hypertension, diabetes, prior preterm birth, large fibroid tumors, asthma, and smoking)."
Finally, an additional Model 3 was used for mothers who had already delivered an infant between 2014 and 2020, prior to the onset of COVID-19. This model compared infant characteristics between an individual mother's offspring with COVID-19 infection as the only treatment and infant health determinants as the only outcome.
Corrections for bias included changes in maternal characteristics such as age between pregnancies, economic status, and zip code of residence at the time of each delivery.
Study findings
Model 1 reveals a significant increase in the probability of preterm deliveries by 1.4 regression percentage points, equivalent to an alarming 29% increased risk. When incorporating Model 2's adjustments, this value falls to a still concerning 15% increased probability of preterm births for mothers infected with COVID-19.
Model 3's between siblings comparisons yield similar results – the same mother was more than 25% more likely to deliver preterm when infected with COVID-19 than before the contraction of the disease.
"Estimation based on sibling comparisons provide the strongest evidence currently available that COVID-19 infection during pregnancy negatively affects infant health."
Demographic analyses revealed that exposure and negative consequences were highest in areas with high unemployment rates and those experiencing high frequencies of wildfire smoke. Notably, COVID-19 was seen to result in preterm births of less than 32 weeks gestation, an ordinarily rare condition corresponding to the highest mortality, morbidity, and developmental risk for newborns.
Encouragingly, early adopters of vaccination against SARS-CoV-2 were observed to be rescued from the demerits of COVID-19-associated effects almost a year earlier than those who did not have access to the vaccines or chose not to receive them.
"The similarity across quintiles in the impact of COVID-19 infection before vaccines were available suggests that the reduction in the harmful effect of COVID-19 infection is due to vaccination uptake rather than alternative health-protective behaviors undertaken by pregnant persons residing in high-vaccination locations."
Conclusions
In the first study using long-term pregnancy and birth data in tandem with within-mother comparisons, researchers elucidated the negative impacts of COVID-19 infections on pregnancy outcomes. Their findings present that COVID-19 infection results in an almost 30% higher risk of preterm delivery, which in extreme cases may be as early as 32 weeks gestational age. These are associated with severe mortality, morbidity, and health outcomes for newborns, some of which may be lifelong.
Vaccination significantly reduced the burden of these conditions, resulting in an observed rescue from preterm births. Unfortunately, reports from the United States (US) reveal that uptake of vaccination boosters has stagnated, especially among racial and socioeconomic minorities, which may induce a resurgence of this trans-generational effect in the future.
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