Early feeding tolerance in small for gestational age infants with normal versus abnormal antenatal Doppler characteristics

Abstract

OBJECTIVES: To determine differences in feeding tolerance amongst preterm small for gestational age (SGA) infants with normal versus abnormal umbilical artery Doppler flow defined as absent or reversed end diastolic flow (AREDF).

METHODS: This was a retrospective cohort study of infants <35 weeks gestational age (GA) and birth weight (BW) <10th percentile. Day of initiation of feeds, days to full feeds and CRIB II scores were the primary outcomes. Clinical characteristics were compared between the groups of SGA infants with normal and AREDF. Multivariable regression models were fit to the data to adjust for potential confounders of the association of AREDF and feeding intolerance.

RESULTS: 120 infants with normal and 64 infants with AREDF were included. The infants with AREDF were smaller (971 g vs. 1183 g, p = 0.0002), less mature (29.9 wks vs. 31.2 wks, p = 0.0009), had higher CRIB II score (7.2 vs. 5.2, p = 0.0033), started feeding later (4.1 days vs. 3.3 days, p = 0.020) and advanced slower to full feeds (17.7 days vs. 13.7 days, p = 0.0017). Necrotizing enterocolitis was similar between the groups (p = 0.18). After adjusting for confounders, Doppler flow was no longer a significant predictor of the initiation (p = 0.37) and advancement of feeds (p = 0.44).

CONCLUSIONS: Infants with AREDF are sicker at birth and have more feeding difficulties; after adjusting for BW and GA, Doppler flow was no longer a significant predictor of feeding intolerance.

Keywords

IUGR growth restriction feeding tolerance

1 Introduction

Intrauterine growth restriction (IUGR) is defined as estimated fetal weight <10th percentile for gestational age and small for gestational age (SGA) infants as infants born at birth weight <10th percentile [1]. Approximately 10% of all pregnancies are affected by fetal growth restriction [2]. However it may be difficult to differentiate between fetuses that are growth restricted and those that are constitutionally small. Doppler indices of fetal umbilical arteries are routinely obtained during antenatal ultrasound particularly for pregnancies with suspected fetal growth restriction. Abnormal umbilical Doppler pattern suggests placental insufficiency as a cause of the IUGR and have been used as predictor of outcome in neonates [3]. The American Congress of Obstetricians and Gynecologists (ACOG) recommends use of umbilical artery Doppler velocimetry in conjunction with standard fetal surveillance such as non-stress tests and biophysical profile in pregnancies complicated by fetal growth restriction as this has been associated with improved outcome in this population and may help in determining the timing of delivery [1].

Infants, who suffered with fetal growth restriction, particularly those with absent or reversal of end diastolic flow (AREDF) in the umbilical artery, tend to have higher perinatal mortality and more severe morbidities such as respiratory distress syndrome (RDS), bronchopulmonary dysplasia (BPD), sepsis, and necrotizing enterocolitis (NEC) when compared to non SGA infants with normal Doppler flows [2 –5]. Abnormal placental function as suggested by abnormal Doppler indices is known to cause redistribution of circulation in the fetus to preserve blood supply to the brain at the expense of visceral organs, which has been implicated in the higher incidence of NEC [6, 7]. However NEC has a multifactorial etiology predominantly affecting preterm neonates [8, 9]. Different strategies have been implemented in most NICUs for decreasing the incidence of NEC such as standardizing feeding regimens to promote initiation and advancement of feeding in a timely manner. While these protocols are stratified based on gestational age (GA) and/or birth weight (BW), they do not differentiate between SGA and appropriate for gestational age (AGA) infants.

Limited number of clinical trials evaluating feeding regimens in SGA cohort yielded controversial results. Leaf et al. reported in the ADEPT trial that preterm IUGR infants with abnormal Doppler flow advanced more rapidly to full feeds if feeds were initiated early [10]. However, Abdelmaaboud et al. showed no differences in feeding tolerance between the infants who started early versus delayed enteral feeds [11]. In the cohort from the original ADEPT trial, Kempley et al. showed that preterm IUGR infants <29 weeks with abnormal Doppler flow advanced slower on feeds compared to IUGR infants with abnormal Doppler flow who were >29 weeks, raising question on whether feeding tolerance is a function of maturity and gestational age rather than the umbilical artery Doppler flow [5]. These trials included only SGA infants with abnormal Doppler indices, not the entire SGA cohort. To our knowledge feeding tolerance in SGA infants with normal versus abnormal Doppler flow indices has not been studied.

The primary aim of our study was to determine if there are any differences in the CRIB II scores (Clinical Risk Index for Babies) between SGA infants with normal and abnormal Doppler indices and to determine if AREDF is associated with differences in advancement of feeds in SGA infants when compared to SGA infants with normal Doppler indices. We hypothesized that SGA infants with abnormal antenatal Doppler indices are sicker after birth than SGA infants with normal Doppler indices and have delayed initiation of feeds and take longer to reach full feeds.

2 Methods

This was a retrospective cohort study of all infants <35 weeks GA and BW <10th percentile who were admitted to the NICU at the Children’s Hospital at Montefiore, Weiler Division from 2006–2013. We included those infants who had normal fetal anatomy on ultrasound imaging and had umbilical artery Doppler measurements performed within two weeks prior to delivery. We excluded from the study those infants with abnormal karyotyping performed either antepartum or post partum, those with major congenital anomalies and those with missing Doppler flow data. The determination of eligibility was made using our comprehensive neonatal database and the Doppler data was obtained from the fetal medicine division ultrasound database. The study was approved by the institutional review board of the Albert Einstein College of Medicine.

Maternal and neonatal baseline demographic characteristics were extracted from the review of the database and medical records. We obtained data on maternal characteristics such as presence of hypertension, pre-eclampsia, gestational diabetes/diabetes mellitus, maternal age, mode of the delivery, and neonatal characteristics such as GA, race, 5 minute Apgar score, BW, birth length (BL), Birth head circumference (BHC). We also collected data on the outcome variables such as day of initiation of feeds, time to achieve full feeds defined as 150 ml/kg/day, time taken to advance from trophic feeds (defined as <20 ml/kg/day of feeds) to full enteral feeds, time to regain BW and type of predominant feeds(defined as >50% feeds of either breast milk or formula). Finally, we obtained data on comorbidities such as presence of NEC (Stage 2 and above –modified Bell staging) [12], RDS, BPD, IVH, PVL, and patent ductus arteriosus (PDA). CRIB II scores, which are validated scores to assess the severity of illness from parameters of the infant routinely recorded in the NICU, were calculated using GA, BW, gender, temperature on admission and base excess [13].

2.1 Feeding protocol

A standardized weight based feeding protocol was followed at the NICU for initiation and advancement of feeds. The protocol was stratified based on birth weight into two groups of infants with birth weight <1000 g and 1001–1500 g. Feeds were initiated as early as possible once the infant was hemodynamically stable with no significant pressor requirement. Feeding volume was advanced in increments of 10–20 ml/kg/day depending on the feeding day and the weight of the infant. However there was no standardized description for feeding intolerance and it largely relied on the discretion of the clinician. This protocol was adhered to regardless of the antenatal umbilical arterial Doppler flow findings.

2.2 Data analysis

Based on the last set of Doppler flow measurements, the eligible infants were categorized into two groups as: (1) those with normal Doppler indices and (2) those with abnormal Doppler indices defined as absent or reversal of end diastolic flow (AREDF). Demographic and clinical characteristics were described using standard summary statistics including mean, standard deviation and frequencies. Baseline characteristics and outcome variables were compared between the two groups using the student’s t-test or Wilcoxon rank sum test for continuous variables and the Chi-square or Fisher’s exact test for categorical variables. Multivariable linear regression analysis was performed to adjust for potential confounders. All covariates that were deemed to be clinically important and which could impact the associations of AREDF and the primary outcomes of day of initiation of feeds and days to full feeds, such as GA, BW, BHC, BL, and type of feed, were included in the regression analysis. P value of <0.05 was considered significant. All analyses were performed using SAS 9.3 (SAS Institute, Cary, NC).

2.3 Power calculation

We expected to have a sample size of 60 –90 infants with abnormal Doppler indices and 120–180 with normal Doppler indices. In addition, we assumed based on prior studies [5, 14] that the standard deviation for time to first feed is 4.6 days and for time to full feed is 13.4 days. Under these assumptions, the study has at least 80% power to detect minimum differences between the abnormal and normal Doppler groups of 2.1 days in the meantime to first feed and 6 days in the mean time to full feed.

3 Results

A total of 252 infants with GA <35 weeks and BW <10th percentile were admitted to the NICU at the Children’s Hospital at Montefiore, Weiler Division between 2006 and 2013. Of these 184 infants were included in the study, 64 had AREDF.

Baseline demographic and clinical characteristics of all infants are described in Table 1. Those infants with AREDF were smaller (971 g vs. 1183 g, p = 0.0002) and less mature (29.9 wks vs. 31.2 wks, p = 0.0009). They also had smaller BL (p = 0.0014) and BHC (p = 0.0007). Lower proportion of infants with AREDF received formula feeds compared to those with normal Doppler flow (22% vs. 52%, p = 0.0052). There were no differences in the other maternal and neonatal demographic and clinical characteristics.

Table 1
Baseline demographic and clinical characteristics

Normal Doppler Abnormal Doppler P-value

flow (N = 120) flow (N = 64)

Female, N(%) 67 (55.8) 32 (50) 0.45

Race, N(%) 0.99

White, N(%) 26 (21.7) 14 (21.9)

African American, N(%) 63 (52.5) 34 (53.1)

Others, N(%) 31 (25.8) 16 (25)

GA(weeks), mean (SD) 31.2 (3) 29.9 (2.7) 0.0009

BW(g), mean (SD) 1183 (371) 971.4 (347.4) 0.0002

BL(cm), mean (SD) 37.5 (4.4) 35.3 (4.1) 0.001

BHC(cm), mean (SD) 27 (3) 25.5 (2.8) 0.0007

5 min Apgar, mean (SD) 8.4 (1) 8 (1.5) 0.12

Vaginal delivery, N(%) 19 (15.8) 5 (7.8) 0.12

Antenatal steroids, N(%) 91 (75.8) 55 (85.9) 0.11

Formula feeds, N(%) 52 (43.3) 22 (34.4) 0.005

Days to BW, mean (SD) 7.6 (3.6) 7.2 (2.8) 0.34

	Normal Doppler	Abnormal Doppler	P-value
Female, N(%)	67 (55.8)	32 (50)	0.45
Race, N(%)	0.99
White, N(%)	26 (21.7)	14 (21.9)
African American, N(%)	63 (52.5)	34 (53.1)
Others, N(%)	31 (25.8)	16 (25)
GA(weeks), mean (SD)	31.2 (3)	29.9 (2.7)	0.0009
BW(g), mean (SD)	1183 (371)	971.4 (347.4)	0.0002
BL(cm), mean (SD)	37.5 (4.4)	35.3 (4.1)	0.001
BHC(cm), mean (SD)	27 (3)	25.5 (2.8)	0.0007
5 min Apgar, mean (SD)	8.4 (1)	8 (1.5)	0.12
Vaginal delivery, N(%)	19 (15.8)	5 (7.8)	0.12
Antenatal steroids, N(%)	91 (75.8)	55 (85.9)	0.11
Formula feeds, N(%)	52 (43.3)	22 (34.4)	0.005
Days to BW, mean (SD)	7.6 (3.6)	7.2 (2.8)	0.34

Abbreviations: GA-Gestational age, BW-Birth weight, BL-Birth length, BHC-Birth head circumference.

The infants with AREDF were sicker at birth as evidenced by their higher CRIB II scores (7.2 vs. 5.2, p = 0.0033). Feeds were initiated later (4.1d vs. 3.3d, p = 0.020) and advanced slower (17.7d vs. 13.7d, p = 0.0017) in infants with AREDF (Table 2). In both groups, infants were kept NPO for similar number of days after feeds were initiated (1.7d vs. 1.4d, p = 0.066), however the group with AREDF advanced slower on feeds beyond the stage of trophic feeds (7.7d vs. 9d, p = 0.040). Larger proportion of infants with AREDF suffered from RDS compared to the infants with normal Doppler (43.8 vs. 26.7, p = 0.019) and had prolonged length of stay (64.4 days vs. 48.8 days, p = 0.006). Rates of NEC were similar between the groups (p = 0.18). There were no differences in other comorbidities between the two groups.

After adjusting for GA, BW, BHC, BL and type of feed, Doppler flow was no longer significantly associated with initiation (p = 0.37) or days to full feeds (p = 0.44) (Table 3). BHC was an independent predictor of the day of initiation of feeds (p = 0.002) and the GA was an independent predictor of the days to achieve full feeds (p < 0.008).

Table 2

Primary and secondary outcomes

	Normal Doppler	Abnormal Doppler	P-Value
	flow (N = 120)	flow (N = 64)
CRIB II score, mean (SD)	5.2(4.5)	7.2(4.4)	0.003
Day of first feeds, mean (SD)	3.3(3.5)	4.1(3.7)	0.020
Day of full feed, Mean (SD)	13.7(13.5)	17.7(13)	0.002
Days from trophic to full feeds, mean (SD)	7.7(8.4)	9(7.6)	0.040
NPO days, mean (SD)	1.4(3.9)	1.7(3.4)	0.066
Length of stay(days), Mean (SD)	48.8(37.9)	64.4(34.3)	0.006
RDS, N(%)	32(26.7)	28(43.8)	0.019
BPD, N(%)	29(24.2)	24(37.5)	0.17
PDA, N(%)	15(12.5)	12(18.8)	0.25
NEC, N(%)	2(1.7)	4(6.3)	0.18
Perforation, N(%)	1(0.8)	2(3.1)	0.28
IVH, N(%)	42(35)	24(37.5)	0.73
PVL, N(%)	5(4.2)	3(4.7)	1.0000

Abbreviations: NPO-Nil per os, RDS-Respiratory distress syndrome, BPD-Bronchopulmonary dysplasia, PDA-Patent ductus arteriosus, IVH-Intraventricular hemorrhage, PVL-Periventricular leukomalacia.

Table 3

Linear regression analysis of day of initiation of feeds and days to full feeds

Variable	Estimate	Standard Error	P-value
Linear regression analysis of day of initiation of feeds with Doppler flow as the main
predictor adjusting for other clinically relevant characteristics
Doppler flow (present vs. absent)	0.4000	0.4435	0.3683
Gestational age	–0.1077	0.2175	0.6211
Birth weight	0.0022	0.0021	0.2974
Birth head circumference	–0.6066	0.1970	0.0024
Birth length	–0.2736	0.1329	0.040
Linear regression analysis of days to full feeds with Doppler flow as the main
predictor adjusting for other clinically relevant characteristics
Doppler flow (present vs absent)	1.0945	1.4019	0.4360
Type of feeds (formula vs breast milk)	2.9813	1.5976	0.0637
Type of feeds (both vs breast milk)	–0.2216	1.6829	0.8954
Gestational age	–1.8328	0.6771	0.0075
Birth weight	–0.0020	0.0066	0.7690
Birth head circumference	–0.4549	0.6124	0.4586
Birth length	–0.8264	0.6124	0.4586

4 Discussion

IUGR infants are associated with significant morbidities predominantly intestinal pathology like NEC and feeding intolerance. Diminished visceral perfusion with consequent tissue hypoxia in the intestinal mucosa has been implicated in this [6, 7]. It has been shown that infants with abnormal antenatal Doppler flow in the umbilical artery are at a higher risk for NEC compared to infants with normal Doppler flow [7, 15]. Though our study was not powered to detect differences in the rates of NEC, we did not notice any difference in the incidence of NEC between the two groups.

Studies which have looked at tolerance of feeds in SGA infants with abnormal antenatal Doppler indices have compared them to the AGA infants with normal Doppler flow [5 , 11]. There is no conclusive evidence that the SGA infants with abnormal Doppler indices when compared to SGA population with normal Doppler flow, tolerate feeds poorly or have a higher propensity to develop NEC; yet some of the providers may be cautious while initiating or advancing feeds in the SGA population more specifically those infants with AREDF. Various strategies have been tried to prevent NEC and cautious advancement of feeds in the IUGR population is one such. It has been shown that IUGR infants with AREDF particularly those with brain sparing are at increased risk for developing NEC [16]. This is thought to be due to the redirection of splanchnic circulation to the more vital organs like brain. It has been corroborated in postnatal studies of splanchnic circulation as well where diminished flow through the superior mesenteric artery was an independent risk factor for development ofNEC [17].

We saw in our cohort that those infants who suffered from AREDF in the umbilical artery were sicker at birth than the infants with normal Doppler flow as evidenced by the higher CRIB II scores. This was similar to the findings of McCowan et al. where they noted higher perinatal morbidities in infants with abnormal Dopplers [18]. These infants are also shown to be smaller and younger than the infants with normal Doppler indices, similar to what we noted in our cohort of infants [3 , 19]. However interestingly we noted that only smaller head circumference was independently associated with a delay in initiation of feeds rather than CRIB II scores which are an indicator of the severity of illness of the infant at birth. This is likely due to smaller head circumference denoting an earlier and more severe in utero compromise [20]. This was contrary to what Bozetti et al. showed in a cohort of 70 infants with IUGR where they noted that feeds were advanced slower in infants with brain sparing when compared to those with no brain sparing [16]. They evaluated Dopplers of the middle cerebral arteries(MCA) in comparison to the Dopplers of the umbilical arteries as an indicator of brain sparing. Our study was limited by the absence of data on the Dopplers of the MCA in all infants.

Our study shows that feeds were advanced slower in infants with AREDF in the umbilical artery. However after controlling for confounders, this difference no longer was significant. GA was independantly associated with time to full feeds which was somewhat similar to what was shown by Kempley et al. in the ADEPT trial. They showed that infants with growth restriction below 29 weeks with abnormal Doppler flow failed to tolerate even a slow advancement regimen compared with infants who were >29 weeks with normal Doppler flow. Our study was different from this study as we looked at feeding tolerance in infants based on Doppler flow rather than GA. We looked at the number of days infant remained NPO as a surrogate for tolerance of feeds. On our preliminary analysis there was no difference in the number of days infants remained NPO after initiation of feeds between the two groups. The number of NPO days was however independently correlated with the advancement of feeds after controlling for factors such as NEC and PDA (Data not shown here). We also noted that the infants with AREDF advanced slower to full feeds feeds beyond the stage of trophic feeds. Though this difference did not persist on the regression analysis, it raises concern about the tolerance of feeds in this group of infants and it may hint towards SGA infants with AREDF having diminished motility compared to those infants with normal Doppler flow. More studies are needed to further explore this finding with evaluationof tolerance of feeds in a prospective controlledmanner.

The strengths of our study include a large cohort of SGA infants with good antenatal follow up and ultrasound data on umbilical artery Doppler indices. We also had a good database of feeding related parameters like the type and volume of feed. However our study was not powered to detect differences in the prevalance of NEC between the two groups. Though we followed a standardized protocol for initiation and advancement of feeds, feeding intolerance and stopping of feeds was at the discretion of the clinician and this was another limitation of the study. Our study was also limited by the absence of data on the MCA Doppler flow to evaluate the effect of brain sparing on the tolerance of feeds.

In conclusion, GA is an independent predictor of feeding tolerance and not antenatal Doppler flow in SGA infants. However from existing literature, we know that SGA infants are at higher risk for perinatal morbidities particularly NEC, regardless of the presence or absence of Doppler flow abnormalities. We recommend that feeding advancements in SGA infants should be made cautiously and should factor the overall clinical picture rather than just the presence or absence of Doppler flow antenatally.

Disclosure statements

The authors report no conflict of interest.

The study was approved by the Institutional Review Board of the Albert Einstein College of Medicine and conducted in accordance with the ethical standards of all applicable national and institutional committees and the World Medical Association’s Helsinki Declaration.

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