Is death a “minimal risk”?

Yesterday’s post (click here) concerned a randomised trial from Botswana (accessible here), which was so poorly designed and executed by the researchers from Boston, that it failed to answer the question it ostensibly asked; which method of neonatal circumcision is best? But at least it provided data on the risks of newborn circumcision by supervised but inexperienced practitioners in Africa.

The abstract and table of complications list 34 adverse events in 30 out of 300 infants, of whom 295 were followed up, a complication rate of 10%. They included 5 cases of bleeding, no infections, 27 removals of too little skin, 14 adhesions or skin bridges, and 2 Plastibell rings migrating proximal to the corona. This latter complication can be catastrophic if not noticed, but if an expert removes it in time, is just a painful scare. One Plastibell ring had to be removed with a ring cutter (above). There were no cases of “removal of too much skin” although the definition of that was strict, namely “>1/2 shaft denuded”.

These complication rates are an order of magnitude higher than other reviews (Gee and Ansell click here; Weiss et al click here ) which report median rates of 0.2% and 1.5% respectively. Ascertainment and classification issues probably explain some of the difference, but the authors don’t even cite these references, or for that matter any other comparative statistics. Nor do they state what rate of complications they would have judged unsafe. They simply conclude “Neonatal male circumcision can be performed [safely] in Botswana […]”. The abstract omits the word safely but this must be a typo. The statement is meaningless without it, and the conclusion of the main paper has safely included.

Alert readers will note that the adverse events above add up to 48 rather than 34. They don’t add up in the paper either, another cause for concern.

What about deaths?

Read the whole paper. At the end of the third paragraph under the heading “study participants”, a section few would ever read, is this:

“Of the 5 infants with no follow-up after the immediate post procedure assessment, 2 moved out of the study area (mothers reported by phone that babies were well) and 3 died. Of these, 2 died of gastroenteritis and one died of suspected neonatal sepsis on his second day of life, with the death reviewed by the study Data Safety Monitoring Committee, Botswana Health Research and Development Committee and Brigham and Women’s Hospital Institutional Review Board [IRB] and not thought to be procedure related.”

Three deaths out of three hundred is a mortality of 1%.  That’s higher than the mortality from a triple coronary bypass in Boston! The deaths are not mentioned in the abstract, not included in the complication tables, and no further details are given. What age were the babies at death? What was the time relation between circumcision and death? The baby who died from neonatal sepsis was only two days old, so he must have died within 48 hours of the operation. What examinations and tests were done? Were autopsies performed? What did they show?

Instead we are essentially told: It’s OK. The IRBs that approved the research, shown a summary by the researchers, decided they were probably not procedure-related. The singular “death reviewed” also suggests the IRB only reviewed the suspected neonatal sepsis death. Did the researchers themselves judge the other two as not related?

Death of healthy term newborns is uncommon, even in Africa. In Botswana, the neonatal mortality rate (death in the first month of life) is 19 per 1000 (UNICEF 2010 click here), and most of those would be from prematurity, birth trauma or asphyxia, or congenital abnormality, all of which were exclusion criteria and should mostly be obvious at birth.

It can be difficult to determine cause of death in newborns, but neonatal death from gastroenteritis among breast-feeding babies, the majority in Africa, is not common. Death of a healthy baby from suspected sepsis within 48 hours of circumcision must be procedure-related until proven otherwise.

The deaths are mentioned again in one other section of the paper – not the abstract, which will be widely read, but towards the end of the discussion section. Here’s what the authors say:

“Finally, the issue of neonatal mortality must be addressed. […] Where diagnostic capabilities are limited, it can be difficult to make a definitive diagnosis as to the cause of a neonate’s death. Therefore, we would strongly recommend that if a provider detects any sign of neonatal illness, that the NMC [neonatal male circumcision] procedure be postponed until the neonate is deemed clinically well. Although NMC has been shown to be very safe in resource-rich settings and should be equally safe in resource-limited settings, it is important that providers perform NMC only when the risks of the procedure can be absolutely minimized, and that the public be educated about the safety of NMC so that neonatal deaths are not erroneously attributed to the procedure.”

In other words. It’s safe in rich countries, so it must be safe in poor ones. If poor babies die after circumcision, they must have died of something else. If any foolish mother blames her healthy baby’s death on the unnecessary operation performed 48 hours earlier, she needs educating.

The ethics of this trial

In Botswana, according to the authors, “neonatal male circumcision is rarely performed”. That means that, in the absence of this research, these babies would not have been circumcised. Here’s The Declaration of Helsinki on research in children.

For a potential research subject who is incompetent, the physician must seek informed consent from the legally authorized representative. These individuals must not be included in a research study that has no likelihood of benefit for them unless it is intended to promote the health of the population represented by the potential subject, the research cannot instead be performed with competent persons, and the research entails only minimal risk and minimal burden.

A 10% complication rate, two life-threatening Plastibell retentions, and three healthy newborns dead. Brigham and Women’s IRB could hardly have foreseen this, but they must be doing some soul searching. Did they approve research with “minimal risk and minimal burden”?

Jim Thornton

For other posts on adult circumcision trials click here, on neonatal risks here, and on ethics here.