Conclusion:
Vaccines currently routinely recommended for pregnant women in the U.S. have not been shown to cause spontaneous abortion (SAb).
Why this is an issue:
The Advisory Committee on Immunization Practices (ACIP) and the American College of Obstetricians and Gynecologists (ACOG) recommend that “all women who are pregnant or who might be pregnant or postpartum during the influenza season receive influenza vaccine. Any licensed, recommended, and age-appropriate IIV or RIV4 may be used. LAIV4 should not be used during pregnancy. Influenza vaccine can be administered at any time during pregnancy, before and during the influenza season.” [4, 170, 171].
The recommendation for IIV in pregnancy was based upon the benefits of the vaccine for prevention of influenza in the mother and infants born to women immunized in pregnancy, and the overall excellent safety profile of IIV among children and adults [803]. SAb is defined in the United States as the loss of a fetus before 20 weeks of gestation (before 24 weeks in some other countries), and occurs in roughly 15-20% of clinically recognized pregnancies [804].
In a 2017 publication, Donahue et al. reported results from a case-control study matched on two age groups examining the risk of SAb following receipt of inactivated influenza vaccines containing A/H1N1pdm2009 antigen in the 2010-11 and 2011-12 seasons [191]. The odds of vaccine receipt in the 28-day exposure window were double among women who had an SAb compared with the control women who had live births or stillbirths (adjusted odds ratio: 2.0; 95% Confidence Interval: 1.1–3.6). In a post-hoc analysis, the study found the risk was almost entirely attributed to women who had received vaccines containing pandemic H1N1 (pH1N1) antigen in the previous year (aOR: 7.7; 95%CI: 2.2–27.3) compared to women unvaccinated in the previous year (aOR: 1.3; 95%CI: 0.7–2.7) [191].
As pointed out by Chambers et al. in an accompanying commentary, SAb is one of the most challenging birth outcomes to study using observational studies. Many clinically unrecognized pregnancies occur and retrospective studies have a difficult time capturing these pregnancies and SAbs [805]. Limitations of the 2017 Donahue et al. study include ascertainment of SAb date, the potential that healthcare seeking for SAb care was associated with vaccination, preferential vaccination among women with comorbidities or other risk factors for SAb, the potential that cases had greater opportunity for vaccination because they sought care for symptoms foreshadowing SAb diagnosis, and others discussed in the paper and commentary [191, 805]. However, a subsequent case-control study from Donahue et al., matched on three age groups and with a population three times the size of the previous study, revealed no significant association between influenza vaccine receipt and SAb, regardless of prior season vaccination status [192].
Epidemiological evidence
One randomized trial recruiting women at 17-34 weeks gestation [193], fourteen observational studies [192, 194-206], two systematic reviews [185, 207], and one meta-analysis [176] have assessed the potential association between influenza vaccine and SAb or a related outcome, and none have found an association.
Steinhoff et al. enrolled 3,693 women in a randomized, placebo-controlled trial of influenza immunization during pregnancy in Nepal. Three participants in the placebo group (0.2%) and 5 in the vaccine group (0.3%) experienced miscarriage (risk ratio: 1.67; 95%CI: 0.40-6.98). 31 participants in the placebo group (1.7%) and 33 in the vaccine group (1.8%) experienced stillbirth (RR: 1.07; 95%CI: 0.66-1.73) [193]. SAb was uncommon in this study given the age of study enrollment (17-34 weeks).
Chambers et al. followed 1,032 American and Canadian women between 2009 and 2012 in a prospective cohort study. 841 of these women received a pH1N1-containing vaccine during pregnancy. No increased risk of SAb was found (adjusted hazard ratio: 0.92; 95%CI: 0.31-2.72). 184 women vaccinated during the first trimester were included in an analysis that showed no increased risk of SAb (aHR: 0.84; 95%CI: 0.27–2.64) [194].
Chambers et al. also recruited 1,730 American and Canadian women between 2010 to 2014 as part of the cohort arm of the Vaccines and Medications in Pregnancy Surveillance System (VAMPSS). 1,263 of these women were exposed to an influenza vaccine during pregnancy. There was no overall increase in risk of spontaneous abortion in first trimester exposure compared to the unexposed (aHR: 1.12; 95%CI: 0.47-2.65). Additionally, women who were vaccinated in the first trimester or any trimester were more likely than unvaccinated women to deliver a live born child (HR: 1.09; 95%CI 1.05, 1.13) [195].
Chavant et al. included 2,415 pregnant women vaccinated between November 2009 and March 2010 in France in a prospective cohort study. 97.6% of these women received a vaccine without adjuvant and 2.4% received an adjuvanted vaccine. They found that exposure to pH1N1-containing vaccines during pregnancy did not increase the risk of adverse pregnancy outcomes. 12 of the 2,246 pregnancies with known outcomes ended in spontaneous abortion. This 0.5% rate is below the base rate in the general population, observed at 10-15%; however, this is probably because only 3.9% of women in this study were vaccinated during their first trimester. Of the 92 women who were vaccinated during their first trimester, 5 experienced SAb [196].
Ma et al. included 226 pregnant women in China in a prospective cohort study. 122 of these women were immunized with pH1N1 vaccine. They found no difference in rates of spontaneous abortion between the vaccinated and unvaccinated group (0.8% vs 1.9%, respectively; P=0.470). However, the trimester of vaccination is not reported [199].
Oppermann et al. included 1,652 pregnant women in Germany in a prospective cohort study. 323 of these women were immunized with pH1N1 vaccine between September 2009 and March 2010. No increased risk of SAb was found (HR: 0.89; 95%CI: 0.36–2.19), although this was reported for all trimesters instead of just first trimester due to the limited number of first trimester vaccinations (n=55) and inability to adjust fully for confounders. The study also showed a higher rate of live births in vaccinated versus unvaccinated cohorts (97.2% vs. 87.9%) [200].
Pasternak et al. studied SAb among 35,408 Danish women using a national register based cohort study. 2,736 of these women were immunized with pH1N1 vaccine. No increased risk of SAb was found (HR: 1.11; 95%CI: 0.71-1.73). The risk of SAb specific to first trimester vaccinations was not reported. No increased risk of fetal death (either spontaneous abortion or stillbirth) was found among all vaccinated (HR: 0.79; 95%CI: 0.53-1.16) or first-trimester vaccinated women (HR: 0.96; 95%CI: 0.63-1.47) [201].
Tavares et al. included 267 pregnant women vaccinated in Britain during the 2009 flu season in a prospective cohort study. Of the 41 (15.4%) women vaccinated during the first trimester with known pregnancy outcomes, 3 ended in SAbs. They reported that this and all adverse events were consistent with the expected rates in their population [202].
De Vries et al. recruited 295 pregnant women who received pH1N1 vaccine for a cohort study in the Netherlands, of which 23 were vaccinated in their first trimester, and reported no increased risk of spontaneous abortions compared with the background rate [206].
Eaton et al. surveyed 5,365 pregnant women in Northern California by telephone, 40.7% of whom were vaccinated in the first trimester, and found no difference in SAb between pH1N1 and seasonal influenza vaccines. The risk of SAb specific to first trimester vaccinations was not reported [806].
Irving et al. found in a 2005-2006 case-control study in the U.S. no association with SAb during the 28 days after receipt of IIV (adjusted matched odds ratio: 1.23; 95%CI: 0.53-2.89). The study included 243 women with SAbs and 243 matched control women. 16 (7%) women with SAb and 15 (6%) matched control group women received influenza vaccine within the 28-day exposure window, all women included in the study were vaccinated before conception or in the first trimester [203].
Sammon et al. found in a retrospective cohort study in the U.K. a reduced risk of SAb and fetal death among pregnant women vaccinated against pandemic influenza. However, this may have been due to residual confounding that was unable to be measured, as suggested by sensitivity analyses [204].
Heikkinen et al. analyzed 4,508 pregnancy outcomes in a mixed prospective and retrospective cohort study in Argentina, Italy, and the Netherlands. Of the cohort, 2,295 (50.9%) women were vaccinated, 92 (4%) in their first trimester. They found no spontaneous abortions among women vaccinated against pandemic influenza, although this was attributed to the high average gestational age at enrollment [205].
Bratton et al. conducted a systematic review and meta-analysis. Their pooled estimate for SAb was not significant (relative risk: 0.91; 95%CI: 0.68-1.22). They did find that women who received influenza vaccine had a lower likelihood of stillbirth (RR: 0.73; 95%CI: 0.55-.96); even when restricted to pH1N1 vaccine (RR, 0.69; 95% CI, 0.53-0.90) [176].
Studies of HPV [549, 807-816] and rubella [216, 817, 818] vaccines inadvertently given during pregnancy have not found an association with SAb or miscarriage. A systematic review of hepatitis B, pneumococcal polysaccharide and meningococcal polysaccharide vaccines in pregnancy [819] and a meta-analysis of smallpox vaccination in pregnancy [820] also found no association with SAb. Studies examining a potential association with SAb among other vaccines are lacking.
Proposed biological mechanism:
Infection with wild-type influenza virus during pregnancy can cause life-threatening illness in pregnant women and increases the risk of SAb, as demonstrated during the 2009 influenza pandemic [821, 822]. Inflammation has been linked to pregnancy loss [823-825]. Although there is a brief inflammatory response in women (pregnant and non-pregnant women after influenza vaccination [826, 827], there is no evidence to support that the brief inflammation is sufficient to cause problems in pregnancy.
References
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2. ACOG Committee Opinion No. 741: Maternal Immunization. Obstetrics and gynecology. 2018;131(6):e214-e7.
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8. Donahue JG, Kieke BA, King JP, Mascola MA, Shimabukuro TT, DeStefano F, et al. Inactivated influenza vaccine and spontaneous abortion in the Vaccine Safety Datalink in 2012-13, 2013-14, and 2014-15. Vaccine. 2019;37(44):6673-81.
