Two recent RCTs in high risk newborns of things I would never have thought of.
The first is a trial of Estradiol and Progesterone supplementation (Trotter A, Steinmacher J, Kron M, Pohlandt F. Neurodevelopmental Follow-Up at Five Years Corrected Age of Extremely Low Birth Weight Infants after Postnatal Replacement of 17β-Estradiol and Progesterone. Journal of Clinical Endocrinology & Metabolism. 2012;97(3):1041-7. http://jcem.endojournals.org/content/97/3/1041.abstract). The idea being that fetuses are usually exposed to these hormones at high concentration during the last half of pregnancy and very preterm babies miss out on this exposure, and that these hormones are also are known to have neuroprotective effects in certain model systems. The reasonable conclusion being that abnormalities of brain development in very preterm infants, even those who do not have intracerebral hemorrhages, might in part be due to a lack of these 2 hormones. Babies < 29 weeks and < 1000 g were randomized. The study was clearly very underpowered for a 5 year developmental outcome (n=83, 71 survivors to 5 years, 61 agreed to inclusion in the study), but did have some suggestive results that should be considered for future studies.
The authors previously published a 15 month follow up of extremely low birth weight infants from another pilot study : (Trotter A, Bokelmann B, Sorgo W, Bechinger-Kornhuber D, Heinemann H, Schmücker G, et al. Follow-Up Examination at the Age of 15 Months of Extremely Preterm Infants after Postnatal Estradiol and Progesterone Replacement. Journal of Clinical Endocrinology & Metabolism. 2001;86(2):601-3. http://jcem.endojournals.org/content/84/12/4531.long). That study was even more underpowered, (30 randomized, 25 survivors, 24 evaluated) the hormone treated babies had higher Bayley motor index, 101 vs 71 for the controls, which was not statistically significant. Is there a place for a larger multicenter trial?
The other trial was from the inimitable Paolo Manzoni. Two carotenoids found in breast-milk were studied because of their potential anti-oxidant effects, and the putative role of oxidative injury in the pathogenesis of Necrotizing Enterocolitis, Retinopathy and Bronchopulmonary Dysplasia. (Manzoni P, Guardione R, Bonetti P, Priolo C, Maestri A, Mansoldo C, et al. Lutein and Zeaxanthin Supplementation in Preterm Very Low-Birth-Weight Neonates in Neonatal Intensive Care Units: A Multicenter Randomized Controlled Trial. Am J Perinatol. 2012(EFirst). Epub 2012/07/10. https://www.thieme-connect.com/DOI/DOI?10.1055/s-0032-1321494). This moderately sized trial (about 115 very low birth weight infants per group) showed non-significant positive effects in all 3 of the target outcomes. As this was a relatively low-risk group (mean gestational age around 30 weeks) the incidence of each of the outcomes was not large (about 10% for RoP and BPD for example) so even 40 to 60% lower incidence (for RoP and BPD respectively) with treatment was not significant. Given the history of carotenoid supplementation for human disease, (beta-carotene led to an increase in lung cancer in adults, rather than the expected decrease Duffield-Lillico AJ, Begg CB. Reflections on the Landmark Studies of β-Carotene Supplementation. Journal of the National Cancer Institute. 2004;96(23):1729-31. http://jnci.oxfordjournals.org/content/96/23/1729.short.) we need to be very careful before widespread use of these agents
These trials point out a few things, that we need much larger trials to find positive results, now that many of our babies have good outcomes, that we need stable funded research networks to be able to quickly mount trials to address questions raised in trials such as these, and that we will have to prioritize which studies to be done in which order.