Brief education to increase uptake of influenza vaccine among pregnant women: a study protocol for a randomized controlled trial

Influenza vaccine has been demonstrated to be both beneficial and safe for pregnant women and their foetus at all stages of pregnancy [22‐24]. Influenza vaccine reduces both maternal complications from influenza and infant morbidity in the first six months of life. The recommendation to vaccinate pregnant women with influenza vaccine was originally proposed in 1960, ten years after the influenza vaccine was first developed [25]. Although the evidence on the safety and benefits of influenza vaccination during pregnancy was limited at the time, the US Surgeon General first recommended women to receive influenza vaccine during pregnancy to prevent flu-related complications and deaths [26]. Given the increasing evidence demonstrating the safety and immunogenicity of influenza vaccination in pregnancy and the maternal antibody transfer to the unborn infant, in 2005 the CDC recommended that all pregnant women receive trivalent inactivated influenza vaccine (TIV) [27]. In 2010, in the first randomised controlled trial, researchers administered influenza vaccine to pregnant women in Bangladesh who were in their third trimester [28]. The vaccine reduced the incidence of febrile respiratory illness in pregnant women by 36% and reduced the incidence of laboratory confirmed influenza in infants up to six months of age by 63%. Further observational studies have shown similar reductions in both maternal and infant morbidity and mortality [29, 30].

In addition, studies have shown that influenza vaccine during pregnancy, even in the first trimester, poses no additional risk to the developing foetus. In a recent study of over 50,000 pregnant women in Denmark, of whom over 7,000 had received the 2009 A/H1N1 influenza vaccine, there was no excess risk of miscarriage or stillbirth among vaccinated women [31]. A smaller study of 323 vaccinated pregnant women and 1,329 matched control subjects also found no excess risk of spontaneous abortion or foetal malformations among participants receiving the 2009 A/H1N1 vaccine, irrespective of time of vaccination [32]. To date, no study has shown any increased risk of vaccine-related maternal complications or adverse foetal outcomes [24, 33‐35]. Given that a single vaccine can protect the pregnant women, the foetus and the infant, a 3-for-1 benefit, in 2012 the WHO [36], recommended that among high risk groups, pregnant women have the highest priority in seasonal influenza vaccination programmes. This recommendation was subsequently adopted by a number of other national governments [23, 37‐39].

Despite the recommendations from the WHO and national governments, the uptake of influenza vaccine among pregnant women in most developed countries is still lower than uptake in general population, with rates ranging from 1.7% to 76.4% [40‐49]. Limited studies have been conducted in Asia, mostly in Hong Kong. A pre-pandemic study by Lau et al. found that only 3.9% of pregnant women had been immunized with seasonal influenza vaccine [50]. Coverage during the 2009–10 A/H1N1 pandemic was 4.9% [51], while a recent population-based post-pandemic study during the 2010–11 influenza season found an uptake rate of 1.7% [48].

A number of studies have found that many pregnant women are still unaware that they should be vaccinated or have substantial concerns about adverse effects of the vaccine on them and/or their foetus [51‐53]. In addition, many health-care providers (HCPs) do not routinely recommend that pregnant women be vaccinated as they themselves are often unaware of the recommendations or also share concerns about adverse effects of vaccination [54‐58]. Furthermore, HCPs often hesitate to recommend vaccination to their pregnant clients, not because they believe the vaccine is actually unsafe during pregnancy [58], but likely because they perceive clients may blame the vaccine, and by extension them, for any negative pregnancy outcomes. Research has shown that pregnant women with more knowledge about the potential complications of influenza and of the safety of the influenza vaccine are more likely to be vaccinated [51, 58, 59].

To date however, few interventions have attempted to increase influenza vaccine uptake among pregnant women. Of the few interventions that have been conducted, most of the studies either have targeted healthcare professionals to encourage them to discuss influenza vaccine with pregnant women and to encourage pregnant women to take the vaccine or have involved multicomponent interventions as such the individual effect of patient-focused intervention cannot be evaluated [60‐68]. Only three studies have investigated patient-targeted interventions, of which one used a historical control group and two were randomised controlled trials (RCTs). Yudin et al. found that an education intervention increased knowledge of influenza and vaccine rates from 19% (historical control) to 56% (post intervention) [68]. Furthermore, Meharry et al. evaluated the impact of providing an educational pamphlet with or without a statement verbalizing the benefit of influenza vaccine to both pregnant women and their infants from birth to six months of age and found that these measures increased vaccination rates from 46.9% (control) to 79% (educational pamphlet only) and 86.1% (educational pamphlet with verbalized benefit statement) [62]. However, Moniz et al. found that providing 12 weekly text messages about the importance of influenza vaccination in pregnancy did not significantly increase vaccination uptake [63]. Given the conflicting results from the few published studies, which were all conducted in North America, it is not clear if patient-oriented interventions can be effective in promoting influenza vaccination uptake among pregnant women, particularly in an Asian or Chinese population.

The low rate of vaccine uptake among this target group and the paucity of evaluated interventions both indicate a clear need to develop and test interventions to increase the low rate of influenza vaccine uptake among pregnant women. In addition, publicly-funded antenatal clinics in Hong Kong provide the majority of care to pregnant women but do not provide influenza vaccination. Therefore, pregnant women must obtain the vaccine from private settings, which are widely dispersed throughout the city. Thus, interventions targeting HCPs may not be effective in this and similar settings. Interventions targeting pregnant women themselves are more likely to be effective in increasing influenza vaccine uptake. If demonstrated to be effective, the proposed intervention could easily be adopted in various antenatal settings. Increasing the uptake of influenza vaccine among pregnant women could prevent unnecessary hospitalizations among pregnant women and newborn infants, both of whom are at greater risk of excess morbidity and mortality from influenza infection.

The aim of this randomised controlled trial is to determine whether a brief educational intervention will increase uptake of influenza vaccine among pregnant women when compared with standard antenatal care. The primary study hypothesis is that the influenza vaccination rate will be increased among participants who receive the brief educational intervention when compared with those who receive standard antenatal care. The secondary study hypotheses are that participants in the intervention group will have a higher rate of self-initiated discussion about influenza vaccination with their healthcare provider, a higher rate of requesting to receive the influenza vaccine, and improved knowledge of and more positive attitudes toward influenza and influenza vaccine, when compared with those who receive standard antenatal care.

Pregnant women attending the antenatal clinics of the four public hospitals will be screened for eligibility. Eligible patients are pregnant women: (a) with a singleton pregnancy; (b) at least 18 years of age; (c) in at least the second trimester of pregnancy; (d) Cantonese speaking; (e) Hong Kong resident; (f) without serious medical or obstetrical complications; (g) have not received the influenza vaccine in this pregnancy; and (h) who will be staying in Hong Kong for at least two weeks after birth.

A research nurse will attend the antenatal clinics at the respective study sites and screen pregnant women for eligibility. Eligible women will be approached and informed about the study. Those who agree to participate will be given more in-depth information about the study details and informed written consent will be obtained. A third party, who will not be involved in any part of the study, will develop a computer-generated randomised treatment allocation sequence for each study site using random block sizes of two to eight. The treatment assignments will each be placed in sequentially numbered, opaque, sealed envelopes. After obtaining informed written consent, the research nurse will select the next envelope in the sequence to determine the treatment allocation. A research assistant, who will not be involved in participant recruitment and will be blinded to the participants’ treatment allocation, will be responsible for the assessment of the study outcomes.

This trial compares standard antenatal care to a brief one-to-one, 10-minute education session by a research nurse explaining the facts of influenza and influenza vaccine and answering participant questions. Briefly, usual antenatal care consists of routine checking of the maternal and foetal health by either clinic midwives or obstetricians along with health education to promote a healthy pregnancy. Special childbirth preparation and breastfeeding classes are available to the pregnant women for no additional cost. Routine antenatal care does not usually encompass specific education or recommendations about influenza vaccination. However, we will provide the standard care group participants with an educational pamphlet on influenza vaccine in pregnancy developed by the Hong Kong Centre for Health Protection (CHP), which is freely available in all antenatal clinics.

The brief education group will receive the usual care plus one-to-one, brief education that will focus on four key recommendations identified from the research literature [52, 60, 70‐73]: (i) inform pregnant women of vaccination recommendations, (ii) encourage discussion with their HCPs, (iii) increase accessibility of vaccine (make referral to clinics where vaccine can be obtained), and (iv) provide credible information from the government official website and provide the website URL. Specifically, for participants in the education group in this study we will inform them about the: (i) WHO and Hong Kong CHP recommendations regarding influenza vaccine during pregnancy, (ii) potential complications associated with influenza infection during pregnancy and for young infants, (iii) safety of influenza vaccine for pregnant women and the foetus, and (iv) potential benefits of influenza vaccine for the pregnant women, the foetus and the infant, and (iv) where and how to get the influenza vaccine in Hong Kong.

To ensure the consistency of intervention, one research nurse will implement the intervention across the four sites. The research nurse has completed extensive education on the international and national vaccination guidelines and the benefits and safety of influenza vaccination for pregnant women, as well as the implementation of randomised controlled trials.

The primary study outcome is the influenza vaccination rate during pregnancy in the control and intervention groups. The secondary study outcomes are the proportion of participants initiating discussion about influenza vaccine with their health care provider, the proportion of participants seeking out influenza vaccine, and the influenza and influenza vaccine knowledge of participants in the control and intervention groups after receiving the intervention.

After recruitment, pregnant women who agree to participate in the study and have signed a written consent form will be asked to complete a standard baseline questionnaire that will include (i) key demographic data (i.e., age, marital status, education level, family income, and employment status); (ii) maternal health data (i.e., pre-existing health conditions, pregnancy related health problems, gravidity and parity, and expected date of confinement), and (iii) influenza and influenza vaccine knowledge. Participants will be followed up by telephone at two to three weeks after their expected confinement date by a study research assistant who will be blinded to their treatment group allocation. During the follow-up telephone interviews, information will be collected on (i) influenza vaccination data (i.e., vaccination status, reasons for receiving or not receiving the vaccine, discussion with HCPs, attempts to receive vaccine, anti-vaccination advice from HCP or family members, and vaccination status of family members); (ii) health status during pregnancy (i.e., perceived health status during pregnancy, pregnancy-induced medical conditions, and respiratory illnesses and symptoms); (iii) actual birth data (i.e., date of birth, gender, gestational age and birth weight); and (iv) postnatal influenza and influenza vaccine knowledge.

Previous Hong Kong studies show that the range of seasonal influenza vaccine uptake among pregnant women ranges from 1.7 to 5.0% [48, 50, 51]. From the literature, studies have shown that with provider-focused interventions, influenza vaccine uptake rates increased from 1 to 2% before the intervention to approximately 37% after the intervention [64‐66, 68]. In addition, the Meharry et al. study evaluating the educational pamphlet plus the verbal statement increased vaccine uptake from 46.9% in the control group to 86.1% in the intervention group [62]. Thus, an estimate of the ‘normal’ prevalence of influenza vaccine uptake among pregnant women in Hong Kong would be 5.0% and an increase to 20% would be highly conservative but still clinically meaningful. Thus, using a study power of .80 and a significance level of .05, then 76 participants would be required for each group calculated using the Gpower z-test [74]. After accounting for a loss to follow-up or dropout rate of around 20%, approximately 92 participants per group are required for a total of 184 participants. Recruitment would begin once the influenza vaccine is available, usually early October, and continue until all participants are recruited.

The primary analyses will compare the proportion of participants in the two study groups who have actually received the influenza vaccine during their pregnancy. We will assess the equivalency of treatment group allocation by comparing the major socio-demographic indicators (age, education, income). Between-group comparisons will be made using a chi-squared test. The intention-to-treat principle will be used with missing values taken as no vaccination. Each estimate will be accompanied by a 95% confidence interval and a 5% level of significance will be used in all statistical tests. Other data analysis will include comparing the proportion of participants initiating discussion of influenza vaccine with their health-care provider and the proportion of participants seeking out influenza vaccination, again using chi-square tests. The knowledge level of the participants will be compared before and after the intervention using chi-squared test and student’s t-test. Data analysis will be performed using the Stata version 13.1 statistical software [75].

Ethical approval for this study was obtained from (1) the Institutional Review Board of the University of Hong Kong/ Hospital Authority Hong Kong West Cluster (HKU/HA HKW IRB) (Ref No. UW 12–439), (2) Kowloon West Cluster Research Ethics Committee (KWC-REC) (Ref.#KW/EX/13-075), and (3) the Ethics Committee of Hong Kong East Cluster (EC-HKEC) (Ref.#HKEC-2013-072).