Lakshmi Sukumaran, MD, MPH,​a Natalie L. McCarthy, MPH,a​ Elyse O. Kharbanda, MD, MPH,b​ Gabriela Vazquez-Benitez, PhD,b​ InfantHeather S. Lipkind, MD, Hospitalizations MS,​c Lisa Jackson, MD, MPH,​d Nicola P. Klein, MD, PhD, and​e Allison L. Naleway,Mortality PhD,f​ David L. McClure, PhD,g​ h i j a RulinAfter C. Hechter, MD,Maternal PhD,​ Alison T. Kawai, ScD, ​ VaccinationJason M. Glanz, PhD,​ Eric S. Weintraub, MPH

BACKGROUND: abstract

The Advisory Committee on Practices currently recommends pregnant women receive influenza and tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis (Tdap) vaccines. There are limited studies of the long-term safety in for vaccines administered during . We evaluate whether maternal receipt of influenza and Tdap vaccines increases the risk of hospitalization or death in the METHODS: first 6 months of life. We included singleton, live birth in the Vaccine Safety Datalink between 2004 and 2014. Outcomes were infant hospitalizations and mortality in the first 6 months of life. We performed a case-control study matching case patients and controls 1:1 and used conditional logistic regression to estimate odds ratios for maternal exposure to RESULTS: influenza and/or Tdap vaccines in pregnancy. There were 413034 live births in our population. Of these, 25222 infants had hospitalizations and 157 infants died in the first 6 months of life. We found no association – – between infant hospitalization and maternal influenza (adjusted odds ratio: 1.00; 95% confidence interval [CI]: 0.96 1.04) or Tdap (adjusted odds ratio: 0.94; 95% CI: 0.88 1.01) – vaccinations. We found no association between infant mortality and maternal influenza – (adjusted odds ratio: 0.96; 95% CI: 0.54 1.69) or Tdap (adjusted odds ratio: 0.44; 95% CI: CONCLUSIONS: 0.17 1.13) vaccinations. We found no association between vaccination during pregnancy and risk of infant hospitalization or death in the first 6 months of life. These findings support the safety of current recommendations for influenza and Tdap vaccination during pregnancy.

What’s Known on This Subject: Influenza and tetanus toxoid, reduced diphtheria toxoid, and a b Immunization Safety Office, Centers for Disease Control and Prevention, Atlanta, Georgia; HealthPartners acellular pertussis vaccines are recommended in Institute, Minneapolis, Minnesota; cDepartment of Obstetrics, Gynecology, and Reproductive Sciences, Yale School of Medicine, Yale University, New Haven, Connecticut; dKaiser Permanente Washington Health Research pregnancy. Although there is evidence that these Institute, Seattle, Washington; eDivision of Research, Kaiser Permanente of Northern California, Oakland, vaccines are safe in pregnant women, there are California; fCenter for Health Research, Kaiser Permanente Northwest, Portland, Oregon; gMarshfield Clinic limited long-term data on infants born to Research Institute, Marshfield, Wisconsin;h Department of Research and Evaluation, Kaiser Permanente vaccinated during pregnancy. Southern California, Pasadena, California; iDepartment of Population Medicine, Harvard Medical School and Harvard Pilgrim Health Care Institute, Boston, Massachusetts; and jInstitute for Health Research, Kaiser What This Study Adds: Influenza and tetanus Permanente Colorado, Denver, Colorado toxoid, reduced diphtheria toxoid, and acellular Dr Sukumaran conceptualized and designed the study, participated in data collection, conducted pertussis vaccines in pregnancy are not associated the analysis, drafted the initial manuscript, and reviewed and revised the manuscript; Ms with an increased risk of hospitalization or death McCarthy participated in the conceptualization and design of the study, designed the data in infants. Our findings contribute to the knowledge collection instruments, collected data, participated in the analysis, and reviewed and revised of the long-term safety of vaccination during the manuscript; Mr Weintraub participated in the conceptualization and design of the study, pregnancy. participated in the analysis, and critically reviewed the manuscript; Drs Kharbanda, Vazquez- Benitez, Lipkind, Jackson, Klein, Naleway, McClure, Hechter, Kawai, and Glanz contributed to the acquisition and interpretation of data and reviewed and revised the manuscript; all authors critically reviewed the final manuscript; and all authors approved the final manuscript as To cite: Sukumaran L, McCarthy NL, Kharbanda EO, et al. submitted and agree to be accountable for all aspects of the work. Infant Hospitalizations and Mortality After Maternal Vacci­ nation. . 2018;141(3):e20173310

Downloaded from www.aappublications.org/news by guest on October 2, 2021 PEDIATRICS Volume 141, number 3, March 2018:e20173310 Article The Advisory Committee on and protection to infants for the We used data on pregnant women

Immunization Practices currently respective diseases1,2,​ 7​ when they are from 5 VSD sites with available data recommends 2 vaccines to be given most vulnerable. ‍ ‍≤ that comprise over 90% of the VSD during each pregnancy; influenza In 2015, the infant ( 12 months) population: Kaiser Permanente vaccine has been recommended at mortality rate in the United Northern California (Oakland, any time during pregnancy since CA), Kaiser Permanente Southern States 8was 589.5 per 100000 live 2004 to prevent maternal 1influenza births,​ and the leading causes of California (Pasadena, CA), Kaiser disease and complications and infant deaths were (1) congenital Permanente Colorado (Denver, tetanus toxoid, reduced diphtheria malformations, deformations, and CO), Marshfield Clinic Research toxoid, and acellular pertussis (Tdap) chromosomal abnormalities; (2) Foundation (Marshfield, WI), and vaccine has been recommended disorders related to low Kaiser Permanente Northwest during each pregnancy since 2012, (Portland, OR). ’ and short ; and (3) sudden with a preference for administration infant death syndrome. In 2010, the ≤ between 27 and 36 weeks gestation, leading causes of hospitalizations We used the validated VSD to protect infants from pertussis 2 in infants 12 months were (1) Pregnancy Episode Algorithm29 to disease. Given the relative proximity acute bronchitis (238 per 10000 identify pregnant women. The of an immunization administered population), (2) jaundice (104 Pregnancy Episode Algorithm uses during pregnancy to a potential per 10000 population), and comprehensive electronic medical infant hospitalization or death, an record and administrative databases (3) pneumonia9 (56 per 10000 observed temporal association with population). Although there have (including diagnosis and procedure maternal influenza or Tdap vaccine been reassuring safety data for codes, laboratory tests, pharmacy during pregnancy and infant death or influenza and Tdap vaccines in which records, and imaging procedures) hospitalization may raise concerns to identify pregnancies, pregnancy maternal acute events,– pregnancy about a possible causal relationship. outcomes, and pregnancy start complications, and10 19 birth outcomes and end dates, and it is able to link were evaluated,​ ‍ ‍ there have – Both pertussis and influenza pregnant women to their infants. been limited safety studies beyond20 24 infections are associated with the immediate neonatal period. ‍ ‍ We included women from the VSD hospitalizations and fatalities in Vaccine safety continues to be a with pregnancies ending in a live infants, and severity is highest birth between January 1, 2004, primary reason why– providers and before infants are eligible for the and June 30, 2014. We required patients choose not25 to27 vaccinate respective vaccines. Approximately during pregnancy. ‍ Although the pregnant women to be enrolled at half of infants <4 months of age with biologic plausibility is unclear for the a VSD site for the duration of the pertussis require hospitalization, and association of maternal vaccination pregnancy episode and to have at the majority of deaths3 from pertussis and infant hospitalization or death, least 1 prenatal care visit. To increase occur in these infants. In 2014, the completeness of data, infants of these there may be concerns of long-term US pertussis case rate in infants <6 effects on infants after any pregnancy pregnant women were required to months4 of age was 169 per 100000 exposure. In this study, we evaluate have a birth record and to have VSD infants. Furthermore, there were whether maternal receipt of influenza site enrollment until 6 months of 8 deaths in infants <3 months of and Tdap vaccines increases the life or until the time of death. We age and 1 death in infants 3 to 11 risk of hospitalization or death in US excluded pregnancies in which a live months of age out of 13 total deaths infants in the first 6 months of life. vaccine was administered because from pertussis in all age groups in Methods live vaccines are contraindicated in 2014. Similarly, infants are at high pregnancy. We also excluded infants ’ risk of hospitalization and death Study Population of multiple gestation pregnancies, from influenza. The US influenza infants born before 34 weeks hospitalization rate ranges from gestation, and infants with major – 1.8 to 7.2 per 10005 in infants <6 The Vaccine Safety Datalink (VSD) birth defects because these infants months of age. For the 2013 2014 is a collaboration between the are at a higher risk of hospitalization influenza season, there were 96 Centers for Disease Control and and death. Furthermore, we excluded laboratory-confirmed, influenza- Prevention and 8 integrated health all infants who died during their associated pediatric deaths, 18 of care systems (sites) and includes delivery hospitalization because ∼ which occurred6 in children aged <6 vaccination and health care data28 on cause of death in these infants is months. Maternal immunization 10 million persons per year. In often a perinatal complication (such ∼ with influenza and Tdap vaccines addition, the VSD includes data on as placental abruption) that would allows for passive antibody transfer 125000 pregnant women annually. likely be unrelated to maternal Downloaded from www.aappublications.org/news by guest on October 2, 2021 2 Sukumaran et al vaccination. Additionally, infants who analysis were selected among by influenza vaccine only and Tdap die during the birth hospitalization infants in the study who survived vaccine only to see if our results may be less likely to be enrolled in the first 6 months of life. Matched would differ by limiting our exposure the VSD and capturedInternational in our data. We controls for the infant hospitalization Sgroups.tatistical Analysis Classificationalso excluded of infants Diseases, with 10th external and respiratory hospitalization Revisioncauses of death ( analyses were selected from infants without death or hospitalization in We measured rates of influenza and [ICD-10] codes S00-T98 the first 6 months of life. All infant Tdap maternal vaccination in our and V00-Y98) and infants with controls were required to have at International Classification of study cohort from 2004 to 2013. We external causes of hospitalizations least 1 diphtheria-tetanus-acellular Diseases, Ninth Revision also measured trends of infant deaths ( pertussis (DTaP) vaccine recorded and hospitalizations during this same [ICD-9] between 6 weeks and 6 months of time period to look for any ecological codes 800-999, E800-E999) due age to ensure infants were accessing associations between maternal to injury and poisonings because the health care system. We matched vaccination and our infant outcomes. these are unlikely to result from a case patients and controls 1:1 using 30 For our main analysis, we performed maternal vaccination. ICD-10 coding optimal matching. Case patients a conditional logistic regression was not available for hospitalization and controls were matched on analysis to estimate the odds of diagnoses in the United States during the basis of VSD site, birth month maternal vaccination in matched the time of this study. and year (within 1 month), and Case-Control Matching – – case patients and controls. In our groups of late – analysis, we determined a priori preterm (34 36 weeks), term (37 41 to include the following potential weeks), and postterm (42 44 weeks). confounders from electronic VSD Among infants meeting inclusion With our optimal matching, we 28 data sources : Kotelchuck Adequacy criteria, those infants with successfully found controls for 100% 31 of Prenatal Care Index,​ race and hospitalizations or deaths within of our case patients by using these ethnicity (non-Hispanic African the first 6 months of life were parameters. Vaccinations American or American Indian versus included in this analysis. Respiratory other races and ethnicities), maternal hospitalization case patients were age, pregnancy complications and a subset of hospitalization case – maternal comorbidities (hemorrhage, patients defined by any respiratory The exposure of interest was – – hypertensive disorders, renal ICD-9 code (033, 460 488, maternal vaccination with any disease, diabetes, thyroid disease, 491 496, 510 519) associated influenza and/or Tdap vaccines cardiovascular disease, epilepsy), with a hospitalization in the during pregnancy. A vaccine during smoking during pregnancy (yes, no, first 6 months of life. For infants pregnancy was defined as one given or unknown), infant DTaP exposure with >1 hospitalization, the first from 7 days after the pregnancy start before outcome (or index date in hospitalization was selected for date to 7 days before the pregnancy matched controls), duration of each category (ie, first all-cause end date. These time windows were birth hospitalization in days, and hospitalization, first respiratory chosen to avoid including exposures gestational age at delivery in weeks. hospitalization). Furthermore, an to vaccinations given before or infant could be included as a death immediately after pregnancy. We We also reviewed medical records – case patient and hospitalization case stratified vaccine exposures as any of infants with respiratory related patient if the infant was hospitalized influenza vaccine (with or without deaths (ICD-10 codes: A37, J00 J99). and later died. In the VSD, deaths are Tdap), any Tdap vaccine (with We reviewed clinical information identified from state death records, or without influenza), and both relating to a potential influenza- or electronic medical records, and influenza and Tdap vaccines in the pertussis-related cause of death administrative sources, and there is same pregnancy. In our evaluation and laboratory data in the 2-week approximately a 1-year lag from the of maternal influenza vaccine, we period preceding death. For influenza time of death to the availability of also repeated our analysis limiting laboratory data, we looked for state death records. Because of lag outcomes to events occurring during positive influenza A or B rapid time in the death data, we evaluated the influenza season (October antigen, polymerase chain reaction deaths occurring from January 1, through May), to ascertain any (PCR), viral culture, and direct 2004, to December 31, 2013, and protective findings that may be more fluorescent antibody test results in hospitalizations from January 1, evident when influenza virus is Bordetellaall respiratory pertussis death case patients. 2004, to December 31, 2014. Matched circulating. We also did a sensitivity For pertussis, we looked for positive controls for the infant mortality analysis stratifying our exposure PCR and culture Downloaded from www.aappublications.org/news by guest on October 2, 2021 PEDIATRICS Volume 141, number 3, March 2018 3 – P test results for any death case patient and mortality in our study [CI]: 0.67 0.94; = .007) compared with the ICD-10 code A37 (whooping population from 2004 to 2013 with controls without hospitalization. cough). (Fig 2). From 2004, there was an Furthermore, when evaluating infant increase in maternal influenza hospitalizations and death occurring We determined a priori that with an vaccination, which became more during periods of influenza virus expected average exposure– rate of dramatic in 2009 after the H1N1 circulation (October through May) 15% for both vaccines throughout 32 34 influenza pandemic. Maternal Tdap and peak influenza virus circulation the study period,​ ‍‍ we would need vaccination increased starting in (November through February), we at least 840 case patients to have 2010 when California recommended found no association with maternal 80% power to detect an odds ratio of pregnant women to receive Tdap in influenza vaccine exposure (data not 1.5. The protocol for this study was pregnancy in response to the 2010 shown). When limiting our exposure approved by the Centers for Disease 35 statewide pertussis epidemic. groups to women receiving influenza Control and Prevention Institutional There was another increase in vaccine without Tdap vaccine and Review Board and institutional Tdap vaccination in 2012 after the Tdap vaccine without influenza review boards at each of the most recent Advisory Committee vaccine, our results were similar to participating VSD sites. All analyses on Immunization Practices our main analysis (Supplemental were conducted by using SAS version recommendation to administer Tdap Table 4). 9.3 (SAS Institute, Inc, Cary, NC). 2 vaccination in every pregnancy. Results Discussion We observed no increase in the infant hospitalization rate or infant mortality rate during the same time During our study period, we period. In our study of maternal influenza identified 500447 pregnancies and Tdap vaccines, we found no ending in a live birth that met We matched case patients with increased risk of infant all-cause enrollment criteria. We excluded eligible controls and compared hospitalizations, hospitalizations 87413 (17.5%) because of characteristics between these from respiratory causes, or all-cause maternal or infant factors (Fig 1). groups (Table 1, Supplemental Table mortality in the first 6 months of Of the remaining 413034 infants, 3). Infants who were hospitalized life. Our study helps strengthen 25222 infants had 1 or more were more likely to have mothers the growing evidence of long-term hospitalizations and 157 infants died. with pregnancy complications, less safety of vaccination in pregnancy for Of the hospitalized infants, 4644 likely to be delivered by cesarean infants. (18.4%) had a respiratory cause for delivery, and less likely to be of their hospitalization; 105 (2.2%) African American non-Hispanic or Our findings are similar to other of these infants had an influenza American Indian race. Mean maternal studies that have evaluated infant ICD-9 code (487, 488), and 137 (3%) age, gestational age at delivery, and mortality and morbidity after had a pertussis ICD-9 code (033.0, length of birth hospitalization were maternal vaccination in pregnancy, 033.9). Of the deaths, 14 (9%) had a statistically significantly different most of which have evaluated the respiratory cause of death; however, between the groups but not clinically safety of adjuvanted H1N1 influenza- none of these deaths were considered different. Infants who died were containing vaccines. Studies of to have been caused by influenza or similar to matched controls. short-term infant mortality in the pertussis infections on the basis of 20 In our adjusted analysis, we found first 7 days of life,​ growth and our laboratory and medical record no significant association between development and health care visits review. Of the 157 infants that died, 23 infant hospitalization or death for infections in the first year of life,​ the age at death ranged from 1 to 22 in the first 6 months of life and early neonatal or childhood death,​ 180 days with a mean of 61 days receipt of maternal influenza and/ and childhood hospitalization and a median of 51 days. The most 21 or Tdap vaccines and no significant rates,​ have not found an increased common causes of death were association between infant risk of these outcomes in children unknown causes (32%), sudden – hospitalization from respiratory of women who received adjuvanted infant death syndrome (21%), and causes and maternal influenza H1N1 influenza containing vaccines certain conditions originating in the vaccine (Table 2). However, the odds in pregnancy. Unlike these previous perinatal period (17%). of maternal Tdap vaccination was studies, however, our study included We analyzed overall trends significantly lower among infants women who received any type of of influenza and/or pertussis with hospitalizations because of influenza vaccine, none of which vaccination in pregnancy and respiratory causes (adjusted odds contain adjuvants in the United trends of infant hospitalization ratio: 0.79; 95% confidence interval States, and we found similar results. Downloaded from www.aappublications.org/news by guest on October 2, 2021 4 Sukumaran et al FIGURE 1 Study population of infants with hospitalization or death in the first 6 months of life in the VSD, 2004–2014. a Infants with continuous enrollment in the VSD until 6 months of age or until the time of death whose mothers were enrolled for the duration of their pregnancy. b Fifteen infants were hospitalization and death case patients. c Defined as ICD-9 codes: 033, 460–488, 491–496, 510–519. d Defined as ICD-10 codes: A37, J00–J99. e Positive influenza A or B antigen, viral culture, PCR, or direct fluorescent antibody test results within 14 days of hospitalization.f Positive B pertussis PCR or culture test results within 14 days of hospitalization.

Our findings are also consistent of the newborn, neonatal sepsis, hospitalization after maternal Tdap with studies in which researchers pneumonia, respiratory distress36,38​ vaccination. have evaluated infant mortality and syndrome, and convulsions. morbidity after Tdap vaccination in There were no differences in Other long-term outcomes that pregnancy. These researchers10, have36​ outcomes between infants of Tdap- have previously been studied after evaluated neonatal37 mortality,​ ‍ vaccinated and unvaccinated mothers maternal Tdap vaccination include NICU admissions,​ length of in these studies. Our study included childhood development13 scores at 13 hospitalization, ventilation a longer follow-up period than these months of life,​ infant24 growth up to requirement, intraventricular previous studies and still showed no 5 to 7 months of age,​ and complex hemorrhage, transient tachypnea increased risk of infant mortality or chronic conditions at 12 months Downloaded from www.aappublications.org/news by guest on October 2, 2021 PEDIATRICS Volume 141, number 3, March 2018 5 44 healthy adherer effect and other differences in people who choose vaccination and those who do not) are contributing to this finding.

This study does have some limitations. The VSD captures data on an insured population, which could translate to better health outcomes than the general population. Additionally, VSD has a high rate of women with adequate prenatal care on the basis of the

Kotelchuck index, which can31 translate to better infant outcomes. A recent study has revealed that despite being a fully insured population, the VSD is comparable to the total FIGURE 2 Rates of maternal influenza and Tdap vaccination, infant hospitalization, and infant mortality in the US population on many45 important VSD, 2004–2013. demographic factors. Moreover, the VSD population size is large, and even groups that typically comprise 17 a smaller proportion of insured of age. The researchers for these pregnancy and infant respiratory populations (ie, lower income studies did not find an increased hospitalizations, which is consistent populations) still have a substantial risk of these infant outcomes after with results of other published– (>2 million individuals) presence in maternal Tdap vaccination during studies that have looked at infant the VSD. There may have been bias pregnancy. Our study managed a 7,39​ 42 pertussis as an outcome. ‍ ‍ related to requiring controls to have larger number of infants and had However, only 3% of infants a DTaP vaccine record to be included similar findings to these studies, hospitalized for respiratory causes further demonstrating long-term in the study. We did this to ensure we safety in infants of Tdap vaccine had a pertussis ICD-9 code. This had access to health care utilization exposure in pregnancy. could indicate that infants with data to avoid misclassifying case pertussis are not being43 appropriately patients as controls. To look for We did find a protective association diagnosed and tested. It is also bias, we repeated our analysis of between maternal Tdap during possible that other factors (eg, the hospitalizations requiring case TABLE 1 Characteristics of Matched Case Patients and Controls for Infant Hospitalizations and Mortality in the First 6 Months of Life in the VSD, 2004–2014 Hospitalization Case Matched Controls (n = Pa Death Case Patients Matched Controls (n P Patients (n = 25 222) 25 222) (n = 157) = 157) Mean age at event in d (range) 36 (1–183) — — 61 (1–180) — — Mean gestational age at delivery in 39 (34–43) 39 (34–43) <.0001 39 (34–41) 39 (34–41) .88 wk (range) Mean maternal age in y (range) 31 (13–54) 31 (13–55) .0005 30 (15–41) 30 (16–41) .23 Mean length of delivery 2.2 (0–103) 2.2 (0–110) <.0001 3.5 (0–41) 2.2 (0–18) .43 hospitalization in d (range) Smoking during pregnancy, % 8.9 9.2 .39 15 10 .35 Pregnancy complications, %b 31.0 28.7 <.0001 34 27 .14 Cesarean delivery, % 23.6 27.9 <.0001 36 31 .52 Adequate prenatal care by 94.2 93.9 .30 92 92 .92 Kotelchuck index, %31 African American non-Hispanic or 5.9 7.2 <.0001 10 6 .14 American Indian race, %

—, not applicable. a P values calculated by χ2 tests for categorical variables and Wilcoxon median 2-sample tests for continuous variables. b Pregnancy complications include hemorrhage, hypertensive disorders, renal disease, diabetes, thyroid disease, cardiovascular disease, and epilepsy.

Downloaded from www.aappublications.org/news by guest on October 2, 2021 6 Sukumaran et al TABLE 2 Matched Case-Control Analysis of Infant Hospitalizations and Death in the First 6 Months of Life in the VSD After Maternal Vaccination, 2004–2014 1:1 Matched Analysis of Hospitalizations 1:1 Matched Analysis of Respiratory 1:1 Matched Analysis of Deaths (n = 50 444) Hospitalizations (n = 9288) (n = 314) Vaccine in Influenzaa Tdapb Bothc Influenza Tdap Both Influenza Tdap Both pregnancy Case patients 38.7 12.8 8.6 38.4 9.9 7.1 32 6 3 exposed, % Controls exposed, % 39.3 13.4 9.0 38.1 11.4 7.4 37 12 8 Crude OR (95% CI) 0.97 (0.93– 0.91 (0.85– 0.94 (0.87– 1.02 (0.93– 0.79 (0.67– 0.93 (0.78– 0.81 (0.49– 0.41 (0.17– 0.25 (0.07– 1.01) 0.97) 1.01) 1.12) 0.93) 1.13) 1.31) 0.99) 0.89) aORd (95% CI) 1.00 (0.96– 0.94 (0.88– 0.97 (0.90– 1.08 (0.97– 0.79 (0.67– 0.97 (0.80– 0.96 (0.54– 0.44 (0.17– 0.32 (0.08– 1.04) 1.01) 1.05) 1.19) 0.94) 1.17) 1.69) 1.13) 1.24) Pe .93 .09 .44 .15 .007 .73 .87 .09 .10 aOR, adjusted odds ratio; OR odds ratio. a Influenza vaccine in pregnancy given with or without Tdap vaccine. b Tdap vaccine in pregnancy given with or without influenza vaccine. c Both influenza and Tdap vaccines given in the same pregnancy. d Adjusting for pregnancy complications, adequacy of prenatal care, smoking during pregnancy, race, maternal age, infant DTaP receipt before event, length of birth hospitalization in days, and gestational age at delivery in weeks. e P values correspond to the aOR.

patients to have a DTaP vaccine and mortality in multiple gestation Our findings support the safety of (98.0% of case patients) and found infants, very preterm infants, and influenza and pertussis vaccinations similar results to our main findings. those with major birth defects during pregnancy for infants of We looked at broad safety outcomes because these infants are at a much vaccinated mothers. (hospitalizations, respiratory higher risk of the outcomes we Abbreviations hospitalizations, and deaths) and studied; therefore, our results are not may not capture true increases generalizable to these populations. in a specific outcome, if such an Finally, we were sufficiently powered CI: confidence interval association was present. We relied for our outcomes of hospitalizations DTaP: diphtheria-tetanus-acellu - on vaccination data from our VSD and hospitalizations from respiratory International Classification lar pertussis electronic data files and may not causes but underpowered for the of Diseases, Ninth Revision ICD-9:  have captured vaccines in pregnancy outcome of death. International occurring outside the health care Classification of Diseases, ICD-10:  system. However, previous internal This is the first study in which infant 10th Revision work looking at influenza vaccination hospitalizations and mortality in the in pregnancy revealed that the first 6 months of life after maternal PCR: polymerase chain reaction VSD vaccine files are over 98% influenza vaccine and Tdap vaccines Tdap: tetanus toxoid, reduced complete in capturing these data are evaluated. In this large case- diphtheria toxoid, and (J. Donahue, DVM, PhD, unpublished control study, we found no increased acellular pertussis observations). We did not evaluate risk of infant hospitalization and VSD: Vaccine Safety Datalink the risks of infant hospitalizations death after vaccination in pregnancy.

The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention. DOI: https://​doi.​org/​10.​1542/​peds.​2017-​3310 Accepted for publication Dec 1, 2017 Address correspondence to Lakshmi Sukumaran, MD, MPH, Immunization Safety Office, Centers for Disease Control and Prevention, 1600 Clifton Rd NE, MS D-26, Atlanta, GA 30333. E-mail: [email protected] PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275). Copyright © 2018 by the American Academy of Pediatrics FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose. FUNDING: Supported by the Centers for Disease Control and Prevention, and no external funding was secured. The Vaccine Safety Datalink Project is funded by the Centers for Disease Control and Prevention.

Downloaded from www.aappublications.org/news by guest on October 2, 2021 PEDIATRICS Volume 141, number 3, March 2018 7 POTENTIAL CONFLICT OF INTEREST: Dr Klein has received research support from GlaxoSmithKline, Sanofi Pasteur, Protein Science, Pfizer, Merck & Co., MedImmune, and Dynavax. Dr Naleway has received research support from Merck, Pfizer, and MedImmune for unrelated studies; the other authors have indicated they have no potential conflicts of interest to disclose.

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Downloaded from www.aappublications.org/news by guest on October 2, 2021 PEDIATRICS Volume 141, number 3, March 2018 9 Infant Hospitalizations and Mortality After Maternal Vaccination Lakshmi Sukumaran, Natalie L. McCarthy, Elyse O. Kharbanda, Gabriela Vazquez-Benitez, Heather S. Lipkind, Lisa Jackson, Nicola P. Klein, Allison L. Naleway, David L. McClure, Rulin C. Hechter, Alison T. Kawai, Jason M. Glanz and Eric S. Weintraub Pediatrics 2018;141; DOI: 10.1542/peds.2017-3310 originally published online February 20, 2018;

Updated Information & including high resolution figures, can be found at: Services http://pediatrics.aappublications.org/content/141/3/e20173310 References This article cites 42 articles, 5 of which you can access for free at: http://pediatrics.aappublications.org/content/141/3/e20173310#BIBL Subspecialty Collections This article, along with others on similar topics, appears in the following collection(s): Gynecology http://www.aappublications.org/cgi/collection/gynecology_sub Maternal and Fetal Medicine http://www.aappublications.org/cgi/collection/maternal_fetal_medici ne_sub Infectious Disease http://www.aappublications.org/cgi/collection/infectious_diseases_su b Vaccine/Immunization http://www.aappublications.org/cgi/collection/vaccine:immunization _sub Permissions & Licensing Information about reproducing this article in parts (figures, tables) or in its entirety can be found online at: http://www.aappublications.org/site/misc/Permissions.xhtml Reprints Information about ordering reprints can be found online: http://www.aappublications.org/site/misc/reprints.xhtml

Downloaded from www.aappublications.org/news by guest on October 2, 2021 Infant Hospitalizations and Mortality After Maternal Vaccination Lakshmi Sukumaran, Natalie L. McCarthy, Elyse O. Kharbanda, Gabriela Vazquez-Benitez, Heather S. Lipkind, Lisa Jackson, Nicola P. Klein, Allison L. Naleway, David L. McClure, Rulin C. Hechter, Alison T. Kawai, Jason M. Glanz and Eric S. Weintraub Pediatrics 2018;141; DOI: 10.1542/peds.2017-3310 originally published online February 20, 2018;

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Pediatrics is the official journal of the American Academy of Pediatrics. A monthly publication, it has been published continuously since 1948. Pediatrics is owned, published, and trademarked by the American Academy of Pediatrics, 345 Park Avenue, Itasca, Illinois, 60143. Copyright © 2018 by the American Academy of Pediatrics. All rights reserved. Print ISSN: 1073-0397.

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