CURRENT TRENDS IN VACCINES AND VACCINOLOGY (ISSN:2631-8970)

Background: The fear of possible adverse events is one of the main factors leading to vaccination delay; however, studies actively monitoring the adverse events in preterm infants are scarce. This study aimed to analyze the occurrence of adverse events associated with BCG, pentavalent, rotavirus, meningococcal C, and 10-Valent pneumococcal vaccines in preterm and full-term infants.

Methods: Cross-sectional study conducted between December 2019 and March 2020. Sociodemographic and clinical variables regarding the adverse events of vaccines were assessed. The Chi-square and Fisher’s exact tests were used for statistical analysis, considering the level of significance of p<0.05.

Results: One hundred and forty-eight infants were included (74 preterm and 74 fullterm). The pentavalent vaccine was more reactogenic in preterm infants since a higher frequency of adverse events (i.e., fever >38ºC and continuous or persistent crying for more than three hours) were observed (p=0.025 and p=0.004, respectively). Fever (p=0.021), irritability (p=0.043), and bloodless diarrhea (p =0.026) were also more common in preterm infants post 10-Valent pneumococcal vaccine administration.

Conclusion: The adverse events of vaccines were mild and more reactogenic in the preterm infants. This corroborates with the Brazilian National Immunization Program guidance regarding the indication and specific recommendations of regular vaccination schedule for preterm infants.

Vaccination; Preterm; Adverse events

• The adverse events of vaccines administered in the first year of life are associated with preterm infants;
• Fever >38°C and continuous or persistent crying for more than three hours were adverse events of the pentavalent vaccine associated with preterm infants;
• Fever and irritability after PCV10 vaccine are associated with preterm infants.

The Brazilian National Immunization Program (PNI) is recognized as one of the best globally due to its extent and incorporated vaccines [1]. Brazil had good vaccine coverage, but since 2015 a worrying decrease in these rates is being observed. The situation is even more alarming in preterm infants [2,3], in which infectious diseases are significant prevalent due to immaturity of the immune system and limited maternal antibodies transfer [4,5].

Toward the risk of morbidity and mortality arising from vaccine-preventable diseases [6],the vaccination delay in preterm infants becomes relevant since they represent 11% of newborns in the world [5]. It is also noteworthy that vaccination coverage has been uneven in the Brazilian territory, with only 44.6% of the municipalities reaching the proposed target for BCG, pentavalent, rotavirus, and meningococcal C vaccines [2].

The fear of possible adverse events is one of the main factors leading to this vaccination delay. Doubts regarding the efficacy and safety of vaccines and the birth weight influence also contribute to this fact [4,5,7]. However, institutions such as the PNI, Specialty Societies, and the World Health Organization (WHO) recommend the vaccination of preterm infants according to the postnatal chronological age, not needing the correction by gestational age or birth weight to the vaccine administration. The exception to this recommendation happens only for the BCG vaccine, in which professionals must wait for the children to reach 2 kilograms, and those preterm infants with known HbsAg negative mother that must wait to receive the hepatitis B vaccine [6,7].

Although preterm infants may present a lower immune response than those full-term infants, vaccines provide sufficient protection and immune memory to be considered safe, tolerable, and immunogenic, confirming the uniformity of vaccination policies for both preterm and full-term infants [7,8]. The incidence of adverse events can be compared between groups of newborns (preterm and full-term), and the clinical condition at the time of the vaccination period is considered the main factor associated with adverse events, especially in the presence of cardiopulmonary involvement [5,9]. Therefore, gestational age and birth weight are not considered determinants of adverse events, and, hence, should not have a significant role in vaccination policy decisions [5,9].

Despite the scientific knowledge that vaccination of preterm infants should be normally recommended, there are still some controversies regarding its adverse events. The analysis of vaccines’ safety in preterm infants is particularly challenging compared with full-term infants, mainly due to clinical conditions inherent to prematurity, which may confuse the differentiation between adverse events and health status [5,9]. An adverse event following immunization (i.e., irritability, temporary inappetence, tachypnea, skin lesions, or apnea) can be observed in healthy preterm infants, especially after administering specific vaccines such as whole-cell diphtheria-tetanus-pertussis (DTP) [7,10-12].

Studies evaluating the safety of vaccination in preterm infants are still controversial [7],and this can be reflected as a factor responsible for the delayed immunization in this group. Other causes for this delay include limited data, mainly in extremely low weight and preterm patients, and the careful action of health professionals in indicating the moment of vaccination [13]. Studies actively monitoring the adverse events in preterm infants are infrequent and hinder a better analysis of this information [14].

In this context, our study evaluated the occurrence of adverse events related to the BCG, pentavalent, rotavirus, meningococcal C, and 10-Valent pneumococcal vaccines (PCV10) in preterm and full-term infants to strengthen public policies and immunization strategies.

A cross-sectional study was carried out with preterm and fullterm infants in the vaccination sector of the Instituto de Medicina Integral Prof. Fernando Figueira (IMIP), located in the city of Recife, Brazil. Data collection took place between December 2019 and March 2020. The research was approved by the research ethics committee of the IMIP (CAAE: 26472219.3.0000.5201) and conducted within the confines of the Declaration of Helsinki. All guardians of the children who agreed to participate in the study signed an informed consent form.

The IMIP is a hospital that exclusively serves the Brazilian Unified Health System and presents an average preterm birth rate of 20%. It is considered a reference center for this group of newborns and has a vaccination sector that performs approximately 100 daily vaccine applications in about 1180 children and 530 adults per month. The vaccine sector of the institute has all the vaccines recommended by the Brazilian Ministry of Health, according to the basic vaccination schedule for children, adolescents, adults, and the elderly.

Those preterm infants (gestational age between 28 and 36 weeks) aging one to eight months, and presenting the Child Health Handbook filled in compliance with the vaccination schedule proposed by the PNI for children in the first six months of life, were included in the preterm group. The criteria for the full-term infant group were similar, except for the gestational age that should be ≥ 37 weeks.

The infants (preterm and full-term) presenting the following morbidities at birth or after were excluded: congenital heart diseases, chronic pneumopathy (e.g., bronchopulmonary dysplasia), hemoglobinopathy, immunodeficiency, congenital malformations, and continuous use of oral corticosteroids or immunosuppressive drugs.

The infants who met the inclusion criteria were identified daily by the researchers in the IMIP vaccination room. The family members were informed about the study purpose and were invited to answer questions related to the adverse events of the BCG, rotavirus, PCV10, meningococcal C, and pentavalent vaccines. The birth weight, sex, race, nutritional status, age of the infant (in months) and maternal age (in years), maternal education, and family income were also collected.

The sample size calculation was performed using the epi-info program and estimated using an adverse event frequency of 70% after vaccination, a significance level of 5%, and a statistical power of 80%. The total optimal number was estimated as 138 children (69 patients in each group). For each preterm infant, one full-term infant was included.

Data are shown in absolute and relative frequencies. The Chisquared or Fisher exact test was used to compare the distribution of the categorical variables. Inferential analyses were performed using the Statistical Package for Social Sciences (IBM Corp.), version 13.0, and the level of significance was set at p<0.05. 

The sample consisted of 148 infants (74 preterm and 74 fullterm). Table 1 shows the sociodemographic, biological, and maternal characteristics of the included infants. We highlight that 57.1% of the preterm infant guardians had a total income of <1 minimum wage, while this income was equivalent to 52.5% among the families of the full-term group. Maternal age ranged predominantly from 20 to 35 years, both in the full-term (73.5%) and preterm (59.7%) groups. Most mothers completed high school (43.9% in the preterm and 46.2% in the full-term group) but no significant difference was observed between groups. Table 2 shows the list of adverse events following BCG vaccination. No significant associations were observed.

Table 3 describes the distributions of local and systemic adverse events related to the pentavalent and PCV10 vaccines. We emphasize that some children received these vaccines on separate days, but no differentiation was performed in our analysis. However, when administered together, the guardians of the infants used to associate the adverse events with the pentavalent vaccine due to its greater reactogenicity. After the pentavalent vaccine, local edema was present in 53.4% of the preterm and 50% of the full-term infants (p = 0.678). Also, fever >38°C and continuous or persistent crying for more than three hours were adverse events of the pentavalent vaccine significantly associated (p=0.025 and p=0.004, respectively) with preterm infants.

Regarding the PCV10, the presence of fever and irritability were significantly associated with preterm infants (p=0.021 and p=0.043, respectively).

Table 4 shows the distribution of local and systemic adverse events of both the rotavirus and meningococcal C vaccines. Regarding the former vaccine, bloodless diarrhea was associated with preterm infants (p =0.026), while no significant associations were observed with the latter. 

The reduction of global prematurity is challenging given the low quality of some prenatal care, the socioeconomic conditions of the population, and the evolution of in vitro fertilization techniques [15,16]. This population presents several risks of infectious diseases, including those that are preventable by vaccines [4,5].The vaccination delay in these infants is frequent, and one of the main reasons is the fear of adverse events [5]. Our study evaluated the occurrence of adverse events of vaccines included in the calendar proposed by the PNI in the first year of life and its association with preterm and fullterm infants.

No association between socioeconomic variables and adverse events after the vaccines were observed. It is worth noting that most of the population assisted by the IMIP presents a low socioeconomic level. However, it is known that low education and maternal age are considered risk factors for prematurity, thus justifying the associations between socioeconomic variables and prematurity and, consequently, with adverse events [15]. Regarding maternal age, a low frequency was observed in mothers aging <20 years and >35 years, even in the group of preterm infants, in which the literature emphasizes that the risk of prematurity increases in mothers under 20 or over 40 years old [15]. Regarding maternal education, most mothers of both groups completed high school, but no associations were observed.

The BCG vaccine is administered within the first days of life, considered safe, and with a low incidence of adverse events [17- 19]. The occurrence of associated adverse events is more related to technical failures during its administration than the immunological status of the newborn [18,19]. Ulcer formation (i.e., greater than 0.39 inches) appears in the first six months after vaccination and affects 0.4 per 1.000 vaccinated infants [18,20,21]. In our sample, a higher percentage of adverse events was observed (9.5% in both groups), probably because of the active monitoring of the adverse events. These finding needs to be better evaluated in future studies.

Although regional adenopathy (axillary, clavicular, or intercostal) is considered frequent by the Brazilian Ministry of Health and affects approximately 10% of vaccinated individuals [22], no cases were reported in this study. This was probably due to the lack of identification by the guardians since the ganglia identification generally requires a physical examination, a procedure that was not performed in our study. The local abscess, either hot (resulted from material contamination during vaccine application) or cold (caused by a vaccine application deeper than adequate), is one of the most frequent local adverse events [20,21]. This corroborates the findings of our study, in which 20% of each group reported this event. The onset of local adverse events was up to 15 days after BCG vaccination, being 75% in the full-term and 50% in the preterm infants.

Regarding the pentavalent vaccine (whole-cell DTP, Haemophilus influenzae type b, Hepatitis B) administered at two, four, and six months of age, its adverse events are usually present in the first 48h to 72h after application [21,23]. Whole-cell DTP is considered the cause of apnea and seizure due to its pertussis component [21], while its other components (i.e., HiB and Hepatitis B) are not associated with systemic or local events of great relevance [21,23].

We emphasize that both groups (preterm and full-term infants) participating in this study received whole-cell DTP, despite the recommendation of the Reference Center for Special Immunobiologicals (CRIE) to replace DTP for acellular DTP in extremely preterm newborns (i.e., less than 1.000g or 31 weeks) [24]. The preterm infants included in this study who fit the CRIE criteria did not receive acellular DTP mainly due to the occasional lack of vaccine in the Brazilian territory during the studied period. In this sense, these infants used classic DTP.

The presence of the pentavalent traditional systemic events (i.e., fever >38ºC, irritability, apnea, and continuous or persistent crying for more than three hours) was significantly more prevalent in preterm infants. It is also essential to consider that fever may have been underestimated since most responsible family members reported prophylactic antipyretic use, despite its recommendation in cases of high fever or history of febrile seizure after previous doses [21]. The continuous or persistent crying for more than three hours was probably due to the administration of DTP, being more prevalent in the latter [25]. Seizures and the hypotonic-hyporesponsive syndrome were not reported, which was already expected since they are rare [26].

Approximately 90% of the preterm and full-term infants presented pentavalent local adverse events three days after vaccine application. Although we have identified that the pentavalent and PCV10 vaccines were applied on separate days in some infants and no separate analysis was performed, it is not possible to specify which isolated vaccine caused the adverse events. Furthermore, some family members were already aware of the greater reactogenicity of the pentavalent vaccine, which may have influenced the findings.

The PCV10 vaccine has been included in the PNI calendar since 2010, and the first two doses are recommended in the second and fourth months of age [21-25]. The total occurrence of local adverse events was not different between groups, a finding that corroborates with the literature [27].

Fever and irritability were systemic events significantly associated with the PCV10 vaccine in preterm infants. Irritability is described as the most common symptom, and, together with fever, it is considered a mild symptom of short duration [21,27,28]. Although the adverse events after vaccination were significantly different between preterm and full-term infants, data comparing the frequency of adverse events to this vaccine are scarce, precluding the possibility of comparing our data to data derived from similar comparisons.

Regarding the rotavirus vaccine, the main systemic events were fever and irritability [29]. These, together with bloody diarrhea and vomiting, presented a similar frequency between preterm and fullterm infants, with most children manifesting within three days after vaccination.

Consequently, the onset of bloodless diarrhea was significantly different between groups, with greater frequency in preterm infants. Although bloodless diarrhea is well documented, further studies are needed to compare its incidence between preterm and full-term infants [30].

The predominance of these adverse events and the manifestation time found are in line with the literature since its peak appears during the first seven days after vaccine administration [30,31].

No defined consensus regarding the prevalence of adverse events in full-term or preterm infants is present in the literature regarding the meningococcal C vaccine [3,32]. Local events are probably greater in full-term infants, while systemic conditions are more present in preterm infants, which can be explained by the clinical conditions inherent to prematurity [3,32]. This was also observed in the present study, in which irritability was slightly more prevalent in preterm than full-term infants, and the local heat was marginally more prevalent in full-term infants. However, none of these findings was statistically significant. It was also observed that the time of onset of local and systemic adverse events related to the Meningococcal C vaccine was significantly more prevalent in the first 72 hours after vaccine application, which is also in agreement with most studies [21,33]. 

In conclusion, the adverse events of vaccines administered in the first year of life are relatively frequent and are associated with preterm infants, specifically the pentavalent, PCV10, and rotavirus vaccines. However, most of these events were considered mild and had a spontaneous resolution. Given the decline in vaccination coverage in recent years, it is necessary to reinforce public policies to guarantee vaccination and safety for all individuals, especially the most vulnerable groups, such as preterm infants.

Recognition of support for the study: Institutional Scientific Initiation Scholarship Program (PIBIC) by the Instituto de Medicina Integral Prof. Fernando Figueira (IMIP) and National Council for Scientific and Technological Development (CNPq).

The authors certify that there is no conflict of interest with any financial organization regarding the material discussed in the manuscript.

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