Thursday, September 15, 2016

Influenza Vaccine Has Been Studied in Pregnant Women

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Summer is very nearly over in the Northern hemisphere. Fall and winter creep ever closer. As the temperatures drop, we begin to think about pulling out our warmer clothes. We shake out our jackets. Those with oil heat make sure their tanks are filled. Others stock up on firewood. The really forward thinking might ensure that their shovels are in decent shape for any snow that may be coming their way.

We're also heading into flu season. Influenza rears its ugly head from fall, through winter, and into early spring. It's one of those diseases that people tend to underestimate and have a lot of misconceptions about. A lot of illnesses people think are the flu are actually different illnesses caused by bacteria, parasites, or different viruses. A lot of people think that it is a fairly benign disease, even though it kills thousands of people in the U.S. every year, and hundreds of thousands worldwide. Then there are the myths about the flu vaccine. Probably the most common mistaken belief is that the vaccine can give you the flu, even though it can't. The available vaccines use either inactivated virus or a severely weakened form of the virus, neither of which will give you the flu.

Suffice it to say, there is a lot of misinformation out there about the flu and the flu vaccine. But there is one population that is more seriously affected, both by the disease itself and by the myths: pregnant women.

Pregnant women are considered a vulnerable population, that is, a group that may be prone to greater risks. There's a greater risk of complications following infection. They may be prone to exploitation. Their fetuses may suffer from exposure to disease, drugs or medications, or environmental contaminants. In research involving pregnant women, a lot of additional measures must be taken to ensure the safety of pregnant women. The greater the uncertainty around an experimental drug, device, or procedure, the more difficult it is to convince an institutional review board to allow the study in pregnant women. This is especially true with products that are not targeted specifically at pregnant women, but rather at a very broad population that may incidentally include women who are pregnant or who may become pregnant.

Like vaccines.

I'll get back to testing vaccines in pregnant women later. First, let's see how all of this comes together: influenza misinformation, pregnant women, and vaccines. A pretty common myth promoted by those who oppose vaccines is that the flu vaccine has never been tested in pregnant women (or some variant of that argument). For reference, they will point to the vaccine package inserts.

For example, the anti-vaccine site Health Impact News asks:
Do doctors and nurses who administer the flu vaccine to pregnant women warn them that these vaccines have not been tested on pregnant women?
They include a link to the insert for one of the flu vaccines out there, Fluzone, and quote from it:
Safety and effectiveness of Fluzone has not been established in pregnant women.
Similarly, Dr. Joe Mercola wrote in 2010:
As I've reported in previous articles, this vaccine has NEVER been tested in pregnant women – until now.
Interestingly, while Mercola is aghast that the flu vaccine has never (in his mind) been tested in pregnant women, he also stated that he did not think that pharmaceutical products should ever be tested in pregnant women. I guess he thinks that pregnant women should just not receive anything, ever, even if there is potential that it might help them or improve their chances for having a healthy child. I wonder if that includes all of those supplements that he sells?

At any rate, the mistake that they, and those who repeat their misinformation, make is that they look to the vaccine package insert as the be-all, end-all of scientific information on the vaccine. They use it as if it were a complete and 100% accurates summation of all that is known about the vaccine. It isn't. Either they misunderstand the role of package inserts, or they know that they are misrepresenting it yet mislead their followers anyway.

A package insert is, first and foremost, a legal document. It instructs physicians on how to prescribe and administer the product, as well as listing adverse reactions, whether they are actually caused by the product or not. It includes information from studies that the manufacturer has conducted, the indications that they have sought and gained FDA marketing approval for, and it might include a smattering of information from other studies. Generally speaking, though, package inserts do not include information on off-label uses of the product. Off-label use includes using the product for any indication, dosing schedule, age range, or population for which the manufacturer has not received FDA approval. The package insert will reflect that, saying, for example, that the product has not been studied in pregnant women.

That does not mean, though, that no one has studied the vaccine in pregnant women. We know that the flu vaccine can help reduce the risk of getting the flu (the actual flu - influenza - not the queasy stomach you got from norovirus or something else). And, yes, how effective it is varies from year to year, but it always provides more protection than not getting the vaccine at all; even when it doesn't prevent infection, it can often lessen the severity of illness. Although there has not been a great deal of study on the effects of influenza infection in pregnant women, we do know that there is some increased risk of adverse pregnancy and fetal outcomes. If the vaccine can reduce the risk of influenza infection and severity of infection, and we know that pregnant women are at greater risk of adverse outcomes if they get infected with the influenza virus, then we should figure out if the vaccine is safe for pregnant women to receive.

Fortunately, unlike anti-vaccine activists who only complain about vaccines, the scientific community actually looks into questions like this. Researchers from around the world have studied vaccines in pregnant women. There have been retrospective studies, prospective studies. Some studies were case-control studies. Others were cohort studies. Some looked at seasonal flu vaccines. A lot have looked at the A/H1N1 pandemic influenza vaccine. With adjuvants? Check. Without adjuvants? Check. Randomized controlled trials? There have been a couple of those, too. There have been systematic reviews, too, combining multiple studies to gain greater power to detect possible problems. And, yes, the U.S. Centers for Disease Control and Prevention, which recommends that pregnant women get the annual flu vaccine, have also studied, and continue to monitor, the flu vaccine in pregnant women.

What have we discovered? There do not appear to be any increased risks of adverse pregnancy outcomes, adverse fetal outcomes, nor adverse infant outcomes. It even looks as though getting a flu vaccine will improve outcomes. Pregnant women who receive the flu vaccine have a lower risk of having a miscarriage, for example. The antibodies that pregnant women produce as a result of vaccination are also passed on to the infant, protecting them for several months, until they are able to mount their own defense against infection.

For those who follow the actual facts about vaccines, this should come as no surprise. However, it is a fairly pernicious myth that just won't die. Tara Haelle wrote about it in 2014, listing a number of studies that had been done.

If all of these studies have been done, and we know that the vaccines are safe for pregnant women to get, why don't the manufacturers add pregnant women to their package inserts?

In order to do so, manufacturers would have to conduct clinical trials to study their vaccines in pregnant women. That is a very, very expensive endeavor. As mentioned before, they would have to get ethics approval before they could begin such a study. That would be rather difficult. On the one hand, it involves testing a product in a vulnerable population. On the other, we already have evidence that the vaccine is safe and provides a benefit to pregnant women, so giving it to one group and giving a placebo to the other would violate the research principle of beneficence. If we know that the product is beneficial and that not giving it leaves one at increased risk, we cannot ethically give it to one group but withhold it from another.

There also is no incentive for a manufacturer to undertake a clinical trial. Remember, the purpose of a manufacturer undertaking a clinical trial is to gain FDA approval to actively market their product for the indication and population(s) in the trial. The flu vaccine is already widely used by pregnant women. There is already a large body of evidence supporting its safe use in pregnant women, allowing physicians to be confident that they are helping to protect their patients. Undertaking clinical trials would be a major expense for vaccine makers with little to no return on investment.

Finally, let's suppose that a manufacturer did undertake a clinical trial for their flu vaccine in pregnant women. They receive ethical approval. They decide that there is some financial benefit to investing in the trial. Would it alter any of the claims of the anti-vaccine community? Probably not. They would only accept the results if they were negative. Any positive result would very likely be swept under the rug with accusations that "of course it was positive; Big PharmaTM needs their money."

One ironic aspect of all this is that there is some evidence that influenza infection during pregnancy might increase risk of autism spectrum disorder. Granted, the evidence is weak at present, and we cannot conclude that there is a causal association. As I mentioned before, there hasn't been a lot of research into the effects of influenza infection, so we don't have a solid grasp on what risks influenza infection poses for pregnant women and their fetuses. It is definitely worth further research, and if this suggestion of a link turns out to be true, then anti-vaccine activists are arguing against something that could help reduce the risk of autism, much as they do for the MMR; congenital rubella syndrome, which results from infection with rubella while pregnant, is one of the known causes of ASDs.

At the end of the day, the next time you hear someone claim that the flu vaccine has never been tested in pregnant women, you can be sure that they have either been lied to, misunderstand package inserts, or perhaps they are just outright lying. They might try to claim that there have been no clinical trials or randomized, placebo-controlled trials, but that's not true either. Flu vaccines have been studied in pregnant women. Flu vaccines have been found to be safe for pregnant women to receive, and that they even have benefits to the newborn.

Here is an annotated list of reviews and studies looking at the flu vaccine in pregnant women that you can use to help dispel that myth. I've also included a handful of studies that examined the risks of influenza infection during pregnancy. This list is not exhaustive, by any means, and there continue to be new studies looking at this question.

Reviews

Bednarczyk RA, Adjaye-Gbewonyo D, & Omer SB. (2012). Safety of influenza immunization during pregnancy for the fetus and the neonate. American Journal of Obstetrics and Gynecology, 207(3 Suppl):S38-S46. - Review. "There is a long history of research findings that highlight the safety of vaccinating pregnant women. This review summarizes nearly 40 years of research on influenza vaccination of pregnant women and the lack of association with adverse fetal or neonatal outcomes."

Fell DB, Platt RW, Lanes A, Wilson K, Kaufman JS, Basso O, & Buckeridge D. (2015). Fetal death and preterm birth associated with maternal influenza vaccination: systematic review. BJOG, 122(1): 17-26. - Systematic review. "Most studies reported no association between fetal death or preterm birth and influenza vaccination during pregnancy. Although several reported risk reductions, results may be biased by methodological shortcomings of observational studies of influenza vaccine effectiveness."

Fiore AE, Shay DK, Haber P, Iskander JK, Uyeki TM, Mootrey G, Bresee JS, & Cox NJ. (2007). Prevention and control of influenza. Recommendations of the Advisory Committee on Immunization Practices (ACIP), 2007. MMWR Recomm Rep 2007 (56):1–54 - Review. "[O]ne study of approximately 2,000 pregnant women who received TIV during pregnancy demonstrated no adverse fetal effects and no adverse effects during infancy or early childhood (326). A matched case-control study of 252 pregnant women who received TIV within the 6 months before delivery determined no adverse events after vaccination among pregnant women and no difference in pregnancy outcomes compared with 826 pregnant women who were not vaccinated (152). During 2000--2003, an estimated 2 million pregnant women were vaccinated, and only 20 adverse events among women who received TIV were reported to VAERS during this time, including nine injection-site reactions and eight systemic reactions (e.g., fever, headache, and myalgias). In addition, three miscarriages were reported, but these were not known to be causally related to vaccination (327). Similar results have been reported in several smaller studies (151,153,328)."

Glezen WP & Alpers M. (1999). Maternal immunization. Clinical Infectious Diseases, 28(2):219-224. - Review. Mentions the Collaborative Perinatal Project, conducted by the National Institute of Neurological and Communicative Disorders and Stroke. This project followed pregnant women and their offspring until 7 years of age, recording exposures during pregnancy (including influenza and poliovirus immunizations), labor and delivery events, and child malformations, hearing impairment, and learning disabilities. "[I]mmunizing agents as a group gave no evidence of being associated with the principal outcomes of the study."

Kharbanda EO, Vazquez-Benitez G, Shi WX, Lipkind H, Naleway A, Molitor B, Kuckler L, Olsen A, & Nordin JD. (2012). Assessing the safety of influenza immunization during pregnancy: the Vaccine Safety Datalink. American Journal of Obstetrics and Gynecology, 207(3 Suppl): S47-S51. - Review. "We describe ongoing analyses of influenza vaccine safety during pregnancy within the Vaccine Safety Datalink that includes the evaluation of acute events, adverse pregnancy and birth outcomes, and congenital anomalies."
Khromava A, Cohen CJ, Mazur M, Kanesa-thasan N, Crucitti A, Seifert H. (2012). Manufacturers' postmarketing safety surveillance of influenza vaccine exposure in pregnancy. American Journal of Obstetrics and Gynecology, 207(3 Suppl): S52-S56. Review. "This article reviews some of the pregnancy registries that have been established for US-licensed vaccines, which includes influenza vaccines, and other postlicensure safety surveillance efforts for monitoring safety in vaccinated pregnant women."

Loubet P, Kerneis S, Anselem O, Tsatsaris V, Goffinet F, & Launay O. (2014). Should expectant mothers be vaccinated against flu? A safety review. Expert Opinion on Drug Safety, 13(12): 1709-1720. - Review. "Available data suggest no evidence of an increased risk for any adverse event for both mothers and fetuses after vaccination against flu during pregnancy."

Mak TK, Mangtani P, Leese J, Watson JM, & Pfeifer D. (2008). Influenza vaccination in pregnancy: current evidence and selected national policies. Lancet Infectious Diseases, 8(1):44-52. - Review. "No serious adverse effects of influenza immunisation in pregnancy have been reported in the few published studies on vaccine safety. There are, however, limited data on safety in the first trimester. Furthermore, the risk from infection and hence the assumed benefit of vaccination in the first trimester are unclear."

McMillan M, Porritt K, Kralik D, Costi L, & Marshall H. (2015). Influenza vaccination during pregnancy: a systematic review of fetal death, spontaneous abortion, and congenital malformation safety outcomes. Vaccine, 33(18): 2108-2117. - Systematic review. "Results do not indicate that maternal influenza vaccination is associated with an increased risk of fetal death, spontaneous abortion, or congenital malformations."

Michiels B, Govaerts F, Remmen R, Vermeire E, & Coenen S. (2011). A systematic review of the evidence on the effectiveness and risks of inactivated influenza vaccines in different target groups. Vaccine, 29(49): 9159-9170. - Systematic review. "The vaccination of pregnant women might be beneficial for their newborns."

Moro PL, Tepper NK, Grohskopf LA, Vellozzi C, & Broder K. (2012). Safety of seasonal influenza and influenza A (H1N1) 2009 monovalent vaccines in pregnancy. Expert Review of Vaccines, 11(8): 911-921. - Review. "Studies conducted before 2009 did not identify any safety concerns after trivalent inactivated influenza vaccine in mothers or their infants. During the 2009-2010 influenza A (H1N1) influenza vaccination program, several monitoring systems were established or enhanced to assess whether adverse events were associated with H1N1 2009 monovalent vaccines (2009 H1N1 influenza vaccines). Data from these systems did not identify any safety concerns in pregnant women who received 2009 H1N1 influenza vaccines or their infants. Although live attenuated influenza vaccines are not recommended in pregnant women, a small number of studies have not shown any safety concern among pregnant women or their infants who were inadvertently exposed to these vaccines."

Naleway AL, Irving SA, Henninger ML, Li DK, Shifflett P, Ball S, Williams JL, Cragan J, Gee J, & Thompson MG; Vaccine Safety Datalink and Pregnancy and Influenza Project. (2014). Safety of influenza vaccination during pregnancy: a review of subsequent maternal obstetric events and findings from two recent cohort studies. Vaccine, 32(6):3122-3127. - Review. "No associations between inactivated influenza vaccination and gestational diabetes, gestational hypertension, preeclampsia/eclampsia, or chorioamnionitis were observed in either cohort. When considered as a whole, these studies should further reassure women and clinicians that influenza vaccination during pregnancy is safe for mothers."

Ortiz JR, Englund JA, & Neuzil KM. (2011). Influenza vaccine for pregnant women in resource-constrained countries: a review of the evidence to inform policy decisions. Vaccine, 29(27): 4439-4452. - Review. "The excellent safety profile and reliable immunogenicity of inactivated influenza vaccine support WHO recommendations that pregnant women be vaccinated to decrease complications of influenza disease during pregnancy." Includes table of studies summarizing designs and outcomes of studies in pregnant women and newborns.

Polyzos KA, Konstantelias AA, Pitsa CE, & Falagas ME. (2015). Maternal influenza vaccination and risk for congenital malformations: a systematic review and meta-analysis. Obstetrics and Gynecology, 126(5): 1075-1084. - Systematic review. "This systematic review did not indicate an increased risk for congenital anomalies after maternal influenza immunization adding to the evidence base on the safety of influenza vaccination in pregnancy."

Tamma PD, Ault KA, del Rio C, Steinhoff MC, Halsey NA, & Omer SB. (2009). Safety of influenza vaccination during pregnancy. American Journal of Obstetrics and Gynecology, 201(6): 547-552. - Review. "Inactivated influenza vaccine can be safely and effectively administered during any trimester of pregnancy. No study to date has demonstrated an increased risk of either maternal complications or untoward fetal outcomes associated with inactivated influenza vaccination. In addition, no scientific evidence exists that thimerosal-containing vaccines are a cause of adverse events among children born to women who received influenza vaccine during pregnancy. Immunization of the mother reduces 1 potential source of viral exposure to the infant, and immunization of other family members will decrease other potential sources. Health care workers caring for pregnant females can play a pivotal role in helping to protect women and newborns from this vaccine-preventable disease and should anticipate questions that expecting mothers may have regarding vaccine safety."

Studies

Abzug MJ, Nachman SA, Muresan P, Handelsman E, Watts DH, Fenton T, Heckman B, Petzold E, Weinberg A, & Levin MJ; International Maternal Pediatric Adolescent AIDS Clinical Trials Group P1086 Protocol Team. (2013). Safety and immunogenicity of 2009 pH1N1 vaccination in HIV-infected pregnant women. Clinical Infectious Diseases, 56(10): 1488-1497. - Prospective study. "Two 30-mcg doses were moderately immunogenic in HIV-infected pregnant women. No concerning vaccine-related safety signals were observed. Seroprotection persisted in most women postpartum. Efficient transplacental antibody transfer occurred, but seroprotection in infants waned rapidly. Vaccination to protect HIV-infected pregnant women and their newborns from new influenza strains is feasible, but more immunogenic platforms should be evaluated."

Beau AB, Hurault-Delarue C, Vidal S, Guitard C, Vayssière C, Petiot D, Montastruc JL, Damase-Michel C, & Lacroix I. (2014). Pandemic A/H1N1 influenza vaccination during pregnancy: a comparative study using the EFEMERIS database. Vaccine, 32(11): 1254-1258. - Prospective cohort study. "There was no significant association between adverse pregnancy outcomes and vaccination with a non-adjuvanted A/H1N1 vaccine during pregnancy."

Bratton KN, Wardle MT, Orenstein WA, & Omer SB. (2015). Maternal influenza immunization and birth outcomes of stillbirth and spontaneous abortion: a systematic review and meta-analysis. Clinical Infectious Diseases, 60(5): e11-19. - Systematic review. "Women in the influenza vaccine group had a lower likelihood of stillbirth (relative risk [RR], 0.73; 95% confidence interval [CI], .55–.96); this association was similar when restricted to the H1N1pdm09 vaccine (RR, 0.69; 95% CI, .53–.90). The pooled estimate for spontaneous abortion was not significant (RR, 0.91; 95% CI, .68–1.22). These analyses add to the evidence base for the safety of influenza vaccination in pregnancy."

Candela S, Pergolizzi S, Ragni P, Cavuto S, Nobilio L, Di Mario S, Dragosevic V, Groth N, & Magrini N; SaFoH1N1 working group. (2013). An early (3-6 weeks) active surveillance study to assess the safety of pandemic influenza vaccine Focetria in a province of Emilia-Romagna region, Italy - part one. Vaccine, 31(10): 1431-1437. - Prospective surveillance study. "No cases of clinically relevant AEs, SAEs, or AESI were observed within a six-week period of vaccine administration. In accordance with existing clinical and post-marketing safety data, the results of this active surveillance study demonstrate a good safety profile for the MF59-adjuvanted A/H1N1 vaccine, Focetria, within the general population."

Chambers CD, Johnson D, Xu R, Luo Y, Louik C, Mitchell AA, Schatz M, & Jones KL; OTIS Collaborative Research Group. (2013). Risks and safety of pandemic H1N1 influenza vaccine in pregnancy: birth defects, spontaneous abortion, preterm delivery, and small for gestational age infants. Vaccine, 31(44): 5026-5032. - Prospective cohort study. "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."

Chambers CD, Johnson DL, Xu R, Luo YJ, Louik C, Mitchell AA, Schatz M, & Jones KL; OTIS Collaborative Research Group. (2016). Safety of the 2010-11, 2011-12, 2012-13, and 2013-14 seasonal influenza vaccines in pregnancy: Birth defects, spontaneous abortion, preterm delivery, and small for gestational age infants, a study from the cohort arm of VAMPSS. Vaccine, 34(37): 4443-4449- Prospective cohort study. "Combining the 2010-2014 influenza seasons, we found a moderately elevated RR for major birth defects overall, but no evidence of a specific pattern; 95% CIs included 1, and this finding could be due to chance. In the combined seasons, we found no meaningful evidence of an increased risk for spontaneous abortion or preterm delivery following exposure to the seasonal influenza vaccine."

Chavant F, Ingrand I, Jonville-Bera AP, Plazanet C, Gras-Champel V, Lagarce L, Zenut M, Disson-Dautriche A, Logerot S, Auffret M, Coubret-Dumas A, Bruel ML, Boyer M, Bos-Thompson MA, Veyrac G, Carlier P, Beyens MN, Lates S, Damase-Michel C, Castot A, Kreft-Jaïs C, & Pérault-Pochat MC. (2013). The PREGVAXGRIP study: a cohort study to assess foetal and neonatal consequences of in utero exposure to vaccination against A(H1N1)v2009 influenza. Drug Safety, 36(6): 455-465. - Prospective cohort study. "This study suggests that exposure to the A(H1N1)v2009 pandemic influenza vaccine during pregnancy does not increase the risk of adverse pregnancy outcomes. However, because of the relatively small number of women exposed during the first trimester, other studies are needed to exclude an increased risk of malformation."

Choe YJ, Cho H, Song KM, Kim JH, Han OP, Kwon YH, Bae GR, Lee HJ, & Lee JK. (2011). Active surveillance of adverse events following immunization against pandemic influenza A (H1N1) in Korea. Japanese Journal of Infectious Diseases, 64(4): 297-303. - Survey. "The non-adjuvanted vaccine was found to be safe for pregnant women, as suggested by other studies (25,26)."

Cleary BJ, Rice Ú, Eogan M, Metwally N, & McAuliffe F. (2014). 2009 A/H1N1 influenza vaccination in pregnancy: uptake and pregnancy outcomes - a historical cohort study. European Journal of Obstetrics, Gynecology, and Reproductive Biology, 178: 163-168. - Retrospective cohort study. "There was no association between vaccination during pregnancy and adverse pregnancy outcomes. Women who were vaccinated were less likely to have a preterm delivery than unvaccinated women."

Conlin AM, Bukowinski AT, Sevick CJ, DeScisciolo C, & Crum-Cianflone NF. (2013). Safety of the pandemic H1N1 influenza vaccine among pregnant U.S. military women and their newborns. Obstetrics and Gynecology, 121(3): 511-518. - Retrospective cohort study. "No adverse pregnancy or newborn health outcomes associated with pandemic H1N1 vaccination during pregnancy were noted among our cohort. These findings should be used to encourage increased vaccine coverage among pregnant women."

Deinard AS & Ogburn P Jr. (1981). A/NJ/8/76 influenza vaccination program: effects on maternal health and pregnancy outcome. American Journal of Obstetrics and Gynecology, 140(3): 240-245. - Prospective case-control study. "This longitudinal, prospective 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 assessments at birth and at 8 weeks of life."

de Vries L, van Hunsel F, Cuppers-Maarschalkerweerd B, van Puijenbroek E, & van Grootheest K. (2014). Adjuvanted A/H1N1 (2009) influenza vaccination during pregnancy: description of a prospective cohort and spontaneously reported pregnancy-related adverse reactions in the Netherlands. Birth Defects Research. Part A, Clinical and Molecular Teratology, 100(10):731-738. - Prospective cohort study. "Compared with the background rate, no increased risk of spontaneous abortions or congenital malformations was observed. There were three spontaneous abortions among 23 first trimester exposures. In the cohort of 281 pregnancies with known outcomes, three major malformations were observed after exposure at any time during pregnancy. In these cases exposure occurred once periconceptional, and twice in the second trimester. Furthermore, no increased risk of adverse pregnancy outcomes or neonatal problems were observed. The spontaneously reported pregnancy-related adverse events showed no unexpected pattern."

Dodds L, Macdonald N, Scott J, Spencer A, Allen VM, & McNeil S. (2012). The association between influenza vaccine in pregnancy and adverse neonatal outcomes. Journal of Obstetrics and Gynaecology Canada, 34(8): 714-720. - Prospective cohort study. "The results of our study showed consistent improvement after maternal influenza vaccination (or a trend towards improvement) in newborn outcomes for all five outcomes analyzed. Newborns whose mother had received the influenza vaccine during pregnancy had significantly lower rates of low birth weight and SGA."

Fabiani M, Bella A, Rota MC, Clagnan E, Gallo T, D'Amato M, Pezzotti P, Ferrara L, Demicheli V, Martinelli D, Prato R, & Rizzo C. (2015). A/H1N1 pandemic influenza vaccination: a retrospective evaluation of adverse maternal, fetal and neonatal outcomes in a cohort of pregnant women in Italy. Vaccine, 33(19): 2240-2247. - Retrospective cohort study. "We did not observe any statistically significant association between the A/H1N1 pandemic influenza vaccination and different maternal outcomes (hospital admissions for influenza, pneumonia, hypertension, eclampsia, diabetes, thyroid disease, and anaemia), fetal outcomes (fetal death after the 22nd gestational week) and neonatal outcomes (pre-term birth, low birth weight, low 5-min Apgar score, and congenital malformations)."

Fell DB, Sprague AE, Liu N, Yasseen AS 3rd, Wen SW, Smith G, & Walker MC; Better Outcomes Registry & Network (BORN) Ontario. (2012). H1N1 influenza vaccination during pregnancy and fetal and neonatal outcomes. American Journal of Public Health, 102(6): e33-40. - Cohort study. "Our results suggest that second- or third-trimester H1N1 vaccination was associated with improved fetal and neonatal outcomes during the recent pandemic. Our findings need to be confirmed in future studies with designs that can better overcome concerns regarding biased estimates of vaccine efficacy."
Fisher BM, Van Bockern J, Hart J, Lynch AM, Winn VD, Gibbs RS, & Weinberg A. (2012). Pandemic influenza A H1N1 2009 infection versus vaccination: a cohort study comparing immune responses in pregnancy. PLoS One, 7(3):e33048. - Cohort study. "Vaccination against pH1N1 confers a similar HAI antibody response as compared to pH1N1 infection during pregnancy, both in quantity and quality. Illness or vaccination during pregnancy confers passive immunity to the newborn."

Heikkinen T, Young J, van Beek E, Franke H, Verstraeten T, Weil JG, & Della Cioppa G. (2012). Safety of MF59-adjuvanted A/H1N1 influenza vaccine in pregnancy: a comparative cohort study. American Journal of Obstetrics and Gynecology, 207(3): 177.e1-8. - Cohort study. "No maternal deaths or abortions occurred among the vaccinated women. No differences between the vaccinated and unvaccinated cohorts were observed for gestational diabetes, preeclampsia, stillbirth, low birthweight, neonatal deaths, or congenital malformations. The risk of premature birth was significantly decreased among the vaccinated women (adjusted proportional hazard, 0.69; 95% confidence interval, 0.51-0.92). No differences were observed in rates of congenital malformations after vaccination in the first (2.1%), second (2.7%), or third (2.1%) trimesters."

Heinonen OP, Shapiro S, Monson RR, Hartz SC, Rosenberg L, & Slone D. (1973). Immunization during pregnancy against poliomyelitis and influenza in relation to childhood malignancy. International Journal of Epidemiology, 2(3): 229-235. - Case-control study. Part of the Collaborative Perinatal Project. Included 2,291 women who were immunized with influenza vaccine while pregnant. "There was no evidence of an excess of malignancies in children exposed in utero to attenuated live polio vaccine, to influenza vaccine, or to spontaneous viral infections."

Horiya M, Hisano M, Iwasaki Y, Hanaoka M, Watanabe N, Ito Y, Kojima J, Sago H, Murashima A, Kato T, & Yamaguchi K. (2011). Efficacy of double vaccination with the 2009 pandemic influenza A (H1N1) vaccine during pregnancy. Obstetrics and Gynecology, 118(4): 887-894. - Cohort study. "The overall incidence of adverse reactions was low, less than 10% for all adverse reactions except for redness, because the vaccine is a split vaccine containing no adjuvant. In participants who received double 2009 H1N1 vaccination during pregnancy, adverse reactions were not markedly augmented or attenuated by the second vaccination. Moreover, early delivery or abortion, malformation, and birth weight were not significantly affected. Nonetheless, the sample size was insufficient to fully evaluate the safety of the vaccine; additional information from larger studies is needed to determine this."

Huang WT, Chen WC, Teng HJ, Huang WI, Huang YW, Hsu CW, & Chuang JH. (2011). Adverse events following pandemic A (H1N1) 2009 monovalent vaccines in pregnant women--Taiwan, November 2009-August 2010. PLoS One, 6(8): e.23049. - Surveillance study. "The passive surveillance provided rapid initial assessment of adverse events after 2009 H1N1 vaccination among pregnant women. Its findings were reassuring for the safety of 2009 H1N1 vaccines in pregnancy."

Irving SA, Kieke BA, Donahue JG, Mascola MA, Baggs J, DeStefano F, Cheetham TC, Jackson LA, Naleway AL, Glanz JM, Nordin JD, & Belongia EA; Vaccine Safety Datalink. (2013). Trivalent inactivated influenza vaccine and spontaneous abortion. Obstetrics and Gynecology, 121(1): 159-165. - Case-control study. "There was no statistically significant increase in the risk of pregnancy loss in the 4 weeks after seasonal inactivated influenza vaccination."

Jackson LA, Patel SM, Swamy GK, Frey SE, Creech CB, Munoz FM, Artal R, Keitel WA, Noah DL, Petrie CR, Wolff M, & Edwards KM. (2011). Immunogenicity of an inactivated monovalent 2009 H1N1 influenza vaccine in pregnant women. The Journal of Infectious Diseases, 204(6): 854-863. - Prospective clinical trial. "Eighteen SAEs were reported for 15 women, and 24 SAEs were reported for 20 infants; all were considered to be unrelated to the vaccine, and the frequency of events was generally balanced across study groups, with 9 of the 15 maternal SAEs and 13 of the 20 infant SAEs reported in the 25-mcg dose group."

Källén B & Olausson PO. (2012). Vaccination against H1N1 influenza with Pandemrix(®) during pregnancy and delivery outcome: a Swedish register study. BJOG, 119(13): 1583-1590. - Cohort study. "A total of 18 612 vaccinated women having 18 844 infants were studied. The risk for stillbirth, preterm birth and low birthweight was lower than in the comparison groups whereas the risk for small for gestational age and a congenital malformation (after vaccination during the first trimester) did not differ from the comparison groups."

Kharbanda EO, Vazquez-Benitez G, Lipkind H, Naleway A, Lee G, & Nordin JD; Vaccine Safety Datalink Team. (2013). Inactivated influenza vaccine during pregnancy and risks for adverse obstetric events. Obstetrics and Gynecology, 122(3): 659-667. - Cohort study. "Our cohort included 74,292 vaccinated females matched on age, site, and pregnancy start date with 144,597 unvaccinated females. We did not observe increased risks within 42 days of vaccination for hyperemesis, chronic hypertension, gestational hypertension, gestational diabetes, proteinuria, or urinary tract infection. Using a risk window from vaccination through pregnancy end, we did not observe increased risks after vaccination for proteinuria, urinary tract infection, gestational hypertension, preeclampsia or eclampsia, chorioamnionitis, puerperal infection, venous complications, pulmonary embolism, or peripartum cardiomyopathy."

Launay O, Krivine A, Charlier C, Truster V, Tsatsaris V, Lepercq J, Ville Y, Avenell C, Andrieu T, Rozenberg F, Artiguebielle F, Tréluyer JM, & Goffinet F; Inserm COFLUPREG Study Group. (2012). 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, 7(12): e52303. - Prospective cohort study. "Despite low vaccine coverage, incidence of pandemic flu was low in this cohort of pregnant women.No effect on pregnancy and delivery outcomes was evidenced after vaccination."

Lim SH, Lee JH, Kim BC, Jung SU, Park YB, & Lee CS. (2010). Adverse reaction of influenza A (H1N1) 2009 virus vaccination in pregnant women and its effect on newborns. Vaccine, 28(47): 7455-7456. - Survey. "This study was focused on the safety of pregnant women who were vaccinated for pandemic (H1N1) 2009 virus, since very little such studies have been done to the best of our knowledge. In our study, various adverse reactions developed after vaccination, but the symptoms were mild and resolved within several days without requiring any treatment or hospitalization."

Lin TH, Lin SY, Lin CH, Lin RI, Lin HC, Chiu TH, Cheng PJ, & Lee CN. (2012). AdimFlu-S(®) influenza A (H1N1) vaccine during pregnancy: the Taiwanese Pharmacovigilance Survey. Vaccine, 30(16): 2671-2675. - Retrospective cohort study. "During the observation period of each cohort, four subjects (2.0%) in the exposed group experienced vaccine-related adverse events that were mild in severity. A total of 17 women (8.6%) in the vaccine exposed group and 40 women (20.2%) in the unexposed group underwent at least one adverse effect during their pregnancy. A total of 72 infants (35.6%) in the exposed group and 101 infants (49%) in the unexposed group had at least one adverse event within 8 weeks after they were born (p < 0.05). The adverse events experienced by the women and their infants were not increased when the vaccine was administered during the first trimester. There were no significant differences between these two groups with regard to preterm delivery rate and stillbirth rate."

Louik C, Ahrens K, Kerr S, Pyo J, Chambers C, Jones KL, Schatz M, & Mitchell AA. (2013). Risks and safety of pandemic H1N1 influenza vaccine in pregnancy: exposure prevalence, preterm delivery, and specific birth defects. Vaccine, 31(44): 5033-5040. - Prospective cohort study. "Among women exposed to pH1N1 vaccine, we found a decreased risk for PTD in the 2010-2011 season; risk was increased in 2009-2010, particularly following exposure in the first trimester, though the decrease in gestational length was less than 2 days. For specific major defects, we found no meaningful evidence of increased risk for specific congenital malformations following pH1N1 influenza vaccinations in the 2009-2010 and 2010-2011 seasons."

Louik C, Kerr S, Van Bennekom CM, Chambers C, Jones KL, Schatz M, & Mitchell AA. (2016). Safety of the 2011-12, 2012-13, and 2013-14 seasonal influenza vaccines in pregnancy: Preterm delivery and specific malformations, a study from the case-control arm of VAMPSS. Vaccine, 34(37): 4450-4459. - Prospective case-control study. "For PTD (1803 fullterm deliveries, 107 PTD for all seasons combined), an elevated adjusted risk was observed for only the 2nd trimester of the 2011-12 season (HR=2.60, 95% CI 1.21, 5.61) - a reduction in gestational length of < 2 days. For the 42 specific defects or categories of defects (2866 cases, 1411 controls for all seasons combined) most adjusted risks were close to 1.0; the highest was 2.38 for omphalocele and the lowest was 0.50 for atrioventricular canal defects. None had lower confidence bounds >1.0. For each season separately, only one elevated OR had a lower 95% CI >1.0: omphalocele in 2011-12 (OR=5.19, 95% CI 1.44, 18.7)."

Ludvigsson JF, Ström P, Lundholm C, Cnattingius S, Ekbom A, Örtqvist Å, Feltelius N, Granath F, & Stephansson O. (2015). Maternal vaccination against H1N1 influenza and offspring mortality: population based cohort study and sibling design. BMJ, 351: h5585. - Prospective, population-based cohort study. "H1N1 vaccination during pregnancy is not associated with adverse fetal outcome or offspring mortality, including when familial factors are taken into account."

Ludvigsson JF, Zugna D, Cnattingius S, Richiardi L, Ekbom A, Örtqvist Å, Persson I, & Stephansson O. (2013). Influenza H1N1 vaccination and adverse pregnancy outcome. European Journal of Epidemiology, 28(7): 579-588. - Retrospective cohort study. "H1N1 vaccination during pregnancy, using an AS03-adjuvanted vaccine, does not appear to adversely influence offspring risks of LBW, preterm birth, SGA, or low Apgar score. Our results suggest that this vaccine is safe for the offspring when used in different stages of pregnancy."

Ma F, Zhang L, Jiang R, Zhang J, Wang H, Gao X, Li X, & Liu Y. (2014). Prospective cohort study of the safety of an influenza A(H1N1) vaccine in pregnant Chinese women. Clinical and Vaccine Immunology, 21(9): 1282-1287. - Prospective cohort study. "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."

Madhi SA, Cutland CL, Kuwanda L, Winberg A, Hugo A, Jones S, Adrian PV, van Niekerk N, Treurnicht F, Ortiz JR, Venter M, Violari A, Neuzil KM, Simões EA, Klugman KP, Nunes MC, & Maternal Flu Trial (Matflu) Team. (2014). Influenza vaccination of pregnant women and protection of their infants. The New England Journal of Medicine, 371(10): 918-931. - Randomized, saline-placebo-controlled trial. "Injection-site reactions (mainly mild to moderate) were more frequent among IIV3 recipients than among placebo recipients in both cohorts, but there were no other significant differences in solicited reactions between the two study groups in either cohort. Data on serious adverse events in both cohorts, including infant and maternal deaths and hospitalizations, are shown in Tables S11 to S23 in the Supplementary Appendix. There were no significant between-group differences with regard to rates of miscarriage, stillbirth, or premature birth or birth weight in the HIV-uninfected cohort (Table 1, and Table S11 in the Supplementary Appendix) and in the HIV-infected cohort (Table 2)." Also notes protection against influenza of mothers and their infants versus placebo controls.

Moro PL, Broder K, Zheteyeva Y, Revzina N, Tepper N, Kissin D, Barash F, Arana J, Brantley MD, Ding H, Singleton JA, Walton K, Haber P, Lewis P, Yue X, Destefano F, & Vellozzi C. (2011). Adverse events following administration to pregnant women of influenza A (H1N1) 2009 monovalent vaccine reported to the Vaccine Adverse Event Reporting System. American Journal of Obstetrics and Gynecology, 205(5): 473.e1-9. - Surveillance study. "Review of reports to VAERS following H1N1 vaccination in pregnant women did not identify any concerning patterns of maternal or fetal outcomes."
Moro PL, Broder K, Zheteyeva Y, Walton K, Rohan P, Sutherland A, Guh A, Haber P, Destefano F, & Vellozzi C. (2011). Adverse events in pregnant women following administration of trivalent inactivated influenza vaccine and live attenuated influenza vaccine in the Vaccine Adverse Event Reporting System, 1990-2009. American Journal of Obstetrics and Gynecology, 204(2): 146.e1-7. - Surveillance study. "No unusual patterns of pregnancy complications or fetal outcomes were observed in the VAERS reports of pregnant women after the administration of TIV or LAIV."

Moro PL, Museru OI, Broder K, Cragan J, Zheteyeva Y, Tepper N, Revzina N, Lewis P, Arana J, Barash F, Kissin D, & Vellozzi C. (2013). Safety of influenza A (H1N1) 2009 live attenuated monovalent vaccine in pregnant women. Obstetrics and Gynecology, 122(6):1271-1278. - Retrospective surveillance study. "Rates of spontaneous abortion, preterm birth, and major birth defects in pregnant women who received live H1N1 vaccine were similar to or lower than published background rates. No concerning patterns of medical conditions in infants were identified."

Munoz FM, Greisinger AJ, Wehmanen OA, Mouzoon ME, Hoyle JC, Smith FA, & Glezen WP. (2005). Safety of influenza vaccination during pregnancy. American Journal of Obstetrics and Gynecology, 192(4):1098-1106. - Cohort study. "Among 7183 eligible mother-infant pairs, only 252 pregnant women (3.5%) received the influenza vaccine...No serious adverse events occurred within 42 days of vaccination, and there was no difference between the groups in the outcomes of pregnancy (including cesarean delivery and premature delivery) and infant medical conditions from birth to 6 months of age. CONCLUSION: Influenza vaccine that was administered in the second or third trimester of gestation was safe in this study population."

Nordin JD, Kharbanda EO, Benitez GV, Nichol K, Lipkind H, Naleway A, Lee GM, Hambidge S, Shi W, & Olsen A. (2013). Maternal safety of trivalent inactivated influenza vaccine in pregnant women. Obstetrics and Gynecology, 121(3): 519-525. - Retrospective cohort study. "Receipt of trivalent inactivated influenza vaccine during pregnancy was not associated with increased risk of adverse events in the 42 days after vaccination, supporting its safety for the mother."

Nordin JD, Kharbanda EO, Vazquez-Benitez G, Lipkind H, Lee GM, & Naleway AL. (2014). Monovalent H1N1 influenza vaccine safety in pregnant women, risks for acute adverse events. Vaccine, 32(39): 4985-4992. - Cohort study. "In this large cohort of pregnant women no acute safety signals were identified within 6 weeks of receipt of MIV."

Nordin JD, Kharbanda EO, Vazquez Benitez G, Lipkind H, Vellozzi C, & Destefano F; Vaccine Safety Datalink. (2014). Maternal influenza vaccine and risks for preterm or small for gestational age birth. Journal of Pediatrics, 164(5): 1051-1057. - Retrospective cohort study. "Receipt of trivalent inactivated influenza vaccine during pregnancy was not associated with increased or decreased risk of preterm or SGA birth. These findings support the safety of vaccinating pregnant women against influenza during the first, second, and third trimesters, and suggest that a nonspecific protective effect of the influenza vaccine for these outcomes does not exist."

Ohfuji S, Fukushima W, Deguchi M, Kawabata K, Yoshida H, Hatayama H, Maeda A, & Hirota Y. (2011). Immunogenicity of a monovalent 2009 influenza A (H1N1) vaccine among pregnant women: lowered antibody response by prior seasonal vaccination. The Journal of Infectious Diseases, 203(9): 1301-1308. - Prospective cohort study. "No severe adverse events occurred among pregnant women and their fetuses throughout the study period. One fetal death was reported on the day after vaccination; however, a pathologic diagnosis indicated that the fetal death had occurred >=7 days before the H1N1 vaccination. Therefore, the fetal death was unrelated to the vaccination. Previous studies about the reactogenicity of seasonal influenza vaccine also reported no severe adverse events among fetuses and infants"

Omer SB, Goodman D, Steinhoff MC, Rochat R, Klugman KP, Stoll BJ, & Ramakrishnan U. (2011). Maternal influenza immunization and reduced likelihood of prematurity and small for gestational age births: a retrospective cohort study. PLoS Medicine, 8(5): e.1000441. - Retrospective cohort study. "This study demonstrates an association between immunization with the inactivated influenza vaccine during pregnancy and reduced likelihood of prematurity during local, regional, and widespread influenza activity periods. However, no associations were found for the pre-influenza activity period. Moreover, during the period of widespread influenza activity there was an association between maternal receipt of influenza vaccine and reduced likelihood of SGA birth."

Omon E, Damase-Michel C, Hurault-Delarue C, Lacroix I, Montastruc JL, Oustric S, & Escourrou B. (2011). Non-adjuvanted 2009 influenza A (H1N1)v vaccine in pregnant women: the results of a French prospective descriptive study. Vaccine, 29(52): 9649-9654. - Prospective cohort study. "569 pregnant women were monitored until delivery. Compared with the general population, the risks of maternal conditions, malformations and neonatal conditions were not statistically different."

Oppermann M, Fritzsche J, Weber-Schoendorfer C, Keller-Stanislawski B, Allignol A, Meister R, & Schaefer C. (2012). A(H1N1)v2009: a controlled observational prospective cohort study on vaccine safety in pregnancy. Vaccine, 30(30): 4445-4452. - Prospective cohort study. "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."

Pasternak B, Svanström H, Mølgaard-Nielsen D, Krause TG, Emborg HD, Melbye M, & Hviid A. (2012). Risk of adverse fetal outcomes following administration of a pandemic influenza A(H1N1) vaccine during pregnancy. JAMA, 308(2): 165-174. - Cohort study. "In this Danish cohort, exposure to an adjuvanted influenza A(H1N1)pdm09 vaccine during pregnancy was not associated with a significantly increased risk of major birth defects, preterm birth, or fetal growth restriction."

Pasternak B, Svanström H, Mølgaard-Nielsen D, Krause TG, Emborg HD, Melbye M, Hviid A. (2012). Vaccination against pandemic A/H1N1 2009 influenza in pregnancy and risk of fetal death: cohort study in Denmark. BMJ, 344:e2794. - Cohort study. "This large cohort study found no evidence of an increased risk of fetal death associated with exposure to an adjuvanted pandemic A/H1N1 2009 influenza vaccine during pregnancy."

Poehling KA, Szilagyi PG, Staat MA, Snively BM, Payne DC, Bridges CB, Chu SY, Light LS, Prill MM, Finelli L, Griffin MR, & Edwards KM; New Vaccine Surveillance Network. (2011). Impact of maternal immunization on influenza hospitalizations in infants. American Journal of Obstetrics and Gynecology, 204(6 Suppl 1): S141-148. - Case control study. "Our results indicate that hospitalized infants whose mothers received influenza vaccine during pregnancy were 45% to 48% less likely to have laboratory-confirmed influenza during their first influenza season compared with infants of unvaccinated mothers. Adding history of influenza-like illness during pregnancy to the analyses had little impact on the odds ratio for having an influenza-positive, hospitalized infant. Given that infants < 6 months of age have the highest hospitalization rate among all children2–6 and that the vaccine is not licensed for that age group,16 these data support that infants born to vaccinated mothers benefit from the transfer of maternally derived antibodies."

Regan AK, de Klerk N, Moore HC, Omer SB, Shellam G, & Effler PV. (2016). Effect of maternal influenza vaccination on hospitalization for respiratory infections in newborns: a retrospective cohort study. The Pediatric Infectious Disease Journal. Epub ahead of print. - Retrospective cohort study. "3,169 infants were maternally vaccinated and 27,859 were unvaccinated; 732 hospitalizations were identified, 528 (69%) of which were for bronchiolitis. There were 21.9 hospitalizations per 100,000 person days among maternally vaccinated infants, and 30.2 hospitalizations per 100,000 person days among unvaccinated infants. Maternally vaccinated infants were 25% less likely to be hospitalized for an acute respiratory illness during influenza season compared with unvaccinated infants (aHR: 0.75, 95% CI: 0.56-0.99, p=0.04). Vaccinations administered in the third trimester were associated with a 33% reduction in the risk of newborn hospitalization (aHR: 0.67, 95% CI: 0.47-0.95, p=0.03). No such reduction was identified for vaccinations administered earlier in pregnancy."
Regan AK, Moore HC, de Klerk N, Omer SB, Shellam G, Mak DB, & Effler PV. (2016). Seasonal trivalent influenza vaccination during pregnancy and the incidence of stillbirth: population-based retrospective cohort study. Clinical Infectious Diseases, 62(10): 1221-1227. - Retrospective cohort study. "Mothers who received seasonal TIV during pregnancy were significantly less likely to experience stillbirth compared with unvaccinated mothers. These results support the safety of seasonal influenza immunization during pregnancy and suggest a protective effect."

Regan AK, Tracey L, Blyth CC, Mak DB, Richmond PC, Shellam G, Talbot C, & Effler PV. (2015). A prospective cohort study comparing the reactogenicity of trivalent influenza vaccine in pregnant and non-pregnant women. BMC Pregnancy and Childbirth, 15: 61. - Prospective cohort study. "No other significant differences in reported symptoms were observed. No serious vaccine-associated adverse events were reported, and less than 2% of each group sought medical advice for a reaction. CONCLUSIONS: We found no evidence suggesting pregnant women are more likely to report adverse events following influenza vaccination when compared to non-pregnant female HCWs of similar age, and in some cases, pregnant women reported significantly fewer adverse events. These results further support the safety of TIV administered in pregnant women."

Richards JL, Hansen C, Bredfeldt C, Bednarczyk RA, Steinhoff MC, Adjaye-Gbewonyo D, Ault K, Gallagher M, Orenstein W, Davis RL, & Omer SB. (2013). Neonatal outcomes after antenatal influenza immunization during the 2009 H1N1 influenza pandemic: impact on preterm birth, birth weight, and small for gestational age birth. Clinical Infectious Diseases, 56(9): 1216-1222. - Retrospective cohort study. "Pregnant women who received H1N1 influenza vaccine were less likely to give birth preterm, and gave birth to heavier infants. The findings support US vaccine policy choices to prioritize pregnant women during the 2009 influenza A (H1N1) pandemic."

Ropero-Álvarez AM, Whittembury A, Bravo-Alcántara P, Kurtis HJ, Danovaro-Holliday MC, & Velandia-González M. (2015). Events supposedly attributable to vaccination or immunization during pandemic influenza A (H1N1) vaccination campaigns in Latin America and the Caribbean. Vaccine, 33(1): 187-192. - "The rate of serious ESAVI reported in LAC (6.91 per million doses) was significantly lower than the rate reported in Europe (38.2 per million doses) and slightly lower than in the United States (8.8 per million doses) and China (7.9 per million doses), where ESAVI notification was also through passive surveillance systems [19], [20] and [21]."

Rubinstein F, Micone P, Bonotti A, Wainer V, Schwarcz A, Augustovski F, Pichon Riviere A, & Karolinski A; EVA Study Research Group Estudio Embarazo y Vacuna Antigripal. (2013). Influenza A/H1N1 MF59 adjuvanted vaccine in pregnant women and adverse perinatal outcomes: multicentre study. BMJ, 346:f393. - Prospective cohort study. "This study showed that adjuvanted MF59 H1N1 vaccination during pregnancy did not result in an increased risk of adverse maternal or perinatal events in a large sample of women. In fact, vaccination was associated with a lower risk of events, both in the overall study population and in the different subgroups in the sensitivity analysis."

Sheffield JS, Greer LG, Rogers VL, Roberts SW, Lytle H, McIntire DD, & Wendel GD Jr. (2012). Effect of influenza vaccination in the first trimester of pregnancy. Obstetrics and Gynecology, 120(3): 532-537. - Retrospective cohort study. "Neonates born to mothers receiving the vaccine in any trimester did not have an increase in major malformations regardless of trimester of vaccination (2% regardless of vaccination group, P=.9). Stillbirth (0.3% compared with 0.6%, P=.006), neonatal death (0.2% compared with 0.4%, P=.01), and premature delivery (5% compared with 6%, P=.004) were significantly decreased in the vaccinated group."

Steinhoff MC, Omer SB, Roy E, El Arifeen S, Raqib R, Dodd C, Breiman RF, & Zaman K. (2012). Neonatal outcomes after influenza immunization during pregnancy: a randomized controlled trial. CMAJ, 184(6): 645-653. - Randomized, controlled trial. "During the period with circulating influenza virus, maternal immunization during pregnancy was associated with a lower proportion of infants who were small for gestational age and an increase in mean birth weight. These data need confirmation but suggest that prevention of influenza infection in pregnancy can influence intrauterine growth."

Sumaya CV & Gibbs RS. (1979). Immunization of pregnant women with influenza A/New Jersey/76 virus vaccine: reactogenicity and immunogenicity in mother and infant. Journal of Infectious Diseases, 140(2): 141-146. - "In this study, 56 women received inactivated influenza A/New Jersey/76 virus vaccine during the second and third trimesters of pregnancy. No significant immediate reactions or increased fetal complications were associated with administration of the vaccine."

Tavares F, Nazareth I, Monegal JS, Kolte I, Verstraeten T, & Bauchau V. (2011). Pregnancy and safety outcomes in women vaccinated with an AS03-adjuvanted split virion H1N1 (2009) pandemic influenza vaccine during pregnancy: a prospective cohort study. Vaccine, 29(37): 6358-6365. - Prospective cohort study. "The adverse events reported were consistent with the events anticipated to be reported by this study population. No adverse events of special interest were reported. The results of this analysis suggest that exposure to the AS03 adjuvanted H1N1 (2009) vaccine during pregnancy does not increase the risk of adverse pregnancy outcomes including spontaneous abortion, congenital anomalies, preterm delivery, low birth weight neonates, or maternal complications. Although limited in size, the fully prospective nature of the safety follow-up of these women vaccinated during pregnancy is unique and offers an important degree of reassurance for the use of the AS03 adjuvanted H1N1 (2009) vaccine in this high risk group for H1N1 infection."

Thompson MG, Li DK, Shifflett P, Sokolow LZ, Ferber JR, Kurosky S, Bozeman S, Reynolds SB, Odouli R, Henninger ML, Kauffman TL, Avalos LA, Ball S, Williams JL, Irving SA, Shay DK, & Naleway AL; Pregnancy and Influenza Project Workgroup. (2014). Effectiveness of seasonal trivalent influenza vaccine for preventing influenza virus illness among pregnant women: a population-based case-control study during the 2010-2011 and 2011-2012 influenza seasons. Clinical Infectious Diseases, 58(4):449-457. - Case-control study. "Influenza vaccination reduced the risk of ARI associated with laboratory-confirmed influenza among pregnant women by about one-half, similar to VE observed among all adults during these seasons."

Toback SL, Beigi R, Tennis P, Sifakis F, Calingaert B, & Ambrose CS. (2012). Maternal outcomes among pregnant women receiving live attenuated influenza vaccine. Influenza and Other Respiratory Viruses, 6(1): 44-51. - Cohort study. "In this cohort, there was no evidence of significant maternal adverse outcomes after receipt of LAIV. These data may offer some reassurance to providers and pregnant women in the event of inadvertent LAIV administration, but do not support the routine use of LAIV in pregnant women."

Trotta F, Da Cas R, Spila Alegiani S, Gramegna M, Venegoni M, Zocchetti C, & Traversa G. (2014). Evaluation of safety of A/H1N1 pandemic vaccination during pregnancy: cohort study. BMJ, 348. - Cohort study. "No increased risk of either fetal or birth outcomes was seen following vaccination, whereas a limited increase in the prevalence of gestational diabetes and eclampsia was observed."

Wortman AC, Casey BM, McIntire DD, & Sheffield JS. (2015). Association of influenza vaccination on decreased stillbirth rate. American Journal of Perinatology, 32(6): 571-576 - Retrospective cohort study. "During the study period, 8,690 pregnant women received the seasonal influenza vaccine antepartum and delivered at our institution. Thirty of these births were complicated by stillbirth as compared with 436 stillbirths in the 76,153 women not vaccinated (0.35 vs. 0.57%, p = 0.006). No association was identified between assigned causes of stillbirth when comparing vaccinated and nonvaccinated women."

Yeager DP, Toy EC, & Baker B 3rd. (1999). Influenza vaccination in pregnancy. American Journal of Perinatology, 16(6): 283-286. - "A total of 448 eligible pregnant women were offered the influenza vaccine at routine prenatal visits. Vaccinated women were interviewed at their subsequent visit regarding adverse effects and attitudes toward future vaccination. Of the 448 women studied, 319 (71.2%) accepted the vaccine. There was no difference in acceptance rates between English- and Spanish-speaking women. Mild adverse reactions were experienced by 5.3%...The influenza vaccine is readily accepted by pregnant women, and is infrequently associated with mild side effects."

Zaman K, Roy E, Arifeen SE, Rahman M, Raqib R, Wilson E, Omer S, Shahid N, Breiman RF, & Steinhoff MC. (2008). Effectiveness of maternal influenza immunization in mothers and infants. The New England Journal of Medicine, 359(15): 1555-1564. - Randomized controlled trial. "A total of 340 women in the third trimester of pregnancy who met the inclusion criteria agreed to participate in the study. The mothers and infants in the two study groups were similar in both demographic and other characteristics (Table 1). Minor local and systemic side effects that occurred during the first 7 days after immunization were similar in the two groups of mothers except for local pain, which was more frequent among the mothers who received pneumococcal vaccine. The difference in the rate of severe adverse events between the two groups was not significant (for details, see the Supplementary Appendix)."

Risks of Influenza During Pregnancy

Centers for Disease Control and Prevention. (2011). Maternal and infant outcomes among severely ill pregnant and postpartum women with 2009 pandemic influenza A (H1N1)--United States, April 2009-August 2010. MMWR: Morbidity and Mortality Weekly Report, 60(35): 1193-1196. - Case review. "This report summarizes the results of that analysis, which found that, among 347 severely ill pregnant women, 75 died from 2009 H1N1, and 272 were admitted to an intensive-care unit (ICU) and survived. Women who survived received antiviral treatment sooner after symptom onset than women who died. Pregnant women with severe influenza who delivered during their influenza hospitalization were more likely to deliver preterm and low birth weight infants than those in the general U.S. population; infants born after their mother's influenza hospitalization discharge were more likely to be small for gestational age."

Gruslin A, Steben M, Halperin S, Money DM, Yudin MH, Boucher M, Cormier B, Ogilvie G, Paquet C, Steenbeek A, Van Eyk N, van Schalkwyk J, & Wong T. (2009). Immunization in pregnancy. Journal of Obstetrics and Gynaecology Canada, 30(12):1149-1154. - Review of literature. "Pregnancy is associated with significant cardiovascular and respiratory demands, as evidenced by increases in stroke volume, heart rate, and oxygen consumption. This is high-lighted in a 1998 study, which reported that the need for hospitalization was four times greater in pregnant than non-pregnant women with influenza...Pregnant women should be offered the influenza vaccine when pregnant during the influenza season." Also notes that maternal antibodies to influenza vaccine are passed on to the child following birth, thus protecting the infant until their immune system is more developed.

MacDonald NE, McNeil S, Allen VM, Scott J, & Dodds L. (2004). Influenza vaccine programs and pregnancy: a need for more evidence. Journal of Obstetrics and Gynaecology Canada, 26(11):961-963 - Commentary. "This commentary provides an overview of maternal morbidity in pandemic and nonpandemic influenza seasons as well as a list of research questions whose answers are needed for evidence-based public health policy in this area." Includes a brief discussion of schizophrenia risk in infants of mothers who were infected with influenza during the first trimester.

Rothberg MB, Haessler SD, & Brown RB. (2008). Complications of viral influenza. American Journal of Medicine, 121(4):258-264. - "Other groups at risk for influenza complications include those who are pregnant or immune suppressed. Compared with non-pregnant women, both high and low-risk pregnant women—especially during the third trimester—have more cardio-pulmonary events during influenza season...Psychiatric complications after influenza infection are considered controversial. Several studies note increased rates of schizophrenia in offspring of women who developed influenza during the second trimester of pregnancy, implying fetal developmental brain abnormalities. This was especially related to the influenza epidemic of 1957 but has been associated with other influenza seasons.

4 comments:

  1. http://aje.oxfordjournals.org/content/184/3/227.full enjoy the read, all those studies are based on ridiculously small samples, and as for the latest out of Western Australia, by an Annette Regan, the whole paper is totally fraud. I suggest you begin talking to pathologists, and not pharma reps.

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    Replies
    1. Angela,

      Thank you for your comment. That study was an interesting read. It supports the safety of influenza vaccination during pregnancy, as well as agreeing that maternal and postnatal benefits exist. The only thing it calls into question is fetal benefits. However, it does not conclude that the fetal benefits seen do not exist, only that the magnitude of such benefits is unlikely to be as large as reported.

      Given that the primary point of the post was to illustrate that influenza vaccine has been studied in pregnant women and found to be safe, I am left wondering: what point were you trying to make?

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    2. I think the point of Angela's posted study was that it somewhat invalidates most studies that demonstrate that the influenza vaccine is beneficial for pregnant women.

      The study title "Detectable Risks in Studies of the Fetal Benefits of Maternal Influenza Vaccination", makes an interesting point, that the influenza attack rate ranges from 5% -20% on any given year, that vaccine uptake is not close to 100%, and the influenza vaccine varies in effectiveness each and every year, ranging from 10-60%, depending on how well the match is (https://www.cdc.gov/flu/professionals/vaccination/effectiveness-studies.htm)

      So if a study is looking at the relationship between whether someone had been vaccinated or not, whether they were infected with influenza or not, and the rate of an adverse effect (in this case it would be pre-term delivery), the study questions how significant the vaccine effect truly was at preventing a person from being infected by the flu, and therefore, the significance of the vaccine effect for a specific pregnancy outcome.

      If the attack rate was 20%, vaccine coverage around 40% for adults (https://www.cdc.gov/flu/fluvaxview/coverage-1516estimates.htm), and effectiveness to be, let's be generous and say 50%, then for any given cohort (depending on how it was sampled), the likelihood for a person to be vaccinated, exposed to the flu virus, and for the vaccine-induced immunity to stop it, would have been 20% x 40% x 50% = 4% (apologies if my math is wrong here).

      If the effect is so little, then I would suspect that current studies would require much LARGER sample sizes in order to determine any conclusive and significant positive or negative effects

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    3. This comment has been removed by the author.

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