Necrotizing Enterocolitis

P. BALAMIENTO, MD
OBJECTIVES

 Present a case of necrotizing enterocolitis in an infant

 Discuss the epidemiology and pathophysiology of necrotizing enterocolitis
 Discuss the diagnostic and therapeutic management of necrotizing enterocolitis
 Maternal History

 22yo G1P0 (0000)

 High school graduate
 2 prenatal visits at a local health center
 Fever at 2 mos AOG, no consult done
 UTI at 3 mos, no medications taken
 No hypertension, diabetes, asthma, cough, UTI
 No cigarette smoking or alcohol
 Maternal History

Tetanus toxoid 2x
Regular intake of multivitamins, folic acid, FeSO4, Ca
Ultrasound at 4 mos: twin pregnancy
Blood type B+
Negative: HIV, VDRL, HBsAg
COVID rapid antigen test: negative
 Birth History

 Born vs cesarean section due to twin gestation in primi

 2nd of twin
 Apgar 7,8
 Birth weight 1370g
 Birth length 40 cm
 HC 29 cm
 Cc 24 cm
 AC 23 cm
PHYSICAL EXAMINATION

Ballard Score 32-33

weeks
 PHYSICAL EXAMINATION

General Awake, alert, in respiratory distress

HR 140 rr 60 temp 36.7

Vital Signs
Weight: 1370 g
Anthropometrics length 40 cm
HC 29
CC 24
AC 23

Pallor, No rash, no jaundice

Skin
Head: normocephalic, flat, open fontanels
HEENT Eyes: pink palpebral conjunctivae, anicteric sclerae
Ears: no preauricular skin tag, patent ear canal
Nose: no alar flaring
Throat: no cleft lip or palate; moist lips
PHYSICAL EXAMINATION
 PHYSICAL EXAMINATION
Neck Supple neck, no masses

Lungs
symmetric chest expansion, subcostal and suprasternal
retractions, good air entry, clear breath sounds
Heart Adynamic precordium, regular rhythm, no murmurs

Gastrointestinal/Genitourinary
globular, Normoactive bowel sounds, soft, no organomegaly,
testes down, good rugae

Extremities Full equal pulses, CRT <2 seconds, no edema, warm extremities
 Birth History

Noted to be pale, tachypneic (60s), subcostal /

supraclavicular retractions  intubated and admitted
Initial Management

 Intubation
 Hooked to mechanical ventilator SIMV FiO2 30 PIP 14 PEEP 5 RR 40
 OGT inserted
 Vitamin K given
 Diagnostics: cbc, blood cs, abg, chest xray APL
 Ceftazidime 100 mkdose
 Amikacin 12 mkdose
 D10 W at 80 mll/kg/day
 10/5/21 Day of Birth 1 am

S/O Ancillary Assessment P

Hgb 189
Hct 59 Neonatal pneumonia Intubated; Mech vent SIMV FIO2
30 RR 30 PIP 12 PEEP 4
Respiratory Wbc 5.8 N 43 L 48 APC
154
Prematurity
distress, ABG pH 7.34 pO2 77.7 Very low birth weight NPO
pCO2 41.5 HCO3 22 BE
-3.7 Sats 94.8 OGT to drain
Retractions D10W with Ca
CBG 73 Diagnostics: cbc, blood typing,
ABG, blood CS, chest xray and
abdominal xray
Ceftazidime 100mkdose
Amikacin 12 mkdose
10/5/21 Day of Birth 1 am

Xray: neonatal pneumonia (haziness right pericardial)

Nonobstructive bowel gas pattern
 10/6/21 Day 1 of life

S/O Ancillary Assessment P

Tolerated Neonatal pneumonia Shifted to NCPAP PIP
NIPPV Prematurity 30 PEEP 4
HR 140s Very low birth weight TFR 110
Rr 50s IVF D10, Na 3, K2,
Ca 3, AA 2
OGT feeding 2 cc q6
by OGT
 10/9/21 Day 4 of life

S/O Ancillary Assessment P

Tfr 140 Neonatal pneumonia Increase feeding until
Cbg 70 Prematurity 20 ml q3
Bm 1x Very low birth weight Ceftazidime d4
1225g (1245) Amikacin d4
Stable VS
Clear breath sounds
no murmur
Andomen soft,
nondistended
 10/10/21 Day 5 of life

S/O Ancillary Assessment P

Tfr 150 Cbc: Hgb: 191, Neonatal pneumonia Increase feeding until
hct .57, wbc: 14.9,
Cbg 82 Neu: .38, Prematurity 24 ml q3
Bm 2x lymph: .21, Very low birth weight Ceftazidime d5
eos: .02, mono: .39,
1230g (1225) plt: 215
Amikacin d5
Stable VS Diagnostics: cbc,
Clear breath sounds Na:132, K:4.1, ica: electrolytes, bilirubins
1.34, total Ca: 10.36
no murmur
Abdomen soft, Total bili: 4.08
Direct: 0.98
nondistended Indirect: 3.1
 10/11/21 Day 6 of life 11pm

S/O Ancillary Assessment P

HR 138 Cxr: resolution of right upper sepsis; Nippv
Sats 91 lung density, right paracradiac
hazy infiltrates, slight HCAP Fio2 30, rr 30, pip12
Subcostal retractions, progression Prematurity peep 3
RR high 60s, good air
Very low Shifted ceftazidime to
entry, rales bilateral ABG
Good pulses pH 7.34 PCO2 35.2 PO2 94.7 birth weight meropenem
sats 97%, HCO3 18.9 BE -68 20mkdose q8
Hgt 167 Continue amikacin
10/11/21 Day 12 of life 33-34 5/7 PCA

resolution of right upper lung density, right paracradiac hazy

infiltrates, slight progression
 10/13/21 Day 8 of life 33-34 1/7 PCA

S/O Ancillary Assessment P

Wt 1240 (1265g) Sepsis Shift IVF d10 Na correction K
Bm 1x Cbc HCAP 2 Ca 3 AA 2
Tfr 170 Neonatal Shift to NCPAP 30/4
Cbg 83
Hgb 150 hct 45 WBC 34.7 pneumonia
N 76 L 12 APC 42 Prematurity Cbc, blood cs
Hr 140s, RR low 50s, no Very low birth
pallor, No retractions weight Transfuse platelet concentrate
Good air entry
Equal breath sounds Meropenem d1
No murmur Amikacin d8
Abdomen soft, nondistended,
Full pulses, no gross
bleeding
 10/14/21 Day 9 of life 33-34 2/7 PCA

S/O Ancillary Assessment P

Wt 1280 (1240g) Cbc Sepsis Resume ogt feeding 1ml q3
No BM x 24h HCAP
Tfr 170 Hgb 150 hct 45 WBC Neonatal Shift o2 to nc 1-2lpm
Cbg 75 34.7 N 76 L 12 APC pneumonia
Prematurity
Stable vs
42 Very low birth Meropenem d3
No retractions weight Amikacin d10
Good air entry
Equal breath sounds
No murmur
Abdomen soft, nondistended,
Full pulses
 10/16/21 Day 11 of life 33-34 4/7 PCA

S/O Ancillary Assessment P

Wt 1275 (1290g) Hgb 173 Sepsis ogt feeding 5ml q3
Bm 1x HCAP
Cbg 66 Hct 52 Neonatal o2 nc 1-2lpm
Tfr 180 WBC 14.3 N 56 L pneumonia
22 APC 25 Prematurity
HR 140s Very low Meropenem d5
Rr 40s birth weight (40mkdose)
No retractions, clear Resume amikacin
breath sounds Platelet transfusion
No murmur Furosemide 0.5 mkdose
Full pulses post BT
 10/17/21 Day 12 of life 33-34 5/7 PCA

S/O Ancillary Assessment P

Wt 1280 (1275g) Blood cs: Klebsiella Sepsis ogt feeding 10ml q3
Bm 2x (Klebsiella
Cbg 66 aerogenes S: amikacin aerogenes) o2 nc 1-2lpm
Tfr 180 R: meropenem HCAP
Neonatal Meropenem d6 (40mkdose)
HR 140s pneumonia Resume Amikacin
Rr 50s Cbg 72 Prematurity
no retractions, clear breath Very low birth Refer to cardio
sounds weight
No murmur Cxr: regression of
Full pulses pneumonia
10/17/21 Day 12 of life 33-34 5/7 PCA
 10/18/21 Day 13 of life 33-34 6/7 PCA

S/O Ancillary Assessment P

Wt 1295 (1280g) Blood cs: Klebsiella Septicemia r/o ogt feeding 15ml q3, start
Bm 1x fungemia dropper feeding
Cbg 72 aerogenes Neonatal
Tfr 180 pneumonia Room air
Prematurity
HR 140s
Cbg 72 Very low birth aminophylline
Rr 50s weight Meropenem d2
no retractions, clear breath (40mkdose)
sounds Amikacin d13
No murmur
No abdominal distention Start fluconazole prophylaxis 3
Full pulses mkdose
 10/19/21 Day 14 of life 34-35 0/7 PCA

S/O Ancillary Assessment P

Wt 1295 (1280g) Normal 2d echo septicemia No cardiac intervention
Bm 2x Neonatal
Cbg 79 pneumonia ogt feeding 15ml q3, start dropper
Tfr 180 Hgb 128 Prematurity feeding

Hct 37 Very low birth Room air

HR 130s weight
Rr 40s WBC 23.1 N 69 L 19 APC Cbc, blood cs
no retractions, clear breath 98
sounds aminophylline
No murmur, normoactive bowel Meropenem d3
sounds (40mkdose)
No abdominal distention Amikacin d14
fluconazole prophylaxis 3 mkdose
Full pulses
 10/20/21 Day 15 of life 34-35 1/7 PCA

S/O Ancillary Assessment P

Wt 1320 (1295g) septicemia Decrease OGT feeding to 12 cc q3
Bm 2x Neonatal
Cbg 79 pneumonia Cbc, blood cs
Tfr 180 Prematurity
aminophylline
Very low birth Meropenem d4
HR 140s weight (40mkdose)
Rr 46s fluconazole q72h
no retractions, clear breath
sounds
No murmur,
Globular, Slight abdominal
distension, AC 26 (23), NABS,
soft
Full pulses
 10/21/21 Day 16 of life 34-35 2/7 PCA

S/O Ancillary Assessment P

Wt 1310 (1320 ) Blood cs: non-albicans Sepsis (Klebsiella OGT feeding to 14 cc q3
Bm 2x aerogenes,
Cbg 79 Candida Candida non-
Tfr 180 albicans) Shift fluconazole to
Neonatal amphotericin B
HR 130s pneumonia
Rr 46s Prematurity aminophylline
no retractions, clear breath Very low birth Meropenem d6
sounds weight (40mkdose)
No murmur,
No abdominal distention
Full pulses
 10/24/21 Day 20 of life 34-35 5/7 PCA

S/O Ancillary Assessment P

Wt 1310 (1320 ) Sepsis (Klebsiella Able to progress feeding
Bm 2x aerogenes,
Cbg 79 Candida non- to 30ml q3 via dropper,
Tfr 180 albicans) able to try direct
Neonatal breastfeeding
HR 130s pneumonia
Rr 46s Prematurity
no retractions, clear breath Very low birth roomed-in at KMC
sounds weight
No murmur,
No abdominal distention
Full pulses
 10/31/21 Day 26 of life 35-36 5/7 PCA
S/O Ancillary Assessment P

Vomiting 2x of previously ingested Hgb 173 NEC IIa Admit to NICU

milk Hct 48 septicemia NPO
Wt 1370 (1250 ) WBC 8.5 N 26 L 57 Neonatal pneumonia D10Na3K2Ca3AA2 at 150
Bm 1x APC 364 Prematurity
Cbg 89 Very low birth weight
Tfr 180 iCa 1.38 Abdominal xray crosstable lateral
Na 132 Cbc, electrolytes
HR 140s K 3.8 amphotericin B d11
Rr 40s Aminophylline OD
no retractions, clear breath sounds Xray; regression of Start piperacillin tazobactam (100
No murmur, opacities inner lung mkdose)
Abdomen globular, NABS, AC zones, ileus Start Metronidazole amphotericin
28cm (23cm baseline), Soft B d12
abdomen
Full pulses
10/31/21 Day 26 of life 35-36 5/7 PCA
 11/1/21 Day 27 of life 35-36 6/7 PCA
S/O Ancillary Assessment P

Wt 1317 (1370) Blood cs Septicemia NPO

Bm 1x NEC 2a OGT to drain
Cbg 89 negative 5 days Neonatal pneumonia Repeat blood cs
Tfr 180 Prematurity
Very low birth weight Refer to surgery for evaluation
HR 140s Aminophylline OD
Rr 50s
no retractions, clear breath
sounds
No murmur,
Globular, hypoactive bowel
sounds, Soft, AC 25.5 cm
(baseline 23 cm)
Full pulses
 11/2/21 Day 28 of life 36-37 0/7 PCA

S/O Ancillary Assessment P

Wt 1360 (1317) Blood cs Septicemia NPO

Bm 1x NEC 2a OGT to drain
Cbg 89 negative 5 Neonatal pneumonia
Tfr 180 days Prematurity piperacillin tazobactam (100
Very low birth weight mkdose) day 2
HR 130s Metronidazole day 1
Rr 40s amphotericin B d13
no retractions, clear breath Refer to surgery for evaluation
sounds Aminophylline OD
No murmur,
Soft abdomen AC 23 cm
(baseline 23 cm)
Full pulses
 11/3/21 Day 29 of life 36 1/7 PCA

S/O Ancillary Assessment P

Wt 1360 (1360) Hgb 142 septicemia NPO day 3

Bm 3x Neonatal pneumonia OGT to drain
Cbg 70 Hct 41 Prematurity
Tfr 180 WBC 6.6 N Very low birth weight Repeat CBC

HR 130s
66 L 18 Shift piptazo to ciprofloxacin
Rr 40s APC 150 Metronidazole day4
no retractions, clear breath Amphotericin d14
sounds Aminophylline OD
No murmur,
Soft abdomen Full pulses
 11/4/21 Day 30 of life 36 2/7 PCA

S/O Ancillary Assessment P

Wt 1390 (1360) Septicemia NPO day 4

Bm 3x NEC 2a OGT to drain
Cbg 70 Neonatal pneumonia
Tfr 180 Prematurity Repeat CBC
Very low birth weight
HR 140s Ciprofloxacin day 1
Rr 40s Metronidazole day 3
no retractions, clear breath Amphotericin d15
sounds Aminophylline OD
No murmur,
Soft abdomen Full pulses
 11/5/21 Day 31 of life 36 3/7 PCA

S/O Ancillary Assessment P

Wt 1390 (1360) septicemia NPO day 5

Bm 0x for 24 h Neonatal pneumonia OGT to drain
Cbg 70 Prematurity
Tfr 180 Very low birth weight Abdominal xray

HR 140s Ciprofloxacin day 2

Rr 50s Metronidazole day 4
no retractions, clear breath Amphotericin d16
sounds Aminophylline OD
No murmur,
Soft nondistended abdomen
Full pulses
11/5/21 Day 31 of life 36 3/7 PCA
Differential Diagnosis

Abdominal distention
 Septic ileus – bacteremia demonstrated; regresses with control of infection
 Hirschprung disease – may present with vomiting, abdominal distention, poor feeding, however:
no delayed meconium passage; Typically presents in older children around time of weaning from
breastfeeding
 Intestinal atresias – no problems in initial feeding; no double bubble, triple bubble, or obstructive
appearance on xray
 Necrotizing enterocolitis – prematurity, low birth weight, can present with nonspecific symptoms
initially, abdominal distention and apnea may be present; high index of suspicion
 Epidemiology and Risk Factors

 important cause of morbidity and mortality in preterm infants

 90% of the cases occur in newborns less than 32 weeks of gestation1
 Incidence of 6–10% of the very low birthweight infants1 and wide
range,1.6% in Japan to 22% in Sweden1
 About 7% with VLBW (<1500 g) will develop NEC2

1 Carlos Z, Ines GG, Alejandro AA, et al. Incidence, treatment, and outcome trends of necrotizing enterocolitis in preterm infants: A Multicenter Cohort Study. Front Pediatr. 2020; 8.doi:
10.3389/fped.2020.00188 https://www.frontiersin.org/articles/10.3389/fped.2020.00188/full Accessed November 16, 2021
2 Fanaroff, Avroy A., Jonathan M. Fanaroff, and Marshall H. Klaus. 2013. Klaus and Fanaroff's care of the high-risk neonate
 Epidemiology and Risk Factors

Risk factors1
 Low birth weight
 Prematurity
 Critical illness
 Formula feeding
 Gut ischemia
 Antepartum hemorrhage
 Prolonged rupture of membranes beyond 36 hours
 5-min Apgar score below 7
1 Fanaroff, Avroy A., Jonathan M. Fanaroff, and Marshall H. Klaus. 2013. Klaus and Fanaroff's care of the high-risk neonate
 Epidemiology and Risk Factors

Risk factors1
 For term infants:
 Cyanotic congenital heart disease
 Polycythemia
 Twin gestation

 Age of onset varies inversely with age of gestation1

 1/2 of term infants with NEC manifest in 1st day of life
1 Fanaroff, Avroy A., Jonathan M. Fanaroff, and Marshall H. Klaus. 2013. Klaus and Fanaroff's care of the high-risk neonate
 Epidemiology and Risk Factors

Protective factors1
 Breastmilk
Contains bifidus factor, enhancing gut colonization with Lactobacillus
Lactoferrin prevents bacterial translocation with combination of
antimicrobial, anti-inflammatory, immunoregulatory, and growth-
promoting properties

1 Fanaroff, Avroy A., Jonathan M. Fanaroff, and Marshall H. Klaus. 2013. Klaus and Fanaroff's care of the high-risk neonate
 Epidemiology and Risk Factors

Protective factors
 Probiotic administration1,2
Lactobacillus rhamnosus GG significantly reduced NEC incidence and
overall mortality

1 Carlos Z, Ines GG, Alejandro AA, et al. Incidence, treatment, and outcome trends of necrotizing enterocolitis in preterm infants: A Multicenter Cohort Study. Front Pediatr. 2020; 8.doi:
10.3389/fped.2020.00188 https://www.frontiersin.org/articles/10.3389/fped.2020.00188/full Accessed November 16, 2021
2 Fanaroff, Avroy A., Jonathan M. Fanaroff, and Marshall H. Klaus. 2013. Klaus and Fanaroff's care of the high-risk neonate
Pathophysiology

 Delicate balance between bowel perfusion,

enteric microbiome, and nutritional intake
 Pathophysiology

Peritoneal cultures in NEC1

 Klebsiella and Enterobacter 63%
 Coagulase negative Staphylococci 30%
 Escherichia coli 21%
 Candida 10%
 Anaerobes 6 %

1 Fanaroff, Avroy A., Jonathan M. Fanaroff, and Marshall H. Klaus. 2013. Klaus and Fanaroff's care of the high-risk neonate
 Clinical Features

 Presentation may be variable and nonspecific

 Most often:
 Temperature instability
 Lethargy
 Abdominal distension
 Retention of feedings
 Occult blood present, sometimes frank hematochezia

1 Fanaroff, Avroy A., Jonathan M. Fanaroff, and Marshall H. Klaus. 2013. Klaus and Fanaroff's care of the high-risk neonate
 Clinical Features

 Apnea
 Bilious vomiting
 Increasing abdominal distention
 Acidosis
 Disseminated intravascular coagulation

1 Fanaroff, Avroy A., Jonathan M. Fanaroff, and Marshall H. Klaus. 2013. Klaus and Fanaroff's care of the high-risk neonate
Clinical Features

 Characteristic xray picture:

 Pneumatosis intestinalis
Gas in intestinal wall
 Portal venous gas
 Free air in peritoneum in case of perforated viscus
Clinical Features

 Characteristic xray picture:

 Pneumatosis intestinalis
Gas in intestinal wall
 Portal venous gas
 Free air in peritoneum in case of perforated
viscus
Clinical Features
Clinical Features
 Management

 Human milk is preferred

for preterm infants due to
various advantages:

1 Section on Breastfeeding. Breastfeeding and the use of human milk. Pediatrics (2012) 129:e827–41. doi:10.1542/peds.2011-3552
 Management

 According to ESPGHAN, the preferred nutrition for premature

infants is fortified human milk1
Due to the high nutrient needs of preterm infants
Sytematic reviews show human milk alone may result in slower growth
rates and lesser increase in head circumference2

1 ESPGHAN Committee on Nutrition, Agostoni C, Braegger C, Decsi T, Kolacek S, Koletzko B, et al. Role of dietary factors and food habits in the
development of childhood obesity: a commentary by the ESPGHAN Committee on Nutrition. J Pediatr Gastroenterol Nutr (2011) 52:662–9.
doi:10.1097/MPG.0b013e3182169253
2 Brown JV, Embleton ND, Harding JE, McGuire W. Multi-nutrient fortification of human milk for preterm infants. Cochrane Database Syst
Rev (2016) (5):CD000343. doi:10.1002/14651858.CD000343.pub3
 Management

 Enteral feeding is preferred but early parenteral nutrition can be a necessary adjunct
 15-20 ml/kg/day of breast milk every 2-3 hours during first week of life
 early versus late (<48 versus >72 h after birth): early feeding associated with
better outcomes
 Rapid versus Slow advancement: rapid advancement (30-35ml/kg/day) with better
outcomes in weight gain and ahcievment of full feeds with no increase in risk of
NEC
 Continuous vs bolus feeding: continuous associated with faster weight gain, earlier
discharge; bolus associated with respiratory instability
1 Kumar RK, Atul S, Umesh V, et al. Optimizing Nutrition in Preterm Low Birth Weight Infants—Consensus Summary. Frontiers in Nutrition. 2017; 4.
https://www.frontiersin.org/article/10.3389/fnut.2017.00020. DOI=10.3389/fnut.2017.00020
 Management

 NGT or OGT: NGT associated with increased airway resistance,

periodic breathing and central apnea

 Enteral Feeding while on ventilator: not contraindicated in preterm

LBW, does not increase risk of GER

1 Kumar RK, Atul S, Umesh V, et al. Optimizing Nutrition in Preterm Low Birth Weight Infants—Consensus Summary. Frontiers in Nutrition. 2017; 4.
https://www.frontiersin.org/article/10.3389/fnut.2017.00020. DOI=10.3389/fnut.2017.00020
 Management

 NPO for up to 2 weeks

 NGT drainage
 IVF
 Broad-spectrum antibiotics
 The suggested antibiotic regimen includes ampicillin, gentamicin, AND clindamycin or
metronidazole1
 Frequent abdominal examination, assessment of abdominal girth, crosstable
lateral xrays for detection of free air
1 Barrie S. Rich, Stephen E. Dolgin; Necrotizing Enterocolitis. Pediatr Rev December 2017; 38 (12): 552–559.
https://doi.org/10.1542/pir.2017-0002
 Management

 Surgical management indications1

Bowel perforation
Worsening clinical status
Refractory DIC
Refractory acidosis

1 Fanaroff, Avroy A., Jonathan M. Fanaroff, and Marshall H. Klaus. 2013. Klaus and Fanaroff's care of the high-risk neonate
Management
 Outcomes

 75% survival for infants >1kg

 10.3% postoperative stricture
 4.4% wound dehiscence
 5.8% intraabdominal abscess
 Among ELBW infants with surgical NEC
 greater severity of disease
 associated with significant growth delay and adverse neurodevelopmental outcomes
1 Fanaroff, Avroy A., Jonathan M. Fanaroff, and Marshall H. Klaus. 2013. Klaus and Fanaroff's care of the high-risk neonate
References

 Fanaroff, Avroy A., Jonathan M. Fanaroff, and Marshall H. Klaus. 2020. Klaus and
Fanaroff's care of the high-risk neonate
 Carlos Z, Ines GG, Alejandro AA, et al. Incidence, Treatment, and Outcome Trends of
Necrotizing Enterocolitis in Preterm Infants: A Multicenter Cohort Study. Frontiers in
Pediatrics. 2020; 8.doi: 10.3389/fped.2020.00188
https://www.frontiersin.org/articles/10.3389/fped.2020.00188/full Accessed
November 16, 2021
 Barrie S. Rich, Stephen E. Dolgin; Necrotizing Enterocolitis. Pediatr
Rev December 2017; 38 (12): 552–559. https://doi.org/10.1542/pir.2017-0002
References

 Section on Breastfeeding. Breastfeeding and the use of human milk. Pediatrics (2012) 129:e827–
41. doi:10.1542/peds.2011-3552
 ESPGHAN Committee on Nutrition, Agostoni C, Braegger C, Decsi T, Kolacek S, Koletzko B, et al.
Role of dietary factors and food habits in the development of childhood obesity: a commentary by
the ESPGHAN Committee on Nutrition. J Pediatr Gastroenterol Nutr (2011) 52:662–9.
doi:10.1097/MPG.0b013e3182169253
 Brown JV, Embleton ND, Harding JE, McGuire W. Multi-nutrient fortification of human milk for
preterm infants. Cochrane Database Syst Rev (2016) (5):CD000343.
doi:10.1002/14651858.CD000343.pub3
 Kumar RK, Atul S, Umesh V, et al. Optimizing Nutrition in Preterm Low Birth Weight Infants—
Consensus Summary. Frontiers in Nutrition. 2017; 4.
https://www.frontiersin.org/article/10.3389/fnut.2017.00020. DOI=10.3389/fnut.2017.00020