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Maternal vaccination against H1N1 influenza and offspring mortality

AbstractStudy 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 275500 births (of which 1203 were stillbirths) from 137886 mothers. Of these offspring, 41183 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 replica van cleef and arpels necklace 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.IntroductionThe World Health Organization declared influenza A(H1N1)pdm09 to be a pandemic influenza in mid 2009.1 2 3 Several pandemic vaccines were produced during this time; Sweden opted for the AS03 adjuvanted monovalent vaccine, Pandemrix (GlaxoSmithKline). This vaccine was offered free of charge to all Swedish residents.Given evidence that pregnant women were especially prone to severe influenza,3 4 vaccination was recommended at any stage of pregnancy. We and others have since examined pregnancy and fetal outcomes in mothers who were vaccinated against H1N1.4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 Most research suggests that H1N1 vaccination has few adverse effects on pregnancy outcomes. Some studies have even found an inverse relation between H1N1 vaccination and adverse pregnancy outcomes, potentially owing to treatment selection bias. Fell et al noted in their recent systematic review that risk estimates for adverse pregnancy outcomes often move closer to the null after adjustment for potential confounders such as education, income levels, smoking, parity, and comorbidity.25 However, no study has considered confounding by familial (that is, genetic and early environmental) factors.Despite the abundance of research on influenza A(H1N1)pdm09 vaccination and pregnancy outcomes, we are unaware of studies exploring mortality in offspring beyond the first week of life (sometimes also included with stillbirths in the joint outcome "perinatal death"17).The primary objective of this population based cohort study was to explore mortality in the offspring of mothers who received influenza A(H1N1)pdm09 vaccination. A secondary objective was to examine stillbirth, early neonatal death, and offspring mortality after taking familial factors into account. To do this we used a sibling design. This design is useful if vaccinated women differ systematically from women not opting for vaccination (for instance, through being more health aware, which would decrease the risk of complications or of having more comorbidities that would increase the risk of complications).MethodsWe linked individual data on influenza A(H1N1)pdm09 vaccinations (Pandemrix26) administered in 2009 10 to pregnant women with information on pregnancy and birth characteristics from the Swedish Medical Birth Register. We added offspring mortality data from the Swedish Cause of Death Register. As described in our study on risk of neurological and immune related diseases in vaccinated people,27 we obtained vaccination data from seven Swedish regions (the counties of Kalmar, stergtland, Stockholm, Vrmland, and Norrbotten plus the healthcare regions of Vstra Gtaland and Skne). These regions comprise around 61% of the Swedish population.27In Sweden, Pandemrix vaccinations were given free of charge from October 2009 through 2010. High risk groups (such as pregnant women) were actively encouraged to have vaccination and were prioritised for the early batches of the vaccine. Recording of vaccination was considered complete in four of the seven regions involved in this study.27 In these regions, registration of vaccinations was required for cost reimbursements. In the remaining three counties (Kalmar, Vrmland, and Norrbotten, representing about 13% of the study population), registration of vaccination was done through a web based system that required personal informed consent. Because of lack of consent (and thereby lack of the recorded personal identity number), classification of exposure (vaccination: yes/no) was not possible in 16 22% of vaccinated people in these counties. We classified these people as unexposed in the main analyses of the study but excluded them van cleef arpels necklace imitation in a subsequent sensitivity analysis.Through the county specific databases, we obtained data on personal identity number,28 as well as date of vaccination. Unlike children, some of whom received two vaccinations, pregnant women received no more than one vaccination. To safeguard the integrity of the study participants, personal identity numbers were replaced by unique serial identification numbers before data elaboration.ParticipantsWe originally retrieved data on 279999 births (includes siblings) between 24 April 1980 and 31 December 2012. We excluded 1232 without data in the Medical Birth Register, 3156 who did not fulfil inclusion criteria (dead or not in study counties before 30 September 2009, or inconsistent migration information), and 111 for other reasons. Thus, the final study sample included 275500 births (of which 1203 were stillbirths) to 137886 women. Table 1 shows characteristics of the participants.Table 1 Characteristics of study participants. Values are numbers (participants) unless stated otherwiseView this table:View popupView inlineFollow upIn the main analysis, we restricted the study participants (n=121979) to births after 30 September 2009. We followed these participants from 22 completed gestational weeks until death or censoring (emigration or end of follow up, which was 22 May 2014), with separate analysis for stillbirth, early neonatal death, and later death (that is, deaths from seven completed days to 4.6 years). For the sibling analysis, we used the whole cohort (279999); however, because comparisons were done within the family, only discordant siblings with at least one event within the family (n=3801, 1130, and 2190) contributed to the analyses of stillbirth, neonatal death, and death in the subsequent period.H1N1 vaccinationThe study exposure was vaccination against influenza A(H1N1)pdm09 (Pandemrix) at any stage of pregnancy. In all, 93156 women who gave birth during the study period were vaccinated with Pandemrix, of whom 44% were vaccinated during pregnancy (n=41183 offspring). Control pregnancies were those for which no record existed of influenza A(H1N1)pdm09 vaccination during pregnancy in a pregnant woman giving birth in any of the seven healthcare regions of this study. We also divided vaccinations according to trimester of pregnancy at the time of vaccination (1 13 weeks, 14 26 weeks, and 27 weeks until delivery).CovariatesData on covariates came primarily from the Medical Birth Register.29 This registry contains prenatal and neonatal data on more than 98% of all births in Sweden since 1973.29 During the first prenatal visit, commonly occurring at the end of the first trimester, pregnant women are interviewed and examined by a midwife.30 They are asked about current smoking habits (0, 1 9, and 10 cigarettes per day) and about medical, obstetric, and gynaecological history. Self reported information about women's height is recorded, and women are weighed. We calculated body mass index (as weight in kilograms/height in meters squared) and categorised it into four groups (31 Information about parity is collected at the time of delivery (1, 2, and 3). A small proportion of women had no data on body mass index (9.6%) or smoking (4.6%). Through the government agency Statistics Sweden, we obtained information on mothers' country of birth (categorised as born in Sweden or born outside Sweden) and disposable annual income (Sibling comparisonsSibling studies take familial factors into account when comparing exposed and unexposed participants. From the Medical Birth Register, we identified all siblings of infants prenatally exposed to the mothers' vaccinations during pregnancy. We were thus able to compare mortality between children with the same mother according to vaccination exposure. By comparing offspring of the same mother discordant for vaccination exposure, we by design adjusted for genetic and environmental factors shared by the siblings.Outcome measureOverall death was the main outcome measure and was examined on the basis of time of occurrence. We specifically studied death during pregnancy imitation van cleef gold necklace (stillbirth from 28 completed gestational weeks until 2008, and from 22 weeks in 2009 and onwards), newborn deaths during the first six days life (early neonatal death), and death thereafter (from seven completed days of life to 4.6 years).Patient involvementNo patients were involved in setting the research question or the outcome measures; nor were they involved in the design and implementation of the study. There are no plans to involve patients in the dissemination of results.StatisticsAll analyses were done in two ways. Firstly, we considered all pregnancies ending after 30 September 2009 (start of the vaccination period) as independent observations. Secondly, we used all pregnancies during which vaccination occurred, together with all other pregnancies of the same woman. We used this latter approach in the within family analyses by conditioning on the mother (stratified Cox).We used Cox regression to estimate hazard ratios for stillbirth, early neonatal mortality (days 0 6), and subsequent mortality (beginning on day 7) in vaccinated compared with non vaccinated women, with fetal/infant age as the study timescale, adjusting for mother's age at birth, body mass index, parity, smoking, country of birth, disposable income, and sex of offspring. We found no evidence of non proportional hazards. In addition, we specifically examined risks of stillbirth, early neonatal death, and offspring mortality according to trimester of vaccination.For the analysis of stillbirth, the exposure (vaccine during pregnancy or during the trimesters) was time dependent. We began follow up at 22 (or 28) gestational weeks. Thus, if the mother was vaccinated before the start of follow up, we considered the fetus to be exposed from the start; otherwise we considered the participant to be unexposed until the date of vaccination. All data presented in the results section represent adjusted estimates.We defined statistical significance as 95% confidence intervals for risk estimates not including 1.0. We used R statistical software (version 3.1.1) to analyse data.ResultsVaccinated mothers tended to be slightly older than non vaccinated mothers (table 1); 42.3% of vaccinated mothers and 48.4% of non vaccinated mothers were nulliparous. Vaccinated mothers were more often born in Sweden than non vaccinated mothers. The mean gestational ages at birth were 39.8 and 39.7 weeks in vaccinated and non vaccinated mothers. For the offspring mortality analysis, children were followed until a mean age of 4.1 years in the vaccinated cohort and 6.4 years in the non vaccinated cohort. Among the unexposed pregnancies in siblings (n=39314), 31496 (80.1%) took place before the pregnancy exposed to Pandemrix, and 7818 (19.9%) took place after the index pregnancy.During pregnancy, 1172 stillbirths, 380 deaths in the early neonatal period, and 706 deaths after the early neonatal period occurred (table 1). Compared with general population controls, offspring of vaccinated mothers were not at increased risk of stillbirth (adjusted hazard ratio 0.83, 95% confidence interval 0.65 to 1.04), early neonatal death (0.71, 0.44 to 1.14), or later death (0.97, 0.69 to 1.36). When we used siblings as controls, corresponding hazard ratios were 0.88 (0.59 to 1.30), 0.82 (0.46 to 1.49), and 0.78 (0.52 to 1.19) (table 2).Table 2 H1N1 vaccination during pregnancy and offspring mortality (stillbirth, early neonatal death, and later death)

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