Prebiotics, Probiotics and the microbiome

Posted on 2 October 2015 by Keith Barrington

A series of interesting recent articles:

Yang J, et al. Application of Laser Capture Microdissection and 16S rRNA Gene Polymerase Chain Reaction in the Analysis of Bacteria Colonizing the Intestinal Tissue of Neonates With Necrotizing Enterocolitis. Pediatr Infect Dis J. 2015;34(10):e279-89. These investigators examined intestinal samples resected during NEC surgery. Some controls with intestinal atresia were also studied. They were able to examine bacteria specifically related to the NEC tissue samples. They found several groups of bugs that were not present in the controls. Enterococcus sp. and Escherichia sp. were frequently found in both infants with NEC and controls, whereas Pseudomonas sp., Klebsiella sp., Acinetobacter sp., Clostridium sp., Ochrobactrum sp. and Arcobacter sp. were detected only in NEC tissue samples. In contrast to other studies they actually showed more bacterial diversity in the NEC babies than the controls, but that may be because of the nature of the controls, the controls had intestinal atresia, so they would all have to be very young, and the control tissue all came from the small intestine, whereas the NEC tissue was from large intestine, with some samples from the small.

Carl MA, et al. Sepsis from the gut: the enteric habitat of bacteria that cause late-onset neonatal bloodstream infections. Clinical infectious diseases. 2014;58(9):1211-8. This study report is difficult to interpret, which is a shame as it seems fascinating. The authors don’t say when they started collecting stools, nor how frequently, but they did find, in many infants who subsequently developed sepsis, that stools that had been collected beforehand were often colonized with organisms which seem identical to the organisms that they isolated from the blood. Those organisms included E coli (2) Serratia (2) and 3 cases of late onset sepsis caused by GBS (which is an unusually high proportion). A sepsis caused by Klebsiella and 2 MRSA were not preceded by intestinal colonization, and another baby had GBS colonization and was infected by a different GBS. Babies who did not develop sepsis did not have these particular organisms. The authors don’t say much about the microbiome of the non-septic babies.

How can we try and get our babies colonized with the good bugs?

Skin to skin contact with the baby’s mother, that’s how. Hendricks-Munoz KD, et al. Skin-to-Skin Care and the Development of the Preterm Infant Oral Microbiome. American journal of perinatology. 2015(EFirst). They showed associations between skin to skin care and development of the microbiome of the babies’ saliva, with “an accelerated pace of oral microbial repertoire maturity”.

Also don’t give them (or their mothers) antibiotics. Arboleya S, et al. Intestinal Microbiota Development in Preterm Neonates and Effect of Perinatal Antibiotics. The Journal of pediatrics. 2014(0). Because, the infants not exposed to antibiotics (either directly or via their mothers) had higher relative amounts of Comamonadaceae, Staphylococcaceae, and unclassified Bacilli . Infants not exposed to antibiotics also had significantly higher percentages of Bifidobacteriaceae, Streptococcaceae, unclassified Actinobacteria, and unclassified Lactobacillales and lower of Enterobacteriaceae than both groups of infants whose mothers received antibiotics.

Also give them human milk, its packed with goodies.

Underwood MA, et al. Human Milk Oligosaccharides in Premature Infants: Absorption, Excretion and Influence on the Intestinal Microbiota. Pediatr Res. 2015. Or at least it is if your mother is not a non-secretor. It seems that some mothers are homozygous for a gene that prevents them secreting fucosylated glycans into their breast milk. It also looks like this is quite common, 6 out of 1 mothers in this study were non-secretors, and this status had a big influence on the intestinal microbiome development. Also the sialylated oligosaccharides were very variable and some mothers produced milk that had oligosaccharides with little fucose or sialic acid.; those mothers’ babies had more dysbiosis than the others.

So choose your mother carefully if you are going to be born prematurely.

Barrett E, et al. The neonatal gut harbours distinct bifidobacterial strains. Archives of disease in childhood Fetal and neonatal edition. 2015. In this study from healthy full term infants they identified over 170 different bifidobacteria strains. Some of the babies were being breast fed, some receiving a formula without prebiotics, and some a formula with added prebiotics. In this case the prebiotics were galacto-oligosaccharides and poly-fructose. They showed that dietary prebiotic supplementation was associated with an increased prevalence of B. longum in infants in addition to increased strain diversity
Endo A, et al. Long-term monitoring of the human intestinal microbiota from the 2nd week to 13 years of age. Anaerobe. 2014;28(0):149-56. Ten subjects donated stool on multiple occasions during the first 13 years of their lives. They changed. Most of the change was in the first 12 months of life. The major changes were int eh relative abundance of the families of bugs, major species did not change dramatically. Probiotic supplementation in early life didn’t seem to have a lasting effect on the microbiome.

Hickey L, et al. Cross-colonization of infants with probiotic organisms in a neonatal unit. Journal of Hospital Infection. 2014;88(4):226-9. In this data from the ProPrems trial, only 3 of the 38 controls tested were cross-colonized with the probiotics they were testing. Which is lower than some other studies, maybe in Melbourne they are better at washing their hands.

And finally, two very nice review articles covering the issues.

Walker WA, Iyengar RS. Breast milk, microbiota, and intestinal immune homeostasis. Pediatr Res. 2015;77(1-2):220-8.

Pacheco AR, et al. The Impact of the Milk Glycobiome on the Neonate Gut Microbiota. Annual Review of Animal Biosciences. 2015;3(1):419-45.

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Neonatal updates

Posted on 2 October 2015 by Keith Barrington

Ong KK, et al. Postnatal growth in preterm infants and later health outcomes: a systematic review. Acta Paediatrica. 2015;104(10):974-86.

This interesting systematic review confirms that the observational studies are fairly consistent, improved growth, and improved head circumference growth are associated with improved outcomes. As for the interventional studies the evidence is much weaker. Of the small number of trials some were only performed after discharge from the NICU, a couple are quite old trials with control groups who received what would now be considered to be inadequate intakes.

I guess the problem now is that it would be difficult to justify a study where one group received recommended intakes, and the other received less nutrition. We know that if you get close to recommended intakes you can get close to intra-uterine growth rates, so randomizing babies to have sub-optimal growth would be problematic.

I think that all we can do is to keep trying to get to optimal growth, and keep an eye on our outcomes.

Jering K, et al. Parenteral Nutrition as an Unexpected and Preventable Source of Mercury Exposure in Preterm Infants. The Journal of pediatrics. 2015;166(6):1533-5. In other nutritional news, TPN can be source of evil as well as good. Aluminium, manganese, and now mercury can be found in it. Although the levels were low, there was detectable mercury in the TPN in this NICU, maybe from sharing equipment for preparation of TPN for adults.

Jary S, et al. Less severe cerebral palsy outcomes in infants treated with therapeutic hypothermia. Acta Paediatr. 2015. Some babies treated with therapeutic hypothermia still develop cerebral palsy. This cohort study shows that they are less severely affected than a historical comparison group before hypothermia.

Brock JW, et al. Bladder Function After Fetal Surgery for Myelomeningocele. Pediatrics. 2015.  Children from the MOMS trial of antenatal surgical closure for meningomyelocele were followed. The bladder function outcomes were all better in the antenatal surgery group. The proportion who were using intermittent catheterisation at 30 months of age was 38% vs 51%, which was not statistically significant, but is quite a substantial difference. The other outcomes showed significantly less trabeculation and less open bladder neck with antenatal surgery.

The authors give a summary of the other results of the MOMS trial.

 In summary, prenatal surgery was associated with less need for cerebrospinal fluid shunt at 12 months and a better composite score for mental development and motor function at 30 months. Prenatal surgery also revealed benefit in several key secondary outcomes including hindbrain herniation, ability to walk unaided, and a better score on the Bayley II Psychomotor Development Index. These results were tempered by an increase in preterm birth and the risk of uterine dehiscence in the prenatal surgery group

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How much phosphorus does a preterm baby need?

Posted on 1 October 2015 by Keith Barrington

Brener Dik PH, et al. Early hypophosphatemia in preterm infants receiving aggressive parenteral nutrition. J Perinatol. 2015;35(9):712-5. This group of neonatologists in Buenos Aires routinely give 3 g/kg/d of lipid, 3 to 3.5 g/kg/d of amino acids, 40 mg/kg/d of calcium gluconate and 20 mg/kg/d of glycerophosphate starting on day 1 to their babies under 1250 grams. By day 6 the babies were often hypercalcemic and hypophosphatemic, especially the IUGR babies. Babies who were more unwell in the first days of life were also more likely to have a low phosphate. 40 mg of calcium gluconate is slightly less than 0.1 mmol of calcium, 20 mg/kg/d of sodium glycerophosphate is about 0.1 mmol/kg/d of phosphorus.

Boubred F, et al. Extremely preterm infants who are small for gestational age have a high risk of early hypophosphatemia and hypokalemia. Acta Paediatr. 2015. In Sweden they give less nutrition on day 1; 2 g/kg/d of protein, 1 g/kg/d of lipid and 6 g of glucose, and then ramp it up over 4 days. On day 1 they give very little phosphorus, thereafter the babies were receiving about 0.6 mmol/kg/d of calcium, and between 0.5 and 0.6 mmol/kg/d of phosphorus. The IUGR babies were much more likely to develop low serum phosphates, and again the peak seems to be about day 4.

Moe K, et al. Administering different levels of parenteral phosphate and amino acids did not influence growth in extremely preterm infants. Acta Paediatr. 2015;104(9):894-9. In this observational study from Copenhagen they report 3 cohorts of preterm babies, in the middle cohort there was an error in their TPN software, so they gave much less phosphorus to the babies, especially during the first 3 days of life, when there was about 0.07 mmol/100 ml of TPN. The babies who got this regime had much more hypophosphatemia, especially if they were IUGR; the authors didn’t find a difference in growth during the first month of life.

Three other recent articles address these issues also :

Bonsante F, et al. Initial amino acid intake influences phosphorus and calcium homeostasis in preterm infants–it is time to change the composition of the early parenteral nutrition. PLoS One. 2013;8(8):e72880. This article (free access) reports a cohort study with varying protein intakes in preterm infants, the babies were all treated in the University hospital in Dijon, but, interestingly none of the authors’ current affiliations are with that hospital, they are from Réunion, Italy and Belgium. They show that the babies who received more amino acids had more hypophosphatemia, even though they also received more phosphorus. The high AA group received 21 mg/kg/d of phosphorus which is about 0.67 mmol/kg/d.

Christmann V, et al. Early postnatal calcium and phosphorus metabolism in preterm infants. Journal of pediatric gastroenterology and nutrition. 2014;58(4):398-403. In this study from Nijmegen babies received much more calcium and phosphorus, quickly getting up to 3 mmol/kg/d of calcium and 1.92 mmol/kg/d of phosphorus, by day 3. By day 4 to 5 many of their babies were hypophosphatemic, and hypercalcemic, at which time they had almost no phosphorus in the urine. So although they were getting lots of phosphorus, it looks like the ratio was not correct.

Pereira-da-Silva L, et al. Early High Calcium and Phosphorus Intake by Parenteral Nutrition Prevents Short-term Bone Strength Decline in Preterm Infants. Journal of Pediatric Gastroenterology & Nutrition. 2011;52(2):203-9. This is the only reference in today’s post that is actually an RCT, from Lisbon this time. About 40 preterm babies per group were randomized to different intakes of Calcium and Phosphorus in their TPN. They either got 45 mg/kg/d of calcium (1.1 mmol) with 36 mg/kg/d of phosphorus (1.16 mmol)  or 75 mg/kg/d of calcium (1.9 mmol) and 44 mg/kg/d of phosphorus (1.42 mmol), which usually started on day 1. The enteral feeds were not changed, so by the end of the first week there was little difference between the groups, and the macronutrient supply was also similar. From week 3 to week 6 there was a progressive reduction in bone strength in the low mineral group, and no reduction in the high group. The authors do not report the incidence of hypophosphatemia.

One thing this review has taught me is that the reporting of mineral intakes and metabolism in preterm infants is often really unclear, even when the study is concentrating on minerals. Could we all please report intakes and balances in mmol?

The other things that are clear, (and I must claim clairvoyance because our TPN standards here have said this for years) is that the requirements for calcium and phosphorus in the first few days of life are not the same as later on in the life of the preterm. The ratio between calcium and phosphorus should be higher for the first few (3-4?) days. Phosphorus is important for cellular metabolism as well as for bone growth. In those first few days we should aim to give enough phosphorus for those requirements, and to avoid hypophosphatemia. At the same time avoiding hypercalcemia and hypocalcemia are important. We might need to give as much as a 1:1 ratio of calcium to phosphorus just after birth, and then progressively switch to a ratio of about 1.6:1 (in mmol).

In fact the paper by Bonsante (a great name for a physician!) suggests something similar, they propose that the appropriate P intake (in mg/kg/d) might be calculated by dividing the Ca intake (also in mg/kg/d) by 2.15 and adding the amino acid intake (in g/kg/d) -1.3 multiplied by 9.8. If a baby is getting 2.5 g/kg/d of amino acids, and 40 mg (1 mmol)/kg/d of calcium this would work out to about 31 mg of phosphorus, which is almost exactly 1 mmol. If they are getting more protein, they would receive a bit more phosphorus, which is consistent with the data from those studies above.

Once the baby starts to grow consistently, then more phosphorus is laid down in bone, and we should probably aim for a ratio of nearer to 1.66 :1 (in mols), which is the ratio of calcium to phosphorus in new bone.

The recommendations of ESPGHAN published in 2005 (available free on-line) only discuss requirements during the growing phase of the preterm, and not during the first few days. They refer to a calcium phosphorus ratio of between 1.3:1 and 1.7:1 (in mols). The total intake they suggest is to vary according to weight gain, and to give 4 mmol of calcium for every 20 g of weight gain. Which I think is difficult to put into practice, as this suggests that you can only decide on how much calcium and phosphorus to give after the babies have already received the TPN and you see how well they grow!

The increased risk of hypophosphatemia in IUGR babies is similar to a “refeeding syndrome” although Bonsante’s group suggest not using that term, they suggest “placental interrupted feeding syndrome” instead, in order to note that you don’t have to be severely malnourished to develop these findings, they occur in AGA preterm also. Do IUGR babies, in the first days of life, need more phosphate? Do they need a higher ratio of phosphorus to calcium? Or both? I think some more observational studies with a higher P administration and an appropriate ratio might help us to know.

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Not neonatology: John Oliver and the refugee crisis

Posted on 1 October 2015 by Keith Barrington

If you have the time, and if you have a heart, watch this:

 

I hope Nageem gets to see this, and one day, maybe she will become an astronaut, who knows.

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Cochrane review featured on their website

Posted on 29 September 2015 by Keith Barrington

Our recently published Cochrane review of resuscitation training programs is now a featured review on their website.

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Photos of preterms

Posted on 29 September 2015 by Keith Barrington

A Québec photographer by the name of Red Méthot has posted a series of photographs of children and adults who were formerly preterm babies. Each holding a black and white photograph of themselves as a baby. Check it out.

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Treating seizures: bumetanide doesn’t seem to work

Posted on 29 September 2015 by Keith Barrington

One of the many frustrating things in neonatology is the treatment of convulsions.

As Gerry Boylan and Ronit Pressler wrote in the introductory section of the excellent issue of Seminars in Fetal and Neonatal Medicine which was all about neonatal seizures,

“Neonatal seizures continue to pose a challenge for clinicians worldwide because they are difficult to diagnose and treat and are associated with poor outcomes.” We have been using this statement, or something very similar, to introduce the topic of neonatal seizures when we give lectures or write papers for the last fifteen years and in that period of time, unfortunately, very little has changed in the management and outcome of neonatal seizures.

It is hard to know if the treatments we give are much use. Does phenobarbitol actually work? A truly evidence-based answer to that question would be “who the hell knows?” It might be a bit less useless than some other drugs, but I don’t think there is good evidence that it works at all. Clinical seizures stop in around 50% of babies after phenobarb, but maybe they would have stopped anyway. EEG documented, electrical seizures often don’t stop after phenobarb, and babies can even have non-convulsive status epilepticus after phenobarb.

Bumetanide is a loop diuretic that is an effective anticonvulsant in neonatal rats. Unfortunately it doesn’t seem to work in human neonates. Pressler RM, et al. Bumetanide for the treatment of seizures in newborn babies with hypoxic ischaemic encephalopathy (NEMO): an open-label, dose finding, and feasibility phase 1/2 trial. The Lancet Neurology. 2015;14(5):469-77. Although they only entered a small number of infants (14) into the study, they were unable to show efficacy, and they had a higher than expected rate of hearing loss.

I think this is great.

Not the result, of course, it would have been really great to find an effective, safe anticonvulsant. But I think it is great that this study was done, that the group was put together and the infrastructure created to get this very high quality investigation performed. Lets hope that the group will stay active, and will be able to evaluate other agents that are creeping into use without good studies. Like levetiracetam, that I can never spell correctly, (so I hope that the site I just copied that from was correct) or topiramate, that I would vote for as I can remember how to spell it.

 

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NRP Works!

Posted on 23 September 2015 by Keith Barrington

When the neonatal resuscitation program was first introduced I think many of us had mixed feelings. I was concerned that some of the initial recommendations were opinion-based rather than evidence-based  (and they weren’t all consistent with my opinions, which are the correct opinions). On the other hand to have a universal standard that could then progressively be improved upon was a good thing, and that has generally happened, NRP has become generally more and more evidence based, and has stimulated the production of more and more evidence. But does it actually work? Does training people in such a standardized, formal program help them to resuscitate better, and most importantly, does it then lead to more babies surviving, and fewer with serious complications.

A group of us, Gene Dempsey, Mohan Pammi, Tony Ryan and I, have just published a Cochrane review addressing that question. The primary question of interest was whether training programs lead to lower perinatal mortality, and lower neonatal morbidity. The secondary questions were to examine how the training is performed; whether boosters or videos or apps or teamwork training, for example, might improve skills and knowledge acquisition and retention, or performance or clinical outcomes.

We found the following: (SFNRT is the rather ponderous acronym I came up with to avoid saying NRP, it stands for standardized formal neonatal resuscitation training; we didn’t limit the searches to just the NRP program, but any similar training approach)

We identified three community-based cluster-randomised trials in developing countries comparing SFNRT with basic resuscitation training (Early Newborn Care). In this setting, there was moderate quality evidence that SFNRT decreased early neonatal mortality (typical RR 0.88, 95% CI 0.78 to 1.00; 3 studies, 66,162 neonates) and when analysed by the approximate analysis method (typical RR 0.85, 95% CI 0.75 to 0.96; RD -0.0044, 95% CI -0.0082 to -0.0006; NNTB 227, 95% CI 122 to 1667). Low quality evidence from one trial showed that SFNRT may decrease 28-day mortality (typical RR 0.55, 95% CI 0.33 to 0.91) but the effect on late neonatal mortality was more uncertain (typical RR 0.47, 95% CI 0.20 to 1.11). None of our a priori defined neonatal morbidities were reported. We did not identify any randomised studies in the developed world.

There were some problems with the analysis, because cluster randomized trials do not always report the ICC, the intra-cluster correlation coefficient, which you need to do all the analyses, the Cochrane collaboration has some ways around this, but it introduces a bit of extra uncertainty into the results.

We identified two trials that compared SFNRT with team training to SFNRT. Teamwork training of physician trainees with simulation may increase any teamwork behaviour (assessed by frequency) (MD 2.41, 95% CI 1.72 to 3.11) and decrease resuscitation duration (MD -149.54, 95% CI -214.73 to -84.34) but may lead to little or no difference in Neonatal Resuscitation Program (NRP) scores (MD 1.40, 95% CI -2.02 to 4.82; 98 participants, low quality evidence).

These two trials were from the same group, and used the same scale of team activity so we could meta-analyze them. The teamwork training improved team behaviour, but didn’t lead to improve scores on the NRP checklist (which didn’t specifically score team behaviours).

We identified two trials that compared SFNRT with booster courses to SFNRT. It is uncertain whether booster courses improve retention of resuscitation knowledge (84 participants, very low quality evidence) but may improve procedural and behavioural skills (40 participants, very low quality evidence).

We identified two trials on decision support tools, one on a cognitive aid that did not change resuscitation scores and the other on an electronic decision support tool that improved the frequency of correct decision making on positive pressure ventilation, cardiac compressions and frequency of fraction of inspired oxygen (FiO2) adjustments (97 participants, very low quality evidence).

The cognitive aid was a poster in the delivery room, it didn’t make a difference mostly because the participants ignored it. The electronic tool is a tablet “app” which when plugged in to the appropriate sensors tells you what to do next to follow the NRP algorithms.

The NNTB that we calculated in those results, means that for every 227 deliveries occurring in a setting where healthcare workers have been trained in SFNRT programs, there is one fewer neonatal death. Which is huge, and very cost effective. SNFRT is not very expensive, but it’s not free either. The equipment, staff time, staff transportation, outreach and so on all have to come from health care budgets which in many parts of the world are severely under pressure. If you only have 10 dollars per year per member of the population to spend (like in Uganda), then you have to choose wisely. Or you could cut down on military spending and corruption, but that is another issue. High fidelity simulations do not seem to have much greater effect than standard training with a Baby Anne manikin and enthusiastic teachers, so the extra expense can be avoided in low and middle income countries.

Spending on SFNRT programs is effective, reduces death, and does not increase disability. It should be a priority for low income countries.

 

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Many unethical pain studies in newborns

Posted on 23 September 2015 by Keith Barrington

Carlo Bellieni and Celeste Johnston (Conflict of Interest flag, I have collaborated with both of them) have just reviewed a couple of recent years research of analgesic interventions in the newborn. Of 46 randomized studies of painful procedures, 70% had an untreated control group, either placebo or without analgesic intervention.

I have ranted about this before: Pain research in the newborn, what is ethical?, well actually having re-read that post it isn’t really a rant, but a lucid, well-considered and well-argued plea to stop randomizing babies to pain.

The new review shows that the article that I was referring to was not a ‘one-off’ but a persistent pattern. A persistent pattern of unethical research. The discussion section ends like this;

we encourage researchers to perform further studies on new pain treatments by comparing them with with those that have already been validated. we are urging parents and ethics review boards to refuse studies that do not provide acceptable analgesia to all babies enrolled in studies… In addition we are calling on medical journals to refuse to publish studies that deny pain relief to control infants undergoing painful procedures.

I think that editorial guidelines of paediatric journals should be revised to include a clear statement that untreated control groups in studies of painful interventions are not ethical and that articles describing studies with such groups will not be accepted.

I only have one disagreement with the article, and it is the statement that for eye examinations there is ‘no validated treatment that exists’. In fact there are interventions which can significantly reduce pain responses, it is true that they are not perfect, and babies still experience discomfort. But there is a systematic review of local anesthetic drops which shows effect (Dempsey E, McCreery K. Local anaesthetic eye drops for prevention of pain in preterm infants undergoing screening for retinopathy of prematurity. Cochrane database of systematic reviews (Online). 2011;9(9):CD007645).

And multi-modal interventions do have some benefit also (O’Sullivan A, et al. Sweeten, soother and swaddle for retinopathy of prematurity screening: a randomised placebo controlled trial. Archives of Disease in Childhood – Fetal and Neonatal Edition. 2010;95(6):F419-F22.)

The data on sucrose alone are somewhat variable, but as many of the studies are small it is not surprising that some do not show an effect,but many do (such as : Boyle EM, et al. Sucrose and non-nutritive sucking for the relief of pain in screening for retinopathy of prematurity: a randomised controlled trial. Arch Dis Child Fetal Neonatal Ed. 2006;91(3):F166-8).

I think an RCT of pain relief for eye examination that did not incorporate most of these items would also be unethical. A control group should have sucrose, a soother, swaddling, and local anesthetic. The efficacy of this combination is not complete, so a randomized addition of other interventions would be a valuable addition to the literature and to the comfort of our babies.

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An astounding betrayal

Posted on 21 September 2015 by Keith Barrington

Some of us may have heard of the problems with the data concerning SSRIs (a commonly used class of antidepressants) and, in particular, young people. It appears that drug companies hid and distorted data from controlled trials, in order to make it appear that the data were positive, and hide the fact that there appeared to be an increase in suicides during the initial phase, at least, of treatment in younger patients.

One study in particular stands out, study 329. This study stands out because it was a very high profile study, of which many questions have been asked, but also because Glaxo Smith Kline eventually agreed to allow complete access to all of the original patient data.

That access has resulted in a new publication in the BMJ, which shows that, in contrast to the original publication, if the data are analyzed as the original protocol specified, and if all the adverse outcome data were appropriately collated, then there was no benefit from the use of the agent in question, paroxetine. Indeed the results show no benefit but an increase in serious adverse events, including suicide attempts.

The original publication reported that the outcomes were positive, but it seems they chose outcomes that appeared positive that were never specified in any of the protocol versions. There was also incomplete, very incomplete, summation of adverse outcomes, leading to erroneous claims of safety.

How could all of this happen? Well the data were all controlled by the company (a predecessor of GSK) who organized the analyses, and employed a ghost writer to draft the first version of the paper. The physicians who eventually were listed as the authors edited the introduction and discussion (making what were mostly “cosmetic” changes). There is a fascinating case study (in a journal I wasn’t aware of called “accountability in research”) of the way this article made it to submission and publication, which contains the following “gems”

 The first draft contained a significant distortion of outcome whereby the list of primary outcomes was expanded from two to eight, four of which separated paroxetine from placebo. This change gave plausibility to the claim that “paroxetine is effective.”

And

(‘Laden’ is the second name of the ghost writer)

Our analysis of the progression of drafts shows that there are few substantial differences between the final published article and the first draft prepared by Laden (Jureidini, 2007). Large portions of the introduction and discussion were re-written, but these changes add little to the substance of the article, and most other changes are little more than copy editing. Throughout the many drafts of this article, the conclusion persists that paroxetine is safe and effective for adolescent depression despite the fact that it failed on both primary and most secondary outcome measures.

That review of the initial publication process also noted that the serious adverse events were downplayed. The new re-analysis of all the original data shows that they weren’t even counted correctly; there were several instances of breaking the blinding of the medication, and coding of the SAE’s varied from one case to another, even when similar events occurred. The evaluation of whether the SAE was related to the medication was sometimes made after the blind had been broken. So, for example, one case of an SAE was ascribed to the study intervention after it was known that the patient was in the placebo arm.

Some of the reported SAE’s were never even transcribed into the study data sheets.

The authors of this re-analysis also note the difficulties with actually performing it, they were allowed a single remote desktop to access files, were not permitted to print anything, and had huge difficulties getting it done as a result. After many thousands of hours of work, I think we can all be grateful that this re-analysis, which could be considered a case study in how to re-analyze publicly available datasets, and also an object lesson in why such datasets should be fully available to the appropriate persons, and not just the extremely limiting access that these authors had, that this re-analysis was as scrupulously done as this.

If anything points out the desperate need for the Alltrials campaign to be successful, it is this publication. How many other articles have been distorted by the sponsors to make their drug seem effective and safe, when in fact they are neither?

In a commentary in the BMJ, accompanying the publication, Peter Doshi is scathing about the response of the journal where the article was originally published, the professional association responsible for the journal, and the university where the first author (that’s the person who is listed as first author, not the person who wrote the article!) works; where he is still head of psychiatry.

The article is still in the literature, still with the same conclusions of efficacy and safety. GSK, you might remember, were sued 3 billion dollars for promoting paroxetine beyond the approved indications, including promotion for adolescents, partly based on this article.

The original article is an astounding betrayal. The authors betrayed the individuals and families who consented, the public in general, including all the subsequent adolescents who have been treated with paroxetine, and the whole world. The big phamaceutical companies are hugely profitable, but they also make huge investments to bring new molecules to market, which subjects them to enormous pressures, to make results of clinical research seem as positive as possible, and minimize the negatives. When the ‘positives’ and ‘negatives’ are the health of patients, the implications are profound. Far more so than for a new children’s toy, or new scent for a perfume range; but the same corporate thinking motivates their actions.

We cannot escape corporate funding for trials of new therapeutic agents, we have to put in place mechanisms to ensure that those trials are well designed, adequately analyzed, and appropriately reported.

Posted in Not neonatology | 3 Comments