The Choice of Population and Outcomes in Neonatal Trials on Hyperbilirubinemia: Are They Relevant? An Analysis of Cochrane Neonatal Reviews

Abstract

<b><i>Background:</i></b> Neonates with jaundice are usually managed according to their serum bilirubin despite an unclear overall correlation between bilirubin levels and patient-important outcomes (PIOs) such as kernicterus spectrum disorder (KSD). <b><i>Objectives:</i></b> We examined data from Cochrane Neonatal reviews to assess whether conditions that constituted KSD were included as key outcomes and how commonly they occurred in the population studied. <b><i>Methods:</i></b> We identified Cochrane reviews, published till November 2017 that evaluated interventions for neonatal jaundice (NNJ). We extracted the following information at the review and study levels: included population, outcomes assessed (in particular, whether PIOs such as KSD were listed as the primary outcomes), as well as their cumulative incidence in the reviews. <b><i>Results:</i></b> Out of 311 reviews, 11 evaluated interventions for NNJ with 78 randomized controlled trials (RCTs) included. Among the reviews, a total number of 148 outcomes were predefined and 30 (20.3%) were PIOs related to KSD, with 11 (36.7%) listed as primary outcomes. Among the 78 included RCTs (total participants = 8,232), 38 (48.7%) enrolled predominantly high-risk and 40 (51.3%) enrolled predominantly low-risk population. A total number of 431 outcomes were reported, and 40 (9.2%) were PIOs related to KSD (of which 37 were from studies with high-risk infants), with 13 (32.5%) listed as primary outcome. Cumulatively, no infant developed KSD across all studies. <b><i>Conclusions:</i></b> There is suboptimal representation of PIOs such as KSD in neonatal trials and Cochrane reviews on NNJ. Over half of the trials included populations with very low risk of KSD, which does not represent judicious use of resources. Amidst our continued search for a more reliable surrogate marker for NNJ, studies should evaluate the whole spectrum KSD alongside serum bilirubin in high-risk populations with sufficiently significant event rates, as this will make the trial methodologically feasible, with findings that will impact the population concerned.

Surrogate Outcomes: An Inevitable Limitation of Hyperbilirubinemia-Driven Randomized Controlled Trials

“…The effect on the affected individual’s families is enormous, and the need for lifelong support continues after parents and close family members have passed on or left the close family circle. Contrary to Lai et al’s [3] contention that studies in low-risk populations are a waste of resources, and we are of the opinion that low-risk populations are the very population groups which should be targeted.…”

“…In the current issue of Neonatology, Lai et al [3] examined data from published Cochrane Neonatal reviews that evaluated interventions for neonatal jaundice. Of 431 outcomes reported in 78 randomized controlled trials up to November 2017, Lai et al [3] found that only 40 (9.2%) had research objectives based on the dreaded patient-important outcome, KSD, while no infant actually developed KSD across all the studies. Furthermore, over half the trials were performed in populations with very low risk of KSD.…”

Commentary on “Sunlight for the Prevention and Treatment of Hyperbilirubinemia in Term and Late-Preterm Neonates”

“…While the trial data do not currently support widespread adoption of this technology, further research could determine whether this promising approach is feasible, acceptable, safe, and effective in remote and rural as well as urban settings with restricted resources for conventional phototherapy, particularly in sub-Saharan Africa and South Asia. Trials should be simple and pragmatic and aim to evaluate outcomes, including bilirubin encephalopathy and mortality, of most importance to infants, their families, and health services [15]. Related questions may include exploring whether there is a subgroup of low-risk infants with mild jaundice who can be safely treated at home with filtered sunlight phototherapy.…”

Evaluation of the Quality of Perinatal Trials: Making the GRADE

“…Some areas of neonatal research, however, assess “surrogate,” rather than infant- and family-important, outcomes more commonly. For example, trials of interventions to prevent bilirubin encephalopathy and kernicterus spectrum disorder have tended to report the effect on serum bilirubin levels rather than on adverse neurodevelopmental outcomes [30]. While this may be a pragmatic approach given the rarity of kernicterus spectrum disorder, particularly in countries with well-resourced perinatal health services, evidence exists that even very plausible surrogate outcomes such as hyperbilirubinaemia may not necessarily predict infant-important outcomes accurately [31, 32].…”