Neonatal Deaths After Hepatitis B Vaccine: The Vaccine Adverse Event Reporting System, 1991-1998

Objective  To evaluate reports of neonatal deaths (aged 0-28 days) after hepatitis B (HepB) immunization reported to the national Vaccine Adverse Event Reporting System (VAERS).

Design  Case series; review of autopsy reports.

Setting  Voluntary reports submitted to VAERS, a passive surveillance system, from the US population.

Patients  All US neonates (0-28 days of age) whose deaths after HepB vaccination given alone were reported to VAERS, occurring from January 1, 1991, through October 5, 1998.

Intervention  None (observational database).

Results  Of 1771 neonatal reports, there were 18 deaths in 8 boys and 9 girls (1 patient unclassified). The mean age at vaccination for these 18 cases was 12 days (range, 1-27 days); median time from vaccination to onset of symptoms was 2 days (range, 0-20 days); and median time from symptoms to death was 0 days (range, 0-15 days). The mean birth weight of the neonates (n = 15) was 3034 g (range, 1828-4678 g). The causes of death for the 17 autopsied cases were sudden infant death syndrome for 12, infection for 3, and 1 case each of intracerebral hemorrhage, accidental suffocation, and congenital heart disease.

Conclusion  Few neonatal deaths following HepB vaccination have been reported, despite the use of at least 86 million doses of pediatric vaccine given in the United States since 1991. While the limitations of passive surveillance systems do not permit definitive inference, these data suggest that HepB immunization is not causing a clear increase in neonatal deaths.

IN 1991, hepatitis B (HepB) vaccine became the first vaccine recommended to be universally administered to neonates.¹ At the time of licensing of the recombinant HepB vaccines in 1986 (Recombivax; Merck & Co Inc, Whitehouse Station, NJ) and 1989 (Engerix; SmithKline Beecham Pharmaceuticals, Philadelphia, Pa), no serious reaction or death had been reported in infants (aged 0-12 months); however, the safety database was based on limited experience in approximately 2000 infants.^2-8

Postmarketing surveillance is an important tool that may identify new or rare adverse events that are only observed after the vaccine is widely used after licensure.^9-15 The national Vaccine Adverse Event Reporting System (VAERS) is a passive surveillance system monitoring postmarketing vaccine safety.¹⁵ It solicits reports of all events temporally related to immunization, some of which may be coincidental.¹⁵ Despite limitations inherent in passive reporting systems such as biased reporting, incomplete reporting, and underreporting; lack of consistent diagnostic criteria; lack of a comparison group; and lack of data as to the number of vaccine doses administered,¹⁵ VAERS has proved a useful tool in identifying and evaluating vaccine-related events such as thrombocytopenia after measles vaccine¹² and alopecia after immunization,¹³ as well as providing further assurance about the safety of HepB^9,10 and hepatitis A vaccines.¹¹ Other strengths include the timely availability of data from a surveillance system that derives data from the entire US population.¹⁵

In a previous study, we reviewed 1991 to 1994 VAERS data that revealed 6 neonatal deaths after HepB vaccination.⁹ These deaths did not seem to be causally related to HepB immunization.⁹ Recently, in response to an inquiry from the Institute of Medicine, we reviewed neonatal deaths after HepB vaccination reported to VAERS for the years 1991 to 1998. This updated review includes all US death reports after HepB vaccine given alone (rather than simultaneously with other vaccines) in neonates (aged 0-28 days), excluding duplicate and foreign reports.

From January 1, 1991, through October 5, 1998, a total of 1771 neonatal (aged 0-28 days) events after receipt of HepB vaccine were reported to VAERS. Eighteen were death reports (Table 1). There were no reports of neonatal deaths in 1991, 1 death in 1992, 7 deaths in 1993, none in 1994 and 1995, 6 deaths in 1996, and 2 each in 1997 and 1998.

Neonatal deaths were reported in 8 boys and 9 girls (sex was not reported in 1 instance). The mean age at vaccination was 12 days (age range, 1-27 days). The median time from vaccination to onset of symptoms was 2 days (range, 0-20 days), and median time from onset of symptoms to death was 0 days (range, 0-15 days). The mean birth weight of the neonates (n = 15) was 3034 g (range, 1828-4678 g). Four cases were reported from New Hampshire, 3 from Pennsylvania, 2 from Texas, and 1 case each from California, Florida, Illinois, Maryland, Minnesota, Missouri, New York, South Carolina, and Virginia. Of 16 reports that included the vaccine manufacturer and lot number, only 2 cases received a dose from the same vaccine brand and lot; these deaths were diagnosed as sudden infant death syndrome (SIDS), and both cases resided in the same state. Cases were reported by physicians (n = 8), nurses (n = 4), state immunization program staff (n = 3), vaccine providers (unspecified) (n = 2), and a relative of the patient (n = 1).

Seventeen autopsy reports were available for review (1 case did not have an autopsy) (Table 1). The causes of death recorded by the medical examiner at autopsy were SIDS (n = 12); infections (1 case each of bronchopneumonia [no causative organism noted], pneumonitis/bronchopneumonia/aspiration of amniotic sac contents in a neonate with persistent fetal circulation, and Enterobacter cloacea pneumonia/sepsis); and 1 case each of intracerebral hemorrhage (presumptive diagnosis based on "bloody cerebrospinal fluid" obtained prior to death in a "shaken" baby—this was the case where an autopsy was not performed), accidental suffocation, and congenital heart disease (Table 1).

This review reveals 18 neonatal deaths after HepB vaccine reported to VAERS during an interval in which at least 86 million doses of pediatric HepB vaccine were distributed in the United States (Centers for Disease Control and Prevention, unpublished data, 1999). There were 12 reports of SIDS; coincidental SIDS deaths are expected following any infant vaccination, however, given the extent of vaccine coverage and the incidence of SIDS.¹⁵ Three reports (bronchopneumonia, pneumonitis/bronchopneumonia/aspiration of amniotic sac contents, congenital heart disease) were initially reported as possible SIDS cases because the infant did not exhibit significant symptoms. The unexpected cause of death was determined at autopsy. At this time, there is no way to prove or disprove a causal relation between HepB immunization and SIDS using individual autopsy reports; however, in cases of unexplained infant deaths, detailed review of autopsy materials by pediatric pathologists should be considered, as causes other than SIDS may be revealed.

Since the 1991 Advisory Committee on Immunization Practices recommendation of universal HepB immunization of infants, no evidence of either an increased trend in the overall number of neonatal deaths¹⁶ or in neonatal deaths after HepB vaccination reported to VAERS was found. From 1985 (before universal HepB immunization of infants) to 1996, the total number of neonatal deaths in the United States decreased from 7.0 to 4.8 deaths per 1000 live births.¹⁶ During the years 1992 to 1996, the number of SIDS cases (the predominant cause of infant deaths) reported to VAERS decreased by nearly 50% (US Food and Drug Administration, unpublished data, 1998). The overall decline in neonatal deaths most likely is due to improvements in prenatal and obstetric care and advances in neonatal intensive care for low-birth-weight infants^17-19; the decrease in SIDS cases reported to VAERS may reflect declining SIDS rates after the American Academy of Pediatrics' 1992 recommendation to put infants to sleep on their backs²⁰ and the 1994 "Back to Sleep" campaign.²¹ However, only an estimated 1% of SIDS cases occur in neonates.¹⁶ These indirect indices, despite their limited interpretability, do provide some reassurance that HepB vaccination is not causing a clear increase in unexplained neonatal or infant deaths.

As events reported to VAERS may be coincidental, detailed epidemiologic studies are needed for more definitive evaluation of potential causal relationships between vaccination and serious events or death.¹⁵

Accepted for publication May 6, 1999.

We thank Frederick Varricchio, MD, PhD; Peter Patriarca, MD; and Gina T. Mootrey, DO, MPH, for critical review of the manuscript, and Carol Krueger, RN, BSN, for technical support.

Editor's Note: This report should help allay the fears of the antivaccine groups; it should, but will it?—Catherine D. DeAngelis, MD

Reprints: Manette T. Niu, MD, Food and Drug Administration, Center for Biologic Evaluation and Research, Division of Biostatistics and Epidemiology, 1401 Rockville Pike, HFM-210, Rockville, MD 20852-1448 (e-mail: niu@cber.fda.gov).