Editorial: Untangling the knottiest neonatal challenges

Successful intensive care depends on imposing order onto complex, interconnected physiologic processes. The intensivist recognizes not only the patient's overarching diagnosis but also understands the many sublayers that comprise the diagnosis. He or she knows that intervening to fix one derangement might lead to complications in another organ system, sometimes long after the intervention itself. High-quality research helps prune away some of this complexity by clarifying disease processes and delineating the circumstances in which a given treatment is effective, safe, and worthwhile. The reviews in this year's neonatology section of Current Opinion in Pediatrics focus on efforts to apply order to some of the field's more sprawling challenges. Each addresses common clinical scenarios that remain formidable, in large part because the set of contingencies each one raises is vast and – at least historically – the available evidence about the benefit of any given clinical approach was thin. The reviews in this section show, however, that accumulating research is establishing a more precise understanding of how to approach these inherently complex scenarios. They chart a course toward greater certainty when managing patients with intricate medical problems with long-term implications. Walker and Cole's (pp. 177–181) discussion of advances in managing infants with ultrashort bowel syndrome is a perfect example. Ultrashort bowel syndrome is a severe subtype of short bowel syndrome; affected patients have only 10–25 cm of intestine distal to the ligament of Treitz or less than 10% of expected bowel length for corrected gestational age. They are subject to a host of potentially life-threatening complications that range from severe infection to essential nutrient malabsorption to liver failure. Until recently, there has been little guidance available in the literature. Patients with ultrashort bowel syndrome are rare, and poor overall survival has made systematic study difficult. Even the most seasoned clinician could be forgiven for feeling adrift in trying to successfully navigate such a case. Yet as Walker and Cole's (pp. 177–181) review makes clear, recent pharmaceutical advances and clinical trials have begun to untangle some of the complexity. Standardization of enteral therapy, liver-sparing lipid formulations, and new medicines are coalescing into a more uniform approach that offers hope to families facing this condition. Neonatal practitioners are frequently called upon to counsel parents contemplating extremely premature delivery at the threshold of viability. This is another familiar circumstance in which a web of interconnected contingencies is further complicated by divergent evidence and opinions. In their excellent contribution, ‘Deliveries at extreme prematurity: Outcomes, approaches, institutional variation and uncertainty,’ Arzuaga and Cummings (pp. 182–187) establish a framework with which to conceptualize – and thereby simplify – these profoundly consequential conversations. Arzuaga and Cummings (pp. 182–187) discuss how overreliance on neonatal morbidity and mortality data – which may be subject to reporting and selection biases, and often fail to reflect recent advances in perinatal and neonatal therapies – has for too long limited the scope of counseling before extremely premature deliveries. They emphasize that conversations around this topic should be grounded on an individualized understanding of the parents’ values and should include discussion of how any given course of action might carry implications for the mother's long-term health. They remind us that epidemiologic morbidity and mortality data used in these conversations must be selected carefully. Such data should reflect any regional or institutional variation from national norms and should incorporate as much fetal data as possible, including variables such as estimated fetal weight and sex, in addition to gestational age. Among topics whose combined complexity, nebulousness, and impact weigh on the minds of neonatal practitioners worldwide, likely few rank higher than how to prevent necrotizing enterocolitis (NEC) among their preterm patients. A potentially devastating, multifactorial disease, episodic in nature, and without any reliable prodrome to prompt an early response, NEC inspires a deep-seated fear in every neonatal ICU. Unfortunately, evidence-based approaches to preventing NEC are few and far between. Provision of early breast milk (either mother's own or donor) is the best supported preventive, but still leaves the field a long way from eradication of this disease. Multiple animal models and many decades of clinical experience suggest that gut bacteria are an important contributor to NEC pathogenesis. Concomitant sepsis from translocation of intestinal bacteria is frequent in NEC, and surgical pathology specimens typically show bacterial invasion into diseased luminal tissue. More recently, key interactions between bacteria and pro-inflammatory intestinal immunological responses have been implicated as important early steps in NEC progression. This line of investigation has advanced rapidly in the era of culture-free microbiome characterization. Multiple studies have shown that dysbiosis in the infant gut frequently precedes NEC. (Dysbiosis is expansion of a potentially pathologic bacterial subpopulation at the expense of a more stabilizing anchor population; it often also involves a decrease in overall microbiome diversity.) Together these facts have led to the hypothesis that replacement of a physiologic gut microbiome through administration of probiotics to at-risk premature infants might be a way to prevent NEC. Evidence from early studies was conflicting but provided reasons for optimism. More recent, larger studies and meta-analyses have further bolstered support for probiotic therapy as a NEC preventive, and many neonatal ICUs have now adopted the practice. But not everyone is convinced that current probiotic practices are well founded or safe. In a pair of well-reasoned and balanced articles, Underwood (pp. 188–194) presents the case for routine administration of probiotics to neonates at risk for NEC, whereas Pell et al. (pp. 195–201) argue that inadequate research evidence, lack of uniform production and regulatory frameworks, and concerns about cross-contamination within the ICU are reasons to study and prepare further before making probiotic administration to premature infants standard-of-care. Reading these two reviews may not leave you more certain about administering (or not) probiotics to NEC-susceptible patients. Both mount compelling arguments that could justify either approach. But together they delineate the exact contours of this ongoing discussion, capturing the full range of considerations that will ultimately inform our field's consensus about if, how, and when to adopt this new preventive modality. Finally, Glass et al. (pp. 202–209) shine welcome light on successful management approaches toward neonates with neurologic disease. The realm of neonatal neurologic illness, treatments, and potential complications is vast and – for many neonatologists – made difficult to conceptualize because of limited long-term follow-up opportunities. Interventions to respond to an immediate neurologic concern, such as seizure or an evolving stroke, are often shadowed by doubt about possible complications that would not manifest until years later. Evidence about how one approach or another might play out in the distant future is often murky or simply nonexistent. Glass et al. (pp. 202–209) describe the successful conceptualization and implementation of a neurointensive care nursery (NICN) at University of California San Francisco's Benioff Children's Hospital. They discuss how establishment of this unique brain-focused neonatal ICU has fostered enhanced clinical collaboration between neonatal and pediatric neurology-trained subspecialists, standardized treatment algorithms, permitted carefully controlled and rigorous study of both near and long-term outcomes, and provided many novel opportunities for interface between the NICN, the surrounding university, and the state of California. The NICN and the capabilities it provides seem motivated by the impulse we introduced at the outset: to de-convolute complex, unwieldy pathophysiologic processes, stripping them down to their component parts so that they can be studied, understood, and corrected. It is a fine example of a certain way of looking at disease – as a category to hold many composite problems, each potentially subject to optimum, evidence-based therapy – that all neonatologists (indeed, all physicians) share. This idea is the driving force behind this issue. We hope you find the articles as engaging, educational, and thought-provoking as we did. Acknowledgements None. Financial support and sponsorship None. Conflicts of interest There are no conflicts of interest.

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