Home / Health / Health outcomes of young children born to mothers who received the pandemic H1N1 vaccine in 2009 during pregnancy: retrospective cohort study

Health outcomes of young children born to mothers who received the pandemic H1N1 vaccine in 2009 during pregnancy: retrospective cohort study

  1. Laura K Walsh, data analyst1 2,
  2. Jessy Donelle, data analyst3
  3. Linda Doddsteacher4
  4. Steven Hawken, assistant professor and scientist2 3 5,
  5. Kumanan Wilson, professor and senior scientist2 3 5,
  6. Eric I Benchimol, associate professor and scientist2 3 6,
  7. Pranesh Chakraborty, associate professor and researcher2 6,
  8. Astrid Guttmann, Professor and Director of Science3 7 8,
  9. Jeffrey C Kwong, Associate Professor and Senior Scientist3 7 9 10,
  10. Noni E MacDonaldteacher4
  11. Justin R Ortiz, Associate Professor11
  12. Ann E. Sprague, Associate Professor1 2 6,
  13. Karina A High, assistant professor and researcher4
  14. Mark C Walker, professor and head of obstetrics and gynecology1 2 5,
  15. Shi Wu Wen, professor and senior scientist2 5,
  16. Deshayne B fell, assistant professor and scientist2 3 6
  1. 1Better Network Registry and Network, Ottawa, ON, Canada

  2. 2University of Ottawa, Ottawa, ON, Canada

  3. 3ICES, Toronto, ON, Canada

  4. 4Dalhousie University, Halifax, NS, Canada

  5. 5Research Institute of the Ottawa Hospital, Ottawa, ON, Canada

  6. 6Research Institute of the Children's Education Center of Eastern Ontario (CHEO), Ottawa, ON, Canada

  7. 7Dalla Lana School of Public Health, University of Toronto, Toronto, ON, Canada

  8. 8Hospital for Sick Children, Toronto, ON, Canada

  9. 9Public Health Ontario, Toronto, ON, Canada

  10. tenDepartment of Family and Community Medicine, University of Toronto, Toronto, ON, Canada

  11. 11Medical School of the University of Maryland, Baltimore, MD, USA
  1. Correspondence to: D Fell dfell {at} cheo.on.ca



Pregnant women are at high risk of serious illness because of documented influenza-related mortality and morbidity during influenza pandemics and seasonal epidemics.12345678910111213 In the United States and Canada, policies recommending that all pregnant women be vaccinated against influenza have been in place for many years.1415161718 Similar policies now exist in other countries, many of which have been implemented in 1920 in response to the 2009 H1N1 pandemic. 20 In addition to directly protecting pregnant women, maternal antibodies derived from a vaccine cross the placenta and confer passive immunity to infants during the first few years. month of life.212223242526 As infants under 6 months of age, the burden of morbidity and mortality associated with childhood flu is highest. 272829, but influenza vaccines are not licensed for use in this group 30, immunization during pregnancy is an important strategy to protect young children from influenza infection31.

Despite strong evidence of benefits for both mothers and newborns, influenza vaccination during pregnancy has been low, even when it is recommended and funded.3233 Safety concerns are one of the reasons invoked for pregnant women not to be immunized, 34353637 and this can also affect health care. willingness of providers to recommend influenza vaccination to their pregnant patients.37 While substantial evidence now supports the safety of maternal influenza vaccination with respect to the outcome of childbirth (premature birth, abnormal Congenital, for example), 383940414243 few studies have evaluated the effects on children's health The first six months of life.444546474849 The lack of information on the long-term effects on the health of children who follow a flu shot during pregnancy may be a potential barrier to higher uptake and has been identified as a lack of evidence for maternal immunization policy worldwide.5051 In this study, we assessed the relationship between pandemic influenza H1N1 in 2009 influenza (pH1N1) during pregnancy and outcomes for pediatric health over the first five years of life.

The methods

Study Design, Data Sources and Population Study

We performed a retrospective cohort study based on the population of infants born to residents of Ontario, Canada, from November 2, 2009 to October 31, 2010. We used the Better Outcomes Registry & Network (BORN) birth registry. from Ontario (https://www.bornontario.ca). / en / about-born /) to identify the study population. This province-wide registry contains maternal and newborn records for all hospital births of at least 500 g or at least 20 weeks of gestational age. In addition to routine sociodemographic and clinical data, information on the receipt of the monovalent influenza vaccine pH1N1 2009 during pregnancy was collected as part of the enhanced surveillance established during the 2009 influenza pandemic. We have linked this one year birth cohort to administrative health databases to determine outcomes for child health over a five year follow-up period. All databases were linked with unique coded identifiers analyzed by ICES (https://www.ices.on.ca/). The administrative databases included the Canadian Institute for Health Information (Hospital Admissions) patient discharge database and the National Health Information System. outpatient care (emergency department visits), each containing clinical diagnoses made during medical consultations, coded with the help of the Canadian adaptation of the International Classification of Diseases. 10th Revision (ICD-10-CA), as well as the Ontario Asthma dataset, which is derived from administrative databases. We also linked to the Ontario Cancer Registry to identify pediatric cancer cases and the registered people database to determine each child's follow-up time and determine infant mortality. A more detailed description of the data sources and the coupling methodology is provided in the additional methods 1.

We excluded infants whose birth registration could not be linked to administrative databases, those born to women who were not continuously eligible for health care in Ontario during pregnancy, those whose records posed data quality issues (eg, duplicate, invalid birth date), and those not eligible for provincial government-funded health care at birth. We also excluded infants whose records lacked information on the 2009 pH1N1 influenza vaccination during pregnancy or who died on the day of their birth.

Measure of exposure and results

The exposure in question was received during pregnancy by the 2009 influenza monovalent influenza vaccine pH1N1, based on the database-specific codes in the birth registry. We classified infants born to mothers with documented pH1N1 2009 immunization during pregnancy among those exposed to vaccination and those whose mothers were not immunized against pandemic influenza 2009 during pregnancy as unexposed . The pandemic influenza vaccination campaign in Ontario began on October 26, 2009. In Canada, two pandemic vaccines have been produced (both by GlaxoSmithKline Biologicals): an unadjuvanted pH1N1 flu vaccine specifically for pregnant women , and an adduct product AS03 (Arepanrix) produced for the general population. The second was not contraindicated during pregnancy if the unadjuvanted product was not available and the risk of influenza was judged to be high5253.

A consensual list of standardized case definitions has been developed to monitor obstetric and neonatal outcomes following vaccination during pregnancy.545556 In the absence of such indications for future outcomes in pediatric health and limited research on this issue. subject, we have pre-specified three groups of infant morbidity. results for our evaluation. First, we focused primarily on immune outcomes (infectious and atopic diseases), as the developing fetal immune system is thought to be sensitive to influences such as maternal vaccination.575859 To assess safety, we included two morbidity outcomes not related to the immune system: have been used in other safety studies in pregnant women (neoplasms, sensory disturbances) 60 and in two cases of non-specific morbidity (use of health care services). emergency and hospital services, complex chronic conditions in pediatrics). Wherever possible, we used standardized clinical registries and validated algorithms to identify the results. In the absence of any established registry or algorithm available, we measured results using diagnostic codes of emergency visits and admissions to the hospital, but not from outpatient primary care visits, to limit the analysis to cases with better measurement in the available databases, as well as more serious clinical implications. Following the development of our original study protocol, we included infant mortality up to the age of 5 as an additional outcome.

Infectious findings included upper and lower respiratory tract infections, gastrointestinal infections, otitis media and a composite of these four categories of infections. Sensory disorders included loss of vision and hearing. We searched for ICD-10-CA diagnostic codes for each of these results in the primary or secondary diagnostic code field positions of the hospital admission databases and medical services. ;emergency. Asthma diagnoses were derived from the Ontario Asthma Data Set, which uses a validated algorithm (sensitivity 89%, specificity 72%) to identify cases of asthma. Asthma from administrative health databases.61 Children in our cohort who were in the Ontario asthma dataset but were coded for an asthma diagnosis before the start of the study. 6-month-old age was not classified as an asthma case unless an asthma diagnosis code could be found in the admissions data bases. hospital or emergency department later during follow-up.62 Confirmed pediatric cancer diagnoses came from the Ontario Cancer Registry. . We have modified an existing algorithm to identify children with a complex chronic disease (expected to last more than 12 months and require specialized care, possibly including hospitalization in a tertiary care facility) .63 We Verified infant mortality from the database of registered persons. See Supplementary Tables A and B for a list of diagnostic codes used to identify all morbidity outcomes.

statistical analyzes

Characteristics of the study population were described using frequencies for categorical variables and medians (interquartile intervals) for continuous variables. We used standardized differences to evaluate the baseline covariate equilibrium between the two groups of exposure, an absolute standardized difference of less than 0.10 being considered as an indication of a well-balanced covariate64.

We used weightings derived from propensity scores to adjust the confounders in our study. We developed a logistic regression model to compute a propensity score for each infant, representing the predicted probability of vaccination against pandemic H1N1 influenza in 2009 during pregnancy. Before running the propensity score models, we used multiple imputation to correct missing values ​​for covariates: 6.9% of the records contained missing information for one or more covariates that we had Intended to include in the propensity score. the percentage of missing data for each of the individual variables was below 1% for most (rural residence, public health unit area, parity, fifth of neighborhood income) and was highest for maternal smoking during pregnancy ( 3.9%). We included the following preselected birth register covariates in propensity score models, which were developed using each of the 10 sets of multiple imputation data: maternal age, parity, maternal smoking , design season, antenatal care provider, pre-existing for maternal medical comorbidity, obstetric complications, antenatal steroid use, multifetal pregnancy, fifth of neighborhood income, rural residence and area of ​​public health units. Subsequently, we developed an inverse likelihood of treatment weights (IPTW), in which the value for each infant exposed to the vaccine was the inverse of the propensity score and the value for each unexposed infant was the highest. inverse of 1 minus the propensity score65. weighted, we normalized the entire population under study by multiplying it by the marginal propensity score.

Follow-up began at the date of birth and continued until the child became ineligible for health care in Ontario (due to emigration or death) or has reached the age of 5 years. However, for the results at the end of the term (asthma, neoplasms, sensory disturbances, mortality), the end of the follow-up corresponds to the date of the event for the persons presenting the result. We used Cox proportional hazards models (asthma, neoplasms, sensory disturbances, mortality), negative binomial models (infectious disease outcomes, use of urgent and inpatient health services) and binomial log models (conditions complex chronic in children) to estimate unadjusted and adjusted risk ratios, incidence rates and risk ratios, respectively, with 95% confidence intervals. To generate adjusted results, we ran weighted models for each result using the stabilized IPTWs generated from each of the 10 multiple imputation datasets. We then statistically combined the resulting β parameters and standard errors to produce a single adjusted point estimate and a 95% confidence interval. For Cox models, we found that the proportional hazards assumption for the exposure variable was met based on the examination of Schoenfeld residual plots and Wald tests for the ## EQU1 ## 39, interaction between exposure status and time.

In the sensitivity analyzes, we examined the results for which the 95% confidence interval around the adjusted point excluded the null value. First, we have limited the study population to infants with at least two good baby visits or primary vaccination visits during the first year of life to make sure that the child had access to the health care system (see Additional Methods 2). We also repeated our main analyzes by further adjusting the number of ambulatory maternal consultations in the six months preceding the indexed pregnancy and the number of non-obstetric hospital admissions in the two years preceding the start of the indexed pregnancy in order to take into account account the different needs of health care. or access. With regard to asthma, we also adjusted the status of the mother's asthma. We recalculated the confidence intervals after the application of a Bonferroni correction to account for several comparisons (n ​​= 10 predefined morbidity results) and examined a negative control result (baseline rate). all-cause injuries) to assess any rival explanations66. additional analyzes to characterize the effect of excluding records with missing information on the pH1N1 influenza vaccination. We used SAS version 9.4 for all analyzes.


Of the 135,807 live births from the Ontario Birth Registry initially eligible, 4,714 (3.5%) could be associated with administrative databases and we excluded 13,687 (10% ) for administrative reasons. Of the remaining 117,406 infants, we excluded 77 (<1%) deaths on the day of birth, as well as 13,080 (11%) who lacked information about the 2009 pH1N1 vaccination during pregnancy, leaving 104,249 live births in our country. final studied population (fig 1). A total of 31,295 children (30%) were born to women vaccinated against pH1N1 from 2009 during pregnancy. In the unweighted study population, vaccinated women were more likely to be over 30 years old and lived in the fifth of the neighborhood's highest incomes. After weighting with stabilized TPI, we found that all measured baseline covariates were well balanced (absolute standardized difference <0.1), indicating an improvement in the comparability of children born to women who had been vaccinated or not with influenza vaccine 2009 pH1N1 during pregnancy (Table 1). ).

The median duration of follow-up for infants exposed and not exposed to the pH1N1 influenza vaccine was five years. A total of 14,459 children (14%) were diagnosed with asthma at follow-up, at a median age of 1.8 years. The proportion of children diagnosed with asthma was highest among mothers born with pre-existing medical comorbidity, particularly asthma, and premature mothers (see Complementary Table C). Of the infectious study results, 34% (n = 35,441) of children had at least one upper respiratory tract infection during follow-up (see Supplementary Table C). Less than 1% of children were diagnosed with a sensory disorder (152 (0.15%), see Supplementary Table D), a neoplasm (145 (0.14%), an additional Table D) or a complex chronic condition. in the child (444 (0.87%), supplementary table E).

We found no significant associations between prenatal exposure to influenza vaccination against pH1N1 2009, upper and lower respiratory tract infections, otitis media, all infections, neoplasms, sensory disturbances, use of urgent and hospital health services, complex chronic conditions in children or chronic diseases. 5 mortality. We found a weak but statistically significant association with asthma (adjusted risk ratio of 1.05, 95% confidence interval 1.02 to 1.09), as well as an association reverse with gastrointestinal infections (adjusted incidence rate ratio of 0.94, 0.91 to 0.98), even after taking into account the potential confusion in the weighted analyzes (Table 2).

Table 2

Association between vaccination against pandemic H1N1 influenza in 2009 during pregnancy and the results for the health of the child

We submitted our conclusions regarding asthma and gastrointestinal infections to several sensitivity analyzes (see Supplementary Table F). First, to ensure contact with the health care system during the first year of life, we limited the analysis to children with at least two healthy or routine baby vaccination visits during their first year of life. year; However, the positive association with asthma and the inverse association with gastrointestinal infections were unchanged. An additional adjustment to the maternal propensity to access pre-pregnancy health care also had a negligible effect on these point estimates. When we used a Bonferroni correction to account for the multiplicity, nor the association with asthma (adjusted risk ratio 1.05, 1.00 to 1.11) nor the association with gastrointestinal infections (ratio of adjusted incidence rate 0.94, 0.88 to 1.00) are statistically significant. There was a slight statistically significant increase in all-cause injury rates (negative control result) in infants exposed to pH1N1 2009 influenza vaccine compared to unexposed infants (adjusted incidence rate ratio of 1.03, 1). , 01 to 1.05), and this association persisted in all cases. sensitivity analyzes. About 11% of the records lacked information on pH1N1 vaccination during pregnancy and were excluded from our analyzes. When we examined the distribution of baseline study variables in infants lacking information on exposure (n = 13,080 infants) and those included in our analyzes (n = 104,249) we found that they were generally comparable. Any difference in characteristics between these two groups (that is, with a standardized difference> 0.1) was largely due to missing data in other variables (Supplementary Table G). The differences in the study results between these two groups were very small and were not clinically informative (see Complementary Table H), and sensitivity analyzes to assess the potential effect of missing data were have not changed our results or interpretation (supplementary table I).


In this large population study of 104,249 children, of whom 31,295 were born to women vaccinated against pH1N1 2009 during pregnancy, we found no association between exposure to the 2009 pH1N1 influenza vaccine. in utero and upper respiratory tract infections respiratory tract infections, otitis media, all infections, neoplasms, sensory disturbances, rate of use of urgent and inpatient health services, complex chronic diseases in pediatrics or mortality up to 39 to 5 years.

Although we observed an increased association between maternal pH1N1 influenza vaccination and childhood asthma in 2009, the low magnitude of association, which was no longer statistically significant after accounting for of the multiplicity, as well as the evidence of a weak correlation with our negative control results, imply that these results must be interpreted with caution. We also observed a significant inverse association between the 2009 anti-pH1N1 influenza vaccination during pregnancy and the persistent pediatric gastrointestinal infections in all sensitivity analyzes. Although we used propensity score methods to adjust differences between vaccine-exposed infants and unexposed infants, this association could still be due to residual confusion, possibly due to increased likelihood of vaccinated mothers Ensure rotavirus immunization in their children. Although the state-funded rotavirus immunization program in Ontario was not operational during our study period, the vaccine was available on prescription for purchase.67 We attempted to account for Rotavirus immunization by means of a sensitivity analysis limited to children accessing regular visits the first year; However, no rotavirus-specific vaccine code was available to allow for a specific fit in our models.

Strengths and weaknesses of the study

The main strength of our study was the availability of a population-based birth registry, containing detailed clinical information on pregnancy and birth, the receipt of the 2009 pH1N1 influenza vaccine during pregnancy, 44 and the linkage with administrative health data to track results so far. 5 years old. Nous ne pouvons pas écarter la possibilité d&#39;une confusion résiduelle de nos résultats en raison de notre incapacité à inclure des facteurs de confusion non mesurés ou inconnus dans les scores de propension68. Cependant, il a été démontré que cette méthode réduisait moins les biais que les méthodes classiques d&#39;ajustement multivariable classiques dans les études utilisant de grandes bases de données administratives. , 69 études sur le vaccin antigrippal incluses70. À l’exception des néoplasmes pour lesquels nous avons utilisé un registre clinique, nous reconnaissons la possibilité d’une erreur de mesure des autres résultats de l’étude. Nous avons utilisé un algorithme validé pour identifier les cas d&#39;asthme pédiatrique61; cependant, des diagnostics d&#39;asthme confirmés cliniquement auraient été préférables. Bien que nous estimions que toute classification erronée de l’asthme aurait probablement été non différentielle en fonction de l’exposition, les femmes vaccinées auraient peut-être été plus susceptibles d’avoir accès aux soins de santé pour leurs nourrissons, ce qui aurait pu biaiser nos résultats. Néanmoins, nos analyses de sensibilité conçues pour rendre compte de la propension maternelle à accéder aux soins de santé n’ont changé aucun des résultats. Dans les analyses de sensibilité, nous n&#39;avons trouvé aucune preuve suggérant que l&#39;exclusion des enregistrements contenant des informations manquantes sur la vaccination contre la grippe pH1N1 pendant la grossesse aurait introduit un biais significatif. Outre des fréquences similaires de caractéristiques initiales et de risque de résultats d&#39;études parmi les enregistrements avec et sans informations complètes sur la vaccination anti-pH1N1, la répétition de nos analyses au sein de sous-groupes de la population étudiée présentant des pourcentages inférieurs d&#39;enregistrements avec des informations manquantes sur la vaccination contre l&#39;influenza pH1N1 a donné des résultats cohérents avec nos analyses primaires. Bien qu&#39;un vaccin antigrippal anti-pH1N1 sans adjuvant ait été produit spécifiquement pour les femmes enceintes au Canada pendant la pandémie, 5 253 d&#39;entre elles ont probablement reçu le vaccin avec adjuvant AS03 utilisé dans la population en général. Nous n&#39;avons pas pu évaluer les produits séparément, car aucune distinction n&#39;a été faite dans le registre des naissances. Enfin, malgré la grande taille de notre étude, nous étions probablement encore sous-développés pour écarter les petites associations pour les résultats les plus rares.

Comparaison avec d&#39;autres études

Malgré des recommandations de longue date concernant la vaccination antigrippale pendant la grossesse, la couverture 14151617181920 a été sous-optimale (par exemple, <20% au Canada, 32 54% aux États-Unis33), probablement en raison de préoccupations persistantes quant à la sécurité de la vaccination pendant la grossesse.343571 Les études sur la vaccination antigrippale pendant la grossesse, qui incluent le suivi des résultats chez le nourrisson au-delà de la période néonatale précoce, ont limité leur évaluation aux six premiers mois et se sont concentrées exclusivement sur les résultats pour la grippe (par exemple, grippe confirmée en laboratoire, admission à l&#39;hôpital pour grippe) .2122252672737475767778 À notre connaissance, seules six études ont évalué les résultats pour la santé d&#39;enfants âgés de plus de 6 mois.444546474849 Deux nourrissons suivis de la naissance à un an et comparant les résultats obtenus entre les mères vaccinées contre la grippe pH1N1 et les mères non vaccinées en 2009. Aucune différence n&#39;a été observée dans les scores de développement ou les visites chez le médecin liées à l&#39;infection dans une petite cohorte de nourrissons néerlandais nés de femmes immunisées avec le vaccin anti-pH1N1 avec adjuvant MF5945, ni dans les taux d&#39;infection grippale ou d&#39;utilisation globale des services de santé (visites à l&#39;urgence et hospitalisations) en une vaste étude canadienne, menée dans la même population que notre étude48. Les quatre autres études ont évalué les résultats au-delà de la première année de vie. Le premier, datant de 1977, ne faisait apparaître aucune association entre la vaccination maternelle grippale saisonnière et les conséquences neurologiques, bien que l’étude comportait des limites importantes, notamment en ce qui concerne un petit échantillon.47 Plus récemment, Hviid et ses collègues ont réalisé une étude de cohorte rétrospective utilisant les données du registre danois du Période de pandémie de grippe H1N1 2009. Parmi les 61 359 nourrissons (6311 nés de femmes vaccinées avec un vaccin antigrippal anti-pH1N1 avec adjuvant AS03), aucun risque accru de morbidités infantiles diverses n&#39;a été observé au cours d&#39;une période de suivi de cinq ans (par exemple, maladies infectieuses et affections neurologiques, auto-immunes ou comportementales). ) .44 L’étude danoise n’a révélé aucune association entre la vaccination antigrippale anti-pH1N1 de 2009 et l’asthme chez l’enfant (rapport de risque du premier trimestre de 1,50, 0,99 à 2,29; deuxième / troisième trimestre: 1,02, 0,89 à 1,16). De manière intéressante, une association inverse significative entre la vaccination contre la grippe pH1N1 de 2009 et les infections gastro-intestinales pédiatriques a également été observée dans la cohorte danoise (rapport de risque 0,84, 0,74 à 0,94) .44 De la même manière que notre évaluation de la mortalité des moins de 5 ans, une étude suédoise a évalué la mortalité des enfants. de 7 jours de vie à 4,6 ans après la vaccination antigrippale anti-pH1N1 au cours de la grossesse avec un vaccin avec adjuvant AS03, aucun lien n’a été trouvé (rapport de risque 0,97, 0,69 à 1,36) .49 Enfin, aucune augmentation globale du risque de trouble du spectre autistique après la grippe vaccination pendant la grossesse (vaccin antigrippal trivalent saisonnier ou vaccin antigrippal anti-pH1N1 sans adjuvant) dans le cadre d&#39;une étude de cohorte menée en Californie auprès de nourrissons nés entre 2000 et 201046.


Globalement, nos résultats indiquent que la vaccination antigrippale contre le pH1N1 en 2009 pendant la grossesse n’a pas été associée à des résultats de santé négatifs sur cinq ans chez les enfants, ce qui est rassurant et cohérent avec une étude récente similaire menée au Danemark. Bien que nous ayons observé une augmentation faible, mais statistiquement significative, de l&#39;asthme infantile et une réduction des infections gastro-intestinales, nous ne sommes au courant d&#39;aucun mécanisme biologique permettant d&#39;expliquer ces résultats. Des études futures dans différents contextes et avec différentes formulations de vaccins antigrippaux seront importantes pour développer la base de preuves sur les résultats à long terme en pédiatrie après la vaccination antigrippale pendant la grossesse.

Qu&#39;est-ce qu&#39;on sait déjà à ce sujet

  • Selon des recherches récentes, l&#39;inquiétude suscitée par l&#39;innocuité est souvent citée parmi les raisons de la faible adoption du vaccin antigrippal chez les femmes enceintes.

  • Le manque d&#39;informations sur les effets à long terme sur la santé des enfants exposés à la vaccination antigrippale in utero pourrait constituer un obstacle à une plus grande adoption du vaccin

Ce que cette étude ajoute

  • Aucune association n&#39;a été observée entre l&#39;exposition au vaccin contre la grippe pandémique H1N1 en 2009 pendant la grossesse et la plupart des résultats pour la santé pédiatrique quinquennaux

  • Ces résultats confirment le profil d&#39;innocuité de la vaccination antigrippale contre la grippe pandémique H1N1 en 2009 pendant la grossesse.


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