Knowledge attitudes and practices toward seasonal influenza vaccine among pregnant women during the 2018/2019 influenza season in Tunisia.

BACKGROUND: The uptake and acceptance of the influenza vaccine (IV) among pregnant women remain unknown in Tunisia despite the increased influenza-related complications and death. The present study aimed to assess the IV uptake and acceptability and to describe related knowledge and attitudes among pregnant women in Tunisia.
METHODS: A cross-sectional study was conducted in 84 Tunisian healthcare facilities over a period of three months (from March to May 2019). All pregnant women aged ≥18 years who sought antenatal care in related health structures were included in this study based on a multistage self-weighted sampling. We measured knowledge and attitudes towards the IV and assessed factors related to willingness for its uptake.
RESULTS: The questionnaire was completed by 1157 pregnant women. More than half of the participants (60.2%; 95% confidence interval [CI] [57.3%-63.0%]) reported awareness about the IV. Among included PW, only 4.6%; 95% CI [3.5%-6.1%] received it during their current pregnancy. However, (36.8%; 95% CI [34.0%-39.6%]) declared their willingness to receive the vaccine in the next pregnancy. Recommendation by healthcare providers, identified to be the most trustful source of information, was the main reason for acceptance. However, the intention to accept the IV by pregnant women was significantly associated with such recommendation and perceived safety and effectiveness of this vaccine.
CONCLUSION: Antenatal care visits are a precious opportunity that should not be missed by health care providers and especially gynecologists to promote the IV uptake by pregnant women in Tunisia.

I. Introduction

Influenza is an acute respiratory infection caused by viruses belonging to the Orthomyxoviridae family. The burden of this disease varies based on characteristics of the circulating strains and the immune status of the population [1].

Pregnant women (PW) have been identified as a group at an increased risk of influenza-related complications and death, during seasonal epidemics and pandemics, due to physiological and immunological changes [2-5]. Furthermore, influenza during pregnancy has been reported to have considerable effects on the fetus and is associated with an increased risk of early spontaneous abortion, neurological birth defects, preterm delivery, stillbirth, low birth weight, and neonatal death in severe cases, especially among babies born during influenza season [2,3].

Several reports have supported the safety, immunogenicity, and effectiveness of the inactivated influenza vaccine (IV) (trivalent inactivated IV) during any term of pregnancy for the mother and the fetus [6-8]. In fact, maternal antibodies produced after vaccinations are transferred to the fetus and newborn via the umbilical cord, placenta, and breastfeeding [9]. The cost effectiveness of the IV was confirmed by several studies [10,11]. Considering these reasons, since 2012, the World Health Organization (WHO) has declared that PW should be given the highest priority if countries consider initiation or expansion of their seasonal influenza vaccination programs [3].

Despite the proven effectiveness of the IV in protecting the mother, fetus, and new born, the rate of maternal influenza immunization remains low in many countries [12-15], and significantly lower than the target of 80% fixed by authorities in 2020 for healthy individuals [16].

In Tunisia, the IV is not free of charge among pregnant women and non-refundable. The uptake and the acceptance of IV among PW remain unknown. The present study was thus conducted to assess IV uptake and acceptability among PW and to describe their knowledge and attitude regarding this vaccine. The findings from this research will constitute an evidence base for the promotion of the IV by the health authorities in charge of the national program of seasonal influenza control and prevention in Tunisia.

II. Methods

1. Study design

A nationwide cross-sectional study was conducted in Tunisia during the 2018/2019 influenza season over a period of three months (from March to May 2019, spring season). The 2018/2019 influenza season in Tunisia began in week 40/2018 (1st October, 2018) and ended in week 18/2019 (May,5th, 2019).

2. Study population

All PW aged ≥18 years who attended a public health center (primary healthcare center, district or regional hospital) for routine antenatal care during any term of pregnancy were included in this survey. Women suffering from cognitive disorders were excluded.

The total population of PW who attended the primary and secondary health care facilities is estimated to be between 10,000 and 100,000.

The calculated sample size was ≃1200 PW after adjustment based on a non-response rate of 20% and a design effect of 2.5.

3. Sampling procedure

A multistage self-weighted sampling method was used to select PW. First, a stratified sampling was performed based on the three Tunisian regions (North, Center and South). Given the limited budget of the survey (limited logistics support and resources), we chose to randomly select one third (n = 8) of the total 24 Tunisian governorates.

We applied the percentage of Women of childbearing age in each region (North, Center and South) to determine the number of selected governorates in each region. Thus, we selected the following governorates in each region (S1 Fig):

Four in northern Tunisia (48.0%*8): Ariana, Ben Arous, Bizerte, Siliana

Three in the central Tunisia (36.7%*8): Sousse, Mahdia, Kairouan

One in southern Tunisia (15.3%*8): Gafsa

The second stage consisted on a stratification by area of residence (urban and rural).

The third stage was the selection by simple random sampling in each governorate of health care centers which offer antenatal care visits from both urban and rural areas. The selection of centers was performed as the survey progressed. Every day, we randomly selected one center among all those that offer medical care consultations for PW on that day. The selected center will not be selected again.

On the day of their visit, investigator(s) were asked to randomly select participants from the exhaustive list of PW consulting the selected health care facility on that day. PW were ordered by order of registration, then they were randomly selected using a random number generator. The number of PW approached to participate to the survey in each health care facility depended on the availability of human and logistic resources.

It should be noted that a pilot study was performed in order to assess the comprehensiveness of questionnaire items, to identify ambiguous questions and to estimate the maximum number of questionnaires that could be properly administrate by one investigator which was equal to 20.

The selection of PW was stopped when we achieved the required sample size.

The calculated sample size was distributed according to the distribution of women of childbearing age between the three Tunisian regions, to the weight of each governorate in the corresponding region and to the weight of the area of residence in each governorate.

More details are presented in S1 Fig.

The survey was conducted in 84 health care facilities: Primary healthcare centers (n = 69; 82%), district hospital (n = 11; 13%) and regional hospital (n = 4; 5%) (S1 and S2 Tables)

4. Data collection

A face-to-face interview was conducted using a standardized questionnaire by interviewers previously trained for this purpose. The interviewers were health care professionals (medical doctor, nurse and midwife) working in public health institutions.

The questionnaire (S1 and S2 Appendix) included 38 items and was divided into four parts: socio-demographic characteristics, pregnancy-related data, knowledge, and attitude regarding influenza and uptake of the IV. A woman was considered to have been vaccinated against influenza at the time of the survey if she reported having received one dose of influenza vaccine during this pregnancy (independent of the term of pregnancy).

Responses to general statements about knowledge and attitude regarding influenza (one statement) and IV (seven statements) were measured using a 5-point Likert scale ranging from strongly disagree (1) to strongly agree (5).

5. Data analysis

EpiInfo software version 7.2.2.6 (developed by Centers for Disease Control and Prevention, U.S) was used for data entry and analyses.

This study included only qualitative variables that were presented as numbers and percentages.

Answers to questions assessed using the 5-point Likert scale were recorded as follows: “strongly agree” responses were combined with the “agree” responses and “strongly disagree.” “Disagree,” “neither agree nor disagree,” and “I don’t know” responses were combined into “other” responses.

Percentages and their 95% confidence interval were weighted according to region, governorate and area of residence.

Pearson’s χ2 test was used for bivariate analysis to assess any associations between willingness to receive the IV among PW during their next pregnancy (variable of interest) and socio- demographic and pregnancy characteristics. History of IV uptake, vaccine uptake during the current pregnancy, knowledge and attitudes about influenza infection and IV were also tested. We calculated weighted crude odds ratios (OR) and their 95% CI according to region, governorate and area of residence in order to assess strength of association between variables.

Differences were considered as statistically significant if the p-value was less than 0.05.

6. Ethical considerations

Ethical approval for this survey was obtained from the Biomedical Ethics Committee of the Pasteur Institute of Tunis. Approval was also obtained from the Tunisian Ministry of Health.

All women included in the survey were informed about the objectives and modalities of the study. Women who agreed to be interviewed provided written informed consent. Participants were also informed that all data collected would be analyzed anonymously and that participation was voluntary.

A unique ID was assigned to each participant, and the hard copy of the questionnaires was stored in a secure location, with access restricted to approved survey personnel.

III. Results

1. Characteristics of the included pregnant women

Overall, 1348 PW attending 84 health care centers were approached to participate in the survey. Among them, 1200 PW accepted to respond to our questionnaire. However, 1157 questionnaires were retained for analysis and 43 were excluded for incomplete data or the presence of an exclusion criterion (age less than 18 years). The response rate was 89% (1200/1348).

More than half (74.7%) of the surveyed PW resided in urban areas. Most women (62.4%) were between 25 and 34 years of age and less than a third had attended university (23.2%).

Regarding pregnancy history, 48.9% and 41.3% were in the second and third trimester of pregnancy, respectively. Nearly two women of five (41.5%) were multigravida and 31.4% reported that the current pregnancy was their first. Furthermore, 17.8% of the surveyed women had comorbidities and 21.0% reported complications prior to or in the current pregnancy, respectively (Table 1).

Table 1

Socio-demographic and pregnancy characteristics of the enrolled women, (n = 1157).

Variables	n	Percentage (%)
Sociodemographic characteristics
Residence area (n = 1157)
Urban	864	74.7
Rural	293	25.3
Age groups (years) (n = 1157)
18–24	146	12.6
25–34	722	62.4
≥35	289	25.0
Educational level (n = 1152)
Primary school or less	293	25.4
Secondary school	590	51.2
University level	267	23.2
Don’t want to answer	2	0.2
Marital status (n = 1136)
Single	4	0.4
Married	1126	99.0
Others situation	3	0.3
Don’t want to answer	3	0.3
Employment status (n = 1140)
Employed	387	33.9
Unemployed	752	66.0
Don’t want to answer	1	0.1
Time required to go from home to antenatal care facility (minutes) (n = 1146)
≤30	929	81.1
31–60	185	16.1
≥61	29	2.5
Don’t know	3	0.3
Pregnancy related characteristics
Number of pregnancies (n = 1148)
1 (this is my first pregnancy)	361	31.4
2	311	27.1
≥3 (multigravida)	476	41.5
Trimester of this pregnancy (n = 1146)
First Trimester (1–13 weeks)	112	9.8
Second Trimester (14–26 weeks)	560	48.9
Third Trimester (≥27 weeks)	474	41.3
Number of antenatal care visits completed by time of survey
1 (this is my first antenatal consultation)	109	9.5
>1	1040	90.5
Comorbidities prior to this pregnancy (n = 1149)
Yes	205	17.8
No	944	82.2
Complications during this pregnancy (n = 1137)
Yes	239	21.0
No	898	79.0
Number of children (n = 1087)
0	372	34.2
1–2	604	55.6
≥3	111	10.2
History of miscarriage, abortion, stillbirth (n = 1148)
Yes	297	25.9
No	851	74.1

2. Influenza vaccine uptake

Among the surveyed PW, 988 had heard of influenza in the past (86.0%; 95% CI [83.9%–87.8%]) and 694 already know about the IV (60.2%; 95% CI [57.3%–63.0%]). Seventy-five (6.7%; 95% CI [5.4%- 8.4%] of PW reported having enough information about side effects of IV.

Among included PW, 78 (7.0%; 95% CI [5.6%–8.6%]) women had received the IV at least once in the past and only 51 (4.6%, 95% CI [3.5%–6.1%]) received the vaccine during the current pregnancy. Seventy-five women (6.7%; 95% CI [5.4%–8.4%]) reported being vaccinated against influenza at least once in the past 5 years.

In addition, 550 (48.4%; 95% CI [45.6%–51.3%] of interviewed women reported that they would accept the vaccination if recommended by the health professionals and offered free of charge.

3. Factors associated with influenza vaccine acceptance in the next pregnancy

Among the included women, 421 (36.8%; 95% CI [34.0%–39.6%]) were willing to receive the IV in their next pregnancy and 154 (14.1%; 95% CI [12.1%–16.4%]) answered “I don’t know.”

The results of bivariate analysis revealed that both of women with comorbidities prior to the current pregnancy and those with complications during the current one were more likely to be willing to receive the IV (OR = 1.9; 95%CI [1.3–2.6], p<10−3 and OR = 1.5; 95%CI [1.1–2.1], p = 0.01 respectively). However, neither the number of antenatal care visits completed at the time of the survey, nor the number of pregnancies, and number of children were significantly associated with the willingness to receive the vaccine (S3 Table).

As presented in Table 2, PW who received the IV at least once in the past were 2.7fold more likely to retake it compared to those who were never vaccinated (OR = 2.7; 95% CI [1.6–4.5]; p<10−3).

Table 2

Knowledge and attitudes towards influenza and influenza vaccination and their association with willingness to receive influenza vaccine during pregnancy .

Variables2	Willing to receive influenza vaccine n (%)*	Crude OR 95% CI3*	p- value
Do you know anyone who has been severely ill with influenza?			0.7
No (n = 632)	272 (43.9)	1
Yes (n = 325)	136 (42.6)	1.0 [0.7–1.3]
Had you heard of the influenza vaccine before?(Q15)
Yes (n = 619)	222 (36.6)	1	<10−3
No (n = 373)	196 (52.9)	1.9 [1.5–2.6]
Do you know anyone who had a bad reaction to influenza vaccine?			0.01
Yes (n = 51)	12 (24.8)	1
No (n = 919)	398 (43.8)	2.4 [1.2–4.8]
Had you enough information about safety and side effects of influenza vaccine?			10−3
No (n = 870)	353 (41.0)	1
Yes (n = 73)	45 (61.5)	2.3 [1.4–3.8]
Do you trust the advice of your health care provider?			0.002
No (n = 81)	23 (27.3)	1
Yes (n = 853)	387 (46.2)	2.3 [1.3–3.9]
Has anyone recommended you receive influenza vaccine during this pregnancy?			<10−3
No (n = 890)	359 (40.8)	1
Yes (n = 92)	56 (61.2)	2.3 [1.5–3.6]
Has anyone discouraged you from receiving influenza vaccine during this pregnancy?			0.3
Yes (n = 81)	30 (36.8)	1
No (n = 895)	382 (43.3)	1.3 [0.8–2.1]
Did you receive the influenza vaccine at least once at the past?			<10−3
No (n = 919)	371 (40.8)	1
Yes (n = 72)	46 (65.1)	2.7 [1.6–4.5]
Influenza vaccine uptake during this pregnancy			0.09
No (n = 946)	393 (42.0)	1
Yes (n = 45)	24 (55.3)	[0.9–3.2]

*: Weighted according to region, governorate and area of residence.

1Persons who answered ‘I do not Know’ to the question concerning willingness to receive influenza vaccine were excluded (n = 154)

2respondent indicated “I don’t know” or “I don’t remember” or skipped the question are not included in Table 2 calculations.

3 Confidence interval.

In addition, participants who were unaware of the IV or adverse events reported by persons who received the IV were 2 times (OR = 1.9; 95% [1.5–2.6]; p<10−3) and 2.4 times (OR = 2.4; 95% CI [1.2–4.8]; p = 0.01) more likely to be willing to accept the vaccine respectively.

Similarly, women who had adequate information regarding the safety and side effects, those who trusted the advice of their healthcare provider, and those who were recommended to receive IV during their pregnancy were more likely to accept the IV (Table 2).

Compared to PW who refused the IV, women who were willing to receive it were more convinced that the vaccine helped in protecting them as well as their fetus, and newborn(p<10-3). They also perceived the vaccine harms as significantly reduced. More details are presented in Table 3.

Table 3

Comparative analysis of knowledge and attitudes about influenza infection and influenza vaccination according to willingness to receive influenza vaccine during pregnancy.

	Willing to receive influenza vaccine		Not willing to receive influenza vaccine
Statements1	N2	Agree3 n (%)	N4	Agree3 n (%)	p-value
• Influenza is more dangerous for pregnant women than no pregnant women (n = 835)	344	295 (85.8)	491	417 (84.9)	0.74
• Influenza vaccine can be dangerous for pregnant women (n = 611)	218	67 (30.7)	393	169 (43.0)	0.003
• Influenza vaccine can be dangerous for the fetus (n = 612)	220	58 (26.4)	392	159 (40.6)	10−3
• Influenza vaccine can be dangerous for the newborn (n = 609)	217	54 (24.9)	392	149 (38.0)	10−3
• Influenza vaccine helps protect pregnant woman against influenza (n = 603)	219	162 (74.0)	384	128 (33.3)	<10−3
• Vaccination of pregnant women against influenza helps protect the fetus (n = 597)	214	133 (62.1)	383	86 (22.5)	<10−3
• Vaccination of pregnant women against influenza helps protect the newborn (n = 602)	217	124 (57.1)	385	82 (21.3)	<10−3
• Women should receive the Influenza vaccine during each pregnancy (n = 602)	215	133 (61.9)	387	45 (11.6)	<10−3

1Statements about influenza concern only participants who had knowledge about influenza while statements about influenza vaccine concern only participants who know that there exists a vaccine.

2 The number of responses for each statement among participants that indicated a willingness to receive influenza vaccine.

3Agree also includes strongly agree”.

4 The number of responses for each statement among participants that indicated unwillingness to receive influenza vaccine.

Healthcare workers were identified as the most trusted source for information on the IV: doctors (87.7%) and other healthcare professionals (nurse, midwife, and pharmacist, among others) in 93.3% of the cases. Furthermore, 74.5% and 34.0% of the surveyed women reported that they would accept the vaccination if recommended by the medical doctor and other health provider respectively. The main three reasons for refusing IV were fear of side effects and concerns regarding self-harm or harm to the fetus (72.1%), concerns about vaccine efficacy (16.2%) and natural immunity inducted by the infection is better than the immunity inducted by the vaccine (11.2%).

IV. Discussion

Similar to the findings of our study, other studies have reported very low vaccine uptake during pregnancy, mainly in developing countries. The low vaccine uptake observed in the present study (4.6%; 95% CI [3.5%-6.1%]) may be explained by the absence of a national policy regarding flu immunization among PW. In fact, in Tunisia, IV is provided free of charge only to the elderly with underlying chronic diseases and healthcare workers in public health settings. Furthermore, the national health insurance does not cover the cost of the vaccine. This low coverage rate seems be related to the lack of awareness of PW regarding the need of IV during pregnancy and of physician recommendation of IV rather than IV availability and health care accessibility. In addition, Tunisia (upper-middle income country) appeared among the only six countries in Africa that adopted national immunization policies or guidelines against seasonal influenza (National program for surveillance and control of influenza since 1980 and Pandemic influenza preparedness and response plan since 2009) and more than 90% of Tunisian population resided less than 5 Km of a primary health care center [17,18]. For instance, in a study conducted in Thailand during the 2012–2013 influenza season, only 4% of the surveyed PW had received the vaccine during their pregnancy [12]. Likewise, according to an administrative estimation of vaccine coverage, only 1% of pregnant Moroccan women were vaccinated in 2016 [19]. Li Richun et al. reported that none of the PW interviewed in a Chinese qualitative study had received the vaccine during the 2015–2016 influenza season [14].

This could be explained by the difference between public health national program goal between countries. In high income countries (HIC), policies are based on a variety of measures, including cost-effectiveness, prevention of work and school absenteeism, prevention of ambulatory care visits, hospitalizations, and death. In low and middle income countries (LMIC), strategies are mainly focused on vaccine-attributable severe disease prevention and program costs. Among the several challenges to influenza vaccine program implementation in those countries (National immunization programs), most notably were limited disease burden data, lack of awareness about influenza disease burden among stakeholders, uncertain impact (benefits and safety) of IV on important public health outcomes, and technical challenges providing vaccination services [20,21]. In fact, higher coverage rate was not correlated with the level of economic development while the influenza management was enhanced when the vaccine was offered free through the public sector [22].

According to a systematic review conducted by WHO, increasing seasonal influenza coverage in the LMIC must overcome several challenges: First, lack of information on influenza disease burden, vaccine effectiveness and impact, a poor definition of individuals at risk of influenza-related complications, and a low perceived severity of influenza disease, places seasonal influenza vaccination low on the list of a country’s public health priorities.

Second, a lack of a cogent immunization policy, high vaccine costs coupled with limited resources for supply and delivery along with public adverse opinions against vaccination limit wider usage of the vaccine in those countries. Third, the low vaccine demand and poor coverage further contributes to the already poor or absent vaccine production capacity to make sustainability a major challenge for the influenza vaccine industry in LMIC [17].

However, the coverage was higher in some developed countries such as the United States (61.2% in November 2019), the United Kingdom which vaccine coverage ranged from 44.1% in England to 56.1% in Northern Ireland in 2014–15 and was 45.2% in 2018–2019 influenza season (from 44.3% in Northern Ireland to 74.2% in Wales) [23-27]. This high flu vaccine uptake could be explained by that the predominant payment mechanism for influenza IV was through the national health services in the European member states and by the implementation of a vaccine coverage monitoring system in this target group. In the UK, the target PW are listed and invited to get the vaccine. In addition, obstetrician-gynecologists doctor closely worked with community midwives to ensure accurate and timely recording updates of PW vaccinated outside general practice [28]. In the USA, coverage rates seem to be higher when a healthcare provider can recommend, offer, and administer the vaccine at the same visit as opposed to making a recommendation and referring the patient elsewhere to receive the vaccine [28].

Those results could be thus explained by the seniority of implementation of national vaccination program among high risk groups (of which PW) which allow to monitor, to evaluate and to remedy deficiencies in high income counties. Unlikely to barriers to the effective implementation of the national immunization strategy among general population and PW in particular in LMIC.

Among the total participants, 36.8% reported their willingness to receive the IV. This proportion was significantly higher than the vaccine uptake assessed among the surveyed PW. However, the proportion was lower than the acceptance rates of the IV reported in other studies: 42% in Thailand, 64.5% in Taiwan, 87% in Pakistan, and 76.3% in China [12,29-31]. Nevertheless, it is important to note that differences in the study populations and methods used while assessing acceptance of the IV may hinder comparison between studies.

The results of our study highlighted that only 48% of women claimed that they would take the vaccine if it was recommended by a health care professional and provided free of charge, which is substantially lower than the target of 80% vaccinated among PW, even if this would be a large improvement from the 4% of PW who reported IV uptake during the current pregnancy. Moreover, three out of four women (75%) declared that they would be willing to take it if it was recommended by a medical doctor, but only 34% if it was recommended by another health care professional.

Prior comorbidities and complications during the current pregnancy were positively associated with willingness to receive the vaccination. This could be explained by a higher perception of vulnerability among this population compared to PW without a medical history.

In addition, we found that prior recommendation to receive IV was significantly associated with a higher rate of acceptance. Similar results were reported by Ditsungnoen et al andOffedu et al [12,32,33]. Furthermore, IV recommendation by healthcare workers was reported as the most important reason for acceptance, and caregivers were identified as the most trusted source of information, as reported in other studies as well [34-36]. Such findings emphasize the role of healthcare professionals in improving the acceptance rate of IV among PW. Therefore, efforts should be paid to increase awareness among healthcare providers regarding the importance of maternal immunization against influenza, and to encourage PW to be vaccinated.

Consistent with the observations of other studies [12,14,29,30], PW who believed in the effectiveness of the IV for the mother, fetus, and newborn were more inclined to be vaccinated. However, concerns regarding dangers of the vaccine to the mother, fetus, and newborn child were negatively associated with willingness to such vaccine as reported in previous studies [37,38]. Clarifications should thus be made concerning vaccine benefits and innocuousness during pregnancy through regular health education programs. In fact, only 6.5% of the participants declared having adequate information on the safety and side effects of the IV.

We also observed, in concordance with other studies [12,29], that a history of IV was significantly associated with willingness to retake the vaccine. Among the PW who had been vaccinated at least once in the past, 65.1%intended to uptake the vaccine during their next pregnancy. These findings suggested that a successful experience of influenza immunization encouraged PW to continue receiving the vaccine. We observed that awareness about IV-related adverse events was negatively associated with willingness to receive the vaccine. Our results showed that PW who believe that the IV could protect both mother and fetus were more likely to accept to receive the vaccine in the next pregnancy. This may be explained by the spread of rather false information regarding the vaccine. Thus, health care professionals should take the lead in the awareness regarding benefits of the influenza vaccination among pregnant woman in the context of properly designed and implemented health education programs. Poor knowledge and negative attitude towards seasonal IV influence the acceptance of IV. Therefore, health care providers’ recommendations are important to PW’s acceptance of IV. Health education, direct and regular communication strategies on IV and influenza infection are necessary to enhance the acceptance of IV vaccination among this high risk group. Drivers of the latter behavior seem to fit the classical framework of the health belief model [31,39].

Strengths and limitations of study

To the best of our knowledge, this is the first nationwide study of its kind in Tunisia. Moreover, unlike other descriptive studies that have a primarily exploratory purpose, the knowledge, attitudes, and practices (KAP) surveys focus on the problem that is being addressed as well as the means that could facilitate its understanding and resolution. KAP surveys chiefly have an interventional purpose, aiming at optimizing practices and promoting health [40]. Therefore, this survey enabled us to derive, for the first time in Tunisia, benchmark information on the knowledge and perceptions regarding the vaccination among this high priority group, as well as data regarding uptake of influenza immunization in PW. The results provided the fundamental information required to develop appropriate recommendations to optimize acceptance and coverage of the vaccination among PW in our country. Our survey was based on a representative sample of all PW aged 18 and over and attending primary and secondary health care centers from public health sector in Tunisia. In addition, a standardized questionnaire was used for data collection, and majority of the questions were open-ended, thus reducing measurement bias.

This survey has some limitations that should be considered for a fair interpretation of the findings. First, the status of influenza vaccination was self-reported by the participants (there’s no yet an IV card in Tunisia); therefore, it could be subject to measurement bias due to poor recall, leading to underestimation of vaccine coverage. This source of bias should be minimal because women tend to memorize events related to pregnancy in our culture. Second, participants with a favorable attitude toward influenza vaccination may be more likely to respond to the questionnaire than those with a negative attitude, thereby introducing a selection bias. Third, our study sample included participants from public health centers alone (primary and secondary health care centers) and may not be representative of all PW in Tunisia. In fact, private and University hospitals were not included. This is especially true regarding PW attending private health settings, who may belong to a higher financial bracket than those attending public centers. Those attending university hospitals may have suffered more from pregnancy related complications. However, a study reported that the majority of the Tunisian population (two out of three) seeks healthcare from the public sector [37].

Fourth, our study was not designed to estimate vaccine coverage and further studies are needed to give a current estimation of this indicator among a largest sample size of PW in Tunisia.

Besides, our data showed that women have a high education level in a significant proportion.

Hence, this selection bias could lead to an overestimation of some of the positive factors associated with vaccination and that, despite this overestimation, our results show that an adequate communication and awareness strategy on vaccination with the high-risk populations for seasonal influenza.

Overall, despite these potential limitations, the main findings of this study advocate for urgent policies and programs to address obvious gaps in the use of IV, by a universally considered high priority group for this intervention in Tunisia.

V. Conclusions

In this study, less than 40% of the surveyed PW were willing to be vaccinated during their next pregnancy and only 4.6% received the IV during their current pregnancy. Presence of comorbidities prior or during pregnancy was the main predictors of this vaccine uptake. Health care providers seem to be main “game changers” influencing maternal IV uptake. IV for PW should be integrated in the Maternal and Child Health preventive program in Tunisia.

In addition, further studies in private health care sector are also needed to better assess the IV acceptance and uptake among PW.

Sampling method.

(PDF)

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Distribution of the selected health care facilities’ number by governorate.

Tunisia, 2018–2019.

(PDF)

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Distribution of the selected health care facilities’ name by governorate, Tunisia, 2018–2019.

(PDF)

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Factors associated with willingness to receive influenza vaccine during pregnancy (n = 999)1.

(PDF)

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Survey’s questionnaire in French language.

(PDF)

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Survey’s questionnaire in English language.

(PDF)

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18 Jun 2021

PONE-D-21-08415

Knowledge Attitudes and Practices toward seasonal influenza vaccine among pregnant women in Tunisia

PLOS ONE

Dear Dr. Bettaieb,

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This study is focusing on assessing the Knowledge Attitudes and Practices toward seasonal influenza vaccine among pregnant women in Tunisia which provides valuable support for the decision makers. However, revising the methodology section is very fundamental for accepting this article.  The concerns were mainly for the methodology section.

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Pasteur Institute of Tunis. Approval was also obtained from the Tunisian Ministry of Health. All women included in the survey were informed about the objectives and modalities of the study. Women who agreed to be interviewed provided written informed consent." Please also add this information to your ethics statement in the online submission form.

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Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: Yes

Reviewer #5: Yes

**********

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Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: Yes

Reviewer #5: I Don't Know

**********

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Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: Yes

Reviewer #5: Yes

**********

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Reviewer #1: 1. Sampling method - needs more clarity, because the author claims that the sample is a representative of the total population and also able generalize

2. How they arrive at Eight governorates out of 24 were randomly selected - Please clarify because the representation from all regions was not proportionate

3. This study included only qualitative data that were presented as numbers and percentages - Explain.

4. First, the status of influenza vaccination was self-reported by the participants – Self reporting could have been done with EVIDENCE CROSS CHECKED BY VACCINATION CARDS, MCH CARDS ETC. ???

Reviewer #2: 1. The Discussion section paragraph 1 and 2 are the repetitions of Aim and Results of the previous sections. I would consider it as redundant and may i suggest to remove it.

2. Suggested to reason out why the Flu shots uptake are high in U.S,UK and Ireland. This may give a lead to adopt it in Tunisia.

Suggested to correct as Strengths and Limitations and NOT as Strength and Limitations -Plural is required

Reviewer #3: This is an interesting manuscript about pregnant women's attitudes towards having an influenza vaccine in Tunisia. A major concern I have about the paper is that while information about women's attitudes to the vaccine have been sought, it appears that the main reason women do not get the vaccine is because it is not offered to them and it is not free of charge. However, I appreciate that the aim of the manuscript is to form an evidence base for the promotion of the vaccine to pregnant women. I think the manuscript could be enhanced by providing some context in the introduction about what vaccines pregnant women in Tunisia are/are not offered and any associated costs to the women. Even if the vaccine was offered access to getting the influenza vaccine could be a barrier to women, especially those who live rurally. This could also be touched on in the introduction.

Minor comments

Study design - Is March to May winter in Tunisia? Add in details about the season.

Study population - Is it normal for pregnant women to attend a public health center? Provide a figure on how many women usually attend these clinics.

Sample size - leave out the equation, just include the sentence about the sample size. This sentence could go with your study population information rather than under its own heading.

Data analysis - Move the sentences together to make two paragraphs.

Ethical considerations - "the" before data is not needed. "will be analyzed" should be "would be analyzed" "is voluntary" should be "was voluntary"

Results

First paragraph "Age" should be "age"

Discussion

You mention that the uptake of other low-income countries are similar to Tunisia. What are the reasons for this? Is it also because the vaccine is not offered/available? Does it cost money?

Reviewer #4: 1.Subject to qualitative data availability and usage, the authors have used two year old data for qualitative study.

2.Sampling among all the three regions are not appropriate, it can be elaborated to give a clear understanding. And what percentage of population has been used in sampling.

3.The study population targeted is all pregnant women more than or equal to 18 years, so less than 18 years of pregnant women can not be the part of sampling.

4.Elaborate the criteria on which the status of influenza vaccination was reported by the targeted population.

Reviewer #5: This paper presents the results of a national survey of attitudes toward influenza vaccination among pregnant women attending antenatal care in Tunisia. The authors report that the majority of women had heard of the vaccine, but only a small minority had been vaccinated, which was related to concerns about the safety and effectiveness of the vaccine. The authors conclude that health care professionals working in antenatal care can increase vaccination rates by encouraging their patients to get vaccinated.

The paper is well-written, with a well-justified aim and an interesting discussion. My main concern is that it is difficult to evaluate whether the results are generalizable to the study population (i.e., to all pregnant women attending antenatal care in the Tunisian public health care sector), as the sampling procedure is not described in detail and the response rate has not been reported. My specific comments can be found below.

Abstract/Introduction:

1. Should vaccine uptake be included in the aims?

2. In reference 16, I cannot find the WHO:s target of 80% of pregnant women being vaccinated.

Methods:

3. The authors write that sampling was stratified by region, but how was the number of governorates sampled from each region determined?

4. What was the second sampling stage? Were hospitals/health care centers sampled within governorates? According to the text, after governorates had been sampled, “stratified sampling was conducted based on the selected governorates”. Could the authors please clarify what was sampled and what the stratification variable(s) was (were)?

5. How were hospitals/health care centers within governorates sampled?

6. Were all women attending antenatal care at the sampled hospitals/health care centers asked to participate, or was a sample of women taken?

7. The authors write that the sample was self-weighted and that “[t]he sample size was distributed according to the distribution of the target population in the different regions.” Does this mean that the number of sampled patients in each governorate was proportional to the size of the total population size?

8. Was the sampling design taken into account in the data analysis? If not, please explain why.

9. The authors explain that the interviewers were trained. However, it is unclear who the interviewers were. Were they, for example, nurses or other health care professionals already working at the hospitals/health care centers, or were they external staff?

10. In the Data Analysis section, I think “qualitative data” should say “qualitative variable”, as the data are quantitative (i.e., numbers), but the variables are qualitative (i.e., ordinal/nominal).

11. In the Data Analysis section, it would be good to mention that odds ratios and 95% confidence intervals were calculated.

Results:

12. How many health care centers/hospitals were sampled?

13. How many health care centers/hospitals were asked to participate in the survey? How many were willing to participate?

14. How many women were assessed for eligibility? How many were considered eligible? How many were excluded? What was the response rate in the survey?

15. In the second paragraph, should the word “nearly” be replaced with “more than”?

16. In the third paragraph, please include not only the percentage, but also the number, of women who received the vaccine in the past or during their current pregnancy.

17. In the third paragraph, should “FIV” be “FV”?

18. In the sixth paragraph, should the word “except” be deleted or replaced with another word?

19. In the last paragraph of the Results section, the authors mention two reasons why women refused getting vaccinated (fear of side effects and concerns regarding self-harm/harm to the fetus). Was this question open-ended? If it was, did the authors consider categorizing all responses, instead of just two? If it was not open-ended, what were the possible responses? The answers “fear of side effects” and “concerns regarding self-harm/harm to the fetus” seem identical to me. Could these answers be combined?

20. In the last paragraph of the Results section, it says that the main reason that patients were not willing get vaccinated was concerns about adverse effects. However, in Table 2, it looks like vaccinated and non-vaccinated women differ more in their beliefs about vaccine effectiveness than vaccine safety. Could this result mean that concerns about lack of effectiveness are an even more important reason for the women’s unwillingness to get vaccinated than concerns about adverse effects?

Discussion/Conclusion:

21. Would it be interesting to mention that only 48% of women claim that they would take the vaccine if it were recommended by a health care professional and provided free of charge, which is substantially lower than the target of 80% vaccinated among pregnant women, even if this would be a large improvement from the current 4%? In addition, would it be interesting to mention that as many as 75% say they would be willing to take it if it was recommended by a doctor, but only 34% if it was recommended by another health care professional?

22. Page 8, Paragraph 3: Is “avail” the right word here?

23. Page 8, last paragraph: Most questions do not seem to be open-ended, as they are multiple-choice.

Table 2:

24. Is there a round-off error in the odds ratio for the first question (“Do you know anyone who has been severely ill with influenza?”)? I get an odds ratio of 0.95 (=136*360/272*189), which rounds up to 1.0.

References

25. Parts of the references are in French.

**********

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Reviewer #1: No

Reviewer #2: No

Reviewer #3: No

Reviewer #4: Yes: Rupam Bharti

Reviewer #5: Yes: Jonathan Bergman

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30 Aug 2021

Rebuttal letter

Tunis, August 29, 2021

Plos One Journal

Dear editors and reviewers

I am pleased, on behalf of all co-authors, to submit to your consideration the revised version of our manuscript newly titled “Knowledge Attitudes and Practices toward seasonal influenza vaccine among pregnant women during the 2018/2019 influenza season in Tunisia” [Submission ID: [PONE-D-21-08415] - [EMID:8bb08bb7b6d30319] by Sonia Dhaouadi and al for publication in Plos One.

We are grateful to the editor and reviewers for taking time to read the manuscript and for their valuable feedback and comments that we have taken into account.

We respond hereafter point by point to all comments raised. All changes and corrections are highlighted in green in the revised version of the manuscript.

I hope that revisions have improved the quality and the clarity of the paper and that it is now suitable for publication in Plos One.

Sincerely,

Sonia Dhaouadi

National Observatory of New and Emerging Diseases, Tunis, Tunisia

sonidhaouadi88@gmail.com

1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at https://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf

Authors’ response: Done

2. Thank you for stating in the text of your manuscript "Ethical approval for this survey was obtained from the Biomedical Ethics Committee of the Pasteur Institute of Tunis. Approval was also obtained from the Tunisian Ministry of Health. All women included in the survey were informed about the objectives and modalities of the study. Women who agreed to be interviewed provided written informed consent." Please also add this information to your ethics statement in the online submission form.

Authors’ response: Done.

3. Please list the names of all of the public health centers where participants were recruited from.

Authors’ response: This information was added in Appendix S2.

4. Please include additional information regarding the survey or questionnaire used in the study and ensure that you have provided sufficient details that others could replicate the analyses. For instance, if you developed the survey or questionnaire as part of this study and it is not under a copyright more restrictive than CC-BY, please include a copy, in both the original language and English, as Supporting Information. If the questionnaire is published, please provide a citation to the (1) questionnaire and/or (2) original publication associated with the questionnaire.

Authors’ response: Questionnaire survey was added in appendix 3 in both French and English languages (Appendix 3 a-b).

5. Please include captions for your Supporting Information files at the end of your manuscript, and update any in-text citations to match accordingly. Please see our Supporting Information guidelines for more information: http://journals.plos.org/plosone/s/supporting-information.

Authors’ response: Done (S1 Table, S1 Appendix, S2 Appendix, S3-a Appendix and S3-b Appendix)

Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction -notice.

Authors’ response:

References added:16, 17, 18,20,21, 22,25,26 and 27.

Reviewer #1: 1. Sampling method - needs more clarity, because the author claims that the sample is a representative of the total population and also able generalize

Authors’ response: We conducted a multiple stage sampling according to region, governorate and area of residence. More details are show in Methods section (paragraph 3: sampling procedure, line 112-line 126) and in appendix S1.

2. How they arrive at Eight governorates out of 24 were randomly selected - Please clarify because the representation from all regions was not proportionate

Authors’ response: Given the limited budget of the survey (limited logistics support and resources), we choose to select the one third of the total 24 Tunisian governorates (24/3=8). Then eight governorates were randomly selected.

3. This study included only qualitative data that were presented as numbers and percentages - Explain.

Authors’ response: In order to facilitate the analysis, we decided to categorize them into qualitative variables.

4. First, the status of influenza vaccination was self-reported by the participants – Self reporting could have been done with EVIDENCE CROSS CHECKED BY VACCINATION CARDS, MCH CARDS ETC. ???

Authors’ response: There’s not yet an influenza vaccination card in Tunisia (Discussion, line 340-line 341)

Reviewer #2: 1. The Discussion section paragraph 1 and 2 are the repetitions of Aim and Results of the previous sections. I would consider it as redundant and may i suggest to remove it.

Authors’ response: We took into account this comment.

2. Suggested to reason out why the Flu shots uptake are high in U.S,UK and Ireland. This may give a lead to adopt it in Tunisia.

Authors’ response: This comment was taken into consideration in Discussion part (line 263-line 277)

In those countries (USA and OK), PW are listed and invited to receive the IV. In addition, the healthcare provider can recommend, offer, and administer the vaccine at the same visit as opposed to making a recommendation and referring the patient elsewhere to receive the vaccine. There’s a close collaboration between medical doctors and midwives to ensure the enhance the coverage rate.

Suggested to correct as Strengths and Limitations and NOT as Strength and Limitations -Plural is required

Authors’ response: Done

Reviewer #3: This is an interesting manuscript about pregnant women's attitudes towards having an influenza vaccine in Tunisia. A major concern I have about the paper is that while information about women's attitudes to the vaccine have been sought, it appears that the main reason women do not get the vaccine is because it is not offered to them and it is not free of charge. However, I appreciate that the aim of the manuscript is to form an evidence base for the promotion of the vaccine to pregnant women. I think the manuscript could be enhanced by providing some context in the introduction about what vaccines pregnant women in Tunisia are/are not offered and any associated costs to the women. Even if the vaccine was offered access to getting the influenza vaccine could be a barrier to women, especially those who live rurally. This could also be touched on in the introduction.

Authors’ response: This idea was taken into account in the introduction. The IV is not free of charge and non-refundable among PW in Tunisia.

Minor comments

Study design - Is March to May winter in Tunisia? Add in details about the season.

Authors’ response: The 2018/2019 influenza season in Tunisia from 1st October 2018 to end of April 2019. The survey’s period (March-May 2019) coincided with spring season in Tunisia.

Study population - Is it normal for pregnant women to attend a public health center? Provide a figure on how many women usually attend these clinics.

Authors’ response: Given the high medical fees of consultation in private sector, PW in Tunisia attended either public and private sector. However, we don’t have exactly the number of PW attending the public health care facilities in public sector.

Sample size - leave out the equation, just include the sentence about the sample size. This sentence could go with your study population information rather than under its own heading.

Authors’ response: Done (the sample size paragraph was eliminated).

Data analysis - Move the sentences together to make two paragraphs.

Authors’ response: Done

Ethical considerations - "the" before data is not needed. "will be analyzed" should be "would be analyzed" "is voluntary" should be "was voluntary"

Authors’ response: Done

Results

First paragraph "Age" should be "age"

Authors’ response: Done

Discussion

You mention that the uptake of other low-income countries are similar to Tunisia. What are the reasons for this? Is it also because the vaccine is not offered/available? Does it cost money?

Authors’ response: In Low and Middle income countries, the low IV coverage could be explained by the difficulty of effective implementation of National Strategic Plan for Vaccines among high risk groups, and by the lack of awareness of burden of disease by decisions-makers and by the target population. In Tunisia, it’s more related to the influenza vaccine awareness among pregnant women and Health care workers than the vaccine supplies and health care access. The vaccine is not free of charge and non-refundable among this group.

Reviewer #4: 1. Subject to qualitative data availability and usage, the authors have used two-year-old data for qualitative study.

Authors’ response: We conducted a quantitative study.

2.Sampling among all the three regions are not appropriate, it can be elaborated to give a clear understanding. And what percentage of population has been used in sampling.

Authors’ response: Please see response to comment 1 reviewer 1.

3.The study population targeted is all pregnant women more than or equal to 18 years, so less than 18 years of pregnant women cannot be the part of sampling.

Authors’ response: For ethical reasons (PW aged less than 18 years must to give the written consent of her legal tutor (her parent or her husband) before participation in the survey. So we decided to include only PW aged 18 years and above.

Indeed, we used the published data for the National Institute of Statistics (INS) about the 2014 population census. The repartition of number of women of childbearing age (15-49 years) by age group was as follows (five-year interval): 15-19, 20-24,25-29,30-34,35-39,40-44 and 45-49 years. We can’t use the age >=18 for the sampling.

4.Elaborate the criteria on which the status of influenza vaccination was reported by the targeted population.

Authors’ response: We took into consideration this comment in method section (line 134-136)

Reviewer #5: This paper presents the results of a national survey of attitudes toward influenza vaccination among pregnant women attending antenatal care in Tunisia. The authors report that the majority of women had heard of the vaccine, but only a small minority had been vaccinated, which was related to concerns about the safety and effectiveness of the vaccine. The authors conclude that health care professionals working in antenatal care can increase vaccination rates by encouraging their patients to get vaccinated.

The paper is well-written, with a well-justified aim and an interesting discussion. My main concern is that it is difficult to evaluate whether the results are generalizable to the study population (i.e., to all pregnant women attending antenatal care in the Tunisian public health care sector), as the sampling procedure is not described in detail and the response rate has not been reported. My specific comments can be found below.

Abstract/Introduction:

1. Should vaccine uptake be included in the aims?

Authors’ response: Yes, assess influenza vaccine uptake was added in the aims au suggested. (Abstract, Background part, line 38).

2. In reference 16, I cannot find the WHO’s target of 80% of pregnant women being vaccinated.

Authors’ response: Reference 16 was updated as mentioned.

Methods:

3. The authors write that sampling was stratified by region, but how was the number of governorates sampled from each region determined?

Authors’ response: We applied the percentage of Women of childbearing age in each region (North, Center and South) to determine the number of selected governorates in each region:

48.03% (North)*8=4 governorates.

36.72% (Center)*8=3 governorates

15.25% (South)*8=1 governorate

The governorates were then randomly selected in each region.

More details are shown in appendix 1.

4. What was the second sampling stage? Were hospitals/health care centers sampled within governorates? According to the text, after governorates had been sampled, “stratified sampling was conducted based on the selected governorates”. Could the authors please clarify what was sampled and what the stratification variable(s) was (were)?

Authors’ response: We conducted a multiple stage sampling according to 3 stratified variables: region, governorate and area of residence. More details are show in Methods section (paragraph 3: sampling procedure, line 112-line 126) and in appendix S1.

5. How were hospitals/health care centers within governorates sampled?

Authors’ response: All public health care centers (primary and secondary health care centers) with antenatal care service were included (Methods, line 124-126)

6. Were all women attending antenatal care at the sampled hospitals/health care centers asked to participate, or was a sample of women taken?

Authors’ response: Yes, all women attending antenatal care at the sampled hospitals/health care centers at the time of the survey were asked to participate.

7. The authors write that the sample was self-weighted and that “the sample size was distributed according to the distribution of the target population in the different regions.” Does this mean that the number of sampled patients in each governorate was proportional to the size of the total population size?

Authors’ response: Yes; that the number of sampled patients in each governorate was proportional to the size of the women of childbearing age’s population size.

.

8. Was the sampling design taken into account in the data analysis? If not, please explain why.

Authors’ response: No, we did a self-weighted sampling taking into account the distribution of the woman of childbearing age according to region governorates and area of residence as we don't have such information for pregnant women.

9. The authors explain that the interviewers were trained. However, it is unclear who the interviewers were. Were they, for example, nurses or other health care professionals already working at the hospitals/health care centers, or were they external staff?

Authors’ response: The interviewers were health care worker in public health sector (Methods, line 130-131).

10. In the Data Analysis section, I think “qualitative data” should say “qualitative variable”, as the data are quantitative (i.e., numbers), but the variables are qualitative (i.e., ordinal/nominal).

Authors’ response: Done

11. In the Data Analysis section, it would be good to mention that odds ratios and 95% confidence intervals were calculated.

Authors’ response: This comment was taken into consideration in Methods part (line 154-155).

Results:

12. How many health care centers/hospitals were sampled?

Authors’ response: 84

13. How many health care centers/hospitals were asked to participate in the survey? How many were willing to participate?

Authors’ response: The sampled 84 health care centers/hospitals were asked to participate in the survey and were willing to participate.

14. How many women were assessed for eligibility? How many were considered eligible? How many were excluded? What was the response rate in the survey?

Authors’ response: The number of pregnant women who were approached to participate in the survey as well as the response rate were added in the first paragraph of result part (line 169-line 172).

15. In the second paragraph, should the word “nearly” be replaced with “more than”?

Authors’ response: Nearly three quarter (74.7%) was replaced by more than half as suggested (line 173 in Results section).

16. In the third paragraph, please include not only the percentage, but also the number, of women who received the vaccine in the past or during their current pregnancy.

Authors’ response: The number of women who received the vaccine at least once in the past and during the current pregnancy was added (line 183-184).

17. In the third paragraph, should “FIV” be “FV”?

Authors’ response: Flu vaccination (FV) was replaced by influenza vaccination (IV) in all the manuscript.

18. In the sixth paragraph, should the word “except” be deleted or replaced with another word?

Authors’ response: except was replaced by both of women (Results, line 192).

19. In the last paragraph of the Results section, the authors mention two reasons why women refused getting vaccinated (fear of side effects and concerns regarding self-harm/harm to the fetus). Was this question open-ended? If it was, did the authors consider categorizing all responses, instead of just two? If it was not open-ended, what were the possible responses? The answers “fear of side effects” and “concerns regarding self-harm/harm to the fetus” seem identical to me. Could these answers be combined?

Authors’ response:

-Question related to the main reasons of IV refuse was an open-ended question (question 30 in the questionnaire). There were three main reasons of IV refuse:

* Fear of side effects” and “concerns regarding self-harm/harm to the fetus (72,1%)

* Concerns about vaccine efficacy (16.2%)

* Natural immunity inducted by the infection is better than the immunity inducted by the vaccine (11.2%) (Results section line 214-217).

20. In the last paragraph of the Results section, it says that the main reason that patients were not willing get vaccinated was concerns about adverse effects. However, in Table 2, it looks like vaccinated and non-vaccinated women differ more in their beliefs about vaccine effectiveness than vaccine safety. Could this result mean that concerns about lack of effectiveness are an even more important reason for the women’s unwillingness to get vaccinated than concerns about adverse effects?

Authors’ response: The question related to the main reasons to refuse IV was an open ended question (question 31 in the questionnaire). Questions related to the vaccine efficacy/vaccine safety presented in Table 3 was a multiple choice question (question 26 in the questionnaire, based on five points Likert scale). The response of interviewed women differed regarding the priority according to the type of question. It seems that vaccine safety concerns were more important than vaccine efficacy concerns when it was a spontaneous response (open ended question), unlike to multiple choice question (inducted response) where vaccine efficacy concerns were more priority.

Discussion/Conclusion:

21. Would it be interesting to mention that only 48% of women claim that they would take the vaccine if it were recommended by a health care professional and provided free of charge, which is substantially lower than the target of 80% vaccinated among pregnant women, even if this would be a large improvement from the current 4%? In addition, would it be interesting to mention that as many as 75% say they would be willing to take it if it was recommended by a doctor, but only 34% if it was recommended by another health care professional?

Authors’ response: This idea was taken into account in discussion section (line 284-290).

22. Page 8, Paragraph 3: Is “avail” the right word here?

Authors’ response: Avail was replaced by uptake as suggested (Discussion line 311).

23. Page 8, last paragraph: Most questions do not seem to be open-ended, as they are multiple-choice.

Authors’ response: Yes, it was a Likert scale question based on 5-point agreement scale (Table 3).

Table 2:

24. Is there a round-off error in the odds ratio for the first question (“Do you know anyone who has been severely ill with influenza?”)? I get an odds ratio of 0.95 (=136*360/272*189), which rounds up to 1.0.

Authors’ response:

OR was rounded to 1.0 in Table 2 as suggested.

References

25. Parts of the references are in French.

Authors’ response:

The English title was added in those references (Ref 9 and 40).

Thank you again for taking the time to share your insightful feedback.

Submitted filename: Response to reviewers-Rebuttal letter PLOS ONE.docx

Click here for additional data file.

15 Oct 2021

26 Nov 2021

Rebuttal letter

Tunis, November 26, 2021

Plos One Journal

Dear editors and reviewers

I am pleased, on behalf of all co-authors, to submit to your consideration the2nd revised version of our manuscript newly titled “Knowledge Attitudes and Practices toward seasonal influenza vaccine among pregnant women during the 2018/2019 influenza season in Tunisia” [Submission ID: [PONE-D-21-08415] - [EMID:8bb08bb7b6d30319] by Sonia Dhaouadi et al for publication in Plos One.

We are grateful to the editor and reviewers for taking time to read the manuscript and for their valuable feedback and comments that we have taken into account.

We respond hereafter point by point to all comments raised. All changes and corrections are highlighted in green in the revised version of the manuscript.

I hope that revisions have improved the quality and the clarity of the paper and that it is now suitable for publication in Plos One.

Sincerely,

Sonia Dhaouadi

National Observatory of New and Emerging Diseases, Tunis, Tunisia

sonidhaouadi88@gmail.com

00216 95334250

Major issues:

1. Methods, Line 113: How did the authors determine that 8 governorates should be sampled? In their rebuttal, they explain that this was determined by budget constraints, as 8 corresponds to 1/3 of Tunisia’s 24 governorates. Pease add this information to the manuscript.

Authors’ response: We took into consideration your suggestion and we added this information to the manuscript (Methods, lines 116-117).

2. Methods, Lines 112-113: It could be clarified how the number of governorates sampled per region was determined. I know this information is provided in Lines 120-123, but the authors provide a much clearer explanation in their rebuttal (i.e. 8 * % of Tunisia’s women of childbearing age living in a region). I recommend that the authors be as clear in the manuscript as they are in their rebuttal.

Authors’ response: Your suggestion was taken into account. Please see Methods section, lines 117-123.

3. Methods, 118-119: It is unclear how area of residence (urban/rural) was relevant to the sampling procedure. According to the authors’ rebuttal, all public health centers in the sampled governorates were included. If so, shouldn’t area of residence be irrelevant?

Authors’ response: We apologize; it seems that we made an error when explaining the sampling method in the rebuttal letter. We meant that all public health centers were targeted by the selection procedure. Indeed, as we explained in the response to comment 4, not all public health centers were selected. In addition, we took into consideration area of residence in the self-weighting process in order to enhance similarity of distribution between our study population and the target population. It should be noted that area of residence refers to the residence of PW and not to the location of the health care facility. Some PW living in rural area may visit health care centers in urban area and vise-versa.

4. Methods, Sampling procedure: In the authors’ rebuttal, it sounds like they performed region-stratified, cluster sampling, meaning that they first randomly sampled governorates from each region and then included all pregnant women attending any public health center in the sampled governorates. If so, this could be clarified in the Sampling Procedure section.

Authors’ response: We reiterate our apology for the error when explaining the sampling method in the rebuttal letter. In fact, we performed a stratification according to region. Governorates were randomly selected (four in the North, three in the Center and one in the South). However, we did not proceed to a cluster sampling. Indeed, in each governorate we randomly selected health care facilities among those offering antenatal care visits as the survey progressed. Every day, we randomly selected one center among all those that offer medical care consultations for PW on that day. The selected center will not be selected again.

On the day of their visit, investigator(s) were asked to randomly select participants from the exhaustive list of PW consulting the selected health care facility on that day. The number of PW approached to participate to the survey in each health care facility depended on the availability of human and logistic resources.

It should be noted that a pilot study was performed in order to assess the comprehensiveness of questionnaire items, to identify ambiguous questions and to estimate the maximum number of questionnaires that could be properly administrate by one investigator which was equal to 20. The sampling procedure was clarified as suggested in sampling procedure (Please see lines 114-136).

5. Results, Line 169: The number of survey respondents was 1200, which is identical to the calculated sample size reported in the Methods section. This seems unlikely if the authors really did recruit all pregnant women attending any public health center during a 3-month period. Are the authors’ sure they didn't recruit consecutive patients and then stop when the calculated sample had been reached?

Authors’ response: Thank you for your comment. In fact, you are right we stopped recruitment of participants when the needed sample size was achieved.

6. S1 Appendix: The sampling method illustrated here looks like it is stratified sampling by region, governorate, and area of residence. As mentioned above, however, only region seems to have been a stratification variable.

Authors’ response: We totally agree with you; region was the only stratification variable.

Details regarding sampling procedure were clarified on Methods section.

7. Rebuttal: The authors explain that they did not take the sampling procedure into account during the analysis due to a lack of information to do so. However, ignoring cluster sampling in an analysis can lead to confidence intervals that are too narrow. Have the authors considered this possibility?

Authors’ response: We totally agree with you. Not considering cluster sampling in analysis can lead to narrow confidence intervals. However, in the present study we did not proceed to a cluster sampling. In fact, we randomly selected daily health care facilities among those offering antenatal care visits as the survey progressed. On the day of their visit, investigator(s) were asked to randomly select participants from the exhaustive list of PW consulting the selected health care facility on that day. The number of PW approached to participate to the survey in each health care facility depended on the availability of human and logistic resources. The details were shown in sampling procedure (Methods). Please see lines (114-136).

Minor issues:

8. Abstract, Line 48: The lower bound of the confidence interval is 57.7% here, but it is 57.6% in the main text (Results, Line 182). Please check this.

Authors’ response: Thank you for your comment. The lower bound of the confidence interval is in fact 57.6%. We corrected the mistake in the abstract (Please see line 48).

9. Abstract, Lines 48-49: The text states that 4.4% of women who were aware of the vaccine received it during their current pregnancy; however, this percentage seems to be calculated based on all 1157 included women (51/1157=4.4%). The same was done in Results, Lines 182-184, both for women who had received the vaccine during the current pregnancy and for those who had received it sometime in the past. Please check this.

Authors’ response: Your suggestion was taken into consideration (Please see line 49 in Abstract and line 199 in Manuscript).

10. Results, Line 163: Could the ID numbers be linked to personal identifiers? If so, the data would be coded/pseudo-anonymized rather than anonymized.

Authors’ response: Data were coded anonymized and the ID number was not linked to personal identifiers.

11. Results, Lines 181-182: Is there a round-off error in the percentage of women who had heard of influenza, 85.5%? I get 988/1157=84.4%. Is there an error in the calculation of women who had heard of the vaccine, 60.3%? I get 694/1157=60.0%.

Authors’ response: In calculation, we only took into account valid percentage.

Women who had heard of influenza: n=988; missing data=2;

The valid percentage=988/1155=85.5%; 95% CI [83.4%–87.5%].

Women who had heard of influenza vaccine:

n=694; missing data=7; The valid percentage=694/1150=60.3%; 95% CI [57.5%–63.2%].

12. Results, Line 187: Consider adding the number of women who would be willing to receive the vaccine, instead of just reporting the percentage.

Authors’ response: This suggestion was taken into consideration: Results, line 207. (Yes=421, No=578, I don’t know=154, missing data=4; the valid percentage=421/1153=36.5%)

13. Discussion, Line 307: How was 6.5% calculated (numerator/denominator)? According to Table 2, 72 patients reported having enough information about side effects. Is 72 the numerator used?

Authors’ response: The calculated percentage regarding information about side effects of IV: 6.5% (valid percentage) =75/1146 (Yes=75; No=1015; I don’t know=56; missing data=11). This information was added in Results section: lines 196-197.

Concerning table 2, we took into account only PW who answered Yes or No about willing to receive IV in the next pregnancy, participants who answered I don’t know about willingness to receive IV were excluded (Please see footnote Table 2). Participants who answered I don’t Know about having enough information about side effects were also excluded. Among the 75 PW who reported they had enough information about IV side effects, two answered I don’t know when asked about willingness to receive IV in the next pregnancy, so they were not included in Table 2.

14. References: There are still French words here.

Authors’ response: All references were corrected into English language.

Response to Editor Dr. Deshayne:

We reported 95% confidence interval of crude odds ratio in text (Results section) to be more informative as suggested (lines 211, 212, 216, 218 and 219)

Thank you again for taking the time to share your insightful feedback and for taken into consideration our request that our manuscript be considered for inclusion in your ongoing Influenza collection (https://collections.plos.org/collection/influenza/)

Submitted filename: Response to reviewers-Rebuttal letter second revision.docx

Click here for additional data file.

17 Dec 2021

15 Feb 2022

Plos One Journal

Dear editors and reviewers,

I am pleased, on behalf of all co-authors, to submit to your consideration the revised version of our manuscript newly titled “Knowledge Attitudes and Practices toward seasonal influenza vaccine among pregnant women during the 2018/2019 influenza season in Tunisia” [Submission ID: [PONE-D-21-08415] - [EMID:8bb08bb7b6d30319] by Sonia Dhaouadi and al for publication in Plos One.

We are grateful to the editor and reviewers for taking time to read the manuscript and for their valuable feedback and comments that we have taken into account.

We respond hereafter point by point to all comments raised. All changes and corrections are highlighted in green in the revised version of the manuscript.

I hope that revisions have improved the quality and the clarity of the paper and that it is now suitable for publication in Plos One.

Sincerely,

Dr Sonia Dhaouadi

National Observatory of New and Emerging Diseases, Tunis, Tunisia

sonidhaouadi88@gmail.com

Minor comments:

1. Page 4: In their rebuttal letter, the authors confirm my previous suspicion that the only stratification variable was region. However, now that the authors have further clarified their work, I think that the sampling procedure was also stratified by area of residence, as healthcare centers were selected from both urban and rural areas.

Authors’ response: Thank you for your comment, area of residence was also considered as suggested as variable of stratification (Methods, sampling procedure, line 122).

2. Page 4, Lines 126-127: The authors explain that patients were randomly selected at healthcare centers, but the authors may also want to explain how this was done in practice. For example, did the study staff enter the total number of patients on the patient list into a computer, which then returned a certain number of randomly selected patients, such as patients 2, 5, and 6 on the list?

Authors’ response: This comment was taken into account in Methods section, sampling procedure, lines 129-130

3. Page 5: The authors have not addressed my question of whether it is appropriate to ignore the sampling procedure in the analysis. If I am not mistaken, Appendix S1 contains all the information required to incorporate this information. (The percentages at each stage of the sampling procedure could be used to construct sampling weights, could they not?)

Authors’ response: Thank you for your comment, this proposition was taken into consideration in the results section, all percentages, crude ORs and their 95% confidence interval were weighted as mentioned according to region, governorate and area of residence.

Thank you again for taking the time to share your insightful feedback.

Submitted filename: Response to reviewers-Rebuttal letter PLOS ONE Feb 2022.docx

Click here for additional data file.

2 Mar 2022

Knowledge Attitudes and Practices toward seasonal influenza vaccine among pregnant women during the 2018/2019 influenza season in Tunisia

PONE-D-21-08415R3

Dear Dr. Bettaieb,

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Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

14 Mar 2022

PONE-D-21-08415R3

Knowledge Attitudes and Practices toward seasonal influenza vaccine among pregnant women during the 2018/2019 influenza season in Tunisia

Dear Dr. Bettaieb:

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