One Babe at a Time: ART and a multiplicity of multiples

Posted on 7 December 2012 by Keith Barrington

I have just written a review article which is in the submission revision process for a journal that shall remain nameless (I don’t know why, but that is the tradition, you don’t say which journal, until it gets accepted) It has been peer reviewed, and for the first time, I can truly say something that I often write in reviewer response letters, but which often isn’t really true, the reviewer really helped to improve the manuscript.

The subject is the pediatric implications of Assisted Reproductive Technologies. I reviewed many of the published articles about what ART does to babies and children. Mostly of course the children turn out fine, and many happy families have been created (or enlarged) by ART. On the other hand there are significant increases in several adverse outcomes: the main one being prematurity, which is largely because of twins, and triplets and more. Twins after ART are almost entirely due to the transfer of multiple embryos into the uterus after successful fertilization in the ‘test-tube’. There are a few twins even when a single embryo is transferred, as the embryo can split in two after transfer. (Single babies also have more complications after ART, but you will have to wait for the paper to have all the details, or do your own lit search.)

Annie Janvier and I started to get interested in this issue when we were in our previous positions, we experienced some very sad situations, with women who were already at very high risk of preterm delivery, for example, having 3 embryos transferred, becoming pregnant with twins and delivering twins at 24 weeks with multiple complications. There were many examples of complications that would have been avoided if a single embryo had been transferred. We wrote a paper in which we calculated the extra human, societal and financial costs of the irresponsible transfer of many embryos.

Since then in Quebec the government, after a consultation process in which Annie was heavily involved, decided to cover the costs of IVF for most women who wish to have the procedure, and accompanied the funding with a restriction on the numbers of embryos that can be transferred. Elective single embryo transfers immediately went from 6% to over 60%. There are some exceptions which allow 2 embryos to be transferred, based on maternal age and previous failed cycles, so we still had 30% with 2 embryos transferred, and a very small number with more than 2 (less than 1%). This has led to the most dramatic and fastest drop in multiple deliveries from ART anywhere. There was an instantaneous drop from 30% of IVF pregnancies being multiples, to 5% for the 1st 6 months of the program. This was accompanied by a modest increase in the total number of cycles. Further regulations changes are likely to completely ban more than 2 embryo transfers. Similar things have happened in the past in Sweden and in Belgium, but it took a little longer for them to achieve their goals. Until recently one of the countries with the highest proportion of multiple embryo transfers and multiple deliveries was Turkey, they had the highest number of triplet deliveries anywhere in the worldIVF triplets

This is a bubble plot showing the percentage of IVF transfers that were 3 or more embryos against the proportion of the pregnancies that result that are triplets. The area of each bubble is proportional to the number of transfers performed (Europe for example had 312,000 procedures and Australia/NZ had 11000). The solid bubbles are the individual countries of Europe, and the open circles are Europe, USA and Australia New Zealand. The data are from the latest publications of various registries: the European is from procedures done in 2008, the USA is from 2009, and the Australian 2010. You can see that the Australian and New Zealand data show almost no 3 embryo transfers and very few triplets (they also have only 8% twins). In 2008 Turkey had a lot of both, in contrast Sweden there were no transfers of more than 2 embryos, but they had one set of triplets, they are the extreme lower left filled circle.

I have a similar graph for twins, but that is part of the manuscript being considered right now by XXXXXX, oops, almost gave the journal name away!

In Turkey they were very worried about this, so in 2010 they passed legislation to limit embryos, using rules which are similar to the Belgium and Quebec rules. (Guzoglu N, Kanmaz HG, Dilli D, Uras N, Erdeve O, Dilmen U: The impact of the new turkish regulation, imposing single embryo transfer after assisted reproduction technology, on neonatal intensive care unit utilization: A single center experience. Human Reproduction 2012, 27(8):2384-2388) they have already seen a big improvement, with many fewer multiples.

One of the problems has been that pediatricians and neonatologists, who look after the end result of ART, have not been active in the debates about whether and how to control and limit the practices in many countries. When we get involved, as Annie Janvier and the Society of Neonatologists did in Quebec, we can have an impact.

In terms of total numbers of babies affected, the USA has the biggest problem at present. They have very very few single embryo transfers, 30% of the pregnancies are twins or more; of about 100000 procedures there were 38000 deliveries of which 1.6% were triplets, that is 1800 babies unnecessarily put at very high risk. The twins numerically are much more frequent, 22,800 twins born, of whom more than half will be preterm, many being extremely preterm. The current lack of regulation in the USA is putting many babies lives and futures at risk, as in several other countries.

Some of the regulations regarding IVF and embryo transfers are completely senseless. In Italy all embryos have to be transferred by law. Embryo freezing or disposal is not permitted, but at least there is a limit of 3 embryos that are allowed to be created. What this means is that the large bubble just below and to the left of Turkey is Italy, nearly 50% of the transfers are 3 embryos, and they have a triplet frequency of 2.7%. This legislation, which is supposed to protect the ‘rights’ of the embryos, actually puts them at risk, increasing the numbers of twins and triplets, and increasing complications and perinatal mortality.

We need to stop being passive in this debate. It is our patients that are suffering from what is an largely avoidable epidemic of multiple births.

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Weekly Updates #16

Posted on 1 December 2012 by Keith Barrington

Sarajuuri A, Jokinen E, Mildh L, Tujulin A-M, Mattila I, Valanne L, Lönnqvist T: Neurodevelopmental burden at age 5 years in patients with univentricular heart. Pediatrics 2012. This study followed infants with univentricular lesions, both hypoplastic left heart syndrome and other single ventricles. about a quarter had major neurodevelopmental dysfunction in both groups, full-scale IQ was lower in patients with HLHS and with single ventricle than controls. One thing I found very interesting were the actual numbers, median IQ was 97 for HLHS, 112 for single ventricle and 121 for the controls. 121! I guess the Finns are very smart people.

Shin M, Kucik JE, Siffel C, Lu C, Shaw GM, Canfield MA, Correa A: Improved survival among children with spina bifida in the united states. The Journal of Pediatrics 2012, 161(6):1132-1137.e1133. Survival to one year of age of infants born with spina bifida continues to improve in the USA, up to 93% overall, there are unexplained ethnic differences in survival (it is over 96% in white families), and survival is lower if the baby also has a serious congenital heart disease, or a high lesion, cervical or thoracic, or if born with very low birth weight.

Lee SK, Ye XY, Singhal N, De La Rue S, Lodha A, Shah PS, for The Canadian Neonatal N: Higher altitude and risk of bronchopulmonary dysplasia among preterm infants. Amer J Perinatol 2012(EFirst). NICUs that were over 400m altitude had more babies with BPD after correcting for all the usual things than NICUs at less than 400m. I think the reliance on diagnosing BPD based on oxygen need is probably the issue here: you may also need more ventilation and O2 and therefore have more lung damage to keep the saturations at usual acceptable levels during the first days of life, but you will then also need some more oxygen to keep the alveolar PO2 at the same level as if you were at sea level. Don’t know what to do about this though, we should all move to the coast.

Natalucci G, Becker J, Becher K, Bickle GM, Landolt MA, Bucher HU. Self-perceived health status and mental health outcomes in young adults born with less than 1000 g. Acta Paediatrica. 2012 As Annie (Janvier) has said many times, we have thousands of publications detailing how screwed up preterm infants are (that is literally tue, there are thousands). In contrast very few studies of how to help them. This balance has changed in many fields, but not yet in neonatology. In contrast there is a growing recognition that most preterm infants turn out just fine! It is easier to write a paper saying that the proportions of preterm infants who have problems is increased by X%, but to recognize that most are functioning at a very acceptable to very high level is harder for people to state. The first sentence of the conclusions of this paper does have that balance, it starts, ‘Health status and mental health of former ELBW adults were overall satisfying. ‘

A similar comment starts ‘what does this mean’ section of the editorial by Michael Msall recently published in Acta. ‘First, the large majority of ELBW survivors (83%) are free of
neurosensory disability. Thus, unprecedented survival without major neurosensory disability can be expected.’ the editorial was commenting on the paper from Maureen Hack’s group, Litt JS, Taylor HG, Margevicius S, Schluchter M, Andreias L, Hack M: Academic achievement of adolescents born with extremely low birth weight. Acta Paediatrica 2012 which detailed the intellectual outcomes of 14 year olds who were babies born at less than 1 kg, that study noted yet again the specific difficulties with mathematics that are more frequent among former extremely preterm infants. They note that such infants might well benefit from specific interventions to improve these skills, but they don’t give any reference to such a program. It is about time we found ways to improve these outcomes, which are already very good, to further benefit our tiniest patients.

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New agents for hemodynamic support; how to evaluate them?

Posted on 1 December 2012 by Keith Barrington

I have only ever prescribed a vasopressin infusion once for a baby. An infant was dying of septic shock and I done everything that I thought might help, without any evident benefit. So I decided to try vasopressin, based on case reports and series in older children and adults, and a few cases in newborns; the baby became immediately anuric, rather than oliguric, and although the blood pressure increased slightly everything else got worse (acidosis, oxygenation etc.)

Vasopressin, as the name implies, has vasoconstrictor effects, it might be helpful therefore if the major pathophysiology is vasodilatation; but when there is cardiac dysfunction it is unlikely to be helpful.

Now I didn’t write a case report of my experience, but another group who saw a positive response did so: (Radicioni M, Troiani S, Camerini PG. Effects of terlipressin on pulmonary artery pressure in a septic cooled infant: an echocardiographic assessment. J Perinatol. 2012;32(11):893-5.) That is of course a major problem with case reports of therapy; people tend to report when things go well, but not when they don’t! I think if everyone who had tried vasopressin (or terlipressin, a long acting analogue) with a poor response wrote up their experience we might have a much more representative literature, but good luck getting them published.

Pellicer A, Riera J, Lopez-Ortego P, Bravo MC, Madero R, Perez-Rodriguez J, et al. Phase 1 study of two inodilators in neonates undergoing cardiovascular surgery. Pediatr Res. 2012.This on the other hand is a much better way to introduce new agents into clinical use. Start with a small RCT with very careful evaluation of PK and PD. This was an RCT in 20 newborn infants who had cardiac surgery at 1 to 4 weeks of age. Many such babies get hemodynamic support after surgery, in this study they were randomized before surgery to either milrinone or levosimendan, which was started during the surgery, and continued for 48 hours, after that the study was no longer masked, as the milrinone continued, but the levosimendan stopped. It would probably be better to compare each to placebo (it was a masked trial) but that would raise its own ethical issues. The authors show very little difference between the agents, which means that either they are equally effective, or equally ineffective (which is the problem with not having a placebo group). One worrying thing the authors showed was the progressive accumulation of active metabolites of levosimendan, that didn’t appear to be cleared very well, and were still detectable 14 days later! There were some minor other differences between the groups, or uncertain significance.

I’m sure there will be another new agent along in a minute, it would be great if the initial reports of use were not case reports, which are completely unreliable and nearly always positive, but small careful RCTs evaluating safety, kinetics, and hemodynamic responses, like Adelina Pellicer’s group have done. Then moving on to adequately powered placebo controlled studies, like the excellent milrinone trial of Mary Paradisis and her co-workers.

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Erythromycin: not another toxic placebo!

Posted on 29 November 2012 by Keith Barrington

Erythromycin is an antibiotic. This much is true. It is active against mycoplasma and against ureaplasmas, but is very poor at actually eradicating them. It also stimulates motilin receptors in the bowel, that is why it increases bowel activity, and may cause diarrhoea in adults and older children taking it. It may also be the reason behind the development of pyloric stenosis in infants who get erythromycin, one of the serious potential complications.

Allergy to erythromycin on the other hand doesn’t seem to occur, I am sure there is  a good reason for this, but I have no idea what it might be.(ask an immunologist if you really care)

Erythromycin has been studied as a treatment for feeding intolerance, this is interesting, (at least for a data nerd like me) as the outcome in many studies has depended on things like volumes of gastric residuals, which themselves are largely useless as outcomes. So if you measure  gastric residuals, and determine your feeding advancement on their volume, you can advance feeds faster on erythromycin than on placebo. In very immature babies there is much less evidence of efficacy, and we know nothing about the embryologic development of motilin receptors. So it might not work in those babies. For any other important clinical outcome as far as I can see there is no evidence of benefit, such as necrotizing enterocolitis or duration of hospital stay.

There are a few systematic reviews out there, on Erythromycin for feeding intolerance in the preterm, including one by my friend Sanjay Patole (who also did one of the trials), he is editing the book for which I am writing this chapter on FGER (that is F****** GER, what I have come to think of it as, during the re-writing of this chapter!) Anyway, there is not a single study ever published according to my literature searches, on the use of erythromycin for reflux (FGER) in the newborn.

It seems that there are people out there using it for reflux, however, which is very depressing. Please don’t.

As well as being associated with pyloric stenosis, erythromycin increases QT duration, due to an effect on the inward potassium channel in the heart I(Kr), and can cause lethal arrythmias. Also, no other prokinetic agent has ever been shown to improve reflux, so it seems very unlikely that erythromycin will either.

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More about reflux: anti-acid medications may also be toxic placebos

Posted on 28 November 2012 by Keith Barrington

While I am still finalizing my long overdue chapter on gastro-esophageal reflux (sorry Sanjay if you are reading this, it is on its way, honestly) I have been reviewing the data on acid blockade as a potential treatment.

Probably the biggest problem with GERD (that is, disease caused by gastro-esophageal reflux) in the newborn, is that it is impossible to diagnose. There is no validated scoring system, and systems used in older children do not transpose to babies. When there have been studies performing objective recordings of esophageal impedance and pH at the same time as recording “symptoms” (this is another of my many peeves, newborn babies do not have symptoms as they can’t tell you how they feel, they have clinical signs), there has been no correlation, babies have just as many useful clinical signs when they are not having reflux as when they are. So any diagnosis of GERD in a newborn is nothing more than a guess. 

(All the references are below).

One thing that could theoretically cause GERD in a newborn is the acidity of the gastric contents, just like in adults where the reflux causes pain, it is entirely possible that in some preterm or term babies reflux causes pain. Unfortunately we don’t know how to differentiate GER discomfort from other causes of fussiness in babies, and anti-acid therapies do not reduce fussiness.

So do anti-acid therapies do anything? They can be divided into 3 groups, histamine receptor blockers (such as ranitidine), proton pump inhibitors, and others. The histamine H2 blockers (H2RB) have been widely used for years, so we have accumulated a lot of observational data, but unfortunately very little scientific useful data, as usual. The observational data show that H2RB use is associated with more infections, more NEC, and higher mortality; not very encouraging then. So do H2RB at least improve clinical symptoms? Well, no. Controlled trials show that GER symptoms improve over time, whether you get H2RB or not. Why might acid blockers infections? We all swallow billions of bugs every day, this includes babies. The stomach contents are usually very acidic, which kills most of the bugs. If you block the acid, you let more bugs through and increase infections. This is even true in older kids with asthma, a really nice large multi-center RCT in children with asthma was published in JAMA this year, the authors were investigating the common assumption that reflux is an important risk factor for asthmatic episodes, so the idea was that blocking gastric acid should prevent asthma spells, and make the kids better. What they actually found was that there was no improvement in asthma at all, but there were more chest infections in the group that had acid blockade. The same thing seems to happen with babies that have a clinical diagnosis of GER, when you reduce their acid production, you don’t affect their symptoms, but you do risk an increase in infections.

One thing that I was reminded about while reviewing the literature for this chapter is some of the other physiological roles of gastric acid, and potential adverse consequences of blocking it: gastric acid is important in the absorption of calcium, magnesium, iron and vitamin B12. So, if you block it, you might well worsen bone mineralization and anemia. Adults who are on PPIs have more osteoporotic bone fractures; so it is reasonable to think that babies on acid blockers might have more osteopenia as well. As far as I know this has not been studied; if anyone has a database that could answer the question please go ahead (and acknowledge my seminal influence in the eventual PNEJM publication! (the prestigious NEJM)) H2 receptor blockers also have behavioral side effects (other adverse reactions can be found here), and interact with other medications (source: http://sideeffectsofxarelto.org/xareltos-original-study-comparing-the-drug-to-warfarin-appears-to-have-been-skewed/).

So to summarize: if you think that a baby has clinical signs due to acid reflux you are as likely to be wrong as right; even if you are right you need to be aware of the toxicities, which include potentially, osteopenia, iron deficiency, and  an increase in infections and NEC; and even if you are right reducing acid output doesn’t improve symptoms any better than placebo, and also has toxicities, so that causing the risk of getting more troubles like in the prilosec lawsuit settlement case.

Is GER of any importance at all in the newborn? I think it would be a mistake to completely dismiss it. Gastric acid does indeed injure the esophageal mucosa after a while, and causes symptoms in older patients. I think it is likely that there are some newborn babies who have clinical signs as a result of acid reflux, and perhaps as a result of non-acid reflux. We need to find out how to identify those babies, and then find evidence based therapies to help them.

Snel A, Barnett CP, Cresp TL, et al. Behavior and gastroesophageal reflux in the premature neonate. Journal of Pediatric Gastroenterology and Nutrition 2000; 30: 18-21.

Moore DJ, Tao BS-K, Lines DR, Hirte C, Heddle ML, Davidson GP. Double-blind placebo-controlled trial of omeprazole in irritable infants with gastroesophageal reflux. The Journal of Pediatrics 2003; 143(2): 219-23.

Terrin G, Passariello A, De Curtis M, et al. Ranitidine is associated with infections, necrotizing enterocolitis, and fatal outcome in newborns. Pediatrics 2012; 129(1): e40-5.

Graham PL, Begg MD, Larson E, Della-Latta P, Allen A, Saiman L. Risk factors for late onset gram-negative sepsis in low birth weight infants hospitalized in the neonatal intensive care unit. Pediatr Infect Dis J 2006; 25(2): 113-7.

Writing Committee for the American Lung Association Asthma Clinical Research C, Holbrook JT, Wise RA, et al. Lansoprazole for children with poorly controlled asthma: a randomized controlled trial. JAMA : the journal of the American Medical Association 2012; 307(4): 373-81.

Orenstein SR, Shalaby TM, Devandry SN, et al. Famotidine for infant gastro-oesophageal reflux: a multi-centre, randomized, placebo-controlled, withdrawal trial. Alimentary Pharmacology & Therapeutics 2003; 17(9): 1097-107.

Yang YX. Chronic proton pump inihibitor therapy and calcium metabolism. Curr Gastroenterol Rep 2012; 14(6): 473-9.

Ito T, Jensen RT. Association of long-term proton pump inhibitor therapy with bone fractures and effects on absorption of calcium, vitamin B12, iron, and magnesium. Curr Gastroenterol Rep 2010; 12(6): 448-57.

Orenstein SR, Hassall E, Furmaga-Jablonska W, Atkinson S, Raanan M. Multicenter, Double-Blind, Randomized, Placebo-Controlled Trial Assessing the Efficacy and Safety of Proton Pump Inhibitor Lansoprazole in Infants with Symptoms of Gastroesophageal Reflux Disease. The Journal of Pediatrics 2009; 154(4): 514-20.e4.

Tham SY, Rogers IM, Samuel KF, Singh A, Ong KK. Does oral lansoprazole really reduce gastric acidity in VLBW premature neonates? The Medical journal of Malaysia 2012; 67(3): 284-8.

Omari TI, Haslam RR, Lundborg P, Davidson GP. Effect of Omeprazole on Acid Gastroesophageal Reflux and Gastric Acidity in Preterm Infants With Pathological Acid Reflux. Journal of Pediatric Gastroenterology & Nutrition 2007; 44(1): 41-4.

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Home again

Posted on 26 November 2012 by Keith Barrington

Back from the trip to Australia, still a bit frazzled.. but we had a great time, the conference was excellent, the hospitality even better, thanks to Peter (and Noni), Lex, Jennifer and Niki.

I have put my presentations on this blog for those who participated, feel free to download if you wish. If there are references missing or other details that you would like, please email me. When you put your mouse on the tab ‘presentations from our group’ just under the photo, you will see Melbourne 2012, just click and the powerpoint files are available.

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Weekly updates 15

Posted on 26 November 2012 by Keith Barrington

Lacey DJ, Stolfi A, Pilati LE: Effects of hyperbaric oxygen on motor function in children with cerebral palsy. Annals of Neurology 2012  Hyperbaric oxygen really, really doesn’t work for treating cerebral palsy. This is the second good trial of hyperbaric oxygen (HBO) in CP, the previous having being performed in Montreal. What I find interesting about this is that the first trial was performed by a group which included one of the enthusiasts of HBO. Even after the first study was clearly negative, showing no benefit whatsoever (for infants with CP of being exposed to HBO treatment compared to controls who had pressurized air as the placebo therapy), Dr Marois participated in a movie trying to promote it. The movie was called ‘medicine under the influence’ (actually médecine sous influence’) an appalling piece of crap of movie making which berated doctors as being under the influence of some sort of malign force (it was never identified in the movie, but I think it could be called ‘science’) which stopped them from helping poor families who were suffering as a result of neonatal intensive care. The first study was an excellent trial published in the lancet, and clearly showed no effect of HBO. This new trial is also a very high quality trial, again published in a very high quality peer reviewed journal, and again shows no effect.

I guess there is one positive effect of HBO in cerebral palsy, it makes money for people running HBO services! Apart from that, there is no rational basis for using HBO for CP, and there should be no more studies.

Poets A, Urschitz MS, Steinfeldt R, Poets CF: Risk factors for early sudden deaths and severe apparent life-threatening events. Archives of Disease in Childhood – Fetal and Neonatal Edition 2012, 97(6):F395-F397. I have been very fortunate in my career to meet and become friends with a number of interesting people who have made great contributions to neonatal care. I often refer to them in posts on this blog, but one I don’t think I have mentioned before is Christian Poets. This is another of his important studies. There are several full term babies who die every year, suddenly and unexpectedly soon after a normal delivery. Annie and I have reported one case,  and there are now a few regional studies examining the incidence of this terrible disaster. This current study was by a team which examined a series of reported cases, and identified risk factors, specifically a primiparous mother, and the baby in a position which was potentially risky. This later factor was defined as ‘lying prone on the breast or abdomen of its mother or close to her in a side position’. Most of the babies were in such a position (25 of 29 cases) but these are commonly used positions anyway (67% of controls). It seems very likely to me, and our case would support this, that the majority of these occurrences are asphyxial events occurring when the mother is exhausted after her delivery (mothers were twice as likely to be asleep when the event occurred as controls), and the baby has a rebreathing and/or airway occlusion episode which is not recognized until the baby is severely ill. Preventing such cases is probably possible by making sure that the mother and baby are under observation whenever the baby is in such a position, and if ever she falls asleep to ensure that the baby is on their back on a firm surface.

Boland RA, Davis PG, Dawson JA, Doyle LW: Predicting death or major neurodevelopmental disability in extremely preterm infants born in Australia. Archives of Disease in Childhood – Fetal and Neonatal Edition 2012. Many of you will be aware of the ‘Tyson calculator’ which estimates mortality and survival without major disability with data that are readily available prior to extremely preterm delivery. The calculator was constructed with data from the NICHD network, and the Melbourne group (not them again!) have looked at whether the calculator is accurate for their patients also. The calculator was indeed accurate for estimating survival of inborn infants, but overestimated severe impairment.

Ang JY, Lua JL, Mathur A, Thomas R, Asmar BI, Savasan S, Buck S, Long M, Shankaran S: A Randomized Placebo-Controlled Trial of Massage Therapy on the Immune System of Preterm Infants. Pediatrics 2012. There are number of small randomized trials of massage of preterm infants. Most have shown some benefit, but the outcomes are different in each study, so it is difficult to be sure what the benefits in real life might be. One thing that seems a little more consistent is a increase in weight gain, which you could hypothesize a mechanism for, the movements might increase muscle mass, and there are also some suggestions that bone mass might increase, again a physical therapy with effects on body composition seems feasible. How on earth massage might have effects on the immune system I have no idea, and in fact the primary outcome of the proportion of NK cells was not affected. A secondary outcome of increased NK cell cytotoxicity was increased in the massage group, but as always, secondary outcomes should be treated with suspicion. Weight gain was also increased in the massage group, again a secondary outcome, but consistent with several other studies.

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NICE! Or mostly so… treatment of early onset neonatal infection

Posted on 20 November 2012 by Keith Barrington

The National Institute of Clinical Excellence in the UK has been a real boon to the NHS, despite attempts to limits its influence by the pharmaceutical companies, the explicit evaluation of risks and benefits of various interventions allows appropriate use of resources.

This year they produced a guideline (and a shorter version they call a guidance) regarding the use of antibiotics for early onset infection in the newborn. The guideline is 320 pages long, and is a complete evaluation of the published literature. Even the guidance is 40 pages long, of which the first 26 are the meat of the guidance. Although I think in general it is very well done (such as the review of clinical signs which should lead to a sepsis evaluation), there are 2 things that I disagree with.

The first is the choice of antibiotics for preliminary treatment of a suspected sepsis in a full term newborn infant. NICE promote the use of benzylpenicillin and gentamicin. In their review of case series from the UK they note that up to 6% of cases of early onset sepsis are due to listeria. Listeria are not covered by benzylpenicillin, but require ampicillin. The reasoning behind the choice of benzylpenicillin is that the spectrum is narrower, therefore less risk of promoting resistance. While this is true, that is done at the expense of having 6% of true sepsis untreated. Is the use of 36 hours of antibiotics in a subgroup of newborns with suspected sepsis an important source of evolutionary pressure for the selection of resistant organisms? Ampicillin will also often treat community acquired E Coli also, another potential benefit. There is inadequate justification for the choice to my mind, and I will continue to promote ampicillin and gentamicin.

The second recommendation that I don’t agree with is the recommendation to take a CRP at baseline and to repeat 18 to 24 hours later.  The problem with that guidance is that there are no clear recommendation about what to do with the results! The recommendation is that if the results are ‘reassuring’ you can stop antibiotics after 36 hours if cultures are negative. But what is a ‘reassuring’ result and trend of CRP? Is there any evidence that an infant with negative cultures and a non-‘reassuring’ trend in CRP benefits from prolonged antibiotic treatment? The observational studies on which the reliance on CRP are based have defined culture negative sepsis according to whether the antibiotics were continued, which often depended on the CRP! So we have a sort of circular argument, non-reassuring CRP leads to prolonged treatment, therefore the infant has culture negative sepsis, therefore we have to measure CRP in order to determine whether or not to stop antibiotics.

In the meantime we have no data that culture negative sepsis benefits from antibiotics, nor that CRPs are cost-effective or affect any measurable outcome.

The problem with this argument is that I don’t know where to go from here. Culture negative sepsis exists. Infants with negative cultures but who have all of the clinical signs of systemic infection are a real phenomenon; but do they benefit from antibiotic treatment? I dunno. Is a CRP a better decision making tool than a clinical exam? I dunno. Oh dear there are too many things that I don’t know, but at least I get to travel a lot to great places to tell people that!

Off to Melbourne tomorrow, but I will try to post a few times while I am gone.

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The Politics of Probiotics

Posted on 15 November 2012 by Keith Barrington

Annie Janvier and John Lantos and I have just published a ‘different view’ article in Acta Paediatrica, which has just appeared on-line. For various reasons we were asked to remove the references, so I list the references that we based our article on below.

Our contention in the article is that probiotics are an innovation in neonatology which is fundamentally different to other innovations such as inhaled nitric oxide, ECMO, or antenatal surgery. The major difference being that you can go and buy probiotics easily anywhere, and many people already do, so denying them to preterm infants is perverse, especially given the preponderance of evidence of benefit in the preterm.

We think that parents should be informed. We think that they should know about the medical evidence. We think they should have the right to choose an intervention that is probably beneficial, and which is easily available to all. We recognize also that there are docs who wish to perform further placebo controlled trials, even if I lost equipoise several years ago, and they want to ask parents for consent for those trials.

For some trials, it is reasonable to prohibit use of the intervention outside of the trial, for probiotics this is not reasonable.

Our final paragraph summarizes our view of the current situation.

‘We think that doctors should allow parents to choose probiotics, no probiotics, or randomization… Parents should be fully informed of the data from completed trials, including a clear description of the reduced mortality and lack of adverse effects in those trials. They should then be allowed to choose whether or not to give their baby probiotics or, alternatively, whether to enrol their baby in a randomized trial. Enrolment in a randomized trial should not be a condition for getting probiotics. This approach -allowing on-going trials to continue but permitting treatment off-protocol- would protect the best interests of babies (they would either get probiotics or they would get randomized to a possibility of getting them), preserve parental autonomy, and be consistent with professional equipoise… Probiotics may be in a regulatory purgatory, but we should not curtail parents’ reasonable choices or allow babies to die as a result of our regulatory paralysis.’

The references follow, and then a table with some details of all the RCTs published so far, which we also had to remove as it was too long otherwise.

Systematic reviews:

Alfaleh K, Anabrees J, Bassler D, Al-Kharfi T. Probiotics for prevention of necrotizing enterocolitis in preterm infants.  Cochrane Database Syst Rev. 2011 Mar 16;(3):CD005496.

Wang Q, Dong J, Zhu Y. Probiotic supplement reduces risk of necrotizing enterocolitis and mortality in preterm very low-birth-weight infants: an updated meta-analysis of 20 randomized, controlled trials. J Pediatr Surg 2012;47(1):241-8.

Deshpande G, Rao S, Patole S, Bulsara M. Updated Meta-analysis of Probiotics for Preventing Necrotizing Enterocolitis in Preterm Neonates. Pediatrics. 2010;125(5):921-30.

Other review articles:

Stenger MR, Reber KM, Giannone PJ, Nankervis CA. Probiotics and prebiotics for the prevention of necrotizing enterocolitis. Curr Infect Dis Rep. 2011;13:13-20.

Thomas DW, Greer FR; American Academy of Pediatrics Committee on Nutrition; American Academy of Pediatrics Section on Gastroenterology, Hepatology, and Nutrition.  Probiotics and prebiotics in pediatrics. Pediatrics. 2010;126:1217-31.

Frost BL, Caplan MS.   Probiotics and prevention of neonatal necrotizing enterocolitis.  Curr Opin Pediatr. 2011 Apr;23(2):151-5.

Degnan FH. The US Food and Drug Administration and probiotics: regulatory categorization. Clin Infect Dis.2008;46 Suppl 2:S133-6; discussion S144-51.

Opinion pieces and editorials about probiotic use:

Soll RF. Probiotics: Are We Ready for Routine Use? Pediatrics 2010;125(5):1071-2.

Neu J, Shuster J. Nonadministration of Routine Probiotics Unethical—Really? Pediatrics. 2010;126(3):e740-e1.

Garland SM, Jacobs SE, Tobin JM, group on behalf of the ProPrems study group. A Cautionary Note on Instituting Probiotics Into Routine Clinical Care for Premature Infants. Pediatrics 2010;126(3):e741-e2.

Beattie LM, Hansen R, Barclay AR. Probiotics for Preterm Infants: Confounding Features Warrant Caution. Pediatrics 2010;126(3):e742-e3.

Millar M, Wilks M, Fleming P, Costeloe K. Should the use of probiotics in the preterm be routine? Archives of Disease in Childhood – Fetal and Neonatal Edition 2010.

Cohort studies of Probiotic use in NICU

Hunter C, Dimaguila MA, Gal P, Wimmer J, Ransom JL, Carlos R, Smith M, Davanzo C: Effect of routine probiotic, lactobacillus reuteri dsm 17938, use on rates of necrotizing enterocolitis in neonates with birthweight < 1000 grams: A sequential analysis. BMC Pediatrics 2012, 12(1):142.

Bonsante F, Iacobelli S, Gouyon JB: Routine probiotic use in very preterm infants: Retrospective comparison of two cohorts. Am J Perinatol 2012(EFirst).

New RCTs, too recent to be in the table below

Fernández-Carrocera LA, Solis-Herrera A, Cabanillas-Ayón M, Gallardo-Sarmiento RB, García-Pérez CS, Montaño-Rodríguez R, Echániz-Aviles MOL: Double-blind, randomised clinical assay to evaluate the efficacy of probiotics in preterm newborns weighing less than 1500 g in the prevention of necrotising enterocolitis. Archives of Disease in Childhood – Fetal and Neonatal Edition 2012.

Publications about Other innovative therapies:

Lantos JD, Frader J.  Extracorporeal membrane oxygenation and the ethics of clinical research in pediatrics.  N Engl J Med. 1990 Aug 9;323(6):409-13.

Hanney S, Mugford M, Grant J, Buxton M.  Assessing the benefits of health research: lessons from research into the use of antenatal corticosteroids for the prevention of neonatal respiratory distress syndrome. Soc Sci Med. 2005;60:937-47.

Barrington KJ, Finer N. Inhaled nitric oxide for respiratory failure in preterm infants.Cochrane Database Syst Rev. 2010 Dec 8;(12)

Wilkinson DJ, Thayyil S, Robertson NJ.  Ethical and practical issues relating to the global use of therapeutic hypothermia for perinatal asphyxial encephalopathy. Arch Dis Child Fetal Neonatal Ed. 2011;96(1):F75-8.

First Author Date Eligibility criterion Total N Age at start Probiotic strain Duration
Kitajima 1997 <1500g 97 <24h B. breve 28 d
Dani 2002 <33wk, <1500g 585 First feed L. GG (?rhamnosus) Until discharge
Costalos 2003 28-32 wks 87 Mean 3d Saccharomyces Boulardii 30 d
Li 2004 <2500g 30 >24h B. breve Until discharge
Bin-Nun 2005 <1500g 145 First feed B. infantis, B. bifidus, Streptococcus thermophilus To 36 wk post-menstrual age
Lin 2005 <1500g 367 7d B. infantis, L. acidophilus 6 wk
Manzoni 2006 <1500g 80 ❤ d L. rhamnosus 6 wk or until discharge
Mohan 2007 <37wk 69 <24h B. lactis 21d
Stratiki 2007 27-36wk 41 B.lactis 30d
Ke 2008 <32 wk 189 Bifidobacteria
Lin 2008 <1500g 434 First feed B. bifidum, L. acidophilus 6 wk
Samanta 2008 <32wk or <1500g 186 When stable, >48h B. infantis,B. bifidum, B. longumL. acidophilus, Until discharge
Huang 2009 <32 wk and <1500 g 183 Bifidobacteria
Manzoni 2009 <1500g 304 Day 3 L. rhamnosus (and lactoferrin) 6wk (<1000g) or 4 wk
Rouge 2009 <32 wk and <1500g 94 First feed B. longum, L. rhamnosus Until discharge
Underwood 2009 <35 wk and 750-2000g 90 <7 days L. rhamnosus or L. acidophilusB. longum, B. bifidum and B infantis 28 days or discharge
Awad 2010 Preterm and term 150 Day 1 L. rhamnosus (live or heat-killed)
Mihatsch 2010 <30wk 183 Mean day 5 of feeds B. lactis Uncertain
Ren 2010 <33wk and 1000-1800g 150 Bifidobacteria
Sari 2010 <33wk or <1500g 221 Day of 1st feed L. sporogenes Until discharge
Braga 2011 750 to 1500g 231 Day 2 L. casei, B. breve 30d
Romeo 2011 <37 wk and <2500g 249 Mean 1.4d L. reuteri, or L. rhamnosus 6 wk or until discharge
Lozano 2012 <2000g 750 <48h L. reuteri Until discharge
Posted in Neonatal Research | Tagged , , | 2 Comments

Premedication for Intubation

Posted on 13 November 2012 by Keith Barrington

There are several studies of what premedication should be used for intubation of the newborn. An analgesic or anesthetic agent should be given in to reduce pain, which also reduces the adverse physiologic consequences of the intubation.

Several studies of different agents exist, and one of the most used agents in clinical practice is morphine. A new study (Norman E, Wikstrom S, Rosen I, Fellman V, Hellstrom-Westas L: Premedication for intubation with morphine causes prolonged depression of electrocortical background activity in preterm infants. Pediatr Res 2012.) examined a subset of a small RCT who had prolonged EEG monitoring. The RCT compared thiopental plus remifentanil to morphine. The thiopental/remifentanil group had EEG suppression after the meds which lasted less than 3 hours; after morphine the suppression lasted more than 24 hours. Also blood pressures were lower in the babies who received morphine.

Morphine is the one agent that has not been shown to improve physiologic responses to intubation, probably because of an onset of activity at 10 to 15 minutes, and usually the intubation has been performed prior to this interval. Fentanyl reduces those responses, as does remifentanil. An RCT comparing remifentanil to fentanyl plus succinylcholine, showed the same effect on physiologic responses of the two regimes.

I don’t know if the thiopental in the regime of Normal et al is really necessary, remifentanil alone is an excellent analgesic, and reduces the physiologic responses with a very short duration of action (as far as we know, in the very preterm there is a need for more data) . Some babies are expected to be extubated very quickly after surfactant and there are concerns regarding the duration of action of fentanyl, now I have never found this to be a problem, as fentanyl causes little respiratory depression, but I do think that remifentanil, with its very short duration of action of a few minutes would be preferable if we had more data. Is it necessary to add a hypnotic agent? That might turn out to be a philosophical question; I think it will be hard to prove an advantage of adding a hypnotic agent to an effective analgesic. (A nice recent review of remifentanil in the newborn: Penido MG, Garra R, Sammartino M, Pereira e Silva Y: Remifentanil in neonatal intensive care and anaesthesia practice. Acta Paediatr 2010, 99(10):1454-1463.)

Posted in Neonatal Research | Tagged , , | 4 Comments