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ELECTRONIC ARTICLE: Thomas J. Moore, Sheila R. Weiss, Sigal Kaplan, and Carol J. Blaisdell Reported Adverse Drug Events in Infants and Children Under 2 Years of Age Pediatrics 2002; 110: e53 [Abstract] [Full text] [PDF]

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Adverse Events and Attributing Causality

David M Reith   (17 November 2002)

Safety First

John Fryer   (18 November 2002)

Adverse Events and Attributing Causality 17 November 2002
David M Reith, Paediatric Clinical Pharmacologist University of Otago Send letter to journal: Re: Adverse Events and Attributing Causality david.reith{at}stonebow.otago.ac.nz David M Reith	Dear Editor I have read with interest the paper by Moore et. al. in the current edition of the electronic version of Pediatrics. I am somewhat concerned at the attribution of causality of adverse events to drugs without considering confounders. The study of adverse events in children is fraught with methodological problems. These include lack of definition of the events (inclusion criteria), consideration of possible confounders (requiring measurement of confounders and complex statistical analysis) and measurment of denominators (number of patients treated with the drug). One major source of confounding that is not discussed in the paper is "confounding by indication". A number of the medications discussed in the paper, such as nitric oxide and indomethacin, are used in neonates that are critically ill and at greater risk of death or other serious adverse events. The indication for which the drug is prescribed confers this greater risk. Palivizimab is also used for the prevention of RSV bronchioloitis in neonates with chronic lung disease. This indication also confers greater risk. The inclusion criteria for the study are not described. What definition of adverse event was used? Was there any screening process at the FDA in order to include an event on the database? Was a review process used in order to determine the likelihood of the event being related to the drug.(Was the drug administered before the outcome? Did the event resolve when the drug was withdrawn? Did the event recur when the drug was again administered?) The objective of the paper is also at variance with the methodology. The study sets out to identify risks, but provides no denominator for the risks. it is therefore not surprising that no numerical estimates of risk, either absolute or relative, are reported in the paper. What is actually reported are numbers of adverse events, with no ability to calculate risks or to establish causality. Although the paper makes a significant contribution to the literature by describing the number of events, the conclusions that can be drawn are limited.
Safety First 18 November 2002
John Fryer, Chemist Send letter to journal: Re: Safety First mail_from_uk{at}btopenworld.com John Fryer	Sir, The article of Dr Moore et al is valuable testimony that chemical toxins do kill infants, and the younger the infants are, the more they are at risk of death from active toxic chemicals. Of course causality is always a difficulty. The once notorious drug, thalidomide is now a big seller again. The benefits outweigh the risks and the increased purity reduces the chance of adverse harm. It is right and proper to warn of harm when to do so may cause a doctor to say, lets wait until the infant is a few months older before trying that particular drug. Remember that most warnings (over 3/4) come from those that gain the most from the sales. They do not want drugs removed from the market if it is recognised that it is inappropriate for a 1 month or even a 1 year old infant. Sensible use can allow "harmful" drugs for an infant with no detoxifying enzymes to be a "useful" and effective drug in a child of two or three if used with care. Doctors and pharmacologists do not report enough adverse events (less than 1/4) and this is where deaths could be reduced from the already low levels from an extensive chemical research programme. Conversely could it be that some deaths not registered as from adverse drug reactions are in fact drug related or possibly even chemical toxin related from chemical compounds met in the environment but not recognised as being an exposure to the now dead infant? A cot death or SIDS infant with internal bleeding, bone fractures, external bruising and extensive congestion is the same autopsy as from a chemical nerve toxin such as VX. John Fryer Chemist