Balancing Risks and Benefits: Primum non nocere Is Too Simplistic
COMMENTARY By:
Neal A. Halsey, MDInstitute for Vaccine Safety Johns Hopkins University Bloomberg School of Public HealthBaltimore, MD 21205
Lynn Goldman, MDDepartment of Environmental Health Sciences Johns Hopkins University Bloomberg School of Public HealthBaltimore, MD 21205
[This material contains technical language. PEDIATRICS Vol. 108 No. 2 August 2001, pp. 466-467.]
The commentary by Seal and Daum entitled "What Happened to Primum non nocere?"1 [“First, do no harm”] that appeared in the May 2001 issue of Pediatrics criticized the July 1999 recommendation of the American Academy of Pediatrics (AAP) and US Public Health Service (USPHS) to delay the birth dose of hepatitis B vaccine for infants born to hepatitis B surface antigen (HBsAg)-negative women to reduce infant exposure to thimerosal.2 The commentary contains incorrect statements and oversimplifies the complex process of balancing multiple risks and benefits when formulating vaccine policy as summarized in the excellent article by Feudtner and Marcuse3 in the same issue. Some professionals had difficulty understanding the need for the July 1999 recommendations because they didn't fully understand the risks from organomercury exposure and the amounts of ethylmercury present in vaccines. Several developments in the past 2 years have reinforced the wisdom of the recommendations made in July 1999.
Seal and Daum stated that methylmercury "might" be harmful to the developing fetal central nervous system. methylmercury is neurotoxic at all ages, and the developing fetal brain is at least 10-fold more sensitive than the adult brain.4
They also incorrectly stated that "no data existed that implicatedethylmercury" as a cause of neurotoxicity. As reviewed by Ball et al,5 ethylmercury from thimerosal has caused significant neurotoxicity in infants, children, and adults. Such data were available at the time of the 1999 recommendations and several references were included in the more complete AAP statement on this issue.6
On July 11, 2000, the Committee on the Toxicological Effects of Methylmercury of the National Research Council (NRC) proposed a resolution of the conflict regarding the appropriate reference dose (RfD) for
methylmercury exposure.7 The Committee proposed an RfD of 0.1 µg/kg/d, the same dose that had been used by the Environmental Protection Agency. The Committee used recently generated data from the Faroe Islands study as the basis for the RfD. The Committee estimated that 60 000 children are born each year in the United States with unsafe levels of methylmercury in their bodies. More recently, the Centers for Disease Control and Prevention found that levels of mercury in women of childbearing age in the United States are at least as high as, and perhaps higher than, the NRC estimates, which were based on modeled exposures.8
The adverse effects from intrauterine low-dose methylmercury exposure are not detected early in life and include alterations in attention, fine motor, and cognitive function that fit in the overall category of learning impairment. The NRC noted that all sources of mercury must be considered when determining the need for interventions. For infants born to women who
have high levels of methylmercury, the possible additive effects from subsequent exposure to ethylmercury (from thimerosal) are not known but are of potential concern, especially given that so many children start out life with mercury levels that exceed recommended guidelines. Moreover, the
potential exposures to ethylmercury from thimerosal alone were in excess of 0.1 µg/kg/d at the time that doses were administered, and such bolus administration would likely result in higher blood levels and subsequent transmission to the brain.9
Based on the NRC report, on January 12, 2001, the Food and Drug Administration (FDA) recommended that pregnant women, women of childbearing age, infants, and very young children not consume swordfish, shark,
tilefish, and mackerel because of unacceptably high levels of methylmercury.10 Swordfish contains an average of 1 part per million of methylmercury, or 28 µg/oz. If a meal is 3 oz, a 55- to 70-kg woman should not consume 84 µg of methylmercury at any point during pregnancy. How would vaccine advisory groups be perceived today if recommendations had not been made to reduce the potential for administration of up to 75 µg of ethylmercury to infants in the first 6 to 8 weeks of age? Most of the exposures to ethylmercury in vaccines were avoidable. The AAP and the USPHS had a responsibility to inform physicians and the public of new information about risks of exposure to mercury from all sources at levels once thought to be safe, and to provide guidance regarding the reduction of exposures from thimerosal.
Seal and Daum implied that exposures to thimerosal were known to be safe in July 1999; however, ethylmercury had not been studied in animals or humans from the standpoint of toxicity to the developing brain. In particular, there were no epidemiologic studies of intellectual development, learning disabilities, or other adverse effects that might be associated with ethylmercury exposure in utero or early in life. Preliminary studies from West Coast health maintenance organizations revealed dose-related evidence of increased risk of learning disabilities, delayed speech, and other abnormalities, but no such relationship was found in an East Coast population.11 Additional studies are being planned by the National Institutes of Health and the Centers for Disease Control and Prevention to determine if there were any toxic effects from thimerosal exposure.
Another misundertanding by Seal and Daum was that manufacturers and the FDA were well on their way to removing thimerosal from vaccines for infants in July 1999. Without strong advocacy from the AAP and USPHS, there would not have been the remarkably rapid removal of thimerosal from vaccines administered to children. As of February 2001, manufacturers were no longer
producing vaccines that contain thimerosal as a preservative for diphtheria, tetanus, and acellular pertussis vaccines combined (DTaP), Haemophilus influenzae, or hepatitis B vaccines that are used in infants.
One of us (N.A.H.) is the principal author of the 1992 AAP statement stablishing the recommendation for universal hepatitis B immunization of infants, and I am well aware of the important benefits of administering hepatitis B vaccine beginning at birth.12 The recommendation to delay the birth dose for low-risk infants in July 1999 was not taken lightly by the AAP or the USPHS.
Although initiating vaccination at birth provides a safety shield against errors in communication about maternal HBsAg status, we cannot depend on this backup because some providers will continue to administer the first dose of hepatitis B vaccine in combination with other vaccines beginning at 6 to 8 weeks of age for infants born to HBsAg-negative mothers. Extra efforts must be made to ensure screening of all women during pregnancy and to minimize errors in communication from obstetric providers to providers of care for newborns.
The process of making sound immunization policy requires careful balancing of many factors as eloquently summarized by Feudtner and Marcuse.3 To maintain public confidence in vaccines, we must ensure the public that safety is taken very seriously, and, when indicated, timely actions are taken to reduce potential risks. Vaccine manufacturers and the FDA should be applauded for the rapid changes in manufacturing and marketing practices that led to an elimination of the use of thimerosal as a preservative in routine vaccines for infants.
FOOTNOTES
Received for publication May 17, 2001; accepted Jun 15, 2001.
Address correspondence to Neal A. Halsey, MD, Johns Hopkins University Bloomberg School of Public Health, Institute for Vaccine Safety, 615 N Wolfe
St, Rm 5515, Baltimore, MD 21205. E-mail: nhalsey@jhsph.eduABBREVIATIONS
AAP, American Academy of Pediatrics; USPHS, US Public Health Service; HBsAg, hepatitis B surface antigen; NRC, National Research Council; RfD, reference
dose; FDA, Food and Drug Administration.REFERENCES available at
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ui
ds=11483816&dopt=Abstract <-- address ends here.
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