In the current pandemic of coronavirus disease 2019 (COVID-19), pregnant women have wrestled with the question of whether they and/or their babies are at higher risk due to the direct or indirect effects of infection by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).
A new study, recently released as a preprint on the medRxiv* server, provides evidence that babies born to mothers who were infected two or more months before delivery are protected by maternal antibodies, besides mounting a robust immune response in case they contract the infection in the perinatal period.
The transfer of passive immunity to the fetus across the placenta depends on the production of high levels of effective neutralizing antibodies in the mother, and their persistence in the fetus for a long period of time. The current study sought to explore this phenomenon in SARS-CoV-2 infection during pregnancy, so as to help shape recommendations for vaccination of expectant mothers and babies against COVID-19.
Many earlier workers showed that maternal COVID-19 antibodies were transferred across the placenta, but most of these infections occurred later in pregnancy. The question remains, at what period of pregnancy does the immune system respond most robustly, and when does transplacental antibody transfer occur most efficiently? If the baby acquires the infection, what kind of immune response occurs? And how long do the antibodies, active or passive, persist in the baby after birth?
The study included 145 mostly Hispanic mothers with SARS-CoV-2 infection, with 147 babies. Of the total number, about 60% (86) presented with symptoms, the majority (78) showing mild to moderate symptoms only.
Of the 147 babies, 16% (23) were shown to be admitted to the neonatal intensive care unit (NICU). All were tested for the virus by reverse transcriptase-polymerase chain reaction (RT PCR) at 24 hours after birth. This yielded a single positive test, in a preterm baby born at 31 weeks.
Serologic tests were done at delivery on 129 mothers, and in 144 samples of cord blood. They were repeated at <14 days, 14-59 days, 60-180 days, and > 180 days from the first positive RT PCR test.
What were the findings?
High correlation between maternal and fetal antibodies
The results show a high correlation between maternal antibodies and fetal passively acquired antibodies. While 65% of mothers were seropositive at delivery, cord blood showed a 58% immunoglobulin G (IgG) antibody positivity rate at this time point.
When paired samples from 125 mother-child dyads were tested, 90% parity was observed (60 seropositive babies of 77 seropositive mothers). Of the remaining eight, seven were born within 45 days of the first positive maternal RT PCR test, and the last at 254 days after the first positive test.
There were 48 seronegative mothers, and 94% (45) of their babies reflected the same finding. Three infants showed IgM in the cord blood, as did their mothers, at the time of delivery. Two of them showed subsequent negative results for both IgG and IgM, the third being lost to follow-up. All three had negative RT PCR tests.
Thus, the paired samples showed a high degree of correlation. The median transplacental IgG transfer ratio was 1. However, it varied from higher levels in mothers with severe or critical COVID-19, to low levels in mothers with asymptomatic or mild-to-moderate infection.
High transfer ratio
When 54 dyads with symptomatic mothers were tested, the transfer ratio was 0.6 at less than 60 days, 1.2 at 180 days, and 0.9 at >180 days. Thus, the cord blood antibody levels were highest relative to fetal blood between 60 and 180 days.
When the trimester in which maternal infection was acquired was compared, the transfer ratio showed the same trend for the first, second and third trimester infections. There was no difference in the transfer ratio at any gestational age, though this is difficult to say, given that 95% of babies were 34 weeks or more at birth.
All babies showed a slow decline in maternally derived IgG over time.
Higher antibody transfer with duration since infection
At 1 – 4, 5 – 12 and 13 – 28 weeks, 8%, 12% and 38% of babies, respectively, were negative for IgGs, with the decline being faster for those who had low initial antibody levels. Later seroconversion was linked to increasing antibody levels, at up to 66, 150 and 123 RFU (relative fluorescence units), respectively. Only two babies had cord blood IgG over 500 RFU, and both were still antibody-positive at 27 weeks.
Infections in infants
Infants born <14 days after the mother first tested positive by RT PCR, but who were seronegative at birth continued to be monitored. At 2-4 weeks after birth, two were seropositive – one the preterm infant mentioned above and another term infant. Both were born to asymptomatic mothers who tested positive when screened at delivery but were seronegative, indicating they were in the acute stage.
The preterm infant had positive meconium (by PCR), as was the mother’s blood. The baby was in the NICU for 17 days but was then discharged home after an uneventful stay. While cord blood was negative by PCR, and serial specimens continued to be negative on days 2, 4 and 8, seroconversion occurred on day 16, with high IgM and IgG titers (1548 and 335 RFU).
At eight weeks, the IgM and IgG values were 134 and 1900 RFU, respectively. However, nasopharyngeal swabs continued to be positive at discharge.
The term baby had a negative nasal swab at 24 hours and was not retested. At two weeks, an IgM of 225 RFU and IgG of 80 RFU were measured. At eight weeks, like the preterm baby, IgM dropped (to undetectable levels) while the IgG went up to 1800 RFU. This baby was followed up at 24 weeks when the IgG had gone down to 650 RFU.
What are the conclusions?
The findings show that while 7% of expectant mothers were SARS-CoV-2-positive at delivery, most had mild or asymptomatic infection. Most were seropositive at the time of delivery, with high correlations between IgG in cord blood and maternal blood.
When the mother was infected 60 or more days before delivery, the baby had a high concentration of passively acquired antibodies in the blood, proportional to maternal IgG levels. The lowest ratio was 60% of that in the maternal blood, while the highest IgG levels occurred at 60-90 days from the first positive maternal test – 20% higher than in the mother.
Two asymptomatic but perinatally infected infants showed evidence of a strong antibody response, comparable to that in adults with severe COVID-19. While infection during childbirth remains a rare event, as indicated by this study, it seems to be most likely when the mother is infected near the time of delivery. This could indicate that such mothers should be isolated from the infant for a couple of weeks, as well as screening the newborn for antibodies.
IgG persistence varied considerably, from two weeks to over 26 weeks. IgM may be a transient finding due to contamination, and should not be used to diagnose vertical transmission without RT PCR confirmation.
These findings show that while antibody transfer occurs at all gestational ages, it is most efficient at two or more months from infection. This should inform the selection of optimal vaccination timing for pregnant women, to maximize the immunity in the newborn.
medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.