Maternal vaccination against pertussis as part of the national immunization program: a qualitative evaluation among obstetric care providers one year after the implementation in December 2019.

BACKGROUND: Immunization of pregnant women with a tetanus-diphtheria-and-acellular-pertussis (Tdap) vaccine is an effective and safe way to protect infants from pertussis before their primary vaccinations. Vaccine uptake among pregnant women is influenced by their care providers' attitudes toward maternal vaccination. This qualitative study aimed to evaluate the implementation of the maternal Tdap vaccination under the National Immunization Program of the Netherlands from the perspective of obstetric care providers. METHODS: In this qualitative and explorative study, we conducted in-depth interviews by telephone with obstetric care providers who were selected from a pool of respondents (convenience sampling) to a questionnaire in a previous study. The interviews were based on a semi-structured interview guide that covered three aspects of the implementation strategy: providers' overall experience with the implementation of maternal Tdap vaccination in the Netherlands; implementation logistics and counseling, and pregnant women referrals to municipal Youth Healthcare Centers. The interviews were recorded, pseudonymized and transcribed verbatim. Transcripts were analyzed according to the Thematic Analysis approach by two researchers independently in two phases of iterative coding, categorizing, reviewing and redefining until ultimately, emergent themes regarding maternal Tdap vaccination implementation were identified. RESULTS: Interviews with 11 midwives and 5 OB-GYN physicians yielded 5 major themes regarding the Tdap vaccination implementation strategy: challenges throughout the implementation process, views on maternal Tdap vaccination, general versus tailored counseling, provider responsibilities in vaccine promotion, and impact of materials for information delivery. Participants indicated that to improve provider attitudes toward Tdap vaccination, its implementation requires clear and transparent information about what is entailed, i.e., what is expected from obstetric care providers, how they can obtain information, and when their actions must be initiated. Participants demanded involvement throughout the implementation planning process. They preferred tailored communication with pregnant women over a generalized approach. CONCLUSION: This study emphasized the importance of involving all relevant healthcare professionals in planning the implementation of maternal Tdap vaccination. Possible barriers perceived by these professionals should be taken into account in order to improve their attitudes toward vaccination, thus to increase uptake among pregnant women.

Study protocol of the PIMPI-project, a cohort study on acceptance, tolerability and immunogenicity of second trimester maternal pertussis immunization in relation to term and preterm infants.

BACKGROUND: Maternal immunization confers passive immunity to the fetus by transplacental antibody transfer. Infants may be better protected against pertussis if the mother received a diphtheriae, tetanus and acellular pertussis (Tdap) vaccination in the second trimester of pregnancy compared to the third trimester. This study evaluates IgG antibody concentrations in term and preterm infants at birth and 2 months after birth after maternal Tdap-vaccination between 200 and 240 w of gestation vs third trimester Tdap-vaccination. Further aims are assessing the determinants that underlie acceptance of second trimester maternal Tdap-vaccination as well as the tolerability of vaccination. METHODS: This prospective cohort study consists of two parts. In the acceptance part, pregnant women complete a questionnaire on determinants that underlie acceptance of a second trimester Tdap-vaccination, which is offered subsequently between 200 and 240 w of gestation. Vaccinated women complete an additional questionnaire on vaccination tolerability. Vaccinated women may also participate in the immunogenicity part, in which blood is drawn from mother at delivery and from infant at birth and 2 months after birth. Women are also eligible for the immunogenicity part if they received a Tdap-vaccination between 200 and 240 w of gestation via the national immunization program and get hospitalized for an imminent preterm delivery. Blood sampling continues until 60 term and 60 preterm mother-infant-pairs have been included. Pertussis-specific IgG antibody concentrations are determined in serum using a fluorescent bead-based multiplex immunoassay. For term infants, non-inferiority in IgG antibody concentrations against pertussis toxin (anti-PT) will be assessed referred to a historical control group in which mothers were Tdap-vaccinated between 300 and 320 w of gestation. For preterm infants, non-inferiority of anti-PT IgG concentrations is referred to as 85% of infants having ≥ 20 international units/mL at 2 months after birth. DISCUSSION: This study investigates acceptance, tolerability and immunogenicity regarding maternal Tdap-immunization between 200 and 240 w of gestation. Its results provide insight into the effects of second trimester Tdap-vaccination on IgG antibody concentrations in term and preterm infants before primary infant vaccinations. Results on acceptance and tolerability guide antenatal care providers in communication with pregnant women and maintain the safety of second trimester Tdap-vaccination. TRIAL REGISTRATION: EU Clinical Trials Register, 2018-002976-41, retrospectively registered 24 July 2019, https://www.clinicaltrialsregister.eu/ctr-search/search?query=2018-002976-41 .

Pertussis hospitalizations among term and preterm infants: clinical course and vaccine effectiveness.

BACKGROUND: Pertussis causes severe disease in young unvaccinated infants, with preterms potentially at highest risk. We studied pertussis in hospitalized infants as related to gestational age (GA) and vaccination history. METHODS: Medical record data of 0-2y old patients hospitalized for pertussis during 2005-2014 were linked to vaccination data. Multivariable logistic regression was used to study the association between GA and vaccination history on the clinical disease course. We compared vaccine effectiveness (VE) against hospitalization for pertussis between term and preterm infants (i.e., <37w GA) using the screening method as developed by Farrington. RESULTS: Of 1187 records, medical data from 676 were retrieved. Of these, 12% concerned preterms, whereas they are 8% of Dutch birth cohorts. Median age at admission was 3 m for preterms and 2 m for terms (p < 0.001). Preterms more often had received pertussis vaccination (62% vs 44%; p = 0.01) and more often had coinfections (37% vs 21%; p = 0.01). Preterms tended more often to have complications, to require artificial respiration or to need admittance to the intensive care unit (ICU). Preterms had longer ICU stays (15d vs 9d; p = 0.004). Vaccinated preterms and terms had a lower median length of hospital stay and lower crude risks of apneas and the need for artificial respiration, additional oxygen, and ICU admittance than those not vaccinated. After adjustment for presence of coinfections and age at admittance, these differences were not significant, except the lower need of oxygen treatment in vaccinated terms. Effectiveness of the first vaccination against pertussis hospitalizations was 95% (95% CI 93-96%) and 73% (95% CI 20-91%) in terms and preterms, respectively. Effectiveness of the second dose of the primary vaccination series was comparable in both groups (86 and 99%, respectively). CONCLUSIONS: Infants hospitalized for pertussis suffer from severe disease. Preterms were overrepresented, with higher need for intensive treatment and less VE of first vaccination. These findings stress the need for alternative prevention, in particular prenatal vaccination of mothers, to reduce pertussis in both groups.

Effectiveness of Early Measles, Mumps, and Rubella Vaccination Among 6-14-Month-Old Infants During an Epidemic in the Netherlands: An Observational Cohort Study.

Background: Routinely, the first measles, mumps, and rubella (MMR) vaccine dose is given at 14 months of age in the Netherlands. However, during a measles epidemic in 2013-2014, MMR vaccination was also offered to 6-14-month-olds in municipalities with <90% MMR vaccination coverage. We studied the effectiveness of the early MMR vaccination schedule. Methods: Parents of all infants targeted for early MMR vaccination were asked to participate. When parent(s) suspected measles, their infant's saliva was tested for measles-specific antibodies. The vaccine effectiveness (VE) against laboratory-confirmed and self-reported measles was estimated using Cox regression, with VE calculated as 1 minus the hazard ratio. Results: Three vaccinated and 10 unvaccinated laboratory-confirmed cases occurred over observation times of 106631 and 23769 days, respectively. The unadjusted VE against laboratory-confirmed measles was 94% (95% confidence interval [CI], 79%-98%). After adjustment for religion and sibling's vaccination status, the VE decreased to 71% (-72%-95%). For self-reported measles, the unadjusted and adjusted VE was 67% (40%-82%) and 43% (-12%-71%), respectively. Conclusions: Infants vaccinated between 6 and 14 months of age had a lower risk of measles than unvaccinated infants. However, part of the effect was caused by herd immunity, since vaccinated infants were more likely to be surrounded by other vaccinated individuals.

Dutch national immunization schedule: compliance and associated characteristics for the primary series.

In the Netherlands, the recommended priming immunization schedule for diphtheria, tetanus, pertussis and polio (DTaP-IPV) is at 2, 3 and 4 months of age. We evaluated the compliance with the recommended schedule, as well as its characteristics. We included all infants born between 2007 and 2012 who received minimally one DTaP-IPV vaccination (n = 1,061,578). Infants complied with the schedule if they received the first vaccination between 6 and 9 weeks of age, and the second and third vaccination 2-6 weeks after the first and second vaccination. We examined associations between compliance and several characteristics using log-binomial regression. Compliance for the first, second and third vaccination was 81.6, 88.3 and 84.2%, respectively. Compliance with the total recommended schedule was 64.5%, and increased from 60.1% for 2007 to 68.5% for 2012. Compliance was higher for full-term infants (65.9%), infants with normal birth weight (66.0%) and when both parents were born in the Netherlands (66.8%). CONCLUSION: Delayed vaccination during the primary vaccination schedule occurs in one sixth of the Dutch children. Efforts to improve compliance should be focused in particular on preterm infants, infants with low birth weight and infants whose parents are not born in the Netherlands. What is Known: • A delayed start of vaccination leads to a longer period at risk for infectious diseases, e.g. pertussis • Delayed vaccination is associated with several factors including prematurity, low birth weight, family size, birth order, low socioeconomic status and health status of the child What is New: • Compliance with the recommended priming immunization schedule for diphtheria, tetanus, pertussis and polio was 64.5%, and increased from 60.1% for 2007 to 68.5% for 2012 • If the first vaccination was delayed, there was a higher chance that the following vaccinations were administered 'out-of-schedule' as well, resulting in even a higher age at second and third vaccination.

Enhanced Bordetella pertussis acquisition rate in adolescents during the 2012 epidemic in the Netherlands and evidence for prolonged antibody persistence after infection.

IntroductionIn 2012 a large epidemic of pertussis occurred in the Netherlands. We assessed pertussis toxin (PT) antibody levels in longitudinal serum samples from Dutch 10-18 year-olds, encompassing the epidemic, to investigate pertussis infection incidence. Methods: Blood was sampled in October 2011 (n = 239 adolescents), then 1 year (2012; n = 228) and 3 years (2014; n = 167) later. PT-IgG concentrations were measured by immunoassay and concentrations ≥50 IU/mL (seropositive) assumed indicative of an infection within the preceding year. Results: During the 2012 epidemic, 10% of participants became seropositive, while this was just 3% after the epidemic. The pertussis acquisition rate proved to be sixfold higher during the epidemic (97 per 1,000 person-years) compared with 2012-2014 (16 per 1,000 person-years). In 2012, pertussis notifications among adolescents nationwide were 228/100,000 (0.23%), which is at least 40 times lower than the seropositivity percentage. Remarkably, 17 of the 22 seropositive participants in 2011, were still seropositive in 2012 and nine remained seropositive for at least 3 years. Discussion: Longitudinal studies allow a better estimation of pertussis infections in the population. A PT-IgG concentration ≥50 IU/mL as indication of recent infection may overestimate these numbers in cross-sectional serosurveillance and should be used carefully.

Tolerability of Early Measles-Mumps-Rubella Vaccination in Infants Aged 6-14 Months During a Measles Outbreak in The Netherlands in 2013-2014.

BACKGROUND: In 2013-2014, a measles outbreak spread through the Netherlands. To protect young infants, measles-mumps-rubella (MMR) vaccination was offered to those aged 6-14 months in municipalities with routine first-dose MMR vaccine coverage of <90%. We assessed the tolerability of this early administration of MMR vaccine. METHODS: After study entry (n = 1866), parents of eligible infants (n = 10 097) completed a questionnaire (n = 1304). For infants who received an early MMR vaccine dose (n = 962), we asked for information about adverse events (AEs) associated with the dose. AE frequencies were compared between infants aged 6-8, 9-11, and 12-14 months. Using multivariable logistic regression, we assessed the association between the risk of AEs and age at early MMR vaccination. RESULTS: The response rate was 13%. Parents of 59 infants (6.1%) and 350 infants (36.4%) who received early MMR vaccination reported local and systemic AEs, respectively. Parents of infants vaccinated at 6-8 months of age reported systemic AEs less frequently (32%) than parents of children vaccinated at 9-11 months (45%) and 12-14 months (43%) of age (P= <.001). For local AEs, there were no differences (5%, 7%, and 10%, respectively;P= .08). Compared with vaccination at 6 months, all older infants except those aged 14 months showed an increased risk for any AE and for systemic AEs starting 5-12 days after vaccination. CONCLUSIONS: Early MMR vaccination is well tolerated, with the lowest AE frequencies found in infants aged 6-8 months. It is a safe intervention for protecting young infants against measles.

Socio-psychological determinants of second trimester maternal pertussis vaccination acceptance in the Netherlands.

BACKGROUND: A maternal tetanus-diphtheria-and-acellular-pertussis (Tdap) vaccine is offered to all pregnant women in the Netherlands in their second trimester since December 2019. However, former studies solely investigated the socio-psychological factors that influence vaccine acceptance among pregnant women in the third trimester. We identified predicting factors for attitude, intention and acceptance of maternal Tdap vaccination during the second trimester of pregnancy. METHODS: As part of a large prospective cohort study, women early in pregnancy completed a questionnaire on determinants regarding acceptance of maternal Tdap vaccination between 20 and 24w of gestation. The vaccine was offered after completion of the questionnaire. A random forest model and Receiver Operating Characteristics (ROC) analyses were carried out to identify the factors most predictive for vaccine acceptance on the whole data set, and also in sensitivity analysis on a subset reflecting the annual nationwide 70% vaccination uptake. RESULTS: Among 1158 participants who were offered a Tdap vaccination between 20 and 24w of gestation, 1098 (94.8%) accepted and 60 (5.2%) rejected the vaccine. Random forest analyses identified intention as most predictive for acceptance, followed by attitude towards vaccination, beliefs regarding safety, risk perception of severity of side effects, moral responsibility, beliefs regarding effectiveness and risk perception of susceptibility of side effects, with a sensitivity of 100% and a specificity of 40%, for which this combination could be improved by the ROC analysis to 82% and 67%, respectively. The sensitivity analysis yielded an order of predictors that generally corresponded with the initial model. CONCLUSIONS: Intention, attitude, beliefs on safety and effectiveness, risk perception of side effects and moral responsibility were most predictive for maternal Tdap vaccine acceptance during the second trimester of pregnancy, in accordance with studies regarding third trimester vaccination. These should be discussed by healthcare professionals early in pregnancy to provide an informed choice towards vaccine acceptance.

Maternal and neonatal antibody levels on pertussis vaccination in pregnant women on immune-modulating therapy for rheumatic disease.

OBJECTIVES: While protection against pertussis following maternal tetanus-diphtheria-and-acellular-pertussis (Tdap) vaccination was demonstrated in healthy term-born infants, no evidence is available on Tdap vaccination in combination with immune-modulating therapy during pregnancy. In this pilot study, we explored whether treatment with tumour necrosis factor alpha inhibitors (TNFis) in pregnant patients with rheumatic disease interferes with Tdap vaccine responses and affects maternal anti-pertussis IgG antibody levels in newborns. METHODS: Patients were included by a rheumatologist during pregnancy in case they received maternal Tdap vaccination in the late-second or early-third trimester of pregnancy. Blood samples were obtained from mothers during the first pregnancy trimester, 3 months after delivery and from the umbilical cord. IgG antibody levels against Tdap-included antigens were measured using a bead-based multiplex immunoassay. Findings on patients exposed to TNFis were compared with those from TNFi-unexposed patients and with data from a historical comparator study among healthy Tdap vaccinated mother-infant pairs (n=53). RESULTS: 66 patients (46 exposed and 20 unexposed to TNFIs) were enrolled. No major differences in IgG antibody levels were observed between TNFi-exposed and unexposed mothers before maternal Tdap vaccination and 3 months after delivery. In cord sera, however, antibody levels against pertussis toxin were significantly lower after TNFi-treatment (35.94 IU/mL, 95% CI 20.68 to 62.45) compared with no TNFi-treatment of mothers with rheumatic disease (94.61 IU/mL, 95% CI 48.89 to 183.07) and lower compared with a cohort of healthy mothers (125.12 IU/mL, 95% CI 90.75 to 172.50). We observed similar differences for filamentous haemagglutinin, pertactin, tetanus toxoid and diphtheria toxoid. CONCLUSION: These preliminary data indicate no major differences in IgG antibody levels on maternal Tdap vaccination in pregnant women with or without immune-modulating treatment, although our findings suggest that TNFis during pregnancy induce lower maternal anti-pertussis-specific protective antibody levels in newborns.

Reactogenicity and safety of second trimester maternal tetanus, diphtheria and acellular pertussis vaccination in the Netherlands.

BACKGROUND: Maternal tetanus-diphtheria-and-acellular-pertussis (Tdap) vaccination is offered to all pregnant women during their second trimester in the Netherlands since December 2019. We assessed second trimester Tdap vaccination reactogenicity and compared with third trimester data from a similar study. For safety assessment, adverse pregnancy outcomes were compared with national data from 2018, before Tdap vaccine-introduction. METHODS: Pregnant women were included between August 2019-December 2021 and received Tdap vaccination between 20 and 24w gestational age (GA). Participants completed a questionnaire on solicited local reactions and systemic adverse events (AEs) within one week after vaccination. Results were compared with historical data on reactogenicity from women vaccinated between 30 and 33w GA (n = 58). Regarding safety-related outcomes, each participant was matched to four unvaccinated pregnant women from the Dutch Perinatal Registry, based on living area, parity and age. RESULTS: Among 723 participants who completed the questionnaire, 488 (67.5 %) experienced ≥ 1 local reaction with pain at the injection site as most reported reaction (62.3 %), and 460 (63.6 %) experienced ≥ 1 systemic AE with stiffness in muscles/joints (38.9 %), fatigue (28.9 %), headache (14.5 %) and common cold-like symptoms (11.0 %) most frequently reported. 4 women (0.6 %) reported fever (≥38.0˚C). Symptoms were considered mild and transient within days. No difference in AEs were found between vaccination at 20-24w versus 30-33w GA. 723 participants were matched to 2,424 unvaccinated pregnant women with no increased rates of premature labor, small-for-gestational-age, or other adverse pregnancy outcomes. CONCLUSIONS: Second trimester maternal Tdap vaccination appears safe and well-tolerated. Comparison between second versus third trimester vaccination yielded no reactogenicity concerns.

Hospitalization due to varicella in the Netherlands.

BACKGROUND: In the Netherlands, incidence of physician's consultations and hospitalizations for varicella is low compared to other countries. Better knowledge about the severity of varicella among Dutch hospitalized patients is needed. Therefore, a medical record research was conducted among hospitalized patients with diagnosis varicella. METHODS: Hospital admissions due to varicella in 2003-2006 were obtained from the National Medical Register. Retrospectively, additional data were retrieved from the medical record of patients hospitalized with varicella in 23 Dutch hospitals using a standardized form. Analyses were performed using descriptive statistics. RESULTS: The study population (N = 296) was representative for all varicella admissions in the Netherlands (N = 1,658) regarding age, sex, duration of admission and type of diagnosis. Complications were recorded in 76% of the patients (37% had at least one relatively severe complication). Bacterial super infections of skin lesions (28%), (imminent) dehydration (19%), febrile convulsions (7%), pneumonia (7%) and gastroenteritis (7%) were most frequently reported. No varicella-related death occurred within the study population and 3% of the patients had serious rest symptoms. CONCLUSIONS: It is not likely that the severity of varicella among hospitalized patients in the Netherlands differs from other countries. A considerable part of the varicella complications among hospitalized patients was rather moderate and can be treated effectively, although in a third of the hospitalized cases with complications, severe complications occurred. These data are relevant in the decision-making process regarding whether or not to introduce routine varicella vaccination in the Netherlands.

Guillain-Barré syndrome: background incidence rates in The Netherlands.

Guillain-Barré syndrome (GBS) is a (sub)acute polyradiculoneuropathy, which may occur following immunization. To interpret the occurrence of GBS after introduction of large-scale immunization programmes, it is important to define recent background incidence rates (IRs) of GBS. We used a general practitioner electronic medical record database to assess age-specific GBS IRs between 1996 and 2008 in The Netherlands. All possible GBS cases were manually reviewed. Validated incident cases were reviewed by a neurologist (B. J.) for diagnostic certainty using the GBS case definition of the Brighton Collaboration (BC). In a population of 638,891 persons, we identified 23 validated incident GBS cases (mean age 46 years). IR was 1.14 per 100,000 person years (95% confidence interval [CI] 0.67-1.61) and was lower for people under 50 years (0.76; 95%CI 0.41-1.32) compared with elderly of 50 years or older (1.80; 95%CI 0.98-3.05). Only six cases fulfilled level 1 or 2 of diagnostic certainty of the BC case definition. IR of GBS increases with age. As vaccinations are often targeted at specific age groups, age-specific rates should be used to monitor GBS observed versus expected rates after introduction of large-scale vaccination programmes.

Parental reports of adverse events following simultaneously given dT-IPV and MMR vaccines in healthy 9-year-old children.

In the Netherlands, children at 9 years of age receive a booster dT-IPV together with their second measles, mumps, and rubella (MMR) vaccination within the national immunization program. Safety is monitored continuously by enhanced passive surveillance. This population-based study was conducted to obtain more information on adverse events after vaccination at 9 years of age. Questionnaires on local and systemic reactions were distributed 1 and 3 weeks after vaccination, respectively, to parents of 1,250 healthy children who received their MMR and diphtheria, tetanus, and inactivated poliovirus injection (dT-IPV) vaccination as scheduled. Response to the questionnaires was 57.0% and 46.5%, respectively. Local reactions occurred in 86.5% of the children within 7 days after vaccination, more often at the dT-IPV (83.4%) than at the MMR site (32.7%). Pain was the most reported symptom (80.8% at the dT-IPV site; 29.1% at the MMR site). Systemic events occurred in 33.4% children within 7 days after vaccination, with headache as the most frequently reported (20.8%). Systemic events occurred in 20.8% children 8-21 days after vaccination. Children with local reactions at only the dT-IPV site had significantly more systemic events (19.3%) than those without local reactions (3.4%, p < 0.01). Such difference was not found for the MMR site. No serious adverse events were reported. Medical intervention was applied to 133 children (130 used analgesics and for three children the GP was consulted by phone). In conclusion, the frequency of reported local reactions is high, especially at the dT-IPV site, but all symptoms were transient. However, the use of reduced antigen content vaccines in association with the occurrence of adverse events is meaningful to explore. Furthermore, the overall rates are useful for monitoring variations in adverse events rates in the general population.

Two doses of pandemic influenza A(H1N1) vaccine: tolerability in healthy young children in the Netherlands.

During the 2009 influenza pandemic, children aged 6 months up to and including 4 years, without chronic illness, were vaccinated with two doses of Pandemrix(®) through mass vaccination in the Netherlands. During the vaccination campaign a warning was issued about fever after the second dose of Pandemrix(®). Therefore, we investigated the tolerability of both doses Pandemrix(®) in these children. Among parents of children eligible for vaccination, 1500 questionnaires were distributed during both, the first and second mass vaccination session. We asked for the occurrence, time interval, and duration of local reactions and systemic adverse events (AEs). The responses were 36.7% and 29.5% after each dose, respectively. Local reactions were reported in 40.4% and 39.3%, most frequently, pain at the injection site. After the first and second dose, 29.6% and 30.7% of all children experienced fever (mean temperature 38.8{degree sign}C). Other systemic AEs were reported in 41.6% and 42.9% of the children. No differences were seen between the first and second dose for all reported AEs except for pallor. One child was hospitalized after the first dose, but a causal relation to the vaccination was considered improbable. In conclusion, fever was frequently reported in children 6 months up to and including 4 years of age after the first and second dose of Pandemrix(®). However, for almost all AEs, including fever, no dose effect was observed. Reported AEs were mostly mild and all were transient.

Background incidence rates of adverse pregnancy outcomes in the Netherlands: Data of 2006-2018.

OBJECTIVE: Maternal vaccination is an effective and safe intervention to protect newborns against infectious diseases shortly after birth. We assessed background rates of adverse pregnancy outcomes before the implementation of a maternal pertussis immunisation programme in the Netherlands, to put into perspective the safety concerns about such outcomes following immunisation. STUDY DESIGN: In this retrospective cross-sectional study, annual numbers of pregnancy outcomes derived from the Dutch Perinatal Registry were used to calculate incidence rates per 10,000 in the 2006-2018 period. Births of ≥500 g birth weight and ≥24 + 0 w gestational age were included. Trends with moving-average-lines over the past 3 years were plotted, with 95 % confidence interval. RESULTS: From 2006 through 2018, yearly numbers of pregnancies ranged between 158,868-175,710. Numbers of newborns ranged between 161,307-178,874, of whom 160,838-178,177 were live-born. Most outcomes were stable over time. Between 2006-2011, occurrence of labour induction increased by 68 %, and postpartum hemorrhage increased by 25 %. Both stabilised from 2011 onwards. Perinatal mortality up to day 7 or 28 postpartum decreased by 38 % and 37 %, respectively. Occurrence of low Apgar score among preterm infants born before 37 + 0 w gestational age and among term infants increased by 19 % and 27 %, respectively. CONCLUSION: Our study on background incidences showed notable increases over time in occurrence of labour induction, postpartum hemorrhage and low Apgar score, while showing a considerable decrease in overall perinatal mortality. These findings should be considered when interpreting data on adverse events occurring since the maternal pertussis immunisation programme was implemented.

More than 10 years after introduction of an acellular pertussis vaccine in infancy: a cross-sectional serosurvey of pertussis in the Netherlands.

BACKGROUND: Pertussis is a respiratory disease and still endemic despite high vaccination coverage. In the Dutch national immunisation programme (NIP) whole cell pertussis (wP) priming vaccines for infants were replaced by acellular pertussis (aP) priming vaccines in 2005. Serosurveillance gives the opportunity to objectively monitor effects of changes in the NIP on infection prevalence and vaccine response in the population over time. METHODS: For this population-based cross-sectional serosurvey a representative sample of Dutch residents (0-89 years) was drawn in 2016/2017. Primary outcome was the percentage of participants with pertussis toxin specific antibody concentrations ≥ 100 IU/ml as an indicator of recent infection, and to identify groups possibly more vulnerable to pertussis infection. Percentages were compared with previous results from 2006/2007. FINDINGS: In total 7621 persons were included in the analysis. An increase in recent infections from 3•5% to 5•9% was found in the population from 7 years and older (n=6013) in 2016/2017 compared with 2006/2007. Most noteworthy increase was seen in 12-18-year-olds who were wP primed and aP boosted. INTERPRETATION: Infection prevalence is still increasing in the Netherlands inducing a risk of pertussis disease in vulnerable (age) groups. Delaying the preschool booster might prolong the period of protection during primary school and thereby possibly protect younger siblings. Extra boosters might be considered for risk populations like older adults and people with (pulmonary) co-morbidities, since they have higher chances of complications and hospitalisation.An unedited Dutch translation of the abstract is available in : Nederlandse samenvatting. FUNDING: The Dutch Ministry of Health, Welfare, and Sport.

Circulation of Bordetella pertussis in the Caribbean Netherlands: a population-based seroepidemiological study.

OBJECTIVES: Pertussis is a respiratory infectious disease caused by Bordetella pertussis. In the Caribbean Netherlands (CN), comprising the islands Bonaire, St Eustatius, and Saba, registration of cases is mandatory for disease surveillance. However, insufficient laboratory facilities hamper case confirmation, and circulation persists. The aim of this seroepidemiological study was to gain insight into B. pertussis circulation in CN, and to investigate what factors contribute to the risk of infection. METHODS: Blood samples and questionnaires were collected for 1829 participants aged 0-90 years. Concentrations of B. pertussis toxin-specific IgG antibodies (anti-Pt) were determined using a bead-based immunoassay to indicate infections within the previous 12 months (based on anti-Pt ≥ 50 IU/mL) in participants without detectable vaccine-induced humoral immunity. Risk factors for recent infection were analyzed using logistic regression models. RESULTS: An estimated 8.2% (95% CI 6.6-10.1) of CN residents aged ≥ 9 years were found to have been recently infected by B. pertussis. Risk factors for a recent infection were age 12-29 years (13.8-14.6%) and Dutch Caribbean or Surinamese origin (10.7%). CONCLUSIONS: B. pertussis infections occur frequently among CN residents aged ≥ 9 years, although few clinical pertussis cases are reported. Transmission to vulnerable individuals seems likely and should be taken into account in optimizing vaccination programs.

Social-psychological determinants of maternal pertussis vaccination acceptance during pregnancy among women in the Netherlands.

BACKGROUND: Maternal Pertussis Vaccination (MPV) during pregnancy became part of the National Immunization Program in the Netherlands late 2019. This study aims to identify social-psychological factors associated with MPV acceptance among Dutch women to add to the current understanding of vaccine hesitancy worldwide, and to inform the development of communication and information campaigns about MPV. METHODS: We conducted a cross-sectional study using an online survey among 611 women (174 pregnant women, 205 women who had given birth in the past two years and 232 women of 20-35 years old). The primary and secondary outcomes were vaccination intention and attitude towards MPV, respectively. Pearson's correlation and regression analyses were used to examine social-psychological and socio-demographic determinants of the outcomes. RESULTS: Vaccination intention was most explained by attitudes towards MPV, beliefs about safety, moral norm and the belief about the effectiveness of MPV (R2 = 0.79). Other factors associated were injunctive norm, anticipated regret of vaccinating, and decisional certainty. Attitudes towards MPV were further explained by descriptive norm, risk perceptions of side effects, and risk perceptions of the baby getting pertussis when not vaccinating, and fear of MPV and of the disease (R2 = 0.76). Finally, pregnant women had a significantly lower intention and less positive attitude towards MPV than non-pregnant women. CONCLUSIONS: Communication about MPV should address the most important determinants of MPV intention and attitude, i.e. beliefs about safety and effectiveness and moral norms. Furthermore, such information may benefit from taking into account affective feelings of pregnant women such as anticipated regret and fear towards MPV. Further research could explore this. The timing of communication about MPV can be important as determinants of MPV acceptance may vary depending on pregnancy status.

Quantifying outcome misclassification in multi-database studies: The case study of pertussis in the ADVANCE project.

BACKGROUND: The Accelerated Development of VAccine beNefit-risk Collaboration in Europe (ADVANCE) is a public-private collaboration aiming to develop and test a system for rapid benefit-risk (B/R) monitoring of vaccines using European healthcare databases. Event misclassification can result in biased estimates. Using different algorithms for identifying cases of Bordetella pertussis (BorPer) infection as a test case, we aimed to describe a strategy to quantify event misclassification, when manual chart review is not feasible. METHODS: Four participating databases retrieved data from primary care (PC) setting: BIFAP: (Spain), THIN and RCGP RSC (UK) and PEDIANET (Italy); SIDIAP (Spain) retrieved data from both PC and hospital settings. BorPer algorithms were defined by healthcare setting, data domain (diagnoses, drugs, or laboratory tests) and concept sets (specific or unspecified pertussis). Algorithm- and database-specific BorPer incidence rates (IRs) were estimated in children aged 0-14 years enrolled in 2012 and 2014 and followed up until the end of each calendar year and compared with IRs of confirmed pertussis from the ECDC surveillance system (TESSy). Novel formulas were used to approximate validity indices, based on a small set of assumptions. They were applied to approximately estimate positive predictive value (PPV) and sensitivity in SIDIAP. RESULTS: The number of cases and the estimated BorPer IRs per 100,000 person-years in PC, using data representing 3,173,268 person-years, were 0 (IR = 0.0), 21 (IR = 4.3), 21 (IR = 5.1), 79 (IR = 5.7), and 2 (IR = 2.3) in BIFAP, SIDIAP, THIN, RCGP RSC and PEDIANET respectively. The IRs for combined specific/unspecified pertussis were higher than TESSy, suggesting that some false positives had been included. In SIDIAP the estimated IR was 45.0 when discharge diagnoses were included. The sensitivity and PPV of combined PC specific and unspecific diagnoses for BorPer cases in SIDIAP were approximately 85% and 72%, respectively. CONCLUSION: Retrieving BorPer cases using only specific concepts has low sensitivity in PC databases, while including cases retrieved by unspecified concepts introduces false positives, which were approximately estimated to be 28% in one database. The share of cases that cannot be retrieved from a PC database because they are only seen in hospital was approximately estimated to be 15% in one database. This study demonstrated that quantifying the impact of different event-finding algorithms across databases and benchmarking with disease surveillance data can provide approximate estimates of algorithm validity.

Discolored leg syndrome after vaccination--descriptive epidemiology.

Discoloration of the leg following vaccination is a relatively unknown entity. We carried out a study of discolored leg syndrome (DLS) during a 10-year consecutive period with the objective of characterizing DLS in infants following vaccination received in the Dutch National Vaccination Program as well as its occurrence and association with different vaccines. Discolored leg syndrome was defined as an even or patchy red, blue or purple discoloration of the leg(s) and/or leg petechiae with or without swelling. All reports of adverse events following immunization that were made to the passive surveillance system between 1994 and 2003 were included-a total of 1162 identified cases. Red, blue, purple discoloration and isolated petechiae were reported in 39, 19, 27 and 14% of these cases, respectively. Of these 1162 cases, 1105 were considered to be related to the vaccination, based on a predefined risk window with symptom onset after vaccination (48 h for discolorations and 2 weeks for petechiae). Of the 1105 cases, about 50% occurred after DTP-IPV+Hib1 vaccinations, and 30% occurred after DTP-IPV+Hib2 vaccinations. Discolored leg syndrome was frequently accompanied by fierce crying (78%). The median time interval between vaccination and the occurrence of DLS was 3.8 +/- 46.7 h, and the median duration was short (2 +/- 61.7 h). Advancing the vaccination schedule from 3 to 2 months of age caused a small increase in DLS. Discolored leg syndrome manifested mainly after the first and/or second vaccination. In addition to dose, the occurrence of DLS may be slightly age-dependent and self-limiting. The pathophysiology is unknown but may be the result of a vasomotor reaction. Future studies should elucidate the recurrence rate, identify risk factors and assess late outcomes.