LIFT-UP: Randomized Controlled Trial of Fortification of Human Milk

AIM: To improve feeding and growth outcomes among very low birthweight (LBW; ≤1.5kg) or very preterm (≤32 weeks gestational age) infants admitted to neonatal intensive care units (NICU) in India through fortification of human milk.

OBJECTIVE: To evaluate (via individually randomized controlled study) the efficacy of feeding routinely and fortified human milk using a standardized clinical protocol to very LBW or very preterm infants in the NICU compared to not feeding routinely fortified human milk using the standardized clinical protocol.

STUDY DESIGN This study is a multi-site individually randomized prospective trial among VLBW or VPT infants admitted to the NICU in study facilities who consume human milk and meet eligibility criteria (along with their mothers).

SCREENING AND ENROLLMENT All infants admitted to the NICU and their mothers will be screened for study eligibility. Screening will be performed within 24 hours of birth for inborn infants and within 48 hours of birth for outborn infants. Eligible dyads with the intention to feed human milk \[mother's own milk (MOM) or pasteurized donor human milk (PDHM)\] whose mothers provide consent will be enrolled into the study.

Once the mother-infant dyad is enrolled and prior to randomization, they will:

Receive the guideline-driven standard of care and be provided access to breast pumps to help initiate and advance breast milk feeding. The guideline-driven standard of care includes facility-based lactation support/feeding counseling + KMC + WASH components designed specifically for small vulnerable newborns and was developed as part of a different study protocol (see NCT06390943).

Adhere to a clinical guideline including targets for initiating and advancing breast milk feeding. Initially, this clinical guideline will help infants achieve breast milk volume intake of at least 60 mL/kg/day, the primary criterion for randomization. After randomization, the clinical guideline will continue to support advancing human milk feeding for all infants advance to 180 mL/kg/day.

RANDOMIZATION Once an infant consumes at least 60 mL/kg/day of breast milk, enrolled dyads will be assessed for eligibility for randomization. Eligible dyads will be randomized individually in a 1:1 ratio to either the intervention or comparison arm. Randomization sequences will be previously generated by the study statistician. If an infant does not consume at least 60 mL/kg/day of breastmilk by day 10 of chronological age, the mother-infant dyad will be administratively withdrawn from the study.

DELIVERY OF INTERVENTION Mothers of infants randomized to the intervention arm will express their breast milk into a standardized measurement cup (or PDHM can be used). Clinical research staff will mix human milk fortifier (HMF) in human milk (either MOM or PDHM, if available) per manufacturer specifications per feed for a minimum of 21 days.

Dyads in both arms will continue to receive the guideline-driven standard of care, access to breast pumps, and follow the volume target and trajectory protocol until they meet stopping criteria. Data will be collected every 24 hours, including a log at every feed, regardless of study arm assignment.

If an infant in either arm does not meet protocolized minimum volume targets or trajectories AND that infant meets weight-based safety net criteria, clinicians will intervene per judgment aligned with national and local protocols.

The intervention will not be continued once the infant meets stopping criteria with the goal of the infant having fully transitioned to exclusive breast milk feeding by then.

STOPPING CRITERIA After the minimum duration of 21 days post-randomization, hospitalized infants should continue to receive volume targeted feeding with or without HMF for as long as they receive expressed breast milk. Once infants transition to full, direct breastfeeding in preparation for discharge or are being discharged per clinician discretion, they will stop adhering to the volume targets and infants in the intervention group will stop receiving fortified human milk.

DISCHARGE FROM FACILITY TO HOME After stopping criteria are met, routine clinical care around infant feeding will be provided. Infants can be discharged home when deemed clinically appropriate per facility protocols and clinician judgment. The guideline-driven standard of care will encourage all mothers to exclusively breastfeed their infants prior to discharge and to continue doing so after discharge.

POST-DISCHARGE FACILITY VISITS All dyads will be followed up at 2 weeks of age, 4 weeks of age, and 3 months of chronological age.

• Length of Stay [Time frame: From date of randomization until the date of facility discharge or date of death from any cause, whichever came first, assessed up to 3 months of age.]
• Feeding intolerance [Time frame: From randomization to facility discharge, assessed up to 3 months of age]
• Weight growth velocity [Time frame: From randomization to facility discharge, assessed up to 3 months of age]
• Length gain [Time frame: From randomization to facility discharge, assessed up to 3 months of age.]
• Head circumference gain [Time frame: From randomization to facility discharge, assessed up to 3 months of age]
• Necrotizing enterocolitis (NEC) [Time frame: From randomization to facility discharge, assessed up to 3 months of age.]
• Sepsis/possible serious bacterial infection (PSBI) [Time frame: From randomization to facility discharge, assessed up to 3 months of age]
• Infant mortality [Time frame: From randomization to 3 months of age]
• Birthweight regain [Time frame: 2 weeks of age]
• Mean weight growth velocity (4 weeks) [Time frame: From randomization to 4 weeks of age]
• Neonatal mortality (4 weeks) [Time frame: From randomization to 4 weeks of age]
• Sepsis/possible serious bacterial infection (PSBI, 4 weeks) [Time frame: From randomization to 4 weeks of age]