Evidence-based neonatology, or science based neonatology?

To many followers of this blog, the title may seem a little strange; is there any difference? Surely science underlies all of our field, and testing treatments in adequately designed trials leads to progressive improvements through the application of evidence-based therapies.

In general, the evidence-based therapies that we have in our field have been based on scientific understanding, basic biochemistry, developmental biology, and so forth, which has led to the development of therapies (I am thinking of surfactant replacement as the shining example) which have then been proven effective in clinical trials. This particular therapy was developed from observations of the role of surfactant in the lung, evidence that infants with HMD lack surfactant, investigations of the various components and development of stable mixtures, which were then tested in animal models, and finally in large multicentre RCTs and showed efficacy. The vital importance of EBM is shown by some counter examples; as one example, the use of immunoglobulins as a treatment of neonatal sepsis had a reasonable scientific basis, with preterm babies have very low Ig concentrations, and knowing that immunoglobulin deficient older children were at very high risk from sepsis. However, the pivotal trial of IgG supplementation was negative.

The problem with evidence-based neonatology, without a science-based foundation, is that interventions without any prior plausibility can be tested, just because someone thinks that maybe it could be a good idea, but without a reasonable scientific basis. Because there has not been an RCT it could be considered that there is no evidence to decide whether an intervention is effective or not. This can lead to the ridiculous situation of performing RCTs of interventions with as much scientific plausibility as a Harry Potter spell. By which I mean homeopathy, acupuncture, osteopathic or chiropractic manipulations, aromatherapy, and any other quackery that you can think of.

Evidence-based medicine has sometimes become divorced from the scientific baseline that should underlie it all. When an intervention is tested that has no real prior plausibility, there is always a risk of a spurious positive result just from random effects. Add to that the fact that, very often, investigations of unscientific interventions are often designed and performed by “true believers”, leading to methodology and interpretation biases. Positive trials can then be interpreted as proving that an intervention which cannot possibly work has actually been shown to be effective.

There are a few recent examples in neonatology of unscientific nonsensical interventions being published as showing that they are effective. Fortunately, I don’t think that applies to homeopathy, at least, I just did a search of Pubmed for randomized trial of homeopathy in the newborn and I found nothing from an NICU, although there were a couple of trials in older children. For anyone not aware, homeopathy requires the administration of enormously diluted substances, which, in their undiluted state, reproduce the symptoms of the disease being treated. Dilutions are usually so extreme that most often, when someone takes a homeopathic medication, they are not getting even a single molecule of the original substance. According to the nonsensical theories that underlie homeopathy this makes them more effective, the more diluted they are, the stronger the effect. Sometimes the medications that are actually sold as being homeopathic remedies do, in reality, contain active ingredients, which may be toxic. Death from atropine contamination of a supposed homeopathic teething remedy has been reported, and hundreds of adverse effects have been noted, which are, of course, not because truly homeopathic remedies are toxic, they are not, they are just water, but it is because some of what are sold as homeopathic remedies actually contain toxins.

Acupuncture is just as unscientific as homeopathy, being based on ideas about a life force (Qi, a very useful word if you are playing Scrabble, but not a scientific concept) which is conducted in meridians. Neither Qi nor the meridians actually exist. There are many RCTs of acupuncture in the literature, and objective evaluations have shown that the better the controls the less the efficacy of acupuncture, for any outcome. Controlled trials have shown that it doesn’t matter where you put the needles, or even if the needles actually puncture the skin. Acupuncture is most often studied as an analgesic, and is sometimes “enhanced” by passing an electrical current between the needles, this is often touted as being a variety of acupuncture, but is actually a variety of TENS. In other words, acupuncture is just a theatrical placebo, and one we should not subject our patients to, it has zero prior plausibility, given the lack of any scientific evidence for the existence of Qi, or the existence of meridians.

It is indeed unfortunate that otherwise sensible physicians can be misled into performing research studies of this nonsense, it becomes a despicable failure when they are performing painful procedures on babies and not giving them appropriate analgesia. The supposed justification for this “research” is that acupuncture is used a lot, even in children, and some studies seem to show analgesia. But, as I already mentioned, the apparent effect of acupuncture on pain gradually becomes less as the studies are better designed.

The most recent investigation of quackupuncture that I saw from an NICU was an investigation of what is called laser acupuncture! (Stadler J, et al. Laser acupuncture versus oral glucose administration for pain prevention in term neonates. Acupunct Med. 2021). That is, shining a light on the skin of the baby, which was supposed to be worth investigating as analgesia prior to heel pokes. But wait, they used the quackupuncture point LI4, which is well known to be the magical non-existent point, “Large Intestine 4” so what could go wrong? What went wrong of course was that the intervention was not blinded (although the person evaluating the videos of the babies responses to the heel poke was supposedly masked) the control intervention was “30% glucose solution over a period of 30 seconds”, but no dose is noted, there is no mention of soother or swaddling or skin-to-skin contact, all of which are effective in markedly reducing pain responses to heel pokes. The PIPP scores increased to a median of 12 in each group, which shows there was inadequate analgesia in both groups. PIPP scores over 7 imply that the pain is substantial, and good analgesic approaches, with swaddling and sucrose and a soother, or with kangaroo care, for example, will usually maintain PIPP scores less than 8, in this study for example, with a higher dose of 0.5 mL of sucrose the median PIPP score was 5 during the procedure, compared to 7 with the lower dose of 0.2 mL. In another study the effects of kangaroo care and sucrose were shown to be equivalent, and the median PIPP score hardly changed across the study, with a median of around 6.

The result of the Stadler et al trial, therefore, showed that acupuncture was basically useless, and so was the control intervention. Of course, as they usually will, the believers in acupuncture try to find some signal in the noise to pretend that maybe shining a light on the babies skin did indeed have an analgesic effect, and they come up with the observation that the heart rate slowed down faster after the laser light “therapy” than after inadequate glucose therapy.

What about ear acupuncture? Well, just as ridiculous as the above trial, is an investigation of sticking magnets to the babies ear, which is touted as being a safer form of TCM (Traditional Chinese Medicine). (Gan KML, et al. Magnetic Non-invasive Auricular Acupuncture During Eye-Exam for Retinopathy of Prematurity in Preterm Infants: A Multicentre Randomized Controlled Trial. Front Pediatr. 2020) Ear acupuncture actually has nothing to do with TCM, it was invented in 1957 by a French physician, Paul Nogier, who thought that the folds in the outer ear resembled a fetus, so he thought that sticking a needle in the stomach of the “fetus” would be good for stomachache. Since then, other points have been made up, which are supposed to represent specific parts of the brain. Because, I guess, people shied away from sticking needles in the ears of the babies, they decided to glue tiny magnets to them instead, the justification given for this, in a previous article, was that magnetic fields have been shown to have biologic effects. Which is true, but the review article they gave as a reference refers to fields up to 8 Tesla! Which is about 8 times more than an MRI and about a trillion times more than the tiny beads that they stuck on the babies ears. And even if there were some measurable effect on blood flow in the skin under the magnetic bead (for example), so what?

The beads were actually moved around the ear, in a procedure laughably called “Battlefield acupuncture”! Supposedly, the name is derived from use in the battlefield of medical practice, and the myth has grown up that it is used by quackupuncturists for acute pain from injuries. The magnetic beads are moved around the ear sequentially, to points which have been invented to represent: (1) Cingulate Gyrus, (2) Thalamus, (3) Shenmen, (4) Cranial Nerve-5 (Ophthalmic branch). This reminds me of witchcraft, casting spells using nonsensical words designed to impress. In this particular case the magic spell was invented in 2001, and the evidence for its efficacy, according to the practitioner that invented it, is that people attending the inventor’s course give him laudatory comments! Who needs science when you have evidence like that! I wonder if, like magic spells, if the beads are moved around in the wrong order, or backwards, then that reverses the effects and may cause mayhem!

Why anyone with a training in medical science would give any credence to this nonsense is beyond me, still less to organise a multi-centre trial of sticking magnets to the ear for pain relief during retinopathy screening. Nevertheless, that happened, and the trivial differences in PIPP scores between the groups, (which are presented as mean and SD, even though this is an ordinal scale) were means of 13.5 and 11.9, with SD of around 4 in each group. The results are actually presented with an incomprehensible table which includes the value of something called the “intercept” and seems to show that the baseline scores were also different between groups, by 0.7.

But doesn’t the “significant” p-value mean that the authors showed an effect, you might ask? Let us for the moment assume (and it is a very big assumption) that the analysis of the videos was indeed completely masked to study group. As mentioned above, the people doing the trial are clearly “true believers”, so it would be completely unsurprising if there had been some “leakage” of information, with some degree of partial unblinding. The person who applied the stickers was unmasked, which scould easily have some impact on the proceedings.

The prior probability of the analgesic efficacy of moving tiny sticky magnets around various made-up spots in the ear is about as close to 0 as it is possible to be; but let us be generous and propose that there is a 0.01% chance that sticking tiny magnets to the ears of preterm babies could affect pain responses, by some undescribed mechanism, dependent on unknown biochemical, cellular, and anatomical pathways. In that case, using Bayesian reasoning, even with a p-value of 0.03, it remains incredibly unlikely that the finding represents a real phenomenon.

I think it is shameful that this study was performed. It is shameful that the ethics review committees of these hospitals approved this study, the Royal Hospital for Women, Sydney, the Royal Alexandra Hospital, Edmonton, and the University Malaya Medical Center, Kuala Lumpur, have a lot to answer for, research is only ethically acceptable if it is scientifically valid. Wasting the resources involved in performing this study, and impacting the lives of the families who consented is shameful. Frontiers in Pediatrics should be ashamed to have published it.

Adequate pain relief for retinopathy screening is a major problem for our patients, and we really need to investigate science-based methods to reduce they distress they experience.

About Keith Barrington

I am a neonatologist and clinical researcher at Sainte Justine University Health Center in Montréal
This entry was posted in Neonatal Research and tagged , . Bookmark the permalink.

2 Responses to Evidence-based neonatology, or science based neonatology?

  1. René Pérez says:

    You are absolutely right, one of my teachers continually told me « a charlatan is not someone who offers magic cures at a fair, but someone who boasts of being a scientist and does not use the scientific method in his daily practice »

  2. Agree. There is little room for scientifically improved products, such as immunoglobulins with efficacy against pathogens that affect newborn infants. Once a product has been shown to be “ineffective”, we close our eyes thenafter for subsequent efforts.

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