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Of the pandemics faced by the US in the 20th century, none were more severe than the influenza A/PR/8/34 (H1N1) outbreak of 1918—the so-called Spanish influenza. Emerging during World War I, this pandemic is estimated to have infected nearly one-third of the global population and killed approximately 50 million people, including 675 000 people in the US. While the pandemic was brief, some individuals experienced reaching effects. Women infected with the flu during pregnancy had children found to have higher rates of heart disease, kidney disease, and diabetes throughout their life course.1 The implications of such findings hold relevance today, as the novel coronavirus SARS-CoV-2 has spread throughout the world. Given the effects observed in the 1918 pandemic and reported birth outcomes related to maternal COVID-19 infection, it is prudent to use the lessons and epidemiology of the 1918 pandemic to inform practice and follow-up of potential long-term health effects associated with maternal COVID-19 infection.
The 1918 influenza was unusual in the vigor with which it affected young adults, but other populations were not spared—including fetuses in utero. Birth rates declined along with an increased rate in stillbirths, but carrying a pregnancy to birth did not ensure that born children avoided the effects of influenza. Rates of congenital malformation and premature birth increased during all waves of the pandemic, contributing to increased infant mortality rates during the spring 1919 wave.2 Premature birth from any cause is a risk for associated conditions, such as kidney or heart disease, later in life,3,4 compounded by any risk that may be associated with in utero exposure to maternal infection.
Like the influenza of 1918, maternal COVID-19 infection during pregnancy has been associated with increased risk of neonatal and perinatal complications. Notably, premature birth rates in mothers infected with COVID-19 have been observed to be significantly elevated from their pre–COVID-19 rate, and low birth weight in children of mothers infected with COVID-19 has also been observed,5 although little evidence has supported that neonates are at major risk of direct harm through processes like vertical transmission.6
However, such outcomes could have long-term effects even in the absence of direct neonatal infection. The Barker hypothesis postulates that interruptions in normal in utero development can have lasting health effects specific to the organ systems developing at that time.3 For example, the heart develops during the first trimester, and as such, children of mothers infected with a disease during this time may bear a higher risk of cardiovascular disease later in life. Conversely, children of mothers infected with a disease in their third trimester, when the kidney is still maturing, may show an increased risk of chronic kidney disease and lower nephron number. The risk to the kidneys is compounded by the higher observed prevalence of preterm birth, as postnatal maturation does not compensate for the lost gestational time, increasing the risk for kidney complications later in life, such as hypertension and chronic kidney disease.3,4 There are several proposed mechanisms for this disruption of development, including reduced supply of both micronutrients and macronutrients during maternal infection, increased cytokine secretion, and an increase in glucocorticoids in response to maternal infection.4
The potential for negative long-term outcomes is not theoretical. In a life-course study of individuals exposed in utero to influenza during the 1918 pandemic, Garthwaite1 found significant increases in heart disease, diabetes, and kidney disease compared with the general population. In a similar study, Almond and Mazumder7 saw comparable increases in negative health outcomes, including significant increases in heart disease, kidney disease, stomach disease, and hypertension, for individuals exposed in utero during the 1918 pandemic. Both studies describe a time-dependent relationship between prenatal exposures and risk of negative health outcomes later in life, with births in May 1919 having the highest rates of diabetes, births in November 1918 having the highest rates of kidney disease, and births between December 1918 and May 1919 having the highest rates of heart disease.1,7 Such a relationship aligns with what may be expected from the Barker hypothesis—that maturing organ systems at the time of maternal infection will face higher risk of deleterious outcomes later in life.
While birth outcomes face increased risk from maternal COVID-19 infection, conclusions drawn from life-course studies by Garthwaite1 and Almond and Mazumder7 from the 1918 pandemic suggest that risk of COVID-19 exposure in utero may have life-course effects. Thus, a life-course study of this population offers an opportunity to gather information to improve their outcomes and contribute to a wider understanding of long-term pandemic effects. Various methodologies are available for conducting life-course studies, including collecting data from large-scale surveys, such as the National Health Institute Survey.1 Surveys can collect substantial health information at one time but are susceptible to recall and self-reporting biases. Focused tracking of patients with health outcomes examined at regular intervals by research personnel allows for a more robust examination of outcomes, including severity and timing. Following a prospective cohort of maternal-child dyads over time offers an opportunity to study the effect of maternal COVID-19 infection on social determinants of health, growth and development, milestones, and biomarkers, such as blood glucose, lipids, viral antibodies, and inflammatory markers. However, intensive follow-up is considerably more resource intensive and risks losing participants to follow-up; methods to mitigate such risks are needed for any long-term study. Some registries, such as the Pregnancy Coronavirus Outcomes (PRIORITY) Registry and MotherToBaby Registry, are already studying short-term outcomes in infants born to mothers who have had COVID-19, including the effect on breastfeeding. This is invaluable research and provides a framework for which longer-term study can be initiated to investigate life-course effects. However, any long-term study faces challenges from the large number of patients with unrecognized COVID-19 infection. The presence of such patients must be considered in recruiting patient cohorts. Furthermore, as the COVID-19 pandemic has not equally affected all populations, any study should be undertaken with consideration toward the particular health risks faced by these populations where COVID-19 has been more prevalent.
Maternal COVID-19 infection has resulted in elevated rates of preterm birth and low birth weight. However, it has yet to be determined if children born to mothers infected with COVID-19 face deleterious long-term health outcomes. The prevalence of perinatal complications already observed combined with observations from life-course studies in past pandemics suggests that these children face potential risk of long-term health outcomes and should be followed up with for observation of those outcomes. The rise in perinatal complications, such as prematurity in children born to mothers infected with COVID-19, not only poses a risk for negative long-term outcomes by itself—particularly to late-maturing organs, such as the kidneys—but also indicates that in utero exposure could have broader implications than are initially apparent. Just as children born during the 1918 pandemic faced differing risks of future negative outcomes depending on when in utero they faced the peaks of the pandemic, the timing of maternal COVID-19 infection may too present higher risk for certain outcomes in these children. As such, these children could be observed for development of negative health outcomes. Registries like the PRIORITY and MotherToBaby registries are already studying short-term effects, but such large-scale databases are needed to examine effects in the longer term as well to determine if these children face a higher relative risk than their counterparts born at a similar time to mothers who were not infected with COVID-19.
Corresponding Author: John McCarthy, BS, Albert Einstein College of Medicine, 1300 Morris Park Ave, New York, NY 10461 (firstname.lastname@example.org).
Published Online: July 19, 2021. doi:10.1001/jamapediatrics.2021.2423
Conflict of Interest Disclosures: None reported.
Additional Contributions: We acknowledge the contributions of Kimberly Reidy, MD (Children’s Hospital at Montefiore, New York, New York), and Abby Basalely, MD (Northwell Health, New Hyde Park, New York), to the development of this article. Neither were compensated for their work.
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McCarthy J, Liu D, Kaskel F. The Need for Life-Course Study of Children Born to Mothers With Prior COVID-19 Infection. JAMA Pediatr. Published online July 19, 2021. doi:10.1001/jamapediatrics.2021.2423
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