The effectiveness of maternal pertussis vaccination for protecting Aboriginal and Torres Strait Islander infants against infection, 2012-2017: a retrospective cohort study.

OBJECTIVES: To evaluate the effectiveness of maternal pertussis vaccination for preventing pertussis infections in Aboriginal and Torres Strait Islander infants under seven months of age. STUDY DESIGN: Retrospective cohort study; analysis of linked administrative health data. SETTING, PARTICIPANTS: Mother-infant cohort (Links2HealthierBubs) including all pregnant women who gave birth to live infants (gestational age ≥ 20 weeks, birthweight ≥ 400 g) in the Northern Territory, Queensland, and Western Australia during 1 January 2012 - 31 December 2017. MAIN OUTCOME MEASURES: Proportions of women vaccinated against pertussis during pregnancy, rates of pertussis infections among infants under seven months of age, and estimated effectiveness of maternal vaccination for protecting infants against pertussis infection, each by Indigenous status. RESULTS: Of the 19 892 Aboriginal and Torres Strait Islander women who gave birth to live infants during 2012-2017, 7398 (37.2%) received pertussis vaccine doses during their pregnancy, as had 137 034 of 259 526 non-Indigenous women (52.8%; Indigenous v non-Indigenous: adjusted odds ratio, 0.66; 95% confidence interval [CI], 0.62-0.70). The annual incidence of notified pertussis infections in non-Indigenous infants declined from 16.8 (95% CI, 9.9-29) in 2012 to 1.4 (95% CI, 0.3-8.0) cases per 10 000 births in 2017; among Aboriginal and Torres Strait Islander infants, it declined from 47.6 (95% CI, 16.2-139) to 38.6 (95% CI, 10.6-140) cases per 10 000 births. The effectiveness of maternal vaccination for protecting non-Indigenous infants under seven months of age against pertussis infection during 2014-17 was 68.2% (95% CI, 51.8-79.0%); protection of Aboriginal and Torres Strait Islander infants was not statistically significant (36.1%; 95% CI, -41.3% to 71.1%). CONCLUSIONS: During 2015-17, maternal pertussis vaccination did not protect Aboriginal and Torres Strait Islander infants in the NT, Queensland, and WA against infection. Increasing the pertussis vaccination rate among pregnant Aboriginal and Torres Strait Islander women requires culturally appropriate, innovative strategies co-designed in partnership with Indigenous organisations and communities.

Factors Predicting Secondary Respiratory Morbidity Following Early-Life Respiratory Syncytial Virus Infections: Population-Based Cohort Study.

Background: The association between early-life respiratory syncytial virus (RSV) infections and later respiratory morbidity is well established. However, there is limited evidence on factors that influence this risk. We examined sociodemographic and perinatal factors associated with later childhood respiratory morbidity requiring secondary care following exposure to a laboratory-confirmed RSV episode in the first 2 years. Methods: We used a probabilistically linked whole-of-population-based birth cohort including 252 287 children born in Western Australia between 2000 and 2009 with follow-up to the end of 2012. Cox proportional hazards models estimated adjusted hazard ratios (aHRs) of the association of various risk factors with the first respiratory episode for asthma, wheezing, and unspecified acute lower respiratory infection beyond the age of 2 years. Results: The analytic cohort included 4151 children with a confirmed RSV test before age 2 years. The incidence of subsequent respiratory morbidity following early-life RSV infection decreased with child age at outcome (highest incidence in 2-<4-year-olds: 41.8 per 1000 child-years; 95% CI, 37.5-46.6), increased with age at RSV infection (6-<12-month-olds: 23.6/1000 child-years; 95% CI, 19.9-27.8; 12-<24-month-olds: 22.4/1000 child-years; 95% CI, 18.2-22.7) and decreasing gestational age (50.8/1000 child-years; 95% CI, 33.5-77.2 for children born extremely preterm, <28 weeks gestation). Risk factors included age at first RSV episode (6-<12 months: aHR, 1.42; 95% CI, 1.06-1.90), extreme prematurity (<28 weeks: aHR, 2.22; 95% CI, 1.40-3.53), maternal history of asthma (aHR, 1.33; 95% CI, 1.04-1.70), and low socioeconomic index (aHR, 1.76; 95% CI, 1.03-3.00). Conclusions: Our results suggest that in addition to preterm and young infants, children aged 12-<24 months could also be potential target groups for RSV prevention to reduce the burden of later respiratory morbidities associated with RSV.

Maternal Pertussis Vaccination, Infant Immunization, and Risk of Pertussis.

OBJECTIVES: Following the introduction of jurisdictional maternal pertussis vaccination programs in Australia, we estimated maternal vaccine effectiveness (VE) and whether maternal pertussis vaccination modified the effectiveness of the first 3 primary doses of pertussis-containing vaccines. METHODS: We conducted a population-based cohort study of 279 418 mother-infant pairs using probabilistic linkage of administrative health records in 3 Australian jurisdictions. Infants were maternally vaccinated if their mother had a documented pertussis vaccination ≥14 days before birth. Jurisdictional immunization records were used to identify receipt of the first 3 infant doses of pertussis-containing vaccines. Infant pertussis infections were identified using notifiable disease records. VE was estimated using Cox proportional hazard models. RESULTS: Pertussis was administered during 51.7% (n = 144 429/279 418) of pregnancies, predominantly at 28-31 weeks' gestation. VE of maternal pertussis vaccination declined from 70.4% (95% confidence interval [CI], 50.5-82.3) among infants <2 months old to 43.3% (95% CI, 6.8-65.6) among infants 7-8 months old and was not significant after 8 months of age. Although we observed slightly lower VE point estimates for the third dose of infant pertussis vaccine among maternally vaccinated compared with unvaccinated infants (76.5% vs 92.9%, P = .002), we did not observe higher rates of pertussis infection (hazard ratio, 0.70; 95% CI, 0.61-3.39). CONCLUSIONS: Pertussis vaccination near 28 weeks' gestation was associated with lower risk of infection among infants through 8 months of age. Although there was some evidence of lower effectiveness of infant vaccination among maternally vaccinated infants, this did not appear to translate to greater risk of disease.

Determining the true incidence of seasonal respiratory syncytial virus-confirmed hospitalizations in preterm and term infants in Western Australia.

Respiratory syncytial virus contributes to significant global infant morbidity and mortality. We applied a previously developed statistical prediction model incorporating pre-pandemic RSV testing data and hospital admission data to estimate infant RSV-hospitalizations by birth month and prematurity, focused on infants aged <1 year. The overall predicted RSV-hospitalization incidence rates in infants <6 months were 32.7/1,000 child-years (95 % CI: 31.8, 33.5) and 3.1/1,000 child-years (95 % CI: 3.0, 3.1) in infants aged 6-<12 months. Predicted RSV-hospitalization rates for infants aged <6 months were highest for infants born in April/May. Predicted rates for preterm infants born 29-32 weeks gestation were highest in March-May, whereas infants born >33 weeks had peak RSV-hospitalization rates from May-June, similar to late preterm or term births. RSV-hospitalization rates in the pre-pandemic era were highly seasonal, and seasonality varied with degree of prematurity. Accurate estimates of RSV-hospitalization in high-risk sub-groups are essential to understand preventable burden of RSV especially given the current prevention landscape.

Inequity of antenatal influenza and pertussis vaccine coverage in Australia: the Links2HealthierBubs record linkage cohort study, 2012-2017.

BACKGROUND: Pregnancy and early infancy are increased risk periods for severe adverse effects of respiratory infections. Aboriginal and/or Torres Strait Islander (respectfully referred to as First Nations) women and children in Australia bear a disproportionately higher burden of respiratory diseases compared to non-Indigenous women and infants. Influenza vaccines and whooping cough (pertussis) vaccines are recommended and free in every Australian pregnancy to combat these infections. We aimed to assess the equity of influenza and/or pertussis vaccination in pregnancy for three priority groups in Australia: First Nations women; women from culturally and linguistically diverse (CALD) backgrounds; and women living in remote areas or socio-economic disadvantage. METHODS: We conducted individual record linkage of Perinatal Data Collections with immunisation registers/databases between 2012 and 2017. Analysis included generalised linear mixed model, log-binomial regression with a random intercept for the unique maternal identifier to account for clustering, presented as prevalence ratios (PR) and 95% compatibility intervals (95%CI). RESULTS: There were 445,590 individual women in the final cohort. Compared with other Australian women (n = 322,848), First Nations women (n = 29,181) were less likely to have received both recommended antenatal vaccines (PR 0.69, 95% CI 0.67-0.71) whereas women from CALD backgrounds (n = 93,561) were more likely to have (PR 1.16, 95% CI 1.10-1.13). Women living in remote areas were less likely to have received both vaccines (PR 0.75, 95% CI 0.72-0.78), and women living in the highest areas of advantage were more likely to have received both vaccines (PR 1.44, 95% CI 1.40-1.48). CONCLUSIONS: Compared to other groups, First Nations Australian families, those living in remote areas and/or families from lower socio-economic backgrounds did not receive recommended vaccinations during pregnancy that are the benchmark of equitable healthcare. Addressing these barriers must remain a core priority for Australian health care systems and vaccine providers. An extension of this cohort is necessary to reassess these study findings.

Association between maternal influenza vaccination and neurodevelopmental disorders in childhood: a longitudinal, population-based linked cohort study.

OBJECTIVE: To assess the association between in utero exposure to seasonal inactivated influenza vaccine (IIV) and the risk of a diagnosis of a neurodevelopmental disorder in early childhood. DESIGN: Retrospective cohort study. SETTING: Population-based birth registry linked with health administrative databases in Western Australia (WA). PARTICIPANTS: Singleton, liveborn children born between 1 April 2012 and 1 July 2016 in WA. EXPOSURE: Receipt of seasonal IIV during pregnancy obtained from a state-wide antenatal vaccination database. MAIN OUTCOME MEASURES: Clinical diagnosis of a neurodevelopmental disorder was recorded from hospital inpatient and emergency department records. We used Cox proportional hazard regression, weighted by the inverse-probability of treatment (vaccination), to estimate the hazard ratio (HR) of neurodevelopmental disorders associated with in utero exposure to seasonal IIV. RESULTS: The study included 140 514 children of whom, 15 663 (11.2%) were exposed to seasonal IIV in utero. The prevalence of neurodevelopmental disorders was 5.4%, including mental or behavioural (0.4%), neurological (5.1%), seizure (2.2%) and sleep disorders (2.7%). Maternal IIV was not associated with increased risk of neurodevelopmental disorders (HR 1.00; 95% CI 0.91 to 1.08). Children exposed in the first trimester had a lower risk of seizure disorders (adjusted HR [aHR] 0.73; 95% CI 0.54 to 0.998), and preterm children exposed any time during pregnancy had a lower risk of sleep disorders (aHR 0.63; 95% CI 0.41 to 0.98). CONCLUSIONS: We did not observe increased risk of neurodevelopmental disorders following in utero exposure to seasonal IIV. Although we observed some evidence for lower risk of seizure and sleep disorders, additional studies are required to confirm.

Timing and temporal trends of influenza and pertussis vaccinations during pregnancy in three Australian jurisdictions: The Links2HealthierBubs population-based linked cohort study, 2012-2017.

BACKGROUND: Antenatal inactivated influenza (IIV) and pertussis-containing vaccines (dTpa) offer protection against severe respiratory infections for pregnant women and infants <6 months of age. Both vaccines are recommended in pregnancy; however, little is known about temporal or jurisdictional trends and predictors of uptake. AIMS: To identify gaps and predictors of IIV and/or dTpa vaccinations in Australian pregnancies from 2012 to 2017. MATERIALS AND METHODS: We conducted a probabilistically linked, multi-jurisdictional population-based cohort study, drawing from perinatal data collections and immunisation databases. We used a generalised linear mixed model with a random effect term to account for clustering of multiple pregnancies within mothers, to calculate vaccination uptake, and identify predictors of uptake by maternal demographic, pregnancy, and health characteristics. RESULTS: Of 591 868 unique pregnancies, IIV uptake was 15%, dTpa 27% and 12% received both vaccines. Pertussis vaccinations in First Nations pregnancies were 20% lower than non-Indigenous pregnancies; dTpa was strongly associated with IIV uptake (risk ratio (RR): 8.60, 95% CI 8.48-8.73). This trend was temporally and jurisdictionally consistent. First Nations women were more likely to have had IIV in pregnancy before the introduction of dTpa in the pregnancy program: (RR: 1.48, 95% CI 1.40-1.57), but less likely after dTpa implementation (RR: 0.78, 95% CI 0.76-0.80). CONCLUSIONS: Inequity in vaccine uptake between First Nations and non-Indigenous pregnancies, and dismal rates of vaccination in pregnancy overall need urgent review, particularly before the next influenza pandemic or pertussis outbreak. If antenatal dTpa is driving IIV uptake, changes in antenatal healthcare practices are needed to ensure vaccines are offered equitably and optimally to protect against infection.

Neuropsychiatric outcomes in offspring after fetal exposure to maternal influenza infection during pregnancy: A systematic review.

Increasing evidence suggests that influenza infection in pregnancy may disrupt fetal neurodevelopment. The impact of maternal influenza infection on offspring neuropsychiatric health has not been comprehensively reviewed. We systematically reviewed comparative studies evaluating associations between maternal influenza infection and neuropsychiatric health outcomes in offspring. We searched MEDLINE, EMBASE, CINAHL, and Web of Science for articles published until January 7, 2022. Included were English studies evaluating neuropsychiatric outcomes in offspring aged > 6 months born to women with and without influenza during pregnancy, defined as clinical or laboratory-confirmed influenza illness, or being pregnant during pandemics/epidemics. Of 12,010 records screened, 42 studies were included. Heterogeneity in study design, exposures, and outcome definitions precluded meta-analyses. Four of 14 studies assessing schizophrenia reported adjusted ratio estimates from 0.5 to 8.2; most 95% CIs contained the null value; study quality was high in three of four. Two studies reported an increased risk of schizophrenia with influenza exposure any time during pregnancy (adjusted incidence rate ratio 8.2, 95% CI: 1.4-48.8; adjusted odds ratio 1.3, 95% CI: 1.2-1.5); another reported a reduced risk with first-trimester exposure (adjusted risk ratio 0.5, 95% CI: 0.3-0.9). Seven studies of autism spectrum disorder reported adjusted ratio estimates from 0.9 to 4.0; all 95% CIs included the null value; study quality was high in four. No conclusions could be drawn about the association between exposure to maternal influenza and neuropsychiatric outcomes due to the limited quantity and quality of available research. Large observational studies with long-term follow-up are required to investigate these associations.

The risk of major structural birth defects associated with seasonal influenza vaccination during pregnancy: A population-based cohort study.

INTRODUCTION: Seasonal inactivated influenza vaccine (IIV) is routinely recommended during pregnancy to protect both mothers and infants from complications following influenza infection. While previous studies have evaluated the risk of major structural birth defects in infants associated with prenatal administration of monovalent pandemic IIV, fewer studies have evaluated the risk associated with prenatal seasonal IIV. METHODS: We conducted a population-based cohort study of 125,866 singleton births between 2012 and 2016 in Western Australia. Birth registrations were linked to the state's registers for congenital anomalies and a state prenatal vaccination database. We estimated prevalence ratios (PR) of any major structural birth defect and defects by organ system. Vaccinated pregnancies were defined as those with a record of IIV in the first trimester. Inverse probability treatment weighting factored for baseline probability for vaccination. A Bonferroni correction was applied to account for multiple comparisons. RESULTS: About 3.9% of births had a major structural birth defect. Seasonal IIV exposure during the first trimester was not associated with diagnosis of any major structural birth defect diagnosed within 1 month of birth (PR 0.98, 95% CI: 0.77, 1.28) or within 6 years of life (PR 1.02, 95% CI: 0.78, 1.35). We identified no increased risk in specific birth defects associated with seasonal IIV. CONCLUSION: Based on registry data for up to 6 years of follow-up, results suggest there is no association between maternal influenza vaccination and risk of major structural birth defects. These results support the safety of seasonal IIV administration during pregnancy.

Maternal influenza vaccination and child mortality: Longitudinal, population-based linked cohort study.

Influenza vaccination is recommended to protect mothers and their infants from influenza. Few studies have evaluated the association between maternal influenza vaccination and child mortality. We aimed to evaluate the association between in utero exposure to seasonal inactivated influenza vaccine (IIV) and mortality among young children. This longitudinal, population-based cohort study included 191,247 maternal-child pairs in Western Australia between April 2012 and December 2017. Maternal vaccine information was obtained from a state-wide antenatal vaccination database. Mortality was defined as a record of a death registration. We used Cox proportional hazard models, weighted by the inverse-probability of treatment (vaccination), to estimate the hazard ratio of child mortality associated with in utero exposure to seasonal IIV. This study found no association between in utero exposure to seasonal IIV and mortality through age five years.

Prenatal influenza vaccination and allergic and autoimmune diseases in childhood: A longitudinal, population-based linked cohort study.

BACKGROUND: Few studies have evaluated the effect of maternal influenza vaccination on the development of allergic and autoimmune diseases in children beyond 6 months of age. We aimed to investigate the association between in utero exposure to seasonal inactivated influenza vaccine (IIV) and subsequent diagnosis of allergic and autoimmune diseases. METHODS AND FINDINGS: This longitudinal, population-based linked cohort study included 124,760 singleton, live-born children from 106,206 mothers in Western Australia (WA) born between April 2012 and July 2016, with up to 5 years of follow-up from birth. In our study cohort, 64,169 (51.4%) were male, 6,566 (5.3%) were Aboriginal and/or Torres Strait Islander children, and the mean age at the end of follow-up was 3.0 (standard deviation, 1.3) years. The exposure was receipt of seasonal IIV during pregnancy. The outcomes were diagnosis of an allergic or autoimmune disease, including asthma and anaphylaxis, identified from hospital and/or emergency department (ED) records. Inverse probability of treatment weights (IPTWs) accounted for baseline probability of vaccination by maternal age, Aboriginal and/or Torres Strait Islander status, socioeconomic status, body mass index, parity, medical conditions, pregnancy complications, prenatal smoking, and prenatal care. The models additionally adjusted for the Aboriginal and/or Torres Strait Islander status of the child. There were 14,396 (11.5%) maternally vaccinated children; 913 (6.3%) maternally vaccinated and 7,655 (6.9%) maternally unvaccinated children had a diagnosis of allergic or autoimmune disease, respectively. Overall, maternal influenza vaccination was not associated with diagnosis of an allergic or autoimmune disease (adjusted hazard ratio [aHR], 1.02; 95% confidence interval [CI], 0.95 to 1.09). In trimester-specific analyses, we identified a negative association between third trimester influenza vaccination and the diagnosis of asthma (n = 40; aHR, 0.70; 95% CI, 0.50 to 0.97) and anaphylaxis (n = 36; aHR, 0.67; 95% CI, 0.47 to 0.95).We did not capture outcomes diagnosed in a primary care setting; therefore, our findings are only generalizable to more severe events requiring hospitalization or presentation to the ED. Due to small cell sizes (i.e., <5), estimates could not be determined for all outcomes after stratification. CONCLUSIONS: In this study, we observed no association between in utero exposure to influenza vaccine and diagnosis of allergic or autoimmune diseases. Although we identified a negative association of asthma and anaphylaxis diagnosis when seasonal IIV was administered later in pregnancy, additional studies are needed to confirm this. Overall, our findings support the safety of seasonal inactivated influenza vaccine during pregnancy in relation to allergic and autoimmune diseases in early childhood and support the continuation of current global maternal vaccine programs and policies.

Association between vaccination status, symptom identification and healthcare use: Implications for test negative design observational studies.

AIM: To test the internal validity of the test-negative design (TND) by investigating associations between maternal influenza vaccination, and new virus detection episodes (VDEs), acute respiratory illness, and healthcare visits in their children. METHODS: Eighty-five children from a birth cohort provided daily symptoms, weekly nasal swabs, and healthcare use data until age 2-years. Effect estimates are summarised as incidence rate ratios (IRR). RESULTS: There was no association between maternal vaccination and VDEs in children (IRR = 1.1; 95 %CI = 0.9-1.2). Influenza-vaccinated mothers were more likely than unvaccinated mothers to both report, and seek healthcare for, acute lower respiratory illness in their children, IRR = 2.4; 95 %CI = 1.2-4.8 and IRR = 2.2; 95 %CI = 1.1-4.3, respectively. CONCLUSION: A key assumption of the TND, that healthcare seeking behaviour for conditions of the same severity is not associated with vaccine receipt, did not hold. Further studies of the performance of the TND in different populations are required to confirm its validity.

Potentially Pathogenic Organisms in Stools and Their Association With Acute Diarrheal Illness in Children Aged <2 Years.

BACKGROUND: Acute diarrheal illness (ADI) causes a substantial disease burden in high-income countries. We investigated associations between potentially pathogenic organisms in stools and ADI by polymerase chain reaction (PCR) in Australian children aged <2 years. METHODS: Children in a community-based birth cohort had gastrointestinal symptoms recorded daily and stool samples collected weekly until their second birthday. Diarrhea was defined as ≥3 liquid or looser than normal stools within a 24-hour period. PCR assays tested for 11 viruses, 5 bacteria, and 4 protozoa. Detections of a new organism or of the same following at least 2 negative tests were linked to ADIs, and incidence rates and estimates of association with ADI were calculated. RESULTS: One hundred fifty-four children provided 11 111 stool samples during 240 child-years of observation, and 228 ADIs were linked to samples. Overall, 6105 (55%) samples tested positive for a target organism. The incidence rate of 2967 new detections was 11.9 (95% confidence interval 11.4-12.3) per child-year, with 2561 (92%) new detections unrelated to an ADI. The relative risk of an ADI was 1.5-6.4 times greater for new detections of adenovirus, enterovirus, norovirus GII, parechovirus A, wild-type rotavirus, sapovirus GI/II/IV/V, Salmonella, Blastocystis, and Cryptosporidium, compared to when these were absent. CONCLUSIONS: Wild-type rotavirus, norovirus GII, sapovirus GI/II/IV/V, adenovirus 40/41, and Salmonella were associated with ADI in this age group and setting. However, high levels of asymptomatic shedding of potential pathogens in stools from children may contribute to diagnostic confusion when children present with an episode of ADI.

Longitudinal, population-based cohort study of prenatal influenza vaccination and influenza infection in childhood.

BACKGROUND: Influenza vaccination is recommended to protect mothers and their infants from influenza infection. Few studies have evaluated the health impacts of in utero exposure to influenza vaccine among children more than six months of age. METHODS: We used probabilistically linked administrative health records to establish a mother-child cohort to evaluate the risk of influenza and acute respiratory infections associated with maternal influenza vaccination. Outcomes were laboratory-confirmed influenza (LCI) and hospitalization for influenza or acute respiratory infection (ARI). Adjusted hazard ratios (aHRs) accounted for child's Aboriginal status and were weighted by the inverse-probability of treatment. RESULTS: 14,396 (11.5%) children were born to vaccinated mothers. Maternally vaccinated infants aged < 6 months had lower risk of LCI (aHR: 0.33; 95% CI: 0.13, 0.85), influenza-associated hospitalization (aHR: 0.39; 95% CI: 0.16, 0.94) and ARI-associated hospitalization (aHR: 0.85; 95% CI: 0.77, 0.94) compared to maternally unvaccinated infants. With the exception of an increased risk of LCI among children aged 6 months to < 2 years old following first trimester vaccination (aHR: 2.28; 95% CI: 1.41, 3.69), there were no other differences in the risk of LCI, influenza-associated hospitalization or ARI-associated hospitalization among children aged > 6 months. CONCLUSION: Study results show that maternal influenza vaccination is effective in preventing influenza in the first six months and had no impact on respiratory infections after two years of age.

Parainfluenza Virus Infection in an Australian Community-based Birth Cohort.

In a community-based birth cohort of 158 Australian infants followed to age 2 years, the incidence rate of human parainfluenza virus (HPIV) was 0.42 (95% CI = 0.33, 0.54) episodes per child-year with episodes occurring year-round, peaking in the spring season. HPIV-3 was the dominant subtype. Overall, 41% of detections were asymptomatic; only 32% of HPIV episodes led to healthcare contact with 1 hospitalization.

Early Childhood Health Outcomes Following In Utero Exposure to Influenza Vaccines: A Systematic Review.

CONTEXT: Vaccination during pregnancy is an effective strategy for preventing infant disease; however, little is known about early childhood health after maternal vaccination. OBJECTIVES: To systematically review the literature on early childhood health associated with exposure to influenza vaccines in utero. DATA SOURCES: We searched CINAHL Plus, Embase, Medline, Scopus, and Web of Science for relevant articles published from inception to July 24, 2019. STUDY SELECTION: We included studies published in English reporting original data with measurement of in utero exposure to influenza vaccines and health outcomes among children <5 years of age. DATA EXTRACTION: Two authors independently assessed eligibility and extracted data on study design, setting, population, vaccines, outcomes, and results. RESULTS: The search yielded 3647 records, of which 9 studies met the inclusion criteria. Studies examined infectious, atopic, autoimmune, and neurodevelopmental outcomes, and all-cause morbidity and mortality. Authors of 2 studies reported an inverse association between pandemic influenza vaccination and upper respiratory tract infections, gastrointestinal infections, and all-cause hospitalizations; and authors of 2 studies reported modest increased association between several childhood disorders and pandemic or seasonal influenza vaccination, which, after adjusting for confounding and multiple comparisons, were not statistically significant. LIMITATIONS: Given the small number of studies addressing similarly defined outcomes, meta-analyses were deemed not possible. CONCLUSIONS: Results from the few studies in which researchers have examined outcomes in children older than 6 months of age did not identify an association between exposure to influenza vaccines in utero and adverse childhood health outcomes.

'Links2HealthierBubs' cohort study: protocol for a record linkage study on the safety, uptake and effectiveness of influenza and pertussis vaccines among pregnant Australian women.

INTRODUCTION: Pregnant women and infants are at risk of severe influenza and pertussis infection. Inactivated influenza vaccine (IIV) and diphtheria-tetanus-acellular pertussis vaccine (dTpa) are recommended during pregnancy to protect both mothers and infants. In Australia, uptake is not routinely monitored but coverage appears sub-optimal. Evidence on the safety of combined antenatal IIV and dTpa is fragmented or deficient, and there remain knowledge gaps of population-level vaccine effectiveness. We aim to establish a large, population-based, multi-jurisdictional cohort of mother-infant pairs to measure the uptake, safety and effectiveness of antenatal IIV and dTpa vaccines in three Australian jurisdictions. This is a first step toward assessing the impact of antenatal vaccination programmes in Australia, which can then inform government policy with respect to future strategies in national vaccination programmes. METHODS AND ANALYSIS: 'Links2HealthierBubs' is an observational, population-based, retrospective cohort study established through probabilistic record linkage of administrative health data. The cohort includes births between 2012 and 2017 (~607 605 mother-infant pairs) in jurisdictions with population-level antenatal vaccination and health outcome data (Western Australia, Queensland and the Northern Territory). Perinatal data will be the reference frame to identify the cohort. Jurisdictional vaccination registers will identify antenatal vaccination status and the gestational timing of vaccination. Information on maternal, fetal and child health outcomes will be obtained from hospitalisation and emergency department records, notifiable diseases databases, developmental anomalies databases, birth and mortality registers. ETHICS AND DISSEMINATION: Ethical approval was obtained from the Western Australian Department of Health, Curtin University, the Menzies School of Health Research, the Royal Brisbane and Women's Hospital, and the West Australian Aboriginal Health Ethics Committees. Research findings will be disseminated in peer-reviewed journals, at scientific meetings, and may be incorporated into communication materials for public health agencies and the public.

Nasal swab bacteriology by PCR during the first 24-months of life: A prospective birth cohort study.

BACKGROUND: Most respiratory bacterial carriage studies in children are based on cross-sectional samples or longitudinal studies with infrequent sampling points. The prospective Observational Research in Childhood Infectious Diseases birth cohort study intensively evaluated the community-based epidemiology of respiratory viruses and bacteria during the first 2-years of life. Here we report the bacteriologic findings. METHODS: Pregnant women in Brisbane, Australia were recruited between September 2010 and October 2012, and their healthy newborn children were followed for the first 2-years of life. Parents kept a daily symptom diary for the study child, collected a weekly anterior nose swab and completed an illness burden diary when their child met pre-defined illness criteria. Specimens were tested for respiratory bacteria by real-time polymerase chain reaction (PCR) assays and those containing human genomic DNA, deemed as high-quality, were analyzed. RESULTS: Altogether 8100 high-quality nasal swab specimens from 158 enrolled children were analyzed. Streptococcus pneumoniae, Moraxella catarrhalis, and Haemophilus influenzae were detected in 42.4%, 38.9%, and 14.8% of these samples, respectively. Concomitant detection of bacteria was common. In contrast, Bordetella pertussis, B. parapertussis, Mycoplasma pneumoniae, Chlamydia pneumoniae, and Simkania negevensis were rarely identified. The prevalence of the three major bacteria was higher with increasing age and in the winter and spring months. Siblings and childcare attendance were the other risk factors identified. CONCLUSIONS: We confirmed the feasibility of frequent nasal swabbing by parents for studying bacterial colonization. PCR detected the major respiratory tract bacteria with expected high frequencies, but atypical bacteria were found rarely in this cohort.

Viruses causing lower respiratory symptoms in young children: findings from the ORChID birth cohort.

INTRODUCTION: Viral acute respiratory infections (ARIs) cause substantial child morbidity. Sensitive molecular-based assays aid virus detection, but the clinical significance of positive tests remains uncertain as some viruses may be found in both acutely ill and healthy children. We describe disease-pathogen associations of respiratory viruses and quantify virus-specific attributable risk of ARIs in healthy children during the first 2 years of life. METHODS: One hundred fifty-eight term newborn babies in Brisbane, Australia, were recruited progressively into a longitudinal, community-based, birth cohort study conducted between September 2010 and October 2014. A daily tick-box diary captured predefined respiratory symptoms from birth until their second birthday. Weekly parent-collected nasal swabs were batch-tested for 17 respiratory viruses by PCR assays, allowing calculation of virus-specific attributable fractions in the exposed (AFE) to determine the proportion of virus-positive children whose ARI symptoms could be attributed to that particular virus. RESULTS: Of 8100 nasal swabs analysed, 2646 (32.7%) were virus-positive (275 virus codetections, 3.4%), with human rhinoviruses accounting for 2058/2646 (77.8%) positive swabs. Viruses were detected in 1154/1530 (75.4%) ARI episodes and in 984/4308 (22.8%) swabs from asymptomatic periods. Respiratory syncytial virus (AFE: 68% (95% CI 45% to 82%)) and human metapneumovirus (AFE: 69% (95% CI 43% to 83%)) were strongly associated with higher risk of lower respiratory symptoms. DISCUSSION: The strong association of respiratory syncytial virus and human metapneumovirus with ARIs and lower respiratory symptoms in young children managed within the community indicates successful development of vaccines against these two viruses should provide substantial health benefits.

Timing of First Respiratory Virus Detections in Infants: A Community-Based Birth Cohort Study.

Background: Determining timing of first virus detection episodes (fVDEs) for different respiratory viruses in infants identifies risk periods and informs preventive interventions, including vaccination. We describe the ages and nature of fVDEs in an infant birth cohort and explore factors associated with increased odds of symptomatic fVDEs. Methods: The Observational Research in Childhood Infectious Diseases (ORChID) study is a community-based birth cohort describing acute respiratory infections in infants until their second birthday. Parents recorded daily symptoms and collected nose swabs weekly, which were batch-tested using polymerase chain reaction assays for 17 respiratory viruses. Results: One hundred fifty-eight infants participated in ORChID. The median age for fVDEs was 2.9 months for human rhinovirus (HRV) but was ≥13.9 months for other respiratory viruses. Overall, 52% of HRV fVDEs were symptomatic, compared with 57%-83% of other fVDEs. Respiratory syncytial virus and human metapneumovirus fVDEs were more severe than HRV fVDEs. Older age and the winter season were associated with symptomatic episodes. Conclusions: Infants do not always experience respiratory symptoms with their fVDE. Predominance of early HRV detections highlights the need for timing any intervention early in life. fVDEs from other respiratory viruses most commonly occur when maternal vaccines may no longer provide protection.