Neonatal Updates

Sehgal A, et al. Systemic arterial stiffness in infants with bronchopulmonary dysplasia: potential cause of systemic hypertension. J Perinatol. 2016.

Elevated systemic pressures are common in infants with moderate or severe BPD; why? Dr Sehgal and his colleagues performed vascular ultrasound in 20 preterm infants with BPD, 7 preterm infants without and 20 term controls. The differences in findings between preterms without BPD and term controls were minor; BP was higher in the babies with BPD, and in addition the aorta intima-media thickness was greater, the stiffness index was greater, and the calculated vascular resistance was higher.

Rao SC, et al. Probiotic Supplementation and Late-Onset Sepsis in Preterm Infants: A Meta-analysis. Pediatrics. 2016;137(3):1-16. Updated systematic review of the effects of probiotic supplementation, this time concentrating on systemic, late-onset sepsis. Probiotics were associated with a 14% reduction in sepsis. The very real previous concerns of the risks of feeding immuno-incompetent preterm babies with live organisms have not been confirmed quite the opposite.

The latest systematic literature search that they performed found now 37 RCTs enrolling over 9,400 babies. I wasn’t aware of 3 of the trials, and there are also 3 or 4 abstracts that I hadn’t seen.  The 3 fully published RCTs that were new to me are :

Tewari VV, et al. Bacillus clausii for Prevention of Late-onset Sepsis in Preterm Infants: A Randomized Controlled Trial. Journal of Tropical Pediatrics. 2015;61(5):377-85.
Van Niekerk E, et al. Probiotics Reduce Necrotizing Enterocolitis Severity in HIV-exposed Premature Infants. Journal of Tropical Pediatrics. 2015;61(3):155-64.

Totsu S, et al. Bifidobacterium and enteral feeding in preterm infants: Cluster-randomized trial. Pediatrics International. 2014;56(5):714-9.

The two from the Journal of Tropical Pediatrics are from India and South Africa respectively, and show positive results, the report from South Africa enrolled babies under 1250 g birthweight, and more than 50% of their mothers were HIV positive. 4/93 placebo babies developed definite NEC compared to 0/91 probiotic babies. There was an apparent reduction in severity of NEC in the HIV exposed babies. From the hospital in New Delhi 244 babies under 34 weeks were enrolled, the incidence of sepsis was relatively low, and slightly, but not significantly lower in the probiotic group (they had very few NEC, 2 in each group).

The Totsu trial was a cluster randomized trial in 19 tertiary NICUs in Japan who enrolled 283 VLBW infants. They had no NEC in either group(!) and significantly less late-onset sepsis with probiotics.

Mychaliska G, et al. Safety and efficacy of perflubron-induced lung growth in neonates with congenital diaphragmatic hernia: Results of a prospective randomized trial. Journal of Pediatric Surgery. 2015;50(7):1083-7. In a previous position I performed a couple of studies of partial liquid ventilation, which I found fascinating, and I hoped it might lead to a new approach to therapy in certain lung diseases, I though that meconium aspiration might be a good candidate disease, but that has become, in my practice at least, much less of  a problem, I think because of room air resuscitation, and more gentle neonatal care. After many years hiatus there is now some new work suggesting that in some babies, that is, babies with diaphragmatic hernia on ECMO, maybe there will be a role. You can make even normal lungs grow by introducing a distending pressure, and the weight of perfluorocarbons is such that they can stimulate lung growth.  A very attractive idea in babies with CDH. Sixteen babies were randomized to either receive partial liquid ventilation with a CPAP of 8 cmH2O while on ECMO, or to have PEEP at 8 cmH2O while on conventional ventilation. The protocol changed a couple of times during the study which makes the results, although interesting, difficult to really interpret. They measured the lung area of the hypoplastic lung on chest x-ray each day, and indeed the lungs did grow. Quite a lot. But the pulmonary hypertension was not any better. Which is disappointing to say the least. I don’t think this is the end of the liquid ventilation story, but it will be hard to think what to do next, how to make the lungs grow and at the same time to remodel their vasculature.

Osman M, et al. Assessment of pain during application of nasal-continuous positive airway pressure and heated, humidified high-flow nasal cannulae in preterm infants. J Perinatol. 2015;35(4):263-7.This was an observational study of PIPP (premature infant pain profile) scores during the initial application of respiratory support with either high flow cannulae (using a 2.4 mm binasal cannula) or CPAP using the INCA prongs. Pain scores were lower when applying the HFNC, and some of the scores in the CPAP group were quite high, 13% had scores over 12. Salivary cortisols also were higher in the CPAP babies.
Carnaghan H, et al. Effect of gestational age at birth on neonatal outcomes in gastroschisis. J Pediatr Surg. 2016.

Early birth of fetuses with gastroschisis was associated with delay in reaching full enteral feeds, prolonged hospitalization, and a higher incidence of sepsis.

No more to say about that.

van Vliet EO, et al. Nifedipine versus atosiban for threatened preterm birth (APOSTEL III): a multicentre, randomised controlled trial. Lancet. 2016.

Atosiban attacks the mechanism of uterine contraction, so it should be better than drugs which block all muscular activity. Or at least have fewer side effects in the mothers; taking lots of nifedipine is not very pleasant. Mothers in this study with threatened preterm labour were randomized; about 250 in each group. This publication is to me a model of a clinical RCT report. In addition to all the CONSORT guidelines there is a text box which includes information from a systematic review of the data before the study, describes the study and why they chose their primary outcome, reports their results and then updates the systematic review with their new data. After all that effort, there was no difference between groups in the composite neonatal morbidity outcome. Nor in delay of delivery of at least 48 hours, nor in the gestational age at eventual delivery, nor in serious adverse effects.

There was an incidence of 5% perinatal mortality in the nifedipine group and 2% in the atosiban group, which may have been due to chance, (RR 2·20 (95% CI 0·91–5·33)) but is enough of a difference that it should mandate further trials. Also, as mentioned above, nifedipine causes headaches, flushing and palpitations (in the mother of course), which may not be life-threatening, but can be quite unpleasant; atosiban, as far as I can see doesn’t usually do any of that; and that is enough for me to say that given our current state of knowledge atosiban should be pursued as a tocolytic agent. If you can get the same clinical outcomes with fewer very uncomfortable side effects, then it seems to me that the balance is on the side of atosiban.

The authors also note the following :

…worldwide nifedipine is not registered for use in pregnancy. This fact is of concern, especially since nifedipine is recommended as a first-line tocolytical drug in international guidelines.

About Keith Barrington

I am a neonatologist and clinical researcher at Sainte Justine University Health Center in Montréal
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