Article

Growth Patterns of Neonates Treated with Thermal
Control in Neutral Environment and Nutrition
Regulation to Meet Basal Metabolism
Shiro Kubota 1,2,†, Masayoshi Zaitsu 3,4,† and Tatsuya Yoshihara 2,5,*
Kubota Life Science Laboratory Co., Ltd., Saga 840-0535, Japan; kubotahp@gmail.com
Kubota Maternity Clinic, Fukuoka 810-0014, Japan
3 Department of Social and Behavioral Sciences, Harvard T.H. Chan School of Public Health, Boston,
MA 02115, USA; m-zaitsu@m.u-tokyo.ac.jp
4 Department of Public Health, Graduate School of Medicine, The University of Tokyo,
Tokyo 113-0033, Japan
5 Clinical Research Center, Fukuoka Mirai Hospital, Fukuoka 813-0017, Japan* Correspondence: tatsuya@clipharm.med.kyushu-u.ac.jp; Tel.: +81-92-662-3608† These authors contributed equally to this work.
1
2

Received: 08 February 2019; Accepted: 05 March 2019; Published: 11 March 2019

Abstract: Little is known about the growth patterns of low birth weight neonates (<2500 g) during
standardized thermal control and nutrition regulation to meet basal metabolism requirements
compared to those of non-low birth weight neonates (2500 g and above). We retrospectively
identified 10,544 non-low birth weight and 681 low birth weight neonates placed in thermocontrolled incubators for up to 24 h after birth. All neonates were fed a 5% glucose solution 1 h after
birth and breastfed every 3 h (with supplementary formula milk if applicable) to meet basal
metabolism requirements. Maximum body-weight loss (%), percentage body-weight loss from birth
to peak weight loss (%/day), and percentage body-weight gain from peak weight loss to day 4(%/day) were assessed by multivariable linear regression. Overall, the growth curves showed auniform J-shape across all birth weight categories, with a low mean maximum body-weight loss
(1.9%) and incidence of neonatal jaundice (0.3%). The body-weight loss patterns did not differ
between the two groups. However, low birth weight neonates showed significantly faster growth
patterns for percentage body-weight gain: β = 0.52 (95% confidence interval, 0.46 to 0.58). Under
thermal control and nutrition regulation, low birth weight neonates might not have disadvantages
in clinical outcomes or growth patterns.
Keywords: growth chart; breastfeeding; physiological body-weight loss; thermal control; basal
maintenance expenditure

1. Introduction
During the first days of life, infants show a physiological phenomenon of temporary bodyweight loss. However, excess body-weight loss in the neonatal period tends to increase risks ofhypoglycemia, hypernatremia, and hyperbilirubinemia, resulting in permanent neurological damage[1]. While the American Academy of Pediatrics criteria currently recommend a cut-off point of 7%
for physiological body-weight loss [2], excess loss resulting from inadequate intake is an emerging
concern among high-risk populations, such as (but not limited to) East-Asian neonates, even after
controlling for genetic polymorphisms [3–6].
In a cohort of non-low birth weight (NLBW) neonates (birth weight 2500 g and above) in Japan
not admitted to the neonatal intensive care unit (NICU), we previously reported a potential
Nutrients 2019, 11, 592; doi:10.3390/nu11030592

www.mdpi.com/journal/nutrients

Nutrients 2019, 11, 592

2 of 11standardized neonatal regimen, a local neonatal protocol involving a combination of thermal control
and nutrition regulation to meet basal metabolism requirements (~50 kcal/kg), in order to reduce theincidence of neonatal jaundice by preventing excess body-weight loss [7]. This combination method
included a neutral thermal environment during the first hours after birth with an ambient room
temperature of ~34 °C (93.2 °F) [8–10]. In contrast to ambient room temperature (~24 °C/75.2 °F), a
neutral thermal environment maintained an optimal body temperature through circulatory stability
and improved digestive function [8–10]. The combination method also included nutrition regulation
to meet the basal metabolism requirement [11], in which neonates were fed a 5% glucose solution 1
h after birth, a convenient method to prevent hypoglycemia and neonatal jaundice [12], followed bybreastfeeding every 3 h with supplementary formula milk if applicable. In previous findings,
compared to either thermal control or nutrition regulation alone, the combination method had better
safety profiles for neonatal growth (e.g., serum glucose levels, circulatory stability, digestive
functions, and metabolism) [7,8].
In addition to gestational age and maternal factors (such as maternal smoking, preeclampsia,
and gestational diabetes), birth weight plays a crucial role in neonatal body weight growth.
Compared to NLBW neonates, low birth weight (LBW) neonates (birth weight <2500 g) are more
likely to be at risk for disadvantages in clinical outcomes or growth patterns, such as excess bodyweight loss, neonatal jaundice, and delayed body-weight growth [13–17]. However, few studies havefocused on LBW neonates not admitted to the NICU, and little is known about the contribution of
our combination method among LBW neonates.
Accordingly, the goal of the present study was to characterize the body-weight growth patterns
and clinical outcomes in this population of neonates who had received the combination method.
Using data from a cohort with NLBW and LBW neonates treated by the combination method, we
examined the detailed patterns of body-weight growth among NLBW and LBW neonates during thefirst days of life. We also examined whether the body-weight growth pattern in LBW neonates
differed from that in NLBW neonates under the combination method.
2. Materials and Methods
2.1. Study Settings
This retrospective, longitudinal study of neonates during the initial days of life used clinical datafrom a cohort of neonates born in Kubota Maternity Clinic in Fukuoka, Japan (1989 to 2017). The
details of the database are described elsewhere [7]. Briefly, Kubota Maternity Clinic was a generalobstetrics and gynecological hospital that provided general obstetrics care and closed in 2017. The
characteristics of the population were similar to those reported in previous studies in Japan [3,18,19].
All neonates were treated with the combination method (standardized thermal control and nutrition
regulation) and discharged by a physician on day 4 or later, when the serum bilirubin level was <15
mg/dL, body weight was recovered from its lowest level, and phototherapy was no longer required.
Since the bilirubin level usually peaks at approximately day 4 among Japanese neonates [18,19],discharge on day 4 or later is the standard practice in Japan. Clinical information on all neonates andtheir mothers had been collected since 1989, except for those who had neonatal asphyxia, congenital
heart failure or malformation, or were transferred to a tertiary hospital (such as a university hospital)
for neonatal intensive care. We obtained a de-identified dataset through a research agreement withthe hospital; the study was approved by the research ethics committees of Hakata Clinic andregistered at UMIN-CTR (UMIN000030011).
We included all 11,445 eligible term and preterm neonates treated with the combination method
who (1) had a birth weight 1700 g and greater, (2) had an Apgar score of 7 or higher, and (3) were notadmitted to the NICU. We excluded 221 neonates with incomplete data (1.9%), yielding a study
population of 11,224 neonates.
2.2. Thermal Control and Nutrition Regulation to Meet Basal Metabolism

Nutrients 2019, 11, 592

3 of 11The details of standardized thermal control and nutrition regulation to meet basal metabolism,a local neonatal regimen, have been described elsewhere [7,8]. Briefly, following delivery in a delivery
room maintained at ~25 °C (77 °F), neonates were immediately wiped with cotton towels,
administered intraoral suction on a warm bed at ~40 °C (104 °F), hugged by their mothers (skin-toskin contact), and placed in a transparent thermo-controlled incubator (N-ideal H-2000, Nakamura
Medical Industry, Tokyo, Japan) within 2 min of birth. Transparent thermo-controlled incubators
were placed next to delivery beds in the delivery room (not placed in the NICU). Neonates remained
visible and were continuously observed, not only by physicians and nurses (e.g., Apgar score), butalso by their mothers. All neonates remained in incubators for at least 2 h. For the first hour, theincubators were set at 34 °C (93.2 °F); for the second hour, the temperature was turned down to 30 °C(86 °F) to help neonates adapt to normal room temperature. After the initial 2 h, NLBW neonates
were transferred to a bed in a standard monitoring room set at ~24 to 26 °C (75.2 to 78.8 °F). LBW
neonates with birth weights of 2000 to 2499 g stayed in incubators for an extra 2 to 12 h, while thosewith birth weights <2000 g stayed in incubators for an extra 12 to 24 h at 28 °C (82.4 °F) before
transferring to a standard monitoring room. The optimal profiles of the neutral environment forthermogenesis, circulatory stability, and actual central/peripheral body temperatures have beenvalidated in previous studies with human neonates [8–10].
For nutritional regulation, neonates were orally fed a 5% glucose solution (10 mL/kg) with 1 mLof vitamin K syrup containing 2 mg menatetrenone 1 h after birth and then breastfed every 3 h [7,12].
If breast milk production was insufficient, neonates were additionally bottle-fed formula milk until
they were sated to maintain a 50 kcal/kg basal metabolism [11]. The oral 5% glucose solution has beenshown to be a convenient method to prevent hypoglycemia, while allowing continuous breastfeeding[7,12]. In addition, supplemental bottle-feeding with formula milk was based on previous findings
suggesting that the estimated calories provided by breast milk were below the basal metabolism a
few days after birth among the study population and that nutrition regulation did not affectbreastmilk production [7]. For NLBW neonates, high-calorie formula milk (16 kcal/20 mL) was
administered for the first 48 h, followed by normal-calorie formula milk (13 kcal/20 mL) after 48 h.
For LBW neonates, high-calorie formula milk was administered throughout the hospital stay.
2.3. Birth Weight Categories
Neonates, whose birth weights were normally distributed (Figure 1), were grouped into NLBW
(2500 g and above; n = 10,544) and LBW (<2500 g; n = 680) neonates. Both groups were further
categorized into a narrower range of birth weights: among LBW neonates, <2000 g (n = 20) and 2000
to 2499 g (n = 660); among NLBW neonates, 2500 to 2999 g (n = 5001), 3000 to 3499 g (n = 4752), 3,500
to 3999 g (n = 757), and 4000 g and above (n = 34).

Nutrients 2019, 11, 592

4 of 11

Figure 1. Distribution of birth weight among 11,224 neonates who received standardized thermal
control and nutrition regulation to meet basal metabolism.

2.4. Assessment of Clinical Outcomes and Changes in Body Weight
Using body-weight measured at birth and every day during the first four days (SW-5200, Toitu,
Tokyo, Japan), we determined the percentage body-weight growth every day [((weight each day −birth weight]/birth weight) × 100%) and maximum body-weight loss (([birth weight − minimum
weight]/birth weight) × 100%). Excess body-weight loss was defined as a maximum body-weight lossof at least 7% [2]. The incidence of neonatal jaundice was defined as use of phototherapy, which was
based on peak bilirubin levels ≥18 mg/dL along with other clinical findings [7].
Due to physiological body-weight loss, we divided the observation period into “decreasing”(before the day of peak weight loss) and “increasing” (after the day of peak weight loss) periods. For
each period, we assessed the percentage body-weight change per day. During the first decreasing
period from birth to peak weight loss, we determined the body-weight loss per day ((birth weight −minimum weight)/day of peak weight loss) and percentage body-weight loss per day (([birth weight− minimum weight]/birth weight) × (100%/day of peak weight loss)). During the latter increasing
period, from peak weight loss to day 4, we determined the body-weight gain per day ((weight at day
4 − minimum weight)/(4 − day of peak weight loss)) and percentage body-weight gain per day((weight at day 4 − minimum weight]/birth weight) × (100%/(4 − day of peak weight loss)).
2.5. Statistical Analysis
To produce growth curves in a growth chart among the 11,674 neonates, we plotted the mean
body weights measured at birth and every day during the first four days separately by birth weightcategories. We directly connected the mean values with lines, because fitted lines such as splines
eliminated the initial drop of body weight in prior analyses (data not shown). We also drew a chartindicating the percentages of body-weight growth stratified by birth weight. In these charts, we
additionally plotted the values measured at day 5 for neonates discharged at day 5 and later (10,336
neonates, 92%) and the values measured at one-month neonatal check-ups (approximately 30 days
after birth; 8071 neonates, 72%).
The background demographics and clinical outcomes were then compared between the LBW
and NLBW neonates by t- or chi-squared tests. In the decreasing period, the regression coefficient (β)
and 95% confidence interval (CI) for the percentage body-weight loss per day against birth weight(referent group, NLBW neonates) were estimated by linear regression. Covariates included sex,
gestational age, Apgar score, Cesarean delivery, maternal age, maternal body mass index, parity,
hypertensive disorders of pregnancy, and birth year. In the increasing period, the same regression
analysis was applied for the percentage body-weight gain per day. In stratified analyses using acontinuous variable of birth weight, a linear regression model was applied for analysis among NLBW
and NLBW neonates, respectively, to check the association between birth weight and percentage
body-weight-growth.
The alpha value was set at 0.05 and all P-values were two-sided. Data were analyzed using
STATA/MP 13.1 (Stata-Corp, College Station, TX, USA).
3. Results
Overall, the growth curves showed a uniform, J-shaped pattern across all birth weight categories(Figure 2). On average, the neonates started to recover their weights within two days of birth and themean maximum body-weight loss (mean (SD)) was low (1.9% (1.5%)). The incidence of neonatal
jaundice was 0.3% and the incidence of excess body-weight loss was 0.4% (Table 1). We did notobserve any neonatal morbidity or mortality events, as well as readmission after discharge, during
the study period. Most of the background distributions differed between the NLBW and LBW
neonates, except for maternal age (Table 1).

Nutrients 2019, 11, 592

5 of 11

Figure 2. Body weight growth curves stratified by birth weights. The mean body weights are shownas connected lines stratified by birth weight categories. Values from day 0 through day 4 were
estimated in 11,224 neonates; values at day 5 and 1 month (approximately 30 days of birth) were
estimated in 10,336 neonates and 8071 neonates, respectively.
Table 1. Background and clinical characteristics of 11,224 neonates who received optimal thermal
control with sufficient nutrition.
Characteristics

FemaleGestational age (weeks)
Birth weight (g)Apgar score at 1 min
Caesarean delivery
Maternal age (years)
Maternal BMI (kg/m2)
Multipara
Hypertensive disorders of pregnancy
Birth year
Maximum weight loss (%)
Excess weight loss 7% and above
Day of peak weight loss
Body-weight loss per day (g)Percentage body-weight loss per day (%) 1

Mean (SD) or number (%)
Total
NLBW neonates (≥2500 LBW neonates (<2500 g)
n = 11,224g) n = 10,544
n = 680
Background characteristics
5468 (49%)
5066 (48%)
402 (59%)
39.0 (1.2)
39.0 (1.1)
37.9 (1.4)
3000 (337)
3,043 (300)2346 (136)
9.6 (0.6)
9.6 (0.6)
9.5 (0.6)
899 (8.0%)
810 (7.7%)
89 (13%)31 (4)
31 (4)
31 (4)
20.0 (2.0)
20.1 (2.0)
19.7 (2.0)
5,256 (47%)
4,982 (47%)
274 (40%)43 (0.4%)
36 (0.3%)
7 (1.0%)2001 (8)2001 (8)2002 (8)Clinical outcomes
1.9 (1.5)
1.9 (1.5)
1.8 (1.5)
44 (0.4%)
39 (0.4%)
5 (0.7%)
1.4 (0.9)
1.4 (0.9)
1.3 (0.9)40 (36)41 (36)31 (29)1.3 (1.2)
1.3 (1.2)
1.3 (1.2)

p<0.001<0.001<0.001<0.001<0.0010.58<0.001<0.001
0.005
0.001
0.056
0.14
0.004
<0.0010.52

Nutrients 2019, 11, 592
Body-weight gain per day (g)Percentage body-weight gain per day (%) 2
Peak bilirubin level at day 4 (mg/dL)
Phototherapy

6 of 1141 (24)1.4 (0.8)
8.5 (2.7)30 (0.3%)

41 (25)
1.4 (0.8)
8.5 (2.7)30 (0.3%)

39 (21)
1.7 (0.9)
8.4 (2.7)
0 (0.0%)0.06<0.001
0.42
0.16

BMI, body mass index; NLBW, non-low birth weight; LBW, low birth weight. 1 Defined as ((birthweight − minimum weight)/birth weight) × (100%/day of peak weight loss). 2 Defined as ((weight at
day 4 − minimum weight)/birth weight) × (100%/(4 − day of peak weight loss])).

Clinical outcomes, including maximum body-weight loss, bilirubin levels, and phototherapy,
did not differ between NLBW and LBW neonates. Although the mean body-weight loss per day(grams) differed, the mean body-weight gain per day (grams) did not differ between groups (Table
1). Compared to those in NLBW neonates, the duration to peak weight loss was shorter (1.4 versus
1.3 days, p < 0.003) and the percentage of body-weight gain per day was higher (1.4 versus 1.7%, p <0.001) in LBW neonates (Table 1). As birth weight decreased, the percentage body-weight gainincreased (Figure 3).

Figure 3. Daily percentages of bodyweight growth against birth weight. Each connected line shows
the change in the percentage bodyweight growth from birth weight (([weight at every day − birthweight]/birth weight) × 100%), stratified by birth weight categories. Values from day 0 through day 4
were estimated in 11,224 neonates; values at day 5 and 1 month (approximately 30 days of birth) were
estimated in 10,336 neonates and 8071 neonates, respectively.

Regression analyses in the decreasing period revealed that, compared to that in NLBW neonates,
the percentage body-weight loss per day did not differ in LBW neonates (Table 2). In the increasing
period, compared to that in NLBW neonates, the percentage body-weight gain per day wassignificantly higher in LBW neonates (Table 2): β = 0.52 (95% CI, 0.46 to 0.58). In stratified analyses inthe decreasing period, a higher percentage of body-weight loss per day was only associated withhigher birth weights in NLBW neonates (Table 3). In the increasing period, a higher percentage ofbody-weight gain per day was significantly associated with lower birth weights across all birthweight categories (Table 3).

Nutrients 2019, 11, 592

7 of 11

Table 2. Body weight growth patterns against birth weight estimated by multivariable linear
regression analysis.
Characteristics

Model 1 3
β (95% CI)
p
Percentage body weight loss per day 1-0.03 (-0.12 to 0.06)
0.52

Model 2 4β (95% CI)

LBW (<2500 g)
0.03 (−0.06 to 0.13)
Female0.05 (0.004 to 0.09)
Gestational week
0.03 (0.01 to 0.05)
Apgar score0.13 (0.09 to 0.17)
Caesarean delivery
0.12 (0.03 to 0.20)
Maternal age
0.003 (−0.003 to 0.01)
Maternal body mass index−0.03 (−0.04 to −0.01)
Multipara
0.21 (0.16 to 0.26)
Hypertensive disorders of pregnancy
0.24 (−0.11 to 0.59)
Birth year
−0.02 (−0.02 to −0.02)
Percentage body weight gain per day 2
LBW (<2500 g)
0.33 (0.26 to 0.39)<0.0010.52 (0.46 to 0.58)
Female−0.12 (−0.15 to −0.10)
Gestational week
0.15 (0.14 to 0.16)
Apgar score−0.02 (−0.04 to 0.01)
Caesarean delivery
0.001 (−0.05 to 0.05)
Maternal age−0.005 (−0.005 to 0.004)
Maternal body mass index
0.001 (−0.01 to 0.01)
Multipara−0.08 (−0.11 to −0.05)
Hypertensive disorders of pregnancy
0.05 (−0.18 to 0.29)
Birth year
−0.02 (−0.02 to −0.01)

p
0.48
0.03
0.001
<0.0010.005
0.34<0.001<0.0010.18<0.001<0.001<0.001<0.001
0.17
>0.99
0.82
0.97
<0.0010.66<0.001β, regression coefficient; CI, confidence interval; LBW, low birth weight. 1 Defined as ((birth weight −minimum weight)/birth weight) × (100%/day of peak weight loss). 2 Defined as ((weight at day 4 −minimum weight)/birth weight) × (100%/(4 − day of peak weight loss)). 3 Simple linear regression
model for body-weight growth patterns against birth weight (referent group, NLBW neonates). Data
were estimated in 10,544 non-low birth weight neonates and 680 low birth weight neonates. 4
Additionally adjusted for potential confounding variables of sex, gestational age, Apgar score,
Cesarean delivery, maternal age, maternal body mass index, parity, hypertensive disorders ofpregnancy, and birth year.
Table 3. Regression coefficients and 95% confidence intervals estimated with a continuous variableof birth weight in regression analyses, stratified by non-low birth weight and low birth weight
neonates.
Characteristics

Birth weight (per 100 g)
Birth weight (per 100 g)
Birth weight (per 100 g)

Percentage Body-Weight-Loss per day 1 Percentage Body-Weight-Gain per day 2
β (95% CI) 3pβ (95% CI)3p
Overall (n = 11,224)
0.01 (−0.003 to 0.01)
0.06−0.05 (−0.06 to −0.05)<0.001
Non-LBW (2500 g and above, n = 10,544)
0.01 (0.001 to 0.02).02−0.04 (−0.05 to −0.03)<0.001
LBW (<2500 g, n = 680)
0.003 (−0.07 to 0.08)
0.93−0.16 (−0.21 to −0.11)<0.001Abbreviations: β, regression coefficient; CI, confidence interval; LBW, low birth weight. 1 Defined as((birth weight − minimum weight)/birth weight) × (100%/day of peak weight loss). 2 Defined as((weight at day 4 − minimum weight)/birth weight) × (100%/(4 − day of peak weight loss)). 3
Multivariable linear regression analysis for body-weight-growth patterns against birth weight,
adjusted for sex, gestational age, Apgar score, cesarean delivery, maternal age, maternal body massindex, parity, hypertensive disorders of pregnancy, and birth year.

4. Discussion
Under a local neonatal regimen involving a standardized thermal control and nutrition
regulation to meet basal metabolism, neonatal growth curves showed a uniform, J-shaped patternwith an initial physiological body-weight loss (~2% loss from birth weight), regardless of birthweight. The incidence of excess body-weight loss was low (<1%), with a short duration to peak weightNutrients 2019, 11, 592

8 of 11

loss (<2 days) and a low incidence of neonatal jaundice (0.3%). Compared to NLBW neonates, LBW
neonates did not appear to have disadvantages in clinical outcomes, including excess body-weightloss and neonatal jaundice. LBW neonates also potentially showed faster body-weight gain patterns,
with a trend suggesting that a higher percentage body-weight gain per day was associated with lower
birth weight.
In the contemporary understanding of neonatal body-weight growth, the gradient of birthweight for the speed of body-weight gain is positive. That is, heavier birth weight neonates enjoy theadvantages of faster body-weight gain and neonatal body-weight growth curves have continuously
shown a divergent pattern across birth weight categories [13–17]. During the second half of thetwentieth century, when perinatal and neonatal medicine and NICU were on the rise, this positive
gradient in birth weight for neonatal body-weight gain was considered a rule of thumb and early
illustrations of this positive gradient date as far back as Dancis et al. in 1948 [13]. Over the course of
the twentieth century, this positive gradient persisted, reflecting larger insensible water loss in lower
birth weight neonates (more premature neonates) [15,17,20]. Part of the reason for our observed
pattern, which may potentially buck the contemporary trend, may be due to the neutral thermal
environment that improves digestive function with circulatory stability, resulting in the neonatal
capability to be fed sufficiently to meet basal metabolism and prolonged thermal regulation in LBW
neonates [8–12]. Additionally, in a recent study with exclusively breastfed neonates, 50% of neonates
recovered their weight around 10 days after birth [21]. By contrast, most of the neonates recovered
their weight by 4 days after birth in our study, suggesting that our nutrition regulation with
supplemental formula milk may successfully meet the basal metabolism in our high-risk population.
Body weight is a robust and straightforward anthropometric indicator to grow neonates. The
criteria for body-weight-growth have been varied, which may partly due to differences in growth
patterns of breastfeeding and formula-feeding based on calorific intakes. For example, in Westerncountries, studies suggest the potential cut-off point of ~5% to 12% for exclusively breastfed neonatesand ~2% to 3% for formula-fed neonates [22–26], while the American Academy of Pediatrics
recommends explicitly the cut-off point of 7% for excess body-weight loss among exclusively
breastfed neonates [2]. By contrast, in Japan, although some studies suggest the potential cut-off pointof ~4% to 10% [3,7], and other expert opinions even support the cut-off point of up to ~15%, anyevidence-based clinical guidelines have yet to be established. Given the emerging concern for excess
body-weight loss from inadequate intake in East-Asian countries including Japan [3–5], physiologicalbody-weight loss would be a body-weight loss for neonates adequately fed to meet basal metabolism,
at least in high-risk populations. Indeed, we observed an initial ~2% body-weight loss as thephysiological loss with a low incidence of neonatal jaundice in our study population. Therefore, ourgrowth chart may help not only healthcare providers but also mothers of neonates in that high-risk
population.
Gestational age and maternal factors during pregnancy may affect neonatal growth pattern. In
previous studies, gestational age ≤38 weeks was associated with an increased risk of neonatal
jaundice [27]. Maternal smoking during pregnancy and preeclampsia were associated with decreased
birth weight, whereas gestational diabetes was associated with increased birth weight [28–30]. In
Finland, comprehensive screening of gestational diabetes was associated with decreased mean birthweight and macrosomia rates but was associated with an increased prevalence of neonatal
hypoglycemia [30]. In our study, gestational age was consistently associated with neonatal growth
pattern. However, significant effects of hypertensive disorders of pregnancy and maternal body massindex were inconsistent under the combination method (although we could not assess the impact ofgestational diabetes due to the limitation of our data). Additionally, no hypoglycemia was observedin our high-risk population. Therefore, in addition to LBW neonates, neonates with gestational age≤38 weeks, maternal smoking, preeclampsia, and gestational diabetes, might benefit the most fromthe combination method.
Some limitations should be noted. First, we did not have a control group with other nutrition
treatments (exclusively breastfeeding and exclusively formula-feeding). In addition, we did not havehourly data of body weight and did not include sick infants who required intravenous infusion

Nutrients 2019, 11, 592

9 of 11[13,25,31]. The thermal regulation also differed between birth weight categories, thereby introducing
potential bias and limiting external generalizability. However, internal validity might be maintained
for the comparison of NLBW and LBW neonates from the same source population. Second, otheranthropometric parameters, such as body length and head circumference, and potential maternal
confounding variables. such as diabetes, were not available [15–17,32]. However, body weight is areliable indicator of neonatal growth [7,15]. Third, use of supplemental feeding is controversial dueto the risk of breastfeeding failure, and excessive weight gain and the combination method mightraise concerns for introducing unintended adverse events [1,33]. However, in previous studies,
supplemental feeding did not affect breast milk production [7] and breastfeeding was not consistently
associated with the reduction of obesity or body fat mass in children or adolescents [34]. In addition,a recent randomized clinical trial concluded that supplementing breastfeeding with early limited
formula milk (10 mL) did not interfere with breastfeeding [35]. Fourth, we were not able to assess theimpact of standardized early skin-to-skin contact on the incidence of hypothermia or hypoglycemia
compared to our early skin-to-skin contact within 2 min. However, in previous studies, profiles ofserum glucose levels and core/peripheral distribution of body temperature were likely better inneonates with thermal regulation compared with those without thermal regulation [7–9]. Therefore,
future studies, including randomized controlled trials, are warranted to further understand how
thermal control and nutrition regulation influence neonatal growth.
Lastly, in the era of early neonatal hospital discharge, standardized thermal regulation andnutrition regulation to meet basal metabolism (without NICU care) may reduce medical expendituresof readmission for phototherapy with costly NICU care among LBW neonates [1,36]. Even in our
high-risk study population, we observed a very low incidence of neonatal jaundice (0.4%), whichcorresponds to the incidence in Western settings [27,37]. Given the very low incidence of neonatal
jaundice, a potential reduction of medical expenditure would be expected by the combination
method, in addition to improved education (clinicians, nurses, and parents) and systemic
institutional and community-wide approaches [38,39]. Due to extra thermal regulation that might
further stabilize cardiopulmonary circulation and improve digestive function, no phototherapy was
required in NLBW neonates [8–10]. In addition, the combination method did not require intravenous
infusion therapy and did not result in neonatal morbidity, mortality, or readmission after discharge,
thereby potentially increasing the efficient use of NICU resources and potentially reducing clinicalcomplications associated with intravenous infusion among LBW neonates. Furthermore, the initial 2
h spent in the incubator might help to avoid the substantially longer incubation required forphototherapy, thereby potentially increasing opportunities for physical contact between mothers andtheir babies.
In conclusion, neonatal body-weight growth patterns were characterized under standardized
thermal control and nutrition regulation, with a low incidence of unfavorable clinical outcomes,
regardless of birth weight category. Under this combination method, LBW neonates might not havedisadvantages in clinical outcomes or growth patterns.
Author Contributions: Conceptualization, S.K.; data curation, S.K., M.Z., and T.Y.; formal analysis, M.Z. andT.Y.; investigation, S.K. and T.Y.; methodology, S.K., M.Z., and T.Y.; project administration, T.Y.; resources, S.K.;
supervision, T.Y.; writing—original draft, M.Z.; writing—review and editing, S.K., M.Z., and T.Y.
Funding: This research received no external funding.
Acknowledgments: We would like to thank Editage (www.editage.jp) for English language editing.
Conflicts of Interest: The authors declare no conflict of interest.

References
1.
2.

Maisels, M.J.; McDonagh, A.F. Phototherapy for neonatal jaundice. N. Engl. J. Med. 2008, 358, 920–928.
Gartner, L.M.; Morton, J.; Lawrence, R.A.; Naylor, A.J.; O’Hare, D.; Schanler, R.J.; Eidelman, A.I.; American
Academy of Pediatrics Section on Breastfeeding. Pediatrics 2005, 115, 496–506.

Nutrients 2019, 11, 592

3.

4.
5.

6.
7.

8.

9.

10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.

21.
22.
23.
24.

25.
26.

10 of 11Sato, H.; Uchida, T.; Toyota, K.; Kanno, M.; Hashimoto, T.; Watanabe, M.; Nakamura, T.; Tamiya, G.; Aoki,
K.; Hayasaka, K. Association of breast-fed neonatal hyperbilirubinemia with UGT1A1 polymorphisms:
211G>A (G71R) mutation becomes a risk factor under inadequate feeding. J. Hum. Genet. 2013, 58, 7–10.
Chen, Y.J.; Chen, W.C.; Chen, C.M. Risk factors for hyperbilirubinemia in breastfed term neonates. Eur. J.
Pediatr. 2012, 171, 167–171.
Chen, C.F.; Hsu, M.C.; Shen, C.H.; Wang, C.L.; Chang, S.C.; Wu, K.G.; Wu, S.C.; Chen, S.J. Influence ofbreast-feeding on weight loss, jaundice, and waste elimination in neonates. Pediatr. Neonatol. 2011, 52, 85–
92.
Seske, L.M.; Merhar, S.L.; Haberman, B.E. Late-onset hypoglycemia in term newborns with poorbreastfeeding. Hosp. Pediatr. 2015, 5, 501–504.
Zaitsu, M.; Yoshihara, T.; Nakai, H.; Kubota, S. Optimal thermal control with sufficient nutrition may
reduce the incidence of neonatal jaundice by preventing body-weight loss among NLBW infants not
admitted to neonatal intensive care unit. Neonatology 2018, 114, 348–354.
Kubota, S.; Koyanagi. T.; Hori, E.; Hara, K.; Shimokawa, H.; Nakano, H. Homeothermal adjustment in theimmediate post delivered infant monitored by continuous and simultaneous measurement of core andperipheral body temperatures. Biol. Neonate 1988, 54, 79–85.
Yoshimura, T.; Tsukimori, K.; Wake, N.; Nakano, H. The influence of thermal environment on pulmonary
hemodynamic acclimation to extrauterine life in normal full-term neonates. J. Perinat. Med. 2007, 35, 236–
240.
Hey, E.N.; Katz, G. The optimum thermal environment for naked babies. Arch. Dis. Child 1970, 45, 328–334.
Gross, S.J.; David, R.J.; Bauman, L.; Tomarelli, R.M. Nutritional composition of milk produced by mothersdelivering preterm. J. Pediatr. 1980, 96, 641–644.
Aoshima, N.; Fujie, Y.; Itoh, T.; Tukey, R.H.; Fujiwara, R. Glucose induces intestinal human UDPglucuronosyltransferase (UGT) 1A1 to prevent neonatal hyperbilirubinemia. Sci. Rep. 2014, 4, 6343.
Dancis, J.; O’Connell, J.R.; Holt, L.E., Jr. A grid for recording the weight of premature infants. J. Pediatr.
1948, 33, 570–572.
Brosius, K.K.; Ritter, D.A.; Kenny, J.D. Postnatal growth curve of the infant with extremely LBW who was
fed enterally. Pediatrics 1984, 74, 778–782.
Itabashi, K.; Takeuchi, T.; Okuyama, K.; Kuriya, N.; Ohtani, Y. Postnatal growth curves of very LBWJapanese infants. Acta Paediatr. Jpn. 1992, 34, 648–655.
Itabashi, K.; Takeuchi, T.; Hayashi, T.; Okuyama, K.; Kuriya, N.; Otani, Y. Postnatal reference growth curves
for very LBW infants. Early Hum. Dev. 1994, 37, 151–160.
Diekmann, M.; Genzel-Boroviczeny, O.; Zoppelli, L.; von Poblotzki, M. Postnatal growth curves for
extremely LBW infants with early enteral nutrition. Eur. J. Pediatr. 2005, 164, 714–723.
Kuboi, T.; Kusaka, T.; Kawada, K.; Koyano, K.; Nakamura, S.; Okubo, K.; Yasuda, S.; Isobe, K.; Itoh, S.
Hour-specific nomogram for transcutaneous bilirubin in Japanese neonates. Pediatr. Int. 2013, 55, 608–611.
Itoh, S.; Kondo, M.; Kusaka, T.; Isobe, K.; Onishi, S. Differences in transcutaneous bilirubin readings inJapanese term infants according to feeding method. Pediatr. Int. 2001, 43, 12–15.
Hammarlund, K.; Sedin, G.; Stromberg, B. Transepidermal water loss in newborn infants. VIII. Relation togestational age and post-natal age in appropriate and small for gestational age infants. Acta Paediatr. Scand.
1983, 72, 721–728.
Paul, I.M.; Schaefer, E.W.; Miller, J.R.; Kuzniewicz, M.W.; Li, S.X.; Walsh, E.M.; Flaherman, V.J. Weight
Change Nomograms for the First Month After Birth. Pediatrics 2016, 138, doi:10.1542/peds.2016-2625.
American Academy of Pediatrics Subcommittee on Hyperbilirubinemia. Management ofhyperbilirubinemia in the newborn infant 35 or more weeks of gestation. Pediatrics 2004, 114, 297–316.
Laing, I.A.; Wong, C.M. Hypernatraemia in the first few days: Is the incidence rising? Arch. Dis. Child. Fetal
Neonatal Ed. 2002, 87, F158–F162.
Academy of Breastfeeding Medicine Protocol Committee. ABM clinical protocol #3: Hospital guidelines forthe use of supplementary feedings in the healthy term breastfed neonate, revised 2009. Breastfeed Med. 2009,
4, 175–182.
Miller, J.R.; Flaherman, V.J.; Schaefer, E.W.; Kuzniewicz, M.W.; Li, S.X., Walsh, E.M.; Paul, I.M. Early
weight loss nomograms for formula fed newborns. Hosp. Pediatr. 2015, 5, 263–268.
Martens, P.J.; Romphf, L. Factors associated with newborn in-hospital weight loss: Comparisons by feeding
method, demographics, and birthing procedures. J. Hum. Lact. 2007, 23, 233–241.

Nutrients 2019, 11, 592

27.
28.
29.
30.

31.
32.

33.

34.

35.

36.
37.
38.

39.

11 of 11Maisels, M.J.; Kring, E. Length of Stay, Jaundice, and Hospital Readmission. Pediatrics 1998, 101, 995–998.
Inoue, S.; Naruse, H.; Yorifuji, T.; Kato, T.; Murakoshi, T.; Doi, H.; Subramanian, S.V. Impact of Maternal
and Paternal Smoking on Birth Outcomes. J. Public Health (Oxf.) 2017, 39, 1–10.
Hung, T.H.; Hsieh, T.T.; Chen, S.F. Risk of Abnormal Fetal Growth in Women with Early- and Late-Onset
Preeclampsia. Pregnancy Hypertens. 2018, 12, 201–206.
Koivunen, S.; Torkki, A.; Bloigu, A.; Gissler, M.; Pouta, A.; Kajantie, E.; Vaarasmaki, M. Towards National
Comprehensive Gestational Diabetes Screening—Consequences for Neonatal Outcome and Care. Acta
Obstet. Gynecol. Scand. 2017, 96, 106–113.
Fonseca, M.J.; Severo, M.; Santos, A.C. A new approach to estimating weight change and its reference
intervals during the first 96 hours of life. Acta Paediatr. 2015, 104, 1028–1034.
Villar, J.; Giuliani, F.; Bhutta, Z.A.; Bertino, E.; Ohuma, E.O.; Ismail, L.C.; Barros, F.C.; Altman, D.G.;
Victora, C.; Noble, J.A.; et al. Postnatal growth standards for preterm infants: The Preterm Postnatal Followup Study of the INTERGROWTH-21(st) Project. Lancet Glob. Health 2015, 3, e681–e691.
Victora, C.G.; Bahl, R.; Barros, A.J.; Franca, G.V.; Horton, S.; Krasevec, J.; Murch, S.; Sankar, M.J.; Walker,
N.; Rollins, N.C. Lancet Breastfeeding Series Group: Breastfeeding in the 21st century: Epidemiology,
mechanisms, and lifelong effect. Lancet 2016, 387, 475–490.
Moschonis, G.; de Lauzon-Guillain, B.; Jones, L.; Oliveira, A.; Lambrinou, C.P.; Damianidi, L.; Lioret, S.;
Moreira, P.; Lopes, C.; Emmett, P.; et al. The effect of early feeding practices on growth indices and obesity
at preschool children from four European countries and UK schoolchildren and adolescents. Eur. J. Pediatr.
2017, 176, 1181–1192.
Flaherman, V.J.; Narayan, N.R.; Hartigan-O’Connor, D.; Cabana, M.D.; McCulloch, C.E.; Paul, I.M. The
Effect of Early Limited Formula on Breastfeeding, Readmission, and Intestinal Microbiota: A Randomized
Clinical Trial. J. Pediatr. 2018, 196, 84–90.
Suresh, G.K.; Clark, R.E. Cost-effectiveness of strategies that are intended to prevent kernicterus innewborn infants. Pediatrics 2004, 114, 917–924.
Eggert, L.D.; Wiedmeier, S.E.; Wilson, J.; Christensen, R.D. The Effect of Instituting a Prehospital-Discharge
Newborn Bilirubin Screening Program in an 18-Hospital Health System. Pediatrics 2006, 117, e855–e862.
Flaherman, V.; Schaefer, E.W.; Kuzniewicz, M.W.; Li, S.X.; Walsh, E.M.; Paul, I.M. Health Care Utilizationin the First Month After Birth and its Relationship to Newborn Weight Loss and Method of Feeding. Acad.
Pediatr. 2018, 18, 677–684.
Bhutani, V.K.; Johnson, L.H.; Schwoebel, A.; Gennaro, S. A Systems Approach for Neonatal
Hyperbilirubinemia in Term and Near-Term Newborns. J. Obstet. Gynecol. Neonatal Nurs. 2006, 35, 444–455.
© 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open accessarticle distributed under the terms and conditions of the Creative Commons Attribution(CC BY) license (http://creativecommons.org/licenses/by/4.0/).