Association of Human Milk Fortifier and Feeding Intolerance in Preterm Infants: A Cohort Study about Fortification Strategies in Southwest China

Abstract

Background: The present strategy of administering human milk fortifier (HMF) in southwest China (swC) is mainly based on European and American populations’ guidelines. Additionally, some southwest Chinese preterm infants have been observed to develop feeding intolerance (FI) after administration of HMF. In order to develop adapted southwest Chinese guidelines for the administration of HMF to preterm infants and improve fortification strategies, a retrospective cohort study was performed to explore the association of the use of HMF and FI. Objective: To explore the association between HMF and FI in preterm infants and provide recommendations for its use in swC. Methods: This cohort study included 298 preterm infants from West China Second University Hospital. Maternal and infant clinical data were collected from electronic patient records. The infant cohort was divided into two groups based on the use/nonuse of HMF. The association between HMF and FI was evaluated using multivariate analysis. Nonlinear relationships and threshold effects were evaluated using generalized additive models and two-piecewise linear regression models. Results: The multivariate analysis confirmed that there is no significant association between HMF use and FI, but significant risk factors for FI include early HMF initiation (p = 0.02), full-strength HMF initiation (p = 0.04), and fast HMF supplementation rates (p = 0.004). Through smooth curve fitting and threshold effect analysis, we found that two inflection points, an initial concentration of HMF > 24 mg/mL and a HMF supplementation rate > 12.5 mg/mL/d, significantly increased FI risk. Conclusions: Routine HMF fortification can be safely used in preterm infants with gestational age < 32 wk or birth weight < 1500 g in swC, and we advise initiating fortification when enteral milk intake reaches 100 mL/kg/day, with an HMF concentration of 1:50 and if tolerated, increase to 1:25 more than 38 h. The recommended HMF supplementation rate differs from current guidelines and provides evidence for developing southwest Chinese guidelines. A prospective trial is needed in order to validate this proposal.

Keywords: breast milk; enteric nutrition; feeding intolerance; human milk fortifier; preterm infant; smooth fitting curve; southwest China; threshold effect.

Figure 1

Patient flow diagram. BW, birth weight; FI, feeding intolerance; GA, gestational age; HMF, human milk fortifier; NICU, neonatal intensive care unit.

Figure 2

Forest plots for multivariate logistic regressions of the use of HMF on FI. FI, feeding intolerance; HM, human milk; HMF, human milk fortifier. Results on the right side reflect an increase in FI.

Figure 3

Estimated probability of experiencing feeding intolerance (FI) by initial concentration of human milk fortifier (HMF), based on a generalized additive model controlling for birth weight (BW), rate of milk supplementation, and HM volume when HMF supplement. The red curve in the middle is the spline smoothing, and the blue curve on both sides represents the 95% confidence interval.

Figure 4

Estimated probability of experiencing feeding intolerance (FI) by rate of human milk fortifier (HMF) supplementation, based on a generalized additive model controlling for gestational age (GA); birth weight (BW); admission temperature; initial concentration of HMF. The red curve in the middle is the spline smoothing, and the blue curve on both sides represents the 95% confidence interval.