Original Paper
Neonatology 2018;114:348–354
DOI: 10.1159/000491817

Received: April 6, 2018
Accepted after revision: July 3, 2018
Published online: August 22, 2018

Optimal Thermal Control with Sufficient Nutrition
May Reduce the Incidence of Neonatal Jaundiceby Preventing Body-Weight Loss Among Non-Low
Birth Weight Infants Not Admitted to Neonatal
Intensive Care Unit
Masayoshi Zaitsu a, b Tatsuya Yoshihara c, d Hiromitsu Nakai e Shiro Kubota c, f
a Department of Social and Behavioral Sciences, Harvard T.H. Chan School of Public Health, Boston, MA, USA;b Department of Public Health, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan;c Kubota Maternity Clinic, Fukuoka, Japan; d Clinical Research Center, Fukuoka Mirai Hospital, Fukuoka, Japan;
e YOU-YOU General Infirmary, Karatsu/Saga, Japan; f Kubota Life Science Laboratory Co., Ltd., Saga, Japan

Abstract
Background: Neonatal jaundice is strongly attributable toexcess body-weight loss as a result of insufficient calorificintake. Objectives: To examine the incidence of neonatal
jaundice (defined by use of phototherapy) and body-weight
loss, as well as their association, among neonates under optimal thermal control with sufficient nutrition, a local protocol for temperature and nutritional regulation. Methods: We
retrospectively identified a cohort of 10,544 neonates (birthweight ≥2,500 g) placed in thermo-controlled incubators for
2 h immediately after birth. Neonates were fed with 5% glucose solution 1 h after birth and breastfed every 3 h (with© 2018 S. Karger AG, Basel
E-Mail karger@karger.com
www.karger.com/neo

supplementary formula milk if applicable) according to basal maintenance expenditure. Total serum bilirubin levels at
day 4 (peak level) were assessed. Phototherapy was performed on the basis of total serum bilirubin level ≥18 mg/dL.
Risk ratio (RR) and 95% CI for the use of phototherapy against
maximum body-weight loss were estimated using Poisson
regression with robust variance. Results: Incidence of phototherapy use was low (0.3%) and the mean total serum bilirubin level was 8.5 mg/dL (SD 2.7 mg/dL), with a low mean
maximum body-weight loss (1.9%) and low incidence of excess body-weight loss ≥7% (0.4%). Maximum body-weightloss was associated with risk of neonatal jaundice (RR 1.27;
95% CI 1.04–1.54), and became significant at approximately
4% of maximum body-weight loss. Conclusion: Optimal
thermal control and sufficient nutrition may greatly reducethe incidence of neonatal jaundice by preventing neonatal
body-weight loss.
© 2018 S. Karger AG, Basel

Tatsuya Yoshihara
Fukuoka Mirai Hospital, Clinical Research Center
Kashii-teriha 3-5-1, Higashi-ku
Fukuoka 813-0017 (Japan)
E-Mail tatsuya @ clipharm.med.kyushu-u.ac.jp

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Keywords
Neonatal jaundice · Physiology · Body temperature ·Body-weight loss · Breastfeeding · Bottle feeding · Prevention

The thermal environment neonates are exposed to in the
few hours after birth is a key environmental determinant forneonatal health. Optimal thermal environment during thattime is an ambient room temperature of ~34 ° C (93.2°F),
which “allows body temperature to remain normal while
oxygen consumption and evaporative water loss are both ata minimum” [1]. In contrast to the ambient room temperature (~24 ° C/75.2°F), this optimal thermal environment
helps neonatal body temperature to remain normal withcirculatory stability [2–4], resulting in improving digestive
function such as prevention of vomiting and promotion of
meconium excretion [2, 3]. As a result, neonates in this neutral thermal environment are fed sufficiently according tobasal maintenance expenditure (~50 kcal/kg) [5], which
may help prevent hypoglycemia and hypernatremia associated with severe neurologic damage [3, 6, 7].
Placing neonates in a neutral thermal environment
with sufficient nutrition, that is, local thermal and nutritional regulation according to basal 50 kcal/kg maintenance expenditure [3, 5], may also have benefits for neonatal hyperbilirubinemia [3]. Neonatal jaundice is a common physiological condition worldwide (incidence
ranges from ~2 to 35%) [8–15], and the toxic effects ofunconjugated hyperbilirubinemia are associated withneurological damage [16, 17]. Additionally, the risk of
neonatal jaundice associated with excess body-weightloss (as a result of insufficient calorific intake) has been
an emerging concern [10, 13, 14], even after adjusting forgene polymorphisms [10]. However, among non-low
birth weight neonates not admitted to the neonatal intensive care unit (NICU), studies evaluating the contributionof this combination method (thermal control with sufficient nutrition) on neonatal jaundice, excess body-weight
loss, and their mutual association remain sparse.
Using data with the combination method among neonates with normal birth weight that were not admitted to
the NICU, we examined the incidence of neonatal jaundice and excess body-weight loss during the first few daysof life. We also examined whether body-weight loss was
associated with the risk of neonatal jaundice within thetreated population.
Materials and Methods
Study Setting and Population
This retrospective, longitudinal study of neonates during theinitial 4 days of life used clinical data from a cohort of neonateswith normal birth weight (January 1989 to June 2017). Data

Neonatal Care Prevents Jaundice

Table 1. Demographic and clinical characteristics of 10,544 neo-nates who received optimal thermal control with sufficient nutrition and their mothers

Characteristicsn (%) or mean ± SD

Total, nFemaleGestational age, weeks
Birth weight, g
Apgar score at 1 min
Cesarean delivery
Maternal age, years
Maternal body mass index
Multipara
Body-weight loss, %Excess body-weight loss ≥7%
Bilirubin level at day 4, mg/dL
Bilirubin level at day 4 ≥15.0 mg/dL
Phototherapy

10,544
5,066 (48.0)
39.0±1.1
3,043±300
9.6±0.6810 (7.7)30.9±4.0
20.1±2.0
4,982 (47.2)
1.9±1.5
39 (0.4)
8.5±2.7
142 (1.3)30 (0.3)

were collected from the database of Kubota Maternity Clinic inFukuoka, Japan, a general obstetrics and gynecological hospitalthat provided general obstetrics care for a general population in
Fukuoka, as well as other areas of Japan and closed in 2017.
There were not any restrictions (such as referral) to access the
hospital. The characteristics of our population (such as gestational age and birth weight) were similar to those reported inprevious studies (Table 1) [10–12]. All neonates were treatedwith the combination method, a local thermal and nutritional
regulation protocol based on basal 50 kcal/kg maintenance expenditure [3, 5], and discharged by a physician on day 4 or later,when serum bilirubin level was < 15 mg/dL, body weight wasrecovered from its lowest level, and phototherapy was no longer
required [11, 18].
Since 1989, the hospital collected clinical information on all
neonates and their mothers (including gestational age, bodyweight, serum bilirubin levels, phototherapy, and maternal age),
except those who had neonatal asphyxia, congenital heart failure
or malformation, or were transferred to a tertiary hospital (such asa university hospital) for neonatal intensive care. We obtained ananonymized dataset through a research agreement with the hospital; the research ethics committees of Hakata Clinic approved thestudy. The research protocol was registered at UMIN-CTR(UMIN000030011).
All eligible 10,747 term and preterm neonates treated with the
combination method (1) with a birth weight ≥2,500 g, (2) Apgar
score ≥7, and (3) who were not admitted to the NICU were included. We excluded neonates with incomplete data (1.9%), yielding a final study population of 10,544 neonates.
Neutral Thermal Environment with Sufficient Nutrition
Body temperature of neonates was optimally regulated with
their neutral thermal environment [2–4]. Following delivery in adelivery room maintained at ~25 ° C (77°F), neonates were immediately wiped with cotton towels, given intraoral suction on awarm bed (~40 ° C [104°F]), hugged by their mothers (skin-to-skin

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Introduction

Measurement of Serum Bilirubin Levels and Body Weight
Blood samples were collected by heel prick [3, 10]. Althoughtranscutaneous bilirubin levels were not measured, total serum
bilirubin levels (mg/dL) at day 4, corresponding peak levels
among Japanese neonates [11, 12], were routinely measured
among 10,541 out of 10,544 neonates using a modified method
based on previous studies involving direct spectrophotometry ofcentrifuged blood samples in micro-hematocrit tubes (BL-200,
Toitu, Tokyo, Japan) [3, 10, 11]. On the basis of bilirubin levels≥18 mg/dL in combination with other clinical findings, phototherapy was performed [3, 10, 18]. However, some neonates (3out of 10,544) presented clinical symptoms of jaundice, such as
yellow skin color, earlier than day 4; thus, these neonates underwent phototherapy before day 4. Definitions of neonatal jaundiceincluded (1) use of phototherapy and (2) total serum bilirubin≥15 mg/dL.

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DOI: 10.1159/000491817

Using body weight measured at birth and every day for the first
4 days (SW-5200, Toitu, Tokyo, Japan), we determined maximum
body-weight loss ([[birth weight – minimum weight]/birth weight]
×100%). Excess body-weight loss was defined as maximum bodyweight loss ≥7% [18].
Statistical Analysis
We assessed the cumulative incidence of neonatal jaundiceand excess body-weight loss by day 4 after birth. For total serum
bilirubin levels, we estimated the coefficient (β) and 95% CI of
maximum body-weight loss using linear regression. For risk of
neonatal jaundice, we estimated risk ratios (RRs) and 95% CIs
for use of phototherapy and total serum bilirubin ≥15 mg/dL
against maximum body-weight loss using Poisson regression
with robust variance [19]. We also drew cubic spline curves(knotted at 5, 27.5, 50, 72.5, and 95th percentile points), using
data up to the 99th percentile of maximum body-weight loss.
Covariates were sex, gestational age, birth weight, Apgar score,cesarean delivery, maternal age, maternal body mass index, andparity.
For supplementary analysis, the incidence of neonatal jaundice, serum bilirubin levels, and maximum body-weight loss wereecologically compared with published data from previous studies[8–10, 12–15].
Alpha was set at 0.05, and all p values were 2-sided. Data wereanalyzed using STATA/MP 13.1 (Stata-Corp, College Station, TX,
USA).

Results

Overall, the cumulative incidence of neonatal jaundice
was low: 0.3% met the criteria for phototherapy and 1.3%
had total serum bilirubin levels ≥15 mg/dL (Table 1). The
mean total serum bilirubin level at day 4 was 8.5 mg/dL(SD 2.7 mg/dL; Fig. 1), while the mean maximum bodyweight loss was 1.9% (SD 1.5%), and incidence of excess
body-weight loss ≥7% was 0.4% (Table 1). We did notobserve any neonatal morbidity or mortality events
through the study period.
A weak association between maximum body-weightloss and bilirubin levels was observed (adjusted β 0.14;
95% CI 0.11–0.17); however, the association remained
clinically insignificant. Although the absolute cumulative
incidence of neonatal jaundice and excess body-weightloss was low, maximum body-weight loss was associatedwith an increased risk of use of phototherapy (adjusted
RR 1.27; 95% CI 1.04–1.54) and total serum bilirubin levels ≥15 mg/dL (Table 2). Indeed, the risk of the use ofphototherapy and total serum bilirubin levels ≥15 mg/dL
became statistically significant at ~4% of maximum bodyweight loss (Fig. 2, 3).
The incidence of neonatal jaundice and averages of total serum bilirubin levels and maximum body-weight loss
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contact), and then placed in a transparent thermo-controlled incubator (N-ideal H-2000, Nakamura Medical Industry, Tokyo, Japan) within 2 min of birth [2, 3]. Transparent thermo-controlled
incubators were placed next to delivery beds in the delivery room:that is, neonates were not placed in an NICU. Neonates remained
visible and were continuously observed not only by physicians andnurses (e.g., Apgar score), but also by mothers.
Neonates remained in incubators for 2 h. For the first hour,
incubators were set at 34 ° C (93.2°F) [2, 3]. Bed linen and clothing
were also warmed at 34 ° C (93.2°F), and neonates were dressed
after their respiration stabilized. For the second hour, the temperature was turned down to 30 ° C (86°F) to help neonates adapt tonormal room temperature. Finally, neonates were transferred to a
bed in a normal monitoring room set at ~24–26 ° C (75.2–78.8°F)[2, 3].
For sufficient nutrition treatment, 1 h after birth, neonates wereorally fed 5% glucose solution (10 mL/kg) with 1 mL of vitamin K
syrup (containing 2 mg menatetrenone) [3]. Orally fed 5% glucose
solution has been shown to be a convenient and efficient method
to prevent hypoglycemia and neonatal jaundice, while allowing
continuous breastfeeding [3, 6]. Neonates were then breastfed every 3 h. To maintain 50 kcal/kg basal maintenance expenditure [5],neonates were additionally bottle-fed with formula milk until they
were sated (if breast milk production was insufficient) [3]. Additional bottle-feeding with formula milk was based on findings­suggesting that production of breast milk was insufficient after a
few days of birth and/or estimated calories provided by breast
milk were below the basal maintenance expenditure among thestudy population [3]. For example, (1) breastfed neonates born toprimipara mothers additionally consumed 55 kcal/kg of formula
milk at day 1, 70 kcal/kg at day 2, and 90 kcal/kg at day 3, whichwere identical to those in formula-fed neonates, (2) breastfed neonates born to multipara mothers showed the same pattern for the
first 2 days, and continued to consume additional formula milk
(70 kcal/kg) from day 2 to 4, and (3) as the additional formula milk
intake substantially decreased after day 6 in neonates born to primipara mothers and day 5 in those born to multipara mothers, thesufficient nutrition strategy did not affect breastmilk production
after a few days of birth. High-calorie formula milk (16 kcal/20 mL)
was given for the first 48 h; then normal-calorie formula milk (13kcal/20 mL) was given after 48 h. The hospital purchased formula milk from Megmilk Snow Brand (Hokkaido, Japan) and Icreo(Tokyo, Japan).

800

Frequency

600

400

200

Fig. 1. Distribution of total serum bilirubinlevel at day 4 in 10,544 neonates who received optimal thermal control and sufficient nutrition.

0

0

5

10

15

20

Total serum bilirubin at day 4, mg/dL

Table 2. Risk of neonatal jaundice associated with maximum body-weight loss in 10,544 neonates, estimated us-

ing multivariable Poisson regression with robust variance

Characteristics

Maximum body-weight loss, %FemaleGestational week
Birth weight per 100 g
Apgar score
Maternal age
Maternal body mass index
Multipara

Use of phototherapy

Total serum bilirubin ≥15 mg/dL

RR (95% CI)

p valueRR (95% CI)

p value

1.27 (1.05–1.54)
0.42 (0.19–0.93)
0.60 (0.45–0.80)
1.05 (0.94–1.17)
0.75 (0.41–1.36)
1.02 (0.92–1.13)
1.12 (0.94–1.34)
0.39 (0.17–0.86)

0.02
0.03
0.001
0.40
0.34
0.69
0.19
0.02

1.21 (1.09–1.34)
0.69 (0.49–0.97)
0.78 (0.67–0.91)
1.04 (0.98–1.12)
0.57 (0.45–0.72)
1.04 (0.99–1.08)
1.02 (0.94–1.12)
0.56 (0.40–0.79)<0.001
0.03
0.001
0.14
<0.001
0.13
0.61
0.001

RR, risk ratio.

Discussion

Under a local thermal and nutrition regulation protocol based on basal maintenance expenditure, we havepresented a low incidence of neonatal jaundice and excess body-weight loss. In this population, mean peak bilNeonatal Care Prevents Jaundiceirubin levels were shifted toward a lower level (population approach) [20], and cumulative incidence of neonatal jaundice was at most 1%; as far as we are aware, thisis the lowest reported incidence (previous reports indicate range from ~2 to 35%) [8–10, 12–15]. Although neonatal jaundice was nearly eliminated by the lowest reported incidence of excess body-weight loss (0.4%) [8,10, 12–15], a residual risk of body-weight loss remained
associated with neonatal jaundice.
While the impact of the combination method against
exclusive breastfeeding was not directly assessed with a
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appeared to be lower than values projected in previous
studies (Table 3). Changes of the type of formula milk
over time did not affect this association (data not shown).

16.0
Risk ratio for total serum bilirubin
15 mg/dL and greater

8.0
4.0
2.0
1.0

8.0
4.0
2.0
1.0
0.5

0.5
0

1

2

3

4

5

6

Maximum body-weight loss of birth weight, %

0

1

2

3

4

5

6

Maximum body-weight loss of birth weight, %Fig. 2. Cubic spline curves showing the risk for receiving photo-Fig. 3. Cubic spline curves showing the risk for total serum biliru-

multivariable analysis, given that the magnitude of RR
ranged from 0.02 to 0.12 in Table 3, we speculate that the
combination method is a clue for emerging concern
about body-weight loss leading to neonatal jaundice, as
well as hypoglycemia and hypernatremia dehydration,
among exclusively breastfed neonates [3, 6–15, 17]. Neonates exclusively breastfed without thermal control
may not have the advantage of improved digestive function [3]. For example, (1) gastric emptying time was better in breastfed neonates with thermal control (< 1 h)than breastfed neonates without thermal control (>1 h),(2) compared with average serum glucose levels during
the first 8 h of birth in breastfed neonates without thermal control (~40 mg/dL) and breastfed neonates withthermal control only (~50 mg/dL), neonates with the
combination method had higher levels (ranging from~50 to 70 mg/dL), and (3) regarding the time required
for serum level of free fatty acids to start decreasing,compared with breastfed neonates without thermal control (8 h of birth) and breastfed neonates with thermal
control only (8 h of birth), neonates with the combination method appeared to start earlier (4 h of birth). In
addition, exclusive breastfeeding may not always provide sufficient calorific intake to neonates according tobasal maintenance expenditure [3]. This problem is illustrated by our observation of a lower incidence ofjaundice in neonates born to multipara mothers com-pared with those born to primipara mothers (RR ranged
from 0.39 to 0.56), who are likely to have lower levels ofbreast milk [3].
However, in the present study, the risk of neonatal
jaundice was already significant at ~4% of body weightloss. Even with our intensive treatment regimen, significant weight loss occurred in a limited number of neonates, predisposing them to jaundice. Therefore, thisgroup might require further preventive intervention andphototherapy without delay [16], and their body-weightloss should not be diagnosed with physiological bodyweight loss.
Some limitations should be considered. First, ourstudy did not have a control group; thus, we could not
perform a direct comparison with multivariable analytic models. However, our supplementary analysis suggests a potential impact of the combination method.
Second, we could not fully assess factors before treatment (such as history of previous neonates who received phototherapy or hemolytic disease) [15]; however, body-weight loss, neonatal sex, and gestational
age may be the most relevant risk factors [8, 10, 13–15],
which coincides with our results. Additionally, although
we could not assess other bilirubin-related outcomes,
such as direct/indirect bilirubin and transcutaneous bilirubin levels, or control for other possible factors suchas genetic variation, genetic factors may not affect thetherapy against percentage of maximum body-weight loss of birthweight. Risk ratios (solid line) and 95% CIs (dashed lines) were
estimated by Poisson regression with robust variance, adjusted forsex, gestational age, birth weight, Apgar score, maternal age, maternal body mass index, and parity.

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bin levels ≥15 mg/dL against body-weight loss. Risk ratios (solidline) and 95% CIs (dashed lines) were estimated by Poisson regression with robust variance, adjusted for sex, gestational age, birthweight, Apgar score, maternal age, maternal body mass index, andparity.

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Risk ratio for receiving phototheraphy

16.0Table 3. Ecological comparison of neonatal jaundice, serum bilirubin level, and body-weight loss with previous studies

Neonatal jaundice

SettingNutrition

Total, n

n (%)

RR

p value

Phototherapya
Flaherman et al. [8], 2017

USA

143,889

3,453 (2.4)

0.12<0.001

Mantagou et al. [9], 2012
Han et al. [15], 2015

Greece
China

7,302
8,215

450 (6.2)
876 (10.6)

0.05
0.03

<0.001<0.001

Sato et al. [10], 2013

Japan

Breast (62.9%), mixed (33.1%),
formula (4.6%)
Unspecified
Breast (36.3%), mixed (25.7%),
formula (38.0%)
Breast-fed

401

56 (14.0)

0.02<0.001

Chen et al. [13], 2012

TaiwanBreast323

114 (35.3)

0.04<0.001

Serum bilirubin level

SettingNutrition

Total, nChen et al. [14], 2011
Chen et al. [14], 2011
Sato et al. [10], 2013
Chen et al. [13], 2012
Chen et al. [14], 2011

TaiwanTaiwanJapan
TaiwanTaiwanFormulaMixed
BreastBreastBreast

30
24
401
323
30

Percentage of body-weight loss

SettingNutrition

Total, nItoh et al. [12], 2001
Itoh et al. [12], 2001
Sato et al. [10], 2013

Japan
Japan
Japan

FormulaBreastBreast

494
177
401

Total serum bilirubin ≥15 mg/dLb

Mean (SD), mg/dL

p valuec

9.8 (3.2)
10.8 (2.4)
12.0 (2.6)
13.2 (2.7)
13.2 (3.0)

0.02<0.001<0.001<0.001<0.001

Mean (SD), %p valued

4.0 (1.7)
6.6 (1.6)
8.4 (2.6)<0.001<0.001<0.001risk of neonatal jaundice when body-weight loss is <5%,and we observed an average body-weight loss of 1.9%
[10].
Despite these limitations, our local protocol of thermal control with sufficient nutrition could be a potential
neonatal treatment. In the era of early neonatal hospitaldischarge, the use of thermal control (without using
NICU care) may also reduce medical expenditures associated with readmission for phototherapy with costly
care in the NICU [8, 16, 17]. At least, the management of
ambient room temperature at ~34 ° C (93.2°F) using air
conditioners and wiping neonates immediately after
birth could be a potential alternative method without using incubators, particularly for (but not limited to) low
and middle-income countries [21]. Additionally, the initial 2 h spent in the incubator could help to avoid thesubstantially longer incubation required for photothera-py and could also reduce the time before discharge,
thereby potentially increasing opportunities for physicalcontact between mothers and their babies in the neonatal
period [6, 16].
Last, while potential drawbacks of reducing total bilirubin levels (such as antioxidant effects) and use of supplemental feeding (such as the risk of breastfeeding failure, excessive weight gain, and diabetes) are controversial[16, 22, 23], supplemental feeding may not affect breastfeeding [3, 6]. Optimal thermal control may upregulatebilirubin conjugation by reducing free fatty acid via fat
oxidation and non-shivering thermogenesis [3]. For theeffect of preventing body-weight loss to potentially reduce neonatal jaundice, an association between bodyweight and heme catabolism may also play a role [24].
Therefore, neonates who are at risk of insufficient calorific intake should undergo clinical treatment with sup-Neonatal Care Prevents Jaundice

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206.253.207.235 - 8/23/2018 2:50:28 PMa Chi-squared test compared with the summary statistics of the current study: the number of phototherapy, 30 out of 10,544 neonates(0.3%).
b Chi-squared test compared with the summary statistics of the current study: the number of total serum bilirubin ≥15 mg/dL at day
4, 142 out of 10,544 neonates (1.3%).
c t test compared with the summary statistics of the current study: total serum bilirubin level at day 4, mean 8.5 (SD 2.7) mg/dL.
dt test compared with the summary statistics of the current study: percentage of maximum body-weight loss, mean 1.9 (SD 1.5).
RR, risk ratio.

plements according to basal maintenance expenditure [3,5, 7].
In conclusion, our results demonstrate a potential
population approach involving a simple combinationof optimal thermal control and sufficient nutrition to
reduce the incidence of neonatal jaundice. The potential of our neonatal regimen should be further assessedin future studies, including randomized controlled trials, in order to challenge the norm of neonatal jaundice.

Disclosure Statement
The authors have no conflicts of interest relevant to this article
to disclose.

Funding Source
No external funding was received for this manuscript. The authors have no financial relationships relevant to this article to disclose.

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