Effectiveness of Maternal mRNA COVID-19 Vaccination During Pregnancy Against COVID-19–Associated Hospitalizations in Infants Aged <6 Months During SARS-CoV-2 Omicron Predominance — 20 States, March 9, 2022–May 31, 2023

Infants aged <6 months are not eligible for COVID-19 vaccination. Vaccination during pregnancy has been associated with protection against infant COVID-19-related hospitalization. The Overcoming COVID-19 Network conducted a case-control study during March 9, 2022-May 31, 2023, to evaluate the effectiveness of maternal receipt of a COVID-19 vaccine dose (vaccine effectiveness [VE]) during pregnancy against COVID-19-related hospitalization in infants aged <6 months and a subset of infants aged <3 months. VE was calculated as (1 - adjusted odds ratio) x 100% among all infants aged <6 months and <3 months. Case-patients (infants hospitalized for COVID-19 outside of birth hospitalization and who had a positive SARS-CoV-2 test result) and control patients (infants hospitalized for COVID-19-like illness with a negative SARS-CoV-2 test result) were compared. Odds ratios were determined using multivariable logistic regression, comparing the odds of receipt of a maternal COVID-19 vaccine dose (completion of a 2-dose vaccination series or a third or higher dose) during pregnancy with maternal nonvaccination between case- and control patients. VE of maternal vaccination during pregnancy against COVID-19-related hospitalization was 35% (95% CI = 15%-51%) among infants aged <6 months and 54% (95% CI = 32%-68%) among infants aged <3 months. Intensive care unit admissions occurred in 23% of all case-patients, and invasive mechanical ventilation was more common among infants of unvaccinated (9%) compared with vaccinated mothers (1%) (p = 0.02). Maternal vaccination during pregnancy provides some protection against COVID-19-related hospitalizations among infants, particularly those aged <3 months. Expectant mothers should remain current with COVID-19 vaccination to protect themselves and their infants from hospitalization and severe outcomes associated with COVID-19.


Introduction
COVID-19 during pregnancy is associated with adverse pregnancy and neonatal outcomes (1).Transplacental transfer of vaccine-induced SARS-CoV-2-specific antibodies has been demonstrated, and severe clinical infant outcomes related to COVID-19 are preventable through maternal vaccination (2,3).Effectiveness of maternal vaccination against COVID-19-related hospitalization (vaccine effectiveness [VE]) among infants aged <6 months was previously estimated to be 38% for infants hospitalized during the period of the SARS-CoV-2 Omicron variant predominance (December 2021-March 2022) (4).This study provides updated estimates of maternal VE among infants aged <6 months and aged <3 months through more recent periods COVID-19 as the primary reason for admission who received a positive SARS-CoV-2 nucleic acid amplification test (NAAT) or antigen test result (case-patients) across 26 hospitals during March 9, 2022-May 31, 2023, were included.Control patients were infants also hospitalized for an acute COVID-19-like illness but who received a negative SARS-CoV-2 test result by NAAT testing during their hospitalization or within 7 days before hospital admission.The odds of maternal receipt of ≥1 mRNA COVID-19 vaccine dose during pregnancy (second dose or higher) were compared with having received no vaccine doses among mothers of case-and control patients.Critical illness among case-patients was described by maternal vaccination status.Critical illness was defined as an illness requiring life support (i.e., receipt of invasive or noninvasive mechanical ventilation, vasopressors, or extracorporeal membrane oxygenation), or resulting in death.Infants were excluded from the analysis if they were born to mothers who 1) received their most recent dose before pregnancy, 2) received only 1 mRNA vaccine dose during pregnancy with no vaccination before pregnancy, 3) received their most recent vaccine dose within the 14 days before delivery, 4) received only 1 dose of a viral vector vaccine, or 5) had unknown or unverifiable vaccination timing or status.During the surveillance period, Omicron BA.1/BA.1.1,BA.2,BA.4,BA.5,BQ.1/BQ1.1,XBB.1.5,and XBB.1.16were the most commonly circulating subvariants.
Maternal vaccination status was ascertained among those who had received ≥2 mRNA vaccine doses, at least one of which occurred during pregnancy, or 1 viral vector vaccine dose followed by ≥1 mRNA vaccine dose during pregnancy.Maternal vaccination status was categorized as 1) unvaccinated (never received COVID-19 vaccine before their infant's delivery) or 2) vaccinated during pregnancy (receipt of a second or higher dose of either a licensed mRNA vaccine, such as BNT162b2 [Pfizer-BioNTech] or mRNA-1273 [Moderna], or a single dose of Ad.26.CoV2.S [Janssen {Johnson & Johnson}] recombinant vaccine before or during pregnancy and ≥1 mRNA vaccine dose during pregnancy).Timing of vaccination was based on the date of receipt of the most recent vaccine dose.The interval between receipt of the last dose and the infant's hospitalization was calculated as the number of inclusive days between those events.VE was calculated as (1 -adjusted odds ratio) x 100% among all infants aged <6 months.Odds ratios were calculated using multivariable logistic regression, comparing the odds of maternal receipt of a COVID-19 vaccine dose during pregnancy with the odds of being unvaccinated between case-and control patients.All models controlled for infant age (in months), sex, race and ethnicity, U.S. Census Bureau region, and month and year of hospital admission.**Generalized estimating equations were used to include study site as a repeated effect.In a secondary analysis, VE among infants aged <3 months was evaluated.Results were not adjusted for multiple comparisons.All analyses were performed using SAS software (version 9.4; SAS Institute).This activity was reviewed by CDC, deemed not research, and was conducted consistent with applicable federal law and CDC policy.† †
The median interval between receipt of the most recent vaccine dose and infant hospitalization was 236 days (Table 2).** Infant receipt of breast milk was missing for 45% of respondents and was not included in the model; infant testing for coinfections was missing for 60% of infants and was not included in the model.§ § Among 360 excluded infants, 288 (80%) were born to mothers who received their last vaccine dose before pregnancy, 55 (15%) to partially vaccinated mothers, three (0.8%) to mothers who completed their primary series or received a booster dose within 14 days of delivery, three (0.8%) to mothers who received only 1 dose of Janssen recombinant vaccine during pregnancy, eight (3%) to mothers whose vaccination status could not be verified, and three (0.8%) to mothers whose timing of vaccination relative to pregnancy was unknown.VE of ≥1 COVID-19 vaccine dose during pregnancy against COVID-19-related hospitalizations among infants aged <6 months was 35% (95% CI = 15%-51%).Among infants aged <3 months, VE was 54% (95% CI = 32%-68%), with a median interval between maternal vaccine dose and infant hospitalization of 219 days.
Among the 377 case-patients, 86 (23%) were admitted to an intensive care unit (ICU), and 50 (13%) were critically ill and required life support (Table 3).Mothers of 42 (84%) of the 50 critically ill infants were unvaccinated.Invasive mechanical ventilation was more common among case-patients with unvaccinated mothers (25 of 295, 8%) than among those whose mothers were vaccinated during pregnancy (one, 1%) (p = 0.02).Overall, 77% of case-patients had no reported underlying health conditions.When limited to the 291 casepatients without underlying health conditions, patterns were similar: 22% were admitted to an ICU, 13% were critically ill, and invasive mechanical ventilation was more common among those whose mothers were unvaccinated (18, 8%) compared with those who were vaccinated (0) (p = 0.02).¶ ¶ ¶ ¶ One infant death before hospital discharge occurred in an infant aged ≥3 months whose mother was unvaccinated during pregnancy.

Discussion
During March 2022-May 2023, maternal receipt of ≥1 COVID-19 vaccine dose during pregnancy was associated with a reduced risk for COVID-19-related hospitalization among infants aged <6 months.Protection was similar to previous estimates of maternal VE during the early period of Omicron variant predominance (4,5), but point estimates were higher when the analysis was limited to infants aged <3 months.This finding aligns with at least one other study, which demonstrated increased protection among infants during the first 90 days of life (6).In the current report, among 377 infants hospitalized with laboratory-confirmed COVID-19, 295 (78%) were born to women who had never received a COVID-19 vaccine dose.Currently, COVID-19 mRNA vaccines are approved in the United States for all persons aged ≥6 months, and these findings indicate that maternal vaccination during pregnancy could help prevent COVID-19-related hospitalization in infants too young to be vaccinated, particularly during the first 3 months of life.
Since the winter of 2022, COVID-19-associated hospitalization rates in infants aged <6 months have been higher than hospitalization rates in any age group except adults aged ≥65 years (7).COVID-19-associated hospitalizations and severe outcomes have occurred among predominantly healthy infants: among those aged <6 months hospitalized during March 20-August 31, 2022, 76% were previously healthy (7).Similarly, in the current report, previously healthy infants accounted for 77% of case-patients, with critical illness occurring in 13%.Maternal vaccination, including receipt of a third dose during pregnancy, has been associated with reduced risk for infant hospitalization (4)(5)(6).Further, maternal vaccination during pregnancy has not been associated with increased risk for adverse pregnancy and infant outcomes (8).Together, these data highlight the importance of early-life protection from severe COVID-19 outcomes through maternal vaccination.

Limitations
The findings in this report are subject to at least six limitations.First, this investigation was not sufficiently powered to assess VE against hospitalizations attributed to specific Omicron subvariants.Second, the sample size was too small to assess VE with precision by vaccine manufacturer, dose number, receipt of bivalent doses, or timing of vaccination during pregnancy.Third, the analysis did not account for previous infection status among women before or during pregnancy, and infection-induced antibodies could provide some protection against infant COVID-19-related hospitalization.Fourth, the analysis did not collect information on maternal characteristics and protective behaviors, which are potential uncontrolled confounders.Fifth, maternal breastfeeding, which can confer maternal COVID-19 antibodies to the infant ( 9), could not be assessed because of the high proportion of missing interview responses.Finally, information on maternal vaccination status and infant race and ethnicity was collected via self-report for a few participants, potentially resulting in differential misclassification.

Implications for Public Health Practice
Maternal receipt of ≥1 COVID-19 vaccine dose during pregnancy was associated with reduced odds of COVID-19-related hospitalization among infants aged <6 months, particularly among those aged <3 months.Additional evaluations should examine VE of maternal receipt of updated COVID-19 vaccines and the impact of potential waning immunity in infants aged ≥3 months.Expectant mothers should be counseled to remain current with COVID-19 vaccination to protect themselves and their infants from hospitalization and severe outcomes associated with COVID-19.* Infants were excluded from analysis if they were born to mothers who had received their most recent dose before pregnancy, received only 1 dose of an mRNA vaccine, received their most recent vaccine dose within 14 days of delivery, received only 1 dose of a viral vector vaccine, or whose vaccination status could not be verified, or timing of vaccination was unknown.† Maternal vaccination status was based on the last date of a COVID-19 mRNA vaccine dose: unvaccinated was defined as mothers who had not received any vaccine dose before or during pregnancy, and vaccinated was defined as mothers who received their last dose of a COVID-19 mRNA vaccine between the first day of pregnancy and 14 days before delivery.Among those vaccinated during pregnancy, mothers could have received ≥1 dose during pregnancy.Mothers could receive 1 dose of Ad.26.CoV2.S (Janssen [Johnson & Johnson]) vaccine before or during pregnancy and 1 dose of an mRNA vaccine during pregnancy.Mothers who received only 1 dose of an mRNA vaccine were considered partially vaccinated and were excluded from the analysis.Mothers whose last vaccine dose occurred before pregnancy were excluded from the analysis.¶ Testing for statistical significance was conducted using a Fisher's exact test.Wilcoxon rank-sum tests were used to compare length of stay.** Critical illness was defined as an illness that led to life support (noninvasive or invasive mechanical ventilation, extracorporeal membrane oxygenation, or vasoactive infusions) or death.Infants with an indication of any of these events were considered to have critical illness.† † The infant receiving extracorporeal membrane oxygenation was not the same as the infant who died.The infant receiving extracorporeal membrane oxygenation was aged <3 months, and the infant who died was aged ≥3 months.The infant missing survival status at discharge was still hospitalized at the time of analysis.§ § Length of stay was calculated among infants alive at discharge (376 among all infants and 290 among infants with no underlying health conditions).The infant missing length of stay was still hospitalized at the time of the analysis.¶ ¶ One infant missing information about survival status at discharge was still hospitalized at the time of analysis.The denominators for the total and unvaccinated columns were reduced by one to account for this missing data.The infant who died was aged ≥3 months.

Summary
What is already known about this topic?Infants aged <6 months are not eligible for COVID-19 vaccination and are at risk for COVID-19-associated complications.Maternal vaccination received during pregnancy could protect infants from COVID-19-related hospitalization.What is added by this report?During the period of recent SARS-CoV-2 Omicron predominance, maternal receipt of an mRNA COVID-19 vaccine during pregnancy reduced the likelihood of COVID-19-related hospitalizations and serious complications among infants aged <6 months.What are the implications for public health practice?Expectant mothers should remain current with COVID-19 vaccination to protect themselves and their infants from hospitalization and severe outcomes associated with COVID-19.
§ Infants were enrolled from 26 pediatric hospitals in 20 states, in all four U.S. Census Bureau regions.Northeast: Boston Children's Hospital (Massachusetts) and Cooperman Barnabas Medical Center (New Jersey); Midwest: Akron Children's Hospital (Ohio), Children's Hospital Medical Center (Ohio), Children's Hospital of Michigan (Michigan), Children's Mercy Kansas City (Missouri), C.S. Mott Children's Hospital (Michigan), Lurie Children's Hospital (Illinois), Mayo Clinic (Minnesota), Minnesota Masonic (Minnesota), Nationwide (Ohio), and Riley Hospital for Children (Indiana); South: Arkansas Children's Hospital (Arkansas), Children's of Alabama (Alabama), Children's Healthcare of Atlanta, Emory (Georgia), Children's Hospital of New Orleans (Louisiana), Medical University of South Carolina Children's Health (South Carolina), Monroe Carell Jr. Children's Hospital at Vanderbilt (Tennessee), Texas Children's Hospital (Texas), University of Mississippi Medical Center (Mississippi), and University of North Carolina at Chapel Hill Children's Hospital (North Carolina); West: Children's Hospital Colorado (Colorado), Children's Hospital Los Angeles (California), University of California, San Francisco Benioff Children's Hospital (California), University of California San Diego-Rady Children's Hospital (California), and Primary Children's Hospital (Utah).