PEDIATRICS Vol. 107 No. 5 May 2001, pp. 1177-1178

COMMENTARY:
What Happened to Primum Non Nocere?

On July 7, 1999, the American Academy of Pediatrics (AAP) and the US Public Health Service (USPHS) jointly indicated that the first dose of hepatitis B vaccine (HBV), often given in the first days after birth, be deferred until infants are about 6 months of age in instances when the infant is born to a hepatitis B-seronegative mother.^1,2 The rationale for this changed recommendation was concern about the safety of thimerosal, a preservative used in many vaccine preparations since 1930. More than 30 vaccines on the market today (10/00) contain thimerosal, an ethyl mercury compound with a mercury content of 49.6%. Although the Food and Drug Administration (FDA) had reviewed thimerosal safety in 1976 and concluded that there were no harmful effects, the FDA Modernization Act, passed by Congress in 1997, mandated testing and analyzing of mercury-containing products. After passage of the FDA Modernization Act, interaction between the FDA and vaccine manufacturers was underway with the aim of encouraging manufacturers to remove thimerosal from all licensed vaccines, as is evidenced from the thorough assessment of the use of thimerosal in vaccine preparations that appears concurrently in this month's issue of Pediatrics.³

To many, the statement issued by the AAP and the USPHS on July 7, 1999, seemed precipitous and caught the medical, scientific, industrial, and regulatory communities by surprise. Although some studies suggested that low-level, frequent exposure to another mercury salt, methyl mercury, might be harmful to the developing fetal central nervous system,⁴ other research efforts provided conflicting data on this point⁵ and no data existed that implicated ethyl mercury, the mercury moiety found in thimerosal. Certainly, it was known that a massive acute mercury ingestion could lead to severe nephropathy or death but no convincing data have implicated thimerosal, given in the course of a pediatric immunization regimen offered in the first 2 years of life, in any clinically important side effect with the exception of infrequent hypersensitivity to this compound.

The decision to recommend delay of the first dose of HBV was made in the presumption that if this dose were given later, the thimerosal content of the vaccine would constitute a smaller mercury exposure on a per kilo basis, and, therefore, be of lower theoretical toxicity. It had previously been determined, for unrelated reasons, that small infants (those weighing <2000 g) were excluded from immunization until they were heavier.

Unfortunately, this change in the vaccine schedule had great potential for negative impact. At a recent workshop on thimerosal safety conducted at the National Institutes of Health in Bethesda, Maryland, in August 1999, it was evident that the recommendation to delay the first dose of HBV had caused confusion in the practicing community. At one institution, it was reported that 3 infants of hepatitis B-seropositive mothers had the initial neonatal dose of HBV deferred by individuals confused by the new AAP/USPHS guidelines.⁶ Furthermore, delay in the receipt of the first HBV dose in the nursery has been associated with delay in the receipt of the complete HBV series^7,8 and of other routine pediatric immunizations.⁷

At the time the AAP/USPHS recommendation was issued, the HBV was well-integrated into the immunization schedule. In inner-city Chicago between 1991 and 1995, the percent of children completing the 4:3:1 series who also completed the HBV series increased dramatically from 7% to 90%.⁷ Additionally, the importance of the birth dose was demonstrated in that children who received a first HBV dose at birth were more likely to receive their first diphtheria, tetanus, and pertussis vaccine dose on time (60.1% vs 36.4%; P < .001) and complete the 4:3:1 series by 19 months (49.8% vs 37.9%; P < .05). This finding was corroborated by a recent analysis of data from the 1998 National Immunization Survey conducted by the Centers for Disease Control and Prevention (CDC) that also demonstrated a higher rate of HBV series completion among children who received the first dose at birth. The CDC investigators found that children who received the first HBV dose within 7 days of birth were more likely to complete the HBV series on time compared with those who received the first dose at 8 to 41 days of age, or at 42 to 91days of age (96.3% vs 91.7% vs 77.3% for 0-7 days, 8-41 days, and 42-91 days; P < .001; 0-7 days vs either group). Thus, the AAP/USPHS recommended delay probably diminished the potential benefits of the birth dose that are relevant not only to HBV series completion, but also possibly to on-time receipt of other childhood vaccines.

It is also clear that withdrawal of thimerosal and other preservatives from pediatric vaccines will probably curtail all manufacture of multi-dose vaccine vials and make single-dose vials the packaging modality of choice for vaccines in the United States. This will certainly increase the cost of preparation of many vaccines as well as the cost of additional storage facility. There is, therefore, a potential to create difficulties for vaccine programs in the United States and especially in developing countries.

In an interim report (September 1999), the AAP indicated that "when sufficient supplies of [a hepatitis B vaccine that does not contain thimerosal] are available," it will be appropriate to resume neonatal hepatitis B immunization.² On September 13, 1999, one thimerosal-free preparation appropriate for birth dose became available and another preparation with thimerosal content decreased in excess of 96% has subsequently become available.^9,10 More directly, the AAP has recently appealed to its membership to resume HBV administration at birth.¹¹ Unfortunately, many hospitals and clinicians have not resumed routine administration of HBV at birth. An August-September 2000 survey of all Chicago area hospitals that provide obstetric services indicated that a substantial number of hospitals that routinely administered the HBV at birth before the AAP/USPHS recommendation have not resumed doing so since the thimerosal-free preparations became available (unpublished data). Similar observations have been made by investigators at the CDC and the University of Wisconsin Medical School.¹¹ Thus, although the rapidity by which many discontinued the HBV birth dose was remarkable, these data suggest that resumption of the birth dose will apparently be much less rapid.

What happened to primum non nocere? Hepatitis B remains a major health concern in the United States and throughout the world. An estimated 1 to 1.25 million Americans are infected with the hepatitis B virus and at least 18 000 children under 10 years of age were infected annually before the introduction of immunization.¹⁰ Did the evidence on thimerosal exposure warrant such a cacophonous disruption in the HBV immunization schedule? The hastiness in promulgating the AAP/USPHS recommendation to suspend the birth dose did not even allow sufficient time for the CDC's Advisory Committee on Immunization Practices to debate the prudence of the change.

The safety concerns of vaccine-related exposure to thimerosal and other mercury compounds should, of course, be addressed by carefully conducted epidemiologic studies. It makes sense, additionally, to eliminate mercury-containing preservatives from vaccine preparations as it becomes feasible in the near future.

However, it was probably unnecessary to recommend a delay in initiating the HBV series with such haste. A more reflective process would have included discussion of the pros and cons of postponing the routine birth dose. Ball et al³ sum up 70 years of experience and correctly conclude that there was no evidence of harm caused by doses of thimerosal found in vaccines. The potential for serious and ongoing impact of the AAP/USPHS recommendation on immunization rates and vaccination policies and practices raises the question of whether the principle of primum non nocere was disregarded in a rush to judgment. As a vaccine community, we must insist that vaccines, like all medical interventions, be as safe as they can possibly be. Just as important, our best delivery strategies for vaccines to all children ensure our best chance of diminishing the enormous burden of hepatitis B and all other vaccine-preventable diseases. In our haste, we must not forget that the agents causing these diseases constitute unacceptable threats to all our children.

John B. Seal, MA
Robert S. Daum, MD, CM
University of Chicago
Department of Pediatrics
Section of Pediatric Infectious Diseases
Chicago, IL 60637-1470

FOOTNOTES

Reprints not available.

Received for publication Oct 17, 2000; accepted Oct 17, 2000.

Address correspondence to Robert S. Daum, MD, University of Chicago, Department of Pediatrics, Section of Pediatric Infectious Disease, MC 6054, 5841 S Maryland Ave, Chicago, IL 60637-1470. E-mail: rsd2{at}midway.uchicago.edu.

ABBREVIATIONS

AAP, American Academy of Pediatrics; USPHS, US Public Health Service; HBV, hepatitis B vaccine; FDA, Food and Drug Administration; CDC, Centers for Disease Control and Prevention.

REFERENCES

1. American Academy of Pediatrics Joint statement of the American Academy of Pediatrics (AAP) and the United States Public Health Service (USPHS). Pediatrics 1999; 104:568-569 [Free Full Text]
2. American Academy of Pediatrics, Committee on Infectious Diseases and Committee on Environmental Health Thimerosal in vaccinesan interim report to clinicians. Pediatrics 1999; 104:570-574 [Free Full Text]
3. Ball LK, Ball R, Pratt RD An assessment of thimerosal use in childhood vaccines. Pediatrics. 2001; 107:000-000
4. Grandjean P, Budtz-Jorgensen E, White RF, Methylmercury exposure biomarkers as indicators of neurotoxicity in children aged 7 years. Am J Epidemiol 1999; 150:301-305 [Abstract/Free Full Text]
5. Davidson PW, Myers GJ, Cox C, Effects of prenatal and postnatal ethylmercury exposure from fish consumption on neurodevelopment: outcomes at 66 months of age in the Seychelles child development study. JAMA 1998; 8:701-707
6. Watson B. Comment. In: Transcript of the National Vaccine Advisory Committee Workshop on Thimerosal in Vaccines; August 12, 1999; Bethesda, MD
7. Lauderdale DS, Oram RJ, Goldstein KP, Daum RS Hepatitis B vaccination among children in inner-city public housing, 1991-1997. JAMA. 1999; 282:1725-1730 [Abstract/Free Full Text]
8. Hussain YR, Daniels D, Smith P, Coronado V, Rodewald L Association between administration of hepatitis B vaccine at birth and completion of the hepatitis B and 4:3:1:3 vaccine series. JAMA 2000; 284:978-983 [Abstract/Free Full Text]
9. CDC Notice to readers: availability of hepatitis B vaccine that does not contain thimerosal as a preservative. MMWR Morb Mortal Wkly Rep 1999; 48:780-782 [Medline]
10. CDC Notice to readers: update: expanded availability of thimerosal preservative-free hepatitis B vaccine. MMWR Morb Mortal Wkly Rep 1999; 49:642
11. Pickering LK. Resume Hep B immunization at birth: AAP. AAP News. 2000(Jun);16:1
12. Margolis H. Be as sure as you can be!: give babies hepatitis B vaccine at birth. Needle Tips Spring/Summer 2000. Available from: URL: http://www.immunize.org