High-Calorie Feeds Look Feasible for Newborns in Opioid Withdrawal, Pilot Trial Finds

Every year, thousands of newborns in the United States begin their lives in withdrawal from opioids they were exposed to in the womb, a condition known as Neonatal Opioid Withdrawal Syndrome, or NOWS. These infants are often irritable, feed poorly, and lose weight faster than clinicians would like, and their care teams face a difficult balancing act: how to deliver enough nutrition to fragile babies whose digestive systems and behavior are disrupted by withdrawal, without undermining the very feeding practices that are known to soothe symptoms and shorten hospital stays. A new randomized pilot study published in the Journal of Perinatology by Frances Y. Cheng of Yale University School of Medicine and colleagues offers some of the first controlled evidence on whether enriching infant feeds with extra calories is a practical and safe strategy for this vulnerable population.

The rationale for the trial rests on a well-documented clinical problem. Infants with NOWS tend to lose more weight after birth than other newborns, and earlier work by the same research group mapped early weight-loss percentile curves in opioid-exposed infants, showing that excessive weight loss is common and can trigger additional medical interventions. Because withdrawal disrupts feeding behavior, some clinicians have wondered whether high-calorie formula, which delivers more energy per milliliter than standard formula, could help these babies maintain their weight and possibly recover faster. But the idea has never been firmly established, and concerns linger about whether concentrated feeds might cause gastrointestinal upset, alter stooling patterns, or interfere with breastfeeding, which multiple studies have linked to milder withdrawal courses and shorter treatment.

To test whether such a trial is even possible, the researchers designed a double-blind randomized pilot study conducted in Connecticut and registered as NCT04419857. Between December 2020 and August 2023, they enrolled infants less than 48 hours old who had been prenatally exposed to methadone or buprenorphine, the two medications most commonly used to treat opioid use disorder in pregnancy. The babies were at risk for excessive weight loss and were being cared for under the Eat, Sleep, Console model, a function-based approach to assessing and treating NOWS that has rapidly replaced older scoring systems in many hospitals since a major randomized trial in the New England Journal of Medicine in 2023 showed it shortened hospital stays and reduced the need for medication.

Eligible infants were randomized to receive either standard-calorie or high-calorie feeds, with the feeding approach kept blinded to families and clinical staff wherever possible. The primary outcomes were deliberately pragmatic, reflecting the purpose of a pilot study: the investigators wanted to know whether they could enroll enough families, whether the randomized feeding assignments were actually followed at the bedside, and whether families stayed in the study. Adherence was measured as the proportion of feeds that followed the assigned approach, and retention was tracked both during the birth hospitalization and for two weeks after discharge, a window in which follow-up of this population is notoriously difficult.

The feasibility results were mixed in ways that are informative for anyone planning a definitive trial. Of 65 eligible infants, 35, or 53.8 percent, were randomized, a rate the authors judged comparable to other feasibility trials in similar settings. Once enrolled, families and staff largely stuck to the protocol: 84 percent of all feeds during hospitalization adhered to the randomized feeding approach, suggesting that a high-calorie feeding strategy can be implemented reliably in a real-world nursery environment. In-hospital retention reached 71.4 percent, but the picture changed sharply after discharge, with only 28.6 percent of families retained at the 14-day follow-up point. That attrition, the authors note, mirrors broader literature on post-discharge follow-up among families affected by opioid use disorder and represents the single biggest obstacle to a full-scale efficacy trial.

On the exploratory clinical outcomes, the two groups looked remarkably similar. There were no significant differences between the standard-calorie and high-calorie groups in demographic characteristics, in the maximum percentage of weight loss from birth, in the length of hospital stay, or in the frequency of stooling. The weight-loss finding, with a p-value of 0.12, and the length-of-stay finding, with a p-value of 0.88, do not rule out effects in either direction, since a pilot study of 35 infants is not powered to detect differences; rather, they establish that neither outcome showed an obvious signal of harm or benefit that would demand immediate changes to practice. The stooling comparison, which addressed concerns that concentrated feeds might slow the gut, was similarly unremarkable at p equal to 0.59.

One exploratory result stood out. Infants in the high-calorie group were more frequently receiving breastmilk at the time of discharge, a difference that reached statistical significance at p equal to 0.04. The finding runs counter to a plausible worry: that introducing fortified or high-calorie formula early might displace breastfeeding and reduce a mother’s milk supply or her confidence in nursing. Prior observational studies, including work showing that breastmilk feeding is associated with shorter treatment courses in NOWS, and clinical protocols from the Academy of Breastfeeding Medicine supporting breastfeeding in the setting of stable maternal opioid agonist treatment, have made the preservation of breastfeeding a central goal of NOWS care. The pilot’s data, while exploratory and drawn from a small sample, suggest that early high-calorie supplementation did not appear to be negatively associated with breastfeeding in this cohort.

The study also contributes to a small but growing evidence base on formula composition for opioid-exposed newborns. An earlier randomized feasibility study by Bogen and colleagues tested standard versus high-calorie formula in methadone-exposed infants, and other trials have examined energy-enriched formula in infants recovering from congenital heart surgery, another population at high risk of growth failure. Meanwhile, a systematic review of milk feed osmolality has raised general questions about the tolerability of concentrated feeds in newborns, making controlled data in the NOWS population particularly valuable. The Yale-led trial adds the important element of randomization under the modern Eat, Sleep, Console care model, which changes the context in which feeding decisions influence pharmacologic treatment and length of stay.

The authors are careful about interpretation, and appropriately so. As a pilot study, its purpose was not to prove that high-calorie feeding works or fails, but to determine whether a definitive randomized trial is achievable and to identify the design features it would need. The enrollment and adherence figures suggest the answer is a qualified yes within the hospital, while the 28.6 percent post-discharge retention signals that any future trial should invest heavily in retention strategies, an area with an established methodological literature ranging from participant-centric contact approaches to systematic reviews of retention interventions in pediatric trials. The statistical framework also had to contend with missing data, a challenge the team addressed using established methods for inference under missingness.

For clinicians caring for the rising number of infants born with opioid exposure, the practical message is one of cautious reassurance rather than a change in practice. High-calorie feeds were delivered as intended in more than four out of five feeds, did not visibly worsen weight loss trajectories, stooling, or hospital stay, and were not associated with reduced breastfeeding at discharge. For researchers, the study maps the terrain for the next step: a larger, adequately powered randomized trial with robust post-discharge follow-up to determine whether enriched nutrition can meaningfully reduce excessive weight loss in NOWS without compromising the human-milk feeding that so much evidence suggests benefits these infants. Until such a trial is completed, feeding decisions for newborns in withdrawal will continue to rest on clinical judgment, family preference, and the growing but still incomplete evidence base this pilot study has helped to build.

Subject of Research: Feasibility of high-calorie versus standard feeding in newborns with Neonatal Opioid Withdrawal Syndrome managed with Eat, Sleep, Console

Article Title: Randomized pilot study comparing standard vs high-calorie feeding in infants with Neonatal Opioid Withdrawal Syndrome

Article References: Randomized pilot study comparing standard vs high-calorie feeding in infants with Neonatal Opioid Withdrawal Syndrome. (n.d.). https://doi.org/10.1038/s41372-026-02913-5

Image Credits: AI Generated

DOI: 10.1038/s41372-026-02913-5

Keywords: Neonatal Opioid Withdrawal Syndrome, high-calorie formula, Eat Sleep Console, randomized pilot study, breastfeeding, neonatal weight loss, methadone exposure, buprenorphine exposure, neonatal nutrition, Journal of Perinatology, clinical trial feasibility, opioid use disorder in pregnancy