MANUSCRIPT CITATION:

Alexander T, Asadi S, Meyer M, Harding JE, Jiang Y, Alsweiler JM, et al. Nutritional Support for Moderate-to-Late–Preterm Infants — A Randomized Trial. N Engl J Med. 2024;390:1493–1504. PMID 38657245.

REVIEWED BY:

Tristan Dear, MD
University of Colorado
tristan.dear@cuanschutz.edu

Jane Stremming, MD
University of Colorado
jane.stremming@cuanschutz.edu

TYPE OF INVESTIGATION:

Treatment

QUESTION:

In moderate-to-late preterm gestation infants (P) who had intravenous access and whose mothers intended to breastfeed, do any of the following interventions of (1) intravenous amino acid solution compared to dextrose solution, (2) milk supplement when mother’s milk was insufficient compared to exclusively mother’s milk, or (3) taste and smell exposure before gastric-tube feeding compared to no taste and smell exposure (I, C) affect body-fat percentage (O) at four months corrected gestational age or time to full enteral feedings (T).

METHODS:

Design: Multicenter, factorial, randomized trial

Allocation: Infants were randomized within 24 hours of birth to one of eight possible combinations of three interventions using a Web-based interface, with stratification according to hospital site, sex, and gestational age (moderate preterm of 32 weeks 0 days to 33 weeks 6 days completed gestation or late preterm of 34 weeks 0 days to 35 weeks 6 days completed gestation).

Blinding: Unblinded

Follow-up period: Four months corrected gestational age for the parenteral nutrition and milk supplement interventions, and time to full enteral feedings of 150 ml/kg/d for the taste and smell intervention.

Setting: Five centers in New Zealand

Patients: 532 patients were randomly assigned

Inclusion criteria
• Born between 32 weeks 0 days and 35 weeks 6 days
• Admitted to a neonatal unit
• Had intravenous access that had been established for clinical reasons
• Mothers intended to breastfeed

Exclusion criteria
• Known chromosomal or genetic abnormality or congenital disorder affecting growth, body composition, or neurodevelopmental outcome
• Specific mode of nutrition indicated

Intervention:
Infants were assigned to three interventions or their comparators: amino acid solution or intravenous dextrose, milk supplement (donor breast milk or infant formula) or exclusively mother’s breast milk, and exposure or no exposure to the taste and smell of milk before each tube feeding. The taste intervention involved placing 0.2 ml of milk into the infant’s mouth with a syringe immediately before the gastric tube feed was initiated, and the smell intervention involved applying 0.1-0.5 ml of milk onto a piece of gauze which was placed near the infant’s nose for the duration of the gastric tube feed.

Infants received supplemental nutrition until mother’s breast milk met daily enteral volumes prescribed by the clinical team.

Outcomes:

The primary outcome for the parenteral nutrition and milk supplement intervention was body-fat percentage at four months corrected gestational age. The primary outcome for the taste and smell intervention was time to full enteral feedings (150 ml/kg/d) or exclusively breast feeding, whichever occurred first.

The secondary outcomes were:
• Time to removal of the nasogastric tube for at least 24 hours or until discharge from the hospital, whichever occurred first
• Number of days in the hospital
• Nutritional intake during weeks one and two of life
• Breastfeeding status at the time of hospital discharge and at four months corrected gestational age
• Body composition at time of hospital discharge and at four months corrected gestational age
• Change in growth measurements and z score from birth to hospital discharge and from birth to four months corrected gestational age

Analysis and sample size:
A sample size of 528 infants was calculated to provide a power of 90% with a two tailed type 1 error rate of less than 0.05 to detect a minimal clinically significant difference of 3% in fat mass at four months corrected gestational age for the parenteral nutrition and milk supplement interventions (280 infants, with 140 infants per intervention) and a reduction in the median time to full enteral feeding from 10 days to 7 days for the taste and smell intervention (480 infants, with 240 per intervention).

Analyses were based on the intention-to-treat principal, and included all infants in the groups to which they were assigned, whether or not they completed or received that intervention.

Protocol deviation was defined as when infants less than five days old received additional nutritional support to which they had not been assigned. Infants five days old and older that received additional nutrition were not classified as protocol deviations and considered an appropriate clinical decision.

Primary analysis was the main effect of each intervention against its comparator, with linear regression models used for parenteral nutrition and milk supplement interventions and the cox proportional-hazards model used for the taste and smell intervention.

Patient follow-up:
Of the 534 infants that underwent randomization, 532 infants were included in the modified intention-to-treat population. 531 (99%) infants were assessed at hospital discharge for parenteral nutrition and milk supplementation interventions and 526 (99%) infants were assessed for the taste and smell intervention. 485 (85%) infants were assessed at 4 months corrected gestational age, however, only 324 (61%) infants underwent body composition analysis for body-fat percentage at 4 months corrected gestational age because some assessments were completed at the infant’s home in the setting of the Coronavirus 2019 pandemic.

MAIN RESULTS:

Maternal and infant baseline characteristics were similar across intervention groups. There was maternal glucocorticoid exposure for 414 infants (77.8%), medical history of maternal diabetes for 101 infants (19%), and caesarean section delivery of 332 infants (62.4%). 277 infants (52.1%) were classified as moderate preterm (32 weeks 0 days to 33 weeks 6 days), and 255 infants (47.9%) were classified as late preterm (34 weeks 0 days to 35 weeks 6 days). Mean anthropometric variables at birth include weight of 2121.8 g, length of 44.5 cm, and head circumference of 31.2 cm. 59 infants (11.1%) were classified as small for gestational age.

Protocol deviations occurred in 2.2% of infants in the parenteral nutrition intervention, 6.1% of infants in the dextrose infusion intervention, 32.8% of infants in the exclusively mother’s own milk intervention, and 7.4% of infants in the taste and smell exposure intervention.

A total of 14 adverse events occurred in 12 infants. Five infants had an extravasation injury requiring treatment or referral to a plastic surgery team, one infant had nonelective removal of a central venous line, three infants had culture proven late-onset sepsis, and three infants had probable late-onset sepsis. Three serious adverse events (necrotizing enterocolitis, gastrointestinal surgery, and death) occurred in one infant that was randomized to the parenteral nutrition, mother’s breast milk only, and no taste and smell exposure interventions.

For primary outcomes: body-fat percentage at 4 months corrected gestational age was similar between the parenteral nutrition (26.0 +/-5.4%) and dextrose (26.2 +/-5.2%) interventions (adjusted mean difference -0.2, with 95% confidence interval (CI) of -1.32 to 0.92, P = 0.72) and between the milk supplement (26.3 +/-5.3%) and mother’s breast milk-only (25.8 +/-5.4%) interventions (adjusted mean difference 0.65, with 95% CI of -0.45 to 1.74, P = 0.25). Time to full enteral feeding was also similar between the taste and smell (5.8 +/-1.5 days) and no taste and smell (5.7 +/-1.9 days) interventions (adjusted hazard ratio 0.95, with CI of 0.80 to 1.14, P = 0.59). There were no significant interactions between primary outcomes.

For secondary outcomes: characteristics of body composition were similar between intervention and comparator groups for all interventions at the time of hospital discharge and at 4 months corrected gestational age. Time to full enteral feeds was similar between parenteral nutrition and dextrose interventions and with milk supplement and mother’s breast milk only interventions. Time to full sucking feeds was also similar between parenteral nutrition/dextrose, milk supplement/mother’s breast milk only, and taste and smell/no taste and smell interventions. Breast milk feeding status at time of hospital discharge and at 4 months corrected gestational age with similar between interventions and groups, as well length of stay in the hospital. Changes in z scores for weight, length, and head circumference from birth to 4 months corrected gestational age and skin fold thickness were similar across interventions and groups.

CONCLUSION:

The authors conclude that a trial of three nutritional interventions implemented until reaching full nutrition of mother’s breast milk in moderate-to-late preterm infants whose mothers intended to breastfeed did not affect time to full enteral feedings or body composition at 4 months corrected gestational age. They conclude that for infants of mothers who intend to breastfeed, the mode of nutritional support should be tailored to best support an eventual transition to exclusive maternal breast milk consumption.

Commentary:

This trial, Nutritional Support for Moderate-to-Late Preterm Infants – A Randomized Trial [1], aimed to assess routine nutritional interventions in moderate-to-late preterm gestation infants, as there is limited literature guiding current nutritional strategies for this population. It examines three interventions (intravenous amino acid solution versus dextrose solution until full enteral feedings were established, milk supplement when mother’s milk was insufficient versus exclusive use of mother’s milk, and taste and smell exposure before gastric tube feeding versus no exposures) and assessed body-fat percentage at 4 months corrected gestational age and time to full enteral feeding. The study found no significant differences in these outcomes.

 

It is well established that nutrition is essential to growth rate, body composition, and neurodevelopment. Historically, preterm infants have faltering growth after delivery and are unable to match their in-utero growth rates, and undernutrition is a primary driver [2]. Interventions that may improve growth include parenteral nutrition, early enteral feeding initiation, and introduction of smell and taste with gavage feeds. There is debate about whether the addition of short-term parenteral nutrition is beneficial to newborns, as evidence in older populations suggests there may be increased morbidities with early introduction of parenteral nutrition [3]. This publication by Alexander et al. suggests that enriched nutritional support is not beneficial to an infant’s short-term growth. Further follow-up is ongoing, with planned assessment of neurodevelopment and growth at 2 years of age [4].

 

This study adds to the growing literature on the addition of smell and taste during tube feedings, demonstrating that while there appear to be minimal adverse effects, there is little identified benefit. A randomized control trial published in 2021 assessed effects of smell and taste during tube feeding on the growth of infants born under 29 weeks gestation and found no difference in weight at the time of discharge [5]. A recent Cochrane review also found that exposure to smell and taste of milk has little effect on time to full sucking feeds [6], consistent with findings in this study.

 

Limitations of this study include applicability only to parents intending to breastfeed, lack of stratification for small for gestation infants, unblinded study design, and high rates of protocol deviation for infants in the exclusively mother’s milk intervention. Infants born at this gestational age often receive milk fortification; however, the authors did not explicitly describe the protocol for fortification. Findings cannot be applied to infants with complicated clinical courses, as most infants reached full enteral feeds by one week of life.

 

The authors conclude that routine nutritional interventions while transitioning to full nutrition of mothers’ milk do not affect time to full enteral feeds or body composition at 4 months corrected age. Thus providers can collaborate with caregivers to develop a feeding plan that will best support establishment of exclusive breast milk feeds. While follow-up is still ongoing, these findings have implications for nutritional options while in the NICU, reinforce the importance of lactation support, and have the potential to reduce healthcare costs and interventions during an infant’s hospital stay.

References

1. Alexander T, Asadi S, Meyer M, Harding JE, Jiang Y, Alsweiler JM, et al. Nutritional Support for Moderate-to-Late–Preterm Infants — A Randomized Trial. N Engl J Med. 2024;390: 1493–1504.
2. Hay WW Jr. Nutritional Support Strategies for the Preterm Infant in the Neonatal Intensive Care Unit. Pediatr Gastroenterol Hepatol Nutr. 2018;21: 234–247.
3. Fivez T, Kerklaan D, Mesotten D, Verbruggen S, Wouters PJ, Vanhorebeek I, et al. Early versus late parenteral nutrition in critically ill children. N Engl J Med. 2016;374: 1111–1122.
4. Bloomfield FH, Harding JE, Meyer MP, Alsweiler JM, Jiang Y, Wall CR, et al. The DIAMOND trial – DIfferent Approaches to MOderate & late preterm Nutrition: Determinants of feed tolerance, body composition and development: protocol of a randomised trial. BMC Pediatr. 2018;18: 220.
5. Beker F, Liley HG, Hughes IP, Jacobs SE, Macey J, Twitchell E, et al. Effects on growth of smell and taste of milk during tube feeding of preterm infants: A randomized clinical trial: A randomized clinical trial. JAMA Pediatr. 2021;175: 1115–1123.
6. Delgado Paramo L, Bronnert A, Lin L, Bloomfield FH, Muelbert M, Harding JE. Exposure to the smell and taste of milk to accelerate feeding in preterm infants. Cochrane Database Syst Rev. 2024;5: CD013038.