Neonates and Their Future: Neurodevelopmental Outcomes

When I started working in the NICU, it was early 1980.  I vividly remember an infant admitted who weighed just under 1 kg, which at that time was thought to be the cut-off for viability.  We admitted the infant who was pink but somewhat lethargic, put him under an oxygen hood to be more comfortable and waited for the inevitable to happen.

After about an hour or so, the infant was actually moving around quite a bit, breathing well and nice and pink!  So, it was decided we would embark on full treatment.  Today, this would be unheard of in the U.S.  Babies at 1 kg would never be left without resuscitation and treatment based on size alone!

The Neonatal Resuscitation Program states that it is reasonable to forego resuscitation at 400 gms as very few infants survive with that birth weight.  This is a very different population from the 900-1000 gm infant.  But, think of the advancements that have been made in the care of these infants since 1980.  Not the least of these, in fact, and perhaps the one with the most impact, is the development of artificial surfactant.  Also, the equipment we used to ventilate babies who needed it was actually just “down-sized” adult equipment.  Babies on ventilators often had pneumothoraces as it was virtually impossible to regulate the volume adequately and they had poor lung compliance which was common in the pre-surfactant era.

So, with all the improvements and advances in care we have seen over the last 30 years, the focus now is on improving outcomes in NICU survivors.  It is generally believed that pushing the threshold of viability further, for instance below 23 weeks, will be very difficult and take many resources and research money, if it would be possible at all.  We have seen many babies over the years who have survived NICU care but whose neurodevelopmental outcome has been compromised.  Preventing sepsis, necrotizing enterocolitis (NEC) and improving overall neurodevelopmental outcome are the focus of research.  Late-onset sepsis and/or NEC are often the cause of late mortality in infants who have survived the initial neonatal period.  Either of these, if survived, can contribute to worse neurodevelopmental outcome and certainly extended stay.  Two important areas of research specific to neurodevelopmental outcome are use of magnesium sulfate prenatally and erythropoietin (epogen), both in term hypoxic-ischemic encephalopathy as well as in preterm infants.

Fairly recently, the use of magnesium sulfate for neuroprotection of the preterm infant has become more common practice.  This observation was first noticed and published in 1995 with the observation that preterm infants exposed prenatally to magnesium sulfate had better neurodevelopmental outcome.  The beneficial effect is most dramatic between 22 and 27 weeks but has been shown to have some benefit up to 34 weeks.1  In spite of these findings, the details of magnesium sulfate administration remain unclear.  The best timing of administration is unknown.  If given around a threatened early labor, is it beneficial to repeat dosing, if the fetus remains undelivered?  Four studies were included in the meta-analysis by Jacquenmyn et al.1  The dosing in these studies ranged from a 4 gm bolus only without maintenance dosing to 6 gm bolus over 20-30 minutes + 2 gms/hr, making it difficult to compare outcomes.  Other studies have started magnesium sulfate up to 24 hours before expected delivery to when dilation reaches 4-8 cm.  It takes about 1 hour for magnesium sulfate to appear in fetal serum and the best outcomes require about a 4-hr minimal administration time, according to studies to date.  How does magnesium sulfate work to improve neurodevelopmental outcome?  Magnesium sulfate has demonstrated an anti-inflammatory effect by decreasing cytokine and free radical production.  This may lead to less apoptosis in the fetal and neonatal brain.  There is a known clear relationship between pro-inflammatory cytokines and cerebral palsy.  There are several other possible mechanisms of action whereby the magnesium sulfate may provide neuro protection.

Erythropoietin use for neuroprotection is another area where there is ongoing research.  There are studies, and in fact, use of epogen use in term infants with hypoxic-ischemic encephalopathy.  These infants have already had damage to the brain and epogen serves to decrease apoptosis (cell death) and has other neuro-regenerative effects.2  Studies are ongoing regarding efficacy and safety of use of epogen in the preterm population.  Higher doses of epogen are needed in order for it to cross the blood brain barrier.  Studies have determined that 1000U/kg is likely the ideal dose in order to accomplish this.2  In addition, neurodevelopmental risks are highest early in life so the epogen must be started earlier than if it were given for red blood cell production.  Safety concerns include bronchopulmonary dysplasia, intracranial hemorrhage, white matter injury, retinopathy of prematurity, necrotizing enterocolitis, patent ductus arteriosus or sepsis, although these have not been seen in neonatal studies.  A Cochrane review found an increased risk of retinopathy of prematurity with early treatment but a more recent meta-analysis found no difference in ROP between epo and no epo groups.3, 4   Leuchter et al found less white matter injury on MRI at term adjusted age on infants who received early high dose epogen.5   So, while additional studies are ongoing, this may be another protective strategy in the early NICU course for very high risk preterm infants.

In addition, we now know that simple good nutrition has been shown to improve neurodevelopmental outcome as well, although it is not really that simple!6  Discovering what the optimal levels of various nutrients for very low birth weight infants has been ongoing for many years.  Specifically, early protein is beneficial in improving neurodevelopmental outcome. In addition, human milk prevents complications such as necrotizing enterocolitis and late onset sepsis.  If these occur during the NICU course, it increases the potential for poor neurodevelopmental outcome.

Finally, back to the infant I remember so vividly from my early NICU days; yes, he did survive and go home as a healthy infant!  He would be 34 or 35 years old today.  I have not kept touch, but trust he is a healthy adult, and perhaps raising his own family.

References:

1. Jacquemyn Y, Zecic A, Van Laere D, Roelens K.  The use of intravenous magnesium in non-preeclamptic pregnant women: fetal/neonatal neuroprotection.  Arch Gynecol Obstet. 2014;12.doi:10.1007/s00404-014-3581-1

2. Juul S.  Neuroprotective role of erythropoietin in neonates .  The Journal of Maternal-Fetal and Neonatal Medicine, 2012; 25(S4): 105–107

3. Ohlsson A, Aher SM. Early erythropoietin for preventing red blood cell transfusion in preterm and/or low birth weight infants. Cochrane Database Syst Rev 2006;CD004863.

4. Xu X-J, Huang H-Y, Chen H-L. Erythropoietin and retinopathy of prematurity: a meta-analysis.  Eur J Pediatr (2014) 173:1355–1364 DOI 10.1007/s00431-014-2332-

5. Leuchter RH-V, Gui L,Poncet A,Hagmann C, Lodygensky GA, Martin E, Koller B, Darqué A, Bucher HU, Hüppi PS.  Association between early administration of high-dose erythropoietin in preterm infants and brain MRI abnormalities at term equivalent age.    JAMA.2014;312(8):817-824. doi:10.1001/jama.2014.9645

6. Hsiao CC, Tsai ML, Chen CC, Lin HC.  Early optimal nutrition improves neurodevelopmental outcomes for very preterm infants.  Nutr Rev. 2014 Aug;72(8):532-40. doi: 10.1111/nure.12110.

 

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