Maternal vaccination against H1N1 influenza and offspring mortality: population based cohort study and sibling design Maternal immunisation with trivalent inactivated influenza vaccine for prevention of influenza in infants in Mali: a prospective, active-controlled, observer-blind, randomised phase 4 trial Influenza vaccination of pregnant women and protection of their infants. Low Rate of Pandemic A/H1N1 2009 Influenza Infection and Lack of Severe Complication of Vaccination in Pregnant Women: A Prospective Cohort Study Year-round influenza immunisation during pregnancy in Nepal: a phase 4, randomised, placebo-controlled trial. A/NJ/8/76 influenza vaccination program: effects on maternal health and pregnancy outcome. Risks and safety of pandemic H1N1 influenza vaccine in pregnancy: birth defects, spontaneous abortion, preterm delivery, and small for gestational age infants. A(H1N1)v2009: a controlled observational prospective cohort study on vaccine safety in pregnancy. Report of the WHO technical consultation on the effect of maternal influenza and influenza vaccination on the developing fetus: Montreal, Canada, September 30-October 1, 2015. Prospective Cohort Study of the Safety of an Influenza A(H1N1) Vaccine in Pregnant Chinese Women
Study question What is the mortality in offspring of mothers who had influenza A(H1N1)pdm09 vaccination during pregnancy ? Methods This was a prospect i ve 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 P and emrix , 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 p and emic 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 Summary Background Despite the heightened risk of serious influenza during infancy , vaccination is not recommended in infants younger than 6 months . We aim ed to assess the safety , immunogenicity , and efficacy of maternal immunisation with trivalent inactivated influenza vaccine for protection of infants against a first episode of laboratory-confirmed influenza . Methods We did this prospect i ve , active-controlled , observer-blind , r and omised phase 4 trial at six referral centres and community health centres in Bamako , Mali . Third-trimester pregnant women ( ≥28 weeks ' gestation ) were r and omly assigned ( 1:1 ) , via a computer-generated , centre-specific list with alternate block sizes of six or 12 , to receive either trivalent inactivated influenza vaccine or quadrivalent meningococcal vaccine . Study personnel administering vaccines were not masked to treatment allocation , but allocation was concealed from clinicians , laboratory personnel , and participants . Infants were visited weekly until age 6 months to detect influenza-like illness ; laboratory-confirmed influenza diagnosed with RT-PCR . We assessed two co primary objectives : vaccine efficacy against laboratory-confirmed influenza in infants born to women immunised any time prepartum ( intention-to-treat population ) , and vaccine efficacy in infants born to women immunised at least 14 days prepartum ( per- protocol population ) . The primary outcome was the occurrence of a first case of laboratory-confirmed influenza by age 6 months . This trial is registered with Clinical Trials.gov , number NCT01430689 . Findings We did this trial from Sept 12 , 2011 , to Jan 28 , 2014 . Between Sept 12 , 2011 , and April 18 , 2013 , we r and omly assigned 4193 women to receive trivalent  inactivated influenza vaccine  ( n=2108 ) or quadrivalent meningococcal vaccine ( n=2085 ) . There were 4105 livebirths ; 1797 ( 87 % ) of 2064 infants in the trivalent inactivated influenza vaccine group and 1793 ( 88 % ) of 2041 infants in the quadrivalent meningococcal vaccine group were followed up until age 6 months . We recorded 5279 influenza-like illness episodes in 2789 ( 68 % ) infants , of which 131 ( 2 % ) episodes were laboratory-confirmed influenza . 129 ( 98 % ) cases of laboratory-confirmed influenza were first episodes ( n=77 in the quadrivalent meningococcal vaccine group vs n=52 in the trivalent inactivated influenza vaccine group ) . In the intention-to-treat population , overall infant vaccine efficacy was 33·1 % ( 95 % CI 3·7–53·9 ) ; in the per- protocol population , vaccine efficacy was 37·3 % ( 7·6–57·8 ) . Vaccine efficacy remained robust during the first 4 months of follow-up ( 67·9 % [ 95 % CI 35·1–85·3 ] by intention to treat and 70·2 % [ 35·7–87·6 ] by per protocol ) , before diminishing during the fifth month ( 57·3 % [ 30·6–74·4 ] and 60·7 [ 33·8–77·5 ] , respectively ) . Adverse event rates in women and infants were similar among groups . Pain at the injection site was more common in women given quadrivalent meningococcal vaccine than in those given trivalent inactivated influenza vaccine ( n=253 vs n=132 ; p<0·0001 ) , although 354 [ 92 % ] reactions were mild . Obstetrical and non-obstetrical serious adverse events were reported in 60 ( 3 % ) women in the quadrivalent meningococcal vaccine group and 61 ( 3 % ) women in the trivalent inactivated influenza vaccine group . Presumed neonatal infection was more common in infants in the trivalent inactivated influenza vaccine group than in those in the quadrivalent meningococcal vaccine group ( n=60 vs n=37 ; p=0·02 ) . No serious adverse events were related to vaccination . Interpretation Vaccination of pregnant women with trivalent inactivated influenza vaccine  in Mali — a poorly re source d country with high infant mortality — was technically and logistically feasible and protected infants from laboratory-confirmed influenza for 4 months . With adequate financing to procure the vaccine , implementation will parallel the access to antenatal care and immunisation coverage of pregnant women with tetanus toxoid . Funding Bill & Melinda Gates Foundation BACKGROUND There are limited data on the efficacy of vaccination against confirmed influenza in pregnant women with and those without human immunodeficiency virus ( HIV ) infection and protection of their infants . METHODS We conducted two double-blind , r and omized , placebo-controlled trials of trivalent inactivated influenza vaccine ( IIV3 ) in South Africa during 2011 in pregnant women infected with HIV and during 2011 and 2012 in pregnant women who were not infected . The immunogenicity , safety , and efficacy of IIV3 in pregnant women and their infants were evaluated until 24 weeks after birth . Immune responses were measured with a hemagglutination inhibition ( HAI ) assay , and influenza was diagnosed by means of reverse-transcriptase-polymerase-chain-reaction ( RT-PCR ) assays of respiratory sample s. RESULTS The study cohorts included 2116 pregnant women who were not infected with HIV and 194 pregnant women who were infected with HIV . At 1 month after vaccination , seroconversion rates and the proportion of participants with HAI titers of 1:40 or more were higher among IIV3 recipients than among placebo recipients in both cohorts . Newborns of IIV3 recipients also had higher HAI titers than newborns of placebo recipients . The attack rate for RT-PCR-confirmed influenza among both HIV-uninfected placebo recipients and their infants was 3.6 % . The attack rates among HIV-uninfected IIV3 recipients and their infants were 1.8 % and 1.9 % , respectively , and the respective vaccine-efficacy rates were 50.4 % ( 95 % confidence interval [ CI ] , 14.5 to 71.2 ) and 48.8 % ( 95 % CI , 11.6 to 70.4 ) . Among HIV-infected women , the attack rate for placebo recipients was 17.0 % and the rate for IIV3 recipients was 7.0 % ; the vaccine-efficacy rate for these IIV3 recipients was 57.7 % ( 95 % CI , 0.2 to 82.1 ) . CONCLUSIONS Influenza vaccine was immunogenic in HIV-uninfected and HIV-infected pregnant women and provided partial protection against confirmed influenza in both groups of women and in infants who were not exposed to HIV . ( Funded by the Bill and Melinda Gates Foundation and others ; Clinical Trials.gov numbers , NCT01306669 and NCT01306682 . ) Background In 2009 , pregnant women were specifically targeted by a national vaccination campaign against p and emic A/H1N1 influenza virus . The objectives of the COFLUPREG study , initially set up to assess the incidence of serious forms of A/H1N1 influenza , were to assess the consequences of maternal vaccination on pregnancy outcomes and maternal seroprotection at delivery . Methods Pregnant women , between 12 and 35 weeks of gestation , non vaccinated against A/H1N1 2009 influenza were r and omly selected to be included in a prospect i ve cohort study conducted in three maternity centers in Paris ( France ) during p and emic period . Blood sample s were planned to assess hemagglutination inhibition ( HI ) antibody against A/H1N1 2009 influenza at inclusion and at delivery . Results Among the 877 pregnant women included in the study , 678 ( 77.3 % ) had serum sample s both at inclusion and delivery , and 320 ( 36.5 % ) received p and emic A/H1N1 2009 influenza vaccine with a median interval between vaccination and delivery of 92 days ( 95 % CI 48–134 ) . At delivery , the proportion of women with seroprotection ( HI antibodies titers against A/H1N1 2009 influenza of 1∶40 or greater ) was 69.9 % in vaccinated women . Of the 422 non-vaccinated women with serological data , 11 ( 2.6 % ; 95%CI : 1.3–4.6 ) had laboratory documented A/H1N1 2009 influenza ( 1 with positive PCR and 10 with serological seroconversion ) . None of the 877 study ’s women was hospitalized for flu . No difference on pregnancy outcomes was evidence d between vaccinated women , non-vaccinated women without seroconversion and non-vaccinated women with flu . Conclusion Despite low vaccine coverage , incidence of p and emic flu was low in this cohort of pregnant women . No effect on pregnancy and delivery outcomes was evidence d after vaccination BACKGROUND Influenza immunisation during pregnancy is recommended but not widely implemented in some low-income regions . We assessed the safety and efficacy in mothers and infants of year-round maternal influenza immunisation in Nepal , where influenza viruses circulate throughout the year . METHODS In this phase 4 , r and omised , placebo-controlled trial , we enrolled two consecutive sequential annual cohorts of pregnant women from the Sarlahi district in southern Nepal . We r and omised mothers 1:1 to receive seasonally recommended trivalent inactivated influenza vaccine or saline placebo in blocks of eight , stratified by gestational age at enrolment ( 17 - 25 weeks vs 26 - 34 weeks ) . Women were eligible if they were married , 15 - 40 years of age , 17 - 34 weeks ' gestation at enrolment , and had not previously received any influenza vaccine that season . We collected serum sample s before and after immunisation , and cord blood from a subset of women and infants . Staff masked to allocation made home visits every week from enrolment to 6 months after delivery . Midnasal swabs for respiratory virus PCR testing were collected during maternal acute febrile respiratory infections , and from infants with any respiratory symptom . We assessed vaccine immunogenicity , safety , and three primary outcomes : the incidence of maternal influenza-like illness in pregnancy and 0 - 180 days postpartum , the incidence of low birthweight ( < 2500 g ) , and the incidence of laboratory-confirmed infant influenza disease from 0 to 180 days . This trial is registered with Clinical Trials.gov , number NCT01034254 . FINDINGS From April 25 , 2011 , to Sept 9 , 2013 , we enrolled 3693 women in two cohorts of 2090 ( 1041 assigned to placebo and 1049 to vaccine ) and 1603 ( 805 assigned to placebo and 798 to vaccine ) , with 3646 liveborn infants ( cohort 1 , 999 in placebo group and 1010 in vaccine group ; cohort 2 , 805 in placebo group and 798 in vaccine group ) . Immunisation reduced maternal febrile influenza-like illness with an overall efficacy of 19 % ( 95 % CI 1 to 34 ) in the combined cohorts ; 9 % efficacy ( -16 to 29 ) in the first cohort , and 36 % efficacy ( 9 to 55 ) in the second cohort . For laboratory-confirmed influenza infections in infants aged 0 - 6 months , immunisation had an overall efficacy for the combined cohorts of 30 % ( 95 % CI 5 to 48 ) ; in the first cohort , the efficacy was 16 % ( -19 to 41 ) , and in the second cohort it was 60 % ( 26 to 88 ) . Maternal immunisation reduced the rates of low birthweight by 15 % ( 95 % CI 3 - 25 ) in both cohorts combined . The rate of small for gestational age infants was not modified by immunisation . The number of adverse events was similar regardless of immunisation status . Miscarriage occurred in three ( 0·2 % ) participants in the placebo group versus five ( 0·3 % ) in the vaccine group , stillbirth occurred in 31 ( 1·7 % ) versus 33 ( 1·8 % ) , and congenital defects occurred in 18 ( 1·0 % ) versus 20 ( 1·1 % ) . Five women died in the placebo group and three died in the vaccine group . The number of infant deaths at age 0 - 6 months was similar in each group ( 50 in the placebo group and 61 in the vaccine group ) . No serious adverse events were associated with receipt of immunisation . INTERPRETATION Year-round maternal influenza immunisation significantly reduced maternal influenza-like illness , influenza in infants , and low birthweight over the entire course of the study , indicating the strategy could be useful in subtropical regions . FUNDING Bill & Melinda Gates Foundation One hundred eighty-nine women who were immunized with Influenza A/New Jersey/8/76 virus vaccine ( InfA/NJ ) just prior to or during their pregnancy were compared with a control group of 517 pregnant women who did not receive the vaccine .  This longitudinal , prospect i ve study demonstrated no association between immunization with InfA/NJ and maternal , perinatal , or infant complications . No teratogenicity was demonstrated , and the two groups of infants did not differ in physical or neurological assessment s at birth and at 8 weeks of life INTRODUCTION There is a need for additional information on the fetal risks and relative safety of the p and emic H1N1 monovalent or trivalent influenza (pH1N1)-containing vaccines in women exposed during pregnancy . METHODS To assess risks and relative safety of the pH1N1-containing vaccines , we conducted a prospect i ve cohort study of  pH1N1-vaccine-exposed and unexposed comparison women residing in the U.S. or Canada who were recruited during pregnancy and followed to outcome between October 2009 and August 2012 . For exposure to the pH1N1 vaccine , adjusted relative risks ( RRs ) and 95 % confidence intervals ( CIs ) were estimated for major birth defects and infants small for gestational age . Adjusted hazard ratios ( HRs ) and 95 % CIs were estimated for spontaneous abortion and preterm delivery for time-varying exposure . RESULTS There were 1032 subjects available for analysis ; 841 women were exposed to a pH1N1-containing vaccine in pregnancy , and 191 women were unexposed to any influenza vaccine in pregnancy . Nine of 328 ( 2.7 % ) first-trimester-exposed pregnancies result ed in an infant with a major birth defect compared to 6/188 ( 3.2 % ) in the unexposed ( adjusted RR 0.79 , 95 % CI 0.26 - 2.42 ) . The HR for spontaneous abortion was not elevated ( adjusted HR 0.92 , 95 % CI 0.31 - 2.72 ) . Adjusted HRs for preterm delivery were elevated for exposure anytime in pregnancy ( 3.28 , 95 % CI 1.25 - 8.63 ) , specifically with exposure in the 1st or 2nd trimester . However , the mean decrease in gestational age in the exposed pregnancies was approximately three days . Adjusted RRs for small for gestational age infants on weight and length approximated 1.0 . CONCLUSIONS For the 2009 - 12 influenza seasons combined , we found no meaningful evidence of increased RR or HR for major birth defects , spontaneous abortion , or small for gestational age infants . There was some evidence of an increased HR for preterm delivery following pH1N1-influenza vaccine exposure ; however the decrease in gestational age on average was approximately three days BACKGROUND A(H1N1)v2009 influenza vaccination  of pregnant women was a challenge for health care providers , as little safety data were available . METHODS We prospect ively followed the pregnancies of women who were vaccinated at any time during pregnancy or ≤ 4 weeks prior to conception and compared these outcomes to a control cohort matched by the estimated date of birth . Primary endpoints : rate of spontaneous abortion and major malformations . Secondary endpoints : preeclampsia , gestational age at birth , and birth weight . RESULTS Pregnancy outcome of 323 women immunized with adjuvanted or non-adjuvanted A(H1N1)v2009 influenza vaccines from 2009 - 09 - 28 to 2010 - 03 - 31 were compared to 1329 control subjects .  The risk for spontaneous abortions ( HR 0.89 ; 95 % CI 0.36 - 2.19 ) and the rate of major malformations ( all trimesters : OR 0.87 ; 95 % CI 0.38 - 1.77 ; preconception and first trimester exposure : OR 0.79 ; 95 % CI 0.13 - 2.64 ) did not vary between the two cohorts . Furthermore , there was no increase in preeclampsia , prematurity , and intrauterine growth retardation in the vaccinated cohort . CONCLUSION The results of our study do not indicate a risk for the pregnant woman and the developing embryo/fetus after H1N1 vaccination . We provide and apply methods novel in observational studies on pregnancy outcome , especially if a single dose exposure is investigated In 2012 , the World Health Organization ( WHO ) released a position paper on influenza vaccination recommending that pregnant women have the highest priority for seasonal vaccination in countries where the initiation or expansion of influenza immunization programs is under consideration . Although the primary goal of the WHO recommendation is to prevent influenza illness in pregnant women , the potential benefits of maternal immunization in protecting young infants are also recognized . The extent to which maternal influenza vaccination may prevent adverse birth outcomes such as preterm birth or small-for-gestational-age birth , however , is unclear as available studies are in disagreement . To inform WHO about the empirical evidence relating to possible benefits of influenza vaccination on birth outcomes , a consultation of experts was held in Montreal , Canada , September 30-October 1 , 2015 . Presentations and discussion s covered a broad range of issues , including influenza virus infection during pregnancy and its effect on the health of the mother and the fetus , possible biological mechanisms for adverse birth outcomes following maternal influenza illness , evidence on birth outcomes following influenza illness during pregnancy , evidence from both observational studies and r and omized controlled trials on birth outcomes following influenza vaccination of pregnant women , and method ological issues . This report provides an overview of the presentations , discussion s and conclusions ABSTRACT To monitor and evaluate the safety of the influenza A(H1N1 ) vaccine in pregnant women and its influence on the fetus and neonate , we performed a prospect i ve study in which 122 pregnant Chinese women who received the influenza A(H1N1 ) vaccine and 104 pregnant women who did not receive any vaccine ( serving as controls ) were observed . The results indicated that the seroconversion rate in the vaccinated group was 90.4 % ( 95 % confidence interval [ CI ] , 82.6 % to 95.5 % ) . The rate of adverse events following immunization in the pregnant women who received the influenza A(H1N1 ) vaccine was 3.3 % . The spontaneous abortion rates in the vaccinated group and the unvaccinated group were 0.8 % and 1.9 % , respectively ( exact probability test , P = 0.470 ) , the prolonged-pregnancy rates were 8.2 % and 4.8 % , respectively ( χ2 = 1.041 , P = 0.308 ) , the low-birth-weight rates were 1.6 % and 0.95 % , respectively ( exact probability test , P = 1.000 ) , and the spontaneous-labor rates were 70.5 % and 75 % , respectively ( χ2 = 0.573 , P = 0.449 ) . All newborns who have an Apgar score of ≥7 are considered healthy ; Apgar scores of ≥9 were observed in 38.5 % and 57.7 % of newborns in the vaccinated group and the unvaccinated group , respectively ( χ2 = 8.274 , P = 0.004 ) . From these results , we conclude that the influenza A(H1N1 ) vaccine is safe for pregnant women and has no observed adverse effects on fetal growth . ( This study has been registered at Clinical Trials.gov under registration no. NCT01842997 .
Pregnant women are at increased risk of morbidity and mortality from influenza and are recognized as a priority group for influenza vaccination .
Despite this , uptake is often poor and one reason cited for this is concerns about safety .
The objective of this study was to perform a systematic review of the safety of inactivated influenza vaccination ( IIV ) in pregnancy .