Important Neonatal Publications

If you are looking for a reading list to make sure you are aware of all the most important neonatal research publications, look no further. My own idiosyncratic personal selection is here. I will add to this as more good studies are published.

You can find many of these articles also at my Mendeley group ‘Recent Neonatal Publications’ under the tag Important References.

If you think of other important stuff, let me know, I will add any I agree with!

In No Particular Order:

This study is interesting because Dr Bartlett, who was THE pioneer of neonatal ECMO, was criticized for not doing a trial; he then did a trial according to some pre-existing suggestions to minimize deaths in potentially life-saving trials. He was then criticized for doing the trial! This randomized trial had an adaptive randomization scheme which increased the likelihood of being put in the treatment arm where you were more likely to survive. So the trial ended with 1 control patient (who died) and 11 ECMO patients who all survived.

10 years later we Brits finally got around to doing a trial in a country with a historic resistance to invasive treatments. 185 infants from around the country were randomized to either stay were they were and continue receiving conventional treatment, or be transported to an ECMO center for ECMO. The main entry criterion was an OI greater than 40, but 40% had an OI greater than 60. Even though this pragmatic design tilts the chances against ECMO and toward control, mortality was much higher among controls, indeed the study was stopped early. Several long term follow up publications have shown that the ECMO treated kids are doing as well or better than the controls, most survivors have cognitive scores in the normal range,  and there are higher respiratory morbidity and increased risk of behavioral problems among controls. Progressive sensorineural hearing loss occurs in both groups.

The largest and best of the full term inhaled NO trials. Significant reduction in the combined outcome of ‘death or ECMO’ among 235 term and near-term infants who were randomized to iNO or placebo if they reached an OI of at least 25.

A sub-study of the NINOS group which enrolled infants with diaphragmatic Hernia until the main study was finished. 53 infants were enrolled. There was no benefit of inhaled NO compared to control for the outcomes of survival or needing ECMO.

  • Adzick, N. S., Thom, E. A., Spong, C. Y., Brock, J. W., Burrows, P. K., Johnson, M. P., Howell, L. J., et al. (2011). A Randomized Trial of Prenatal versus Postnatal Repair of Myelomeningocele. New England Journal of Medicine, 364, 993-1004.

183 mothers were randomized to either prenatal or postnatal repair of a meningomyelocele. The study was stopped by the data safety committee, when they analyzed the results of the first 158 women whose babies were old enough to have evaluation for the primary outcome, that is surviving without a VP shunt up to 12 months of age. It doesn’t seem like the results of the other randomized women have been presented anywhere as yet, which is weird. usually when a study is stopped early the results of everyone enrolled should be analyzed and presented, which might mean waiting until all the participants have reached the age fo the primary outcome. I guess they wanted to get this into print quickly, just hope we will eventually get to see all the data.

Anyway many fewer babies needed a shunt, many fewer  had hindbrain herniation, more could walk without assistance and functional scores were higher, with prenatal compared to postnatal surgery.

One of several meta-analyses of probiotics to prevent NEC. A clear reduction in NEC (RR0.35) and in mortality (RR 0.42). This meta-analysis included a trial sequential analysis, confirming the results, and showing that we already knew this a while ago!

The meta-analysis was criticized by a number of individuals, including one comment that we couldn’t apply the results in the US because none of the studies were american. Another criticized the methodology, but it was co-authored by a statistician who thinks that we should not weight trials in meta-analysis, which I think no-one else agrees with.

The early CPAP arm of the SUPPORT factorial trial. 1300 babies 24 to 28 weeks gestation were randomized to get either CPAP starting in the delivery room, or intubation in the delivery room followed by surfactant within an hour. There was no significant difference in the primary outcome (death or BPD) most of the non-significant differences were better in the CPAP group.

The oxygen target ranges arm of the factorial SUPPORT trial. 1300 babies 24 to 28 weeks gestation were randomized to target saturation limits of either 85 to 89% or 91 to 95%. Severe retinopathy was more frequent in the high saturation group, death was more frequent in the low saturation group.

  • Kirpalani, H., Whyte, R. K., Andersen, C., Asztalos, E. V., Heddle, N., Blajchman, M. A., Peliowski, A, Rios A, La Corte M, Connelly R, Barrington KJ, Roberts RS. (2006). The Premature Infants in Need of Transfusion (PINT) study: a randomized, controlled trial of a restrictive (low) versus liberal (high) transfusion threshold for extremely low birth weight infants. The Journal of pediatrics, 149(3), 301-307

Randomized trial comparing 2 transfusion algorithms in preterms weighing less than 1 kg at birth. No obvious advantage of higher transfusion threshold, with consequently higher hemoglobin concentrations, and higher volume of blood transfused.

150 preterm infants with stage 3 retinopathy and plus disease in either zone 1 or zone 2 posterior were randomized to either intravitreal bevacizumab (Avastin) or retinal surgery with laser. Infants who got the Avastin were more likely to regress and stay regressed. NO long term functional data as yet, but it looks very promising.

  • Morley, C. J., Davis, P. G., Doyle, L. W., Brion, L. P., Hascoet, J. M., & Carlin, J. B. (2008). Nasal CPAP or intubation at birth for very preterm infants. The New England journal of medicine, 358(7), 700-708.

The COIN trial. 610 babies between 25 and 28 weeks randomized to CPAP starting at 5 minutes of age if they needed respiratory support, compared to intubation and ventilation. Surfactant was given according to the attending staff. CPAP group babies were intubated if they had a lot of apnea, a CO2 over 60 with an acidosis or more than 60% O2. There was no difference in survival without BPD, but there was somewhat less severe BPD in the CPAP group, and more pneumothoraces in the CPAP group.

  • Saigal, S, Stoskopf, B. L., Feeny, D., Furlong, W., Burrows, E., Rosenbaum, P. L., & Hoult, L. (1999). Differences in preferences for neonatal outcomes among health care professionals, parents, and adolescents. JAMA, 281(21), 1991-1997.

This questionnaire study showed marked differences between doctors and nurses on the one had, and adolescents (half of whom were extremely low birth weight) and their parents on the other, with regard to whether being severely handicapped was worse than being dead. Health care professionals were much more negative than parents or adolescents, for a whole range of health care outcomes. 

  • Saigal, S, Stoskopf, B., Streiner, D., Boyle, M., Pinelli, J., Paneth, N., & Goddeeris, J. (2006). Transition of Extremely Low-Birth-Weight Infants From Adolescence to Young Adulthood: Comparison With Normal Birth-Weight Controls. JAMA, 295(6), 667-675.

As they reach early adulthood, extremely low birth weight infants are transitioning to independence, with very little apparent difference compared to normal birth weight controls.

  • Schmidt, B, Davis, P., Moddemann, D., Ohlsson, A., Roberts, R. S., Saigal, S., Solimano, A., et al. (2001). Long-term effects of indomethacin prophylaxis in extremely-low-birth-weight infants. The New England journal of medicine, 344(26), 1966-1972.
The primary publication from the TIPP trial showed no effect on survival without long term disability among infants randomized to prophylactic indomethacin compared to placebo. This study confirmed other data which showed the that there are fewer intraventricular/periventricular hemorrhages with indomethacin, both minor and more serious ones. But this did not translate into an overall improvement in developmental scores. In fact if we examine the data we can see that there is a reduction in severe IVH/PVH from 13% to 9%. If the only cerebral/neurological effect of indomethacin is a reduction in severe hemorrhage of this magnitude then it would be surprising if this study of 1200 babies would be powerful enough to detect a long term outcome difference. Even a well designed large multicenter trial like this can’t really expect to detect a difference in development in only 4% of the subjects. This would make you expect to find that a subgroup analysis, including higher risk infants (such as just boys for example) might show a long term outcome difference. 

  • Ohlsson A, Roberts RS, Schmidt B, Davis P, Moddeman D, Saigal S, Solimano A, Vincer M, Wright L, the Trial of Indomethacin Prophylaxis in Preterms (TIPP) Investigators: Male/Female Differences in Indomethacin Effects in Preterm Infants. The Journal of Pediatrics 2005, 147(6):860-862.
  • Schmidt, Barbara, Roberts, R. S., Davis, P., Doyle, L. W., Barrington, K. J., Ohlsson, A., Solimano, A., et al. (2007). Long-term effects of caffeine therapy for apnea of prematurity. The New England journal of medicine, 357(19), 1893-902.

The primary outcomes of the CAP trial. 2006 infants less than 1250 g birth weight, eligible for methylxanthines at less than 10 days of age, randomized to caffeine or placebo. At 18 to 22 months of corrected age infants who had received caffeine were more likely than babies in the placebo group to survive without a neuological or developmental problem. There was less cerebral palsy, and better cognitive development. The outcomes up to 5 years of age are also now published. Schmidt B, Anderson PJ, Doyle LW, Dewey D, Grunau RE, Asztalos EV, Davis PG, Tin W, Moddemann D, Solimano A et al: Survival Without Disability to Age 5 Years After Neonatal Caffeine Therapy for Apnea of Prematurity. JAMA: The Journal of the American Medical Association 2012, 307(3):275-282 The 5 year outcomes confirm the lack of adverse outcomes, the cognitive differences have been erased by environmental effects, but worse grades of cerebral palsy were still more frequent in the controls.

  • Tyson, J. E., Kennedy, K. A., Lucke, J. F., & Pedroza, C. (2007). Dilemmas Initiating Enteral Feedings in High Risk Infants: How Can They Be Resolved?: The Evidence Base Supporting Nutritional Practices for Very Low Birth Weight Infants. Seminars in Perinatology, 31, 61-73 

This is a good review article which points out how little we know about feeding small preterm infants, and how to go about finding the evidence we need.

A completely unbiased evaluation of the recent neonatal literature puts this one in the ‘most important’ group. We showed that with identical, clearly described, outcomes many fewer people would resuscitate a newborn, and especially a preterm newborn, than an older child or adult. Even markedly worse outcomes in older children and adults were preferred over a smaller risk of a poor outcome in the preterm. Dr Janvier has gone on to show the same tendency in the US, Ireland, Norway and Australia.

  • Boost II UK Collaborative Group, Boost II Australia  Collaborative Group, Boost II New Zealand Collaborative Group, Stenson BJ, Tarnow-Mordi WO, Darlow BA, Simes J, Juszczak E, Askie L, Battin M et al: Oxygen saturation and outcomes in preterm infants. The New England journal of medicine 2013, 368(22):2094-2104. 

Publication of the combined outcomes of 3 trials that were co-ordinated as part of the NeoProm collaboration. Together with the SUPPORT trial and the Canadian Oxygen Trial (COT) the evidence is very clear that targeting saturations between 85 and 89% increases mortality compared to 91 to 95%, but the higher saturations lead to more severe retinopathy, but with modern treatment do not lead to more serious visual impairment.

  • Schmidt B, Whyte RK, Asztalos EV, Moddemann D, Poets C, Rabi Y, Solimano A, Roberts RS, Canadian Oxygen Trial G: Effects of targeting higher vs lower arterial oxygen saturations on death or disability in extremely preterm infants: a randomized clinical trial. JAMA 2013, 309(20):2111-2120.

The results of COT in isolation showed very little; including no difference in the primary outcomes or in the incidence of retinopathy or mortality.

  • Brocklehurst P, Farrell B, King A, Juszczak E, Darlow B, Haque K, Salt A, Stenson B, Tarnow-Mordi W: Treatment of neonatal sepsis with intravenous immune globulin. The New England journal of medicine 2011, 365(13):1201-1211.

This very large multi-center RCT (n=3500) showed no effect of intravenous immune globulin as a treatment for suspected sepsis, and subgroup analysis of those with proven sepsis was also negative. Previous small trials had suggested benefit, this trial puts that to rest. I don’t know if there is a difference according to whether the blood cultures were actually positive or not, but the outcomes are absolutely identical for the groups as a whole so that doesn’t seem likely.

  • Jacobs SE, Tobin JM, Opie GF, Donath S, Tabrizi SN, Pirotta M, Morley CJ, Garland SM: Probiotic Effects on Late-onset Sepsis in Very Preterm Infants: A Randomized Controlled Trial. Pediatrics 2013.

In one sense this large multicenter RCT from Australia and New Zealand was a negative trial. The primary outcome (late-onset sepsis) was no different among the 550 VLBW babies under 32 weeks randomized to placebo compared to probiotics (ABCDophilus containing a lactobacillus, a bifidobacterium and a streptococcus). However there were 4.4% of controls who developed NEC and 2 % of the probiotic babies, a significant reduction.

5 Responses to Important Neonatal Publications

  1. Otilia Bianchi says:

    Thank you for your paper tips, found it great

  2. omayma says:

    It is really great and very useful. But I have a question: Is the good neonatologist is the one Who knows to show up with name of trials: TIPP,TOBY, TRAGI, CAP,in he morning rounds and otherwise as a clinician : empty??

    • I don’t think the two things are incompatible, in act I think that a knowledge of the best available evidence is essential to being a good clinician, but it is not sufficient, you also need an ability to examine and take a history, an understanding of the limitations and strengths of various tests, a compassionate approach to parents and families and the humility to ask for the opinions of others.
      The names of the trial s are useful tags that can help you remember their findings, and I think that funky appropriate abbreviated names make it easier to communicate about them, its easier to say the PINT trial than, that RCT of different hemoglobin transfusion thresholds!

  3. anshuman paria says:

    well i think…a good neonatologist is one who knows the clinics real well,can preempt early and uses all possible avenues to use updated knowledge…be it from TIPP, CAP or any other fancy acronym…but it distills down to improved and intact survival…..anshuman

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