The Journal of Maternal-Fetal & Neonatal Medicine
ISSN: 1476-7058 (Print) 1476-4954 (Online) Journal homepage: http://www.tandfonline.com/loi/ijmf20
Optimising enteral nutrition in growth restricted extremely preterm neonates – a difficult proposition P. Shah, E. Nathan, D. Doherty & S. Patole To cite this article: P. Shah, E. Nathan, D. Doherty & S. Patole (2015) Optimising enteral nutrition in growth restricted extremely preterm neonates – a difficult proposition, The Journal of Maternal-Fetal & Neonatal Medicine, 28:16, 1981-1984, DOI: 10.3109/14767058.2014.974538 To link to this article: http://dx.doi.org/10.3109/14767058.2014.974538
Accepted online: 10 Oct 2014.Published online: 04 Nov 2014.
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Date: 05 October 2015, At: 00:38
http://informahealthcare.com/jmf ISSN: 1476-7058 (print), 1476-4954 (electronic) J Matern Fetal Neonatal Med, 2015; 28(16): 1981–1984 ! 2014 Informa UK Ltd. DOI: 10.3109/14767058.2014.974538
ORIGINAL ARTICLE
Optimising enteral nutrition in growth restricted extremely preterm neonates – a difficult proposition P. Shah1, E. Nathan2,3, D. Doherty2,3, and S. Patole1,4 Department of Neonatal Paediatrics, KEM Hospital for Women, Perth, Australia, 2Women and Infants Research Foundation, KEM Hospital for Women, Perth, Australia, 3School of Women’s and Infant’s Health, KEM Hospital for Women, Perth, Australia, and 4Centre for Neonatal Research and Education, University of Western Australia, Perth, Australia
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1
Abstract
Keywords
Background: Optimising enteral nutrition of extremely preterm neonates (EP: Gestation 528 weeks) with intrauterine growth restriction (IUGR) has always been difficult considering their higher risk of necrotising enterocolitis (NEC), and frequency of feed intolerance. Aim: To evaluate the nutritional outcomes in EP neonates with IUGR. Methods: Data on demographic characteristics, feeding details (e.g. type of milk, postnatal age at start), and outcomes to discharge or death were collected from the medical notes for all EP neonates, who survived first 72 h of life, between January 2009 and December 2010. A standardised feeding protocol was followed during the study period. Results: 38/220 (17.3%) EP neonates admitted during the study period had IUGR. The mean (IQR) age at start of minimal enteral nutrition [7 (5–10) versus 5 (4–8) days, p ¼ 0.005), and nutritional (1 ml/2hourly) feeds [12 (8–15) versus 9 (7–13) days, p ¼ 0.034] was significantly delayed in IUGR compared to non-IUGR neonates. IUGR neonates reached full enteral feeds (150 ml/kg/day) at a significantly late median (IQR) postnatal age [32 (21–40) versus 24 (17–31) days, p ¼ 0.009), taking longer time to achieve this milestone [20 (15–34) versus 16 (12–4) days, p ¼ 0.008). The incidence of postnatal growth restriction was significantly higher in IUGR versus non-IUGR (73% versus 45%, p ¼ 0.003) neonates. The incidence of Stage II NEC was low [18/220 (8.1%)] to make valid statistical comparisons. Conclusion: Optimising enteral nutrition in growth restricted extremely preterm neonates is difficult using the current strategies for enteral nutrition.
Feeding, growth restriction, intrauterine, necrotising enterocolitis, neonates, preterm
Introduction Enteral feeding of extremely preterm neonates with intrauterine growth restriction (IUGR) has always been a difficult issue to address for those involved in neonatal intensive care [1–4]. In the intrauterine life, blood flow to the head is often preserved at the expense of the visceral organs in growth restricted preterm neonates (brain sparing effect) [5–7]. Intrauterine hypoxia of the gut and increased oxygen demand during enteral feeds in a vulnerable and immature host relate to the feeding difficulties and increased risk of necrotising enterocolitis (NEC) in these neonates [7,8]. Preferential use of mother’s or donor breast milk, early minimal enteral feeds, and standardised feeding protocols with cautious advancement of feeds are frequently used to facilitate gastrointestinal adaptation and feed tolerance and
Address for correspondence: Prof Sanjay Patole, Department of Neonatal Paediatrics, KEM Hospital for Women, 374 Bagot Road, Subiaco, City of Perth, Western Australia 6008, Australia. Tel: 61-8-93401260. Fax: 61-8-93401266. E-mail: [email protected]
History Received 25 December 2013 Revised 4 October 2014 Accepted 6 October 2014 Published online 4 November 2014
reduce the risk of NEC in preterm neonates [4,9–11]. Benefits of such strategies in optimising enteral nutrition in preterm very low birth weight (VLBW) neonates with IUGR have been reported by various investigators [12]. However, whether these strategies achieve such success in extremely preterm (gestation528 weeks) neonates with IUGR is not clear. KEM Hospital for Women is the sole tertiary neonatal referral centre for the state of Western Australia. The unit admits 100 extremely preterm neonates per year. Considering the significance of optimising enteral nutrition in extremely preterm neonates we aimed to audit the nutritional outcomes in this population in our unit.
Participants and methods Design This was a retrospective analysis of prospectively collected data on extremely preterm neonates. Participants All extremely preterm neonates (gestation: 528 weeks at birth) admitted between January 2009 and December 2010
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and survived the first 72 h of life were eligible for inclusion in the study. Ethical approval Approval from the institutional ethics committee was obtained prior to commencing the study. Data collection Data on demographic characteristics, feeding details (e.g. type of milk, postnatal age at start), and outcomes to discharge from the nursery or death were collected from the medical notes using a standardised, pre-piloted data collection form.
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Definitions IUGR was defined as birth weight 510th percentile for gestational age. NEC was defined by the modified Bell Staging criteria [13]. Minimal enteral nutrition (MEN) was defined as any volume of milk feeds at start. Starting of nutritional feeds (NF) was defined as enteral feed reaching the volume of 1 ml 2 hourly. Time to full feeds (TFF) was defined as the time taken to establish enteral feeds of 150 ml/kg/day enterally after start of MEN. Extrauterine growth retardation was defined as weight under 10th percentile for corrected age at discharge. Enteral feeding protocol for the unit Breast milk was preferred for feeding. In the absence of mother’s milk, pasteurised donor milk was used. Feeds were given as two hourly intermittent boluses through orogastric tube before graduating to 3 hourly and eventually suck feeds. Starting of feeds: Feeds were initiated as early as possible in presence of clinical stability defined as: (1) No respiratory assistance or minimal assistance (e.g. mean airway pressure: 8 cm H2O, CPAP 5–6 cm H2O and oxygen 30%). (2) No need for inotrope or colloidal support to maintain blood pressure within ‘‘normal’’ range. (3) No hemodynamically significant PDA requiring indomethacin. (4) No sepsis or sepsis treated with antibiotics for 48 h and without respiratory or haemodynamic instability. MEN was started at 5 or 10 ml/kg/day for neonates with gestation 25 weeks and/or IUGR and for those with gestation 26 weeks respectively. Guidelines for starting, continuing or stopping MEN were at the discretion of the attending neonatologist. Volume increments: (1) Started at 15 ml/kg/day and upgrade by 7.5 ml/kg every 12 h for neonates with gestation 25 weeks and/or IUGR. (2) Started at 20 ml/kg/day and upgrade by 10 ml/kg every 12 h for neonates with gestation 26 weeks. (3) The volumes of feed increments were increased by 7.5 ml or 10 ml//kg every 8 h for neonates with gestation 25 weeks and/or IUGR and 26 weeks respectively after reaching feeds of 100 ml/kg/day. The maximum total enteral feeds were 170 ml/kg/day increased from 150 ml/ kg/day in increments of 10 ml/kg/day at 48-hour intervals. Withholding feeds: Feeds were withheld if any time the pre-feed aspirates were 30% of the total 2 previous feeds, frank bile or aspirate positive for bile or blood, concerns of abdominal distension, 12 h during the blood transfusion.
J Matern Fetal Neonatal Med, 2015; 28(16): 1981–1984
Statistical approach Categorical data were summarised using frequency distributions and continuous data using median, interquartile range (IQR) and range. Univariate comparisons were conducted using the Chi-square test and Fisher exact test for categorical data and the Mann–Whitney test for continuous data. Statistical tests were two-sided and p values 50.05 were considered statistically significant. The analysis was performed using SPSS 18.0 for Windows (SPSS, Chicago, IL)
Results A total of 220/236 extremely preterm neonates survived the first 72 h of life with median (IQR) gestation and birth weight as 26 (24–27) weeks and 813 (660–964) g, respectively; 56.8% were males and 93% were inborn. There were 38 (17.27%) neonates with IUGR with lower birth weight (Table 1). A significantly higher percentage of these neonates had maternal PIH compared with non-IUGR neonates. Maternal ante-partum haemorrhage (APH), prolonged rupture of membranes (PROM), and chorioamnionitis were more frequent in non-IUGR neonates (Table 1). Nutritional outcomes The mean (IQR) age at start of MEN, and nutritional feeds was significantly delayed, and the volume of nutritional feeds was significantly higher in IUGR versus non-IUGR neonates (Table 2). Enteral feeds of 50, 100, and 150 ml/kg/day were reached at a significantly late postnatal age and the time to reach 150 ml/kg/day feeds was significantly longer in IUGR versus non-IUGR neonates. IUGR neonates spent a longer time off feeds compared to non-IUGR neonates, however, this did not reach statistical significance (p ¼ 0.06). Incidence of postnatal growth retardation was significantly higher, and the duration of hospital stay was significantly longer, in IUGR versus non-IUGR neonates. The incidence of Stage II NEC, as well as need for surgery and mortality related to the illness
Table 1. Demographic characteristics.
Variable Gestation (weeks) Birth weight (grams) Male gender Antenatal glucocorticoids Complete Single dose None Mode of delivery Vaginal Emergency C-Section Elective C-Section Inborn Apgar 57 at 5 minutes CRIB score Maternal PIH Maternal APH Chorioamnionitis PROM Maternal Antibiotics
IUGR (n ¼ 38)
Non-IUGR (n ¼ 182)
p value
25.8 (±1.3) 618 (±157) 19 (50%)
25.8 (±1.3) 861 (±186) 106 (58%)
0.905 50.001 0.351
28 (74%) 8 (21%) 2 (5%)
119 (65%) 49 (27%) 14 (8%)
9 12 17 36 5 12 20 7 1 6 17
85 64 33 169 46 11 13 76 36 62 119
(24%) (32%) (45%) (95%) (14%) (±2) (53%) (18%) (3%) (16%) (46%)
(47%) (35%) (18%) (93%) (26%) (±2) (7%) (42%) (20%) (34%) (65%)
Data are represented as mean (±sd) and number (%).
0.620
0.001 1.000 0.125 0.258 50.001 0.007 0.011 0.027 0.026
Difficulties in enteral feeding of growth-restricted EP neonates
DOI: 10.3109/14767058.2014.974538
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Table 2. Nutrition related outcomes.
Variable
N
Minimal enteral feeds (MEN) Age at start Volume Type EBM PDHM Nutritional feeds (NF) Age at start Volume at start Postnatal age at feeds of: 50 ml/kg/day 100 ml/kg/day 150 ml/kg/day Time to reach feeds of: 50 ml/kg/day 100 ml/kg/day 150 ml/kg/day Number of episodes of NBM 412 h after NF Total hours of NBM after MEN Stage II NEC Surgical treatment Death Postnatal growth retardation Duration of hospital stay Survival
36
IUGR (n ¼ 38)
N
Non-IUGR (n ¼ 182)
p value
179 7 (5–10) 5 (3–6)
5 (4–8) 5 (3–7)
0.005 0.807
33 (94%) 2 (6%)
163 (91%) 16 (9%)
0.744
34
179 12 (8–15) 19 (14–20)
33
9 (7–13) 13 (12–16)
0.034 50.001
14 (10–19) 17 (13–23) 24 (17–31)
0.037 0.005 0.009
(5–12) (8–16) (12–24) (1–3)
0.307 0.060 0.008 0.076
(36–192) (8%) (50%) (21%) (45%) (73–115) (96%)
0.06 0.745 0.382 0.533 0.003 0.005 0.006
179 16 (11–24) 21 (16–29) 32 (21–40)
33
179
33
8 12 20 3
(5–12) (10–23) (15–34) (2–4)
176
7 11 17 2
33 38 4 4 33 38 38
120 4 1 2 24 105 31
(60–246) (11%) (25%) (50%) (73%) (86–127) (82%)
179 182 14 14 178 182 182
80 14 7 3 80 90 174
EBM – expressed breast milk; PDHM – pasteurised donor human milk. Data are represented as median (25th–75th percentile, minimum-maximum) and number (%).
was low to make valid statistical comparisons between IUGR and non-IUGR neonates (Table 2).
Discussion Our results indicate the difficulties in optimizing enteral nutrition of extremely preterm (gestation 528 weeks) neonates with IUGR. They are consistent with those reported by other investigators [1]. Despite efforts towards adhering to the standardised feeding protocol, we were able to start minimal enteral and nutritional feeds only at a significantly late postnatal age than desired. This delay relates to signs of ileus of prematurity (e.g. distended ‘‘ropy’’ abdomen with visible bowel loops, large and/or bile stained gastric residuals, failure to pass meconium) which are difficult to distinguish from those of NEC. Feed volumes of 50, 100, and 150 ml/kg/day were reached significantly late in IUGR neonates. The median (IQR) time to reach from 100 ml/kg/day to 150 ml/kg/day of feeds was significantly higher in IUGR versus non-IUGR neonates [20 (14–33) versus 16 (11–23) days, p ¼ 0.008]. These findings may relate to the frequent stoppage of feeds due to feed intolerance and fear of NEC at higher milk volumes in this high-risk cohort. The clinically significant longer duration for which feeds were withheld in IUGR neonates supports this hypothesis. Lack of statistically significance of this finding is probably due to a small sample size. It is important to note that despite the late commencement of feeds, the postnatal age (32 versus 28 days) and time taken reach full enteral feeds (32 versus 28 days) in IUGR neonates was comparable to those reported by other investigators [1].
Considering their higher risk for developing NEC, initiation of enteral feeding is frequently delayed in preterm neonates with IUGR [8]. The results of a recent randomised controlled trial are important in this context. Leaf et al. [14] randomly allocated preterm IUGR neonates (gestation 535 weeks) with abnormal umbilical artery Dopplers to commence feeds early (day 2, n ¼ 202), or late (day 6, n ¼ 202) after birth. A standard protocol with the same rate of feed increment for both groups was followed. Full feeds were achieved earlier in the early versus late group (median: 18 versus 21 days), with no significant difference in the incidence of NEC (18% versus 15%). It is important to know that the median gestation of neonates enrolled in this trial was 31 weeks, making it difficult to extrapolate these results to extremely preterm IUGR neonates with gestation 528 weeks. Kempley et al. [1] have recently conducted a post-hoc analysis of subgroup data from the ADEPT trial. They reported that growth-restricted neonates529 weeks’ gestation with abnormal antenatal Doppler failed to tolerate even the careful feeding. Full feeds were achieved later in neonates 529 weeks compared with 29 weeks [Median (IQR) age: 28 (22–40) versus 19 (17–23) days, HR 0.35 (95% CI: 0.3–0.5)]. The incidence of NEC was significantly higher in those with gestation 529 versus 29 weeks [32/83 (39%) versus 32/312 (10%), RR: 3.7, (95% CI 2.4–5.7)]. Neonates 529 weeks tolerated very little milk for the first 10 days of life and reached full feeds 9 days later than predicted from the trial regimen. Mihatsch et al. [12] have previously reported that VLBW neonates with IUGR, increased umbilical artery resistance,
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and brain sparing tolerate enteral feeding as well as appropriate-for-gestational-age VLBW infants. They enrolled 124 inborn VLBW neonates in a prospective trial evaluating early enteral nutrition with a standardized feeding protocol (daily feed increment: 16 ml/kg birth weight). Feed tolerance was assessed as the age at which full enteral feeds (FEF: 150 ml/kg daily) were achieved. Full enteral feeds were achieved at 15 (range, 12–21) days of age for all neonates. IUGR [FEF: 14 (12–21) days], increased umbilical artery resistance [FEF: 14 (11–16) days], and brain sparing [FEF: 15 (14–20) days] were not associated with early feeding intolerance. The positive results of this study may relate to the lack of enrolment of adequate number of extremely preterm neonates. Karagianni et al. [15] have studied the effect of early (5 days) versus delayed (6 days) initiation of MEN on the incidence of NEC and feeding intolerance in preterm neonates with IUGR and abnormal antenatal Dopplers in a randomized, non-blinded pilot trial. All neonates received parenteral feeding within 48 h of life. The median (range) gestation and birth weight of the neonates enrolled in the early versus delayed initiation of MEN groups were 32.0 (27.0–34.0) versus 31.3 (27.0–34.0) weeks and 1080 (680–1440) versus 1130 (440–1420) grams respectively. Of the 84 infants enrolled, 81 completed the study; 40 received early MEN [Median (range) age: 2 (1–5) days and 41 received delayed MEN [Median (range) age: 7 (6–14) days. The incidence of NEC and feeding intolerance was not significantly different between groups. It was concluded that early MEN in preterm infants with IUGR and abnormal antenatal Dopplers may not have a significant effect on the incidence of NEC or feeding intolerance, and birth weight seemed to be an independent risk factor for NEC, irrespective of the timing of MEN introduction. Inclusion of relatively mature neonates with higher birth weight makes it difficult to extrapolate these findings to extreme preterm neonates with IUGR. Arnon et al. [16] have recently reported the results of their study assessing very early versus delayed enteral feeds in stable preterm neonates (gestation537 weeks) with IUGR. Enrolled neonates (30 in each) were randomly allocated to a very early (within 24 h of birth) or delayed (after 24 h of birth) feeding regimen. All neonates had in utero evidence of absent or reverse diastolic flow. Neonates unable to start early feeding were excluded. Those included in the very early feeding regimen achieved full enteral feeds sooner than controls (98 ± 80–157 versus 172 ± 123–261 h of age, respectively; p ¼ 0.004) and were discharged home earlier (p ¼ 0.04). No NEC was documented in both groups. Gastric motility was improved at day seven after feeding initiation in both study groups, with no difference between groups. The applicability of these results to extremely preterm is however questionable considering the gestational age, and stable status of the enrolled neonates. Overall, our results indicate that optimising enteral nutrition is difficult in extremely preterm neonates (gestation 528 weeks) with IUGR. Caution is needed in interpreting these results considering the observational nature of our study, and its small sample size that also makes it difficult to comment on the risk of NEC following attempts to optimise enteral
J Matern Fetal Neonatal Med, 2015; 28(16): 1981–1984
nutrition in this high-risk cohort. It is also important to note that there was inequality in the number of neonates in both groups with only 38 IUGR compared with 182 non IUGR neonates. The strength of our study relates to the fact that it involves prospectively collected data on extremely preterm neonates from a large sole regional tertiary neonatal referral centre. Despite the limitations, it is reassuring to note that our results are consistent with those reported by Kempley et al. Further research is required to develop strategies for optimising enteral nutrition in extremely preterm neonates with IUGR.
Declaration of interest The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article.
References 1. Kempley S, Gupta N, Linsell L, et al.; on behalf of the ADEPT Trial Collaborative Group. Feeding infants below 29 weeks’ gestation with abnormal antenatal Doppler: analysis from a randomised trial. Arch Dis Child Fetal Neonatal Ed 2014;99:F6–F11. 2. Bozzetti V, Tagliabue PE, Visser GH, et al. Feeding issues in IUGR preterm infants. Early Hum Dev 2013;89:S21–3. 3. Fanaro S. Strategies to improve feeding tolerance in preterm infants. J Matern Fetal Neonatal Med 2012;25:54–6. 4. Hay Jr WW. Strategies for feeding the preterm infant. Neonatology 2008;94:245–54. 5. Gilbert WM, Danielsen B. Pregnancy outcome associated with intrauterine growth restriction. Am J Obstet Gynecol 2003;188: 1596–9. 6. Ancott SW, Donohue PK, Northington FJ. Increased morbidity in severe early intrauterine growth restriction. J Perinato 2004;24: 435–40. 7. Barone G, Maggio L, Saracino A, et al. How to feed small for gestational age newborns. Italian J Paediatr 2013;39:28. 8. Dorling J, Kempley S, Leaf A. Feeding growth restricted preterm infants with abnormal antenatal Doppler results. Arch Dis Child Fetal Neonatal Ed 2005;90:F359–63. 9. Berseth CL, Nordyke C. Enteral nutrients promote postnatal maturation of intestinal motor activity in preterm infants. Am J Physiol 1993;264:G1046–51. 10. Berseth CL, Bisquera JA, Paje VU. Prolonging small feeding volumes early in Life decreases the incidence of necrotizing enterocolitis in very low birth weight infants. Pediatrics 2003;111: 529–34. 11. Patole S. Strategies for prevention of feed intolerance in preterm neonates: a systematic review. J Matern Fetal Neonatal Med 2005; 18:67–76. 12. Mihatsch WA, Pohlandt F, Franz AR, Flock F. Early feeding advancement in very low-birth-weight infants with intrauterine growth retardation and increased umbilical artery resistance. Pediatr Gastroenterol Nutr 2002;35:144–8. 13. Bell MJ, Ternberg JL, Feigin RD, et al. Neonatal necrotizing enterocolitis. Therapeutic decisions based upon clinical staging. Ann Surg 1978;187:1–7. 14. Leaf A, Dorling J, Kempley S, et al; Abnormal Doppler Enteral Prescription Trial Collaborative Group. Early or delayed enteral feeding for preterm growth-restricted infants: a randomized trial. Pediatrics 2012;129:e1260–8. 15. Karagianni P, Briana DD, Mitsiakos G, et al. Early versus delayed minimal enteral feeding and risk for necrotizing enterocolitis in preterm growth-restricted infants with abnormal antenatal Doppler results. Am J Perinatol 2010;27:367–73. 16. Arnon S, Sulam D, Konikoff F, et al. Very early feeding in stable small for gestational age preterm infants: a randomized clinical trial. J Pediatr (Rio J) 2013;89:388–93.
ISSN: 1476-7058 (Print) 1476-4954 (Online) Journal homepage: http://www.tandfonline.com/loi/ijmf20
Optimising enteral nutrition in growth restricted extremely preterm neonates – a difficult proposition P. Shah, E. Nathan, D. Doherty & S. Patole To cite this article: P. Shah, E. Nathan, D. Doherty & S. Patole (2015) Optimising enteral nutrition in growth restricted extremely preterm neonates – a difficult proposition, The Journal of Maternal-Fetal & Neonatal Medicine, 28:16, 1981-1984, DOI: 10.3109/14767058.2014.974538 To link to this article: http://dx.doi.org/10.3109/14767058.2014.974538
Accepted online: 10 Oct 2014.Published online: 04 Nov 2014.
Submit your article to this journal
Article views: 76
View related articles
View Crossmark data
Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=ijmf20 Download by: [University of Otago]
Date: 05 October 2015, At: 00:38
http://informahealthcare.com/jmf ISSN: 1476-7058 (print), 1476-4954 (electronic) J Matern Fetal Neonatal Med, 2015; 28(16): 1981–1984 ! 2014 Informa UK Ltd. DOI: 10.3109/14767058.2014.974538
ORIGINAL ARTICLE
Optimising enteral nutrition in growth restricted extremely preterm neonates – a difficult proposition P. Shah1, E. Nathan2,3, D. Doherty2,3, and S. Patole1,4 Department of Neonatal Paediatrics, KEM Hospital for Women, Perth, Australia, 2Women and Infants Research Foundation, KEM Hospital for Women, Perth, Australia, 3School of Women’s and Infant’s Health, KEM Hospital for Women, Perth, Australia, and 4Centre for Neonatal Research and Education, University of Western Australia, Perth, Australia
Downloaded by [University of Otago] at 00:38 05 October 2015
1
Abstract
Keywords
Background: Optimising enteral nutrition of extremely preterm neonates (EP: Gestation 528 weeks) with intrauterine growth restriction (IUGR) has always been difficult considering their higher risk of necrotising enterocolitis (NEC), and frequency of feed intolerance. Aim: To evaluate the nutritional outcomes in EP neonates with IUGR. Methods: Data on demographic characteristics, feeding details (e.g. type of milk, postnatal age at start), and outcomes to discharge or death were collected from the medical notes for all EP neonates, who survived first 72 h of life, between January 2009 and December 2010. A standardised feeding protocol was followed during the study period. Results: 38/220 (17.3%) EP neonates admitted during the study period had IUGR. The mean (IQR) age at start of minimal enteral nutrition [7 (5–10) versus 5 (4–8) days, p ¼ 0.005), and nutritional (1 ml/2hourly) feeds [12 (8–15) versus 9 (7–13) days, p ¼ 0.034] was significantly delayed in IUGR compared to non-IUGR neonates. IUGR neonates reached full enteral feeds (150 ml/kg/day) at a significantly late median (IQR) postnatal age [32 (21–40) versus 24 (17–31) days, p ¼ 0.009), taking longer time to achieve this milestone [20 (15–34) versus 16 (12–4) days, p ¼ 0.008). The incidence of postnatal growth restriction was significantly higher in IUGR versus non-IUGR (73% versus 45%, p ¼ 0.003) neonates. The incidence of Stage II NEC was low [18/220 (8.1%)] to make valid statistical comparisons. Conclusion: Optimising enteral nutrition in growth restricted extremely preterm neonates is difficult using the current strategies for enteral nutrition.
Feeding, growth restriction, intrauterine, necrotising enterocolitis, neonates, preterm
Introduction Enteral feeding of extremely preterm neonates with intrauterine growth restriction (IUGR) has always been a difficult issue to address for those involved in neonatal intensive care [1–4]. In the intrauterine life, blood flow to the head is often preserved at the expense of the visceral organs in growth restricted preterm neonates (brain sparing effect) [5–7]. Intrauterine hypoxia of the gut and increased oxygen demand during enteral feeds in a vulnerable and immature host relate to the feeding difficulties and increased risk of necrotising enterocolitis (NEC) in these neonates [7,8]. Preferential use of mother’s or donor breast milk, early minimal enteral feeds, and standardised feeding protocols with cautious advancement of feeds are frequently used to facilitate gastrointestinal adaptation and feed tolerance and
Address for correspondence: Prof Sanjay Patole, Department of Neonatal Paediatrics, KEM Hospital for Women, 374 Bagot Road, Subiaco, City of Perth, Western Australia 6008, Australia. Tel: 61-8-93401260. Fax: 61-8-93401266. E-mail: [email protected]
History Received 25 December 2013 Revised 4 October 2014 Accepted 6 October 2014 Published online 4 November 2014
reduce the risk of NEC in preterm neonates [4,9–11]. Benefits of such strategies in optimising enteral nutrition in preterm very low birth weight (VLBW) neonates with IUGR have been reported by various investigators [12]. However, whether these strategies achieve such success in extremely preterm (gestation528 weeks) neonates with IUGR is not clear. KEM Hospital for Women is the sole tertiary neonatal referral centre for the state of Western Australia. The unit admits 100 extremely preterm neonates per year. Considering the significance of optimising enteral nutrition in extremely preterm neonates we aimed to audit the nutritional outcomes in this population in our unit.
Participants and methods Design This was a retrospective analysis of prospectively collected data on extremely preterm neonates. Participants All extremely preterm neonates (gestation: 528 weeks at birth) admitted between January 2009 and December 2010
1982
P. Shah et al.
and survived the first 72 h of life were eligible for inclusion in the study. Ethical approval Approval from the institutional ethics committee was obtained prior to commencing the study. Data collection Data on demographic characteristics, feeding details (e.g. type of milk, postnatal age at start), and outcomes to discharge from the nursery or death were collected from the medical notes using a standardised, pre-piloted data collection form.
Downloaded by [University of Otago] at 00:38 05 October 2015
Definitions IUGR was defined as birth weight 510th percentile for gestational age. NEC was defined by the modified Bell Staging criteria [13]. Minimal enteral nutrition (MEN) was defined as any volume of milk feeds at start. Starting of nutritional feeds (NF) was defined as enteral feed reaching the volume of 1 ml 2 hourly. Time to full feeds (TFF) was defined as the time taken to establish enteral feeds of 150 ml/kg/day enterally after start of MEN. Extrauterine growth retardation was defined as weight under 10th percentile for corrected age at discharge. Enteral feeding protocol for the unit Breast milk was preferred for feeding. In the absence of mother’s milk, pasteurised donor milk was used. Feeds were given as two hourly intermittent boluses through orogastric tube before graduating to 3 hourly and eventually suck feeds. Starting of feeds: Feeds were initiated as early as possible in presence of clinical stability defined as: (1) No respiratory assistance or minimal assistance (e.g. mean airway pressure: 8 cm H2O, CPAP 5–6 cm H2O and oxygen 30%). (2) No need for inotrope or colloidal support to maintain blood pressure within ‘‘normal’’ range. (3) No hemodynamically significant PDA requiring indomethacin. (4) No sepsis or sepsis treated with antibiotics for 48 h and without respiratory or haemodynamic instability. MEN was started at 5 or 10 ml/kg/day for neonates with gestation 25 weeks and/or IUGR and for those with gestation 26 weeks respectively. Guidelines for starting, continuing or stopping MEN were at the discretion of the attending neonatologist. Volume increments: (1) Started at 15 ml/kg/day and upgrade by 7.5 ml/kg every 12 h for neonates with gestation 25 weeks and/or IUGR. (2) Started at 20 ml/kg/day and upgrade by 10 ml/kg every 12 h for neonates with gestation 26 weeks. (3) The volumes of feed increments were increased by 7.5 ml or 10 ml//kg every 8 h for neonates with gestation 25 weeks and/or IUGR and 26 weeks respectively after reaching feeds of 100 ml/kg/day. The maximum total enteral feeds were 170 ml/kg/day increased from 150 ml/ kg/day in increments of 10 ml/kg/day at 48-hour intervals. Withholding feeds: Feeds were withheld if any time the pre-feed aspirates were 30% of the total 2 previous feeds, frank bile or aspirate positive for bile or blood, concerns of abdominal distension, 12 h during the blood transfusion.
J Matern Fetal Neonatal Med, 2015; 28(16): 1981–1984
Statistical approach Categorical data were summarised using frequency distributions and continuous data using median, interquartile range (IQR) and range. Univariate comparisons were conducted using the Chi-square test and Fisher exact test for categorical data and the Mann–Whitney test for continuous data. Statistical tests were two-sided and p values 50.05 were considered statistically significant. The analysis was performed using SPSS 18.0 for Windows (SPSS, Chicago, IL)
Results A total of 220/236 extremely preterm neonates survived the first 72 h of life with median (IQR) gestation and birth weight as 26 (24–27) weeks and 813 (660–964) g, respectively; 56.8% were males and 93% were inborn. There were 38 (17.27%) neonates with IUGR with lower birth weight (Table 1). A significantly higher percentage of these neonates had maternal PIH compared with non-IUGR neonates. Maternal ante-partum haemorrhage (APH), prolonged rupture of membranes (PROM), and chorioamnionitis were more frequent in non-IUGR neonates (Table 1). Nutritional outcomes The mean (IQR) age at start of MEN, and nutritional feeds was significantly delayed, and the volume of nutritional feeds was significantly higher in IUGR versus non-IUGR neonates (Table 2). Enteral feeds of 50, 100, and 150 ml/kg/day were reached at a significantly late postnatal age and the time to reach 150 ml/kg/day feeds was significantly longer in IUGR versus non-IUGR neonates. IUGR neonates spent a longer time off feeds compared to non-IUGR neonates, however, this did not reach statistical significance (p ¼ 0.06). Incidence of postnatal growth retardation was significantly higher, and the duration of hospital stay was significantly longer, in IUGR versus non-IUGR neonates. The incidence of Stage II NEC, as well as need for surgery and mortality related to the illness
Table 1. Demographic characteristics.
Variable Gestation (weeks) Birth weight (grams) Male gender Antenatal glucocorticoids Complete Single dose None Mode of delivery Vaginal Emergency C-Section Elective C-Section Inborn Apgar 57 at 5 minutes CRIB score Maternal PIH Maternal APH Chorioamnionitis PROM Maternal Antibiotics
IUGR (n ¼ 38)
Non-IUGR (n ¼ 182)
p value
25.8 (±1.3) 618 (±157) 19 (50%)
25.8 (±1.3) 861 (±186) 106 (58%)
0.905 50.001 0.351
28 (74%) 8 (21%) 2 (5%)
119 (65%) 49 (27%) 14 (8%)
9 12 17 36 5 12 20 7 1 6 17
85 64 33 169 46 11 13 76 36 62 119
(24%) (32%) (45%) (95%) (14%) (±2) (53%) (18%) (3%) (16%) (46%)
(47%) (35%) (18%) (93%) (26%) (±2) (7%) (42%) (20%) (34%) (65%)
Data are represented as mean (±sd) and number (%).
0.620
0.001 1.000 0.125 0.258 50.001 0.007 0.011 0.027 0.026
Difficulties in enteral feeding of growth-restricted EP neonates
DOI: 10.3109/14767058.2014.974538
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Table 2. Nutrition related outcomes.
Variable
N
Minimal enteral feeds (MEN) Age at start Volume Type EBM PDHM Nutritional feeds (NF) Age at start Volume at start Postnatal age at feeds of: 50 ml/kg/day 100 ml/kg/day 150 ml/kg/day Time to reach feeds of: 50 ml/kg/day 100 ml/kg/day 150 ml/kg/day Number of episodes of NBM 412 h after NF Total hours of NBM after MEN Stage II NEC Surgical treatment Death Postnatal growth retardation Duration of hospital stay Survival
36
IUGR (n ¼ 38)
N
Non-IUGR (n ¼ 182)
p value
179 7 (5–10) 5 (3–6)
5 (4–8) 5 (3–7)
0.005 0.807
33 (94%) 2 (6%)
163 (91%) 16 (9%)
0.744
34
179 12 (8–15) 19 (14–20)
33
9 (7–13) 13 (12–16)
0.034 50.001
14 (10–19) 17 (13–23) 24 (17–31)
0.037 0.005 0.009
(5–12) (8–16) (12–24) (1–3)
0.307 0.060 0.008 0.076
(36–192) (8%) (50%) (21%) (45%) (73–115) (96%)
0.06 0.745 0.382 0.533 0.003 0.005 0.006
179 16 (11–24) 21 (16–29) 32 (21–40)
33
179
33
8 12 20 3
(5–12) (10–23) (15–34) (2–4)
176
7 11 17 2
33 38 4 4 33 38 38
120 4 1 2 24 105 31
(60–246) (11%) (25%) (50%) (73%) (86–127) (82%)
179 182 14 14 178 182 182
80 14 7 3 80 90 174
EBM – expressed breast milk; PDHM – pasteurised donor human milk. Data are represented as median (25th–75th percentile, minimum-maximum) and number (%).
was low to make valid statistical comparisons between IUGR and non-IUGR neonates (Table 2).
Discussion Our results indicate the difficulties in optimizing enteral nutrition of extremely preterm (gestation 528 weeks) neonates with IUGR. They are consistent with those reported by other investigators [1]. Despite efforts towards adhering to the standardised feeding protocol, we were able to start minimal enteral and nutritional feeds only at a significantly late postnatal age than desired. This delay relates to signs of ileus of prematurity (e.g. distended ‘‘ropy’’ abdomen with visible bowel loops, large and/or bile stained gastric residuals, failure to pass meconium) which are difficult to distinguish from those of NEC. Feed volumes of 50, 100, and 150 ml/kg/day were reached significantly late in IUGR neonates. The median (IQR) time to reach from 100 ml/kg/day to 150 ml/kg/day of feeds was significantly higher in IUGR versus non-IUGR neonates [20 (14–33) versus 16 (11–23) days, p ¼ 0.008]. These findings may relate to the frequent stoppage of feeds due to feed intolerance and fear of NEC at higher milk volumes in this high-risk cohort. The clinically significant longer duration for which feeds were withheld in IUGR neonates supports this hypothesis. Lack of statistically significance of this finding is probably due to a small sample size. It is important to note that despite the late commencement of feeds, the postnatal age (32 versus 28 days) and time taken reach full enteral feeds (32 versus 28 days) in IUGR neonates was comparable to those reported by other investigators [1].
Considering their higher risk for developing NEC, initiation of enteral feeding is frequently delayed in preterm neonates with IUGR [8]. The results of a recent randomised controlled trial are important in this context. Leaf et al. [14] randomly allocated preterm IUGR neonates (gestation 535 weeks) with abnormal umbilical artery Dopplers to commence feeds early (day 2, n ¼ 202), or late (day 6, n ¼ 202) after birth. A standard protocol with the same rate of feed increment for both groups was followed. Full feeds were achieved earlier in the early versus late group (median: 18 versus 21 days), with no significant difference in the incidence of NEC (18% versus 15%). It is important to know that the median gestation of neonates enrolled in this trial was 31 weeks, making it difficult to extrapolate these results to extremely preterm IUGR neonates with gestation 528 weeks. Kempley et al. [1] have recently conducted a post-hoc analysis of subgroup data from the ADEPT trial. They reported that growth-restricted neonates529 weeks’ gestation with abnormal antenatal Doppler failed to tolerate even the careful feeding. Full feeds were achieved later in neonates 529 weeks compared with 29 weeks [Median (IQR) age: 28 (22–40) versus 19 (17–23) days, HR 0.35 (95% CI: 0.3–0.5)]. The incidence of NEC was significantly higher in those with gestation 529 versus 29 weeks [32/83 (39%) versus 32/312 (10%), RR: 3.7, (95% CI 2.4–5.7)]. Neonates 529 weeks tolerated very little milk for the first 10 days of life and reached full feeds 9 days later than predicted from the trial regimen. Mihatsch et al. [12] have previously reported that VLBW neonates with IUGR, increased umbilical artery resistance,
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P. Shah et al.
and brain sparing tolerate enteral feeding as well as appropriate-for-gestational-age VLBW infants. They enrolled 124 inborn VLBW neonates in a prospective trial evaluating early enteral nutrition with a standardized feeding protocol (daily feed increment: 16 ml/kg birth weight). Feed tolerance was assessed as the age at which full enteral feeds (FEF: 150 ml/kg daily) were achieved. Full enteral feeds were achieved at 15 (range, 12–21) days of age for all neonates. IUGR [FEF: 14 (12–21) days], increased umbilical artery resistance [FEF: 14 (11–16) days], and brain sparing [FEF: 15 (14–20) days] were not associated with early feeding intolerance. The positive results of this study may relate to the lack of enrolment of adequate number of extremely preterm neonates. Karagianni et al. [15] have studied the effect of early (5 days) versus delayed (6 days) initiation of MEN on the incidence of NEC and feeding intolerance in preterm neonates with IUGR and abnormal antenatal Dopplers in a randomized, non-blinded pilot trial. All neonates received parenteral feeding within 48 h of life. The median (range) gestation and birth weight of the neonates enrolled in the early versus delayed initiation of MEN groups were 32.0 (27.0–34.0) versus 31.3 (27.0–34.0) weeks and 1080 (680–1440) versus 1130 (440–1420) grams respectively. Of the 84 infants enrolled, 81 completed the study; 40 received early MEN [Median (range) age: 2 (1–5) days and 41 received delayed MEN [Median (range) age: 7 (6–14) days. The incidence of NEC and feeding intolerance was not significantly different between groups. It was concluded that early MEN in preterm infants with IUGR and abnormal antenatal Dopplers may not have a significant effect on the incidence of NEC or feeding intolerance, and birth weight seemed to be an independent risk factor for NEC, irrespective of the timing of MEN introduction. Inclusion of relatively mature neonates with higher birth weight makes it difficult to extrapolate these findings to extreme preterm neonates with IUGR. Arnon et al. [16] have recently reported the results of their study assessing very early versus delayed enteral feeds in stable preterm neonates (gestation537 weeks) with IUGR. Enrolled neonates (30 in each) were randomly allocated to a very early (within 24 h of birth) or delayed (after 24 h of birth) feeding regimen. All neonates had in utero evidence of absent or reverse diastolic flow. Neonates unable to start early feeding were excluded. Those included in the very early feeding regimen achieved full enteral feeds sooner than controls (98 ± 80–157 versus 172 ± 123–261 h of age, respectively; p ¼ 0.004) and were discharged home earlier (p ¼ 0.04). No NEC was documented in both groups. Gastric motility was improved at day seven after feeding initiation in both study groups, with no difference between groups. The applicability of these results to extremely preterm is however questionable considering the gestational age, and stable status of the enrolled neonates. Overall, our results indicate that optimising enteral nutrition is difficult in extremely preterm neonates (gestation 528 weeks) with IUGR. Caution is needed in interpreting these results considering the observational nature of our study, and its small sample size that also makes it difficult to comment on the risk of NEC following attempts to optimise enteral
J Matern Fetal Neonatal Med, 2015; 28(16): 1981–1984
nutrition in this high-risk cohort. It is also important to note that there was inequality in the number of neonates in both groups with only 38 IUGR compared with 182 non IUGR neonates. The strength of our study relates to the fact that it involves prospectively collected data on extremely preterm neonates from a large sole regional tertiary neonatal referral centre. Despite the limitations, it is reassuring to note that our results are consistent with those reported by Kempley et al. Further research is required to develop strategies for optimising enteral nutrition in extremely preterm neonates with IUGR.
Declaration of interest The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article.
References 1. Kempley S, Gupta N, Linsell L, et al.; on behalf of the ADEPT Trial Collaborative Group. Feeding infants below 29 weeks’ gestation with abnormal antenatal Doppler: analysis from a randomised trial. Arch Dis Child Fetal Neonatal Ed 2014;99:F6–F11. 2. Bozzetti V, Tagliabue PE, Visser GH, et al. Feeding issues in IUGR preterm infants. Early Hum Dev 2013;89:S21–3. 3. Fanaro S. Strategies to improve feeding tolerance in preterm infants. J Matern Fetal Neonatal Med 2012;25:54–6. 4. Hay Jr WW. Strategies for feeding the preterm infant. Neonatology 2008;94:245–54. 5. Gilbert WM, Danielsen B. Pregnancy outcome associated with intrauterine growth restriction. Am J Obstet Gynecol 2003;188: 1596–9. 6. Ancott SW, Donohue PK, Northington FJ. Increased morbidity in severe early intrauterine growth restriction. J Perinato 2004;24: 435–40. 7. Barone G, Maggio L, Saracino A, et al. How to feed small for gestational age newborns. Italian J Paediatr 2013;39:28. 8. Dorling J, Kempley S, Leaf A. Feeding growth restricted preterm infants with abnormal antenatal Doppler results. Arch Dis Child Fetal Neonatal Ed 2005;90:F359–63. 9. Berseth CL, Nordyke C. Enteral nutrients promote postnatal maturation of intestinal motor activity in preterm infants. Am J Physiol 1993;264:G1046–51. 10. Berseth CL, Bisquera JA, Paje VU. Prolonging small feeding volumes early in Life decreases the incidence of necrotizing enterocolitis in very low birth weight infants. Pediatrics 2003;111: 529–34. 11. Patole S. Strategies for prevention of feed intolerance in preterm neonates: a systematic review. J Matern Fetal Neonatal Med 2005; 18:67–76. 12. Mihatsch WA, Pohlandt F, Franz AR, Flock F. Early feeding advancement in very low-birth-weight infants with intrauterine growth retardation and increased umbilical artery resistance. Pediatr Gastroenterol Nutr 2002;35:144–8. 13. Bell MJ, Ternberg JL, Feigin RD, et al. Neonatal necrotizing enterocolitis. Therapeutic decisions based upon clinical staging. Ann Surg 1978;187:1–7. 14. Leaf A, Dorling J, Kempley S, et al; Abnormal Doppler Enteral Prescription Trial Collaborative Group. Early or delayed enteral feeding for preterm growth-restricted infants: a randomized trial. Pediatrics 2012;129:e1260–8. 15. Karagianni P, Briana DD, Mitsiakos G, et al. Early versus delayed minimal enteral feeding and risk for necrotizing enterocolitis in preterm growth-restricted infants with abnormal antenatal Doppler results. Am J Perinatol 2010;27:367–73. 16. Arnon S, Sulam D, Konikoff F, et al. Very early feeding in stable small for gestational age preterm infants: a randomized clinical trial. J Pediatr (Rio J) 2013;89:388–93.
