Review on the effects of influenza vaccination during pregnancy on preterm births

Figures & data

Table 1. Summary of observational studies reporting on the association of maternal influenza vaccination and preterm deliveries

Reference and country	Study date and population	Study design and data collection	Trimester
Van der Maas et al. 2015; Holland^27	Random sample of pregnant women, eligible for vaccination between Nov-Dec 2009.	Cross-sectional linkage study. Perinatal database. Information on vaccination status was self-reported.	2^nd and 3^rd. No results by trimester.
Cleary, et al. 2014; Dublin, Ireland^45	Pregnancies during Dec 2009 to Sep 2010. Singleton deliveries.	Retrospective cohort study using discharge records. Information on vaccination status and type of vaccine was self-reported at delivery.	1^st 8%, 2^nd 57%, 3^rd 35%. No results by trimester.
Nordin, et al. 2014; Seven Vaccine Safety Datalink sites, USA^34	Pregnancies during 2004–05 through 2008–09 influenza seasons. Live-births with BW ≥500g and GA ≥22 weeks.	Retrospective match cohort study. Perinatal database. Information on vaccination status was obtained from electronic medical registries and medical claims data.	1^st 28%, 2^nd 43%, 3^rd 29%. Results overall and by trimester.
Beau, et al. 2014; France^48	Deliveries from 21 Oct 2009 to 30 Nov 2010.	Population-based retrospective match cohort study. Perinatal database. Information on vaccination status was obtained from health units databases.	1^st 8%, 2^nd 52%, 3^rd 40%. No results by trimester.
Legge, et al. 2014; Nova Scotia, Canada^39	Deliveries from 1 Nov 2010 to 31 Mar 2012. Singleton live-births with BW ≥500g and GA ≥20 weeks.	Population-based retrospective cohort study. Perinatal database that also collected self-reported information on vaccination status.	Not reported
Adedinsewo et al. 2013; Georgia, USA^49	Deliveries from 1 Jan 2005 to 31 Dec 2008. Live-births.	Population-based retrospective cohort study. Information on vaccination status and type of vaccine was self-reported.	Not reported
Chambers et al. 2013; USA and Canada^46	Pregnancies during Oct 2009 to Apr 2012.	Prospective cohort study. Outcomes and information on vaccination status, type of vaccine and vaccination date collected by telephonic interview and medical records.	1^st 32%, 2^nd 33%, 3^rd 14%. Results overall and by trimester.
Louik at al. 2013; Four regional centers in the USA^37	Pregnant women during the 2009/10 or 2010/11 season. Singleton live-births.	Retrospective case control study. Within 6 months of delivery, mothers of eligible infants were interviewed by telephone. Information on vaccination status, type of vaccine and vaccination date confirmed by the provider.	1^st 36%, 2^nd 38% or 3^rd26%. Results overall and by trimester.
Ludvigsson et al. 2013; Stockholm County, Sweden^36	Pregnancies conceived between Feb 2009 to Jan 2010. Singleton live-births.	Population-based retrospective cohort study. Perinatal database. Information on vaccination status was obtained from health units databases.	1^st 34%, 2^nd 40%, 3^rd 36%. No results by trimester.
Cantu et al. 2013; USA^47	Prenatal visits during 1 Oct to 31 Dec 2009 and 2010. Singleton births.	Retrospective cohort study. Information on vaccination status was obtained from perinatal and clinic vaccination logs.	Not reported
Rubinstein, et al. 2013; 49 public hospitals in Argentina^29	Deliveries from Sep 2010 to May 2011. Live-births with BW ≥500 g or GA ≥22 weeks.	Cross-sectional study. Data abstraction from medical records and participants survey. Information on vaccination status and vaccination date based on documentation in any official registry.	1^st 39%, 2^nd 49%, 3^rd 10%. No results by trimester.
Richards, et al. 2013; Kaiser Permanente Georgia and Mid-Atlantic States, USA^30	Deliveries from 26 Apr 2009 to 17 Apr 2010. Third trimester live-births.	Population-based retrospective cohort study. Information on vaccination status, type of vaccine and vaccination date from electronic medical records.	2^nd or 3^rd. No results by trimester.
Haberg et al. 2013; Norway^10	Pregnancies during 2009 to 2010. Singleton births.	Nationwide registry-based retrospective cohort study. Information on vaccination status from the immunization registry.	1^st 9%, 2^nd 42%, 3^rd 49%. No results by trimester.
Launay et al. 2012; Paris, France^40	Enrolment of pregnant women between 12 and 35 weeks GA from 12 Oct 2009 to 3 Feb 2010.	Prospective cohort study. Information on vaccination status self-reported.	2^nd or 3^rd. No results by trimester.
Dodds et al. 2012; Nova Scotia, Canada^44	Deliveries from 1 Apr 2006 to 31 Oct 2009. Singleton births with BW >500g and GA >20 weeks.	Population-based retrospective cohort study. Perinatal electronic database. Information on vaccination status self-reported collected on the same database.	Not reported
Heikkinen et al. 2012; The Netherlands, Italy, and Argentina^42	Pregnancies during Jan to Aug 2010 in The Netherlands, May to Jun 2010 in Italy, Jul to Aug 2010 in Argentina.	Observational cohort study with active enrolment and retrospective. Information on vaccination status self-reported and if vaccine was reported when possible was confirmed by vaccination records.	1^st 4%, 2^nd 57%, 3^rd 39%. No results by trimester.
Sheffield et al. 2012; Dallas, Texas, USA^Citation28	Pregnancies during Oct to Mar between 2003 and 2008.	Retrospective cohort study. Perinatal electronic database also containing information on vaccination status.	1^st 5%, 2^nd or 3^rd 95%. No results by trimester.
Kallen et al. 2012; Sweden^Citation41	Deliveries from Oct 2009 to Dec 2010.	Nationwide registry-based retrospective cohort study. Information on vaccination status from incomplete national health registers and self-reported.	1–19 week of gestation 41%, 20–26 week of gestation 28%, 27–36 week of gestation 31%. Results overall and by trimester.
Pasternak et al. 2012; Denmark^Citation31	Deliveries from 2 Nov 2009 to 30 Sep 2010. Singleton live-births.	Nationwide registry-based retrospective cohort study. Information on vaccination status and vaccination date was obtained from health units databases.	1^st 5%, 2^nd or 3^rd 95%. Results by trimester.
Oppermann et al. 2012; Germany^Citation32	Pregnancies during 1 Apr 2009 to 31 Jul 2010.	Prospective observational cohort study. Maternal surveys collecting history of vaccination and pregnancy outcomes; hospital discharge summaries were also reviewed.	Not reported
Fell et al. 2012; Ontario, Canada^Citation43	Deliveries from 2 Nov 2009 to 30 Apr 2010. Singleton live-births with BW ≥500g and GA ≥20 weeks.	Population-based retrospective cohort study. Perinatal electronic database. Information on vaccination status and type of vaccine self-reported.	Not reported
Lin et al. 2012; Taiwan^Citation38	Pregnancies during Oct 2009 to Feb 2010.	Retrospective cohort study. Pregnancy outcomes extracted from chart reviews. Information on vaccination status from clinical database.	1^st 5%, 2^nd 41%, 3^rd 53%. No results by trimester.
Omer et al. 2011; Georgia, USA^Citation33	Deliveries from 1 Jun 2004 to 30 Sep 2006.	Population-based retrospective cohort study. Surveillance data collected from maternal surveys. Information on vaccination status self-reported.	Not reported
Munoz et al. 2005; Texas, USA^Citation35	Deliveries from 1 Jul 1998 to 30 Jun 2003. Singletons born to healthy women.	Retrospective match cohort study. Perinatal electronic database. Information on vaccination status from clinical database.	2^nd or 3^rd. No results by trimester.

* Preterm birth defined as: birth at <37 weeks gestational age, except stated otherwise.

^a Preterm birth: birth at 22–<37 weeks gestational age.

^b Preterm birth: birth at 20–<37 weeks gestational age.

^c Preterm birth: birth at 27–36 weeks gestational age.

^d Preterm birth not define.

GA: gestational age; BW: birth weight.

Table 2. Product used and adjusted risk measures in observational studies reporting on the association of maternal influenza vaccination and preterm deliveries

Reference	Product	Analyses	Results
Nordin, et al. 2014 ^34	Seasonal not containing A/H1N1pdm09	OR calculated by conditional logistic regression. Vaccinated women were matched with unvaccinated by propensity score (1:1).	aOR: 0.97 (0.93 to 1.02), aOR: 0.99 (0.91 to 1.08) 1^st trimester, aOR: 0.96 (0.90 to 1.03) 2^nd trimester, aOR: 0.98 (0.87 to 1.09) 3^rd trimester
Adedinsewo, et al. 2013 ^49	Seasonal not containing A/H1N1pdm09	OR adjusted for covariates identified during the control period.	aOR: 0.83 (0.60 to 1.17)
Dodds, et al. 2012 ^44	Seasonal not containing A/H1N1pdm	OR calculated by logistic regression with adjustment for potential confounders.	aOR: 0.84 (0.69 to 1.02)
Omer, et al. 2011^Citation33	Seasonal not containing A/H1N1pdm09	OR calculated by logistic regression with adjustment for potential confounders. Stratification by influenza circulation.	aOR: 0.83 (0.55 to 1.26) overall period, aOR: 0.27 (0.08 to 0.86) period with widespread influenza activity
Munoz, et al. 2005^Citation35	Seasonal not containing A/H1N1pdm09	Vaccinated women matched with unvaccinated (1:3.5) for maternal age at delivery, month of delivery, and type of insurance.	OR: 0.67 (0.32 to 1.32)
Legge, et al. 2014 ^39	Seasonal containing A/H1N1pdm09	OR calculated by logistic regression adjusted for potential confounding variables found to be associated with vaccination in a backward stepwise regression model.	aOR: 0.75 (0.60 to 0.94)
Chambers, et al. 2013 ^46	A/H1N1pdm09 with (28%) or without seasonal (2009/10) or seasonal containing A/H1N1pdm09 (2010/12)	HR calculated by Cox regression with vaccination as a time-varying exposure adjusted for potential confounding variables.	aHR: 3.28 (1.25 to 8.63) overall anytime in pregnancy, aHR: 3.32 (1.20 to 9.18) 2009/10 season anytime in pregnancy, aHR: 2.25 (0.88 to 5.75) 20010–12 seasons anytime in pregnancy
Louik, at al. 2013 ^37	A/H1N1pdm09 with or without seasonal (Oct 2009-Jul 2010) or seasonal containing A/H1N1pdm09 (Aug 2010–Jul 2011)	HR calculated by Cox regression with vaccination as a time-varying exposure. Vaccinated women were matched with unvaccinated by propensity score.	aHR: 1.03 (0.50 to 2.10) overall anytime in pregnancy, aHR: 2.82 (1.16 to 6.86) 2009/10 season overall anytime in pregnancy, aHR: 2.17 (0.65 to 7.20) 2009/10 season monovalent anytime in pregnancy, aHR: 0.22 (0.06 to 0.83) 20010/11 season anytime in pregnancy
Cantu, et al. 2013 ^47	A/H1N1pdm09 with or without seasonal (2009/10) or seasonal containing A/H1N1pdm09 (2010/12)	RR adjusted for potential confounders by multivariable logistic regression.	aRR: 1.2 (0.9 to 1.6)
Richards, et al. 2013 ^30	A/H1N1pdm09 with or without seasonal	OR calculated by logistic regression adjusted for potential confounding variables.	aOR: 0.63 (0.47 to 0.84)
Fell, et al. 2012^Citation43	A/H1N1pdm09 with (8.5%) or without seasonal	RR calculated by logistic regression with adjustment for potential confounders.	aOR: 0.95 (0.88 to 1.02)
Cleary, et al. 2014 ^45	A/H1N1pdm09	OR calculated by logistic regression adjusted for potential confounding variables.	aOR: 0.72 (0.58 to 0.89)
Beau, et al. 2014 ^48	A/H1N1pdm09 (93% unadjuvanted vaccine, Panzema)	HR calculated by Cox regression with vaccination as time-varying exposure. Adjusted measures using conditional forward stepwise regression. Vaccinated women were matched with unvaccinated (1:2).	aOR: 0.82 (0.64 to 1.06)
Ludvigsson, et al. 2013 ^36	AS03-A/H1N1pdm09 (Pandemix)	OR calculated by logistic regression with adjustment for potential confounders.	aOR: 0.99 (0.89 to 1.10)
Haberg et al. 2013 ^10	AS03-A/H1N1pdm09 (Pandemix)	HR calculated using gestational age as the time metric variable and adjusted for potential confounders.	aHR: 1.0 (0.93 to 1.09)
Kallen, et al. 2012^Citation41	AS03-A/H1N1pdm09 (Pandemix)	OR adjusted by the Mantel–Haenszel method for potential confounders.	aOR: 0.86 (0.77 to 0.96), aOR: 0.95 (0.85 to 1.08) 1–19 week of gestation, aOR: 1.09 (0.94 to 1.26) 20–26 week of gestation, aOR: 0.81 (0.69 to 0.96) 27–36 week of gestation
Pasternak, et al. 2012^Citation31	AS03-A/H1N1pdm09 (Pandemrix)	OR calculated by logistic regression. Vaccinated women were matched with unvaccinated by propensity score (1:1).	aOR: 1.32 (0.76 to 2.31) 1^st trimester, aOR: 1.0 (0.84 to 1.17) 2^nd and 3^rd trimesters
Van der Maas, et al. 2015 ^27	2-doses MF59-A(H1N1)pdm (Focetria)	ORs calculated by logistic regression adjusted for potential confounding variables.	aOR: 0.98 (0.59 to 1.62)
Rubinstein, et al. 2013 ^29	MF59-A/H1N1pdm09 (Focetria)	OR calculated by logistic regression adjusted for potential confounders.	aOR: 0.79 (0.69 to 0.90)
Heikkinen, et al. 2012 ^42	MF59-A/H1N1pdm09 (Focetria)	OR calculated by logistic regression with stepwise approach for potential confounders and proportional hazard models that adjust for differential follow-up time.	aOR: 0.75 (0.55 to 1.01), adjusted proportional hazard: 0.69 (0.51 to 0.92)

aOR: adjusted odds ratio; aHR: adjusted hazard ratio; aRR: adjusted risk ratio.

Sheffield JS, Greer LG, Rogers VL, Roberts SW, Lytle H, McIntire DD, Wendel GD, Jr. Effect of influenza vaccination in the first trimester of pregnancy. Obstet Gynecol 2012; 120:532-7; PMID:22914461; http://dx.doi.org/10.1097/AOG.0b013e318263a278

 PubMed Web of Science ®Google Scholar

Chambers CD, Johnson D, Xu R, Luo Y, Louik C, Mitchell AA, Schatz M, Jones KL, Group OCR. Risks and safety of pandemic H1N1 influenza vaccine in pregnancy: birth defects, spontaneous abortion, preterm delivery, and small for gestational age infants. Vaccine 2013; 31:5026-32; PMID:24016809; http://dx.doi.org/10.1016/j.vaccine.2013.08.097

 PubMed Web of Science ®Google Scholar

Nordin JD, Kharbanda EO, Vazquez Benitez G, Lipkind H, Vellozzi C, Destefano F, Vaccine Safety D. Maternal influenza vaccine and risks for preterm or small for gestational age birth. J Pediatr 2014; 164:1051-7 e2; PMID:24582484; http://dx.doi.org/10.1016/j.jpeds.2014.01.037

 PubMed Web of Science ®Google Scholar

Adedinsewo DA, Noory L, Bednarczyk RA, Steinhoff MC, Davis R, Ogbuanu C, Omer SB. Impact of maternal characteristics on the effect of maternal influenza vaccination on fetal outcomes. Vaccine 2013; 31:5827-33; PMID:24120677; http://dx.doi.org/10.1016/j.vaccine.2013.09.071

 PubMed Web of Science ®Google Scholar

Launay O, Krivine A, Charlier C, Truster V, Tsatsaris V, Lepercq J, Ville Y, Avenell C, Andrieu T, Rozenberg F, et al. Low rate of pandemic A/H1N1 2009 influenza infection and lack of severe complication of vaccination in pregnant women: a prospective cohort study. PloS one 2012; 7:e52303; PMID:23300637; http://dx.doi.org/10.1371/journal.pone.0052303

 PubMed Web of Science ®Google Scholar

Glynn RJ, Schneeweiss S, Sturmer T. Indications for propensity scores and review of their use in pharmacoepidemiology. Basic Clin Pharmacol Toxicol 2006; 98:253-9; PMID:16611199; http://dx.doi.org/10.1111/j.1742-7843.2006.pto_293.x

 PubMed Web of Science ®Google Scholar

Cantu J, Biggio J, Jauk V, Wetta L, Andrews W, Tita A. Selective uptake of influenza vaccine and pregnancy outcomes. J Mater-Fetal Neonatal Med 2013; 26:1207-11; PMID:23406444; http://dx.doi.org/10.3109/14767058.2013.775419

 PubMed Web of Science ®Google Scholar

Lin TH, Lin SY, Lin CH, Lin RI, Lin HC, Chiu TH, Cheng PJ, Lee CN. AdimFlu-S((R)) influenza A (H1N1) vaccine during pregnancy: the Taiwanese Pharmacovigilance Survey. Vaccine 2012; 30:2671-5; PMID:22342546; http://dx.doi.org/10.1016/j.vaccine.2012.02.008

 PubMed Web of Science ®Google Scholar

Louik C, Ahrens K, Kerr S, Pyo J, Chambers C, Jones KL, Schatz M, Mitchell AA. Risks and safety of pandemic H1N1 influenza vaccine in pregnancy: exposure prevalence, preterm delivery, and specific birth defects. Vaccine 2013; 31:5033-40; PMID:24016804; http://dx.doi.org/10.1016/j.vaccine.2013.08.096

 PubMed Web of Science ®Google Scholar

Beau AB, Hurault-Delarue C, Vidal S, Guitard C, Vayssiere C, Petiot D, Montastruc JL, Damase-Michel C, Lacroix I. Pandemic A/H1N1 influenza vaccination during pregnancy: a comparative study using the EFEMERIS database. Vaccine 2014; 32:1254-8; PMID:24486369; http://dx.doi.org/10.1016/j.vaccine.2014.01.021

 PubMed Web of Science ®Google Scholar

Richards JL, Hansen C, Bredfeldt C, Bednarczyk RA, Steinhoff MC, Adjaye-Gbewonyo D, Ault K, Gallagher M, Orenstein W, Davis RL, et al. Neonatal outcomes after antenatal influenza immunization during the 2009 H1N1 influenza pandemic: impact on preterm birth, birth weight, and small for gestational age birth. Clin Infect Dis 2013; 56:1216-22; PMID:23378281; http://dx.doi.org/10.1093/cid/cit045

 PubMed Web of Science ®Google Scholar

Pasternak B, Svanstrom H, Molgaard-Nielsen D, Krause TG, Emborg HD, Melbye M, Hviid A. Risk of adverse fetal outcomes following administration of a pandemic influenza A(H1N1) vaccine during pregnancy. JAMA 2012; 308:165-74; PMID:22782418; http://dx.doi.org/10.1001/jama.2012.6131

 PubMed Web of Science ®Google Scholar

Haberg SE, Trogstad L, Gunnes N, Wilcox AJ, Gjessing HK, Samuelsen SO, Skrondal A, Cappelen I, Engeland A, Aavitsland P, et al. Risk of fetal death after pandemic influenza virus infection or vaccination. N Engl J Med 2013; 368:333-40; PMID:23323868; http://dx.doi.org/10.1056/NEJMoa1207210

 PubMed Web of Science ®Google Scholar

Kallen B, Olausson PO. Vaccination against H1N1 influenza with Pandemrix((R)) during pregnancy and delivery outcome: a Swedish register study. BJOG 2012; 119:1583-90; PMID:22901103; http://dx.doi.org/10.1111/j.1471-0528.2012.03470.x

 PubMed Web of Science ®Google Scholar

Cleary BJ, Rice U, Eogan M, Metwally N, McAuliffe F. 2009 A/H1N1 influenza vaccination in pregnancy: uptake and pregnancy outcomes - a historical cohort study. Eur J Obstet, Gynecol Reproduct Biol 2014; 178:163-8; PMID:24793932; http://dx.doi.org/10.1016/j.ejogrb.2014.04.015

 PubMed Web of Science ®Google Scholar

Fell DB, Sprague AE, Liu N, Yasseen AS,3rd, Wen SW, Smith G, Walker MC, Better Outcomes R, Network O. H1N1 influenza vaccination during pregnancy and fetal and neonatal outcomes. Am J Public Health 2012; 102:e33-40; PMID:22515877; http://dx.doi.org/10.2105/AJPH.2011.300606

 PubMedGoogle Scholar

Rubinstein F, Micone P, Bonotti A, Wainer V, Schwarcz A, Augustovski F, Pichon Riviere A, Karolinski A, Antigripal EVASRGEEyV. Influenza A/H1N1 MF59 adjuvanted vaccine in pregnant women and adverse perinatal outcomes: multicentre study. BMJ 2013; 346:f393

 Google Scholar

Heikkinen T, Young J, van Beek E, Franke H, Verstraeten T, Weil JG, Della Cioppa G. Safety of MF59-adjuvanted A/H1N1 influenza vaccine in pregnancy: a comparative cohort study. Am J Obstet Gynecol 2012; 207:177e1-8; http://dx.doi.org/10.1016/j.ajog.2012.07.007

 Web of Science ®Google Scholar

Oppermann M, Fritzsche J, Weber-Schoendorfer C, Keller-Stanislawski B, Allignol A, Meister R, Schaefer C. A(H1N1)v2009: a controlled observational prospective cohort study on vaccine safety in pregnancy. Vaccine 2012; 30:4445-52; PMID:22564554; http://dx.doi.org/10.1016/j.vaccine.2012.04.081

 PubMed Web of Science ®Google Scholar

Omer SB, Goodman D, Steinhoff MC, Rochat R, Klugman KP, Stoll BJ, Ramakrishnan U. Maternal influenza immunization and reduced likelihood of prematurity and small for gestational age births: a retrospective cohort study. PLoS Med 2011; 8:e1000441; PMID:21655318; http://dx.doi.org/10.1371/journal.pmed.1000441

 PubMed Web of Science ®Google Scholar

Dodds L, Macdonald N, Scott J, Spencer A, Allen VM, McNeil S. The association between influenza vaccine in pregnancy and adverse neonatal outcomes. J Obstet Gynaecol Can 2012; 34:714-20; PMID:22947404

 PubMedGoogle Scholar

Legge A, Dodds L, MacDonald NE, Scott J, McNeil S. Rates and determinants of seasonal influenza vaccination in pregnancy and association with neonatal outcomes. CMAJ 2014; 186:E157-64; PMID:24396098; http://dx.doi.org/10.1503/cmaj.130499

 PubMed Web of Science ®Google Scholar

Ludvigsson JF, Zugna D, Cnattingius S, Richiardi L, Ekbom A, Ortqvist A, Persson I, Stephansson O. Influenza H1N1 vaccination and adverse pregnancy outcome. Eur J Epidemiol 2013; 28:579-88; PMID:23715672; http://dx.doi.org/10.1007/s10654-013-9813-z

 PubMed Web of Science ®Google Scholar

Munoz FM, Greisinger AJ, Wehmanen OA, Mouzoon ME, Hoyle JC, Smith FA, Glezen WP. Safety of influenza vaccination during pregnancy. Am J Obstet Gynecol 2005; 192:1098-106; PMID:15846187; http://dx.doi.org/10.1016/j.ajog.2004.12.019

 PubMed Web of Science ®Google Scholar