Incidence rates of influenza illness during pregnancy in Suzhou, China, 2015–2018

Background Data on influenza incidence during pregnancy in China are limited. Methods From October 2015 to September 2018, we conducted active surveillance for acute respiratory illness (ARI) among women during pregnancy. Nurses conducted twice weekly phone and text message follow‐up upon enrollment until delivery to identify new episodes of ARI. Nasal and throat swabs were collected ≤10 days from illness onset to detect influenza. Results In total, we enrolled 18 724 pregnant women median aged 28 years old, 37% in first trimester, 48% in second trimester, and 15% in third trimester, with seven self‐reported influenza vaccination during pregnancy. In the 18‐week epidemic period during October 2015 to September 2016, influenza incidence was 0.7/100 person‐months (95% CI: 0.5–0.9). In the cumulative 29‐week‐long epidemic during October 2016 to September 2017, influenza incidence was 1.0/100 person‐months (95% CI: 0.8–1.2). In the 11‐week epidemic period during October 2017 to September 2018, influenza incidence was 2.1/100 person‐months (95% CI: 1.9–2.4). Influenza incidence was similar by trimester. More than half of the total influenza illnesses had no elevated temperature and cough. Most influenza‐associated ARIs were mild, and <5.1% required hospitalization. Conclusions Influenza illness in all trimesters of pregnancy was common. These data may help inform decisions regarding the use of influenza vaccine to prevent influenza during pregnancy.


| INTRODUCTION
Pregnant women are known to be at risk for severe influenza disease and influenza-associated morbidity and mortality. [1][2][3][4] During the 2009 influenza pandemic, influenza illnesses were observed to be associated with complications during pregnancy including maternal mortality and loss of pregnancy. [5][6][7][8] The World Health Organization (WHO) and national public health authorities have recommended vaccination, the best tool for preventing influenza illness and complications associated with infection, for high risk groups including for pregnant women. 9,10 However, despite recommendation from the Chinese Center for Disease Control and Prevention (China CDC), 11 seasonal influenza vaccination coverage during pregnancy in China is less than 1%. 12 In China, there are significant barriers to promoting seasonal influenza vaccination in pregnant women including an absolute contraindication for this population in the Chinese Pharmacopeia until the latest revision in 2020, healthcare worker reluctance to recommend this vaccination to pregnant women, and women's concerns about vaccine safety or lack of awareness of vaccination. [13][14][15][16] Knowledge of influenza infection during pregnancy is also limited.
Previous studies found that only 20% of surveyed pregnant women were aware that influenza infection could cause serious harm during pregnancy and 61% reported an interest in learning about prevention and control of influenza. 17 Data are needed to evaluate burden of influenza virus infection during pregnancy in China, to enhance risk communication and to inform future prevention and control measures including increasing influenza vaccine uptake within this population. We conducted active surveillance among pregnant women in Suzhou, China, to assess influenza incidence in a population at risk for influenza disease.

| Study design and participants
From October 2015 to September 2018, we conducted active surveillance for laboratory-confirmed influenza-associated acute respiratory illness (ARI) among pregnant women in Suzhou. Suzhou is a city located in eastern China with an estimated population of approximately 10 million in 2015. 18 Influenza surveillance data from Suzhou and similar geographic areas have demonstrated semi-annual seasonal patterns with peak activity typically occurring in January-February and June-August. 19 The enrollment methodology and description of the cohort profile of the China Respiratory Illness Surveillance among Pregnant women (CRISP) have been published previously. 12 In brief, from October 2015 to September 2018, nurses consented and enrolled pregnant women in different trimesters of pregnancy (first trimester defined as 1-12 weeks gestation, second as 13-26 weeks gestation, and third as 27 weeks to gestation) from two prenatal care facilities that provide prenatal care services to 17% of women residing in Suzhou during pregnancy 20 and one pre-marriage health center. Prenatal care facilities were selected as enrollment sites because more than 95% of pregnant women who had a live birth or stillbirth delivery after 28 weeks gestation in Suzhou had made at least one prenatal care visit at a prenatal care facility and because pregnancy status would be confirmed by ultrasound as part of routine care. 20 We selected a premarriage health center, which offers pregnancy testing to couples, as an enrollment site to identify women who may have been early in their pregnancies. Pregnant women who lived in and planned to deliver in Suzhou were considered eligible for enrollment. Pregnant women who sought non-routine prenatal care such as confirmation of low progesterone and threatened miscarriage were excluded.

| Enrollment of the annual cohort
Study nurses enrolled pregnant women into annual cohorts from October to September of each study year that was defined as the influenza season in the national influenza surveillance protocol. 21 Most individuals in each cohort were enrolled before November.
However, to ensure enrollment of adequate numbers of first trimester pregnant women and to ensure sufficient numbers of pregnant women to follow during the summer, we continuously enrolled first trimester pregnant women from the October-September period, which allowed us continuous observations throughout the year ( Figure 1).
Upon enrollment, study nurses conducted face-to-face interviews using a structured questionnaire to collect data on the participant's demographics, health conditions, pregnancy-associated conditions, health behaviors, social behaviors, and self-reported influenza vaccination status. For health conditions, chronic diseases referred to any medical problem diagnosed by a doctor or other health care provider before pregnancy that lasted for at least 6 months such as diabetes, asthma, heart disease, or cancer. Pregnancy-associated conditions referred to a newly developed condition identified during pregnancy by enrollment such as gestational diabetes or high blood pressure.
Health and social behaviors included dietary supplement intake, smoking, alcohol, and self-reported changes in working hours and social activities.

| Follow-up for ARI episodes and laboratory testing
After enrolling pregnant women in active surveillance, study nurses conducted twice weekly follow-up starting at the enrollment date until the delivery date or the end of pregnancy/loss of pregnancy with phone call and WeChat text message (a free, instant messaging application widely used in China) alternatively to identify episodes of ARI.
An ARI episode was defined as ≥1 respiratory symptom (cough, sore throat, stuffy nose, chest pain, and difficulty breathing) and ≥1 systemic symptom (feverish, temperature ≥38 C, chills, and headache) or ≥2 respiratory symptoms. When a current illness or recent illness was identified, the study nurse used a standardized questionnaire to collect data on illness onset date, symptoms, and hospital admission.
Participants reporting ARI were encouraged to visit the study hospital's respiratory illness department (ambulatory clinics) or offered a house call for testing to ensure specimen collection ideally within 24 h but up to a maximum 10 days from illness onset. Study nurses collected both a nasal and a throat swab with double-headed disposable virus sampling tube (YOCON Biology Technology Company, Beijing). Respiratory specimens were transported to the Suzhou CDC laboratory within 24 h of collection at 4 C and were analyzed using real-time reverse transcription polymerase chain reaction to test for influenza virus subtype/lineage.

| Data analysis
The cohorts were considered open, and eligible participants could be enrolled at any time during the study period. An enrolled participant was considered to have complete data if she completed the enrollment interview, responded to weekly surveillance contacts by study nurses until delivery or termination of pregnancy, and had perinatal records available for review. Those who were lost to followup (no response to any contact for at least two consecutive weeks despite multiple attempts), voluntarily withdrew, or left Suzhou before the end of pregnancy only contributed the person-time for which there was available data. If a pregnant woman was enrolled in an annual cohort but delivered after the end of the surveillance year, the person-time was split between the two surveillance years. To streamline cohort management and reporting, the full analytic population for each surveillance year included those contributing person-time from the previous surveillance year if applicable.
We calculated incidence rate over the influenza epidemic periods of each influenza surveillance year. The start of each influenza epidemic period was defined as the first day of three consecutive influenza reporting weeks in which the percentage of specimens testing positive for any influenza virus infection was higher than 5%. The end of each influenza epidemic period was defined as the day before the first of three consecutive influenza reporting weeks in which the percentage of specimens testing positive for influenza was below 5%. 22 In the influenza incidence rates calculation, illness episodes were considered as distinct episodes if they occurred at least 2 weeks apart, from the end of symptoms for one episode to the onset of any new symptom, and the population at risk was defined as women pregnant for 2 weeks or more during the epidemic period.
Our primary outcome was the influenza incidence identified through ARI screening. For secondary outcomes, we evaluated the influenza incidence using influenza-like illness (ILI) case definitions for screening. ILI was defined as a measured temperature ≥38 C and cough/sore throat.
We described demographic, clinical, and knowledge and practices related to influenza vaccination. Chi-square or Fisher exact tests were used to compare proportions where appropriate. Incidence rate was F I G U R E 1 Flow chart of enrollment and follow-up of the annual cohorts of China Respiratory Illness Surveillance among Pregnant Women (CRISP), Suzhou, 2015/2016-2017/2018 seasons. After enrolling pregnant women, study nurses conducted twice weekly follow-up starting at the enrollment date until the delivery date or the end of pregnancy/loss of pregnancy with one phone call and one WeChat text message (a free, instant messaging application widely used in China) to identify episodes of acute respiratory illness (ARI). An ARI episode was defined as ≥1 respiratory symptom (cough, sore throat, stuffy nose, chest pain, and difficulty breathing) and ≥1 systemic symptom (feverish, temperature ≥38 C, chills, and headache) or ≥2 respiratory symptoms calculated as the number of new cases per 100 person-month. Since the total number of missed swabs was minimal, those with missing swabs contributed person time but did not contribute to the total number of influenza positive cases; 95% confidence interval (CI) for person-month rate was simulated with bootstrapping. Fisher exact test was used to compare person-month rates. All tests were two sided, and a p < 0.05 was considered as statistically significant. R version 3.5.3 was used for statistical analysis. Of all participants, 40% reported decreased working hours during pregnancy, 52% reported a reduction in general social interactions, and 57% reported reduced social activities with friends during pregnancy (Table 1).
Of the 18 724 women, 61% reported knowing of influenza vaccination. Only 7/18 724 (0%) reported that they had been vaccinated during pregnancy. Only 0.6% reported influenza vaccination in the prior year and 0.6% reported influenza vaccination among family members in the prior year. The proportion vaccinated during pregnancy did not differ significantly across cohorts (Table 1).

| Factors associated with the incidence estimates
No significant difference in influenza incidence was observed by age or education level. Influenza incidence varied significantly when using different surveillance case definitions. Using ILI as the surveillance case definition had significantly lower influenza incidence (0.4 per 100 person-months) than using ARI (1.2 per 100 person-months) in overall of the epidemic periods (p < 0.001). The findings regarding demographic characteristics' and case definitions' difference in influenza illnesses were consistent over the entire study period (Table 2). These findings were also consistent when expanding the observation outside of the epidemic period (data not shown).
In the overall cohort, ARI incidence decreased significantly in the second trimester (10.0 per 100 person months) and in the third trimester (7.6 per 100 person-months) in comparison with the first trimester (21.0 per 100 person-months) during the epidemic periods (Table 3). This observation was consistent in all three cohorts.
However, in the overall cohort, we found no significant differences in the influenza incidence by trimester, which was 1. distancing behavioral changes during pregnancy. Influenza incidence was similar across trimesters. Using ILI as a case definition missed more than half of the total influenza illnesses compared with broader ARI criteria. Over the three cohorts, 1.6-5.1% of influenza-associated ARI cases required hospitalization.
Prior to this study, there were limited data on influenza incidence and epidemiology of infection during pregnancy in China. 23 By following cohorts of pregnant women over multiple seasons using a sensitive case definition and highly sensitive and specific molecular diagnostics, we found that during influenza epidemic periods in 2015-2018 in Suzhou, women were frequently infected with influenza during pregnancy and in some cases had illness requiring hospitalization. Our estimated influenza incidence rates were similar with a prospective cohort study in three middle income countries that showed women had a 0.7-0.9% risk of influenza per month of pregnancy during the 2017-2018 influenza seasons. 24 Our incidence estimates were higher than influenza incidence rates observed in influenza vaccination clinical trials in other low and middle income countries. [25][26][27][28] One reason for this difference was that unlike some other studies, our case definition included non-febrile influenza illnesses. Requiring the presence of measured fever in the case definition as with ILI substantially reduced the number of  The start of each influenza epidemic period was defined as the first day of three consecutive influenza reporting weeks in which the percentage of specimens testing positive for any influenza virus infection was higher than 5%. The end of each influenza epidemic period was defined as the day before the first of three consecutive influenza reporting weeks in which the percentage of specimens testing positive for influenza was below 5%. b ARI: acute respiratory illness, defined as ≥1 respiratory symptom (cough, sore throat, stuffy nose, chest pain, and difficulty breathing) and ≥1 systemic symptom (feverish, temperature ≥38 C, chills, headache); or ≥2 respiratory symptoms with onset within the last 10 days. c ILI: influenza-like illness, defined as a measured temperature ≥38 C and cough/sore throat with onset within the last 10 days. Applying the overall cohort influenza incidence rates during pregnancy of our study to a 12-week-long epidemic period, our result is comparable with the estimates in unvaccinated adults aged 18-64 years based on a modeling study from the United States, which estimated a cumulative seasonal incidence of symptomatic influenza of 4.3%-7.9% in seasons of moderate severity. 33  China, which showed that 0.2% of participants reported influenza vaccination within the last 12 months, and none during pregnancy. 12,13 During the time of these studies, pregnancy was listed as a contraindi-  Acute respiratory illness (ARI) defined as ≥1 respiratory symptom (cough, sore throat, stuffy nose, chest pain, and difficulty breathing) and ≥1 systemic symptom (feverish, temperature ≥38 C, chills, headache) or ≥2 respiratory symptoms with onset within the last 10 days. b The start of each influenza epidemic period was defined as the first day of three consecutive influenza reporting weeks in which the percentage of specimens testing positive for any influenza virus infection was higher than 5%. The end of each influenza epidemic period was defined as the day before the first of three consecutive influenza reporting weeks in which the percentage of specimens testing positive for influenza was below 5%.
Knowledge, Attitudes, and Practices study among pregnant women in China found that barriers to influenza vaccination included low perceived susceptibility to influenza and preference for nonpharmaceutical interventions to prevent infections. 37

| CONCLUSIONS
Influenza illnesses in all trimesters of pregnancy were common in Suzhou, China, and we found that non-febrile influenza illnesses were more frequent than febrile influenza illnesses during pregnancy.

CONFLICT OF INTERESTS
No conflict of interest declared.

PEER REVIEW
The peer review history for this article is available at https://publons. com/publon/10.1111/irv.12888.

DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available from the corresponding author upon reasonable request.