Human milk fortification strategies for improved in-hospital growth of preterm infants

Figures & data

Table 1: Enteral protein and energy requirements of a 1 kg preterm infant compared to the nutritional content of unfortified and fortified mature human milk

Enteral protein and energy requirements				Nutritional content
				Human milk, unfortified (11)			Human milk, standard fortified (1 g FM85/20 ml milk) (11,17)
				Milk volume (ml)			Milk volume (ml)
Nutrient	Unit	AAP (14)	ESPGHAN (15)	150	180	200	150	180	200
Protein (g/day)		3.4 to 4.2	3.5 to 4.0	1.4 to 1.8	1.6 to 2.2	1.8 to 2.4	2.9 to 3.3	3.4 to 4.0	3.8 to 4.4
Energy	kcal/day	110 to 130	110 to 135	98 to 105	117 to 126	130 to 140	124 to 131	149 to 158	165 to 175
	kJ/day^*	462 to 546	462 to 567	412 to 441	491 to 529	546 to 588	521 to 550	626 to 664	693 to 735
Protein:energy ratio	g/100 kcal	2.6 to 3.8	3.2 to 3.6	1.3^** to 1.8^*** (1.6^****)			2.2^** to 2.7^*** (2.4^****)
	g/100 kJ	0.6 to 0.9	0.8 to 1.0	0.3^** to 0.4^*** (0.37^****)			0.5^** to 0.6^*** (0.6^****)

* 4.2 kJ/kcal used in conversion.

** Lowest protein and highest energy used in calculation.

*** Highest protein and lowest energy used in calculation.

**** Mid-values of protein and energy used in calculation.

Table 2: Outcomes of alternative human milk fortification intervention strategies

Alternative fortification strategy	Study		Intervention				Outcomes in terms of in-hospital growth		Other outcomes, including adverse effects	Reference
	Design	Sample	Initiation of standard fortification	Initiation of alternative fortification	Volume and type of milk	Type of fortifier and supplement	Growth parameter	p-value
Super-fortification	Randomised controlled trial:	n = 84	When volume of intake at:	When volume of intake at:	Full volume (ml/kg/d):	Fortifier:	W gain (g/d)	0.38	Feeding tolerance:	^20
	Moderate (MF) and Aggressive fortification (AG) compared to Standard fortification (SF)		90 to 100 ml/kg/d	150–170 mL/kg	SF: 155 ± 4.6	Eoprotin (Milupa, Germany) (Cow’s milk based)	W gain (g/kg/d)	0.24	NS differences in feeding tolerance, residuals, abdominal distension, frequency of stooling
		GA ≤32wk	GA (weeks): SF: 31	Day of life:	MF: 154 ± 6
			MF: 30.5	MF: 12	AG: 156 ± 6.9
									1 Patient in MF group developed NEC
			AG: 30.5	AG: 10	(p = 0.59)		L at discharge (cm)	0.85	Biochemistry:
			(p = 0.18)
		BW ≤1500 g	W (g):	Duration:	Type:		HC (cm/wk)	0.001	NS differences in S-urea, S- calcium, S-phosphorous, S-ALP
			SF: 1106	Until discharge from hospital	Human milk (no indication if donor milk was used)				Blood gas within normal range; no metabolic acidosis
			MF: 1066
			AG: 1097
			(p = 0.73)
Adjustable fortification (AF)	Prospective observational intervention:	n = 58	When volume of intake at:	When volume of intake at:	Median volume (ml/kg/d):	Fortifier:	W velocity (g/kg/d)	0.053	Feeding tolerance:	^22
			80 ml/kg/d	not clear from article	SF: 141 (90–160)`	Aptamil Eoprotin (Milupa, Germany) (Cow’s milk based)	L velocity(mm/d)	0.008	NS differences in “feeding interruption” (abdominal distention and/or GRV > 50% and/or vomiting)
	SF plus additional protein supplement (based on weekly S-BUN levels) compared to SF (Historical control group)	GA ≤32wk	Median age:	Day of life:	AF: 143.5 (125 −163)		HC velocity (mm/d)	<0.001
			Day of life: 8 (for SF and AF)	17	(p = 0.135)		Daily growth index for W (%)	0.026
		BW ≤1500 g		Mean W (g):	Type:	Protein supplement:	Daily growth index for L (%)	0.027	Clinical outcome:
				1501 (±252)	Exclusively fed	Protifar (Nutricia, Netherlands)	Daily growth index for HC (%)	0.003	Similar between groups: NEC, BPD, ROP requiring laser treatment
				Duration:	mother’s own milk		Subgroup analysis of GA ≤ 28wk:
				At least two weeks (median duration 21d)			W velocity (g/kg/d)	0.192
							L velocity (mm/d)	0.04
							HC velocity (mm/d)	0.004
							Daily growth index for W (%)	0.09
							Daily growth index for L (%)	0.053
							Daily growth index for HC (%)	0.027
Adjustable fortification	Randomised controlled trial:	n = 32	When volume of intake at:	When volume of intake at:	Full volume:	Fortifier:	W gain (g/d)	< 0.01	Feeding tolerance:	^24
			90 ml/kg/d	150 ml/kg/d	150 to 160 ml/kg/d	FM85 (Nestle, Italy)	W gain (g/kg/d)	< 0.01	NS differences in feeding intolerance as defined by: emesis, withholding of feeds, abdominal distention
	Fortifier and additional protein supplement (based on twice-weekly S-BUN levels) compared to SF	GA ≤34wk		Day of life:			L gain (mm/d)	> 0.05	No study infant had NEC or systemic infection
				19		Protein supplement:			Biochemistry:
		BW ≤1700 g		Duration:	Type:	Pro-Mix (Corpak Medsystems, USA)	HC gain (mm/d)	<0.05	S-albumin, S-creatinine and S-calcium: did not change significantly
				Until W of 2000 g (at least 14 days)	Own mother’s milk or banked donor milk				S-BUN, S-phosphorous, S-ALP: NS increased
Adjustable fortification	Randomized controlled trial:	n = 61	When volume of intake at:	When volume of intake at:	Prescribed volume of intake:	Fortifier:	W gain (g/kg/d)	NS	Feeding tolerance:	^23
			Full enteral feeding	Full enteral feeding	160 ml/kg/d	Aptamil			No information given
	Fortifier and additional protein supplement (based on S-BUN level) compared to SF	GA≤32wk					L gain (cm/wk)	NS
		BW 580 to 1250 g		Duration:	Type:	Protein supplement:	HC gain (cm/wk)	NS	Biochemistry:
				Until discharge or transfer to other hospital or when >50% of milk taken directly from breast	Own mother’s milk and banked donor milk	Protifar (Nutricia, Netherlands)	In ELBW sub-group (W 580–980 g; GA 23–30wk):		Significantly higher S-urea levels
							W gain (g/kg/d)	0.05	NS lower pH levels
							Length gain (cm/wk)	0.04	Metabolic acidosis and increased S- creatinine: not more than previously seen
							HC gain (cm/wk)	0.02
Target fortification (TF)	Prospective clinical trial:	n = 10 (plus 20 for matched-pairs)	When volume of intake at:	When volume of intake at:	Feeding volume:	Fortifier:	W gain similar between groups but feeding volume in SF group significantly higher than in IF group (p < 0.001)		Feeding tolerance:	^25
			Not indicated	Step-wise introduction over a 3 day period, full amount of target fort on day 4	147 ± 5 ml/kg/d (TF)	Similac (Abbott Nutrition, USA)			No feeding intolerance seen (GRV > 50% previous feeding volume; emesis; abdominal distention; decrease/delay/discontinuation of feeds)
	Fortifier plus additional protein, fat and carbohydrate supplements (based on human milk analysis) compared to SF (matched-paired groups of infants in the same neonatal unit)	GA <32w			155±5 mL/kg (SF)	Supplements:
		BW <1500 g				Protein:
		n = 10 (plus 20 for matched-pairs)		Volume of intake not indicated		Beneprotein (Nestle Health Care Nutrition, USA)	Linear relationship between milk intake and wt gain seen in IF group but not in SF group		Biochemistry:
		GA <32w		Day of life:		Fat:			S-TG,S- BUN,S- protein, S-albumin and glucose all within normal ranges .No metabolic acidosis seen
				30		Microlipid (Nestle HealthCare Nutrition, USA)
		BW <1500 g		Duration:	Type:	Carbohydrate:
				Minimum of 3 consecutive weeks	Own mother’s milk	Polycose (Abbott Nutrition, USA)
Target fortification	Prospective randomised trial:	n = 78	When volume of intake at:	When volume of intake at:	Feeding volume:	Fortifier:	W velocity (g/kg/d)	0.03	No cases of NEC or death reported	^26
			100 ml/kg/day or sooner	Once standard fortified feeds tolerated	Not indicated	Prolact+H^2MF (Prolacta Bioscience, USA)	L velocity (cm/wk)	0.02
	Fortifier plus additional human milk cream supplement (based on human milk analysis) compared to SF	GA		Day of life:			HC (cm/wk)	0.21
		SF 27.7±2.1		Not indicated
		TF 27.6±1.6 (p = 0.88)
		BW 750 to 1250 g		Duration:	Type:	Supplement:	W velocity from time		NS in number of sepsis episodes
				Until 36 weeks PMA or when weaned from fortification	Own mother’s milk and pasteurised donor milk	Fat:	BW regained (g/d)	0.02
						Prolact CR (Prolacta Bioscience, USA)	W velocity from time
							BW regained (g/kg/d)	0.02
							L velocity from birth (cm/wk)	0.01
							HC from birth (cm/wk)	0.58

Notes: AF: adjustable fortification, ALP: alkaline phosphatase, BPD: bronchopulmonary dysplasia, BUN: blood urea nitrogen, BW: birth weight, ELBW: extremely low birth weight, GA: gestational age, GRV: gastric residual volume, HC: head circumference, L: length.

n: sample size, NEC: necrotising enterocolitis, NS: non-significant, PMA: postmenstrual age, ROP: retinopathy of prematurity, SF: standard fortification, TF: target fortification, TG: serum triglycerides, W: weight, wk: weeks.

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