early versus delayed minimal enteral

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Early Versus Delayed Minimal EnteralFeeding and Risk for Necrotizing Enterocolitis

in Preterm Growth-Restricted Infants withAbnormal Antenatal Doppler ResultsParaskevi Karagianni, M.D.,1 Despina D. Briana, M.D.,2 George Mitsiakos, M.D.,1

Anestis Elias, M.D.,1 Theodoros Theodoridis, M.D., D.F.F.P.,3

Elias Chatziioannidis, M.D.,1 Maria Kyriakidou, P.T., M.Sc., N.D.T.,1

and Nikolaos Nikolaidis, M.D.1

ABSTRACT

We studied the effect of early (5 days) versus delayed (6 days) initiation ofminimal enteral feeding (MEF) on the incidence of necrotizing enterocolitis (NEC) andfeeding intolerance in preterm infants with intrauterine growth restriction (IUGR) andabnormal antenatal Doppler results. We performed a randomized, nonblinded pilot trial ofinfants receiving early or delayed MEF in addition to parenteral feeding within 48 hours oflife. Demographic data, maternal preeclampsia, antenatal steroid exposure, Dopplerstudies, as well as cases of NEC and feeding intolerance were all recorded. Of the 84infants enrolled, 81 completed the study: 40 received early (median age: 2 days, range: 1 to5 days) and 41 delayed (median age: 7 days, range: 6 to 14 days) MEF. The incidence ofNEC and feeding intolerance was not significantly different between groups (p 0.353 andp 0.533, respectively). Birth weight was an independent risk factor for NEC in bothgroups. Early MEF of preterm infants with IUGR and abnormal antenatal Doppler resultsmay not have a significant effect on the incidence of NEC or feeding intolerance.Furthermore, birth weight seems to be an independent risk factor for the developmentof NEC, irrespectively of the timing of MEF introduction.

KEYWORDS: Prematurity, intrauterine growth restriction, necrotizing enterocolitis,

minimal enteral feeding, Doppler

Necrotizing enterocolitis (NEC) is the mostcommon gastrointestinal emergency in newborn in-fants.1 Among all neonatal intensive care unit (NICU)admissions, the incidence of NEC ranges from 1 to

7.7%, and 90% of cases occur among preterm infants.2

Observational studies suggest that when prematurity isfurther complicated by intrauterine growth restriction(IUGR), the incidence of NEC is even higher.35 IUGR

12nd NICU and Neonatology Department, Aristotle University ofThessaloniki, G.P.N. Papageorgiou, Thessaloniki, Greece; 2HonoraryClinical Fellow, Newborn Unit, Kings College Hospital, London,United Kingdom; 31st Department of Obstetrics and Gynecology,Aristotle University of Thessaloniki, G.P.N. Papageorgiou, Thessaloniki,Greece.

Address for correspondence and reprint requests: ParaskeviKaragianni, M.D., 2nd NICU and Neonatology Department, G.P.N.Papageorgiou, Ring Road, Nea Efkarpia, 56403 Thessaloniki, Greece

(e-mail: [email protected]).Am J Perinatol 2010;27:367373. Copyright # 2010 by Thieme

Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001,USA. Tel: +1(212) 5844662.

Received: June 13, 2009. Accepted after revision: October 2, 2009.Published online: December 10, 2009.DOI: http://dx.doi.org/10.1055/s-0029-1243310.ISSN 0735-1631.

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caused by placental insufficiency is characterized byblood flow redistribution to the vital organs (brain,myocardium, and adrenal glands), while other organs,including the gastrointestinal tract, are deprived fromsufficient blood flow.6,7 As a consequence of gut ische-mia/hypoxia, IUGR infants are thought to have im-paired gut function after birth, which may result in

intestinal disturbances, ranging from temporary intoler-ance of enteral feeding to full-blown NEC.35,8,9

Although the exact cause of NEC is unknown,several contributing mechanisms have been identified.More than 90% of NEC cases are seen after feeding. 2

During neonatal life, reperfusion injury is implicated inthe induction of inflammatory cascades.10,11 The in-testinal wall becomes susceptible to bacterial invasionafter exposure to milk, further propelling the cycle ofinflammation and vascular damage.1012 As enteralfeeding may increase the risk of NEC in pretermIUGR infants, its initiation is often postponed. How-

ever, such a policy exposes infants to the risks ofprolonged parenteral nutrition, delayed establishmentof oral feeding, and prolonged duration of intensivecare and hospital stay.13

In this respect, minimal enteral feeding (MEF) ofvery low-birth-weight infants has been introduced as astrategy to improve feeding tolerance and prevent com-plications of prolonged parenteral nutrition.14 AlthoughMEF has been shown to improve the clinical outcome

with no additional increase in the relative risk of anycomplication, limited information is currently availableregarding the effect of early versus delayed introductionof MEF on feeding intolerance or NEC outcomes inIUGR infants.1518 Additionally, most trials of enteralfeeding in preterm infants have showed conflictingresults.15,19 Thus, the feeding protocol that would bemore suitable for preterm infants with IUGR andabnormal antenatal Doppler results is not known.

In the absence of accepted standards for feedingpreterm infants with IUGR and abnormal antenatalDoppler results, the present study aimed to examinethe effect of early versus delayed introduction of MEFon the incidence of NEC and feeding intolerance inpreterm infants with IUGR and abnormal fetal bloodflow.

MATERIALS AND METHODSFrom May 2004 to May 2008, all singleton preterminfants admitted in our level III NICU with a gestationalage of 27 to 34 weeks, birth weight 10th customizedcentile,20 abnormal antenatal Doppler results, arterialcord blood pH 7.0 (base deficit 12 mmol/L), and5-minute Apgar score >5 were eligible to participate inthis pilot study. Exclusion criteria were major congenitalanomalies and infections, signs of genetic syndromes,and gastrointestinal tract anomalies. Moreover, infants

needing exchange transfusion or inotropic drug admin-istration were not included in the study.

Gestational age was determined from the date ofthe last menstrual period when reported as normal and

was confirmed by sonographic measurement of crownrump length during the first trimester of pregnancy.Birth weight was measured with an electronic scale.

The Gestation Related Optimal Weight (www.gestation.net) computer-generated program was used to calculatethe customized centile for each pregnancy, taking intoconsideration significant determinants of birth weight,such as maternal height and booking weight, ethnicgroup, parity, gestational age, and gender.20

Fetal blood flow pulsatility was measured basedon obstetric decisions, including evaluation of suspectedIUGR. Only blood flow pulsatility measurements of theumbilical, uterine, and cerebral artery performed within7 days before birth were acceptable for the study. Thelast measurement before birth was used for the analysis.

Flow velocity waveforms were analyzed by the pulsatilityindex (PI), defined as the difference between peaksystolic and end diastolic value, divided by the timeaverage velocity.21,22 Distribution of fetal blood flow

was characterized by the umbilical artery/middle cerebralartery PI ratio. We defined a pathological fetal perfusionby a PI of uterine arteries and umbilical artery above the90th percentile for the corresponding gestational age andby a PI of middle cerebral artery below the 10thpercentile for the corresponding gestational age of anormal group.21,22

The study protocol was approved by the ethicscommittee of our hospital. All mothers provided signedinformed consent before enrollment. Within 48 hours oflife, the infants were randomly assigned to one of twofeeding groups. The first group (group I) received early(5 days) bolus MEF (birth weight 1000 g: daily 12 1 mL breast milk or pretermformula; Nenatal; Nutricia Nederland BV, Zoetermeer,the Netherlands); the other group (group II) receivedbolus delayed (6 days) MEF (birth weight 1000 g: daily 12 1 mL breast milk or pretermformula; Nenatal). MEF was administered during the

first week of life.23 Afterward, feedings were cautiouslyadvanced every 24 hours by 15 mL/kg, whenever morethan 50% of the calculated amount had been givenduring the previous 24 hours.24 Nursing and medicalstaff as well as the researchers were aware of groupassignment. All infants received parenteral feedingaccording to the standard protocol.

All infants were closely monitored for residuals,bilious aspirates, and abdominal distension. More spe-cifically, the gastric residual volume was checked beforeeach feeding. At a volume equal to or less than 5 mL, thescheduled amount was given; otherwise the difference up

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Six infants (15%) in group I and 4 (9.8%) ingroup II presented with NEC, and 14 infants (35%) ingroup I and 15 (36.6%) in group II presented withfeeding intolerance. In the latter, feeding volumes werereduced or withheld, but neither of the infants required

withholding of feeding for more than 48 hours.The incidence of NEC and feeding intolerance wasnot significantly different between the two groups(p 0.353 and p 0.533, respectively). The relativerisk for NEC was 1.538 times greater in group Icompared with group II (95% confidence interval [CI]0.469 to 5.043). Two cases of NEC in group I requiredsurgical intervention. The number of neonatal deaths

was not significantly different between the two groups(p 0.512).

Of all studied infants, 10 (12.35%) presented withNEC (Bells stage II) and 39 (25.6%) presented withfeeding intolerance. An analysis was performed to iden-tify the potential relationship between NEC and sig-nificant perinatal parameters (Table 2). Neonates withNEC were delivered at significantly earlier gestationalage and at lower birth weights (p 0.023 andp 0.006,respectively). A regression analysis was performed tofurther assess the contribution of significant variablesto the development of NEC. Birth weight significantlycontributed to the development of NEC (odds ratio0.996, 95% CI 0.992 to 0.999). Neonates who experi-enced NEC had higher mortality (three of five, oddsratio 14.786; 95% CI 2.012 to 40.909, p 0.012). Themain cause of death was sepsis.

Table 1 Patient Characteristics

Group I (n40) Group II (n41)

Gestational age (wk) 32.0 (27.034.0) 31.3 (27.034.0)

Birth weight (g) 1080 (6801440) 1130 (4401420)

Birth weight centile 0.25 (0.15) 0.12 (0.55)

Gender (male),n (%) 17 (42.5%) 16 (39%)

Maternal age (y) 32.0 (6.3) 32.5 (5.0)

Parity (primigravida),n (%) 25 (62.5%) 23 (56%)

Mode of delivery (caesarean section),n (%) 39 (97.5%) 41 (100%)

Maternal preeclampsia,n (%) 9 (22.5%) 10 (24.4%)

Antenatal steroid exposure,n (%) 33 (82.5%) 32 (78%)

Apgar 1 min 7.0 (3.08.0) 7.0 (4.08.0)

Apgar 5 min 8.0 (5.09.0) 8.0 (5.09.0)

Arterial cord blood pH 7.4 (0.04) 7.35 (0.1)

Arterial cord blood base deficit (mmol/L) 1.5 (2.1) 2.8 (3.1)

Table 2 Patient Characteristics with Respect to NEC

No NEC (n71) NEC (n10) pValue

Gestational age (wk)* 32.2 (27.034.0) 30.3 (27.033.5) 0.023

Birth weight (g)* 1160 (4401440) 950 (6801130) 0.006

Birth weight centiley 0.04 (0.3) 0.30 (0.9) 0.415

Gender (male),n (%)z 28 (39.4%) 5 (50%) 0.380

Maternal age (y)* 33.2 (5.3) 33.5 (5.0) 0.876

Parity (primigravida),n (%)z 40 (56.3%) 8 (80%) 0.134Mode of delivery (caesarean section),n (%)z 70 (98.6%) 10 (100%) 0.877

Maternal preeclampsia,n (%)z

17 (23.9%) 2 (20%) 0.570

Antenatal steroid exposure,n (%)z 57 (80%) 8 (80%) 0.632

Apgar 1 min* 7.0 (3.08.0) 7.5 (6.08.0) 0.184

Apgar 5 min* 8.0 (5.09.0) 8.5 (8.09.0) 0.873

Arterial cord blood pHy 7.35 (0.06) 7.37 (0.04) 0.674

Arterial cord blood base deficit (mmol/L)y 2.4 (2.8) 0.5 (1.7) 0.195

Neonatal deaths,n (%)z 2 (2.8%) 3 (30%) 0.012

*Mann-Whitney Utest was used; data presented as median (range).yThe ttest was used for probability value; data presented as mean standard deviation.zFisher exact test was used; data presented as n (%).NEC, necrotizing enterocolitis.



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DISCUSSIONThe results of this randomized, nonblinded pilot trial inpreterm infants with IUGR and abnormal antenatalDoppler results suggested that early introduction ofMEF may not have a significant effect on the incidenceof NEC or feeding intolerance. Furthermore, althoughnot the primary outcome of this study, birth weight was

found to be a significant independent risk factor for thedevelopment of NEC, irrespectively of the timing ofMEF introduction.

Preterm infants with IUGR often have prenatalhemodynamic disturbances, such as decreased PI of themiddle cerebral artery, and/or increased PI or absent ofreversed and diastolic flow (AREDF) in the umbilicalartery.6,7,28 These prenatal hemodynamic abnormalitieshave been associated with increased perinatal mortalityand morbidity, including NEC, especially if therehas been antenatal detection of AREDF in the fetalaorta or umbilical artery, as also recorded in our

study.3,4,8,9,15,28,29

Furthermore, postnatal physiologicalstudies have shown persistent flow abnormalities insuperior mesenteric artery blood flow velocity in theseinfants during the first days of life.11,3032Therefore, thegradual recovery of intestinal perfusion during the firstdays of life provides a sound rationale for a modest delayin enteral feeding.

On the other hand, delaying enteral feeding couldbe detrimental. Parenteral nutrition is usually used as analternative source of nutrients, but side effects arecommon.13,3336 In this respect, MEF of very low-birth-weight infants has been introduced into clinicalpractice as an alternative approach to delayed enteralintake.14,37 This approach has recognized benefits, in-cluding enhanced endocrine and exocrine hormonalactivity, improved growth of intestinal mucosa, matura-tion of gut motility, and improved overall clinical out-come, with no proven increase in the relative risk offeeding intolerance or NEC.1618,38

In our study, which has specifically includednonasphyxiated at birth,39 preterm IUGR infants

with abnormal Doppler results, there was no significanteffect of early introduction of MEF on the incidence ofNEC or feeding intolerance. In agreement, the findingsof previous studies did not support a delay in enteral

feeding based on prenatal Doppler pathology, as ahigher risk for NEC could not be proven.19,40 How-ever, with the sample size of the present study, adifference in the incidence of NEC of25 to 30%should have been detected, to get a statistically signifi-cant result. Furthermore, based on the outcome of thisreport, the number of infants needed to enroll in arandomized controlled trial to adequately test ourhypothesis is 618 infants per group. Therefore, a largersample size is needed to draw definite conclusionsregarding the effect of early MEF on measures ofclinical outcome.

Moreover, maternal preeclampsia did not prove tobe an independent risk factor for the development ofNEC in our study. In contrast, a previous report inpreterm, very low-birth-weight infants demonstrated asignificant association between maternal hypertensivedisorders and the development of NEC.41 The authorsspeculated that the reduced uteroplacental blood flow in

preeclampsia may result in birth asphyxia with redistrib-ution of blood flow, bowel ischemia, and NEC.41,42

However, the population of this study was defined bymaternal hypertensive disorders, rather than IUGR.41

On the other hand, the infants of our cohort were notasphyxiated at birth.39 Nevertheless, primary hypoxia-ischemia has not been previously suggested to be a riskfactor for NEC in preterm infants.43 Finally, prenatalsteroid exposure had no effect on the incidence of NEC,and birth weight was a significant independent riskfactor for the development of NEC, in agreement withprevious reports.9,41,4446

In conclusion, the results of this randomizedpilot trial suggest that early introduction of MEF inpreterm infants with IUGR and abnormal antenatalDoppler results may not have a significant effect on theincidence of NEC or feeding intolerance. Furthermore,birth weight was found to be a significant independentrisk factor for the development of NEC, irrespectivelyof the timing of MEF introduction. However, becauseof the relatively small number involved, these datashould be seen as preliminary, and larger randomizedcontrolled trials are required to further elucidate therole of feeding protocols and determine the factors thatmay play an important role in the pathogenesis ofNEC in preterm infants with IUGR and abnormalfetal blood flow.

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