Balancing Risks and Benefits: Primum non nocere Is Too Simplistic

COMMENTARY By:
Neal A. Halsey, MD
Institute for Vaccine Safety
Johns Hopkins University Bloomberg School of Public Health
Baltimore, MD 21205
Lynn Goldman, MD
Department of Environmental Health Sciences
Johns Hopkins University Bloomberg School of Public Health
Baltimore, 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 implicated
ethylmercury” 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
establishing 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: [email protected]
ABBREVIATIONS
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_uids=11483816&dopt=Abstract 

 

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