These data demonstrate that seasonal influenza virus vaccination elicits a significant inflammatory response among pregnant women. The response was most robust at two days post-vaccination for C-reactive protein, with a similar, though nonsignificant, pattern of response for TNF-α. No statistically significant changes in IL-6 or MIF were evidenced. However, the power to detect effects was limited by sample size. Thus, despite changes in immune regulation previously reported in pregnancy, vaccination resulted in a transient inflammatory response among pregnant women. As there was no nonpregnant comparison group in this study, and participants in previous studies are not demographically equivalent to the current study [39
], the magnitude or duration of response during pregnancy versus nonpregnancy is unknown.
The utility of vaccination as a model for examining differential risk for adverse outcomes is dependent on sufficient variability in responses, allowing for meaningful classification of individuals as high versus low responders. In the current study, substantial variability was evidenced, as indicated by large standard deviations relative to mean increases and resulting high coefficients of variation. From a research standpoint, the presence of this variability may be of greater importance than the average magnitude of response overall. For example, we have previously reported that pregnant women with greater depressive symptoms exhibited significant inflammatory responses in terms of serum MIF at one week post-vaccination although there was not a statistically significant increase in MIF among women overall [41
The assessment of in vivo
inflammatory responses and factors affecting such responses has important applications in the context of pregnancy. Pregnancy is a period of tight inflammatory control. Attenuation of inflammatory responses during pregnancy has been reported in both human and animal models [24
] and lack of such adaptation has been associated with adverse pregnancy outcomes. For example, peripheral blood mononuclear cells (PBMCs) stimulated in vitro
with antigen or mitogen showed decreased proinflammatory cytokine production and increased antiinflammatory cytokine production during healthy pregnancy ending in full term delivery as compared to nonpregnancy, with the strongest effects seen in the third trimester [28
]. In contrast, among pregnancies that subsequently ended in miscarriage or small for gestational age babies, PBMCs exhibited greater
proinflammatory cytokine production and reduced
antiinflammatory cytokine production as compared to cells from both nonpregnant women and healthy pregnancies [28
Inflammatory processes may also contribute to gestational hypertension and preeclampsia which affect 6–8% of all pregnancies and are responsible for 40% of medically-indicated preterm deliveries [31
]. These disorders are characterized by high levels of circulating inflammatory markers [31
]. Many features of preeclampsia, including impaired lipid metabolism and endothelial dysfunction, can be induced by proinflammatory cytokines [46
] and the clinical severity of preeclampsia correlates with the degree of dysregulation seen in cytokine function [47
]. Inflammation associated with infections may disrupt lipid metabolism and cause endothelial damage, predisposing women to the development of hypertensive disorders of pregnancy [48
]. Therefore, women prone to exhibit exaggerated inflammatory responses to immune triggers may show increased risk of these disorders and related increased risk of preterm birth.
Studies in pregnant women to-date have relied on in vitro methodology. As compared to in vitro models, examination of similar processes in the in vivo setting provides rich data regarding inflammatory processes in the complex natural environment. Thus, vaccination provides a model that may be useful in understanding differences in risk for pregnancy-related conditions with an inflammatory component, including preterm birth and preeclampsia.
These research directions are suggested in relation to conceptualizing vaccination as a mild inflammatory trigger that may serve as a model for understanding a general propensity toward inflammatory responding. However, there are important gaps in our knowledge of the effects of vaccination on fetal health. Relatedly, the wisdom of universal vaccination for healthy pregnant women is a topic of debate [6
]. Due to the known risks of influenza infection in pregnancy and evidence for no effects of vaccination on birth outcomes including preterm labor, rates of C-section, or fetal malformation [8
], vaccination is considered beneficial and is currently standardly recommended to all pregnant women [1
]. There is strong evidence that exposure to infectious agents during the prenatal period influences developmental outcomes including stress reactivity, disease susceptibility, and risk for disorders including schizophrenia and cerebral palsy [49
]. Thus, by preventing infection, vaccination may mitigate long-term risks for offspring health. The inflammatory response elicited by vaccination is considerably milder and more transient than that elicited by infection [55
], arguing for protective benefits of vaccination. However, as demonstrated in the current study, there is substantial variability in the magnitude of response to vaccination. Thus, continued research is needed to further delineate whether the mild inflammatory response elicited by vaccination is benign for fetal development. In particular, birth cohort studies examining maternal cytokine responses to vaccination in conjunction with long-term offspring health outcomes are warranted [7
Despite current recommendations for routine immunization, historically, vaccination coverage among pregnant women in the U.S. has been low. According to data from the National Health Interview Survey (NHIS), only 11.3% of pregnant women were vaccinated during the 2008–2009 flu season [5
]. Reflecting substantial public health efforts and greater public awareness of risk during the 2009–2010 influenza pandemic, coverage of pregnant women was markedly higher; it is estimated that 50.7% of pregnant women received seasonal vaccination and 46.6% received the 2009 H1N1 vaccine [56
]. Among pregnant women who did not receive seasonal vaccine during the 2009–2010 season, 47.7% indicated safety concerns for the baby and 45.2% indicated safety concerns for themselves were a factor [56
]. Similarly, among women who didn’t receive the novel H1N1 vaccine, 63.6% cited safety concerns for the baby and 61.4% had safety concerns for themselves. Utilizing vaccination as research model promotes current clinical recommendations and may ultimately serve to increase vaccine acceptance by provision of greater safety data.
An important limitation of this study is that women were assessed primarily in the first trimester or early second trimester of pregnancy and that no nonpregnant comparison group was assessed. Due to the small sample size, assessment of effects of stage of gestation or statistically controlling for stage of gestation was not possible. Prior data on in vitro
inflammatory responses indicate that, as compared to nonpregnant women, pregnant women show attenuation of inflammatory responses which is greatest during the third trimester [28
]. The extent to which similar effects are seen in the context of in vivo
immune triggers is unknown. In addition, this study did not permit examination of effects of behavioral, demographic, or psychosocial variables on the trajectory of inflammatory responses. Key potential modifiers of this response include race, smoking, sleep, body mass index, prior vaccine exposure, and prior influenza exposure which may be influenced by the number of children in one’s household. A clear future direction using vaccination as an in vivo
model is to examine the extent to which these factors predict differential inflammatory responding.
Women in this study were assessed during two different influenza seasons; however, data at one and two days post-vaccination were collected in the same influenza season and this is when an inflammatory response was noted. This time course of response is similar as that noted in nonpregnant samples [34
], thus we believe these effects are reliable. However, it is certainly possible that the inflammatory response to vaccination is affected by the specific viral strains in a given flu season, in part due to different rates of prior exposure to specific strains. Future research using larger samples assessed in different vaccine years would help to address this issue. In this study, a decrease in IL-6 from baseline to one-week post-vaccination approached statistical significance (p
= 0.06). Additional studies are needed to document if this is a consistent and reliable effect. If so, this may indicate a temporary “overshooting” as the body regains homeostasis following exposure to an inflammatory trigger. Finally, each woman was assessed at only a single follow-up timepoint. Women assessed at each follow-up timepoint were recruited from the same clinic and were demographically similar in terms of age, race, BMI, and parity. However, because the kinetic across different individuals likely differs, even minimal differences between groups may affect responses at a given timepoint. Thus, future research should ideally follow the same women at multiple timepoints to most clearly describe the inflammatory response trajectory following vaccination.
In sum, this study demonstrates that trivalent influenza virus vaccine (TIV) elicits a measurable inflammatory response during pregnancy, and that considerable variability is seen between women in the magnitude of this response. Thus, vaccination may serve as a useful model for examining individual differences in propensity toward inflammatory responses to immune triggers; this model may have implications for understanding risk of adverse pregnancy outcomes. The inflammatory response elicited by TIV is substantially milder and more transient than seen in infectious illness, arguing for the clinical value of vaccination. However, given the current clinical recommendation of routine immunization of healthy pregnant women, further research is warranted to confirm that the mild inflammatory response elicited by vaccination is benign in pregnancy.