Efficacy of Docosahexaenoic Acid for the Prevention of Necrotizing Enterocolitis in Preterm Infants: A Randomized Clinical Trial
Abstract
:1. Introduction
2. Materials and Methods
2.1. Study Design and Participants
2.2. Randomization and Intervention
2.3. Main Outcome Measure: Confirmed Necrotizing Enterocolitis
2.4. Adverse Events
2.5. Clinical Course and Management
2.6. Fatty Acid Profile in Erythrocytes and Human Milk
2.7. Sample Size and Statistical Analysis
3. Results
3.1. Confirmed Necrotizing Enterocolitis
3.2. Adverse Events
3.3. Clinical Course and Management
3.4. Fatty Acid Profile in Erythrocytes and Human Milk
4. Discussion
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Clinical Trial registration ID
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Fatty Acid | GROUP | |
---|---|---|
DHA Intervention (Algal Oil) | Control (High-Oleic Sunflower Oil) | |
Capric | 1.0 | 0.0 |
Lauric | 4.3 | 0.0 |
Myristic | 14.0 | 0.1 |
Palmitic | 12.2 | 5.2 |
Palmitoleic | 1.9 | 0.1 |
Stearic | 0.7 | 3.8 |
Oleic | 18.9 | 58.9 |
Linoleic | 1.3 | 29.2 |
Gamma-Linolenic | 0.4 | 0.3 |
Alpha-Linolenic | <0.1 | 1.2 |
Eicosenoic | <0.1 | 0.3 |
Arachidonic | <0.1 | 0.0 |
Eicosapentaenoic | <0.1 | 0.0 |
Behenic | 0.2 | 0.7 |
Docosahexaenoic | 44.3 | 0.0 |
Nervonic | 0.1 | 0.0 |
GROUP | p | ||
---|---|---|---|
DHA n = 100 | Control n = 100 | ||
At Birth | |||
Born by cesarean section, n (%) | 96 (96) | 99 (99) | 0.391 |
Received antenatal steroid, n (%) | 48 (48) | 42 (42) | 0.601 |
Gestational age, weeks | 30 (29, 32) | 31 (30, 32) | 0.513 |
Male sex, n (%) | 52 (52) | 47 (47) | 0.572 |
Apgar score at minute 5 ≥ 7, n (%) | 96 (96) | 95 (95) | 1.000 |
At Baseline | |||
Corrected gestational age, weeks | 31.0 (29.8, 32.3) | 31.1 (28.0, 32.5) | 0.306 |
GROUP | p | |||
---|---|---|---|---|
DHA n = 100 | Control n = 93 | NEC n = 7 | ||
Birthweight 1000–1250 g, n (%) | 40 (40) | 44 (47) | 4 (57) | 0.460 |
Birthweight 1251–1500 g, n (%) | 60 (60) | 49 (53) | 3 (43) | |
Small for gestational age, n (%) | 14 (14) | 12 (13) | 1 (14) | 0.974 |
Twins, n (%) | 23 (23) | 30 (32) | 2 (29) | 0.354 |
Severe asphyxia at birth, n (%) | 9 (9) | 10 (11) | 0 | 0.627 |
Severity of disease (CRIB) at baseline | 2.0 (1, 5.0) | 1.0 (1, 4.5) | 1.0 (0, 6.0) | 0.760 |
Hemoglobin at baseline, g/dl | 15.7 (14.2, 17.7) | 16.5 (14.8, 18.0) | 14.1 (12.9, 16.8) | 0.150 |
Respiratory distress syndrome, n (%) | 90 (90) | 84 (90) | 7 (100) | 0.681 |
Suspected or confirmed sepsis, n (%) | 66 (66) | 57 (61) | 7 (100) | 0.112 |
PDA, n (%) | 18 (18) | 21 (23) | 3 (43) | 0.259 |
Apnea, n (%) | 36 (36) | 24 (26) | 4 (57) | 0.110 |
Apnea events in week 1, n | 1 (1, 2) | 1 (1, 2) | 1 | 0.780 |
Apnea events in week 2, n | 2 (1, 2) | 1.5 (1, 3) | 1 (1, 1.5) | 0.669 |
Apnea events during hospitalization, n | 3.0 (2, 5) | 3.0 (1, 7) | 4.5 (1.3, 8) | 0.881 |
Requirement for phase III ventilator support, n (%) | 65 (66) | 62 (67) | 6 (86) | 0.552 |
Duration with SpO2 < 85% in week 1, h | 5.5 (2.0, 12.0) | 4 (2.0, 6.0) | 0 | 0.219 |
Duration with SpO2 < 85% in week 2, h | 7.0 (5.0, 13.5) | 4 (3.5, 8.0) | 0 | 0.146 |
Retinopathy of the prematurity, n (%) | 23 (23) | 23 (25) | 0* | 0.325 |
Antibiotics used, n (%) | 97 (97) | 92 (99) | 7 (100) | 0.589 |
Postnatal age at antibiotic start, h | 8 (4, 24) | 8 (4, 24) | 8 (4, 48) | 0.937 |
Antibiotic duration, days | 26 (17, 42) | 27 (19, 42) | 28 (25, 38) | 0.950 |
Postnatal steroid use, n (%) | 21 (21) | 21 (23) | 3 (43) | 0.408 |
Ibuprofen use, n (%) | 9 (9) | 6 (7) | 1 (14) | 0.665 |
Omeprazole during intervention period, n (%) | 43 (43) | 41 (46) | 2 (29) | 0.671 |
Duration of omeprazole use during intervention period, days | 4 (1, 6) | 4 (2, 7) | 4.5 (3, 6) | 0.759 |
Infants with RBC transfusion during intervention period, n (%) | 38 (38) | 32 (34) | 3 (43) | 0.821 |
Number of RBC transfusions during intervention period, n | 1 (1, 1) | 1 (1, 1) | 1.5 (1, 2) | 0.467 |
Length of NICU stay, days | 9.5 (2, 18) | 12.0 (3, 21) | 18.0 (9, 31) | 0.166 |
Length of hospital stay, days | 45 (35, 55) | 46 (38, 53) | 47 (26, 66) * | 0.888 |
Nutritional intake variable | GROUP | p | ||
---|---|---|---|---|
DHA n = 100 | Control n = 93 | NEC n = 7 | ||
Week One of Postnatal Age | ||||
Total fluid volume, mL/kg/day | 100 (88, 108) | 97 (88, 105) | 89 (75, 104) | 0.437 |
Infants receiving TPN before EF, n (%) | 50 (57) | 48 (59) | 6 (86) | 0.327 |
Postnatal age at starting TPN, days | 2.0 (1.7, 2.4) | 2.7 (1.0, 2.4) | 3.0 (1.8, 4.0) | 0.851 |
Lipid supply by TPN, g/kg/day | 2.0 (0.6, 3.8) | 2.1 (0.4, 2.9) | 2.0 (1.4, 2.4) | 0.877 |
Postnatal age at starting EF, days | 4.0 (2.0, 6.5) | 4.3 (2.5, 6.2) | 7.0 (4.1, 9.1) | 0.176 |
Lipid intake-EFF, g/kg/day | 1.1 (0.5, 2.3) | 1.2 (0.6, 2.0) | 0.5 (0.2, 1.2) | 0.151 |
Fatty Acid Intake from EFF, mg/kg/day | ||||
Linoleic acid | 69 (32, 231) | 100 (31, 217) | 38 (11, 107) | 0.282 |
Alpha-linolenic acid | 26 (10, 44) | 23 (10, 39) | 9 (4, 22) | 0.154 |
Arachidonic acid | 5 (2, 9) | 5 (2, 8) | 2 (0.8, 5) | 0.171 |
Docosahexaenoic acid | 5 (2, 9) | 5 (2, 8) | 2 (0.8, 5) | 0.161 |
Week Two of Postnatal Age | ||||
Total fluid volume, mL/kg/day | 136 (125, 147) | 138 (123, 147) | 127 (99, 131) | 0.081 |
Lipid supply by TPN, g/kg/day | 1.8 (0.8, 2.4) | 1.8 (0.8, 2.3) | 2.1 (1.4, 2.5) | 0.717 |
Lipid intake-EFF, g/kg/day | 4.5 (2.5, 5.8) | 4.2 (2.9, 5.7) | 1.2 (0.4, 3.9) | 0.059 |
Fatty Acid Intake from EFF, mg/kg/day | ||||
Linoleic acid | 576 (209, 880) | 506 (119, 833) | 82 (21, 505) | 0.106 |
Alpha-linolenic acid | 86 (48, 111) | 79 (35, 108) | 23 (8, 74) | 0.064 |
Arachidonic acid | 17 (10, 22) | 16 (7, 22) | 7 (1.4, 15) | 0.088 |
Docosahexaenoic acid | 17 (10, 22) | 16 (7, 22) | 7 (1.4, 15) | 0.088 |
Human Milk Intake | ||||
Infants fed any volume of human milk, n (%) | 18 (18) | 13 (14) | 0 | 0.382 |
Infants fed human milk during first week post-enteral feeding, n (%) | 11 (11) | 4 (4.2) | 0 | 0.157 |
Intake during first week post-enteral feeding, mL/kg/day | 3.9 (2.1, 10.3) a | 4.9 (0.7, 9.9) b | 0 c | 0.003 |
Infants fed human milk during second week post-enteral feeding, n (%) | 11 (11) | 6 (6.5) | 0 | 0.376 |
Intake during second week post-enteral feeding, mL/kg/day | 8.3 (2.4, 17.2) a | 5.4 (1.8, 20.3) b | 0 c | 0.052 |
Infants fed human milk during third week post-EF, n (%) | 9 (9) | 7 (7.5) | 0 | 0.679 |
Intake during third week post-enteral feeding, mL/kg/day | 6.7 (2.6, 23.1) a | 7.9 (4.1, 13.6) a | 0 b | 0.029 |
Infants fed human milk during fourth week post-EF, mL/kg/day, n (%) | 12 (12) | 7 (7.5) | 0 | 0.390 |
Intake during fourth week post-enteral feeding, mL/kg/day | 5.6 (2.6, 12.7) a | 4.3 (1.5, 6.2) b | 0 c | 0.043 |
Intake during hospital stay, mL/kg/day | 14 (7, 37) | 12 (3, 60) | 0 | 0.448 |
Time required to reach full enteral feeding, days | 15 (12, 22) | 17 (12, 22) | 20 (16, 46) | 0.161 |
Fatty Acid | DHA n = 100 | Control n = 93 | NEC n = 7 | p | DHA n = 100 | Control n = 93 | NEC n = 7 |
---|---|---|---|---|---|---|---|
In Baseline Erythrocyte Membranes | In Human Milk during Hospital Stay | ||||||
Lauric | 0.34 (0.15, 0.67) | 0.38 (0.22, 0.79) | 0.36 (0.15, 0.67) | 0.534 | 7.6 (7.0, 9.6) | 6.6 (6.6, 7.2) | - * |
Myristic | 0.71 (0.57, 1.06) | 0.80 (0.61, 1.24) | 1.02 (0.71, 1.06) | 0.252 | 9.0 (7.7, 9.5) | 8.8 (8.2, 9.4) | - * |
Palmitic | 32.5 (29.9, 40.7) | 33.4 (32.2, 42.3) | 31.7 (30.3, 48.0) | 0.463 | 22.0 (20.1, 26.9) | 24.7 (24.2, 25.2) | - * |
Palmitoleic | 1.12 (0.78, 1.42) | 1.18 (0.80, 1.48) | 1.47 (1.0, 2.50) | 0.055 | 2.3 (2.1, 2.6) | 2.3 (2.2, 2.4) | - * |
Stearic | 17.4 (15.9, 18.9) | 16.9 (4.3, 23.6) | 17.1 (15.8, 19.0) | 0.485 | 6.6 (6.1, 6.7) | 7.0 (6.6, 7.3) | - * |
Oleic | 16.7 (15.2, 18.8) | 16.6 (14.6, 19.3) | 16.7 (16.0, 18.8) | 0.894 | 33.7 (31.6, 34.9) | 32.0 (31.9, 32.9) | - * |
Linoleic | 5.1 (4.0, 7.4) | 5.0 (4.1, 7.3) | 3.6 (2.2, 7.3) | 0.473 | 16.1 (15.9, 17.4) | 15.5 (14.4, 17.0) | - * |
Alpha-linolenic | 0.12 a (0.09, 0.30) | 0.10 b (0.07, 0.17) | 0.07 b (0.07, 0.17) | 0.042 | 1.2 (1.1, 1.5) | 1.1 (1.0, 1.2) | - * |
Arachidonic | 14.67 (5.07, 20.11) | 15.50 (5.51, 20.2) | 13.5 (4.3, 18.9) | 0.829 | 0.6 (0.5, 0.6) | 0.5 (0.5, 0.6) | - * |
Eicosapentaenoic | 0.54 (0.24, 0.83) | 0.53 (0.27, 0.70) | 0.40 (0.31, 0.69) | 0.782 | 0.03 a (0.03, 0.06) | 0.10 b (0.09, 0.12) | - * |
Nervonic | 2.82 (2.0, 3.4) | 2.62 (2.11, 3.4) | 2.90 (2.0, 3.1) | 0.896 | 0.03 (0.04, 0.05) | 0.03 (0.03, 0.04) | - * |
Docosahexaenoic | 2.92 (1.2, 3.4) | 2.99 (0.95, 3.7) | 3.0 (2.0, 4.0) | 0.812 | 0.22 a (0.16, 0.27) | 0.35 b (0.33, 0.36) | - * |
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Bernabe-García, M.; Calder, P.C.; Villegas-Silva, R.; Rodríguez-Cruz, M.; Chávez-Sánchez, L.; Cruz-Reynoso, L.; Mateos-Sánchez, L.; Lara-Flores, G.; Aguilera-Joaquín, A.R.; Sánchez-García, L. Efficacy of Docosahexaenoic Acid for the Prevention of Necrotizing Enterocolitis in Preterm Infants: A Randomized Clinical Trial. Nutrients 2021, 13, 648. https://doi.org/10.3390/nu13020648
Bernabe-García M, Calder PC, Villegas-Silva R, Rodríguez-Cruz M, Chávez-Sánchez L, Cruz-Reynoso L, Mateos-Sánchez L, Lara-Flores G, Aguilera-Joaquín AR, Sánchez-García L. Efficacy of Docosahexaenoic Acid for the Prevention of Necrotizing Enterocolitis in Preterm Infants: A Randomized Clinical Trial. Nutrients. 2021; 13(2):648. https://doi.org/10.3390/nu13020648
Chicago/Turabian StyleBernabe-García, Mariela, Philip C. Calder, Raúl Villegas-Silva, Maricela Rodríguez-Cruz, Luis Chávez-Sánchez, Leonardo Cruz-Reynoso, Leovigildo Mateos-Sánchez, Gabriel Lara-Flores, Augusto R. Aguilera-Joaquín, and Luisa Sánchez-García. 2021. "Efficacy of Docosahexaenoic Acid for the Prevention of Necrotizing Enterocolitis in Preterm Infants: A Randomized Clinical Trial" Nutrients 13, no. 2: 648. https://doi.org/10.3390/nu13020648