Skip to main content
SpringerLink
Log in

Early versus late fortification of breast milk in preterm infants: a systematic review and meta-analysis

  • Review
  • Published:
European Journal of Pediatrics Aims and scope Submit manuscript

Abstract

This systematic review and meta-analysis assessed the effects of early fortification (EF) versus late fortification (LF) of breast milk (BM) on growth of preterm infants. Randomized and quasi-randomized controlled trials (RCTs) dealing with the effects of EF versus LF on growth parameters, incidence of adverse events, and duration of hospital stay in preterm infants were included. Data were pooled using the RevMan 5.3 software. Quality of evidence for predefined outcomes was analyzed by GRADE. Available evidence (3 RCTs, 309 preterm infants) showed no statistically significant difference between EF and LF of BM for any of the growth parameters—weight (standardized mean difference (SMD) 0.13; 95% confidence interval (CI) − 0.09, 0.36); length (SMD 0.02; 95% CI − 0.20, 0.25); and head circumference (SMD − 0.10; 95% CI − 0.33, 0.12). Total parenteral nutrition days were similar. Duration of hospital stay was significantly higher with EF (MD 4.29; 95% CI 0.84, 7.75) with a trend of non-significant increase in feed intolerance and necrotizing enterocolitis (NEC).

Conclusion: Very low quality evidence did not find any significant difference in growth parameters of preterm infants in association with EF or LF of BM. A significant increase in hospital stay and non-significant increase in feed intolerance and NEC were associated with EF.

PROSPERO registration number: CRD42019139235

What is Known:

• Fortification of breast milk with essential macro- and micronutrients is necessary for optimization of nutrition in preterm infants.

• There is no consensus regarding the breast milk feeding volume at which fortification should be initiated.

What is New:

• Very low quality evidence showed no significant difference between early and late fortification of breast milk on growth parameters of preterm infants.

• Early fortification was associated with non-significant increase in feed intolerance and necrotizing enterocolitis and a significant increase in hospital stay.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

Abbreviations

BW:

Birth weight

CI:

Confidence interval

DHM:

Donor human milk

EF:

Early fortification

ESPGHAN:

European Society for Paediatric Gastroenterology, Hepatology, and Nutrition

GA:

Gestational age

GRADE:

Grading of Recommendations Assessment, Development and Evaluation

HC:

Head circumference

HMF:

Human milk fortifier

IQR:

Interquartile range

LF:

Late fortification

LBW:

Low birth weight

MD:

Mean difference

MOM:

Mother’s own milk

NEC:

Necrotizing enterocolitis

PRISMA:

Preferred Reporting Items for Systematic Reviews and Meta-Analyses

PROSPERO:

Prospective Register of Systematic Reviews

RCT:

Randomized controlled trial

RoB:

Risk of bias

RR:

Risk ratio

SD:

Standard deviation

SMD:

Standardized mean differences

References

  1. Lager S, Powell TL (2012) Regulation of nutrient transport across the placenta. J Pregnancy 2012:179827

    Article  Google Scholar 

  2. Ziegler EE (2011) Meeting the nutritional needs of the low-birth-weight infant. Ann Nutr Metab 58:8–18

    Article  CAS  Google Scholar 

  3. Gartner LM, Morton J, Lawrence RA, Naylor AJ, O’Hare D, Schanler RJ et al (2005) American Academy of Pediatrics, Section on Breastfeeding. Breastfeeding and the use of human milk. Pediatrics 115:496–506

    Article  Google Scholar 

  4. American Academy of Pediatrics, Section on Breastfeeding (2012) Breastfeeding and the use of human milk. Pediatrics 129:e827–e841

    Article  Google Scholar 

  5. Arslanoglu S, Corpeleijn W, Moro G, Braegger C, Campoy C, Colomb V, ESPGHAN Committee on Nutrition et al (2013) Donor human milk for preterm infants: current evidence and research directions. J Pediatr Gastroenterol Nutr 57:535–542

    Article  Google Scholar 

  6. Agostoni C, Buonocore G, Carnielli VP, De Curtis M, Darmaun D, Decsi T, ESPGHAN Committee on Nutrition et al (2010) Enteral nutrient supply for preterm infants: commentary from the European Society of Paediatric Gastroenterology, Hepatology and Nutrition Committee on Nutrition. J Pediatr Gastroenterol Nutr 50:85–91

    Article  CAS  Google Scholar 

  7. John A, Sun R, Maillart L, Schaefer A, Hamilton Spence E, Perrin MT (2019) Macronutrient variability in human milk from donors to a milk bank: implications for feeding preterm infants. PLoS One 14:e0210610

    Article  CAS  Google Scholar 

  8. Gathwala G, Chawla M, Gehlaut VS (2007) Fortified human milk in the small for gestational age neonate. Indian J Pediatr 74:815–818

    Article  Google Scholar 

  9. Mukhopadhyay K, Narnag A, Mahajan R (2007) Effect of human milk fortification in appropriate for gestation and small for gestation preterm babies: a randomized controlled trial. Indian Pediatr 44:286–290

    PubMed  Google Scholar 

  10. Thanigainathan S, Abiramalatha T (2019) Early fortification of human milk versus late fortification to promote growth in preterm infants. Cochrane Database Syst Rev 8:CD013392

    Google Scholar 

  11. Brown JV, Embleton ND, Harding JE, McGuire W (2016) Multi-nutrient fortification of human milk for preterm infants. Cochrane Neonatal Group, editor. Cochrane Database Syst Rev 5:CD000343

    Google Scholar 

  12. Picaud JC, Buffin R, Gremmo-Feger G, Rigo J, Putet G, Casper C, Working group of the French Neonatal Society on fresh human milk use in preterm infants (2018) Review concludes that specific recommendations are needed to harmonise the provision of fresh mother’s milk to their preterm infants. Acta Paediatr 107:1145–1155

    Article  CAS  Google Scholar 

  13. Yigit S, Akgoz A, Memisoglu A, Akata D, Ziegler EE (2008) Breast milk fortification: effect on gastric emptying. Matern Fetal Neonatal Med 21:843–846

    Article  Google Scholar 

  14. Morgan JA, Young L, McGuire W (2011) Pathogenesis and prevention of necrotizing enterocolitis. Curr Opin Infect Dis 24:183–189

    Article  Google Scholar 

  15. Moher D, Liberati A, Tetzlaff J, Altman DG, The PRISMA Group (2009) Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med 6:e1000097

    Article  Google Scholar 

  16. Higgins JPT, Thomas J, Chandler J, Cumpston M, Li T, Page MJ, Welch VA (eds) (2019) Cochrane handbook for systematic reviews of interventions, 2nd edn. John Wiley & Sons, Chichester

    Google Scholar 

  17. Wan X, Wang W, Liu J, Tong T (2014) Estimating the sample mean and standard deviation from the sample size, median, range and/or interquartile range. BMC Med Res Methodol 14:135

    Article  Google Scholar 

  18. Review Manager (RevMan) [Computer program]. Version 5.3 (2014) Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration

  19. Borenstein M, Hedges L, Higgins J, Rothstein H (2013) Comprehensive Meta-Analysis Version 3. Biostat, Englewood

    Google Scholar 

  20. Schünemann H, Brożek J, Guyatt G, Oxman A, editors (2013) GRADE handbook for grading quality of evidence and strength of recommendations. The GRADE Working Group. Available from: guidelinedevelopment.org/handbook

  21. GRADEpro GDT: GRADEpro Guideline Development Tool [Software] (2015) McMaster University (developed by Evidence Prime, Inc.). Available from: gradepro.org

  22. Tillman S, Brandon DH, Silva SG (2012) Evaluation of human milk fortification from the time of the first feeding: effects on infants of less than 31 weeks gestational age. J Perinatol 32:525–531

    Article  CAS  Google Scholar 

  23. Lapointe M, Barrington KJ, Savaria M, Janvier A (2016) Preventing postnatal growth restriction in infants with birthweight less than 1300 g. Acta Paediatr 105:e54–e59

    Article  CAS  Google Scholar 

  24. Fan WQ, Gan A, Crane O (2018) Commencing nutrient supplements before full enteral feed volume achievement is beneficial for moderately preterm to late preterm low birth weight babies: a prospective, observational study. Nutrients 10(10)

  25. Huston RK, Lee ML, Rider ED, Stawarz ML, Hedstrom DM, Pence MM, Chan VL, Chambers MJ, Rogers SP, Seger NC, Riemann LA, Cohen HS (2019) Early fortification of enteral feedings for infants <1250 grams birth weight receiving a human milk diet including human milk based fortifier. J Neonatal-Perinatal Med:1–7. https://doi.org/10.3233/NPM-190300

  26. Sullivan S, Schanler RJ, Kim JH, Patel AL, Trawöger R, Kiechl-Kohlendorfer U et al (2010) An exclusively human milk-based diet is associated with a lower rate of necrotizing enterocolitis than a diet of human milk and bovine milk-based products. J Pediatr 156:562–567.e1

    Article  CAS  Google Scholar 

  27. Shah SD, Dereddy N, Jones TL, Dhanireddy R, Talati AJ et al (2016) Early versus delayed human milk fortification in very low birth weight infants-a randomized controlled trial. J Pediatr 174:126–131.e1

    Article  Google Scholar 

  28. Alizadeh Taheri P, Sajjadian N, Asgharyan Fargi M, Shariat M (2017) Is early breast milk fortification more effective in preterm infants?: a clinical trial. J Perinat Med 45:953–957

    Article  Google Scholar 

  29. Abdelhamid AE, Chuang SL, Hates P, Fell JM (2013) Evolution of in vitro cow’s milk protein-specific inflammatory and regulatory cytokine responses in preterm infants with necrotising enterocolitis. J Pediatr Gastroenterol Nutr 56:5–11

    Article  CAS  Google Scholar 

  30. Penn AH, Altshuler AE, Small JW, Taylor SF, Dobkins KR, Schmid-Schobein GW (2012) Digested formula but not digested fresh human milk causes death of intestinal cells in vitro: implications for necrotizing enterocolitis. Pediatr Res 72:560–567

    Article  CAS  Google Scholar 

  31. Taylor SN, Basile LA, Ebeling M, Wagner CL (2009) Intestinal permeability in preterm infants by feeding type: mother’s versus formula. Breastfeed Med 4:11–15

    Article  Google Scholar 

  32. Premkumar MH, Pammi M, Suresh G (2019) Human milk-derived fortifier versus bovine milk-derived fortifier for prevention of mortality and morbidity in preterm neonates. Cochrane Database Syst Rev 11:CD013145

    Google Scholar 

  33. Mihatsch W, Franz A, Hogel J, Pohlandt F (2002) Hydrolyzed protein accelerates feeding advancement in very low birth weight infants. Pediatrics 110:1199–1203

    Article  Google Scholar 

  34. Picaud JC, Rigo J, Normand S, Lapillonne A, Reygrobellet B, Claris O, Salle BL (2001) Nutritional efficacy of preterm formula with a partially hydrolyzed protein source: a randomized pilot study. J Pediatr Gastroenterol Nutr 32:555–561

    Article  CAS  Google Scholar 

  35. Ng DH, Klassen JR, Embleton ND, McGuire W (2019) Protein hydrolysate versus standard formula for preterm infants. Cochrane Database Syst Rev 7:CD012412

    PubMed  Google Scholar 

  36. Arslanoglu S, Boquien CY, King C, Lamireau D, Tonetto P, Barnett D, Bertino E, Gaya A, Gebauer C, Grovslien A, Moro GE, Weaver G, Wesolowska AM, Picaud JC (2019) Fortification of human milk for preterm infants: update and recommendations of the European Milk Bank Association (EMBA) working group on human milk fortification. Front Pediatr 7:76

    Article  Google Scholar 

  37. Godden B, Collins CT, Hilditch C, McLeod G, Keir A (2019) Does early compared to late fortification of human milk for preterm infants improve clinical outcomes? J Paediatr Child Health 55:867–872

    Article  Google Scholar 

  38. Alyahya W, Simpson J, Garcia AL, Mactier H, Edwards CA (2020) Early versus delayed fortification of human milk in preterm infants: a systematic review. Neonatology 117:24–32

    Article  Google Scholar 

Download references

Systematic review registration

The protocol for this systematic review was registered in the International Prospective Register of Systematic Reviews (PROSPERO) database (Registration number CRD42019139235).

Author information

Authors and Affiliations

  1. Department of Neonatology, All India Institute of Medical Sciences, Rishikesh, Uttarakhand, 249203, India

    Sriparna Basu, Jaya Upadhyay & Poonam Singh

  2. Department of Pediatrics, All India Institute of Medical Sciences, Gorakhpur, India

    Manish Kumar

Authors
  1. Sriparna Basu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jaya Upadhyay
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Poonam Singh
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Manish Kumar
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Prof Sriparna Basu, Dr. Jaya Upadhyay, Dr. Poonam Singh, and Dr. Manish Kumar conceptualized and planned this systematic review and meta-analysis and independently searched the literature. Dr. Jaya Upadhyay, Dr. Poonam Singh, and Dr. Manish Kumar individually collected the study details and outcome data using a predetermined form designed for this purpose. Disagreement was resolved by discussion with Prof Sriparna Basu. Risk of bias for each study was assessed individually. All authors approved the final manuscript as submitted and agreed to be accountable for all aspects of the work.

Corresponding author

Correspondence to Sriparna Basu.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest

Additional information

Communicated by Daniele De Luca

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

ESM 1

Web Figure 1 Change in growth parameters after exclusion of the study of Sullivan et al. (PNG 20 kb)

High resolution image (TIF 37 kb)

ESM 2

Web Figure 2: Incidence of complications after exclusion of the study of Sullivan et al. (PNG 20 kb)

High resolution image (TIF 32 kb)

ESM 3

Web Figure 3: Meta-regression for outcomes (PNG 150 kb)

High resolution image (TIF 251 kb)

ESM 4

Web Figure 4: Funnel plots for outcomes (PNG 111 kb)

High resolution image (TIF 222 kb)

ESM 5

Web Table 1: Electronic search strategy (DOCX 13 kb)

ESM 6

Web Table 2 (DOCX 21 kb)

ESM 7

Web Table 3: Meta-regression co-efficient; A - Weight/Weight change, B - Length/Length change, C - Head circumference/Head circumference change, D – Incidence of necrotizing enterocolitis, E - Incidence of sepsis (DOCX 13 kb)

ESM 8

Web Table 4: Publication bias by Egger’s regression intercept; A - Weight/Weight change, B - Length/Length change, C - Head circumference/Head circumference change, D - Necrotizing enterocolitis, E - Incidence of sepsis (DOCX 13 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Basu, S., Upadhyay, J., Singh, P. et al. Early versus late fortification of breast milk in preterm infants: a systematic review and meta-analysis. Eur J Pediatr 179, 1057–1068 (2020). https://doi.org/10.1007/s00431-020-03677-6

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00431-020-03677-6

Keywords

Search

Navigation