Early Feeding Advancement in Very Low-Birth-Weight InfantsWith Intrauterine Growth Retardation and Increased Umbilical

Artery Resistance

*Walter Alexander Mihatsch, *Frank Pohlandt, *Axel Rainer Franz, and Felix Flock

*Departments of Pediatrics and Obstetrics, Ulm University, Ulm, Germany

ABSTRACTBackground: To investigate whether intrauterine growth re-tardation (birth weight 90th percentile measuredby Doppler velocimetry), or brain sparing (increased umbilicalartery resistance and decreased middle cerebral artery resis-tance index

enrolled in a study of early enteral feeding tolerance after fol-lowing a new feeding protocol. The institutional ethics com-mittee approved the study protocol. Exclusion criteria weremajor congenital malformations and anomalies that may inter-fere with nourishing (e.g., hydrops). Eligibility was assessedafter the attending physician decided to initiate milk feeding.Informed written parental consent was obtained. Initially, allinfants received parenteral nutrition, which was gradually de-creased with increasing enteral intake.

Doppler Sonographic Examinations

Doppler velocimetry of the placental and fetal vessels wasperformed within 1 week before delivery for the followingreasons: suspected fetal compromise, maternal hypertension,antepartum hemorrhage, preterm labour, or prelabor rupture ofthe membranes. Trained sonographers performed Doppler ve-locimetry using a GE Logic 500 (General Electric, 42655Solingen, Germany), a Voluson 530D (Kretztechnik GmbH,45768 Marl, Germany), or a Toshiba Powervision 6000(Toshiba Medical Systems GmbH, 81241 Munich, Germany)ultrasound device. Doppler velocimetry was performed using ahigh-pass filter of 100 MHz or less, with the woman in asemirecumbent position during fetal quiescence and fetal ap-nea. Umbilical artery Doppler studies were performed in amidsegment of the umbilical cord. Increased umbilical arteryresistance was defined as a resistance index above the 90thpercentile for gestational age (15). Brain sparing was defined asthe combination of increased umbilical artery resistance withresistance index of the medial cerebral arteries below the 5thpercentile (16,17). For every measurement, the resistance indexwas calculated for three to five characteristic waveforms andthe median resistance index was recorded.

Gestational age was determined by the first day of the lastmenstrual cycle and confirmed or corrected by the result of thefirst sonographic investigation before the 10th week of gesta-tion. Intrauterine growth retardation was defined as birthweight below the 10th percentile for gestation (18). Suspectedearly onset bacterial infection was defined as a C-reactive pro-tein concentration >10 mg/L within the first 72 hours of life.

Feeding Protocol

Within the first hours of life, bolus gavage feeding of 5%glucose, every 2 to 3 hours, was started at 16 mL/kg birthweight daily. As soon as a sufficient amount of meconium hadbeen passed (19), bolus milk feeding was started at the discre-tion of the attending physician. Human milk feeding was en-couraged. Human milk was fortified after full enteral feeds(150 mL/kg birth weight daily) were achieved. Preterm infantformula (Aptamil Prematil or Aptamil Prematil HA; MilupaGmbH, Friedrichsdorf, Germany) was fed if human milk wasnot available. The infants were fed every 2 (2 cm); and blood in the stools. 5% Glu-cose glycerin enemas (10:1 mixture, 5 mL/kg) were adminis-tered twice daily until the infants passed spontaneously at leastone stool per day. After extubation or intubation, feedings werewithheld for 6 hours. Laxatives were not administered duringthe study. Oral medications were not given until full enteralfeeds (150 mL/kg birth weight daily) were achieved.

Data Collection and Analysis

Demographic variables were recorded for all infants. Thestudy period covered the first 4 weeks of life. Feeding tolerancewas assessed as the age at which full enteral feeds (150 mL/kgbirth weight daily) were achieved. The cumulative intake ofany human milk from the beginning of milk feeding until fullenteral feeds were achieved was calculated and expressed aspercentage of the cumulative milk intake within this period oftime. Necrotizing enterocolitis was diagnosed according to theBell stages (21). Wilcoxon tests were used for categoric dataanalysis, and forward selection multivariate logistic regressionanalysis was used to determine the factors independently asso-ciated with the age at full feeds (level of significance was P 2), both were AGA, and fetal Doppler velocimetry wasnot available.

In 18 of the 35 infants with IUGR, length and headcircumference at birth also were below the 10th percen-tile for gestation (IUGR type 1), and in 17, only the birthweight was below the 10th percentile (IUGR type 2).However, we found no significant difference betweenthese two subgroups with regard to the age at whichfeeds began: 4 days (range, 25 days) versus 3 days(range, 24 days); P 0.49; IUGR type 1 versus type 2;the time to achieve full feeds after initiation of milkfeeds, 11 days (range, 913 days) versus 10 days (range,1012 days); P 0.98); and the age at full feeds, 14days (range, 1219 days) versus 13 days (range, 1115days); P 0.53).

We found no significant difference between infantswith IUGR and AGA infants in the age at starting feeds,the time to achieve full feeds after initiation of milkfeeds, or the age at full feeds (Table 2). Doppler veloc-imetry had been performed in only 68 infants. Increasedumbilical artery resistance was found in 18 and brainsparing in 10 infants. In infants with increased umbilicalartery resistance or brain sparing, milk feeding was ini-tiated significantly later; however, we noted no signifi-cant difference in the time to achieve full feeds afterinitiation of milk feeds and in the age at full feeds (Table2). When birth weight and gestational age were con-

trolled for in a multivariate regression model to deter-mine the factors significantly associated with the age offull enteral feeds, neither IUGR, increased umbilical ar-tery resistance, nor brain sparing proved to be signifi-cantly associated (Table 3).

DISCUSSION

These data confirmed previously reported findingsthat variables such as birth weight probably are moreimportant predictors of postnatal morbidity than IUGRand fetal Doppler flow (13,14). In VLBW infants,growth status and maturity are inextricable confounded,the most mature infants also being the most growth re-tarded. Gestational age and birth weight were associatedsignificantly with feeding tolerance, measured as the ageat full feeds, whereas IUGR, increased umbilical arteryresistance, and brain sparing did not show any significantassociation (Tables 2 and 3). The detrimental effects ofpoor growth status and poor Doppler blood flow on gas-trointestinal function might have been blunted by matu-rity, confirming the findings of others who reported evena misleading protective effect of IUGR against in-hospital death in VLBW infants (22).

Although, the time until full feeds decreased with in-creasing gestational age and birth weight, only 32% ofthe variation of the age at full feeds (Table 3, r2 0.32)was determined by the clinical characteristics availableat the infants admission. Other criteria, for instance theavailability of human milk, the type of formula (hydro-lyzed or nonhydrolyzed protein preterm infant formula),nosocomial infections, or the feeding protocol itself,might have been far more important. Nevertheless, basedon the presented data, we find no need to develop aspecific feeding protocol of extremely slow advancementof feeds for the subgroups of VLBW infants with IUGR,increased umbilical artery resistance, or brain sparing.

TABLE 1. Clinical characteristics

All infants AGA infants IUGR infants

n 124 89 35gestational age (wk) 28.2 (22.335.9) 27.1 (22.232.3) 29.3 (24.135.9)*Birth weight (g) 890 (4201500) 940 (4201490) 780 (4501500)Length at birth (cm) 35 (26.542.5) 35.5 (2842) 33 (26.542.5)Head circumference at birth (cm) 25.1 (2031) 25 (2031) 25.2 (2031)Apgar 5 minutes 8 (210) 8 (210) 8 (210)Apgar 10 minutes 9 (310) 9 (310) 9 (310)Umbilical artery pH 7.27 (6.767.46) 7.28 (6.767.46) 7.26 (6.957.46)Umbilical artery base deficit 6.1 (22.2 to 1.1) 6.5 (22.2 to 1.7) 6 (18 to 1.1)Male (%) 54 (44%) 38 (43%) 16 (46%)Antenatal betamethasone 111 (90%) 75 (86%) 36 (97%)Suspected early onset bacterial infection 14 (11%) 12 (2.3%) 2 (0.5%)Less than 10% of human milk available 83 (67%) 58 (66%) 25 (68%)Necrotizing enterocolitis (Bell stage 2) 2 (2%) 2 (2%) 0 (0%)

Data is shown as median and range or n (%)* P 0.007, P 0.03AGA, appropriate for gestational age; IUGR, intrauterine growth retardation.

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The incidence of necrotizing enterocolitis (Bell stage2) was too small (n 2) to draw sound conclusions.

The current study has some limitations. First, the at-tending physicians were aware of the clinical character-istics of the infants and may have had the intention toslow down the feeding advancement in infants withIUGR or increased umbilical artery resistance. In fact,milk feedings were initiated significantly later in infantswith increased umbilical artery resistance and brain spar-ing. However, there was a standardized feeding protocol,and the speed with which the feedings were advancedwas the same in all groups (Table 2).

The definition of IUGR did not consider height of theparents, birth rank, maternal age, or pregravid weightbecause these data were not available. Some of the in-fants who were defined as growth retarded in fact mighthave been constitutionally small and therefore misclas-sified (23). However, we found no difference in feedingtolerance between proportionally growth retardedVLBW infants (IUGR type 1) who might have been

small from early on and disproportionally growth re-tarded VLBW infants who might have had poor placentalfunctioning during the second or third trimester of preg-nancy (IUGR type 2).

More important, prenatal Doppler studies were avail-able in only 55% of the infants studied. Because of theroutine obstetric management, prenatal Doppler studieswere performed only when fetal compromise was sus-pected and when there was enough time before deliveryto perform the studies. In addition, these Doppler studieswere obtained within the week before delivery, and thelength of time that fetal circulation was compromisedremained unknown.

Finally, the present feeding protocol anticipated prob-lems with enteral feeding in all VLBW infants. Routineenemas were given twice daily to all infants until theybegan regular bowel movements. Five percent glucosefeeding was initiated within the first hours of life, butmilk was introduced only after the infants had started topass a sufficient amount of meconium (19). Although, noeffect of IUGR and increased umbilical artery resistanceon feeding tolerance was found at a rate of 16 mL/kgbirth weight daily, feeding intolerance may occur if in-take is increased more rapidly.

CONCLUSION

Intrauterine growth retardation, increased umbilicalartery resistance index, and brain sparing were not inde-pendently associated with early feeding intolerance inVLBW infants who were fed according to a standardizedfeeding protocol, if birth weight and gestational age werecontrolled for. Full enteral feeds were achieved at thesame postnatal age in VLBW infants with IUGR, in-creased umbilical artery resistance, or brain sparing as inappropriate-for-gestational-age VLBW infants. There-fore, developing special feeding protocols for varioussubgroups of VLBW infants is unnecessary.

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TABLE 2. Association between intrauterine growth, fetalDoppler studies, and nutrition

NAge at starting

feeds (d)

Time to achieve fullfeeds after starting

milk feeds (d)

Age at fullenteral

feeds (d)

IUGR 37 4 (24) 11 (916) 14 (1221)P 0.65 P 0.23 P 0.60

No IUGR 87 3 (24) 12 (1016) 15 (1221)IUR 20 4 (35) 10 (913) 14 (1116)

P 0.02 P 0.16 P 0.80No IUR 51 3 (24) 11 (1018) 14 (1121)BS 11 4 (47) 10.5 (1014) 15 (1420)

P 0.05 P 0.99 P 0.53No BS 27 3 (24) 10 (917) 13 (1121)

Data is sown as median (25th to 75th percentile).IUGR, intrauterine growth retardation; IUR, increased umbilical ar-

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TABLE 3. Multiple regression model: variables determiningthe age at full enteral feeds. Total goodness of fit of the

model r2 = 0.32

Variables includedin the model

Pvalue

Regressioncoefficient b

Contributionto r2

Constant 43.0Gestational age (wks) 0.011 0.643 0.28Birth weight (100 g) 0.031 0.529 0.02Antenatal betamethasone 0.042 1.34 0.02

Variables excluded P value

Increased umbilical artery resistance 0.17Apgar score at 10 minutes 0.31Brain sparing 0.38Apgar score at 5 minutes 0.45Apgar score at 1 minute 0.58Umbilical artery pH 0.73Intrauterine growth retardation 0.73

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