Exposure to COVID-19 could pose a risk to the health and aging of individuals who aren’t even born yet, according to a newly published analysis by USC researchers.
In the article, University Professors Eileen Crimmins and Caleb Finch of the USC Leonard Davis School of Gerontology and Keck School of Medicine neonatology fellow Molly Easterlin note that by the end of 2020, approximately 300,000 infants could be born to mothers infected by SARS-CoV-2, the virus that causes COVID-19.
Millions more will be born into families who have experienced tremendous stress and upheaval due to the pandemic even if they haven’t been infected themselves, the authors added.
While the longer-term effects of COVID-19 on infants is yet to be seen, researchers can find some insight from the past, including the 1918 flu pandemic and previous coronavirus illnesses such as SARS in 2002 and MERS in 2012, Finch said.
“The 1918 influenza pandemic had long-term impacts on the cohort exposed in utero, which experienced earlier adult mortality and more diabetes, ischemic heart disease and depression after age 50,” he said.
“It is possible that the COVID-19 pandemic will also have long-term impacts on the cohort that was in utero during the pandemic, from exposure to maternal infection and/or the stress of the pandemic environment.”
Maternal viral infections can affect fetuses through multiple pathways, from direct transmission through the placenta to inflammatory responses that disturb in-utero metabolism and negatively affect growth.
While direct maternal-fetal transmission of the virus and severe birth defects appear to have been rare during previous coronavirus outbreaks, there were increases in preterm delivery and low birth weight during both the 2002 SARS and 2009 H1N1 influenza outbreaks, which are possible consequences of increased inflammation.
While studies on COVID-19 and pregnancy are still in their early stages, there have already been some concerning results that merit a closer look in ongoing studies, the authors wrote.
Increased rates of preterm birth may be linked to maternal SARS-CoV-2 infections, and other studies indicate that severe illness is correlated with a higher risk of stillbirth.
Other potential dangers, including the increased risk of blood clots presented by both pregnancy and severe COVID-19, also need further study.
“We suggest that to capture the consequences of viral exposure in utero for childhood development and adult health, COVID-19 birth cohort studies consider immediate collection of data from the mother, fetus, neonate, and placenta,” Easterlin said.
“These initial data should be followed by analysis of child growth and development and lifelong study of health, behavioral patterns, and cognitive functioning.”
In addition to the direct risks posed by infection, the COVID-19 pandemic has also increased levels of stress, unemployment, food insecurity, and domestic violence, and diminished or disrupted prenatal care.
For these reasons, the researchers suggest that cohort studies also include non-infected mothers and children as well as compare the COVID-19 cohort to children born before or after the pandemic and include various socioeconomic measures.
“The inclusion of information on social and economic stresses will allow comparisons between countries taking different measures to reduce spread of the virus,” Crimmins said.
“These types of comparisons may give us further insights beyond the effects of COVID, such as socioeconomic and social policies that may decrease risk of preterm birth.”
Outcomes in newborns born to mothers with positive/suspected SARS-CoV-2 infection: what is known
Newborn health and infection outcomes
Several reports on newborns born to mothers with positive/suspected SARS-CoV-2 infection have been released in recent weeks. While the original data came primarily from China and consisted of small samples of case studies, recent studies reporting on larger cohorts representing four diverse epicenters, China (including Wuhan and additional regions; n=86 newborns tested),29 Northern Italy (n=42),8 the United Kingdom (n=244),30 and New York City (n=101),31 have provided more robust evidence.
Together, the published literature (Table 1) suggests that newborns are unlikely to be affected by maternal SARS-CoV-2 infection. Of 836 total newborns studied to date (with attempt made to exclude studies with repeat populations), 35 newborns (4.2%) tested positive via polymerase chain reaction (PCR).
Further, the majority of studies reported no respiratory or other illness in newborns born to mothers with positive/suspected SARS-CoV-2 infection (Table 1). General indicators of newborn health, where reported, also seem promising. Apgar scores were at least 7 at 5 min in 98.8% of newborns, which is consistent with the US. national average of 98.9%.32
Notably, the only six neonates with 5 min Apgars below 7 were born very premature,8 , 33, 34, 35 and even several studies including critically ill mothers reported normal Apgar scores in newborns.29 , 31 , 36 , 37 SARS-CoV-2 in mothers does appear to be associated with a slightly higher risk of delivering preterm, but this difference seems to be driven by maternal disease severity in critically ill mothers.
Approximately 22% of newborns studied thus far were born premature (gestational age less than 37 weeks), compared to the U.S. national average of 10%.38 This number, however, is confounded by several studies that report only on severely and critically ill mothers and their newborns.
It is currently unclear if asymptomatic or mildly symptomatic mothers, which comprise approximately 80-90% of cases,3 , 9 , 31 have an increased risk of delivering prematurely. On the other hand, preterm birth has been reported in up to 29% of mothers with severe disease and 88% of mothers with critical disease,39 and likely occurs iatrogenically, as a result of acute respiratory distress and other severe complications in this subset of women.
The few studies in which newborns have become infected report favorable outcomes. PCR-confirmed infected newborns have been documented to show typical mild to moderate symptoms associated with SARS-CoV-2, including cough, respiratory distress, fever, and pneumonia,36 , 40, 41, 42 but some newborns are asymptomatic.8 , 35 , 39 , 43, 44, 45
Symptomatic newborns generally recover in one to two weeks with no subsequently reported negative health outcomes, though long-term follow-up is currently lacking. One exception is a neonate born at 30 5/7 weeks gestation to a critically ill mother who tested negative at birth, but developed pneumonia and tested positive at day of life (DOL) 7. As of publication, at approximately one month of age, this neonate was still intubated, but in stable condition.36
Notably, three of the PCR-confirmed SARS-CoV-2 positive newborns tested negative at birth but positive upon retesting two to 15 days later, suggesting routes of infection other than direct vertical transmission from the mother.36 , 39 , 44 Nine additional newborns have shown elevated levels of SARS-CoV-2 IgG or IgM antibodies in cord blood,30 , 46, 47, 48 which was reported as evidence of vertical transmission.
However, the reliability of serology tests to diagnose SARS-CoV-2 is disputed49 and some of these antibodies may have passively crossed the placental barrier from the mother, thus potentially conferring protection rather than disease.50
Furthermore, these newborns tested negative via PCR and showed no symptoms suggestive of infection (note these newborns are not considered SARS-CoV-2 positive in Table 1). To our knowledge at the time of publication, no newborn critical illness or death can be attributed solely to SARS-CoV-2, as severely afflicted neonates have all been premature and/or suffered from other comorbidities.33 , 36
Although newborns infected with SARS-CoV-2 seem to recover and fare well, there are a few cases of poor outcomes or death due to critical maternal disease status, irrespective of neonatal infection. Hantoushzadeh and colleagues36 reported on nine critically ill pregnant women infected with SARS-CoV-2 in Iran, of whom seven mothers died. Unfortunately, three neonates of two of the mothers who died (including one set of twins) also died.
Both mothers were intubated for acute respiratory distress syndrome (ARDS) and one spontaneously delivered a stillborn neonate at 30 3/7 weeks gestation, while the other suffered septic shock and intrauterine fetal death (IUFD) of both twins at 24 0/7 weeks gestation. Yan and colleagues29 reported a similar case from China of a neonate born to a mother intubated with severe pneumonia and septic shock, in which the neonate died of asphyxia shortly after birth.
Although alarming, these cases are indeed rare and the risk of severe outcomes does not appear to be associated with pregnancy: a recent study from New York found that 9.8% of pregnant women were admitted to the ICU for worsening respiratory status in one hospital, compared to 15.1% of non-pregnant women,51 and data from our group3 , 9 , 31 suggest that pregnant women may present asymptomatically or with mild symptoms at a higher rate (90%) than the general population estimate reported by Wu and McGoogan (81%).52
Routes of potential perinatal transmission and postnatal infection in newborns
Preventing potential neonatal infection and developing appropriate guidelines for neonatal care relies on understanding the potential routes of transmission from mother to newborn. Toward this effort, several groups have tested placenta specimens, amniotic fluid, maternal vaginal secretions, and breast milk for SARS-CoV-2.29 , 46 , 48 , 53, 54, 55, 56, 57, 58
Of these studies, most report negative results in all specimens in addition to negative newborn nasopharyngeal samples.29 , 46 , 48 , 53, 54, 55, 56, 57 Interestingly, in one case report, the newborn became infected, but these specimens tested negative,40 providing evidence against the possibility of perinatal transmission through breast milk or vaginal delivery.
Of note, Wu and colleagues58 reported one SARS-CoV-2 viral RNA positive breast milk sample in the mother of a non-infected newborn, but other studies that tested breast milk do not corroborate this finding.40 , 48 , 53 , 54 , 56 , 59 , 60
Taken together, while reassuring in supporting the safety of vaginal birth and, largely, breastfeeding, these findings of negative maternal specimens leave the route of transmission unclear in the few newborns who do test positive. Most likely, these newborns become infected via the same route as the rest of the population, via community or household-acquired transmission.
As mentioned above, three of the PCR-positive newborns in the literature to date seemingly acquired the virus postnatally, following negative neonatal testing. An additional five newborns were not tested at birth, but tested positive one to seventeen days later after varying postnatal practices were employed.
These cases of delayed positive swabs are rare, but important in considering potential transmission routes and appropriate postnatal care. One newborn who was directly breastfed and whose nasopharyngeal swab, maternal breast milk, placental, and amniotic fluid samples were PCR-negative after birth became positive upon retest at DOL15.44
Interestingly, however, this newborn remained asymptomatic, and the cord blood and maternal breast milk tested positive for IgG antibodies at birth, leading the authors to speculate that maternal breast milk antibodies actually protected the newborn from more severe, symptomatic infection.
The one neonate who remained intubated at the time of publication36 also tested negative at birth before developing pneumonia at DOL2 and testing positive at DOL7. This neonate remained isolated in the neonatal intensive care unit (NICU) following birth, so it is unlikely that infection was acquired postnatally.
Likewise, a newborn born to a severely ill mother in the United States tested negative at birth and positive at DOL2,39 but because postnatal care practices were not included in the report, potential routes of transmission cannot be speculated on.
Although these cases raise the concern that SARS-CoV-2 infection may not be detected in the first test, other studies that followed up on both positive and negative newborns provide evidence to the contrary: one study found that three SARS-CoV-2-infected newborns were positive at DOL2 and negative by DOL7,33 while several studies that repeatedly tested negative newborns did not find infection in retests.31 , 48 , 57 , 60
Additional late and/or distinct positives include two newborns in Italy who tested positive on DOL1 and DOL3, respectively, after their mothers were diagnosed with SARS-CoV-2 during the postpartum period and thus had contact with newborns without personal protective equipment prior to maternal diagnosis.8 Similarly, two newborns in China who had been discharged from the hospital subsequently tested positive at DOL5 and DOL17.61
Although such instances of late positive swabs may raise concern regarding postnatal care that allows for mother-newborn contact, available data from groups who allow rooming-in and breastfeeding are encouraging. Our group has published data on a relatively large cohort of women and newborns in which breastfeeding with masks and appropriate hand and breast hygiene was encouraged and newborns were housed in isolettes kept six feet away from mothers.9 , 31
Although two of these newborns tested indeterminate, or “presumptive positive,” they showed no clinical evidence of infection and no infants in the study tested positive on re-test.31 In the same study that showed two cases of newborn infection due to unprotected contact with undiagnosed mothers,8 the authors reported ten instances of mothers who directly breastfed with a mask whose newborns did not become infected, suggesting that respiratory droplets are more likely to spread the virus from mother to newborn than breast milk.
Lowe and Bopp11 also reported on a newborn who was breastfed and not isolated from the mother, who was not retested after a negative swab at 24 h but was followed for 10 days postnatally and remained well and asymptomatic. The first case study from India also allowed breastfeeding and postnatal contact between mother and newborn, and the newborn tested negative for SARS-CoV-2 at DOL7.10
In total, none of the studies that allowed breastfeeding and mother-newborn contact with masks and handwashing reported any subsequently positive newborns, whereas almost all of the studies with infected newborns had employed formula-feeding and separation policies postnatally.
While this preliminary data on limited postnatal infection transmission are promising, additional follow-up data beyond the immediate postnatal period is needed. The current newborn testing data relies primarily on nasopharyngeal swabs performed at birth or within the first few days of life with varying numbers of repetitions (Table 1).
With the exception of the aforementioned instances of delayed positive swabs, studies that do report repeated testing and longer follow-up periods generally show negative newborns continue to test negative, and positive newborns do not seem to have any additional complications.
o our knowledge, however, only seven studies report follow-up periods beyond approximately the first two weeks of life.31 , 36 , 41 , 57 , 61, 62, 63 Immediate and long-term clinical outcomes in both infected and non-infected newborns born to mothers with positive SARS-CoV-2 infection will be an essential topic for research in the coming months and years.
Returning to evidence-based practices of neonatal care
The understandable trepidation regarding unknown effects of COVID-19 on newborns has thus far driven policies of strict separation between newborns and mothers with positive/suspected SARS-CoV-2 infection, but the body of evidence on neonatal outcomes that we review here suggests these practices may be unnecessary.
A recent New England Journal of Medicine opinion article expressed the importance of relying on scientific evidence, particularly as the uncertainty and fear surrounding a global pandemic leaves physicians, as well as the general public, more likely to succumb to cognitive error and weigh anecdotal reports disproportionately.64
While frightening case studies of critically ill mothers and inexplicably infected newborns do exist, they must be considered within the greater context of newborns and SARS-CoV-2-infected mothers studied. Direct breastfeeding following hand and breast hygiene in combination with mask wearing has not been reported to cause neonatal SARS-CoV-2 infection to date.
The 35 newborns reported as SARS-CoV-2-positive in the literature did not seem to become infected as a result of these policies: most were either in the presence of their mothers prior to maternal diagnosis and therefore without protective policies in place, or were solely formula-fed and separated from their mothers postnatally.
Further, there is significant evidence suggesting the danger of isolating newborns early in life. Mother-newborn separation during the immediate postpartum period is associated with long-lasting deficits in maternal behavior and feelings of competency,23 as well as infant self-regulation and mother-infant relationships.22
Additionally, newborns show altered heart rate variability during separation from their mothers,24 and a plethora of evidence from animal models shows that early life mother-offspring contact regulates the development of autonomic and neuroendocrine systems in mammals.15, 16, 17, 18, 19, 20, 21
Interventions that enhance mother-infant contact are also associated with short- and long-term improved neurodevelopmental and behavioral outcomes in newborns and children,65 , 66 further underscoring the importance of this early exposure to the mother during development.
Breastfeeding practices
Evidence of the importance of direct breastfeeding and, imperatively, of its ability to protect against infection during neonatal development is also expansive.
Breastfeeding has repeatedly been shown to lower rates of upper and lower respiratory tract and gastrointestinal infections in newborns.25 , 67 , 68
The mechanism of this protection likely stems from bioactive factors in breast milk, including maternal immune cells, proteins, healthy bacteria, and human milk oligosaccharides, that support the development of the immune response, mucosal barrier, and microbiome in newborns.26
The assortment of oligosaccharides in human breast milk, in particular, provides nutrients for microbiota in the colon, supporting the establishment of a healthy microbiome in newborns,28 which is linked to improved health and reduced risk of obesity, diabetes, and other metabolic diseases for the duration of the child’s life.69 , 70
Although some published guidelines recommended that mothers with positive/suspected SARS-CoV-2 infection feed expressed breast milk as an alternative to direct breastfeeding,5 there is significant evidence to suggest that the mode of breastfeeding is an essential component of promoting a healthy newborn microbiome.
One study found that exposure to areola skin in addition to maternal milk was necessary to developing the microbiome, and that newborns fed a mix of formula and breast milk had a microbiome composition that was more similar to those that were exclusively formula-fed.71
Other studies have shown that feeding methods other than direct, exclusive breastfeeding were associated with increased risk of asthma72 and negative microbiota parameters including depletion of bifidobacteria and enrichment of potential pathogens.73
Bathing practices
While few studies have reported on newborn bathing in the context of SARS-CoV-2, some published guidelines encouraged immediate bathing of newborns in an effort to reduce risk of infection spread.5, 6, 7
The studies that have discussed the timing of bathing do not differ in newborn outcomes: two studies that bathed newborns immediately after birth54 , 74 reported no SARS-CoV-2-positive newborns, but our group also reported no positive results in our larger cohort of newborns who had delayed bathing, while the two newborns with indeterminate results received early baths.31
Delayed bathing, which is defined as delaying the first bath until at least 24 h of life, is recommended by the World Health Organization and has a range of benefits for newborns.75 Delaying the first bath has been shown to decrease rates of hypothermia and hypoglycemia in newborns,27 , 76 while improving exclusive breastfeeding.27 , 77, 78, 79
Retaining the vernix and amniotic fluid by delaying bathing aids in temperature regulation, and the scent of amniotic fluid helps to guide newborns during breastfeeding.80 Importantly, delayed bathing allows sustained postnatal contact with maternal microbes from vaginal secretions, as well as amniotic fluid and fetal membranes, which has been shown to contribute to the development of the newborn’s microbiome.81
While a major impetus to bathe early as an infection control policy is to reduce the risk of exposure to pathogens for both newborns and hospital staff, several groups have tested vaginal secretions and amniotic fluid and shown that SARS-CoV-2 is not detected in these specimens.29 , 40 , 46 , 48 , 53 , 55, 56, 57 , 82
Conclusions
The available data on newborn outcomes, and the postnatal care practices used in the context of these outcomes, suggest that a re-framing of the perceived neonatal risk imposed by SARS-CoV-2 is necessary.
In the over 800 newborns reported on in the literature, the incidence of vertical transmission has proven to be low. Additionally, adverse newborn outcomes seem to be a function of maternal disease status in the small subset of newborns with critically ill mothers, rather than illness due to SARS-CoV-2 infection.
Furthermore, postnatal transmission through any route other than respiratory particles shared between mother and newborn appears to be unlikely. The benefits conferred by early exposure to the mother, direct breastfeeding, and delayed bathing have a far more substantial body of supporting evidence, and therefore, the established benefits of these practices appear to outweigh the risk of viral transmission to the newborn. While more long-term follow-up data and studies on routes of transmission in the few newborns who are infected at birth are greatly needed, the preliminary evidence on outcomes in newborns born to SARS-CoV-2-infected mothers is reassuring.
Reference link : https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7376345/
More information: Molly Crimmins Easterlin et al, Will prenatal exposure to SARS-CoV-2 define a birth cohort with accelerated aging in the century ahead?, Journal of Developmental Origins of Health and Disease (2020). DOI: 10.1017/S204017442000104X
