In this large study which included >30,000 infants, we found that receipt of at least two doses of mRNA COVID-19 vaccine during pregnancy was associated with a decreased risk of infants testing SARS-CoV-2 positive during their first 6 months of life. Maternal vaccination with at least two doses reduced the infant’s risk of testing SARS-CoV-2 positive initially by 84% which decreased to 56% by 6 months of life in the Delta dominant period. Receipt of one dose especially during the third trimester was also associated with a reduced risk of infants testing positive for SARS-CoV-2 during the first 6 months of life during the Delta dominant period. However, vaccination during pregnancy was less effective at protecting infants against SARS-CoV-2 infection during the Omicron period. As infants aged, protection provided by maternal vaccination decreased during both periods.
Although the study was unable to directly estimate VE against hospitalization due to the small number of hospitalized cases, it found that over the entire study period, the incidence rate of hospitalization during the first 6 months of life was much lower among the infants whose mothers were vaccinated during pregnancy compared with those whose mothers were not vaccinated. These results suggest that in addition to providing protection against testing positive, vaccination during pregnancy also provides protection against hospitalization (severe disease) in infants during their first 6 months of life as previously reported recently18,19.
Our findings that receipt of at least two doses of COVID-19 vaccine during pregnancy was effective at protecting infants during the Delta period are similar to those reported in a recent Norwegian study showing that mRNA COVID-19 vaccination during pregnancy was associated with a 71% decreased risk of testing positive for SARS-CoV-2 in infants during their first 4 months of life during the Delta period17. During the Delta period, we found that protection extended through the infant’s first 6 months of life. However, in contrast with the Norwegian study which reported that infants of mothers who were vaccinated had a 33% decreased risk of testing positive during the first 4 months of life during the Omicron period17, our study found a 13% reduced risk that was not statistically significant. The difference between the two studies might be due to population characteristics and the timing of follow-up as ours went through May 31, 2022, while the Norwegian study ended in April 2022.
The finding that maternal vaccination was less effective at protecting infants during the Omicron dominant period is also consistent with previous studies which have reported decreased effectiveness of mRNA COVID-19 vaccines during Omicron among children and adults14,20. Recently another study reported that the effectiveness of mRNA COVID-19 vaccines against infections and hospitalizations among pregnant people was higher during the Delta period than during the Omicron period21.
Our additional supplemental analysis suggests that pregnant persons who received at least one vaccine dose before pregnancy should complete their vaccination series during pregnancy to provide protection to their children during the first 6 months of life.
We observed that infants’ protection through vaccination during pregnancy decreased as they aged from 2 months to 6 months. These findings are consistent with the diminishing of pregnancy-derived antibodies in infants over time22. A recent study found that the mean titer of maternally derived antibodies in infants of vaccinated mothers were higher at age 2 months compared with antibody titers at age 6 months23.
Despite several studies showing that vaccination during pregnancy is safe for pregnant people24,25,26,27,28, vaccine uptake has been suboptimal in this group29. In the present study, the mothers of only 32% of infants in the cohort received at least 2 doses during pregnancy. While this proportion might not be representative of the proportion of vaccinated pregnant women within KPNC because of our exclusion criteria, more efforts are needed to promote COVID-19 vaccines for pregnant persons because vaccination provides protection to mothers and their infants until they are old enough to receive their own COVID-19 vaccines.
Our study was strengthened both by its large sample size and our ability to follow infants through 6 months of age. In addition, our study period included two different SARV-CoV-2 variants, which allowed estimation of the effectiveness of vaccination during pregnancy in infants during both the Delta and Omicron variant periods. Our primary cohort analysis used calendar days as the underlying scale to ensure that we compared infants of vaccinated and unvaccinated mothers on the same calendar days because vaccination status during pregnancy and risk of SARS-CoV-2 infection varied over the study period. In this primary design, all eligible infants meeting inclusion criteria were included without sampling which improved power and minimized bias related to selection. Furthermore, it was reassuring that both the cohort and the secondary TND yielded vaccine effectiveness estimates in the same direction. Although both approaches adjusted for the same confounding factors, the effectiveness estimates from the TND were higher than those from the cohort design, which is consistent with our previous analyses of influenza vaccine effectiveness in which we also observed that the TND tended to result in higher vaccine effectiveness estimates than did our cohort analyses30. The TND, a case-control study, has been commonly used in studies of the effectiveness of influenza vaccines and more recently COVID-19 vaccines. The cohort analyses may be biased toward the null if some infected infants were misclassified as uninfected due to the absence of a SARS-CoV-2 test result in the medical record. The TND analyses avoid this bias by limiting the analysis to infants who were tested for SARS-CoV-2. Thus, this design better adjusts for healthcare-seeking behavior31,32, but it may also introduce other biases including selection bias33.
The study had limitations worth noting. Vaccinations were limited only to those received during pregnancy. We did not assess whether vaccines received before pregnancy or immediately after pregnancy were associated with a reduced risk of testing positive for SARS-CoV-2 in infants. The study did not adjust for maternal SARS-CoV-2 infections during pregnancy due to the inability of capturing home testing results. We, therefore, were unable to assess whether maternal infection provided some protection to their infants. Additional limitations include the inability to estimate the effectiveness of vaccines received prior to pregnancy onset. It is possible that our exclusion criteria may have resulted in a final sample that may not be reflective of all KPNC infants. During the study period, home testing became more prevalent. It is possible that this practice may have led to some misclassification of the outcome, and we were unable to assess whether this misclassification was differential between vaccinated and unvaccinated mothers. We did not have genotyping data to confirm the variant that infected infants who tested positive and instead relied on state data regarding circulating strain predominance in the Northern California region. Like all observational studies, our study results are susceptible to residual confounding.
In conclusion, in this population-based cohort study, we found that infants born to mothers who received at least two doses of an mRNA COVID-19 vaccine during pregnancy were at lower risk of testing positive for SARS-CoV-2 and were at lower risk of hospitalization during the first 6 months of life compared with infants whose mothers were unvaccinated during pregnancy. Maternal vaccination was protective, but protection was lower during the Omicron period than during Delta. Protection during both periods decreased as infants aged from 2 months to 6 months. Overall, the study results support recommendations for vaccination during pregnancy to protect both mothers and their infants.