Glycative Stress Research
Online edition : ISSN 2188-3610
Print edition : ISSN 2188-3602
Received : May 22, 2016
Accepted : July 12, 2016
Published online : September 30, 2016

Original Article

Ketone body elevation in placenta, umbilical cord,
newborn and mother in normal delivery
Tetsuo Muneta 1), Eri Kawaguchi 1), Yasushi Nagai 2), Momoyo Matsumoto 2), Koji Ebe 3),
Hiroko Watanabe 4), Hiroshi Bando 5)1) Muneta Maternity Clinic, Ichihara, Chiba, Japan
2) Nagai Mothers Hospital, Misato, Saitama, Japan
3) Takao Hospital, Kyoto, Japan4) Osaka University Graduate School of Medicine, Osaka, Japan
5) Tokushima University/Kitajima Taoka Hospital, Tokushima, Japan

Abstract

Background: Low carbohydrate diets (LCD) have been recently prevalent in the medical and health field, especially indiabetes mellitus. We have applied LCD on thousands of patients with metabolic diseases and reported the clinical effect of
LCD so far. Through our experience and research concerning LCD, the physiological role of glucose and ketone bodies during
the pre- and post-partum period was investigated in this study.
Subjects and methods: Subjects were 60 normal pregnant woman who had a normal delivery in full-term, without anabnormal glucose intolerance. Methods included the measurement of the value of ketone bodies in the umbilical cord
blood, placental tissue fluid and maternal blood, associated with the value of blood glucose. As ketone bodies, the value of
3-hydroxybutyric acid (3-OHBA, beta-hydroxybutyric acid) was measured. 3-OHBA and glucose values were measured by
the electrode method using Precision Exceed Kit (Abbott) and the conventional enzymatic cycling method, with comparison
investigation of the data from two kits.
Results: The average 3-OHBA levels were as follows: 2,235.0 μmol/L in the placenta, 779.2 μmol/L in the umbilical cord
blood, in which the former is significantly higher than the latter (p < 0.001), 240.4μmol/L in the newborn after four days,and 366.7μmol/L after 30 days. The standard 3-OHBA level in a healthy man is less than 85 μmol/L. Glucose levels in theumbilical cord and placenta were 78.6 mg/dL vs 74.9 mg/dL, with no significant difference, and was the same as that of thepregnant woman. Accuracy management of the two kits revealed a significant correlation ( r = 0.94, p < 0.001). 3-OHBA
values of the maternal blood and umbilical cord blood were extremely elevated from the standard level, with a mutual
significant correlation (r = 0.724, p < 0.001, n = 416).
Conclusion: This clinical study concerning ketone bodies during pre- and post-partum period was investigated, andrevealed that 1) a clinically rapid useful kit for ketone bodies had high reliability and validity compared with conventional
kit, 2) elevated values of 3-OHBA were shown in the placental tissue fluid, umbilical cord, newborn and maternal blood, 3)
3-OHBA would be a physiologically indispensable element in nutrition metabolism for fetus and newborn at least until 30
days, with further development of investigation for ketone bodies.

KEY WORDS: ketone bodies, 3-hydroxybutyric acid (β-hydroxybutyric acid), placenta, umbilical cord, newborn,
Introduction

Metabolic syndrome such as obesity and diabetes mellitus
has recently increased, and low carbohydrate diets (LCD)
have been noted in the medical and health field. Bernstein,
Atkins and others have developed LCD 1, 2), and LCD has
been widespread.
By the treatment of LCD, fat and fatty acid in the

body tends to burn for a long time. It causes elevated blood
ketone bodies, which have sometimes been regarded ashigh riskfactors, because of insufficient correct differential
diagnosis of hyperketonemia whether it is ketoacidosis or
ketosis.
As a matter of fact, ketone diets were applied to infants
with epilepsy for a long time, associated with hyperketonemia

Corresponding to: Tetsuo Muneta, MD
Muneta Maternity Clinic
Address: 320-7 Neda, Ichihara, Chiba, 290-0024 JAPANTEL: +81-436-24-4103 E-mail: czf 06641@nifty.com
Co-authors: Kawaguchi E, eric_planet212@yahoo.co.jp ; Nagai Y, nagai@nagai-cl.com ;Matsumoto M, matsumoto@nagai-cl.com ; Ebe K, koji.ebe@gmail.com ;Watanabe H, watanabe@sahs.med.osaka-u.ac.jp ; Bando H, pianomed@bronze.ocn.ne.jp_ 133 _

Glycative Stress Research 2016; 3 (3): 133- 140(c) Society for Glycative Stress ResearchKetone Bodies Elevation in Placenta, Umbilical Cord, Newborn and Motherand without any complications. This treatment has been
recommended by international guidelines such as CochraneLibrary and National Institute for Health and Care Excellence(NICE) 3 - 5 ) .
As for LCD and research of ketone bodies, we havecontinued LCD movement for more than 12 years. Ebe K.
first started in Japan in 1999 with lots of books, and Bando
H. developed this movement with medical presentations 6 - 9).
After that, Ebe K. established the Japan carbohydrate
restriction clinical promotion association, and Muneta T has
broadened activity in OB/GYN and pediatrics fields 10, 11).
Our study has come to the next stage. Firstly we could
measure the value of ketone bodies from the umbilical cord,and from the placenta tissue fluid, in which the validity of themeasurement was investigated and clarified. Furthermore,
the value of ketone bodies in maternal blood, placenta,
umbilical cord, and newborn system was firstly investigatedand argued in this report.

Subjects and methods
Subjects were 60 normal pregnant women who hada normal delivery in full-term, without any abnormal
glucose tolerance or gestational diabetes mellitus. As ketone
bodies, the value of 3-hydroxybutylic acid (3-OHBA, betahydroxybutylic acid) was measured. Methods included themeasurement of the values of 3-OHBA in umbilical cord
blood, placental tissue fluid and maternal blood, associatedwith the value of blood glucose.
The measurement of 3-OHBA and glucose was performed
from the placental tissue fluid obtaining by slow and softpressure for placenta without circulating blood. We used thePrecision Exceed Kit ( No. 44562003, registration 22300

AMX00567000; Abbott Japan, Kashiwa, Chiba, Japan) for
measurement of 3-OHBA. The standard value of 3-OHBA
in the blood of a healthy man is less than 85 μmol/L, andits measurement range is 30 to 8,000 μmol/L. The detail of
this kit can be obtained in the HP of Abbott Co., Inc. 12, 13).
The data of 3-OHBA obtained from the Precision
Exceed Kit was compared with those from the conventional
enzymatic cycling method at usual professional laboratories,
and the validity of Precision Exceed Kit was investigated.
Furthermore, we had 4 types of specimen including theumbilical blood, placental tissue fluid, mother blood andnewborn blood, and 2 measure kit for 3-OHBA which are
Precision Abbott and conventional enzyme cycling method.
The summarized protocol is shown in Table 1.
Ketone bodies include three chemicals, 1) acetoacetate(AcAc), the source of the two other ketone bodies, if
not oxidized to form usable energy, 2) acetone, not anenergy source, but instead exhaled or excreted as waste, 3)3-hydroxybutyric acid (3-OHBA, beta-hydroxybutyric acid),
not technically a ketone, but reversibly produced from AcAc,
with useful energy 14, 15). In this study, we have measured
3-OHBA levels as ketone bodies.

Statistical analyses
Data were shown as the mean ± standard deviation. For
statistical analyses, correlation coefficients were calculated
according to the Mann-Whitney U test in the comparison of
two groups. We used two apparatuses for statistical analyses,
which were the JMP (Version 8) statistical analysis software(JMP Japan Division of SAS Institute Japan Ltd., Minatoku, Tokyo, Japan) and the Microsoft Excel analytical tool.

Table 1. 3-OHBA and glucose values in the umbilical cord, placenta, and newborn.

Range

Average

Mediann

Kit

300 〜 2,500

779.2

729.5

60

a)

Placental tissue fluid

1,200 〜 5,200

2,235.0

2,114.5

60a)Newborn (4 days)

100 〜 800

240.4

200.0

99

a)

Newborn (30 days)

200 〜 700

366.7

400.0

24

a)

Umbilical cord (delivery)

30 〜 1,900

254.6

161.0

416

b)

Mother blood

30 〜 4,400

285.4

65.0

416

b)

Umbilical cord (delivery)

35 〜 136

78.6

79.0

55

c)

Placental tissue fluid

20 〜 189

74.9

68.0

57

c)

3-OHBA (μmol/L)
Umbilical cord (delivery)

Glucose (μmol/L)

Values of 3-OHBA are measured by a) Precision Exceed, Abbott and b) the conventional enzyme cycling method kit. c) Glucose values are simultaneouly
measured by the same kit as a). 3-OHBA: 3-hydroxybutyric acid, beta-hydroxybutyric acid.

_ 13 4 _Glycative Stress Research

Ethical considerations
The present study was conducted in compliance withthe ethical principles of the Declaration of Helsinki (Note ofClarification added at the 2004 World Medical Association
General Assembly in Tokyo) and Japan’s Act on the Protectionof Personal Information, and with reference to the Ministerial
Ordinance on Good Clinical Practice (GCP) for Drugs(Ordinance of Ministry of Health and Welfare No.28 of March
27, 1997) and the Ethical Guidelines for EpidemiologicalResearch established by Japan’s Ministry of Health,Labour and Welfare, and Ministry of Education, Culture,
Sports, Science and Technology. The present study was
conducted after examination and approval for the ethics andappropriateness of the study at a meeting of the Muneta
OB/GYN Clinic Ethics Committee for Scientific Research
Involving Human Subjects, including several experts(Approval number #105-2).

Results

1) The 3-OHBA value in the umbilical cord, placenta andnewborn, with glucose value shown in Table 1. The 3-OHBA
level in the placental tissue fluid was 2,235.0 μmol/L on
average, and was 779.2 μmol/L in the umbilical cord blood;
the former was significantly higher than the latter (p < 0.001).

The 3-OHBA value in the newborn (4 days and 30 days) wasmuch higher than the standard level. Furthermore, glucose
level in umbilical cord and placenta was almost the samewith no significant difference.
2) The 3-OHBA value in placental tissue fluid wassignificantly higher than that of the umbilical cord (p < 0.001,
Fig. 1 ). The former was revealed to be about three times
higher than the latter, and was 20 ~ 30 fold higher than thestandard blood level (less than 85 μmol/L).
3) The glucose level in the placental tissue fluid was 75 ~80 mg/dL, which was not significantly different than theumbilical cord of all pregnant woman (Fig. 2).
4) Accuracy management of 3-OHBA by precision exceed
was investigated. Figure 3 showed the correlation of 3OHBA data by two measurements via the electrode method(Precision Exceed, Abbott) and the enzymatic cycling method(conventional kit in professional laboratory), with significant
correlation (p < 0.001).
5) The 3-OHBA values of maternal blood and umbilical cord
blood are shown in Fig. 4, with significant correlation (p <0.001, n = 416). These data were from the enzymatic cycling
method, which has been used as the standard method inusual professional laboratories.

5000
150
4000

glucose level (mg/dL)

3-OHBA by professional laboratory (µmol/L)

n.s.

200

6000

p < 0.001

3000

2000

100

50

1000

0

0
umbilical cord

placenta

umbilical cord

Fig. 1. 3-OHBA values in the umbilical cord and placenta
tissue.

Results are expressed as mean ± standard deviation (n = 60each). The mean 3-OHBA value in the placental tissue issignificantly higher than that in the umbilical cord by the
Mann-Whitney U test (p < 0.001). 3-OHBA: 3-hydroxybutyricacid, beta-hydroxybutyric acid.

placenta

Fig. 2. Glucose level in the umbilical cord and placenta
tissue.

_ 135 _

Results are expressed as mean ± standard deviation (umbilicalcord, n = 55; placenta, n = 57). Neither level has any significant
difference by the Mann-Whitney U test. n.s.: not significant.

Ketone Bodies Elevation in Placenta, Umbilical Cord, Newborn and Mother

3-OHBA by professional laboratory (µmol/L)

1600

1200

800

400

0
0

500

1000

1500

2000

2500

3-OHBA measured by precision exceed (µmol/L)

Fig. 3. Accuracy management of 3-OHBA by precision exceed.

Correlation of 3-OHBA data between two measurements, electrode and enzymatic cycling
methods are shown. Significant correlation is observed (r = 0.94, p < 0.001, n = 31).
3-OHBA: 3-hydroxybutyric acid, beta-hydroxybutyric acid.

3-OHBA by professional laboratory (µmol/L)

2500

2000

1500

1000

500

0
0

500

1000

1500

2000

2500

3000

3500

4000

4500

3-OHBA in pregnant mother (µmol/L)

Fig. 4. 3-OHBA values in the maternal and umbilical cord.

Maternal and umbilical cord values of 3-OHBA are measured by enzymatic cycling method, in which a significant
correlation is observed (r = 0.724, p < 0.001, n = 416 ). 3-OHBA: 3-hydroxybutyric acid, beta-hydroxybutyric acid.

_ 13 6 _Glycative Stress Research

Discussion

According to a Dietary Intervention Randomized
Controlled Trial (DIRECT) study in Europe, LCD without
calorie restriction (CR) was compared to a Mediterranean
diet with CR and fat restriction with CR, in which LCD showed
the predominance effect 16, 17). In Japan, the coauthors havevigorously treated thousands of patients with obesity, metabolic
syndrome and other diseases 6- 11) . Further development would
be expected through Japan’s low carbohydrate restriction
clinical promotion association in the future 18). As LCD has
become more popular, the correct understanding concerning
hyperketonemia and differential diagnosis of ketosis andketoacidosis become more widely spread.

diagnosis 29).
Historically speaking, the measurement of 3-OHBA
in blood had been used for the management of diabetic
ketoacidosis, and after that rapid enzymatic methods weredeveloped 30, 31) . The first of these systems is marketed by
GDS Dianostics (Elkart, IN, USA), which needs only 2 min
to work, with dilution of serum at a specific temperature.
A second generation system was introduced by Abbott
Laboratories (Bedford, MA, USA). The Precision XtraTM
needs a finger stick blood specimen (5 μL) within 30 seconds,
and is accurate for 3-OHBA from 30 ~ 8,000 μmol/L 32).
These environments allowed users to obtain 3-OHBA
and glucose values immediately in clinical settings. That is
why we could investigate and summarize this report.

2) Ketone bodies

4) Data Analysis

1) Low carbohydrate diet (LCD)

From an evolutionary perspective, ketosis has been
considered the physiological response to fasting in Homosapiens 19-21).
Ketone bodies and glucose metabolism, we can consider
for vertebrae evolution 22). The eggs of oviparous animals,
such as amphibian and birds species, contain no carbohydrates,
but have fat and protein, which can feed and grow up toembryo. This evolution was transmitted to mammal species.
At first, a fertilized egg was implanted, and after that, huge
nucleated red blood cells have been seen, during yolk sachematopoiesis. This phenomenon indicates that metabolism
may be possible without carbohydrates.
Recently, the physiological role of ketone bodies has
been clarified, including various beneficial functions 20, 23).
Ketone bodies have provided non-glucose substrate to thehypertrophied brain, sparing muscles from destruction forglucose synthesis. It has a protective role for epileptogenesis
by preventing both after-discharge generation and propagationin kindling seizures 24, 25) . Furthermore, it has a protectiverole for nerve cells and neurons, and a prophylaxis effectfor Alzheimer’sand Parkinson’s disease 25-28). Thus, ketone
bodies may aggressively become a protective energy sourcefor brain in several reports 14, 15).

3) Clinical application

This study has spread the clinical application for themeasurement of ketone bodies.
Data obtained from the Electrode method (Fig. 3 )revealed extremely high significant correlation with thoseby enzyme cycling method (p < 0.001), suggesting its rapid
usefulness in clinical setting.
Before this report, we came to know that Abbott Co.,
Ltd. had no experience or no data to measure the serum or
plasma of a newborn. Therefore this is the first report of thelevel of 3-OHBA in the blood of newborns at 4 and 30 daysby rapid procedure using a small amount of blood, as well as
in the placenta, umbilical cord and mother.
Accuracy management was successful, as a highly
significant coefficient was found (r = 0.97) with reliability
and validity. The standard value of 3-OHBA in the bloodfor a normal healthy man is less than 80 μmol/L, and themeasurement range is 30 ~ 8,000 μmol/L 12, 13). Using thesekits, further data and speculation would be expected infuture investigation. For clinical application of this kit,
pregnant women with nausea and vomiting in emergency
treatment were utilized, with successful rapid and adequate

The authors have begun to develop LCD for patients
including pregnant women, infants and newborns, with
continuous research of glucose and ketone bodies. Based on
several previous investigations on LCD and ketone bodies 11, 12),
we summarized this study. This is the first report to clarify
the physiological metabolism of glucose and ketone bodies
in the placenta, umbilical cord, mother and newborn.
Firstly, Table 1 and Fig. 1 showed that the ketone bodies’
value was extremely high in the placental tissue fluid,
approximately 20 ~ 30 fold higher than the standard level(85 μmol/L), and three times that of the umbilical cord. By
contrast, the glucose values in the umbilical cord and placenta
were almost the same with no significant difference, and the
glucose levels were same as that of a healthy man (Fig. 2).
These results would suggest that nutrition metabolism in a
fetus may depend on the fatty acid metabolism.
Successively, the 3-OHBA value in a newborn at 30 days
was still high (366.7 μmol/L in average, Table 1), suggestingthat ketone bodies may be involved in the energy production
for the growth process of a newborn until at least one month.
Future investigation on nutrition balance (glucose, protein,lipid), glucose intake amount, element of breast milk or
artificial milk and energy in/out would be necessary tofurther clarify.

5) Newborn and ketone bodies

3-OHBA data (n = 416) of a mother and umbilical cordon delivery were measured by conventional enzymatic cycling
method (Fig. 4 ), with mutual significant correlation. When
we observe 3-OHBA values in the mother blood, about 70%of them were elevated from the standard level (85 μmol/L).
The average values of ketone bodies were 2,235 μmol/
L in the placenta, 779.2 μmol/L in the umbilical cord, 366.7μmol/L in a newborn of 30 days, 240.4 μmol/L in a newbornof 4 days, and less than 85 μmol/L in normal adults (Table 1).
Elevated 3-OHBA in the newborn would suggest that newborns
may start producing ketone bodies in the liver, formerly
given from the placenta.
Furthermore, two more factors would be involved in thegrowth of newborns, which are preparation for starvation
after delivery due to rapid growth of fat tissue of the fetus in
the third trimester, and the high amount of fat in breast milk
supporting lipid metabolism.
Our results are compatible with the report of Akram M
et al. 33) for elevated ketone bodies in newborns and mothers.
There is some possibility and speculation concerning the_ 137 _

Ketone Bodies Elevation in Placenta, Umbilical Cord, Newborn and Mothermetabolism of newborns. Fukao T et al. reported that the
FFA/total ketone body ratio is useful for evaluation of ketone
body metabolism and that defects in ketogenesis include
mitochondrial hydroxymethylglutaryl-coenzyme A (HMGCoA) synthase (mHS) deficiency and HMG-CoA lyase (HL)
deficiency 34).
Newborns from the high glucose mother group revealed
higher 3-OHBA ( p = 0.040), lactate ( p = 0.040), andtriglyceride ( p < 0.001), suggesting that pregnancy state
would influence the metabolism of carbohydrate, lipids
and the degradation pathways of amino acids, inducing
to metabolism transportation from the mother across theplacenta 35).
Moreover, lactate may become the focus of lipid
and glucose metabolism in the future. Babies which were
≥ 35 weeks, ≤ 48 hours old and at risk of hypoglycemia,
were investigated by measurement of plasma glucose,
β-hydroxybutyrate, lactate and insulin concentrations 36).
Glucose and β-hydroxybutyrate levels were low, butlactate level varied widely. Infants of diabetics had lower
β-hydroxybutyrate and higher insulin concentrations. Thesefindings suggest that lactate, rather than ketones, may provide
alternative cerebral fuel in hypoglycemic newborns 36). Platt
MW et al. also stated the paradigm shift for metabolism of
newborn brains into lactate instead of glucose 37).

6) Pregnancy and ketone bodies

We cannot find previous reports for the relationship of
ketone bodies values in the umbilical cord and mother ondelivery with a large sample size (Fig. 4). Furthermore, thesedata were from the conventional professional laboratory withhigh validity. As a result, elevated 3-OHBA levels in theumbilical cord and maternal blood with mutual correlation
were observed for the first time in this study.
Maternal 3-OHBA value had significant correlation
with that of the umbilical cord, and showed about half level(Fig. 4). Influencing factors are considered to be as follows:
1) the transition of ketone bodies from placenta to maternal
blood vessel, 2) the ratio of the transition and gradient, 3)
metabolism difference between newborn and mother, 4)carbohydrate intake of mother in a few days of delivery, anddehydration, 5) relationship with hyperlipidemia in third
trimester , 6) fetus environment and metabolism concerning
ketone bodies, fat and glucose.
Metabolite profiles of arterial and venous umbilical cord
plasma and maternal plasma were obtained by 1H nuclear
magnetic resonance (NMR) spectroscopy 38). As for 3-OHBA
concentration, mother vs umbilical cord plasma showed 2.87
vs 0.91 μmol/L in normo-ponderal full-term (FT) delivery,and 1.06 vs 0.57 μmol/L in very-low-birth-weight (VLBW)
delivery.
These data seem to be consistent with our results forconcentration and ratio from mother and umbilical cord. The
measured number was 8 in Tea I et al. 38) and 416 in our study,
indicating that our data would become the fundamental
comparison of 3-OHBA between mother and umbilical cord
(Fig. 4).
The placenta has been known to transaminate aminoacids such as leucine, isoleucine and valine to theirrespective alpha-ketoacids, which are released into theumbilical and uterine circulation and contribute to placental
ammonia production, consistent with the high level of betahydroxybutyrate in maternal plasma. Further evaluation
would be expected with our fundamental data of this study.

7) Fetus and ketone bodies

There have been some reports concerning ketone bodies
and fetuses/newborns.
Firstly, Rizzo T et al. 39) reported that elevated 3-OHBA
during pregnancy attenuated intelligence quotient after
several years. This is one of the causes for the prevalent
misunderstanding that elevated ketone bodies would berisky in clinical settings.
This report, however, has several questionable points,
such as: 1) slightly elevated level of 3-OHBA of 100 ~ 180
μmol/L, 2) probable unstable blood glucose profile, 3) possible
elevated postprandial glucose and mean amplitude of glycemic
excursions (MAGE), 4) existing oxidative stress risk associatedwith factors 1)-3) influencing intelligence quotient.
On the other hand, our research has clarified the following:1) in Pregnant women with morning sickness have ketone
body levels more than 3,000 μmol/L, 2) placental tissue fluid
always contains ketone bodies no lower than 2,000 μmol/L,3) newborns from 4 to 30 days have elevated 3-OHBA,
approximately 240 ~ 367 μmol/L. From these data, thedecreased intelligence quotient due to hyperketonemia foundby Rizzo’s 39) seems to have no relation to ketone bodies.
Consequently, LCD often induces elevated ketone bodylevels, but it is not risky in light of the intrauterine environmentof a fetus. Currently, ketone bodies can produce energy
efficiently in the environment without enough oxygen, andgive positive effects on cranial nerves 26). Ketone bodies in
the placenta were proved to exist in such high concentration
physiologically, indicating that ketone bodies may be
not risky, nor lower the intelligence quotient nor haveteratogenicity.
Secondly, pregnant mice were investigated by being
given two types of food: an ordinary diet ( 9.3 ~ 15.5 kcal/
day, fat 5%, carbohydrate 76.1%, protein 18.9%) and a
ketogenic diet (20.1 ~ 33.5 kcal/day, fat 67.4%, carbohydrate
0.5%, protein 15.3%) 40, 41).
However, this report seemed to have a fundamental
problem in research design. Muridae species such as mouseand rat originally eats seeds of grass that are equal to cereal
or low fat food. Animal experimentation with food is completely
different from study in medicine giving oral or venous
administration. Everyone knows the famous and incorrect
medical report of about 100 years ago wherein an experimentof giving high fat food to rabbits caused extreme arterosclerosisin the carotid artery, which was of a similarly incorrect design.
Therefore, the results of Sussman 40, 41) would be difficult toapply to that of human.
Furthermore, special food for humans with only 0.5%of carbohydrate cannot be prepared or made in ordinary
situations.
Thirdly, Japan Society of Obstetrics and Gynecology has
been responsible for the diagnosis and treatment of pregnant
women in Japan. In relation to this association, Japan
Gynecologist Association press conference was held in
February, 2016, with the comment “Pregnancy and nutrition– Do not deliver small babies, nor grow them too big –” 42).
Their presentation included a series of medical study on miceexperiment by Sussuman 40, 41). However, this seemed not to beappropriate educational content for ordinary expecting women.
The desirable slogan should include adequate knowledge
and advice about nutrition.
In contrast, there is a reliable medical review concerning_ 13 8 _Glycative Stress Researchpregnancy and diabetes 43). The influence of gestational
diabetes mellitus was investigated by meta-analysis of twelve
studies involving 6,140 infants. The results were that infants
aged 1~2 years from diabetic mothers had significantly lower
scores of mental and psychomotor development compared tocontrol infants. Consequently, we should consider not ketone
bodies, but glucose and glycative changes from now on.

8) Limitation and future of study

Previous reports for the relationship of ketone bodyvalues in the umbilical cord and mother on delivery have notincluded so great a sample size, indicating our data would
become the fundamental and useful report in this field.
From the axis of mother – placenta – umbilical cord
– fetus, concentration of gradient and movement of ketone
bodies would be considered. Value of 3-OHBA in the placenta
is extremely elevated, about three times that of the umbilicalcord, and maternal value is half that of the umbilical cord.
These data would indicate that the placenta may produce
ketone bodies and supply its energy to the fetus. On contrast,
even if maternal ketone bodies might move to placental tissue,
the influence is subtle because of 1/6 of 3-OHBA level inmatenal blood compared to the placenta.
Consequently, we speculate that the limitation of thisstudy would be a lack of data from fetuses, so we have planned
to investigate the fetus in detail.
Another major problem seems to be glucose and glycative
influence 20, 21). The prevalence of gestational diabetes mellitus(GDM) seems to be 12.08% in Japan according to theguideline 44), and the ratio of pregnant women with obesity
and/or metabolic syndrome would be around 8%. Then, in
our OB/GYN clinic, about 20% of subjects would probably
be advised to be on LCD treatment, and others would haveno particular health problems.

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Our results showed that elevated 3-OHBA was seen in
70% of subjects. Associated with statistical data, probably
50 ~ 60% of the pregnant mothers without any complications
may show elevated 3-OHBA. Therefore, we plan to investigate
the difference between diabetic and non-diabetic groups in
future research.

Conclusion

We investigated clinical study concerning ketone bodies
during pre- and post-partum period, and concluded that
1) a clinically rapid useful kit for ketone bodies had highreliability and validity compared with conventional kits, 2)
the elevated values of 3-OHBA were shown in the placental
tissue fluid, umbilical cord, newborn and maternal blood, 3)
3-OHBA would be a physiologically indispensable elementin nutrition metabolism for fetus and newborn at least until
30 days, with further development of ketone body research.

Acknowledgement

A summary version of this article was presented at
the 17th and 18th Scientific Meeting of Japan Society ofMetabolism and Clinical Nutrition in 2014 and 2015.

Statement of conflict of interest
Non contributory.

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for low carbohydrate diet (LCD). Toyo Keizai Publishing
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diet: Clinical efficacy with more than 2000 cases in Japanfor the treatment of metabolic syndrome. World Organizationof Family Doctors-19th Europe Conference, Lisbon, 2014.
(abstract)10) Muneta T, Kawaguchi E, Matsumoto M, et al. The effectof low carbohydrate diet (LCD) for gestational diabetes
and its verification: Is hyperketonemia clinically due to
LCD risky? (2nd report). The Journal of Metabolism andClinical Nutrition. 2014; 17: S-203. (abstract in Japanese)11) Muneta T, Kawaguchi E, Nagai Y, et al. Investigation of
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