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 Table of Contents  
Year : 2021  |  Volume : 10  |  Issue : 4  |  Page : 251-254

Severe feeding intolerance in extremely preterm neonates successfully treated with human milk derived human milk fortifier: A case series

1 Department of Pediatrics, McMaster Children's Hospital, McMaster University, Hamilton, ON, Canada
2 Division of Neonatology, Jim Pattison Children's Hospital, University of Saskatchewan, Saskatoon, SK, Canada

Date of Submission23-Dec-2020
Date of Acceptance14-Aug-2021
Date of Web Publication24-Sep-2021

Correspondence Address:
Stientje Esther Rai
McMaster Children's Hospital, McMaster University, 1280 Main Street W, HSC-4F, Hamilton, ON, L8S 4K1
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jcn.jcn_210_20

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Feeding intolerance in preterm infants can be severe and can lead to clinical suspicion and diagnostic testing for other acute abdominal surgical pathologies and hence delay achievement of full enteral feeds. We present two cases of extremely premature infants who presented with recurrent severe feeding intolerance following fortification of human milk with a bovine human milk fortifier (HMF). Subsequently, both infants had an extensive workup for their symptoms. Each infant was eventually tried on a human HMF which led to the complete resolution of symptoms in each case. This case series highlights that clinicians should consider the use of human HMF for preterm infants with severe feeding intolerance secondary to the use of bovine HMF.

Keywords: Case series, exclusive human milk diet, feeding intolerance, human milk-derived human milk fortifier, preterm infants

How to cite this article:
Lofiego P, Samedi V, Rai SE. Severe feeding intolerance in extremely preterm neonates successfully treated with human milk derived human milk fortifier: A case series. J Clin Neonatol 2021;10:251-4

How to cite this URL:
Lofiego P, Samedi V, Rai SE. Severe feeding intolerance in extremely preterm neonates successfully treated with human milk derived human milk fortifier: A case series. J Clin Neonatol [serial online] 2021 [cited 2022 Dec 4];10:251-4. Available from: https://www.jcnonweb.com/text.asp?2021/10/4/251/326608

  Introduction Top

Achieving adequate growth in very low birth weight (VLBW) infants is of utmost importance to optimize their short- and long-term outcomes.[1] Human milk is the best source of nutrition for infants (term and preterm).[2],[3] However, human milk alone does not have a sufficient amount of nutrients to attain adequate growth in babies born preterm.[4] Hence, human milk is routinely fortified with a human milk fortifier (HMF) to provide additional protein, carbohydrate, minerals, trace elements, vitamins, and electrolytes.[5] The most commonly used fortifiers contain protein derived from a bovine source (bovine HMF). However, a fortifier with protein derived from human donors is also available (human HMF).

Feeding intolerance is a commonly encountered problem in preterm infants and results from an immature gastrointestinal (GI) tract.[6],[7] Nonspecific symptoms can range in severity and can mimic acute surgical conditions. The use of human HMF (rather than bovine HMF) has previously been reported to result in improved feeding tolerance, faster achievement of full enteral feeds,[8] and a reduction in necrotizing enterocolitis,[9] although a recent randomized controlled trial (RCT) did not find a difference in feeding intolerance between human and bovine HMF.[10]

We describe two cases of VLBW infants who upon introduction of bovine HMF to their expressed breast milk (EBM) feeds, developed severe symptoms of feeding intolerance.

  Case Reports Top

Case 1

A male infant born at 25 + 4 weeks gestational age (GA) was delivered vaginally after an uneventful pregnancy until his mother presented in labor and was found to be fully dilated. The infant had a fairly benign neonatal course. He received two doses of surfactant, was successfully extubated to continuous positive airway pressure (CPAP) on day of life (DOL) two, and came off respiratory support at 37 + 6 weeks corrected GA (cGA). He did not have a PDA. The infant had a positive newborn screen for congenital adrenal hyperplasia and received maintenance hydrocortisone until a molecular genetic test was reported negative on DOL 86.

Enteral feeds of EBM were started on DOL three and the infant reached full enteral feeds on DOL ten. Bovine HMF was introduced on four occasions: DOL 13, DOL 21, DOL 29, and 34. With each attempt, the infant developed severe symptoms of feeding intolerance that led to the administration of a stress dose of hydrocortisone (given the suspected adrenal insufficiency on newborn screen), a partial septic workup, antibiotics, and a period of nil per os (NPO) for 48 h on each occasion. Abdominal X-rays were nonspecific with gaseous distension, no bowel wall edema, no pneumatosis, and no free air. The last blood culture on DOL 34 was positive for coagulase-negative staphylococcus, and although it was believed to be a contaminant, he was treated for 10 days with vancomycin. Given the frequent episodes of significant symptoms that were temporally related to the introduction of bovine HMF, the patient's feeds were fortified with human HMF on DOL 42. He tolerated it well without any further symptoms of feeding intolerance. His growth improved from averaging 10.8 to 15 g/k/day after the introduction of human HMF [Graph 1].

Case 2

A male infant born at 26 weeks GA was delivered through emergency cesarean section due to the maternal hypertension and atypical Hemolysis, Elevated Liver Enzymes, Low Platelet Count syndrome. Her pregnancy was complicated by intrauterine growth restriction secondary to poor umbilical artery Doppler. He received two doses of surfactant, was extubated to CPAP on DOL ten, and came off respiratory support at 35 + 4 weeks cGA. He did not have a PDA.

Enteral feeds were started on DOL three, and full enteral feeds of EBM were achieved on DOL 14, and bovine HMF was started. Four days later, he developed significant feeding intolerance and was placed NPO. Serial abdominal X-rays showed no signs of necrotizing enterocolitis (NEC). Feeds were restarted and fortified with bovine HMF was attempted again on DOL 21. He developed feeding intolerance and worsening abdominal distention, and by DOL 32 was placed NPO again. A Replogle tube was placed to decompress his abdomen. A barium enema was performed as the radiologist reported that the abdominal X-ray was suggestive of atypical Hirschsprung's disease [Figure 1]. The barium enema was also reported to be suggestive of Hirschsprung's disease [Figure 2]. Pediatric surgery was consulted and felt the imaging and symptomatology was more consistent with the immaturity of the GI tract, and a biopsy was not performed. Feeds were restarted the same day and fortified with human HMF given the persistent feeding intolerance symptoms with each attempt to fortify with bovine HMF. He subsequently had no further symptoms of feeding intolerance until he was transitioned to preterm formula. He again developed abdominal distention and was placed NPO. He received rectal washouts for a week (despite adequate stools) and eventually underwent a rectal suction biopsy that ruled out Hirschsprung's disease. Subsequently, he was placed back on EBM with human HMF without further symptoms of feeding intolerance and was eventually transitioned to plain EBM.
Figure 1: Case 2 abdominal X-ray

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Figure 2: Case 2 barium enema

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  Discussion Top

We described two cases of ELBW infants who developed severe feeding intolerance within a few days of attempting to introduce bovine HMF to their EBM feeds. Symptoms were so severe that each infant was suspected to have a surgical condition: the first infant presented with symptoms concerning for septic ileus and/or NEC, whereas the second received a surgical workup to rule out Hirschsprung's disease. Human HMF was eventually successfully used for each infant and both were able to tolerate and reach full feeds as per the local feeding guidelines without further symptoms of feeding intolerance.

It is well established that human milk is superior to formula which contains bovine protein and lacks other beneficial bioactive components found in human milk.[11] It is important to note that the proportion of total protein intake provided by HMF in an infant receiving fully fortified EBM feeds is roughly 50%. As the proportion of human milk intake of total intake increases, a dose-dependent reduction in NEC has been observed.[12] The pathophysiology of feeding intolerance (and NEC) and its relationship to bovine protein exposure is not well understood. Exposure to the formula has been shown to lead to dysbiosis of the intestinal microbiome that precedes NEC.[13] Similarly, several studies support the hypothesis that exposure to bovine HMF leads to dysbiosis of the intestinal microbiome and subsequent development of feeding intolerance and NEC.[14],[15]

Only a few studies have reported on a direct comparison between bovine HMF and human HMF added to EBM. Assad et al. found that preterm infants <28 weeks who were fed EBM with human HMF experienced less feeding intolerance, achieved full feeds faster, had a lower incidence of NEC, compared to those who were fed EBM with bovine HMF.[8] The OPTIMUM trial found no difference in the primary outcome of feeding intolerance between infants fed either human or bovine HMF.[10] However, they did see a statistically significant higher incidence of ROP, a trend toward a higher incidence in late-onset sepsis (P = 0.07), and a recently published corrigendum reported a trend toward a higher risk of a positive morbidity index (death, NEC, ROP, BPD, or sepsis).[16] Lucas et al. recently reported a reanalysis of data from a previous trial[17] and concluded that infants receiving bovine HMF had a higher risk of NEC, NEC requiring surgery or death, and a reduced head circumference compared to those receiving human HMF.[9] The limited evidence remains somewhat controversial, hence additional well-designed RCTs are needed to assess the efficacy and safety of fortifiers.

To balance the still limited evidence with the high cost of human HMF, we have revised our local feeding guidelines to include human HMF as a “rescue” fortification option: fortification is initiated with bovine HMF, however, should the infant develop symptoms of feeding intolerance within 48 h of initiating bovine HMF on two separate occasions, the infant is switched to human HMF.

  Conclusion Top

These two case reports highlight that there may be clinical situations that warrant the use of human HMF, especially in cases of severe feeding intolerance that prevents (or slows) the attainment of fully fortified enteral feeds necessary to meet nutritional needs for adequate growth in extremely premature infants.

Informed consent

Written consent was obtained from the parents of each patient for publication of this case series and accompanying images.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the parents have given their consent for images and other clinical information to be reported in the journal. The parent understands that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

  References Top

Belfort MB, Rifas-Shiman SL, Sullivan T, Collins CT, McPhee AJ, Ryan P, et al. Infant growth before and after term: Effects on neurodevelopment in preterm infants. Pediatrics 2011;128:e899-906.  Back to cited text no. 1
Ziegler EE. II. Advantages of human milk in feeding premature infants. J Pediatr Gastroenterol Nutr 2015;61 Suppl 1:S3.  Back to cited text no. 2
Lechner BE, Vohr BR. Neurodevelopmental outcomes of preterm infants fed human milk: A systematic review. Clin Perinatol 2017;44:69-83.  Back to cited text no. 3
Tudehope D, Fewtrell M, Kashyap S, Udaeta E. Nutritional needs of the micropreterm infant. J Pediatr 2013;162:S72-80.  Back to cited text no. 4
Radmacher PG, Adamkin DH. Fortification of human milk for preterm infants. Semin Fetal Neonatal Med 2017;22:30-5.  Back to cited text no. 5
Neu J, Li N. The Neonatal Gastrointestinal Tract: Developmental Anatomy, Physiology, and Clinical Implications. Neoreviews 2003;4:7e-13.  Back to cited text no. 6
Neu J. Gastrointestinal development and meeting the nutritional needs of premature infants. Am J Clin Nutr 2007;85:629S-34S.  Back to cited text no. 7
Assad M, Elliott MJ, Abraham JH. Decreased cost and improved feeding tolerance in VLBW infants fed an exclusive human milk diet. J Perinatol 2016;36:216-20.  Back to cited text no. 8
Lucas A, Boscardin J, Abrams SA. Preterm infants fed cow's milk-derived fortifier had adverse outcomes despite a base diet of only mother's own milk. Breastfeed Med 2020;15:297-303.  Back to cited text no. 9
O'Connor DL, Kiss A, Tomlinson C, Bando N, Bayliss A, Campbell DM, et al. Nutrient enrichment of human milk with human and bovine milk fortifiers for infants born weighing <1250 g; a randomized clinical trial. Am J Clin Nutr 2018;108:108-16.  Back to cited text no. 10
Boquien CY. Human milk: An ideal food for nutrition of preterm newborn. Front Pediatr 2018;6:295.  Back to cited text no. 11
Meinzen-Derr J, Poindexter B, Wrage L, Morrow AL, Stoll B, Donovan EF. Role of human milk in extremely low birth weight infants' risk of necrotizing enterocolitis or death. J Perinatol 2009;29:57-62.  Back to cited text no. 12
Pammi M, Cope J, Tarr PI, Warner BB, Morrow AL, Mai V, et al. Intestinal dysbiosis in preterm infants preceding necrotizing enterocolitis: A systematic review and meta-analysis. Microbiome 2017;5:31.  Back to cited text no. 13
Yuan Z, Yan J, Wen H, Deng X, Li X, Su S. Feeding intolerance alters the gut microbiota of preterm infants. PLoS One 2019;14:e0210609.  Back to cited text no. 14
Chan GM, Lee ML, Rechtman DJ. Effects of a human milk-derived human milk fortifier on the antibacterial actions of human milk. Breastfeed Med 2007;2:205-8.  Back to cited text no. 15
O'connor DL, Kiss A, Tomlinson C, Bando N, Bayliss A, Campbell D, et al. Corrigendum for O'Connor et al. Nutrient enrichment of human milk with human and bovine milk–based fortifiers for infants born weighing <1250 g: A randomized clinical trial. Am J Clin Nutr 2018;108:108-16. Am J Clin Nutr 2019;110:529.  Back to cited text no. 16
Sullivan S, Schanler RJ, Kim JH, Patel AL, Trawöger R, Kiechl-Kohlendorfer U, et al. 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 2010;156:562-7.e1.  Back to cited text no. 17


  [Figure 1], [Figure 2]


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