Chronic Disease and Immunosuppression Increase the Risk for Nonvaccine Serotype Pneumococcal Disease: A Nationwide Population-based Study.

BACKGROUND: Demography is changing, with people living longer with comorbidities. In this nationwide population-based study, we investigated the serotype-specific invasive pneumococcal disease (IPD) risk in individuals with comorbidities, and effects of the pneumococcal conjugated vaccine (PCV) child immunization program. METHODS: Cases included 14 096 IPD episodes in Sweden during 2006-2015. Controls (n = 137 289), matched to cases by age, sex, region, and calendar time, were selected from the general population. Comorbidity data was obtained through health registers and grouped as immunocompromising (IC) or chronic medical conditions (CMC). RESULTS: The prevalence of CMC and IC among elderly cases was 33.9% and 39.4%. New risks identified for IPD were sarcoidosis, inflammatory polyarthropathies, systemic connective tissue, and neurological diseases. The odds ratio (OR) for IPD caused by non-PCV13 compared with PCV13 serotypes was higher in individuals with CMC/IC. Serotypes associated with the highest risk were 16F, 15C, 35F, 19F, and 23A (OR 3-5 for CMC, >10 for IC). Most comorbidities increased post-vaccination, and absolute increases of IPD caused by non-PCV13, PPV23-non-PCV13, and non-PCV13/non-PPV23 serotypes were higher in individuals with IC/CMC compared with healthy persons. Non-PCV13 serotypes 6C, 9N, 11A, 22F, 23A and 35F increased more in those with comorbidities. Mortality due to non-PCV13 serotypes increased in individuals with IC/CMC, while remaining stable in persons without comorbidities. CONCLUSIONS: The PCV child immunization program associates with an increased disease burden of non-vaccine serotypes in individuals with comorbidities. These data are important for vaccine design and optimization of current vaccination strategies.

Cost-effectiveness of pneumococcal vaccination for elderly in Sweden.

INTRODUCTION: The aim was to assess cost-effectiveness of including pneumococcal vaccination for elderly in a national vaccination programme in Sweden, comparing health-effects and costs of pneumococcal related diseases with a vaccination programme versus no vaccination. METHOD: We used a single-cohort deterministic decision-tree model to simulate the current burden of pneumococcal disease in Sweden. The model accounted for invasive pneumococcal disease (IPD) and pneumonia caused by pneumococci. Costs included in the analysis were those incurred when treating pneumococcal disease, and acquisition and administration of the vaccine. Health effects were measured as quality-adjusted life years (QALY). The time-horizon was set to five years, both effects and costs were discounted by 3% annually. Health-effects and costs were accumulated over the time-horizon and used to create an incremental cost-effectiveness ratio. The 23-valent polysaccharide vaccine (PPV23) was used in the base-case analysis. The 13-valent pneumococcal conjugate vaccine PCV13 was included in sensitivity analyses. RESULTS: A vaccination programme using PPV23 would reduce the burden of pneumococcal related disease significantly, both when vaccinating a 65-year-old cohort and a 75-year-old cohort. IPD would decrease by 30% in the 65-year-old cohort, and by 29% in the 75-year-old cohort. The corresponding figures for CAP (communicable acquired pneumonia) are 19% and 15%. The cost per gained QALY was estimated to EUR 94,000 for vaccinating 65-year-olds and EUR 29,500 for 75-year-olds. With one dose PCV13 given instead of PPV23, the cost per gained QALY would increase by around 400% for both cohorts. The results were robust in sensitivity analyses. CONCLUSION: Introducing a vaccination programme against pneumococcal disease for 65-year-olds in Sweden is unlikely to be cost-effective, whereas it for 75 year-olds and using PPV23 can be considered good value for money. Our model indicates that vaccine price needs to be reduced by 55% for vaccination of 65-year-olds to be cost-effective, given a threshold of EUR 50,000.

Epidemiology and control of meticillin-resistant Staphylococcus aureus in Stockholm County, Sweden, 2000 to 2016: overview of a "search-and-contain" strategy.

To review the epidemiology and measures to control meticillin-resistant Staphylococcus aureus, MRSA, in Stockholm between 2000 and 2016 from the perspective of the Department of Communicable Disease Control and Prevention, Stockholm County Council, Sweden. Age, sex, and place of acquisition of their MRSA on all patients reported to the department were reviewed. Measures for control included surveillance through mandatory reporting of cases, screening patients with risk factors for MRSA, strict adherence to basic nursing hygienic principles, isolation of MRSA positive patients in single rooms in dedicated MRSA wards, and cohorting of staff. An MRSA team was created at the Department of Infectious Diseases, Karolinska University Hospital, for follow-up of all cases. Several administrative meetings and cooperative groups were formed that are still in function. From 2000 to 2016, there were 7373 MRSA cases reported. Healthcare-associated MRSA, HA-MRSA, was successfully controlled, and from 2006 onwards, very limited HA-MRSA transmission or outbreaks occurred. However, incidence increased overall, from 9.5 per 100,000 in 2000 to 37.3 per 100,000 in 2016, due to increase of MRSA acquired abroad and of MRSA acquired in the Swedish community. Surveillance and control measures have been successful in containing HA-MRSA in Stockholm, Sweden, but incidence has increased substantially due to imported cases and spread in the Swedish community. The strategy may be termed "search-and-contain" since screening, infection control, follow-up, and advice on personal hygiene were cornerstones of control, whereas eradication of carriage was not.

Clinical presentation of intussusception in Swedish children under 3 years of age and the validity of diagnostic coding.

PURPOSE: Intussusception has been associated with rotavirus vaccine. The rotavirus vaccine will soon be introduced in the Swedish national immunization program. A validation of the diagnosis of intussusception among Swedish children in the Swedish National Patient Register is needed, as a basis for future vaccine safety surveillance by Swedish registers. METHODS: This diagnostic study reviewed the medical admission records of 392 Swedish children with intussusception from 1987 to 2013. The records were randomly selected by The National Board of Health and Welfare from all Sweden and from both pediatric and pediatric surgery care. Positive predictive values (PPV) were calculated to study the concordance between the diagnosis coded in the Swedish Patient Register and the accepted international criteria of case definitions. RESULTS: The PPV for a definitive diagnosis, based on certain radiology findings or surgery, was 84%. When clinically probable cases were added the PPV was 87%. When cases of possible intussusception were added the PPV was 89%. The PPV for the 240 children under 1 year was 88%. CONCLUSION: Swedish health care registers can be used in the evaluation of incidences of intussusception when rotavirus vaccine will be introduced, due to a high validity of the diagnosis of intussusception in the registers.

Impact of repeated influenza vaccinations in persons over 65 years of age: A large population-based cohort study of severe influenza over six consecutive seasons, 2011/12-2016/17.

BACKGROUND: A forty-year debate on the potential negative effects of repeated seasonal influenza vaccination has been inconclusive, with multiple observational studies of various design providing heterogeneous results too inadequate to inform vaccination policy. METHODS: A large population-based cohort study including over one-million observations in individuals over age 65 from six consecutive seasons (2011/12-2016/17) in Stockholm County, Sweden. Current season vaccine effectiveness (VE) against severe, mostly hospital-attended, influenza was assessed using Cox multivariate regression analyses adjusting for demographic variables, comorbidities and previous seasonal influenza vaccination status. RESULTS: In none of the six seasons was VE significantly different in persons vaccinated in the current season only, compared to those who had been vaccinated in both the current and the previous season. Neither were there any differences in VE during the seasons 2014/15-2016/17 when comparing persons vaccinated during the current season only vs. those vaccinated during one-three or four-five previous influenza seasons. In contrast, persons only vaccinated during one or more previous years had no protection during the current season. CONCLUSIONS: Persons above 65 years are the largest group at risk for severe or complicated influenza and policy should support their yearly seasonal influenza vaccination, which is to-date the best preventive measure available for all risk groups. No negative effects of repeated seasonal vaccination were seen in this large population-based cohort of older persons with severe influenza, which strengthens the recommendation that persons belonging to this age group should be vaccinated yearly.

Experiences and consequences of living with extended-spectrum ß-lactamase-producing bacteria: A qualitative study.

BACKGROUND: The number of people who become carriers of antibiotic-resistant extended-spectrum ß-lactamase (ESBL)-producing bacteria is steadily increasing. A carrier of ESBL can potentially be stressful for individuals, affecting their daily lives. METHODS: The purpose of this study was to increase the understanding of experiences and consequences of being an ESBL carrier. A modified version of the grounded theory was used to analyze 16 open interviews. RESULTS: The analysis resulted in the core category "to handle the new life situation." The results showed a lack of information being passed by attending doctors to study participants about ESBL and the consequences for their daily lives. This insufficient information initially caused fear and anxiety, leading to participants instead searching for information themselves using the Internet. Armed with this information, they developed strategies to continue with their lives as before. As patients they experienced staff that were respectful, showed no stigmatization toward ESBL carriership, and used correct hygiene routines. CONCLUSIONS: When the information from the attending doctor about ESBL carriers is insufficient, patients often use the Internet to obtain additional information. With the use of this information, patients develop strategies to cope with their lives.

Parental conceptions of the rotavirus vaccine during implementation in Stockholm: A phenomenographic study.

In 2014, Stockholm became the first Swedish county to introduce the rotavirus vaccine, which is given from as early as six weeks of age. The aim of this study was to describe parental conceptions of rotavirus infection and vaccination during its implementation as part of the child immunization program, as their support is vital for any new vaccine. The study followed a descriptive, qualitative design with a phenomenographic approach. Ten in-depth interviews with parents were conducted in Stockholm County, transcribed and analyzed to describe qualitatively different conceptions of rotavirus infection and vaccination. Four main categories were identified: to vaccinate without doubt, hesitant to vaccinate, risky to vaccinate, and unnecessary to vaccinate. All the parents had in common the desire to protect their children from suffering, either by vaccinating their child in order to avoid rotavirus infection or by not vaccinating their child because of concerns about the side effects. It is important that child health-care professionals understand the variations of conceptions that influence the parents' decisions and that these conceptions may differ considerably. Individualized parental information about rotavirus infection and vaccination would help to achieve a successful implementation of the vaccination program.

Comparison of the Impact of Pneumococcal Conjugate Vaccine 10 or Pneumococcal Conjugate Vaccine 13 on Invasive Pneumococcal Disease in Equivalent Populations.

Background: Pneumococcal conjugate vaccine 10 (PCV10) and pneumococcal conjugate vaccine 13 (PCV13), are used in childhood immunization programs worldwide, but direct comparisons of impacts against invasive pneumococcal disease (IPD) in equivalent populations have not been performed. We compared the vaccines (prevaccination 2007-2009 vs postvaccination 2013-2016) in Sweden, where the 21 counties use either PCV10 or PCV13 (introduced 2009-2010). Methods: All IPD episodes (n = 16992) were recorded in Sweden during 2005-2016. Of 14 186 isolates from 2007-2016, 13 468 (94.9%) were characterized with serotyping and 12 235 (86.2%) with antibiotic susceptibility. Poisson models assessed changes in incidence over time. Results: Invasive pneumococcal disease incidences decreased between 2005 and 2016 in vaccinated children (by 68.5%), and in the whole population (by 13.5%), but not among the elderly (increased by 2%) due to a substantial increase in nonvaccine types (NVTs). In 2016, NVTs constituted 72% of IPD cases in the elderly. Serotype 6A declined in PCV10 and PCV13 counties, whereas serotype 19A increased in PCV10 counties. There was no effect against serotype 3. Cross-protection was found between 6B and 6A but not between 19F and 19A. Serotype 6C increased in PCV10 counties, but not in PCV13 counties, suggesting cross-protection with 6A, which is included in PCV13. In the elderly, the increase in NVTs, excluding 6C, was more pronounced in PCV13 counties. Conclusions: The overall impact of IPD incidences was not statistically different irrespective of vaccine used. The incidence of serotypes, where the effect of the vaccines differed, will influence the cost-effectiveness of which vaccine to use in immunization programs. The dominance of NVTs suggests a limited effect of current pediatric PCVs against IPD in the elderly.

Receiving early information and trusting Swedish child health centre nurses increased parents' willingness to vaccinate against rotavirus infections.

AIM: Rotavirus vaccines are effective against severe infections, but have a modest impact on mortality in high-income countries. Parental knowledge and attitudes towards vaccines are crucial for high vaccination coverage. This study aimed to identify why parents refused to let their infant have the vaccination or were unsure. METHODS: This cross-sectional study was based on 1,063 questionnaires completed by the parents of newborn children in 2014. Stepwise logistic regression was used to identify the main predictors. RESULTS: Most (81%) parents intended to vaccinate their child against the rotavirus, while 19% were unwilling or uncertain. Parents with less education and children up to five weeks of age were more likely to be unwilling or uncertain about vaccinating their child. Factors associated with a refusal or uncertainty about vaccinating were not having enough information about the vaccine, no intention of accepting other vaccines, paying little heed to the child health nurses' recommendations, thinking that the rotavirus was not a serious illness and not believing that the vaccine provided protection against serious forms of gastroenteritis. CONCLUSION: Early information, extra information for parents with less education and close positive relationships between parents and child health nurses were important factors in high rotavirus vaccination rates.

Mid-season real-time estimates of seasonal influenza vaccine effectiveness in persons 65 years and older in register-based surveillance, Stockholm County, Sweden, and Finland, January 2017.

Systems for register-based monitoring of vaccine effectiveness (VE) against laboratory-confirmed influenza (LCI) in real time were set up in Stockholm County, Sweden, and Finland, before start of the 2016/17 influenza season, using population-based cohort studies. Both in Stockholm and Finland, an early epidemic of influenza A(H3N2) peaked in week 52, 2016. Already during weeks 48 to 50, analyses of influenza VE in persons 65 years and above showed moderately good estimates of around 50%, then rapidly declined by week 2, 2017 to 28% and 32% in Stockholm and Finland, respectively. The sensitivity analyses, where time since vaccination was taken into account, could not demonstrate a clear decline, neither by calendar week nor by time since vaccination. Most (68%) of the samples collected from vaccinated patients belonged to the 3C.2a1 subclade with the additional amino acid substitution T135K in haemagglutinin (64%) or to subclade 3C.2a with the additional haemagglutinin substitutions T131K and R142K (36%). The proportion of samples containing these alterations increased during the studied period. These substitutions may be responsible for viral antigenic change and part of the observed VE drop. Another possible cause is poor vaccine immunogenicity in older persons. Improved influenza vaccines are needed, especially for the elderly.

Acquisition of extended spectrum ß-lactamases during travel abroad-A qualitative study among Swedish travellers examining their knowledge, risk assessment, and behaviour.

BACKGROUND: Travel to foreign countries involves the risk of becoming a carrier of antibiotic-resistant bacteria, especially when the destination is a country with a high prevalence of this type of bacteria. AIM AND METHODS: The aim of this study was to learn about the knowledge of antibiotic resistance, and the behaviour and risk-taking among travellers, who had become carriers of extended spectrum beta-lactamases (ESBL)-producing bacteria during travel to a high-prevalence country. A modified version of grounded theory was used to analyse 15 open interviews. RESULTS: The analysis resulted in a core category: A need for knowledge to avoid risk-taking. Before the journey, the participants did not perceive there to be any risk of becoming a carrier of antibiotic- resistant bacteria. The low level of knowledge of antibiotic-resistant bacteria and transmission routes influenced their behaviour and risk-taking during their journey, resulting in them exposing themselves to risk situations. After their trip, the majority did not believe that their personal risk behaviour could have caused them to become carriers of ESBL. CONCLUSION: The participants' lack of knowledge of antibiotic-resistant bacteria resulted in unconscious risk-taking during their journey, which may have resulted in becoming carriers of ESBL-producing bacteria.

Real-time real-world analysis of seasonal influenza vaccine effectiveness: method development and assessment of a population-based cohort in Stockholm County, Sweden, seasons 2011/12 to 2014/15.

Real-world estimates of seasonal influenza vaccine effectiveness (VE) are important for early detection of vaccine failure. We developed a method for evaluating real-time in-season vaccine effectiveness (IVE) and overall seasonal VE. In a retrospective, register-based, cohort study including all two million individuals in Stockholm County, Sweden, during the influenza seasons from 2011/12 to 2014/15, vaccination status was obtained from Stockholm's vaccine register. Main outcomes were hospitalisation or primary care visits for influenza (International Classification of Disease (ICD)-10 codes J09-J11). VE was assessed using Cox multivariate stratified and non-stratified analyses adjusting for age, sex, socioeconomic status, comorbidities and previous influenza vaccinations. Stratified analyses showed moderate VE in prevention of influenza hospitalisations among chronically ill adults ≥ 65 years in two of four seasons, and lower but still significant VE in one season; 53% (95% confidence interval (CI): 33-67) in 2012/13, 55% (95% CI: 25-73) in 2013/14 and 18% (95% CI: 3-31) in 2014/15. In conclusion, seasonal influenza vaccination was associated with substantial reductions in influenza-specific hospitalisation, particularly in adults ≥ 65 years with underlying chronic conditions. With the use of population-based patient register data on influenza-specific outcomes it will be possible to obtain real-time estimates of seasonal influenza VE.

Risk for Congenital Malformation With H1N1 Influenza Vaccine: A Cohort Study With Sibling Analysis.

BACKGROUND: Earlier studies reporting varying risk estimates for congenital malformation in offspring of mothers undergoing vaccination against H1N1 influenza during pregnancy did not consider the potential role of confounding by familial (genetic and shared environmental) factors. OBJECTIVE: To evaluate an association between maternal H1N1 vaccination during pregnancy and offspring malformation, with familial factors taken into account. DESIGN: Population-based prospective study. SETTING: Sweden. PARTICIPANTS: Liveborn offspring born between 1 October 2009 and 1 October 2011 to mothers receiving monovalent AS03-adjuvanted H1N1 influenza vaccine (Pandemrix [GlaxoSmithKline]) during pregnancy. A total of 40 983 offspring were prenatally exposed to the vaccine, 14 385 were exposed within the first trimester (14 weeks), and 7502 were exposed during the first 8 weeks of pregnancy. Exposed offspring were compared with 197 588 unexposed offspring. Corresponding risks in exposed versus unexposed siblings were also estimated. MEASUREMENTS: Congenital malformation, with subanalyses for congenital heart disease, oral cleft, and limb deficiency. RESULTS: Congenital malformation was observed in 2037 (4.97%) exposed offspring and 9443 (4.78%) unexposed offspring. Adjusted risk for congenital malformation was 4.98% in exposed offspring versus 4.96% in unexposed offspring (risk difference, 0.02% [95% CI, -0.26% to 0.30%]). The corresponding risk differences were 0.16% (CI, -0.23% to 0.56%) for vaccination during the first trimester and 0.10% (CI, -0.41% to 0.62%) for vaccination in the first 8 weeks. Using siblings as comparators yielded no statistically significant risk differences. LIMITATIONS: The study was based on live births, and the possibility that data on miscarriage or induced abortion could have influenced the findings cannot be ruled out. Study power was limited in analyses of specific malformations. CONCLUSION: When intrafamilial factors were taken into consideration, H1N1 vaccination during pregnancy did not seem to be linked to overall congenital malformation in offspring, although risk increases for specific malformations could not be ruled out completely. PRIMARY FUNDING SOURCE: Swedish Research Council and Swedish Council for Working Life and Social Research.

Unaltered pneumococcal carriage prevalence due to expansion of non-vaccine types of low invasive potential 8years after vaccine introduction in Stockholm, Sweden.

OBJECTIVE: To evaluate the carriage prevalence, serotype distribution, and antibiotic resistance for pneumococcal carriage isolates collected 4-8years after introduction of pneumococcal conjugate vaccines (PCVs) in Stockholm, Sweden, and to identify risk factors for carriage and calculate the invasive disease potential for emerging serotypes. METHODS: Nasopharyngeal aspirates were collected from 3024 children aged 0-<5years at regular visits at 23 Child Health Centers in Stockholm County in 2011-2015, and from 787 parents in 2014-2015. The invasive disease potential was calculated for serotypes using invasive disease isolates from 824 patients of all ages identified in the Stockholm County during the same time period as the carriage isolates. RESULTS: A total carriage prevalence of 30% did not change during the study period. Non-vaccine types (NVT) dominated (94% by 2015) and the most common serotypes in descending order were 11A, 23B, 35F and 21. Risk factors for carriage were: age ⩾3months-<3years, having siblings, attending day-care and having travelled abroad the last 3months. Antibiotic resistance remained low. The invasive disease potential was high for NVT 8, 9N, 12F, and 22F, while low for a majority of emerging NVTs in carriage. CONCLUSION: The carriage prevalence remained the same 4-8years after vaccine introduction, but serotype replacement became almost complete. A majority of emerging NVTs in carriage showed a low invasive disease potential. Carriage studies are an important complement to invasive disease surveillance to understand the full effect of PCV vaccine programs.

Influenza epidemiology among hospitalized children in Stockholm, Sweden 1998-2014.

BACKGROUND: Influenza remains a common reason for the hospitalization of children. There is a need for long term studies that are also population based. We describe the epidemiology of severe influenza in a defined population 1998-2014. METHOD: Retrospective study of annually collected data of virologically confirmed influenza in hospitalized children 0-17 years living in the catchment area (230,000 children). We gathered information about comorbidity and complications from case records, and compared Influenza A, B and A(H1N1)pdm09 with respect to these factors. RESULTS: A total of 922 children with influenza were hospitalized. The mean rate remained unchanged at 22.5-24.2 per 100,000 children per year. There were two major outbreaks: influenza A(H3N2) in 2003-2004 and the A(H1N1) pandemic in 2009-2010. The proportion of children with influenza B increased from 8% during the first half of the study period to 28% during the second half. The highest admission rate was found in children <3 months of age, 169 per 100,000. Children with influenza B were older than those with influenza A. Comorbidity was found in 34%, complications in 41%, and 11% needed intensive care management. The mortality rate was 0.17/100,000 children. CONCLUSION: Influenza remains an important reason for the hospitalization of children, especially during the first years of life. The increasing proportion of influenza B may have to be considered when recommending influenza vaccines.

Effects of PCV7 and PCV13 on invasive pneumococcal disease and carriage in Stockholm, Sweden.

The effects of pneumococcal conjugated vaccines (PCVs) need to be investigated. In Stockholm County, Sweden, PCV7 was introduced in the childhood immunisation programme in 2007 and changed to PCV13 in 2010.Over 90% of all invasive isolates during 2005-2014 (n=2336) and carriage isolates, 260 before and 647 after vaccine introduction, were characterised by serotyping, molecular typing and antibiotic susceptibility, and serotype diversity was calculated. Clinical information was collected for children and adults with invasive pneumococcal disease (IPD).The IPD incidence decreased post-PCV7, but not post-PCV13, in vaccinated children. Beneficial herd effects were seen in older children and adults, but not in the elderly. The herd protection was more pronounced post-PCV7 than post-PCV13. PCV7 serotypes decreased. IPD caused by PCV13 serotypes 3 and 19A increased post-PCV7. Post-PCV13, serotypes 6A and 19A, but not serotype 3, decreased. The serotype distribution changed in carriage and IPD to nonvaccine types, also in nonvaccinated populations. Expansion of non-PCV13 serotypes was largest following PCV13 introduction. Serotype diversity increased and nonvaccine clones emerged, such as CC433 (serotype 22F) in IPD and CC62 (serotype 11A) in carriage. In young children, meningitis, septicaemia and severe rhinosinusitis, but not bacteraemic pneumonia, decreased.Pneumococcal vaccination leads to expansion of new or minor serotypes/clones, also in nonvaccinated populations.

Maternal vaccination against H1N1 influenza and offspring mortality: population based cohort study and sibling design.

STUDY QUESTION: What is the mortality in offspring of mothers who had influenza A(H1N1)pdm09 vaccination during pregnancy? METHODS: This was a prospective population based cohort study in seven healthcare regions in Sweden based on vaccinations taking place between 2 October 2009 and 26 November 2010. H1N1 vaccination data were linked with pregnancy and birth characteristics and offspring mortality data in 275,500 births (of which 1203 were stillbirths) from 137,886 mothers. Of these offspring, 41,183 had been exposed to vaccination with Pandemrix, a monovalent AS03 adjuvanted H1N1 influenza vaccine, during fetal life. A primary comparison group consisted of pregnancies of women who were not vaccinated during the same calendar period. In a second comparison, non-exposed siblings of infants prenatally exposed to vaccination were used as controls. Cox regression was used to estimate hazard ratios for stillbirth, early neonatal mortality (days 0-6 after birth), and subsequent mortality (beginning on day 7) in vaccinated versus non-vaccinated women, adjusting for mother's age at delivery, body mass index, parity, smoking, country of birth, and disposable income and for sex of offspring. STUDY ANSWER AND LIMITATIONS: The results of this study suggest that AS03 adjuvanted H1N1 vaccination during pregnancy does not affect the risk of stillbirth, early neonatal death, or later mortality in the offspring. During follow-up, 1172 stillbirths, 380 early neonatal deaths, and 706 deaths thereafter occurred. Compared with general population controls, this corresponded to adjusted hazard ratios of 0.83 (95% confidence interval 0.65 to 1.04) for stillbirth, 0.71 (0.44 to 1.14) for early neonatal death, and 0.97 (0.69 to 1.36) for later death. When siblings were used as controls, adjusted hazard ratios were 0.88 (0.59 to 1.30) for stillbirth, 0.82 (0.46 to 1.49) for early neonatal death, and 0.78 (0.52 to 1.19) for later death. Limitations of the study include lack of data on miscarriage before gestational week 22, inability to ascertain which mothers had pandemic flu during pregnancy, and lack of data on factors influencing the decision to vaccinate during pregnancy. WHAT THIS STUDY ADDS: H1N1 vaccination during pregnancy is not associated with adverse fetal outcome or offspring mortality, including when familial factors are taken into account. FUNDING, COMPETING INTERESTS, DATA SHARING: This project was supported by grants from the Swedish Research Council and the Swedish Council for Working Life and Social Research. NF was employed at the Swedish Medical Product Agency at the time of the study.