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Nutritional Factors That Affect the Postnatal Metabolic Adaptation of Full-Term Small- and Large-for-Gestational-Age Infants

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To document metabolic adaptation to ex utero life in small- (SGA) and large-for-gestational-age (LGA) infants in relation to fetal nutrition and postnatal feeding practices. In a prospective study, 65 SGA (< or = second centile) and 39 LGA (> or = 98th centile) full-term infants were recruited. Anthropometry was performed within the first 48 hours. There was full support of breastfeeding and close clinical observation. Blood glucose and ketone body (kb) concentrations were measured prefeed for the first 7 postnatal days. Infants were exclusively breastfed (BF), breastfed with formula milk supplementation (FS), or exclusively formula milk fed (FF). Within the SGA group, a measure of "thinness," the midarm circumference/head circumference ratio, was significantly correlated to the number of episodes of blood glucose < 2.00 mmol/L. Epoch (age at sampling) analysis in this group showed no difference in blood glucose levels across the different feeding groups but revealed a statistically significant greater kb concentration for infants who were exclusively breastfed. For SGA infants, the median peak kb concentration (peak kb) was significantly different for BF, FS, and FF groups. Multiple regression analysis for the SGA group demonstrated that peak kb concentration was negatively related to the volume of formula milk, independent of blood glucose levels and neonatal anthropometry. For LGA infants, low blood glucose levels were offset by kb concentrations equivalent to those observed in infants who were appropriate for gestational age. Neonatal ability to generate kb when blood glucose values are low depends more on successful breastfeeding than on size for gestational age or neonatal nutritional status. Routine blood glucose monitoring of LGA infants with no additional risk factors is not necessary. Routine formula milk supplementation for LGA and SGA infants should not be recommended.
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Nutritional Factors That Affect the Postnatal Metabolic Adaptation of
Full-Term Small- and Large-for-Gestational-Age Infants
Laura de Rooy, MRCPH*, and Jane Hawdon, FRCP, PhD‡
ABSTRACT. Objective. To document metabolic adap-
tation to ex utero life in small- (SGA) and large-for-
gestational-age (LGA) infants in relation to fetal nutri-
tion and postnatal feeding practices.
Methods. In a prospective study, 65 SGA (<second
centile) and 39 LGA (>98th centile) full-term infants
were recruited. Anthropometry was performed within
the first 48 hours. There was full support of breastfeed-
ing and close clinical observation. Blood glucose and
ketone body (kb) concentrations were measured prefeed
for the first 7 postnatal days. Infants were exclusively
breastfed (BF), breastfed with formula milk supplemen-
tation (FS), or exclusively formula milk fed (FF).
Results. Within the SGA group, a measure of “thin-
ness,” the midarm circumference/head circumference ra-
tio, was significantly correlated to the number of epi-
sodes of blood glucose <2.00 mmol/L. Epoch (age at
sampling) analysis in this group showed no difference in
blood glucose levels across the different feeding groups
but revealed a statistically significant greater kb concen-
tration for infants who were exclusively breastfed. For
SGA infants, the median peak kb concentration (peak
kb) was significantly different for BF, FS, and FF groups.
Multiple regression analysis for the SGA group demon-
strated that peak kb concentration was negatively related
to the volume of formula milk, independent of blood
glucose levels and neonatal anthropometry. For LGA in-
fants, low blood glucose levels were offset by kb concen-
trations equivalent to those observed in infants who
were appropriate for gestational age.
Conclusion. Neonatal ability to generate kb when
blood glucose values are low depends more on successful
breastfeeding than on size for gestational age or neonatal
nutritional status. Routine blood glucose monitoring of
LGA infants with no additional risk factors is not neces-
sary. Routine formula milk supplementation for LGA
and SGA infants should not be recommended. Pediatrics
2002;109(3). URL: http://www.pediatrics.org/cgi/content/
full/109/3/e42; small for gestational age, large for gesta-
tional age, breastfeeding, ketone bodies, hypoglycemia.
ABBREVIATIONS. kb, ketone body; AGA, appropriate for gesta-
tional age; IUGR, intrauterine growth restriction; SGA, small for
gestational age; LGA, large for gestational age; SDS, standard
deviation score; BF, breastfed; FS, formula supplemented; FF,
formula fed.
Neonatal metabolic adaptation is the process
whereby the fetus adapts from a continuous
supply of intravenous glucose in utero to a
fast-feed cycle and a diet based primarily on milk
(fat). In the first few postnatal hours, blood glucose
levels will normally decline.
1
This decline is usually
self-limiting even in an infant who is not fed and
cannot be considered pathologic. After this initial
decline, there is usually a brisk ketogenic response to
low blood glucose levels. This phenomenon is seen
in many mammalian species and is known as “suck-
ling ketogenesis.”
2
There is evidence that these ke-
tone bodies (kb) provide an alternative energy source
for the neonatal brain,
3
but to date, there has been
little study of the factors that influence production of
kb.
4
Previous work by Hawdon and Ward-Platt
5,6
documented the normal kb response in infants who
are appropriate for gestational age (AGA) and also
showed that certain groups of vulnerable infants,
such as term infants with intrauterine growth restric-
tion (IUGR) or preterm infants, seemed unable, un-
der some circumstances, to mount a kb response.
These infants were thus doubly at risk, ie, low blood
glucose levels with no alternative cerebral fuels. This
study investigated neonatal adaptation in infants
who were small for gestational age (SGA; at high risk
of IUGR) in relation to both fetal nutritional status
and postnatal feeding practices.
Concerns for the infant who is large for gestational
age (LGA) stem mainly from a perceived “continu-
um of risk” associated with infants of mothers who
have diabetes.
7
Pederson, in the 1950s, suggested
that in pregnancies complicated by diabetes, mater-
nal hyperglycemia might lead to fetal hyperglyce-
mia, and so to fetal hyperinsulinism.
8
This in turn
would result in macrosomia of the newborn. Ele-
vated plasma insulin levels in these infants in the
immediate postnatal period would lead to inhibition
of gluconeogenesis, glycogenolysis, lipolysis, and ke-
togenesis, placing these infants at risk of low blood
glucose levels with a paucity of alternative fuels. It
has not yet been documented whether LGA infants
whose mother does not have diabetes are similarly at
risk.
METHODS
Patients
Sixty-five SGA and 39 LGA infants were recruited (Table 1). Of
these, 58 SGA infants and 24 LGA infants had metabolic studies
as in some instances, parents consented to anthropometry and
clinical monitoring but declined consent for metabolic samples.
All infants were full term, ie, 36 completed weeks’ gestation,
From the *Homerton Hospital, London, University College London Hospi-
tals, London, United Kingdom; and ‡Neonatal Unit, University College
London Hospitals, London, United Kingdom.
Received for publication Apr 2, 2001; accepted Nov 7, 2001.
Reprint requests to (L.dR.) 18 Topsham Rd, SW17 8SJ, London, UK. E-mail:
laura.derooy@bartsandthelondon.nhs.uk
PEDIATRICS (ISSN 0031 4005). Copyright © 2002 by the American Acad-
emy of Pediatrics.
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healthy, and free of major congenital abnormalities. The SGA
infants were on or below the second centile for birth weight, and
the LGA infants were on or above the 98th centile. In this way, we
hoped to select infants who were most at risk of abnormal meta-
bolic adaptation. Sixty-one appropriately grown infants (birth
weights between the 10th and 90th percentile) were randomly
selected for comparison of perinatal variables as well as growth
and neurologic variables on follow-up. The AGA group did not
undergo metabolic studies, as normal values for the metabolic
parameters presented have been previously established for this
group.
6
Maternal, obstetric, and perinatal factors were recorded.
Anthropometry
Anthropometric measures were performed on each infant
within 48 hours of birth, including head circumference, length,
birth weight, mid-arm circumference, knemometry (kneeheel
length), and skinfold thicknesses (subscapular, quadriceps, tri-
ceps). Birth weight, length, and head circumference standard de-
viation scores (SDS) were calculated using the British 1990 growth
reference.
9
Mid-arm circumference and mid-arm circumference/
head circumference ratio SDS were calculated using the formula
SDS (x mean)/SD, where the mean for gestation is taken from
normative data from Sasanow et al.
10
We performed anthropom-
etry to enable us to distinguish infants who had experienced true
IUGR from small normalinfants.
Blood Sampling
Prefeed blood glucose monitoring was performed on both SGA
and LGA infants as clinically indicated (at least 6 hourly within
the first 24 hours and as indicated thereafter). A heel-prick sample
was collected into a fluoride oxalate tube and analyzed for clinical
purposes using a Yellow Springs instrument (2300 Stat Plus; Yel-
low Springs Instruments, Farnborough, Hants, UK). One hundred
microliters of the same sample was immediately drawn using the
Wiretrol System (Drummond Scientific Co, Broomall, PA) and
placed in a 1.5-mL microcentrifuge tube containing 0.46 mol/L 5%
perchloric acid and centrifuged in the cold. The supernatant was
collected and frozen at 20°C.
Biochemical Assays
These samples were later analyzed by automated microenzy-
matic methods adapted for the Cobas Bio centrifugal analyzer at
Great Ormond Street Hospital for Sick Children. Lactate and
pyruvate were analyzed using the lactate dehydrogenase reaction,
glucose was analyzed using hexokinase, acetoacetate and
-hy-
droxybutyrate were analyzed using
-hydroxybutyrate dehydro-
genase, alanine was analyzed using alanine dehydrogenase, and
glycerol was analyzed using glycerokinase and glycerol-3-phos-
pate dehydrogenase. The endpoint in each case was a change in
fluorescence at 450 nm attributable to reduction or oxidation of
nicotinamide, adenine, and dinucleotide. Very low values
(0.0010.005 mmol/L) were reported as below limits for de-
tection.The kb concentration was obtained by summing the
acetoacetate and
-hydroxybutyrate concentrations.
Feeding Regimens
Infants were fed according to maternal choice. Breastfed infants
were given formula supplementation on clinical grounds, such as
persistent low blood glucose levels or evidence of dehydration, or
at maternal request. Formula milk intake was recorded as millili-
ters/kilogram/day. There were 3 feeding groups: infants who
were exclusively breastfed (BF), infants who received formula
supplementation in addition to breastfeeds (FS), and infants who
were exclusively formula fed (FF). Expert breastfeeding help and
advice were enlisted when required from qualified midwives. A
number of infants received intravenous treatment. Six SGA infants
received intravenous dextrose for a low blood glucose value alone;
1 SGA infant received intravenous therapy for a low blood glucose
value and a raised packed cell volume. Two LGA infants (both
born to mothers with documented diabetes) received intravenous
dextrose for low blood glucose values. Infants who received in-
travenous dextrose for whatever reason were excluded from met-
abolic analyses as the process of metabolic adaptation may be
altered and delayed in this group. Therefore, of 65 SGA and 39
LGA infants recruited, metabolic results were available on 58 and
24, respectively; of these, 7 SGA infants and 2 LGA infants re-
ceived intravenous treatment. Thus, the results of 51 SGA and
22 LGA infants were included in the final metabolic analysis
(Table 1).
Clinical Observations
A single observer (L.dR.) performed close clinical observation
of all study infants. All infants were assessed at least once a day
until discharge. This included a prefeed blood glucose value, a
weight, and a clinical and neurologic assessment, as well as an
evaluation of feeding. In many instances, infants were reassessed
3 or 4 times during each 24-hour period. Continued support and
reassurance were offered throughout the postnatal stay by the
researcher (L.dR.).
Statistical Analysis
As kb concentrations have a positively skewed distribution
(this is further compounded by reporting very low levels as be-
low the level of detection), the values are log transformed or
analyzed using nonparametric statistical tests. For avoiding the
confounding effect of repeated measures, summary statistics,
namely the peak kb concentration, the minimum blood glucose
level, and the kb concentration at the minimum blood glucose
TABLE 1. Nutritional Factors That Affect the Postnatal
Metabolic Adaptation of Full-Term SGA and LGA Infants
SGA LGA
Number recruited 65 39
Metabolic results available 58 24
IVI for hypoglycemia alone 6 2
Other IVI 1 0
Number analyzed
(metabolic results)
51 22
BF (%) 11 (22) 13 (59)
FS (%) 23 (45) 7 (32)
FF (%) 17 (33) 2 (9)
IVI indicates intravenous infusion.
TABLE 2. Epoch Analysis: Number of Data Points Utilized
SGA LGA
04412 1224 2448 4872 72 04412 1224 2448 4872 72
BF 5 5 5 10 5 3 10 14 4 12 2
FS 7 19 17 20 14 10 3 2 2 5 1 1
FF 13 13 6 15 7 2 2 1 1 2 1 1
TABLE 3. Multiple Regression Analysis
SGA LGA
PValue PValue
Formula milk intake* .002 .437
Formula milk intake.001 .187
* Dependent variable: kb concentration at minimum blood glucose
concentration 24 hours. Independent variables: minimum blood
glucose concentration; birthweight SDS; length SDS; mid-arm cir-
cumference/head circumference ratio; triceps, subscapular, and
quadriceps skinfold thicknesses; formula milk intake.
Dependent variable: peak kb. Independent variables: blood glu-
cose concentration at peak kb; birthweight SDS; length SDS; mid-
arm circumference/head circumference ratio; triceps, subscapu-
lar, and quadriceps skinfold thicknesses; formula milk intake.
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level, were derived for each infant. Epoch analysis was also per-
formed for blood glucose and kb levels, whereby each infant
contributes 1 value to the mean/median shown for each epoch.
When a infant was sampled more than once during an epoch,
mean/median values of those samples were used (Table 2).
To determine whether a neonatal anthropometric marker of
fetal malnutrition could predict the magnitude of the peak kb
response, we then examined factors that could be expected to have
an influence on peak kb production in a multiple regression
analysis (Table 3). We analyzed LGA and SGA infant groups
separately. Peak kb and kb at minimum blood glucose level were
used as dependent variables. Birth weight SDS; length SDS;
knemometry; mid-arm circumference/head circumference ratio;
triceps, subscapular, and quadriceps skinfold thicknesses; con-
comitant blood glucose level; and formula milk intake were used
as independent variables. Formula milk intake (mL/kg/d) was
measured on the day when the peak kb or kb at minimum blood
glucose was recorded.
Ethical approval for the study was granted by the joint UCL/
UCLH Committees on the Ethics of Human Research. Informed
consent was obtained from parents in the immediate postnatal
period.
RESULTS
Perinatal Characteristics
Table 4 summarizes the maternal, obstetric, and
perinatal factors for all infants. Comparing the SGA,
AGA, and LGA infant groups, there were significant
differences across the groups with respect to mater-
nal height, parity, smoking, and parental socioeco-
nomic group. This suggests an excess morbidity in
the SGA infant group, which reflects findings in
previous studies.
11,12
Problems in pregnancy were
not significantly different between the groups. How-
ever, SGA, LGA, and AGA infants had different
problems: there were 5 cases of maternal substance
abuse in the SGA group, with none in the other
groups. Also, there were 2 cases of maternal diabetes
in the LGA group, with none among the SGA or
AGA infants. Twenty-three infants were born to
mothers with pregnancy-induced hypertension: 2
LGA infants, 9 SGA infants, and 13 AGA infants. No
case of pregnancy-induced hypertension was diag-
nosed before 34 weeksgestation. Pregnancy-in-
duced hypertension and maternal substance abuse
are not thought to result in specific problems related
to blood glucose control in the neonate, except when
they result in a growth-restricted infant. In addition,
2 mothers with infants in the LGA group were
treated for hypothyroidism; both mothers were eu-
thyroid during pregnancy, and no specific problems
related to maternal hypothyroidism were noted in
TABLE 4. Maternal, Obstetric, and Perinatal Factors
SGA AGA LGA P(Compares
SGA, AGA, LGA)
P(Compares
SGA, LGA)
Number of infants 65 39 61
Mean maternal height/cm (range) 160 (147175) 165 (147181) 165 (153183) .001.765
Median parity (range) 0 (07) 1 (02) 0 (05) .001§.001
Maternal smoking (%) 27 (42) 23 (38) 4 (10) .003.002
Maternal alcohol (units/wk) (range) 1.64 (010) 1.69 (014) 0.95 (15) .241.004
Socioeconomic group (%) .001§.006
1 6 (9) 22 (36) 9 (23)
2 13 (20) 20 (33) 13 (33)
3 16 (25) 11 (18) 7 (18)
4 4 (6) 2 (3) 3 (8)
5 26 (40) 6 (10) 7 (18)
Problems in pregnancy* (%) 20 (30) 14 (23) 14 (36) .307
Delivery (%) .337.752
Vaginal 35 (54) 23 (38) 21 (54)
Cesarean 23 (35) 27 (44) 12 (31)
Other 7 (11) 11 (18) 6 (15)
Fetal distress (%)17 (26) 4 (7) 6 (15) .012
* Includes diabetes, maternal substance abuse, pregnancy-induced hypertension, maternal hypothyroidism on treatment; 1minute
Apgar 5 or cardiotocograph abnormalities suggestive of fetal distress plus the presence of meconium in the liquor; Analysis of
variance/ttest; §Kruskal-Wallis test; Mann-Whitney Utest;
2
test.
TABLE 5. Anthropometry
SGA LGA
Birth weight/g (range) 2358 (16512840) 4446 (36905000)
Birth weight SDS (range) 2.4 (3.531.7) 2.3 (1.73.5)
Length/cm (range) 44.0 (41.552.0) 52.8 (47.058.0)
Length SDS (range) 1.8 (3.90.4) 1.3 (1.43.4)
HC/cm (range) 32.6 (29.635.4) 36.1 (34.039.0)
HC SDS (range) 1.6 (3.130.2) 1.2 (0.043.8)
MAC/cm (range) 8.6 (6.810.8) 12.1 (9.014.3)
MAC SDS* 1.8 3.3
MAC/HC ratio 0.26 (0.160.34) 0.34 (0.260.40)
MAC/HC ratio SDS* 1.4 3.5
Knemometry/mm 113.8 (86.7127.0) 144.0 (115.5152.8)
Quadriceps skinfold thickness/mm 4.6 (3.07.4) 11.0 (6.415.0)
Subscapular skinfold thickness/mm 3.4 (2.45.2) 7.6 (4.411.2)
Triceps skinfold thickness/mm 3.8 (2.25.7) 7.9 (5.411.5)
HC indicates head circumference; MAC, mid-arm circumference.
* Data from Sasanow et al.
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these infants. The number of cesarean deliveries was
similar across the groups. Fetal distress (defined as a
1-minute Apgar of 5 or cardiotocographic abnor-
malities suggestive of fetal distress plus the presence
of meconium in the liquor) was significantly differ-
ent across the groups: 6 SGA infants were intubated
as part of their resuscitation, compared with 3 LGA
infants and 1 AGA infant.
Anthropometry
Anthropometry on all infants is shown in Table 5.
A mean birth weight SDS of 2.4, with length and
head circumference SDS scores of 1.8 and 1.6,
respectively, indicates that the SGA group was un-
derweight, with relatively preserved length and
head growth. This is supported by other measures of
Fig 1. Blood glucose concentration ver-
sus postnatal age, SGA and LGA infants.
E, BF; u, FS; Œ, FF.
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thinness, such as the mid-arm circumference and the
mid-arm circumference/head circumference ratio.
Considerable overlap in the range of neonatal mea-
sures of intrauterine nutrition (eg, mid-arm circum-
ference, skinfold thicknesses) indicates that even
when using an exclusion criterion of second cen-
tile, some small well-nourishedinfants have been
included in the SGA group.
Metabolic Studies
Within the SGA infant group, a measure of thin-
ness, the mid-arm circumference/head circumfer-
ence ratio, was significantly correlated to the number
of episodes of blood glucose 2.00 mmol/L (P
.025, Pearsons coefficient ⫽⫺0.325).
The change in blood glucose levels over time for
Fig 2. Kb concentration (mmol/L)
versus postnatal age, SGA and LGA
infants. E, BF; u, FS; Œ, FF; , sta-
tistical significance; , AGA infants
(Hawdon et al
6
).
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the SGA and LGA infant groups is illustrated in the
epoch analysis shown in Fig 1. No significant differ-
ence is shown in blood glucose values across differ-
ent feeding groups for the SGA infants in any epoch,
whereas for the LGA group, a much larger spread of
blood glucose values is apparent, as illustrated for
AGA infants in previous work.
6
Figure 2 shows the change in blood kb levels over
time for SGA and LGA infants. These data show that
SGA and LGA BF infants achieve a rise in kb pro-
duction, which was not consistently observed in FF
groups. FS infants had an intermediate response. So,
although blood glucose values remained equivalent
across the feeding groups with time, kb levels were
greatest for the BF group, especially the SGA infants.
Significant differences in kb concentration between
feeding groups is shown for SGA infants at 12 to 24,
24 to 48, and 48 to 72 hours (illustrated with stars).
Blood ketone values for AGA infants (from Hawdon
et al,
6
previous work) are shown for comparison.
Our summary statistic, median peak kb concentra-
tion (Table 6), is significantly higher in the BF group
compared with other feed groups for the SGA infants
analyzed separately. We further explored the rela-
tionship between the blood glucose concentration
and kb response by finding the kb concentration at
the lowest blood glucose level for each infant at 24
hours of age (Fig 3, Table 6). Especially at low blood
glucose values, infants who receive breast milk show
some of the highest values for blood kb concentra-
tion. Our data show that exclusive formula feeding
does not necessarily protect against low blood glu-
cose values. Hence, the SGA FF infant could be dou-
bly at risk of both low blood glucose values with a
reduced kb response. No BF infant had both low
blood glucose and low kb levels. For LGA infants,
low blood glucose values were offset by kb concen-
trations of the same order of magnitude previously
demonstrated for AGA infants
6
(Fig 3).
In the multiple regression analysis (Table 3), no
anthropometric measure was found to be signifi-
cantly related to peak kb. Formula milk intake
(mL/kg/d), however, remained significant for the
SGA group after correcting for other biological
variables, including blood glucose values (see
Methods).
DISCUSSION
Many studies concerned with IUGR are bedeviled
by the problem of definition: fetal malnutrition and
SGA are not synonymous. By using an arbitrary
cutoff point within a population, some small normal
infants will be included. In a study by Deter et al,
13
only 40% of infants with IUGR were SGA (10th
centile), where IUGRwas defined using a specific
neonatal growth assessment score. As with all nor-
mally distributed variables, individuals within the
extremes of the distribution may be normalor may
have entered this area by virtue of an underlying
pathologic process.
Our anthropometric data show that even when
using stringent weight criteria (second centile),
small normal infants are still included in the group.
However, in the SGA group, a measure of thinness,
the mid-arm circumference/head circumference ra-
tio, was significantly correlated to the number of
episodes of low blood glucose values, confirming
earlier work
14
and indicating that it remains impor-
tant to identify those who are truly growth restricted.
Clinical vigilance, supported by simple measures
such as the mid-arm circumference/head circumfer-
ence ratio, could be used to identify those infants
who, although having a birth weight above 2.5 kg,
are still thinand therefore at risk. Interventions
such as screening for hypoglycemia, clinical obser-
vations, but more especially expert breastfeeding
support could then be targeted to this group. A
similar strategy could be used to exclude small nor-
mal infants from interventions.
Our data clearly illustrate that formula feeding
does not protect against low blood glucose values for
small infants. This is noteworthy, especially as most
of our small FF infants were fed at 100 mL/kg/day
from the first day. BF infants, however, had equiva-
lent blood glucose values but an augmented kb re-
sponse in the same order of magnitude as their AGA
counterparts.
6
Is there a biologically plausible expla-
nation for this finding?
Mammalian animal studies have shown that the
postnatal induction of the enzymes involved in
-ox-
idation within the mitochondria requires the pres-
ence of long-chain fatty acids.
15
The carnitine palmi-
toyltransferase system, which controls movement of
long-chain fatty acids into the mitochondria, repre-
sents a major rate-limiting step in ketogenesis in the
suckling rat. Long-chain fatty acids play a pivotal
role in the posttranscriptional regulation of carnitine
palmitoyltransferase 1 during the immediate postna-
tal period. We speculate that a factor present in
breast milk but absent in formula milk augments
ketogenesis in human neonates in the same way.
Carnitine is known to have a central role in
-oxida-
tion of fats: it is responsible for the transport of fatty
acyl-coenzyme A across the inner mitochondrial
TABLE 6. Median Peak kb and kb Concentrations
Breast
Milk
Breast and
Formula Milk
Formula
Milk
PValue*
Median peak kb concentrations (mmol/L)
SGA 0.875 0.435 0.126 .0001
LGA 0.406 0.844 0.0172 .057
kb concentrations (mmol/L) at lowest
blood glucose 24 h
SGA 0.770 0.380 0.055 .0001
LGA 0.610 0.490 0.0151 .075
* Kruskal-Wallis test.
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membrane.
16
During the suckling period, the de-
mand for carnitine exceeds the rate of endogenous
synthesis by up to 50%.
17
Indeed, healthy, full-term
infants fed formulas devoid of carnitine showed re-
duction in ketogenesis and an accumulation of fatty
acid precursors in the plasma. Although breast milk
and cows milkderived formulas contain equivalent
amounts of carnitine,
18
it may well be that there are
significant differences in bioavailability. When com-
pared with breastfed control subjects, infants who
were fed a standard formula that was not supple-
mented with carnitine demonstrated markers of car-
nitine deficiency.
19
Furthermore, we hypothesized
that high intakes of energy and protein associated
with early formula feeding may switch offor
dampen the crucial glucagon surge, central to regu-
lation of fuel availability in the immediate postnatal
period.
Fig 3. Kb concentration at lowest
blood glucose at 24 hours postnatal
age, SGA and LGA infants. E, BF; u, FS;
Œ, FF.
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Clinicians may fear
20
that a kb response in a neo-
nate is indicative of starvation,as in adult physi-
ology. However, we argue that neonatal ketogenesis,
as in many mammalian species, is a normal adaptive
response that enables the transition from fetal to
infant metabolism.
Multiple regression analysis showed that it was
not possible to predict confidently the ability of a
neonate to respond to the normal levels of low blood
glucose found within the first few postnatal days
with a kb response using anthropometric markers of
thinness. Small, fatinfants did not respond with
higher kb peaks than small, thininfants. There
may have been too little variation in the selected
subgroups to demonstrate an effect, and this is some-
thing that could be usefully explored in additional
work. However, infants who received breast milk
alone consistently demonstrated an augmented kb
response compared with FF infants.
LGA infants whose mother did not have docu-
mented diabetes do not represent a high-risk group.
Although low blood glucose levels did occur, this
was offset by a normal kb response, as previously
shown for AGA infants.
6
Any study that considers breastfeeding and the
human neonate would do well to consider the socio-
demographic factors that have an impact on breast-
feeding patterns in the United Kingdom. Women
who choose to breastfeed their infants are more
likely to come from a higher social class and to be
older than women who choose to formula feed.
21
Multiple antenatal insults, for example, substance
abuse plus pregnancy-induced hypertension, were
more likely in the SGA, FF group.
22
There is, to our
knowledge, no known relationship between blood
chemistry values and socioeconomic group, except
as a proxy for growth restriction. Recognizing that
adding a large number of variables may obscure a
true association, we found no relation between blood
glucose and mode of delivery or presence of fetal
distress.
Astudy effectwas noted: toward the end of the
study period, midwives were confidently encourag-
ing smaller infants to breastfeed, using the safe-
guards and protocols set in place for the study. Jun-
ior pediatricians and midwives worked together to
admit, monitor, and safeguard the well-being of vul-
nerable infants on the postnatal ward, creating, in
effect, a transitional careenvironment.
Breast milk is the food of choice for all newborn
infants. Our data show that it is practicable, safe, and
desirable to breastfeed even those infants previously
considered to be at risk of abnormal neonatal adap-
tation, namely SGA and LGA infants.
ACKNOWLEDGMENTS
We thank Sally Lawrence and Suzanne Colsen for expert mid-
wifery support throughout the study and Dr A. Williams and Prof
M. Cornblath for critical review of the manuscript.
We gratefully acknowledge the assistance of the Department of
Biochemistry at Great Ormond Street Hospital for Children NHS
Trust for all metabolic assays.
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... Metabolic adjustment is the process whereby the newborn adapts from a continuous supply of glucose through the placenta to a fast feed cycle and a diet mostly of maternal milk [1]. In the few hours after birth blood glucose generally declines and is self-limiting even in the infant who is not fed [1]. ...
... Metabolic adjustment is the process whereby the newborn adapts from a continuous supply of glucose through the placenta to a fast feed cycle and a diet mostly of maternal milk [1]. In the few hours after birth blood glucose generally declines and is self-limiting even in the infant who is not fed [1]. After the initial decline in blood glucose there is a brisk ketogenic response. ...
... After the initial decline in blood glucose there is a brisk ketogenic response. This phenomenon, known as suckling ketogenesis, is observed in many mammalian species including the human [1]. These ketone bodies (KB), namely 3-β-hydroxyl-butyrate (3-β-OHB) and acetoacetate (Ac Ac), produced by the liver from fatty acids, provide alternative energy for the CNS [1,2]. ...
... Variation in feedings practice had also been shown to influence growth. Compared to their formula fed peers, exclusively breastfed infants had been shown to grew better [20]. ...
... Exclusive breastfeeding, defined as giving infants only breast-milk without other food or water for the first 6 months age, is the cornerstone of child growth and development as it provides essential and optimal nutrition for child [21]. However, its practice in mothers of SGA may face more challenges than in AGA mothers [20]. Concerns regarding the infants' size often cause parents or health workers to add formula milk to the infants' diet. ...
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... 17 The availability of alternative fuels including ketones, lactate, and some amino acids to maintain cerebral cellular metabolism has long been proposed as an important mechanism to prevent injury when glucose availability is reduced. 18,19 However, the relationship between glucose, lactate, and ketone concentrations and cerebral function in the neonate is unclear. Higher circulating insulin concentrations suppress free fatty acid release and hepatic β-oxidation, so ketones are largely absent in babies with hypoglycaemia in the first 48 h 20 and, therefore, unlikely to provide any neurological protection. ...
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Neonatal hypoglycaemia is associated with adverse development, particularly visual-motor and executive function impairment, in childhood. As neonatal hypoglycaemia is common and frequently asymptomatic in at-risk babies—ie, those born preterm, small or large for gestational age, or to mothers with diabetes, it is recommended that these babies are screened for hypoglycaemia in the first 1–2 days after birth with frequent blood glucose measurements. Neonatal hypoglycaemia can be prevented and treated with buccal dextrose gel, and it is also common to treat babies with hypoglycaemia with infant formula and intravenous dextrose. However, it is uncertain if screening, prophylaxis, or treatment improves long-term outcomes of babies at risk of neonatal hypoglycaemia. This narrative review assesses the latest evidence for screening, prophylaxis, and treatment of neonates at risk of hypoglycaemia to improve long-term neurodevelopmental outcomes.
... [3,4] On the other hand, BF infants exhibit fat-based metabolism, [4] which results in elevated ketone bodies in the blood that is independent of blood glucose levels and neonatal anthropometry. [4,6] Increased ketone bodies have important implications for the growing infant brain, as the brain has a high energy demand, and ketones provide ≈30% of the total energy requirement. [7] Ketone bodies also provide carbon skeletons for brain lipids such as fatty acids and sterols. ...
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