First hepatitis B vaccine uptake in neonates prior to and during the COVID-19 pandemic

Abstract

Introduction

Routine vaccination for hepatitis B is recommended at birth, and most infants should be vaccinated within 24 h of life. Historically, vaccination rates have been less than ideal, and routine vaccination has been further complicated by the COVID-19 pandemic, with decreased uptake of many vaccines. This retrospective study assessed hepatitis B vaccination rates at birth before and after the start of the COVID-19 pandemic and explored the factors associated with lower vaccination rates.

Methods

Infants born at a single academic medical center in Charleston, South Carolina from November 1, 2018 through June 30, 2021 were identified. Infants were excluded if they died or received ≥ 7 days of systemic steroid therapy within the first 37 days of life. Maternal and infant baseline characteristics and uptake of the first hepatitis B vaccine during hospital admission were recorded.

Results

A total of 7808 infants were included in the final analysis, with an overall vaccine uptake of 91.6 %. Of the 3880 neonates in the pre-pandemic group, 3583 (92.3 %) were vaccinated, versus 3571 (90.9 %) of 3928 neonates in the pandemic group (rate difference = 1.4 %; 95 % confidence interval −2.8 % to 5.7 %, p = 0.52). Factors independently associated with lower vaccine uptake included being of non-Hispanic white race, born to a married mother, birth weight < 2 kg, and parental refusal of erythromycin eye ointment at birth.

Conclusion

The COVID-19 pandemic did not significantly affect the uptake of inpatient neonatal hepatitis B vaccination. Several patient-specific factors were associated with suboptimal vaccination rates in this population.

1. Introduction

Hepatitis B is a highly contagious viral infection that can be spread through vertical transmission from mother to child, sexual contact, or other means of contact with infected bodily fluids. The U.S. Department of Health and Human Services estimates that 1,000 infants are infected each year through vertical transmission [1]. Appropriate medical care and vaccination are essential for preventing potentially lethal chronic infection in infants born to hepatitis B-positive mothers. Rates of neonatal hepatitis B vaccination have been historically less than ideal, with only 79.8 % of United States infants born from 2018 through 2019 receiving their birth dose of the hepatitis B (HepB) vaccine [2]. The first dose of hepatitis B vaccination is significant because it not only gives 70–95 % protection from perinatal hepatitis B [3], but it also is an indicator for future vaccination. A delayed first dose of the HepB vaccine has been associated with lower rates of completion of the rest of the hepatitis B series, as well as other childhood vaccines [4]. A 2019 study found that only 45 % of infants who did not receive their HepB vaccine at birth had received all the recommended vaccines at 2 years, compared to 65 % of the infants who received their first hepatitis vaccine at birth [5].

Both the American Academy of Pediatrics and Centers for Disease Control and Prevention’s Advisory Committee on Immunization Practices’ guidelines for childhood immunizations are followed across most United States (U.S.) medical centers. Both recommend that any medically stable infant born to a hepatitis B surface antigen (HBsAg) negative mother and weighing at least 2 kg (kg) should receive their first hepatitis B vaccination within 24 h of birth. A medically unstable infant ≥ 2 kg will receive their HepB vaccine once medically stable. If an infant is <2 kg at birth and has an HBsAg-negative mother, they should receive the vaccine at one month of age or at hospital discharge, whichever comes first. If the infant is born to an HBsAg-positive mother, the hepatitis B vaccine and hepatitis B immunoglobulin are given within 12 h of birth. If the mother has an unknown HBsAg status, the hepatitis B vaccine should be given within 12 h. Furthermore, hepatitis B immunoglobulin should be given within 12 h if the infant is <2 kg or within 7 days of birth if  ≥ 2 kg unless the mother’s status can be determined within that time frame [3], [6]. Based on this guidance, practically all infants should be vaccinated for hepatitis B either within the first 30 days of their birth or by discharge.

The uptake of vaccinations has been complicated by the COVID-19 pandemic. Early studies have shown decreased rates of routine vaccination during the start of the pandemic worldwide [7], [8], [9], [10], [11]. It is unclear if hepatitis B vaccination at birth would be similarly affected since this is typically given in the hospital, and how the rates would change through the different stages following the pandemic [8]. This research aims to fill a gap in the literature on the birth dose of the HepB vaccine uptake during COVID-19. The objective of the study was to determine birth hepatitis B vaccination rates prior to the COVID-19 pandemic at the Children’s Hospital of a large academic medical center in the southeastern U.S., the impact of the pandemic on hepatitis B immunization uptake, and potential factors associated with lower rates of vaccination.

2. Methods

2.1. Study design and population

In this retrospective, single-center study, infants eligible for hepatitis B immunization and born at the Children’s Hospital of a large academic medical center in Charleston, South Carolina between November 1, 2018 through June 30, 2021 were identified. Infants that expired, received systemic steroids for seven days or more, or were transferred to a different hospital within the first 37 days of life were excluded. While most infants should receive their first dose of the HepB vaccine by one month of life, infants that received their immunization by 37 days of life while hospitalized were considered compliant to allow flexibility for extenuating circumstances (e.g., delay in attaining parental consent).

Patients were divided into two groups based on the start of the COVID-19 pandemic: pre-pandemic (i.e., those born 11/1/2018 through 2/29/2020) and pandemic (i.e., those born 3/1/2020 through 6/30/2021). March 1, 2020, was used as the start of the COVID-19 pandemic. While the first COVID-19 case in South Carolina was documented on March 7, 2020, several states in the U.S. had documented cases on March 1, 2020, and thus, this date was selected. Demographic and clinical data were also obtained to describe factors associated with decreased uptake of the first HepB vaccination. Our Institutional Review Board reviewed the methods and data analysis involved in this study (IRB ID: Pro00115392) under the exempt category.

2.2. Outcomes

The primary objective of this study was to compare the uptake of the birth dose of the HepB vaccine before and after the start of the COVID-19 pandemic. The secondary objective was to explore baseline characteristics and other factors that may be associated with lower rates of the birth dose of the HepB vaccine. Infant-specific factors considered include sex, ethnicity/race, gestational age, birth weight, Apgar scores at one and five minutes, length of stay, erythromycin eye ointment administration, and intramuscular vitamin K administration. Gestational age was considered pre-term if <37 weeks or term if 37 weeks or longer. Maternal-specific factors investigated were age, marital status, type of insurance, and location of residence. The location of residence was considered either rural or urban. This was determined using 2010 Rural-Urban Commuting Area codes based on zip code, where scores of less than four were considered urban and four or greater were rural [12].

2.3. Statistical analyses

Continuous data are presented as medians and interquartile ranges, while categorical data are presented as frequencies and percentages. Data were analyzed using chi-square and Fisher's exact tests where appropriate. A rate difference and corresponding 95 % confidence interval were estimated for the primary outcome [13]. To evaluate factors that were independently associated with unvaccinated status, a multivariable logistic model was utilized. Factors were entered into the multivariable model if they had a p-value ≤ 0.2 in the univariate analysis. For the multivariable model, backward elimination was utilized and p values < 0.05 were considered significant. To abate multicollinearity, if two variables were correlated, one was dropped from the model based on clinical relevance. SPSSv27 (IBM Corp., Armonk, NY) was used to perform statistical analysis.

3. Results

A total of 8053 infants were born between November 1, 2018 through June 30, 2021. One hundred and sixty-two patients were excluded due to receiving 7 or more days of systemic steroids and 83 were excluded due to expiring within 37 days of birth, resulting in 7808 infants included in the analysis. There were 3880 infants born in the pre-pandemic period and 3928 during the pandemic.

3.1. Baseline characteristics

Baseline characteristics between pre-pandemic and pandemic groups are detailed in Table 1 . Overall, 49 % of infants born during the study period were non-Hispanic white, and approximately 51 % were male. The majority were born after 37 weeks gestation or longer (77.4 %) and were 2 kg or more (90.2 %). Approximately 45 % of infants' mothers had commercial insurance, most lived in an urban setting (93.4 %), and were unmarried (54.4 %). The maternal age was 26 years or older for the majority of included individuals (75 %). There were a few small but statistically significant differences between the baseline characteristics of the pre-pandemic and pandemic groups, including percent with non-Hispanic white race, born to an English-speaking mother, born to a mother at least 26 years of age, mother with four of more pregnancies, APGAR score less than seven at 1 min after birth, and coverage by commercial insurance.

Table 1.

Characteristics among those born pre-pandemic versus during the COVID-19 pandemic.

	Pre-pandemic N = 3880 n (%)	Pandemic N = 3928 n (%)	P
Female	1928 (50)	1930 (49)	0.62
Pre-Term (<37 weeks)	881 (23)	886 (23)	0.49
Birth Weight < 2 kg	398 (10)	369 (9)	0.20
Non-Hispanic White Race	1787 (46)	1947 (50)	0.002
APGAR Score < 7 at 1 Minute	673 (17)	606 (15)	0.02
APGAR Score < 7 at 5 Minutes	186 (5)	160 (4)	0.12
Erythromycin Not Administered	132 (3)	166 (4)	0.06
Vitamin K Not Administered	61 (2)	70 (2)	0.47
Commercial Insurance	1625 (42)	1878 (48)	<0.001
Urban Location of Residence	3618 (93)	3672 (93)	0.68
Born to Married Mother	1753 (45)	1801 (46)	0.55
Born to English Speaking Mother	3566 (92)	3682 (94)	0.002
Born to Mother ≥ 26 Years	2853 (74)	2971 (76)	0.03
Born to Mother with ≥ 4 Pregnancies	554 (14)	499 (13)	0.04

3.2. Outcomes

Of the 3880 neonates in the pre-pandemic group, 3583 (92.3 %) were vaccinated versus 3571 (90.9 %) of 3928 in the pandemic group (rate difference = 1.4 %; 95 % confidence interval −2.8 % to 5.7 %, p = 0.52). Vaccine uptake by month is shown in Fig. 1 .

Fig. 1.

Uptake of First Dose of Hepatitis B Vaccine by Month and Year.

There were several factors associated with lower rates of vaccination in the univariate analysis (Table 2 ). Infants born prematurely, with birth weight < 2 kg, or with low to moderate Apgar scores (<7) at one minute from birth had lower vaccine uptake. Maternal characteristics associated with lower vaccination rates in the univariate analysis included being married, non-Hispanic white race, having commercial insurance, or English as their preferred language. Additionally, infants that did not receive intramuscular vitamin K or erythromycin eye ointment at birth had lower uptake of the neonatal HepB vaccine in the univariate analysis.

Table 2.

Univariate analysis of factors associated with unvaccinated status.

	Unvaccinated N = 654 n (%)	Vaccinated N = 7154 n (%)	P
Female	320 (49)	3538 (49)	0.80
Pre-Term (<37 weeks)	186 (28)	1561 (22)	<0.001
Birth Weight < 2 kg	123 (19)	644 (9)	<0.001
Non-Hispanic White	376 (57)	3358 (47)	<0.001
APGAR Score < 7 at 1 Minute	132 (20)	1147 (16)	0.01
APGAR Score < 7 at 5 Minutes	38 (6)	308 (4)	0.07
Erythromycin Not Administered	143 (22)	155 (2)	<0.001
Vitamin K Not Administered	55 (8)	76 (1)	<0.001
Commercial Insurance	328 (50)	3175 (44)	0.004
Urban Location of Residence	614 (94)	6676 (93)	0.17
Born to Married Mother	354 (54)	3200 (45)	<0.001
Born to English Speaking Mother	633 (97)	6615 (92)	<0.001
Born to Mother ≥ 26 Years	505 (77)	5319 (74)	0.11
Born to Mother with ≥ 4 Pregnancies	102 (16)	951 (13)	0.10

Four factors were found to be significantly associated with unvaccinated status in the multivariable model (Table 3 ). These included being of non-Hispanic white race, born to a married mother, birth weight < 2 kg, and parental refusal of erythromycin eye ointment at birth.

Table 3.

Factors significantly associated with unvaccinated status in the multivariable model.

	Odds Ratio	95 % Confidence Interval	P
Non-Hispanic White	1.34	1.13–1.61	0.002
Birth Weight < 2 kg	3.12	2.50–3.90	<0.001
Erythromycin Not Administered	13.23	10.30–17.01	<0.001
Born to Married Mother	1.21	1.01–1.46	0.04

4. Discussion

In the study population (N = 7808), 91.6 % of infants received their first HepB vaccine during hospitalization within the first 37 days of life and rates did not change during the COVID-19 pandemic. While there were a few statistically significant differences in the baseline characteristics of the pre-pandemic and pandemic groups, they are likely not clinically significant or a result of the pandemic, as the majority of the infants would have been conceived prior to the pandemic. In addition, the factors associated with lower vaccination rates were split between the two groups. Patients with APGAR score < 7 at one minute from birth or born to mothers with ≥ 4 pregnancies were more common in the pre-pandemic group, while those with non-Hispanic white race, born to an English-speaking mother, or with coverage by commercial insurance were more common in the pandemic group. The overall rate of HepB vaccination is higher than reported in prior studies, including a 2019 study at a large academic medical center in Washington state which reported a 75.5 % vaccination rate for infants ≥ 2 kg during hospitalization [14]. Of note, at our institution, key birth interventions are included in an admission order set including the HepB vaccine, intramuscular vitamin K, erythromycin eye ointment, and glucose gel for the treatment of neonatal hypoglycemia. Implementation of admission order sets has been associated with increased rates of vaccination in previous studies [15], [16]. For example, in 2015, the Children’s Hospital at Montefiore improved their HepB vaccine uptake within 12 h of life from 13 % to 65 % with the addition of the HepB vaccine to the post-delivery newborn order set [15]. The time period used in our study of 37 days was selected to allow for extenuating circumstances that might occur in a tertiary care institution but may have resulted in a higher vaccination rate than seen in other trials. For example, the United States Immunization Survey uses a time period of birth to age of three days when calculating percent of infants who received their birth dose of the HepB vaccine [2].

While there was a slight decrease in vaccine uptake throughout the study period, the difference was not significant, which suggests that the COVID-19 pandemic did not have an immediate impact on neonatal HepB vaccine uptake at our institution. This differs from reports of vaccination rates for other routine vaccines, which decreased at the start of the COVID-19 pandemic [8], [17]. Suggested causes of decreased routine vaccine uptake are related to factors in the outpatient setting: hesitation to attend well-child visits, social distancing policies, and lack of healthcare workers, among others [17]. The birth dose of the HepB vaccine is typically given while in the hospital, allowing many of these difficulties to be avoided. We hypothesized factors may have influenced HepB vaccine uptake including vaccine hesitancy, decreased trust in the healthcare system, and availability for parental consent. The decreased uptake of one vaccine may result in a similar response to a different vaccine, as suggested by the decrease in the measles, mumps, and rubella vaccine from 2013 to 2015 that coincided with negative media coverage of the HPV vaccine [18]. There was a substantial amount of hesitancy around the COVID-19 vaccines, with greater vaccine hesitancy found in those with black or other/mixed race, or white race in Republican-leaning states [19]. Decreased trust in healthcare professionals and increased reliance on alternative sources of information have also been connected to vaccine hesitancy [20]. A national survey conducted from December 2020 to January 2021 found that 32 % of participants had decreased trust in the healthcare system associated with the pandemic [21]. Despite the potential effects of COVID-19, it appears that these factors did not result in a significant change in HepB vaccine uptake based on our study.

Being married, English-speaking, or having commercial insurance was associated with lower uptake of neonatal HepB vaccine in the univariate analysis in our study. These results are in contrast with a 2015 study at a large academic medical center in Iowa that found married women and those with employer/school-based insurance were significantly more likely to have infants that received their birth dose of HepB vaccine [22]. However, the study was consistent with ours in the finding of lower uptake of the HepB vaccine among Caucasian mothers. Nonetheless, it is unclear why the studies differed in the aforementioned factors, although the passage of time and difference in location could be contributory. In the United States, being married, Asian or white, or having health insurance for all members of the household is associated with greater wealth [23]. In a 2019 meta-analysis on childhood vaccine hesitancy, one common factor seen in trials was the perceived contextual factors of risk [20]. They noted that some parents felt affluence resulted in a lower risk of vaccine-preventable diseases compared to those living in poverty, which may be related to why we saw greater vaccine hesitancy in these select groups. Being married also potentially adds a second person to the vaccine decision-making process who may have hesitancy about vaccination. Another factor that may have played a role amongst vaccine hesitant mothers is an increase in salutogenic parenting which places greater emphasis on the promotion of healthy living, wellness, and natural immunity over the use of traditional Western medicine and pharmaceuticals, for example, extended breastfeeding, lowering exposure to chemicals or toxins (e.g. thimerosal, erythromycin eye ointment, and vitamin K), and avoiding overly stressing the immune system early in life by altering vaccine schedules [24].

The remaining factors associated with lower uptake of the birth dose HepB vaccine appear to be related to the clinical status of the infant at birth. Infants that experience pre-term birth, have a birth weight of<2 kg, or Apgar scores<7 at one minute from birth were less likely to receive their HepB vaccine in the univariate analysis. It is possible that parents may be uncomfortable with timely vaccination if their child appears more vulnerable at birth. At the study institution, the HepB vaccine is tracked beyond birth, but it is a manual time-consuming process with multiple team members involved. It is likely beneficial to create and implement systems within the electronic health record that ensures that HepB vaccination is tracked and prioritized beyond birth.

Similar to previous literature [25], this study also showed an association between missing HepB vaccination and rejection of other key birth interventions (i.e., erythromycin eye ointment). It may be beneficial to target education to these populations to ensure the benefits and safety of key birth interventions, as well as risks associated with refusing these interventions, are clearly communicated, preferably before the infant's birth.

There are several limitations to this study. First, the study was retrospective; it was not feasible to ascertain all factors that may have led to the refusal of hepatitis B vaccination. It may be beneficial to have a prospective study in a similar population. This would allow the opinions of the family, providers, and surrounding staff to be measured and quantified. Similarly, the appropriateness of vaccine timing based on patient-specific factors as recommended by the American Academy of Pediatrics and Advisory Committee on Immunization Practices (e.g., maternal HBsAg, infant weight at birth and medical stability, etc.) was not parsed out [3], [6]. Further, we chose to exclude infants if they received seven or more days of systemic steroids. While delaying the HepB vaccine with systemic steroid use is a common practice at our institution, it is not recommended by major guidelines. This exclusion could impact the generalizability of our findings. Nonetheless, <5 % of all identified individuals were excluded for any reason. Moreover, the 37-day time frame for assessing vaccination status was chosen because medically unstable infants or those <2 kg at birth may receive the HepB vaccine later in their hospitalization. The 37-day time frame allowed flexibility for minor delays in vaccination but may make the vaccination rate difficult to compare to studies using different time frames. Further, additional baseline characteristics, such as maternal HBsAg status, COVID-19 vaccination status, educational level, income, and prenatal care were not collected either because these data were incomplete or not available in our institution’s data warehouse. Similarly, we were not able to assess the infant unit of admission and comorbidities.

5. Conclusion

The COVID-19 pandemic did not significantly affect the uptake of the first inpatient neonatal hepatitis B vaccination in this analysis of ∼8,000 infants. Several patient-specific factors were associated with suboptimal vaccination in the multivariate analysis, including being of non-Hispanic white race, born to a married mother, birth weight < 2 kg, and parental refusal of erythromycin eye ointment at birth. This information will provide direction for future research and quality improvement opportunities.

6. Contributorship

SSG, THC, and AMD initiated the study. All authors retrieved relevant background literature. ERW performed statistical analyses. AMD drafted the initial manuscript. All authors interpreted the results and revised the manuscript. All authors attest they meet the ICMJE criteria for authorship and have approved the final article.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Data availability

The data that has been used is confidential.