Review of the status and challenges associated with increasing influenza vaccination coverage among pregnant women in China

ABSTRACT

Influenza vaccination coverage in pregnant women in China remains low. In this review, we first provide an overview of the evidence for the use of influenza vaccination during pregnancy. Second, we discuss influenza vaccination policy and barriers to increased seasonal influenza vaccination coverage in pregnant women in China. Third, we provide case studies of successes and challenges of programs for increasing seasonal influenza vaccination in pregnant women from other parts of Asia with lessons learned for China. Finally, we assess opportunities and challenges for increasing influenza vaccination coverage among pregnant women in China.

KEYWORDS:

• Pregnant women
• influenza vaccine
• vaccination policy

Introduction

Pregnancy is associated with physiologic and immunological changes that may increase the risk for severe disease from respiratory infections.^1–4 Pregnant women are at high risk for complications associated with influenza virus infection and influenza-related morbidity and mortality.^5,6 In particular, during the 2009 H1N1pdm09 pandemic, pregnant women were observed to experience complications associated with severe influenza virus infections, including excess maternal mortality and loss of pregnancy.^7,8 Additionally, data from high-income countries have shown that pregnant women are at higher risk for influenza-associated hospitalizations than non-pregnant women.^9,10 Some studies have suggested increased risk for pregnancy complications attributable to maternal influenza, such as stillbirth,¹¹ spontaneous abortion,¹² preterm birth,^13,14 fetal growth restrictions,¹⁵ and other maternal morbidities,¹⁶ although others have not.¹⁷ Reported influenza illness incidence among pregnant women in the developed world varies significantly by the study.¹⁸ While incidence data from low and middle-income countries are limited, preliminary findings from active surveillance of a cohort of pregnant women in China indicate substantial laboratory-confirmed influenza-associated acute respiratory illness burden in this population, ranging from 1.1–2.7/100 pregnancy-months during 2017–18 influenza season peaks.^18,19 In this review, we examine the current status of and key challenges associated with influenza vaccination coverage among pregnant women in China.

Table 1. Current status of key issues affecting influenza vaccination coverage among pregnant women in China

Technical Guidance	China CDC has recommended influenza vaccination for pregnant women since 2014	Feng L, Hum Vaccine Immunother. 2015 Feng LZ, Zhonghua LiuXing Bing Xue Za Zhi, 2018
Regulatory Barriers
Classification of vaccination	Influenza vaccination designated as a Category 2 vaccine, which is voluntary, and typically paid out-of-pocket and not covered by government health insurance Vaccine manufacturer is required to pay compensation or Category 2 vaccine injuries	Yu W, Vaccine 2018 Fei L, Med La Rev, 2017
Designation in Chinese Pharmacopeia	Pregnancy listed as an absolute contraindication to seasonal influenza vaccination	Chinese Pharmacopoeia Commission, 2017
Opportunities and strengths
Domestic influenza vaccination production capacity	China’s first influenza vaccine licensed in 1997 China has eight influenza vaccine manufacturers as of 2017 One manufacturer produces seasonal influenzas vaccination meeting WHO-prequalification standards	Zheng Y, BMC Infec Dis, 2018 World Health Organization. WHO Prequalified Vaccines
National Immunization Advisory Committee	Established by the National Health Commission in 2017 Authorized China CDC to establish technical working groups to review evidence in support of making recommendations to the National Health Commission, which has the authority to make establish national vaccine policy As has been done in other countries, influenza working group of the National Immunization Advisory Committee can serve as a platform to address specific maternal immunization issues	Chinese Center for Disease Control and Prevention, 2017 Beiji RH, Vaccine, 2018
National Health Commission	Issued a notice in October 2018 requiring healthcare workers to promote influenza vaccination among patients*	National Health Commission, 2018
Antenatal care system	97% of women utilize services from the antenatal care system at least once during pregnancy System has been used successfully for public health vaccinations initiatives as part of the preconception program	National Health Commission, Chinese Health Statistics Yearbook, 2018 National Health Commission, 2017
Challenges
Off-label vaccine usage	National Immunization Advisory Committee has yet to make an “off-label” vaccine recommendations that differs from the Chinese Pharmacopeia Off-label recommendations are specific to a country’s legal landscape, and a legal pathway for authorizing maternal influenza immunization will need to be identified for China	Neels P, Vaccine, 2017
Vaccine supply	From 2004–2014, China had an estimated annual influenza vaccination supply up to 58.8 million doses From 2004–2014, 426 million were considered recommended for influenza vaccination Assuming increased demand for influenza vaccination in the future, current supply is insufficient for recommended population, expanding vaccine access in the future may require developing priority recipient groups among high risk populations recommended for influenza vaccination	Yang J, Vaccine, 2016
Healthcare worker knowledge and behaviors	Healthcare workers have low awareness of the safety and benefit of influenza vaccine Few healthcare workers have been received an influenza vaccination Few pregnant women reported receiving recommendations to be vaccinated from healthcare workers	Bu L, Chinese Health Service Management, 2017 Song Y, Vaccine, 2017
Patient hesitancy	Recent nationwide vaccine safety scandals involving vaccines other than influenza have shaken public trust Pregnant women have declined influenza vaccination citing concerns about potential harm to fetus and harm to self	Cao L, Hum Vaccine Immunother, 2018 Song Y, Vaccine, 2017

*The issuance does not mention specific patient populations to whom health-care workers should recommend influenza vaccination.

Evidence of benefit of influenza vaccination in pregnancy

Influenza vaccination is the most effective way to prevent influenza virus infection and has been shown to have similar immunogenicity in pregnant women and non-pregnant women of child-bearing age.^20,21 Vaccination may prevent complications associated with influenza virus infection during pregnancy.^14,21–30 The hospital-based Pregnancy Influenza Vaccine Effectiveness Network, consisting of sites in Australia, Canada, Israel, and the United States, retrospectively reviewed records of 19,450 acute respiratory or febrile illness hospitalizations with clinician-ordered influenza testing.³¹ From 2010 to 2016, the adjusted overall influenza vaccine effectiveness was 40% (95% CI = 12%–59%) against laboratory-confirmed influenza-associated hospitalization during pregnancy.³¹ Data from low-income countries have also described the benefits of influenza vaccination for pregnant women and infants. For example, a phase four, randomized, placebo-controlled trial of year-round influenza immunization during pregnancy in Nepal conducted during 2011–2013 showed that the number of adverse events was similar regardless of immunization status.³² Year-round maternal influenza immunization significantly reduced maternal influenza-like illness, influenza in infants, and low birthweight over the study period.³²

Influenza vaccination of pregnant women is an important strategy for preventing influenza infection in infants <6 months, who are too young to receive influenza vaccine and are at risk for infection with influenza virus.³³ An enhanced surveillance study in Chinese children younger than 5 years from 2011 to 2016 found that influenza-associated hospitalization rates were 11 (95% CI: 8–15) per 1,000 children in infants aged 0–5 months compared with 8 (95% CI: 7–10) per 1,000 children aged 6–23 months and 5 (95% CI: 4–5) per 1,000 children aged 24–59 months.³⁴ Vaccination during pregnancy can help to protect the neonate from infectious diseases through the transplacental transfer of vaccine-specific maternal immunoglobulin G (IgG) antibodies,³⁵ and after birth, may provide benefit to the infant through the transfer of vaccine-specific maternal antibodies during breastfeeding.^36–38 A randomized phase four trial with 4193 pregnant women in Mali demonstrated an influenza vaccine efficacy against laboratory-confirmed influenza in infants of 37.3% until age 3 months, with an efficacy that remained robust through the fifth month.³⁹ No serious adverse events related to vaccination were reported.³⁹ Another trial in South Africa, evaluating vaccine efficacy of inactivated influenza vaccine administered during pregnancy, found the attack rate of laboratory-confirmed influenza until 24 weeks post-partum was 3.6% within the unvaccinated control group and 1.8% within the vaccinated group, indicating a vaccine efficacy of 50.4 %.⁴⁰ A study of 200 infants <6 months observed a significant reduction in fever and influenza virus infection incidence in the group with mothers vaccinated during pregnancy compared with the infants with unvaccinated mothers.⁴¹

Despite the known benefits of influenza vaccination in pregnancy, available data particularly from low and middle income countries are limited in their ability to estimate the potential full impact of maternal immunization programs.⁴² Given the known increased risk of influenza-associated complications in pregnant women, maternal influenza vaccination continues to be a robust area of research to evaluate a broad array of potential benefits in different healthcare and sociodemographic settings.⁴²

Review of safety of influenza vaccination in pregnancy

The safety of vaccinating pregnant women with inactivated influenza vaccine has been carefully studied. The World Health Organization’s Global Advisory Committee on Vaccine Safety (GACVS) has reviewed evidence on the safety of vaccinating in pregnancy, with consideration of both the pregnant women and the developing fetus. The review concluded that “the excellent and robust safety profile of multiple inactivated influenza vaccine preparations over many decades, and the potential complications of influenza disease during pregnancy, support WHO recommendations that pregnant women should be vaccinated. Ongoing clinical studies of the effectiveness, safety, and benefits of influenza vaccination in pregnant women in diverse settings will provide additional data that will aid countries in assessing influenza vaccine use for their own populations”.⁴³ Since the publication in the GACVS report in 2014, there have been multiple systematic reviews of influenza vaccine safety in pregnancy that have not identified increased risk of poor birth outcomes including preterm birth, congenital abnormalities, low birth weight or fetal death.^23,44–48 Additionally, a recently published Cochrane review stated that “We did not find any evidence of an association between influenza vaccination and serious adverse events in the comparative studies considered in this review.”²¹ Finally, US CDC maintains up-to-date information on evidence relating to the safety of influenza vaccination during pregnancy that serves as a public resource.⁴⁹ US CDC collects and regularly reviews safety data for considerations on updates to vaccination recommendations.

Influenza vaccination policy in pregnant women

In 2012, the WHO Strategic Advisory Group of Experts on Immunization recommended that countries considering the initiation or expansion of seasonal influenza vaccination programs give the highest priority to pregnant women.⁵⁰ Although the United States has continuously recommended influenza vaccination to pregnant women since the 1960s,⁵¹ as of the 2010s, in Asia, only two countries in the Southeast Asian region and 12 countries in the Western Pacific Region have national policies that designate pregnant women as a target population.^52–54

In China, the National Health Commission (NHC) has the sole authority for making national immunization policy. Although not official government policy, in 2014, the Chinese Center for Disease Control and Prevention (China CDC) first developed technical guidance for influenza vaccination that included recommendations for pregnant women, in addition to children aged 6–59 months, adults ≥60 years, persons with specific chronic diseases, healthcare workers, and family members and caregivers of infants <6 months.⁵⁵ The 2018–2019 update to the seasonal influenza technical guidance continued the recommendation for influenza vaccination for pregnant women.⁵⁶

Despite these recommendations, influenza vaccination in high-risk populations in China faces two major barriers. The first is seasonal influenza vaccination’s classification as a Category 2 vaccine under the Regulations on Administration of Vaccine and Vaccination.⁵⁷ Per the regulations, Category 1 vaccines are government-recommended vaccines for all children less than 14 years of age, which are assessed prior to enrollment in school to ensure the protection of school children. Category 1 vaccines are government-purchased vaccines made available through the Expanded Program on Immunization (EPI) at no charge. On the other hand, Category 2 vaccines, such as seasonal influenza vaccine, are available upon request, and health-care workers are not incentivized to recommend. Category 2 vaccines are typically paid for out-of-pocket and are neither part of the national Expanded Program on Immunization nor covered by government health insurance. Another distinction between Category 1 and 2 vaccines is the funding source for compensation from injuries due to vaccines. The vaccine manufacturer pays compensation for Category 2 vaccine injuries, while government pays compensation for injuries caused by vaccines in the national program.⁵⁸ Although several municipal governments have implemented immunization programs that support reduced-price or free seasonal influenza vaccination for certain high-risk populations such as school-age children and elderly residents,⁵⁹ these programs have not included vaccination for pregnant women.

A second important barrier to increasing vaccination of pregnant women is that the Chinese Pharmacopeia, which is overseen by the State Medical Products Administration, has listed pregnancy as an absolute contraindication to seasonal influenza vaccination since 2005.⁶⁰ The inconsistency in Chinese Pharmacopeia and China CDC technical guidance creates confusion for patients and health-care workers regarding eligibility for influenza vaccination. Additionally, given concerns about medical malpractice and liability, this contraindication logically must increase vaccine hesitancy in health-care workers and pregnant women.⁶¹ Given these barriers, seasonal influenza vaccination coverage among pregnant women in China was estimated as <1.5% from 2004 to 2014.⁵⁹ Similarly, low coverage estimates (<1%) have been reported from two studies of pregnant women in Suzhou, China in 2013 and 2016.^62,63 China’s implementation of a seasonal influenza vaccination program for pregnant women is nascent (Table 1).

Efforts to increase other maternal vaccination in China

Although China’s EPI has successfully achieved high childhood vaccination coverage with vaccines such as the measles, mumps, and rubella (MMR) vaccine, China has not established a national platform for adult vaccination. Despite ongoing efforts to develop a primary care infrastructure in China, primary care is often underutilized due to factors such as the public’s lack of trust in the quality of care, and the lack of a gatekeeping function by primary care providers.⁶⁴ Additionally, the lack of clinical and public health data system integration creates barriers to implementing clinical decision support into routine primary care practice.⁶⁵ While antenatal care services were estimated to be utilized at least once by 97% of pregnant women in 2017,⁶⁶ these platforms are not typically used for routine vaccination services. Use of the 2009 H1N1pdm09 vaccine in pregnant women in China provides lessons learned for framing the potential for promoting seasonal influenza vaccination in this population.

2009 H1N1pdm09 vaccination

In September 2009 during the H1N1pdm09 pandemic, China became the first country in the world where pandemic vaccine was available for mass-vaccination.⁶⁷ Priority groups for voluntary free vaccination initially included security services, students, teachers and persons with chronic disease.⁶⁸ High H1N1pdm09 virus infection-associated mortality in pregnant women in China⁶⁹ and WHO recommendations for this population⁷⁰ prompted the expansion of China’s H1N1pdm09 vaccination recommendation in December 2009 to include pregnant women.⁷¹ The expanded recommendation was also supported by an evaluation of vaccine safety data from other countries and consensus of an expert panel on risk assessment organized by the Ministry of Health and the State Food and Drug Administration.⁷¹ However, although China, a country with ~15.9 million live births that year, administered 89.6 million doses of the vaccine from September 2009–March 2010, only 35,000 recipients were pregnant women.⁷²

Although vaccine safety data documented no pregnancy-related adverse events such as preterm birth, stillbirth or abortion,^73,74 pregnant women reported concerns about receiving the vaccination, and only 12% expressed a willingness to be vaccinated.⁷⁵ Additionally, health-care providers, including China CDC staff, were hesitant to vaccinate pregnant women.⁷⁶ The 2009 H1N1pdm09 vaccination experience demonstrates that patient and provider vaccine hesitancy was a significant barrier to increasing vaccination uptake among pregnant women in China, despite the evidence-based recommendation for vaccinating this high-risk population in the setting of a public health emergency.

Case studies of influenza vaccination during pregnancy from Asia with lessons learned for China

Although pregnant women are a population recommended for vaccination in many countries in Asia, seasonal influenza coverage among pregnant women remains suboptimal (<10%) in the majority of these countries.^62,77,78 We present an overview of several case studies from Asia of successes and challenges vaccinating pregnant women with seasonal influenza to explore possible lessons learned for the Chinese vaccination program.

Hong Kong special administrative region (SAR), China

The Hong Kong Special Administrative Region (SAR) Scientific Committee on Vaccine Preventable Diseases recommended influenza vaccination for pregnant women in the second or third trimester since the 2005/06 influenza season⁷⁹ and expanded the recommendation to include all pregnant women in the following year.⁸⁰ Beginning in the 2013/14 influenza season, pregnant women were recommended to have the highest priority for vaccination. The Center for Health Protections encourages pregnant women to receive influenza vaccination through free or subsidized programs.⁸¹ The Vaccination Subsidy Scheme is available to all pregnant women and provides a subsidy per dose of influenza vaccination provided through enrolled private doctors. The Government Vaccination Program is available to a subset of pregnant women who receive social welfare benefits and provides free vaccination through clinics administered by the Department of Health and the Hospital Authority.⁸¹

Despite recommendations to vaccinate all pregnant women after the 2006/07 influenza season, two studies found that uptake of H1N1pdm09 vaccine in pregnant women was only 6.2% during the 2009 pandemic, and seasonal influenza vaccination uptake among pregnant women was only 1.7% during the 2010/11 influenza season, which was lower than uptake of 11.5% in children aged 12–23 during the 2010/2011 influenza season reported in one study.^82,83 A multi-center qualitative study evaluating factors associated with influenza vaccine uptake among pregnant women in Hong Kong identified the following factors related to poor acceptance of influenza vaccination: misconceptions about the risk of influenza infection to themselves or their fetus, confusion about prevention versus treatment for influenza, doubts about vaccine safety and efficacy, lack of receipt of a health-care worker’s recommendation, and negative influence from the media.⁸⁴ Positive factors that encouraged influenza vaccination included concerns about the risk of influenza especially when there is perceived high prevalence, beliefs that vaccine is beneficial for the fetus, and having received health-care worker recommendations and reassurance about the safety of the influenza vaccine. However, the Hong Kong College of Obstetricians and Gynecologists did not have specifically published material addressing the seasonal influenza vaccine and instead referred to materials from the Department of Health.⁸⁴ At the time of the study, another barrier to vaccination was that influenza vaccine was not part of routine antenatal care; pregnant women needed to obtain the vaccine at their own expense from their family physician or other private clinics.⁸⁴ This access barrier was addressed in 2016/17 when eligibility for the Vaccination Subsidy Scheme was expanded to cover all pregnant women.⁸⁵ More recent published figures on vaccine coverage among pregnant women in Hong Kong are not available.

Despite its advanced health system and recommendation from the Center for Health Protection, Hong Kong has low influenza vaccination rates among pregnant women, highlighting challenges related to vaccinating a population that shares a similar culture with pregnant women in mainland China. One lesson learned is that health-care workers can influence their patients’ willingness to be vaccinated. Nevertheless, it may be important for health-care workers to receive support to recommend vaccination through their medical societies in addition to health departments.

South Korea

Starting in 1997, South Korea’s National Immunization Program (NIP) has offered influenza vaccination targeting low-income elderly adults. Since then, the recommendation has expanded to include high-risk populations including pregnant women.^86–88 Additionally, domestic influenza vaccination production began in 2009.⁸⁶ As a result, during the 2011/12 influenza season, 43.6% of the total population was vaccinated, including more than 80% of adults >65 years.⁸⁸

Trends in influenza vaccination rates in South Korea from 2005 to 2014 have been evaluated using the Korea National Health and Nutrition Examination Surveys. From 2005 to 2014, total influenza vaccination coverage increased from 38.0% to 44.1%. Among the recommended groups for influenza vaccination, adults aged ≥65 years (range 70.0–79.8%) and children <5 (range 64.6–78.9%) had higher vaccination rates than people with chronic diseases (range 29.6–42.6%) and pregnant women (range 9.4–37.8%).⁸⁹

Several factors may have contributed to lower vaccination coverage in pregnant women compared to older adults and young children. Previous studies in Korea have highlighted that vaccine deferral was most often related to concern about adverse effects, and that the most common reason for accepting vaccination was a physician’s recommendation.^90–93 However, an assessment of perceptions and attitudes of Korean obstetricians revealed that although 94.8% of those surveyed recognized that influenza vaccination was recommended, only 26.5% strongly recommended vaccination to pregnant women.⁹⁴ Another factor that may affect coverage is the receipt of financial aid for influenza vaccination. During 2004–2014, adults ≥65 and children <5 received financial aid under NIP for influenza vaccination while people with chronic diseases and pregnant women did not. Although the effect of financial aid on influenza uptake in pregnant women is unknown, it should be noted that the addition of financial aid for adults ≥65 was credited with increasing influenza vaccination rates (40–60% pre to 80% post).^86,95,96

South Korea’s experience with influenza vaccination demonstrates that a well-designed immunization program coupled with domestic influenza vaccination production can create mechanisms for successfully increasing influenza vaccination coverage in recommended populations.

Kazakhstan

Kazakhstan has developed a successful program for introducing influenza vaccination among pregnant women. Beginning in 2011, the Government of Kazakhstan recommended influenza vaccination for all pregnant women in the second and third trimesters.⁹⁷ The program provided vaccination to pregnant women from October–December at primary health-care clinics as part of the antenatal care program. Supported by the Ministry of Health, the maternal influenza vaccination program included skill development workshops for health-care workers related to influenza and pregnant women, training of immunization nurses to ensure safe vaccination, and annual awareness campaigns for women of reproductive age as well as messaging through mass media outlets.⁹⁷ The proportion of pregnant women vaccinated against seasonal influenza increased from 4.6% in the 2011/12 influenza season to 92.3% in the 2015/16 influenza season.⁹⁷

Kazakhstan’s maternal influenza vaccination program demonstrates the success of integrating the influenza vaccination program within the antenatal care program to provide a setting for vaccine delivery targeted to pregnant women. Further, combining vaccine recommendations with targeted messaging to vaccine recipients and targeted training to vaccine providers can substantially increase vaccine coverage for vulnerable populations.

Opportunities and challenges for increasing influenza vaccination in China

Opportunities and strengths

China has multiple opportunities and strengths for addressing the current suboptimal influenza vaccination coverage among pregnant women. China’s first influenza vaccine was licensed in 1997, and as of 2017, China has 8 influenza vaccine manufacturers, all of which manufacture influenza vaccine with regulatory oversight provided by China’s National Medical Products Authority.⁹⁸ To date, one of China’s manufacturers produces seasonal influenza vaccine meeting global standards of quality and safety (WHO-prequalified) – Hualan Biological Engineering Inc. The WHO package insert for this prequalified influenza vaccine has no contraindication for vaccination during pregnancy, and states that “the vaccine could be administered with caution in pregnant women and nursing mothers.”⁹⁹

With regard to immunization policy, China CDC has continuously recommended influenza vaccination for pregnant women since 2014. China has had a national immunization technical advisory group (NITAG) since 1982, and in 2017, the NHC established a new National Immunization Advisory Committee (NIAC). The NIAC makes evidence-based recommendations for inclusion of vaccines into China’s EPI system and on existing EPI vaccines and has authorized China CDC to establish technical working groups including an influenza working group. Working groups review evidence to support NIAC in making recommendations for NHC to consider for national policy.¹⁰⁰ This mechanism allows evaluation of emerging evidence to update influenza vaccine policies and also provides a formalized setting for prioritizing high-risk populations for scale-up of influenza vaccine particularly when vaccine supply may be limited. Finally, as in other countries, the NIAC influenza working group can contribute to addressing specific maternal immunization questions such as how the population is classified with respect to compensation and injury claims occurring with vaccines used in pregnancy.¹⁰¹

On a policy level, the National Health Commission issued a notice in October 2018 requiring health-care workers to promote influenza vaccination among patients and their family members.¹⁰² Although the notice does not mention specific patient populations, this notice is significant because it represents the first time that the National Health Commission has issued a statement regarding health-care workers and influenza vaccination. Although the effect of this policy on influenza vaccination will need to be assessed, its issuance demonstrates that the National Health Commission desires health-care workers to recommend influenza vaccination to their patients.¹⁰²

An additional asset for deploying influenza vaccination to pregnant women is China’s established antenatal care system. Since 97% of women utilize antenatal care services at least once during pregnancy,⁶⁶ the system can serve as a setting for both the delivery of influenza vaccination to pregnant women and the deployment of interventions encouraging health-care providers to recommend influenza vaccine and provide educational resources for pregnant women.⁹⁷ A uniform health system platform such as the antenatal care system can also be used to optimize data collection and evaluate influenza immunization programs including assessing vaccine coverage rates, monitoring vaccine availability, adverse events, and targeting of financial resources. Finally, in the future, the antenatal care system could serve as a platform for the introduction of subsidized vaccination programs.

China has successfully used the antenatal care system for public health vaccination initiatives as part of the preconception program, which is designed to help couples prepare for pregnancy.¹⁰³ For example, based on the results of a China CDC vaccination pilot for rubella, the preconception program has now initiated a program for promoting rubella vaccination. Similarly, if there were a government recommendation for influenza vaccination of pregnant women, the antenatal care system could serve as a point of delivery for vaccination and for educational materials.

Challenges

China also faces significant policy, health system, and patient belief challenges related to increasing seasonal influenza vaccination coverage among pregnant women. The Chinese Pharmacopeia’s contraindication on seasonal influenza vaccination during pregnancy represents the most immediate policy challenge to increasing influenza vaccine coverage in pregnant women. Since China CDC already recommends influenza vaccination for pregnancy based on international data supporting vaccine effectiveness and safety in this population,⁵⁵ removing the Chinese Pharmacopeia’s designation would eliminate a major regulatory barrier toward implementing a maternal influenza vaccination program. NIAC may be able to address this challenge. However, NIAC has yet to make “off-label” vaccine recommendations that differ from the Chinese Pharmacopeia. Since off-label recommendations are specific to a country’s legal landscape, a legal pathway for authorizing maternal influenza immunization will need to be identified for China.¹⁰⁴ As an example, although influenza vaccination of pregnant women has been recommended for decades in the United States, it was only relatively recently that government authorities identified remaining legal and programmatic hurdles to vaccinating pregnant women that should be addressed to instill confidence in providers to vaccinate pregnant women.¹⁰⁵ The National Vaccine Advisory Committee stated that, “although [US] CDC already recommends the use of vaccines during pregnancy, certain ethical, policy, educational, and research barriers need to be addressed to improve uptake of currently recommended vaccines and promote the development of additional maternal immunizations.”¹⁰⁵ It is likely that China will need to do the same.

Assuming increased demand for influenza vaccination coverage in the future, vaccine supply would represent another major barrier for increasing influenza vaccination coverage in China. Although China has domestic vaccine production capacity, from 2004 to 2014, China had an estimated annual influenza vaccination supply up to 58.8 million doses, with 72% manufactured in China.⁵⁹ However, during the same period, 426 million were considered recommended for receipt of influenza vaccination.⁵⁹ The influenza vaccine supply faced further pressure during the 2018/19 influenza season when reductions in domestic production resulted in a 39% decrease in the available vaccine in China (unpublished data). Given the size of the population eligible for influenza vaccine and current supply limitations, the only immediate solution would be to develop priority recipient groups among the high-risk populations recommended for influenza vaccination.

Another challenge to increasing influenza vaccine coverage among pregnant women is that health-care workers do not recommend the vaccine for this population. For example, in a 2013 knowledge, attitude and practice (KAP) study on influenza vaccination of 1623 pregnant women in Suzhou, only 4% reported receiving a recommendation from a health-care worker.⁶² Although this behavior may be explained partially by the Chinese Pharmacopeia’s contraindication, studies have found that health-care workers in China also have low awareness of the safety and benefit of influenza vaccine.¹⁰⁶ A study of influenza vaccine coverage in health-care workers in Qingdao found less than 5% had been vaccinated against influenza.⁶² Before influenza vaccine uptake can be successfully increased among pregnant women in China, it is necessary to educate health-care workers on vaccine benefits. If successful, increasing vaccine uptake among health-care works would serve as a means to overcome provider vaccine hesitancy during patient encounters.

Patient beliefs and hesitancy are another major barriers. Although not involving influenza vaccine, recent nationwide vaccine safety scandals have shaken public trust in vaccination.¹⁰⁷ A lack of confidence in the vaccination system may increase vaccine hesitancy among the general population. Pregnant women may be especially sensitive to concerns about vaccine safety because of perceived risks to the fetus. In the KAP of 1673 pregnant women in Suzhou, the most commonly cited reasons for declining influenza vaccine included fear of harm to the fetus (83%) and fear of harm to self (28%).⁶² Although these concerns will likely always be present, studies from other countries have found that educational information about the vaccine benefits and safety and receipt of health-care worker recommendations can increase a pregnant women’s willingness to be vaccinated against seasonal influenza.^83,108 In a survey of 1807 pregnant women who delivered in public hospitals in Managua, Nicaragua, receipt of influenza vaccination recommendation from a health-care worker was positively associated with receipt of influenza vaccination (aOR: 14.22; 95% CI: 10.45–19.33) and vaccination coverage was 71%.¹⁰⁹ These findings highlight the critical importance of health-care worker recommendations for increasing influenza vaccination coverage in pregnant women.

Next steps

While China CDC technical guidelines recommend vaccination of pregnant women, the technical guidelines alone are insufficient for increasing influenza vaccine uptake in this population because of systematic and regulatory barriers. A whole health sector approach will be needed to overcome these challenges. We suggest engaging key stakeholders (NHC, National Medical Products Administration, the Pharmacopeia committee, the Vaccine Injury Compensation Program, NIAC, China CDC, medical societies, and vaccine manufacturers) in strategic planning to review evidence and identify a pathway to remove the contraindication to vaccination during pregnancy, leading to a government recommendation for influenza vaccination during pregnancy. Such a recommendation should be in the context of strategic planning for increased use of influenza vaccine in other high-risk populations for both seasonal protection and pandemic preparedness.

Limitations

As this review focuses on the status and obstacles of implementing maternal influenza immunization in China as recommended by WHO and China CDC, it does not include a comprehensive analysis of the evidence associated with the risks and benefits of vaccinating pregnant women for seasonal influenza. In addition, although there are numerous diverse vaccination programs throughout the region, this review selected only three case studies to describe lessons learned in maternal influenza immunization in Asia which may inform maternal immunization in China.

Conclusions

China is currently in the early stages of implementing programs to increase seasonal influenza vaccination coverage. Although pregnant women are at increased risk of complications associated with influenza virus infection and there is evidence to support the benefit and safety of influenza vaccine in this population,^20,110 influenza vaccination coverage among pregnant women in China remains very low. Despite China CDC recommendations to vaccinate this population,⁵⁵ significant policy, health system, and patient belief challenges prevent providers from confidently recommending influenza vaccination to pregnant women. Increasing seasonal influenza vaccination among pregnant women will require a comprehensive approach. Legally removing the contraindication to vaccinating pregnant women in China would be the single most important first step. Until then, efforts to promote vaccination of pregnant women are likely to continue to fall short of what is needed to protect pregnant women and very young infants from influenza virus infection.

Disclosure of potential conflicts of interest

The findings and conclusions in this report are those of the authors and do not necessarily represent official positions of the US Centers for Disease Control and Prevention or the Chinese Center for Disease Control and Prevention.

Correction Statement

This article has been republished with minor changes. These changes do not impact the academic content of the article.