Table 1.

Overview of the included studies.

First Author, Year, Country [Reference]	Main Inclusion Criteria	Number of Randomized Infants	Bioactive Factor	Initiation and Duration of the Study Intervention	Gestational Age, Weeks *	Birth Weight, g *	Primary Outcome(s)	Secondary Outcome(s)	Other Reported Outcome(s)
Hormones and growth factors
El-Ganzoury, 2014, Egypt [19]	GA ≤ 33 weeks	- 20 - 20 - 20 - 30	- RhG-CSF (4.5 µg/kg/day) - RhEPO (88 IU/kg/day) - RhG-CSF (4.5 µg/kg/day) and EPO (88 IU/kg/day) - Placebo	Start: on the day that enteral feeding was initiated, duration: until an enteral intake of 100 ml/kg/day, or for a maximum of 7 days, whichever came first.	- 30.8 ± 1.8 - 30.2 ± 1.8 - 30.4 ± 1.9 - 30.5 ± 1.5	- 1260 ± 270 - 1310 ± 310 - 1190 ± 280 - 1360 ± 290	Time to full enteral feeding, NEC	-	Mortality, duration of hospital stay
Omar, 2020, Egypt [20]	GA ≤ 32 weeks	- 60 - 60	- RhEPO (88 IU/kg/day) - Placebo	Start: on the day that enteral nutrition was initiated, duration: until an enteral intake of 150 ml/kg/day, or for a maximum of 10 days, whichever came first.	- 32.0 (31.0–32.0) - 32.0 (30.5–32.0)	- -	-	Time to full enteral feeding, growth velocity, NEC	Mortality
Hosseini, 2019, Iran [21]	GA ≤ 28 weeks and BW < 1250 g	- 50 - 50 - 50	- Synthetic amniotic fluid containing rhG-CSF (225 ng/mL) - Synthetic amniotic fluid (5 mL/kg/day) containing rhG-CSF (225 ng/mL) and rhEPO (4400 µU/mL) - Standard care	Start: day 3 postpartum, duration: 21 days	- 27.7 ± 1.7 - 28.7 ± 2.6 - 27.7 ± 1.5	- 948 ± 179 - 1065 ± 189 - 998 ± 173	NEC	Sepsis, ROP, IVH, mortality	-
Juul, 2003, USA [22]	BW 700–1500 g	- 15 - 17	- RhEPO (1000 IU/kg/day) - Placebo	Start: at least 30 mL/kg/day enteral nutrition, duration: 2 weeks	- 27.8 ± 1.8 - 28.8 ± 2.1	- 1070 ± 255 - 1145 ± 259	-	-	Growth velocity, NEC
Corpeleijn, 2008, The Netherlands [23]	BW 750–1250 g	- 50 - 49	- Formula with bovine IGF-1 (10 µg/100 mL) - Standard formula	Start: day 3-7 postpartum, duration: 4 weeks	- 29 (26-33) # - 28 (25-33)	- 975 (750-1250) # - 920 (750-1250)	Time to full enteral feeding, growth velocity	Intestinal permeability, lactase activity	NEC, IVH, mortality, duration of stay at the NICU
Shamir, 2013, Israel [24]	GA 26–33 weeks and BW > 750 g	- 4 - 4	- Rh-insulin (400 µU/mL milk) - Placebo	Duration: 28 days	-	- 1285 (1058-1570) - 1205 (836-1619)	Time to full enteral feeding, growth velocity	-	-
El-Kabbany, 2020, Egypt [25]	GA < 36 weeks, sepsis	- 20 - 20	- Melatonin (20 mg) - Standard care	Single dose	- 32.4 ± 2.6 - 32.9 ± 2.1	-	-	Mortality, duration of hospital stay	-
Canpolat, 2006, Turkey [26]	GA ≤ 34 weeks, stage I NEC	- 8 - 10	- RhG-CSF (20 µg/kg/day) - Placebo	Start: first day of NEC diagnosis, duration: 5 days	- 30.8 ± 1.6 - 30.9 ± 1.7	- 1269 ± 394 - 1206 ± 280	NEC severity and progression	-	Duration of hospital stay
Vitamins
Sun, 2019, China [27]	GA < 28 weeks, <96 h of age	- 132 - 130	- Vitamin A (1500 IU/day) - Placebo	Start: on the day that enteral feeding was initiated, duration: 28 days or until discharge, whichever came first	- 26.8 ± 1.9 - 27.1 ± 2.0	- 982 ± 234 - 984 ± 217	Composite of mortality or type I ROP, BPD	Sepsis, NEC, ROP, IVH, mortality, duration of hospital stay	-
Wardle, 2001, United Kingdom [28]	BW < 1000 g	- 77 - 77	- Vitamin A (5000 IU/kg/day) - Placebo	Start: day 1 postpartum, duration: up to and including day 28 postpartum	- 26 (25–27) - 26 (25–27)	- 806 (710–890) - 782 (662–880)	-	NEC, BPD, ROP, IVH, mortality	-
Basu, 2019, India [29]	BW < 1500 g, requiring invasive or non-invasive respiratory support at 24h of life	- 98 - 98	- Vitamin A (10,000 IU on alternate days) - Placebo	Start: 24h postpartum, duration: 28 days	- 30.9 ± 2.9 - 30.7 ± 2.7	- 1185 ± 194 - 1163 ± 181	-	Sepsis, NEC, BPD, ROP, IVH, mortality	-
Bell, 2013, USA [30]	GA < 27 weeks and BW < 1000 g	- 62 - 31	- Vitamin E (dl-α-tocopheryl acetate) (50 IU/kg) - Placebo	Single dose within <4 h	- 25 (24–26) - 25 (24–26)	- 700 (610–840) - 680 (600–850)	-	-	Sepsis, NEC, IVH, mortality
Barekatain, 2018, Iran [31]	GA ≤ 30 weeks	- 40 - 40	- Vitamin E (form not reported) (10 IU/day) - Placebo	Start: day of birth, duration: 3 days	- 28.4 ± 1.5 - 28.6 ± 1.4	- 1174 ± 162 - 1192 ± 176	IVH	Sepsis, NEC	Mortality
Pathak, 2003, USA [32]	GA ≤ 32 weeks and BW ≤ 1250 g	- 15 - 15	- Vitamin E (α-tocopherol) (50 IU/day) - Placebo	Duration: 8 weeks or until discharge, whichever came first	- 27.9 ± 1.9 - 27.9 ± 1.5	- 928 (170) - 899 (159)	-	-	Sepsis, NEC, duration of hospital stay
Carotenoids
Dani, 2012, Italy [33]	GA ≤ 32 weeks	- 58 - 56	- Lutein (0.14 mg/day) and zeaxanthin (0.006 mg/day) - Placebo	Start: day 1-7 postpartum, duration: until discharge	- 28.8 ± 2.4 - 28.3 ± 2.4	- 1130 ± 330 - 1130 ± 360	ROP	ROP requiring laser- or cryo-treatment, sepsis, NEC, BPD, IVH, mortality	-
Manzoni, 2013, Italy [34]	GA < 32 + 6 weeks	- 113 - 116	- Lutein (0.14 mg/day) and Zeaxanthin (0.0006 mg/day) - Placebo	Start: <48 h postpartum, duration: until 36 weeks PMA	- 30.1 ± 1.8 - 29.7 ± 2.6	- 1336 ± 417 - 1271 ± 386	Threshold ROP, NEC stage ≥2, BPD	ROP of all stages, NEC of all stages, sepsis, IVH, mortality	-
Costa, 2013, Italy [35]	GA ≤ 34 weeks	- 38 - 39	- Lutein (0.5 mg/kg/day) and zeaxanthin (0.02 mg/kg/day) - Placebo	Start: day 7 postpartum, duration: until 40 weeks PMA or until discharge, whichever came first	- 30.7 ± 2.3 - 30.1 ± 2.2	- 1438 ± 466 - 1391 ± 452	-	-	Time to full enteral feeding, sepsis, NEC, BPD, IVH, mortality, duration of hospital stay
Romagnoli, 2011, Italy [36]	GA ≤ 32 weeks	- 31 - 32	- Lutein (0.5 mg/kg/day) and zeaxanthin (0.02 mg/kg/day) - Placebo	Start: day 7 postpartum, duration: until 40 weeks PMA or until discharge, whichever came first	- 30.0 ± 1.9 - 29.7 ± 1.9	- 1351 ± 438 - 1311 ± 398	ROP	-	Sepsis, NEC, BPD, IVH, mortality, duration of hospital stay
Enzymes
Casper, 2016, (10 European countries) [37]	GA < 32 weeks	- 207 - 208	- RhBSSL added to formula or pasteurized human milk (15 mg/100 mL) - Placebo	Start: enteral nutrition of at least 100 mL/kg/day, duration: 4 weeks	- 28.8 ± 1.7 - 28.8 ± 1.7	- 1179 ± 299 - 1167 ± 294	Growth velocity	Antibodies against rhBSSL	NEC
Trace elements
Aggarwal, 2016, India [38]	GA < 32 weeks and BW < 1500 g	- 55 - 59	- Selenium (10 µg/day) - Placebo	Start: day 1 postpartum, duration: until day 28 of life	- 31.7 ± 0.6 - 31.6 ± 0.6	- 1473 ± 46 - 1455 ± 54	Sepsis	ROP, mortality	Meningitis, IVH, duration of hospital stay
Terrin, 2013, Italy [39]	GA 24–32 weeks or BW 401–1500 g	- 97 - 96	- Zinc (9 mg/day) - Standard care	Start: day 7 postpartum, duration: until 42 weeks PMA or until discharge, whichever came first	- 28 (28–29) § - 28 (27–29)	- 1114 (1056–1172) § - 1033 (969–1097)	Sepsis, NEC, BPD, ROP	Mortality, growth velocity	Time to full enteral feeding, IVH, duration of hospital stay
Compounds of plasma membrane lipids
Picaud, 2002, France [40]	Appropriate-for-gestational-age preterm infants	- 10 - 10 - 10	- LD cholesterol (<0.03 g/L) - MD cholesterol (0.15 g/L) - HD cholesterol (0.30 g/L)	Start: at the end of the second week of life, duration: until 40 weeks PMA	- 29.7 ± 1.6 - 29.3 ± 1.8 -29.9 ± 1.6	- 1174 ± 281 - 1209 ± 229 - 1321 ± 281	-	-	Growth velocity
Tanaka, 2013, Japan [41]	BW < 1500 g	- 12 - 12	- Formula with higher dose SM (20% of all phospholipids) - Standard formula (SM 13% of all phospholipids)	Start: <24 h postpartum, duration: not reported	- 29.1 ± 2.1 - 30.1 ± 2.3	- 1116 ± 254 - 1100 ± 353	Neurodevelopment at 6, 12 and 18 months corrected age	-	-
Creatine
Bohnhorst, 2004, Germany [42]	GA < 32, postconceptional age <36 weeks and symptoms of AOP severe enough to require treatment with caffeine	- 19 - 19	- Creatine monohydrate (200 mg/kg/day) - Placebo	Duration: 2 weeks	- 27 (25–30) # - 27 (25–30)	- 1040 (580–1400) # - 1015 (440–1525)	-	-	Growth velocity
Immunoglobulins
Lawrence, 2001, Australia [43]	BW ≤ 1500 g	- 768 - 761	- IgG (1200 mg/kg/day) - Placebo	Start: on the day that enteral nutrition was initiated, duration: 28 days	- 28.6 ± 2.6 - 28.4 ± 2.6	-	NEC, mortality	-	-
Nucleotides
Scopesi, 2006, Italy [44]	GA 30–37 weeks	Not reported	- Nucleotide enriched formula - Standard formula	Start: day 2 postpartum, duration: 2 weeks	- 33.7 ± 2.5 - 33.1 ± 1.3	-	-	-	Growth velocity

* Data are presented as mean ± SD or median (IQR), unless otherwise stated, ^# Median (range), ^§ Mean (95% CI), BW: birth weight, GA: gestational age, VLBW: very low birth weight, PMA: postmenstrual age, LD: low-dose, MD: medium-dose, HD: high-dose, SM: sphingomyelin, RhEPO: recombinant human erytropoetin, RhG-CSF: recombinant human granulocyte colony stimulating factor, RhBSSL: recombinant human bile salt-stimulated lipase, IgG: immunoglobulin G, NEC: necrotizing enterocolitis, ROP: retinopathy of prematurity, BPD: bronchopulmonary dysplasia, IVH: intraventricular hemorrhage.