COVID-19 vaccination is recommended for persons who are pregnant, breastfeeding, trying to get pregnant now, or who might become pregnant in the future, to protect them from COVID-19.^§ Infants are at risk for life-threatening complications from COVID-19, including acute respiratory failure (1). Evidence from other vaccine-preventable diseases suggests that maternal immunization can provide protection to infants, especially during the high-risk first 6 months of life, through passive transplacental antibody transfer (2). Recent studies of COVID-19 vaccination during pregnancy suggest the possibility of transplacental transfer of SARS-CoV-2–specific antibodies that might provide protection to infants (3–5); however, no epidemiologic evidence currently exists for the protective benefits of maternal immunization during pregnancy against COVID-19 in infants. The Overcoming COVID-19 network conducted a test-negative, case-control study at 20 pediatric hospitals in 17 states during July 1, 2021–January 17, 2022, to assess effectiveness of maternal completion of a 2-dose primary mRNA COVID-19 vaccination series during pregnancy against COVID-19 hospitalization in infants. Among 379 hospitalized infants aged <6 months (176 with COVID-19 [case-infants] and 203 without COVID-19 [control-infants]), the median age was 2 months, 21% had at least one underlying medical condition, and 22% of case- and control-infants were born premature (<37 weeks gestation). Effectiveness of maternal vaccination during pregnancy against COVID-19 hospitalization in infants aged <6 months was 61% (95% CI = 31%–78%). Completion of a 2-dose mRNA COVID-19 vaccination series during pregnancy might help prevent COVID-19 hospitalization among infants aged <6 months.

Using a test-negative, case-control study design, vaccine performance was assessed by comparing the odds of having completed a 2-dose primary mRNA COVID-19 vaccination series during pregnancy among mothers of case-infants and control-infants (those with negative SARS-CoV-2 test results) (6). Participating infants were aged <6 months and admitted outside of their birth hospitalization to one of 20 pediatric hospitals during July 1, 2021–January 17, 2022. During this period, the SARS-CoV-2 Delta variant was the predominant variant in the United States through mid-December, after which Omicron became predominant.^¶ Case-infants were hospitalized with COVID-19 as the primary reason for admission or had clinical symptoms consistent with acute COVID-19,** and case-infants had a positive SARS-CoV-2 reverse transcription–polymerase chain reaction (RT-PCR) or antigen test result. No case-infant received a diagnosis of multisystem inflammatory syndrome. Control-infants were those hospitalized with or without COVID-19 symptoms and with negative SARS-CoV-2 RT-PCR or antigen test results. Enrolled control-infants were matched to case-infants by site and were hospitalized within 3–4 weeks of a case-infant’s admission date. Baseline demographic characteristics, clinical information, and SARS-CoV-2 testing history were obtained through parent or guardian interviews performed by trained study personnel during hospitalization or after discharge, and electronic medical record review of the infant’s record. Mothers were asked about their COVID-19 vaccination history, including number of doses and whether a dose had been received during pregnancy, location where vaccine was received, vaccine manufacturer, and availability of a COVID-19 vaccination card. Study personnel reviewed documented sources, including state vaccination registries, electronic medical records, or other sources (e.g., documentation from primary care providers) to verify vaccination status.

Mothers were considered vaccinated against COVID-19 if they completed a 2-dose series of either Pfizer-BioNTech or Moderna mRNA COVID-19 vaccine, based on source documentation or by plausible self-report (provision of vaccination dates and location). Maternal COVID-19 vaccination status was categorized as 1) unvaccinated (mothers who did not receive COVID-19 vaccine before their infants’ hospitalization) or 2) vaccinated^†† (mothers who completed their 2-dose primary mRNA COVID-19 vaccine series during pregnancy ≥14 days before delivery). SARS-CoV-2 infection status of the mother during pregnancy or after delivery was not documented in this evaluation. Mothers were excluded if they were partially vaccinated during pregnancy (1 dose during pregnancy and none before pregnancy) or vaccinated after pregnancy (71), received Janssen (Johnson & Johnson) COVID-19 vaccine (four), received 2 doses of COVID-19 vaccination before pregnancy (seven), or received >2 doses of COVID-19 vaccine ≥14 days before delivery (10).

Descriptive statistics (Pearson chi-square tests and Fisher’s exact tests for categorical outcomes or Wilcoxon rank-sum tests for continuous outcomes) were used to compare characteristics of case- and control-infants; p-values <0.05 were considered statistically significant. Effectiveness of maternal vaccination (i.e., vaccine effectiveness [VE]) against infant COVID-19 hospitalization was calculated using the equation VE = 100% × (1 – adjusted odds ratio of completing 2-doses of COVID-19 mRNA vaccines during pregnancy among mothers of case-infants and control-infants), determined from logistic regression models. Models were adjusted for infant age and sex, U.S. Census region, calendar time of admission, and race/ethnicity (6). Other factors were assessed (e.g., infant’s underlying health conditions, Social Vulnerability Index, and behavioral factors) but were not included in the final model because they did not change the odds ratio of vaccination by >5% or because data on many infants were not available (e.g., breastfeeding history, prematurity, or child care attendance). In a secondary analysis, effectiveness of maternal receipt of the second dose of COVID-19 vaccination early in pregnancy (within the first 20 weeks) and late in pregnancy (21 weeks through 14 days before delivery) was assessed. Statistical analyses were conducted using SAS (version 9.4; SAS Institute). Procedures were approved as public health surveillance by each participating site and CDC and were conducted consistent with applicable federal law and CDC policy.^§§

During July 1, 2021–January 17, 2022, among 483 eligible infants in 20 pediatric hospitals in 17 states, 104 (22%) were excluded; 71 excluded infants were born to mothers partially vaccinated during pregnancy or vaccinated after delivery, 10 were born to mothers who received a third vaccine dose ≥14 days before delivery, and 23 were excluded for other reasons.^¶¶ Among the remaining 379 hospitalized infants (176 case-infants and 203 control-infants), the median age was 2 months, 80 (21%) had at least one underlying medical condition, and 72 (22%) were born premature (Table 1). Among case-infants, 16% of mothers had received 2 COVID-19 vaccine doses during pregnancy, whereas 32% of control-infant mothers were vaccinated. Case- and control-infants had similar prevalences of underlying medical conditions (20% and 23%, respectively; p = 0.42) and prematurity (23% and 21%, respectively; p = 0.58). Case-infants were more commonly non-Hispanic Black (18%) and Hispanic (34%) than were control-infants (9% and 28%, respectively).

Among case-infants, 43 (24%) were admitted to an intensive care unit (ICU) (Table 2). A total of 25 (15%) case-infants were critically ill and received life support during hospitalization, including mechanical ventilation, vasoactive infusions, or extracorporeal membrane oxygenation (ECMO); among these critically ill infants, one (0.4%) died. Of the 43 case-infants admitted to an ICU, 88% had mothers who were unvaccinated. The mothers of the one case-infant who required ECMO and one case-infant who died were both unvaccinated.

VE of a completed 2-dose maternal primary mRNA COVID-19 vaccination series during pregnancy against COVID-19–associated hospitalization in infants aged <6 months was 61% (95% CI = 31% to 78%) (Table 3). Among 93 mothers classified as vaccinated, 90 (97%) had documented dates of vaccination. Effectiveness of a completed 2-dose COVID-19 vaccination series early in pregnancy (first 20 weeks) was 32% (95% CI = –43% to 68%), although the confidence interval was wide and should be interpreted with caution, and later in pregnancy (21 weeks through 14 days before delivery) was 80% (95% CI = 55% to 91%).