WO2021002403A1

WO2021002403A1 - Method for determining undernutrition risk and/or low body-weight child birth risk in subject

Info

Publication number: WO2021002403A1
Application number: PCT/JP2020/025894
Authority: WO
Inventors: 達弥江原; 泰明和田; 風華田畑; 洋平北村
Original assignee: 森永乳業株式会社
Priority date: 2019-07-02
Filing date: 2020-07-01
Publication date: 2021-01-07
Also published as: JPWO2021002403A1; JP7342121B2

Abstract

Provided is a method for determining undernutrition risk and/or low body-weight child birth risk in a subject. The invention comprises determining the undernutrition risk and/or the low body-weight child birth risk in the subject using the blood albumin redox state as an indicator.

Description

How to determine undernutrition risk and / or low birth weight infant risk in a subject

The present invention relates to a method for determining undernutrition risk and / or low birth weight infant risk in a subject.

It is known that infants weighing less than 2500 g at birth (low birth weight infants) are at high risk of diabetes, hypertension, coronary artery disease, enhanced stress response pathways, and impaired neuropsychiatric development. In Japan, birth weight has been declining since peaking in the 1970s for both men and women. In Japan, the proportion of low birth weight infants has increased for both men and women since the 1970s, and has remained high at around 10% of the number of births in the 2010s, which is extremely high among OECD member countries. It has been pointed out that the background to this is the thinness and undernutrition of young women, which has become a social issue.

Galectin-3 is known as a marker that reflects the risk of lowering birth weight (Patent Document 1).

Serum albumin level or plasma albumin level is widely used as a nutritional marker (Non-Patent Document 1).

Albumin takes two forms, a reduced form and an oxidized form. In a healthy human, the ratio of the amount of reduced albumin to the total amount of albumin in serum (total amount of reduced albumin and oxidized albumin) is 70% or more (Non-Patent Document 2). It is known that the ratio of reduced albumin decreases and the ratio of oxidized albumin increases due to aging, illness, strenuous exercise, etc. (Non-Patent Document 2). It is considered that oxidative stress is involved in this shift in the redox balance of albumin (Non-Patent Document 2).

It is known that when healthy growing rats are maintained on a low-protein diet, the albumin redox balance shifts to the oxidative predominance (Non-Patent Document 3). This shift in the redox balance of albumin correlates with a decrease in the rate of albumin synthesis in the liver (Non-Patent Document 3).

International release 2016/024627

An object of the present invention is to provide a method for determining undernutrition risk and / or low birth weight infant risk in a subject.

As a result of diligent research, the present inventors have found that the redox state of albumin in the blood of a pregnant woman correlates with the nutritional state of the pregnant woman and / or the birth weight of the child of the pregnant woman, and completed the present invention. I let you.

That is, the present invention can be exemplified as follows.
[1]
A method for determining undernutrition risk and / or low birth weight infant risk in female subjects.
A method comprising the step of determining undernutrition risk and / or low birth weight infant risk in the subject using data reflecting the redox state of albumin in the blood sample separated from the subject as an index.
[2]
The method further comprises a step of measuring the data prior to the step.
[3]
The method, wherein the subject is a pregnant woman.
[4]
The method, wherein the blood sample is whole blood, plasma, or serum.
[5]
The method, wherein the blood sample is isolated from the subject during a period of 24 to 30 weeks gestation.
[6]
The method, wherein the risk of undernutrition and / or the risk of birth of a low birth weight infant is determined to be high when the value of the data converted to the ratio of the amount of reduced albumin to the total amount of albumin is low.
[7]
The method, wherein the risk of undernutrition and / or the risk of birth of a low birth weight infant is determined to be high when the value of the data converted to the ratio of the amount of reduced albumin to the total amount of albumin is 85% or less.
[8]
The method, wherein the risk of undernutrition and / or the risk of birth of a low birth weight infant is determined to be high when the value of the data converted to the ratio of the amount of reduced albumin to the total amount of albumin is 82% or less.
[9]
The method, wherein the risk of undernutrition and / or the risk of birth of a low birth weight infant is determined to be high when the value of the data converted to the ratio of the amount of reduced albumin to the total amount of albumin is 78% or less.
[10]
The method, wherein the risk of undernutrition and / or the risk of birth of a low birth weight infant is determined to be high when the value of the data converted to the ratio of the amount of reduced albumin to the total amount of albumin is 75% or less.
[11]
The method, wherein the risk of undernutrition and / or the risk of birth of a low birth weight infant is determined to be high when the value of the data converted to the ratio of the amount of reduced albumin to the total amount of albumin is decreased.
[12]
When the value of the data converted to the ratio of the amount of reduced albumin to the total amount of albumin is lower than the past value, it is determined that the risk of undernutrition and / or the risk of birth of a low weight infant is high.
Data reflecting the redox state of albumin in a blood sample separated from the subject during the period from pre-pregnancy to 16 weeks gestation, in which the past value was converted into the ratio of the amount of reduced albumin to the total amount of albumin. The method described above, which is the value of.
[13]
When the value of the data converted to the ratio of the amount of reduced albumin to the total amount of albumin is lower than the past value by 3 percentage points or more, it is determined that the risk of undernutrition and / or the risk of birth of a low-weight infant is high. The above method.
[14]
When the value of the data converted to the ratio of the amount of reduced albumin to the total amount of albumin is lower than the past value by 7 percentage points or more, it is determined that the risk of undernutrition and / or the risk of birth of a low-weight infant is high. The above method.
[15]
When the value of the data converted to the ratio of the amount of reduced albumin to the total amount of albumin is 10 percentage points or more lower than the past value, it is determined that the risk of undernutrition and / or the risk of birth of a low-weight infant is high. The above method.
[16]
The method, wherein the value of the data is a value corrected according to the length of the storage period and the storage temperature of the blood sample.
[17]
The method, wherein the subject has a risk factor for undernutrition and / or birth of a low birth weight infant.
[18]
The risk factors are multiple pregnancies, preterm birth experience, miscarriage experience, lack of prenatal management, undernutrition, leanness, obesity, poor weight gain, overweight, stress, younger pregnancy, older pregnancy, anemia, smoking. , Drinking, diabetes, hypertension, infections, inflammation, placental dysfunction, placental dysplasia, uterine disorders, and cervical disorders, one or more factors selected from the above method.
[19]
A kit for determining undernutrition risk and / or low weight infant birth risk in female subjects, which comprises reagents for measuring data reflecting the redox status of albumin in blood samples isolated from female subjects.
[20]
Use of data reflecting the redox status of albumin in blood samples isolated from said subjects as markers of malnutrition risk and / or low birth weight infant risk in female subjects.
[21]
A nutritional composition for reducing the risk of undernutrition and / or the risk of birth of a low birth weight infant in women, which has a function of increasing the ratio of reduced albumin to the total amount of albumin in the blood of women.
[22]
A method for reducing the risk of undernutrition and / or the risk of birth of a low birth weight infant in a woman, which comprises administering the nutritional composition to the woman.

It is a figure which shows the chromatogram when the reduced albumin and the oxidized albumin were analyzed by HPLC. It is a figure which shows the influence of calorie restriction in a rat on the serum albumin concentration. It is a figure which shows the influence which calorie restriction in a rat has on the reduced albumin ratio of serum. It is a figure which shows the correlation between the reduced albumin ratio of the serum of a mother animal in a rat, and the birth weight of a pup. It is a figure which shows the correlation between the reduction amount of the reduced albumin ratio of the serum of a mother animal in a rat, and the birth weight of a pup. It is a figure which shows the fluctuation of the reduced albumin ratio when human plasma is stored at 4 degreeC. It is a figure which shows the reduction rate of the reduced albumin ratio when human plasma is stored at 4 degreeC. It is a figure which shows the fluctuation of the reduced albumin ratio when human plasma is stored at -25 ° C. It is a figure which shows the reduction rate of the reduced albumin ratio when human plasma is stored at -25 ° C.

Hereinafter, the present invention will be described in detail.

<1> Method of the present invention In the present invention, the redox state of albumin in blood can be used to determine the risk of undernutrition and / or the risk of birth of a low birth weight infant in a subject. In the present invention, the redox state of albumin in blood can be used, in particular, to determine the risk of low birth weight. That is, the undernutrition risk and / or the low birth weight infant risk in the subject can be determined by using the redox state of albumin in the blood as an index. Specifically, the undernutrition risk and / or the low birth weight infant risk in the subject can be determined by using the data reflecting the redox state of albumin in the blood sample separated from the subject as an index. .. In other words, the redox status of albumin in the blood (specifically, data reflecting the redox status of albumin in blood samples isolated from the subject) is undernutrition risk and / or low in the subject. It can be used as a marker to determine the risk of birth of a heavy infant.

That is, the present invention is a method for determining undernutrition risk and / or undernutrition risk in a subject, and uses data reflecting the oxidative reduction state of albumin in a blood sample isolated from the subject as an index. Provided is a method comprising a step of determining undernutrition risk and / or underweight infant birth risk in the subject. This process is also referred to as a "judgment process". The method may further include a step of measuring the data before the determination step. This process is also called a "measurement process". That is, the method is a method for determining undernutrition risk and / or undernutrition risk in a subject, and measures data reflecting the oxidative reduction state of albumin in a blood sample isolated from the subject. The method may include a step of determining the undernutrition risk and / or the risk of giving birth to a low-weight infant in the subject using the data as an index.

The present invention is also a method for obtaining data used as an index for determining undernutrition risk and / or underweight infant birth risk in a subject, and albumin in a blood sample isolated from the subject. Provided is a method including a step of measuring data reflecting the redox state of. For the same process, the description of the measurement process can be applied mutatis mutandis. In this method, data reflecting the measured redox status of albumin may be regarded as data used as an index for determining undernutrition risk and / or low birth weight infant risk in a subject. In other words, by performing the measurement step, it is possible to obtain data used as an index for determining the risk of undernutrition and / or the risk of birth of a low weight infant in the subject. "Measuring data" or "acquiring data" may be read as "manufacturing data".

These methods are collectively referred to as the "method of the present invention".

"Subject" means a human individual to be determined for undernutrition risk and / or low birth risk. The subject referred to here is also referred to as a "target subject" to distinguish it from the control subject described later. The subject is a female subject. The subject may or may not be a pregnant woman. The subject may be a pre-pregnant individual. The "pre-pregnant individual" may mean an individual who is not pregnant and may become pregnant in the future. The subject may be, in particular, a pregnant woman. The subject may or may not be a healthy person. The subject may be, for example, an individual who does not currently develop IUGR (intrauterine growth retardation) and / or does not develop it in the future. Subjects may or may not have undernutrition and / or risk factors for low birth weight infants. Subjects may, in particular, have risk factors for undernutrition and / or birth of low birth weight infants. Such risk factors include, for example, multiple pregnancies, preterm birth experience, miscarriage experience, lack of prenatal management, undernutrition, leanness, obesity, poor weight gain, overweight, stress, younger pregnancy, older age. Pregnancy, anemia, smoking, drinking, diabetes, hypertension, infections, inflammation, placental dysfunction, placental dysplasia, uterine disorders, and cervical disorders. The subject may have one or more risk factors.

"Blood sample" means a sample containing blood albumin. Examples of blood samples include whole blood treated products such as serum and plasma, and whole blood. Blood samples include, in particular, serum and plasma. Serum or plasma is obtained, for example, by allowing whole blood to stand or centrifuge. The blood sample may be used as it is in the measurement step, or may be appropriately subjected to pretreatment and then used in the measurement step. The blood sample may be used in the measurement step after being appropriately diluted or concentrated, for example. The blood sample may or may not be used in the measurement step immediately after being separated from the subject. The blood sample may be used in the measurement step after a predetermined period of time has elapsed after being separated from the subject, for example. The passage of a predetermined period is also referred to as "preservation of blood sample". In addition, the predetermined period is also referred to as a "storage period".

The time when the blood sample is separated from the subject is not particularly limited. The time when the blood sample is separated from the subject can be appropriately set according to various conditions such as the purpose of determining the undernutrition risk and / or the birth risk of a low weight infant of the subject. The time when the blood sample is separated from the subject includes the period before pregnancy and the period during pregnancy. The period during pregnancy is, for example, after the start of pregnancy, after 4 weeks gestation, after 8 weeks gestation, after 12 weeks gestation, after 16 weeks gestation, after 20 weeks gestation, after 24 weeks gestation, gestation. It may be 28 weeks or later, or 32 weeks or later, until gestation, up to 40 weeks gestation, up to 34 weeks gestation, up to 30 weeks gestation, up to 26 weeks gestation, 22 weeks gestation. It may be up to 18 weeks gestation, or a combination of them. The period during pregnancy includes, in particular, a period of 24 to 30 weeks of gestation. In addition, "the blood sample is separated from the subject at a certain period" may mean that the blood sample is separated from the subject at any time during the certain period. "Pre-pregnancy period" may mean a period during which the child is not pregnant and may become pregnant in the future. The "pre-pregnancy period" is, for example, 5 years, 4 years, 2 years, 1 year, 9 months, 6 months, 4 months, 3 months, 2 months, or before the start of pregnancy. It may be the period from one month before the start of pregnancy.

<Measurement process>
The measurement step is a step of measuring data reflecting the redox state of albumin in a blood sample separated from a subject. The value of the data that reflects the redox state of albumin measured here is also referred to as the "current value" to distinguish it from the past values described later.

The data reflecting the redox state of albumin is not particularly limited as long as it reflects the ratio of the amount of oxidized albumin to the amount of reduced albumin. Data reflecting the redox state of albumin include the ratios described in (A) and (B) below:
(A) Ratio of reduced albumin amount to oxidized albumin amount, ratio of reduced albumin amount to total albumin amount, ratio of total albumin amount to oxidized albumin amount;
(B) Ratio of oxidized albumin amount to reduced albumin amount, ratio of oxidized albumin amount to total albumin amount, ratio of total albumin amount to reduced albumin amount.

The ratio of the amount of reduced albumin to the total amount of albumin is also called "reduced albumin ratio".

The means for measuring the data reflecting the redox state of albumin is not particularly limited. The data reflecting the redox state of albumin can be measured by an appropriate method according to the type of data.

For example, the ratio of the component amounts as exemplified above can be calculated by measuring at least two component amounts selected from the oxidized albumin amount, the reduced albumin amount, and the total albumin amount. The total albumin amount can be calculated as the total amount of the reduced albumin amount and the oxidized albumin amount. The means for measuring the amount of each component is not particularly limited. The amount of each component can be measured by an appropriate method according to the type of component. The amount of each component can be measured, for example, by a known method for quantifying a compound. Examples of such a method include HPLC, UPLC, LC / MS, GC / MS, MALDI-TOF / MS, CE / MS, NMR and the like. These methods can be used alone or in combination as appropriate. When a plurality of component amounts are measured, the component amounts may be measured separately or collectively. In addition, "measuring a certain component amount" means to acquire data reflecting the certain component amount in an arbitrary form that can be used to calculate data reflecting the redox state of albumin. You can do it. Examples of the data reflecting a certain component amount include raw data obtained by a method for measuring each component amount as illustrated above and data obtained by processing the raw data.

When the blood sample is used in the measurement step after a predetermined period has passed after being separated from the subject, for example, for various conditions such as the length of the predetermined period (the length of the storage period) and the storage temperature. Therefore, the value of the data reflecting the redox state of albumin may be appropriately corrected and used in the prediction step.

For example, the reduced albumin ratio can decrease during storage of blood samples. That is, the reduced albumin ratio depends on the number of storage days (X1) after the blood sample is separated from the subject, for example, when the storage temperature is a refrigerating temperature such as 0 to 10 ° C (for example, 4 ° C). The reduction rate (Y1) of the reduced albumin ratio calculated by the following formula (I) may be shown. Further, for example, when the storage temperature is a freezing temperature such as −35 ° C. to −15 ° C. (for example, −25 ° C.), the following depends on the number of storage days (X2) after the blood sample is separated from the subject. The reduction rate (Y2) of the reduced albumin ratio calculated by the formula (II) may be shown. When the storage temperature fluctuates during the storage of the blood sample, the reduced albumin ratio can be appropriately calculated based on the number of storage days at each temperature. For example, a blood sample obtained by storing it at a refrigerating temperature such as 0 to 10 ° C. (for example, 4 ° C.) for X1 days and obtaining a reduction rate of the reduced albumin ratio of Y1 is −35 ° C. to -15 ° C. (for example, -25 ° C.). The number of days until the reduction rate of the reduced albumin ratio of Y1 is obtained at a freezing temperature such as (° C.) (referred to as X2') is equal to that of the stored blood sample. Therefore, for example, after storing the blood sample at a refrigerating temperature such as 0 to 10 ° C. (for example, 4 ° C.) for X1 days, X2 at a freezing temperature such as −35 ° C. to -15 ° C. (for example, -25 ° C.). A blood sample stored for days is equivalent to a blood sample stored for X2'+ X2 days at a freezing temperature such as −35 ° C. to −15 ° C. (eg, −25 ° C.). Therefore, the reduction rate Y of the reduced albumin ratio of the blood sample in this case can be calculated by substituting the number of storage days (X2'+ X2) into X2 of the formula (II). The "reduced albumin ratio reduction rate" means the ratio of the reduced albumin ratio reduction value due to storage to the reduced albumin ratio value at the time when the blood sample is separated from the subject. Also in the case of other storage temperatures, the relational expression between the number of storage days (X) and the reduction rate (Y) can be created, and the reduction rate (Y) of the reduced albumin ratio can be calculated. Further, the reduced albumin ratio may show a decrease rate of 28% when the storage temperature is more than −70 ° C. (for example, 0 to 10 ° C.) and the storage period is 19 days or more. Further, the reduced albumin ratio may show a decrease rate of 28% when the storage temperature is more than −70 ° C. (for example, −35 ° C. to −15 ° C.) and the storage period is 56 days or more. Further, the reduced albumin ratio may show a reduction rate of 0% regardless of the number of storage days when the storage temperature is −70 ° C. or lower (that is, correction may not be necessary). Therefore, by correcting the measured value of the reduced albumin ratio with the reduction rate, the corrected value of the reduced albumin ratio that can be used in the prediction step (that is, the reduced type at the time when the blood sample is separated from the subject). Albumin ratio) can be calculated. That is, the corrected value of the reduced albumin ratio that can be used in the prediction step (that is, the reduced albumin ratio at the time when the blood sample is separated from the subject) is the measured value of the reduced albumin ratio and the reduced albumin. It can be calculated by the following formula (III) based on the reduction rate (Y) of the ratio. If the storage temperature changes during storage of the blood sample, the reduction rate at each storage temperature can be calculated and the total value can be used for correction as the reduction rate. For blood samples whose storage history (for example, storage days and storage temperature) is unknown, blood is used, for example, at a storage temperature of more than −70 ° C. (for example, 0 to 10 ° C.) until the decrease in the reduced albumin ratio stops. The sample can be further stored and the correction can be performed with the reduction rate at the time when the reduction of the reduced albumin ratio stops is 28%. For blood samples whose storage history (for example, storage days and storage temperature) is unknown, reduced albumin can be stored even if the blood sample is further stored at a storage temperature exceeding −70 ° C. (for example, 0 to 10 ° C.). If no decrease in the ratio is observed, it is determined that the decrease in the reduced albumin ratio has been completed, and the reduction rate can be set to 28% for correction. Specifically, for example, at a storage temperature of more than −70 ° C. (for example, 0 to 10 ° C.), 1 day or more, 2 days or more, 3 days or more, 4 days or more, 5 days or more, 6 days or more, or 7 days. If the decrease in the reduced albumin ratio is not observed even after the blood sample is stored, it may be judged that the decrease in the reduced albumin ratio is completed.

Y1 (%) = 4.9694ln (X1) + 13.918 (R ² = 0.9556) ・・・ (I)

Y2 (%) = 6.1728ln (X2) + 2.1133 (R ² = 0.962) ・・・ (II)

Correction value = Measured value * 100 / (100-Y) ・・・ (III)

<Judgment process>
The determination step is a step of determining the undernutrition risk and / or the birth risk of a low-weight infant in the subject by using the value of data reflecting the redox state of albumin in the blood sample separated from the subject as an index.

The "undernutrition risk in the subject" includes the presence or absence and degree of undernutrition in the subject and the degree of undernutrition.

"At risk of undernutrition in a subject" means, for example, that the subject may be undernourished now and / or that the subject may be undernourished in the future. May mean. "There is no risk of undernutrition in the subject" means, for example, that the subject is unlikely to be undernourished now and / or that the subject is unlikely to be undernourished in the future. May mean. "High risk of undernutrition in a subject" means, for example, that the subject is likely to be undernourished now, that the subject is likely to be undernourished in the future, and / Alternatively, it may mean that the severity of undernutrition is high when the subject develops undernutrition. "Low risk of undernutrition in a subject" means, for example, that the subject is unlikely to be undernourished now, that the subject is unlikely to be undernourished in the future, and / Alternatively, it may mean that the severity of undernutrition is low when the subject develops undernutrition. "Subjects will be undernourished in the future" means that subjects who are not currently pregnant will be undernourished if they become pregnant in the future, or that subjects who are currently pregnant continue to be pregnant. It is mentioned that it causes malnutrition.

The "risk of birth of a low birth weight infant in a subject" includes the possibility and degree of birth of a low birth weight in the child of the subject and the degree of low weight.

"There is a risk of giving birth to a low birth weight infant in the subject" may mean, for example, that the child of the subject may be born with a low birth weight. "There is no risk of birth of a low birth weight infant in the subject" may mean, for example, that the child of the subject is unlikely to be born with a low birth weight. "High risk of birth of a low birth weight infant in a subject" means, for example, that the subject's child is likely to be born underweight and / or when the subject's child is born underweight. It may mean that the severity of underweight is high. "Low risk of birth of a low birth weight infant in a subject" means, for example, that the subject's child is unlikely to be born underweight and / or when the subject's child is born underweight. It may mean that the severity of underweight is low. Examples of the child of the subject include a child who is currently pregnant with the subject and a child who will become pregnant in the future.

The "present" may mean the time when the blood sample is separated from the subject.

"Future" may mean a period after the present. The "future" is after the present and the period until childbirth.

In the method of the present invention, for example, the risk of birth of a low weight infant that does not fall under IUGR may be determined.

The determination step can be carried out, for example, using the high or low value of the data reflecting the redox state of albumin (that is, whether the value of the data reflecting the redox state of albumin is high or low) as an index. The level of the value of the data reflecting the redox state of albumin can be determined, for example, by comparing the value of the data reflecting the redox state of albumin with a predetermined threshold value. In other words, the determination step can be performed, for example, by comparing the value of the data reflecting the redox state of albumin with the threshold value. That is, "the value of the data reflecting the redox state of albumin is high" may mean, for example, that the value of the data reflecting the redox state of albumin is higher than the threshold value. "The value of the data reflecting the redox state of albumin is higher than the threshold value" means, for example, that the value of the data reflecting the redox state of albumin is equal to or higher than the threshold value and reflects the redox state of albumin. It may mean that the value of the data to be used is above the threshold, or that the value of the data reflecting the redox state of albumin is statistically significantly higher than the threshold. "The value of the data reflecting the redox state of albumin is higher than the threshold value" specifically means, for example, that the value of the data reflecting the redox state of albumin is 1.01 times or more of the threshold value. 1.02 times or more, 1.03 times or more, 1.05 times or more, 1.07 times or more, 1.1 times or more, 1.2 times or more, 1.3 times or more, or 1.5 times or more. It may mean that. Further, "the value of the data reflecting the redox state of albumin is low" may mean, for example, that the value of the data reflecting the redox state of albumin is lower than the threshold value. "The value of the data reflecting the redox state of albumin is low compared to the threshold" means, for example, that the value of the data reflecting the redox state of albumin is below the threshold and reflects the redox state of albumin. It may mean that the value of the data to be used is below the threshold, or that the value of the data reflecting the redox state of albumin is statistically significantly lower than the threshold. "The value of the data reflecting the redox state of albumin is low compared to the threshold value" specifically means, for example, that the value of the data reflecting the redox state of albumin is 0.99 times or less of the threshold value. 0.98 times or less, 0.97 times or less, 0.95 times or less, 0.93 times or less, 0.9 times or less, 0.85 times or less, 0.8 times or less, or 0.7 times or less. It may mean that.

The value of the data reflecting the redox state of albumin may be classified into a dangerous range based on, for example, a threshold value. The values of the data reflecting the redox state of albumin may be divided into non-hazardous ranges, for example, based on the threshold value. Specifically, the value of the data reflecting the redox state of albumin may be classified into a dangerous range and a non-dangerous range based on, for example, a threshold value. “Danger range” refers to the range of data values that reflect the redox status of albumin that are likely to be undernutrition risk and / or low birth weight infant risk in the subject. "Non-risk range" refers to the range of data values that reflect the redox status of albumin that are likely to be free of undernutrition risk and / or low birth weight infant risk in the subject. That is, if the value of the data reflecting the redox state of albumin is within the risk range, it may be determined that there is a high possibility that the subject is at risk of undernutrition and / or birth of a low weight infant. On the other hand, if the value of the data reflecting the redox state of albumin is in the non-hazardous range, it may be determined that there is a high possibility that the subject is not at risk of undernutrition and / or birth of a low birth weight infant.

For example, if the value of the data reflecting the redox state of albumin converted to the ratio selected from the above ratio (A) is low, there is a risk of undernutrition and / or a risk of birth of a low weight infant in the subject, or It may be judged to be high. For example, undernutrition risk and / or low birth weight infant birth in a subject when the value of the data reflecting the redox state of albumin converted to the ratio selected from the above ratio (A) is lower than the threshold value. It may be determined that there is a risk or that it is high. In this case, the range considered to be lower than the threshold value may be the dangerous range. Specifically, for example, the values of data reflecting the redox state of albumin converted to the reduced albumin ratio are 85% or less, 84% or less, 83% or less, 82% or less, 81% or less, 80% or less. , 79% or less, 78% or less, 77% or less, 76% or less, 75% or less, 74% or less, 73% or less, 72% or less, 71% or less, or 70% or less in the subject. It may be determined that there is or is at risk of undernutrition and / or birth of a low weight infant. In particular, undernutrition risk in subjects when the data values that reflect the redox state of albumin converted to the reduced albumin ratio are 85% or less, 82% or less, 78% or less, or 75% or less. And / or undernutrition may be determined to be at risk or high risk of birth. In addition, it was determined that the lower the value of the data reflecting the redox state of albumin converted to the ratio selected from the above ratio (A), the higher the risk of undernutrition and / or the risk of birth of a low weight infant in the subject. You may.

For example, if the value of the data reflecting the redox state of albumin converted to the ratio selected from the above ratio (A) is high, there is no risk of undernutrition and / or risk of birth of a low weight infant in the subject, or It may be determined that it is low. For example, undernutrition risk and / or low birth weight infant birth in a subject when the value of the data reflecting the redox state of albumin converted to the ratio selected from the above ratio (A) is higher than the threshold value. It may be determined that there is no or low risk. In this case, the range considered to be higher than the threshold value may be the non-hazardous range. In addition, it was determined that the higher the value of the data reflecting the redox state of albumin converted to the ratio selected from the above ratio (A), the lower the risk of undernutrition and / or the risk of birth of a low weight infant in the subject. You may.

For example, if the value of the data reflecting the redox state of albumin converted to the ratio selected from the above ratio (B) is high, there is a risk of undernutrition and / or a risk of birth of a low weight infant in the subject, or It may be judged to be high. For example, undernutrition risk and / or low birth weight infant risk in a subject when the value of data reflecting the redox state of albumin converted to the ratio selected from the above ratio (B) is higher than the threshold value. It may be determined that there is or is high. In this case, the range considered to be higher than the threshold value may be the dangerous range. In addition, it was determined that the higher the value of the data reflecting the redox state of albumin converted to the ratio selected from the above ratio (B), the higher the risk of undernutrition and / or the risk of birth of a low weight infant in the subject. You may.

For example, if the value of the data reflecting the redox state of albumin converted to the ratio selected from the above ratio (B) is low, there is no risk of malnutrition and / or risk of birth of a low weight infant in the subject, or It may be determined that it is low. For example, undernutrition risk and / or low birth weight infant risk in a subject when the value of data reflecting the redox state of albumin converted to the ratio selected from the above ratio (B) is lower than the threshold value. It may be determined that there is no or low. In this case, the range considered to be lower than the threshold value may be the non-hazardous range. In addition, it was determined that the lower the value of the data reflecting the redox state of albumin converted to the ratio selected from the above ratio (B), the lower the risk of undernutrition and / or the risk of birth of a low weight infant in the subject. You may.

It should be noted that "a ratio of a certain component amount meets a certain criterion (for example, low or high, low or high compared to a threshold value, is in a certain range)" or "albumin converted into a ratio of a certain component amount". The value of the data reflecting the redox state of the album meets a certain criterion (for example, low or high, low or high compared to the threshold value, in a certain range) "reflects the redox state of albumin. It means that the value of the data is in the range where the ratio of the certain component amount is considered to meet the certain criterion (for example, low or high, low or high relative to the threshold, in a certain range). However, it does not require that the ratio of the certain component amount is actually used for the judgment.

That is, for example, "reduced albumin ratio meets certain criteria (eg, low or high, low or high relative to threshold, in a range)" or "oxidation of albumin converted to reduced albumin ratio". "The value of the data reflecting the reduction state meets a certain criterion (for example, low or high, low or high relative to the threshold, in a certain range)" means that the value of the data reflecting the redox state of albumin is in a certain range. The value means that the reduced albumin ratio is in the range considered to meet the certain criteria (eg, low or high, low or high relative to the threshold, in a range) and is actually reduced. It does not require that the type albumin ratio was used in the determination.

In addition, "a certain index (for example, the value of the data which reflects the oxidation-reduction state of albumin converted to the ratio of a certain component amount, the ratio of a certain component amount, or the value of the data which reflects the oxidation-reduction state of albumin)) Is undernutrition risk and / or undernutrition risk in the subject if meets certain criteria (eg, low or high, low or high relative to the threshold, in a range) "Determining high or low" means that the subject is determined to have, no, high, or low risk of undernutrition and / or birth of a low-weight infant, at least to the extent that the criteria are met. Does not require that the risk of undernutrition and / or the risk of birth of a low-weight infant be determined in the subject to the extent that the criteria are not met. However, in one embodiment, "a value of data reflecting the oxidative reduction state of albumin converted to a certain index (for example, a ratio of a certain component amount, a ratio of a certain component amount, or a oxidative reduction state of albumin) is reflected. Undernutrition risk and / or undernutrition birth risk in subjects when the values of the data to be used meet certain criteria (eg, low or high, low or high relative to the threshold, in a range) If "yes, no, high, or low", then there is no, yes, low, or high risk of undernutrition and / or birth of a low-weight infant in the subject, respectively, to the extent that the criteria are not met. You may judge.

The threshold value can be appropriately set by those skilled in the art according to various conditions such as the type of data reflecting the redox state of albumin and the desired determination accuracy. The means for determining the threshold value is not particularly limited. The threshold can be determined, for example, according to a known method used for data analysis to divide a population into two groups.

The threshold value can be determined, for example, based on the value of data reflecting the redox state of albumin in the blood sample measured for the control subject. Data that reflect the redox state of albumin in a blood sample measured for a control subject is also referred to as "control data". The control data may be used in the determination step by being used in determining the threshold. The control data may be used for comparison with data reflecting the redox state of albumin, specifically by being used to determine the threshold. In other words, the determination step may include, for example, a step of comparing data reflecting the redox state of albumin with control data.

Control subjects include positive and negative controls. "Positive control" may mean a subject who may be determined to be at or at high risk of undernutrition and / or birth of a low birth weight infant. “Negative control” may mean a subject who may be determined to have no or low risk of undernutrition and / or birth of a low birth weight infant. Positive controls include individuals who have experienced malnutrition before the blood sample was isolated, individuals who were undernourished at the time the blood sample was isolated, and low after the blood sample was isolated. Nutrients, individuals who have given birth to undernourished babies before their blood samples were separated, individuals who gave birth to undernourished babies after their blood samples were separated, and individuals with a combination of these properties. Can be mentioned. Negative controls include individuals who have never been undernourished before the blood sample was isolated, individuals who were not undernourished at the time the blood sample was isolated, and after the blood sample was isolated. Individuals who did not undernourish, individuals who had never given birth to a low-weight infant before the blood sample was isolated, individuals who did not give birth to a low-weight infant after the blood sample was isolated, the nature of their combination Examples include individuals with. The threshold may be determined solely based on the values of the data reflecting the redox status of albumin measured for the positive control, or only based on the values of the data reflecting the redox status of albumin measured for the negative control. It may be determined based on the values of the data reflecting the redox status of albumin measured for both positive and negative controls. The threshold may usually be determined based on the values of data that reflect the redox status of albumin measured for both positive and negative controls. The number of positive and negative controls is not particularly limited as long as a threshold is obtained that allows determination of undernutrition risk and / or low birth risk for low birth weight with the desired accuracy. The number of positive and negative controls may be one, two or more, respectively. The number of positive and negative controls may usually be more than one, respectively. The number of positive and negative controls may be, for example, 5 or more, 10 or more, 20 or more, or 50 or more, respectively. The number of positive and negative controls may be, for example, 10,000 or less, 1000 or less, or 100 or less, respectively.

When determining the threshold based solely on the values of the data reflecting the redox status of albumin measured for the positive control, for example, the data reflecting the redox status of albumin measured in multiple individuals of the positive control. A value selected from the range from the upper limit to the lower limit of the value, for example, an average value, may be set as a threshold value. Further, for example, in the distribution of data values reflecting the redox state of albumin measured in a plurality of individuals of the positive control, the threshold value may be determined so that a predetermined ratio of the positive control is included in the risk range. The predetermined ratio may be, for example, 70% or more, 80% or more, 90% or more, 95% or more, 97% or more, or 100%.

When determining the threshold based solely on the values of the data reflecting the redox status of albumin measured for the negative control, for example, the data reflecting the redox status of albumin measured in multiple individuals of the negative control A value selected from the range from the upper limit to the lower limit of the value, for example, an average value, may be set as a threshold value. In addition, for example, in the distribution of data values reflecting the redox state of albumin measured in a plurality of individuals of the negative control, the threshold value may be determined so that a predetermined ratio of the negative control is included in the non-hazardous range. .. The predetermined ratio may be, for example, 70% or more, 80% or more, 90% or more, 95% or more, 97% or more, or 100%.

When determining the threshold based on both the value of the data reflecting the redox state of albumin measured for the positive control and the value of the data reflecting the redox state of albumin measured for the negative control, for example, The threshold may be determined such that a predetermined proportion of positive controls is within the risk range and a predetermined proportion of negative controls is within the non-risk range. It is preferable that the proportion of positive controls contained in the dangerous range and the proportion of negative controls included in the non-dangerous range are both high. These proportions may be, for example, 70% or more, 80% or more, 90% or more, 95% or more, 97% or more, or 100%, respectively. When it is difficult to increase both of these ratios, for example, a threshold value is set so that either ratio is preferentially increased according to various conditions such as the purpose of use of the determination result by the method of the present invention. You may. For example, positive controls to reduce false-negative rates if the goal is to provide as close a risk mitigation treatment as possible to subjects at risk of undernutrition and / or birth of low birth weight infants. The threshold value may be set so that the proportion of those included in the danger range is preferentially increased.

The threshold value may be determined using software, for example. For example, statistical analysis software may be used to determine a threshold that allows the most statistically appropriate distinction between negative and positive controls. Examples of such software include statistical analysis software such as "R".

In addition, the target subject itself can be mentioned as the control subject. That is, for example, the risk of undernutrition and / or the risk of giving birth to a low weight infant may be determined by using the change in the redox state of albumin in the blood of the subject as an index. "The value of the data reflecting the redox state of albumin is high" may include the case where the value of the data reflecting the redox state of albumin is increased. "The value of the data reflecting the redox state of albumin has increased" may specifically mean that the value of the data reflecting the redox state of albumin is higher than the past value. .. Further, "the value of the data reflecting the redox state of albumin is low" may include the case where the value of the data reflecting the redox state of albumin is lowered. "The value of the data reflecting the redox state of albumin has decreased" may specifically mean that the value of the data reflecting the redox state of albumin is lower than the past value. .. That is, as the threshold value, past values can also be mentioned.

For example, if the value of the data reflecting the redox state of albumin converted to the ratio selected from the above ratio (A) decreases, there is a risk of undernutrition and / or a risk of birth of a low weight infant in the subject. Alternatively, it may be determined to be high. For example, when the value of the data reflecting the redox state of albumin converted to the ratio selected from the above ratio (A) is lower than the past value, the risk of undernutrition and / or the weight of the subject is low. It may be determined that the risk of birth is high or high. In addition, the greater the degree of decrease in the value of the data reflecting the redox state of albumin converted to the ratio selected from the above ratio (A), the lower the nutritional risk and / or the low birth weight infant risk in the subject. It may be determined that it is high.

For example, if the value of the data reflecting the redox state of albumin converted to the ratio selected from the above ratio (B) increases, there is a risk of undernutrition and / or a risk of birth of a low weight infant in the subject. Alternatively, it may be determined to be high. For example, when the value of the data reflecting the redox state of albumin converted to the ratio selected from the above ratio (B) is higher than the past value, the risk of undernutrition and / or the weight of the subject is low. It may be determined that the risk of birth is high or high. In addition, the greater the degree of increase in the value of the data reflecting the redox state of albumin converted to the ratio selected from the above ratio (B), the lower the nutritional risk and / or the low birth weight infant risk in the subject. It may be determined that it is high.

"Past value" means the value of data reflecting the redox state of albumin in a blood sample separated from the target subject in the past (that is, at a certain point in the past). A certain point in the past can be appropriately set according to various conditions such as the separation time of the blood sample used in the measurement step. The measurement interval of the data reflecting the redox state of albumin (that is, the interval between the time when the blood sample for measuring the past value and the time when the blood sample for measuring the current value is separated) is, for example, 1 week or more, 2 weeks or more, 4 weeks or more, 8 weeks or more, 12 weeks or more, 16 weeks or more, 20 weeks or more, 24 weeks or more, 28 weeks or more, 5 years or less, 4 years or less, It may be 2 years or less, 1 year or less, 40 weeks or less, 36 weeks or less, 32 weeks or less, 28 weeks or less, 24 weeks or less, 20 weeks or less, or 16 weeks or less, and it is a consistent combination thereof. May be good. Some points in the past include the pre-pregnancy period and the period during pregnancy. The period during pregnancy adopted as a certain point in the past is, for example, after the start of pregnancy, after 4 weeks gestation, after 8 weeks gestation, after 12 weeks gestation, after 16 weeks gestation, after 20 weeks gestation. , Or after 24 weeks gestation, up to 28 weeks gestation, up to 24 weeks gestation, up to 20 weeks gestation, up to 16 weeks gestation, up to 12 weeks gestation, or 8 weeks gestation It may be a period up to, or a combination of them. The period during pregnancy adopted at some point in the past includes, in particular, the period from the onset of pregnancy to the 16th week of gestation. Some points in the past include, in particular, the period from pre-pregnancy to 16 weeks gestation. Specifically, for example, the value of data (past value) reflecting the redox state of albumin in the blood sample separated from the subject during the period from pre-pregnancy to 16 weeks gestation and 24 to 30 weeks gestation. It is possible to compare with the value (current value) of the data reflecting the redox state of albumin in the blood sample separated from the subject during the period of. The target subject at some point in the past may be, for example, a positive control or a negative control.

For example, the reduced albumin ratio is 3% points or more, 4% points or more, 5% points or more, 6% points or more, 7% points or more, 8% points or more, 9% points or more, compared with past values. , Or 10 percentage points or more, the risk of low nutrition and / or the risk of birth of a low-weight infant in the subject may be determined to be high or high.

When the change in the redox state of albumin in the blood of the subject is used as an index, the increase or decrease in the risk of undernutrition and / or the risk of birth of a low weight infant in the subject may be determined. "At risk of undernutrition and / or risk of birth of a low birth weight infant" may include cases where the risk of undernutrition and / or the risk of birth of a low birth weight infant is increased. "Increased undernutrition risk and / or low birth weight risk" specifically means that undernutrition risk and / or low birth weight infant risk is higher than at some point in the past. You can. Also, "no or low risk of undernutrition and / or low birth weight infant" may include cases where the risk of undernutrition and / or low birth weight infant is reduced. "Reduced risk of undernutrition and / or low birth weight infant" specifically means that the risk of undernutrition and / or low birth weight infant is lower than at some point in the past. You can.

In any case, the measured values, threshold values, and other numerical values used for the determination can be appropriately corrected and used according to the type of data that reflects the redox state of albumin. For example, when the ratio of reduced albumin is X%, the ratio (%) of the amount of oxidized albumin to the total amount of albumin is calculated as 100-X.

The determination result by the method of the present invention determines whether to implement measures for reducing the risk of undernutrition and / or the risk of birth of a low weight infant (hereinafter, also referred to as “risk reduction measures”) for the subject. Can be used as an index for In other words, by implementing the method of the present invention, an index for deciding whether to implement risk mitigation measures for a subject is obtained. That is, for example, when it is determined by the method of the present invention that there is or is high risk of undernutrition and / or birth of a low birth weight infant in the subject, it is decided to carry out risk reduction measures for the subject. You can. For pre-pregnancy subjects, for example, risk mitigation in preparation for a future pregnancy (ie, to reduce the risk of undernutrition and / or the risk of birth of a low birth weight infant during a future pregnancy) Treatment may be performed. Pregnant subjects may be given risk mitigation measures, for example, to reduce the risk of undernutrition and / or the risk of birth of a low birth weight infant in the current pregnancy. In addition, for example, when it is determined by the method of the present invention that the subject has no or low risk of undernutrition and / or birth of a low birth weight infant, it is determined not to perform risk reduction measures for the subject. You can do it. The risk mitigation procedure may be a medical practice or a non-medical practice. Risk mitigation measures include nutritional intervention. The nutritional intervention can be carried out, for example, by utilizing the composition of the present invention described below. Regarding the use of the composition of the present invention, the description of the risk reduction method of the present invention described later can be applied mutatis mutandis.

The method of the present invention may be carried out before the implementation of the risk mitigation measures, during the implementation of the risk mitigation measures, or after the implementation of the risk mitigation measures. The method of the present invention may be carried out, in particular, prior to the implementation of risk mitigation measures. By performing the method of the present invention before performing the risk mitigation treatment, for example, an index for deciding whether to start the risk mitigation treatment can be obtained. In addition, by implementing the method of the present invention during the implementation of risk mitigation measures, for example, an index for determining whether to continue risk mitigation measures can be obtained. In addition, by carrying out the method of the present invention after performing the risk mitigation measures, for example, an index for determining whether to carry out the risk mitigation measures again can be obtained. That is, for example, if the method of the present invention determines that a subject has or is at risk of undernutrition and / or birth of a low birth weight infant, it is determined that the risk mitigation treatment is started, continued, or re-executed. You can. Also, for example, if the method of the present invention determines that the subject has no or low risk of undernutrition and / or birth of a low birth weight infant, it is determined not to start, continue, or repeat the risk mitigation treatment. You can do it.

<2> Kit of the present invention The present invention provides a kit that can be used to carry out the method of the present invention. The kit is also referred to as a "kit of the present invention".

The kit of the present invention includes a kit for determining undernutrition risk and / or low birth weight infant risk in a subject, and a kit for determining undernutrition risk and / or low birth weight infant birth risk in a subject. Examples include kits for acquiring data used as indicators. The kit of the present invention can be used, for example, to measure data reflecting the redox state of albumin in a blood sample separated from a subject (for example, for calculating data reflecting the redox state of albumin). It may be configured (so that the data used can be measured). That is, the kit of the present invention specifically reflects, for example, data that reflects the redox state of albumin in a blood sample isolated from a subject (eg, reflects the redox state of albumin). It may be a kit containing components (for measuring the data used to calculate the data). Examples of the data used for calculating the data reflecting the redox state of albumin include the amount of oxidized albumin, the amount of reduced albumin, and the data reflecting the total amount of albumin. Such components include reagents and instruments. Specific examples of such components include sample preparation reagents and detection reagents. Examples of the sample preparation reagent include a reagent for preparing a sample used for measuring data (for example, data used for calculating data reflecting the redox state of albumin) from a blood sample. Specific examples of the sample preparation reagent include a buffer solution for diluting a blood sample. Examples of the detection reagent include reagents for detecting the amount of oxidized albumin, the amount of reduced albumin, and total albumin, respectively. Specific examples of the detection reagent include a liquid used as a mobile phase of HPLC. Such components can be appropriately set according to various conditions such as means for measuring data reflecting the redox state of albumin.

<3> Program of the present invention The present invention provides a program for causing a computer to execute the steps included in the method of the present invention. The program is also referred to as "the program of the present invention".

That is, in the present invention, the computer may execute the steps included in the method of the present invention. The computer may perform some or all of the steps included in the methods of the invention. The computer may perform, for example, a measurement step and / or a determination step.

Specifically, for example, a medical person can separate a blood sample from a subject, perform pretreatment if necessary, and set it in a measuring device. The computer causes the measuring device to measure the value of data reflecting the redox state of albumin in the blood sample (for example, the amount of oxidized albumin, the amount of reduced albumin, the amount of total albumin, etc., and the amount of components of albumin. The value of the data reflecting the redox state is calculated), and the measurement result can be obtained. The computer can also determine the risk of undernutrition and / or the risk of birth of a low birth weight infant in the subject based on the measurement results. The computer can further output the determination result obtained in this way, so that the medical personnel can acquire the determination result.

The program of the present invention may be recorded and provided on a computer-readable recording medium. "Computer-readable recording medium" means that information such as data and programs is accumulated by electrical, magnetic, optical, mechanical, or chemical action, and the accumulated information is read from the computer. A recording medium that can be used. Such recording media include floppy (registered trademark) disks, magneto-optical disks, CD-ROMs, CD-R / W, DVD-ROMs, DVD-R / Ws, DVD-RAMs, DATs, 8 mm tapes, and memory cards. , Hard disk, ROM (read-only memory), SSD. Further, in the program of the present invention, each step executed by the computer may be recorded as a separate program.

<4> Composition of the present invention The composition of the present invention is a composition having a function of increasing the ratio of reduced albumin in the target blood.

The fact that the composition of the present invention has a function of increasing the ratio of reduced albumin in the target blood is that, for example, the composition of the present invention is administered to a subject, the ratio of reduced albumin in the target blood is measured, and the ratio is the same. Can be confirmed by confirming whether or not the amount of blood increased as compared with that before administration.

By using the composition of the present invention, specifically, by administering the composition of the present invention to a subject, the risk of undernutrition and / or the risk of birth of a low weight infant can be reduced in the subject. That is, the composition of the present invention may be a composition for reducing the risk of undernutrition and / or the risk of birth of a low birth weight infant.

The description of the subject in the method of the present invention can be applied mutatis mutandis to the subject to which the composition of the present invention is administered. The subject to which the composition of the invention is administered may or may not be a subject that may or may not be determined to be at risk of undernutrition and / or risk of birth of a low birth weight infant. The subject to which the composition of the invention is administered may be, in particular, a subject that may be determined to be at or at high risk of undernutrition and / or birth of a low birth weight infant.

The composition of the present invention may be, for example, a food or drink composition or a pharmaceutical composition. The composition of the present invention may be, in particular, a food or drink composition.

Specifically, the composition of the present invention (for example, a food or drink composition or a pharmaceutical composition) may be a nutritional composition. "Nutrition composition" may mean a composition effective for nutritional intake. The composition of the present invention may be, for example, adjusted in nutritional balance. Specifically, the composition of the present invention may contain, for example, nutrition necessary for pregnancy and / or lactation in a well-balanced manner. In addition, the composition of the present invention may be fortified with nutrition, for example. Specifically, the composition of the present invention may be fortified with the nutrition required for pregnancy and / or lactation, for example. Nutritional enhancement may also include caloric enhancement. Nutrition includes proteins, sugars and lipids. For example, nutritional balance adjustments or nutritional enhancements may improve a subject's nutritional status, thereby reducing the risk of undernutrition and / or the risk of birth of a low birth weight infant.

The food and drink composition may be, for example, the food and drink itself, or may be a material used for manufacturing the food and drink. Ingredients include, for example, seasonings, food additives, and other food and beverage ingredients. Specific examples of food and drink compositions include flour products, instant foods, processed agricultural products, processed marine products, processed livestock products, dairy products (fermented milk, cheese, prepared milk for infants, etc.), fats and oils, and basic seasonings. , Complex seasonings, frozen foods, confectionery, beverages, and other commercially available foods and drinks. As food and drink compositions, specifically, health foods, functional foods, enteric nutritional foods, special purpose foods, health functional foods (specified health foods, nutritional functional foods, functional foods, etc.), nutritional supplements Foods and non-medicinal products are also included. The food and drink composition may be, for example, a supplement, and specifically, a tablet-shaped supplement. Specific examples of the food and drink composition include prepared milk containing a well-balanced nutritional requirement for pregnancy and / or lactation, and ingredient-adjusted milk containing fortified nutrients such as protein, sugar, lipid, and calories. Can be mentioned. In ingredient-adjusted milk, nutrition may be fortified, for example, 1.25 times or more of normal.

The food and drink composition can be provided and sold as a food or drink labeled with uses (including health use) such as reduction of malnutrition risk and / or birth risk of low weight infants. In addition, the food and drink composition can be provided and sold by displaying "pregnant person", "lactating person" and the like as the ingestion target.

"Display" includes all actions for informing the consumer of the use, and if the expression is such that the use can be recalled or analogized, the purpose of the display, the content of the display, and the display are displayed. Regardless of the object, medium, etc., all fall under "display". In particular, the display is preferably performed in such a way that the consumer can directly recognize the application.

As a display, specifically, the act of transferring, delivering, transferring or displaying for the purpose of delivery, importing, advertising, price regarding the product or the packaging of the product related to the food or drink composition. Examples include the act of describing the above-mentioned use in a table or transaction document and displaying or distributing it, or describing the above-mentioned use in the information containing these and providing it by an electromagnetic (Internet, etc.) method. Examples of the display include labeling on packaging, containers, catalogs, pamphlets, promotional materials such as POPs at sales sites, and other documents.

In addition, as the display, a display approved by the government or the like (for example, a display obtained based on various systems established by the government and performed in a manner based on such approval) is preferable. In addition, as labeling, health foods, functional foods, enteric nutritional foods, special purpose foods, health functional foods (for example, specified health foods, nutritional functional foods, functional foods), nutritional supplements, pharmaceutical departments Labeling as a foreign product can be mentioned. Labels approved by the government, etc. include labels approved by the Consumer Affairs Agency. Labels approved by the Consumer Affairs Agency include those approved by foods for specified health uses and similar systems. Specifically, the labeling approved by the Consumer Affairs Agency includes labeling as a food for specified health use, labeling as a food for specified health use with conditions, labeling indicating that it affects the structure and function of the body, and reduction of disease risk. Labeling, labeling of functionality based on scientific grounds, etc., and more specifically, Cabinet Office Ordinance on permission of labeling for special purposes stipulated in the Health Promotion Law (August 31, 2001) Labeling as food for specified health use (particularly labeling for health use) and similar labeling specified in Cabinet Office Ordinance No. 57) of Japan can be mentioned.

<5> Risk Reduction Method of the Present Invention The risk reduction method of the present invention is a method for reducing the risk of undernutrition and / or the risk of birth of a low weight infant in a subject, including the step of administering the composition of the present invention to the subject. .. This process is also referred to as "administration process".

By the risk reduction method of the present invention, specifically, by administering the composition of the present invention to a subject, the risk of undernutrition and / or the risk of birth of a low weight infant can be reduced in the subject.

Note that "administering the composition of the present invention to a subject" may be synonymous with "making the subject ingest the composition of the present invention". Ingestion may be voluntary (free intake) or compulsory (forced intake). Specifically, the administration step may be a step of supplying the composition of the present invention to the subject and thus allowing the subject to freely ingest the composition of the present invention. The administration may be oral administration or parenteral administration. Parenteral administration includes, for example, tube administration and rectal administration.

The administration mode of the composition of the present invention (for example, administration target, administration time, administration period, number of administrations, dose, and other conditions relating to administration) has an effect of reducing undernutrition risk and / or low birth weight infant risk and the like. As long as the desired effect of is obtained, there is no particular limitation. The administration mode of the composition of the present invention can be appropriately set according to various conditions such as the type of the composition of the present invention, the type of the subject to be administered, the age, and the health condition.

The administration period of the composition of the present invention is, for example, 1 week or more, 2 weeks or more, 4 weeks or more, 8 weeks or more, 12 weeks or more, 16 weeks or more, 20 weeks or more, 24 weeks or more, 28 weeks or more. May be 5 years or less, 4 years or less, 2 years or less, 1 year or less, 40 weeks or less, 36 weeks or less, 32 weeks or less, 28 weeks or less, 24 weeks or less, 20 weeks or less, or 16 weeks or less. It may be a consistent combination thereof. The composition of the present invention may be administered once per day, or may be administered in multiple divided doses per day, for example. In addition, the composition of the present invention may be administered, for example, daily or once every few days. The compositions of the present invention may be administered daily, in particular. The dose of the composition of the invention at each dose may or may not be constant.

Hereinafter, the present invention will be described in more detail with reference to non-limiting examples.

<Example 1> Evaluation of the relationship between the albumin redox balance of mothers and the birth weight of offspring in rats Wistar rats on the first day of pregnancy were purchased from Japan SLC. They were divided into the following three groups so that their body weights would not be biased, and they were fed with AIN-93G, which is a normal purified sample, and maintained until the day of delivery.
A: Free intake group, B: 20% calorie restriction group, C: 40% calorie restriction group

Blood was collected from the tail vein on the 9th day of pregnancy in the early stage of pregnancy, the 16th day of pregnancy in the middle stage, and the 19th day of pregnancy in the late stage of pregnancy, and the obtained blood was centrifuged to obtain serum. The resulting serum was stored at -80 ° C until analysis. The mother gave birth to a baby on the 21st or 22nd day of gestation. The weight of the offspring was weighed immediately after delivery and used as the birth weight.

Albumin coloring reagent (A / G B-Test Wako, manufactured by Fuji Film Wako Pure Chemical Industries, Ltd.) was added with 2 μL of stored serum to 500 μL to obtain a mixed solution. The absorbance of the obtained mixed solution was measured at a wavelength of 620 nm, and the serum albumin level in the serum after storage was calculated.

After storage, 2 μL of serum was diluted with 58 μL of PBS and subjected to HPLC analysis according to the method of Karl Oettl (2010) Methods in Enzymology, 474, 181-195 to calculate the reduced albumin ratio. The conditions for HPLC analysis were as follows.
Equipment: NANOSPACE S1-2 (manufactured by Shiseido Co., Ltd.)
Column: Shodex Asahipak 502N 7C column (Showa Denko KK)
Column temperature: 37 ° C
Detection wavelength: Excitation wavelength 280 nm, fluorescence wavelength 340 nm
Mobile phase: Solution A (0.4 M sodium sulfate, 50 mM sodium acetate (pH 4.85))
Solution B (0.4 M sodium sulfate, 50 mM sodium acetate (pH 4.85), 10% ethanol)
Mobile phase condition: The mixing ratio of solution A / solution B was changed from 100/0 to 20/80 in 80 minutes.
Flow rate: 0.5 mL / min Sample injection volume: 15 μL
Standard: Rat serum albumin (manufactured by Sigma-Aldrich Co.) and glutathione (manufactured by Fuji Film Wako Pure Chemical Industries, Ltd.) were mixed at a weight ratio of 1:10 to prepare. The standard was subjected to HPLC analysis under the above conditions, and the retention times of reduced albumin and oxidized albumin were determined (Fig. 1).

For each sample, a perpendicular line is drawn at the position of the minimum value between the peak of reduced albumin and the peak of oxidized albumin in the HPLC chromatogram to divide the peak, and the area of reduced albumin with respect to the total peak area value of albumin. The ratio of the values was calculated and used as the reduced albumin ratio.

The serum albumin level of the mother animal was significantly lower in the 40% calorie restriction group than in the control group on the 19th day of pregnancy (Fig. 2). On the other hand, the ratio of reduced albumin in mothers was lower in the 20% and 40% calorie restricted groups than in the control group on both the 16th and 19th days of gestation (Fig. 3). A positive correlation was found between the ratio of reduced albumin in the mother on the 19th day of gestation and the birth weight of the offspring (Fig. 4). A negative correlation was found between the decrease in the reduced albumin ratio of the mother and the birth weight of the offspring between the 9th and 19th days of gestation (Fig. 5).

<Example 2> Changes in albumin redox balance with storage of blood sample over time Reduced albumin is stable at -70 ° C or lower, but spontaneous oxidation of reduced albumin progresses depending on the storage state of blood sample, and reduction of blood sample The type albumin ratio decreases. For example, in clinical examination, plasma or serum after blood collection may be temporarily refrigerated and then cryopreserved at -30 to -20 ° C. Therefore, the fluctuation of the reduced albumin ratio when plasma was refrigerated at 4 ° C was investigated.

Plasma of 6 adult women in their 20s and 30s was stored in a refrigerator set at 4 ° C for 23 days. After storage, 2 μL was diluted with 58 μL of PBS and subjected to HPLC analysis according to the method of Karl Oettl (2010) Methods in Enzymology, 474, 181-195, and the time course of the reduced albumin ratio of plasma was examined. .. The conditions for HPLC analysis were as follows.
Equipment: NANOSPACE S1-2 (manufactured by Shiseido Co., Ltd.)
Column: Shodex Asahipak 502N 7C column (Showa Denko KK)
Column temperature: 35 ° C
Detection wavelength: Excitation wavelength 280 nm, fluorescence wavelength 340 nm
Mobile phase: Solution A (0.4 M sodium sulfate, 50 mM sodium acetate (pH 4.85))
Solution B (0.4 M sodium sulfate, 50 mM sodium acetate (pH 4.85), 10% ethanol)
Mobile phase condition: Keep the mixing ratio of solution A / solution B at 100/0 for 0 to 5 minutes, change the mixing ratio of solution A / solution B from 100/0 to 40/60 in 5 to 25 minutes, 25 The mixing ratio of solution A / solution B was maintained at 40/60 in about 30 minutes.
Flow rate: 1.0 mL / min Sample injection volume: 15 μL

The ratio of reduced albumin decreased with time until the 18th day of storage, and remained almost constant after the 19th day of storage (Fig. 6). That is, the reduction rate of the reduced albumin ratio became almost constant after the 19th day of storage. The reduction rate of the reduced albumin ratio after the 19th day of storage was about 28% (Table 1). The reduction rate of the reduced albumin ratio was calculated by the following formula:
Reduction rate of reduced albumin ratio = 100-100 × (reduced albumin ratio after storage / reduced albumin ratio before storage)

A relationship represented by the following formula (I) was observed between the number of storage days (X) at 4 ° C. and the reduction rate (Y) of the reduced albumin ratio (Fig. 7). Therefore, the reduced albumin ratio before storage can be calculated by correcting the measured value of the reduced albumin ratio of the blood sample stored at 4 ° C. with the reduction rate calculated by the formula (I). The formula (I) can be applied not only when the blood sample is stored at 4 ° C. but also when it is stored at the ambient temperature (for example, 0 to 10 ° C.).

Y (%) = 4.9694ln (X) + 13.918 (R ² = 0.9556) ・・・ Equation (I)

Furthermore, since the reduction rate (Y) of the reduced albumin ratio due to natural oxidation is almost constant at about 28%, the reduction rate of the reduced albumin ratio of a blood sample with sufficiently advanced natural oxidation is corrected as 28%. be able to.

<Example 3> Changes over time in albumin redox balance with storage of blood samples Changes in the ratio of reduced albumin when plasma was frozen and stored at -25 ° C were investigated.

Plasma of three adult males in their 30s and 40s was stored in a freezer set at -25 ° C for 60 days. After storage, 2 μL was diluted with 58 μL of PBS and subjected to HPLC analysis according to the method of Karl Oettl (2010) Methods in Enzymology, 474, 181-195, and the time course of the reduced albumin ratio of plasma was examined. .. The conditions for HPLC analysis were as follows.
Equipment: NANOSPACE S1-2 (manufactured by Shiseido Co., Ltd.)
Column: Shodex Asahipak 502N 7C column (Showa Denko KK)
Column temperature: 35 ° C
Detection wavelength: Excitation wavelength 280 nm, fluorescence wavelength 340 nm
Mobile phase: Solution A (0.4 M sodium sulfate, 50 mM sodium acetate (pH 4.85))
Solution B (0.4 M sodium sulfate, 50 mM sodium acetate (pH 4.85), 10% ethanol)
Mobile phase condition: Keep the mixing ratio of solution A / solution B at 100/0 for 0 to 5 minutes, change the mixing ratio of solution A / solution B from 100/0 to 40/60 in 5 to 25 minutes, 25 The mixing ratio of solution A / solution B was maintained at 40/60 in about 30 minutes.
Flow rate: 1.0 mL / min Sample injection volume: 15 μL

The ratio of reduced albumin decreased with time until the 56th day of storage, and remained almost constant after the 56th day of storage (Fig. 8). That is, the reduction rate of the reduced albumin ratio became almost constant after the 56th day of storage. The reduction rate of the reduced albumin ratio after the 56th day of storage was about 28% (Table 2). The reduction rate of the reduced albumin ratio was calculated by the following formula:
Reduction rate of reduced albumin ratio = 100-100 × (reduced albumin ratio after storage / reduced albumin ratio before storage)

The relationship represented by the following formula (II) was observed between the number of storage days (X) at -25 ° C and the reduction rate (Y) of the reduced albumin ratio (Fig. 9). Therefore, the reduced albumin ratio before storage can be calculated by correcting the measured value of the reduced albumin ratio of the blood sample stored at -25 ° C with the reduction rate calculated by the formula (II). The formula (II) can be applied not only when the blood sample is stored at -25 ° C, but also when it is stored at the ambient temperature (for example, -15 to -35 ° C).

Y (%) = 6.1728ln (X) + 2.1133 (R ² = 0.962) ・・・ Equation (II)

<Example 4> Evaluation of the relationship between the albumin redox balance of pregnant women and the birth weight of offspring Sera of 27 to 30 weeks gestation were obtained from 54 healthy pregnant women. Serum from any of the 3 individuals was selected and stored in a refrigerator set at 4 ° C for 7 days. The stored serum was subjected to HPLC analysis under the conditions described in Example 2 to examine the time course of the reduced albumin ratio of the serum. No change in the ratio of reduced albumin during storage was observed (Table 3).

The serum albumin level in serum was measured by the method described in Example 1. The reduced albumin ratio of serum was measured by HPLC analysis under the conditions described in Example 2. In addition, from Table 3, it was judged that the spontaneous oxidation of reduced albumin was sufficiently advanced in the serum used in this example, and the measured value of the reduced albumin ratio was corrected with the reduction rate set to 28%, and the serum was examined. The reduced albumin ratio (hereinafter, also referred to as “corrected value of reduced albumin ratio”) at the time of separation from the person was calculated. The serum albumin value was 4.4 ± 0.3 g / dL, the measured value of the reduced albumin ratio was 61.7 ± 3.4%, and the corrected value of the reduced albumin ratio was 85.7 ± 4.7%. The corrected value of the reduced albumin ratio obtained here was a value close to the reduced albumin ratio of the plasma of the adult female obtained in Example 2 before storage.

The subjects (that is, 54 pregnant women) are divided into quartiles according to the birth weight of the offspring, 25% tile or less is in the low birth weight group (2617.0 ± 77.4 g; n = 14), and the rest is in the control group (3236.4 ±). 45.8 g; n = 40). Group comparisons were made for subject background factors (ie, age, height, non-pregnant weight, and non-pregnant BMI), serum albumin levels, and reduced albumin ratio. Significant differences between groups were observed in height (p = 0.008), measured value of reduced albumin ratio (p = 0.039), and corrected value of reduced albumin ratio (p = 0.039) (Table 4).

After confirming that multicollinearity is not observed between the height and the corrected value of the reduced albumin ratio, the birth weight should be 25% tile or less by multiple logistic regression analysis (stepwise variable increase / decrease method). I created a model to predict. The correction values for height and reduced albumin ratio are significant and independent dependent variables, and the unit odds ratio for each factor is 0.79 for height (95% confidence interval 0.65-0.92) and 0.79 for corrected albumin ratio for reduced albumin (95%). The confidence interval was 0.63-0.94))).

ROC (recover operating characteristics) analysis was performed using this model, and as a cutoff value for predicting that the birth weight will be 25% tile or less, a height of 158 cm and a correction value of reduced albumin ratio of 85.4% were obtained. Was done.

As described above, it was clarified that the risk of malnutrition and / or the risk of birth of a low weight infant in a subject can be sharply determined by using the redox state of albumin in blood as an index. In particular, in the case of pregnant women, the risk of undernutrition and / or the risk of birth of a low-weight infant is sharply determined even by using the serum albumin level or plasma albumin level, which are known nutritional markers due to factors such as an increase in blood volume, as an index. On the other hand, if the oxidative-reduction state of albumin in blood is used as an index, the undernutrition risk and / or the birth risk of a low-weight infant in a subject can be sharply determined.

<Example 5>
Multiple pregnancies, preterm birth experience, abortion experience, lack of prenatal management, undernutrition, leanness, obesity, poor weight gain, overweight, stress, younger pregnancy, older pregnancy, anemia, smoking, drinking, diabetes, Examples of pregnant women from 24 to 30 weeks gestation with high blood pressure, infection, inflammation, placental dysfunction, placental dysplasia, uterine disorders, or cervical disorders from blood collected during a maternity examination. The reduced albumin ratio is measured using the method described in 2 to diagnose the risk of birth of a low-weight infant. For pregnant women with reduced albumin ratios of 85% or less, 82% or less, 78% or less, or 75% or less, for example, maternal milk during pregnancy and / or lactation (specifically, pregnancy and / Or prepared milk with a well-balanced combination of nutrients necessary for the lactation period), ingredient-adjusted milk with fortified nutrients such as protein, sugar, lipids, and calories (for example, one with 1.25 times or more fortification). The risk of birth of low-weight infants is reduced by administering nutritionally-adjusted foods such as prepared milk for adults or nutritional supplements.

According to the present invention, the risk of undernutrition and / or the risk of birth of a low weight infant in a subject can be determined.

Claims

A method of determining undernutrition risk and / or low birth weight infant risk in female subjects.
A method comprising the step of determining undernutrition risk and / or low birth weight infant risk in the subject using data reflecting the redox state of albumin in the blood sample separated from the subject as an index.
The method according to claim 1, further comprising a step of measuring the data before the step.
The method according to claim 1 or 2, wherein the subject is a pregnant woman.
The method according to any one of claims 1 to 3, wherein the blood sample is whole blood, plasma, or serum.
The method according to any one of claims 1 to 4, wherein the blood sample is separated from the subject during the period of 24 to 30 weeks of gestation.
Any one of claims 1 to 5, wherein when the value of the data converted into the ratio of the amount of reduced albumin to the total amount of albumin is low, the risk of undernutrition and / or the risk of birth of a low-weight infant is determined to be high. The method described in.
Claims 1 to 6, wherein when the value of the data converted into the ratio of the amount of reduced albumin to the total amount of albumin is 85% or less, the risk of undernutrition and / or the risk of birth of a low-weight infant is determined to be high. The method according to any one item.
Claims 1 to 6, wherein when the value of the data converted into the ratio of the amount of reduced albumin to the total amount of albumin is 82% or less, the risk of undernutrition and / or the risk of birth of a low-weight infant is determined to be high. The method according to any one item.
Claims 1 to 6, wherein when the value of the data converted into the ratio of the amount of reduced albumin to the total amount of albumin is 78% or less, the risk of undernutrition and / or the risk of birth of a low-weight infant is determined to be high. The method according to any one item.
Claims 1 to 6, wherein when the value of the data converted into the ratio of the amount of reduced albumin to the total amount of albumin is 75% or less, the risk of undernutrition and / or the risk of birth of a low-weight infant is determined to be high. The method according to any one item.
Any of claims 1 to 10, wherein it is determined that the risk of undernutrition and / or the risk of birth of a low-weight infant is high when the value of the data converted into the ratio of the amount of reduced albumin to the total amount of albumin is decreased. The method described in item 1.
When the value of the data converted to the ratio of the amount of reduced albumin to the total amount of albumin is lower than the past value, it is determined that the risk of undernutrition and / or the risk of birth of a low weight infant is high.
Data reflecting the redox state of albumin in a blood sample separated from the subject during the period from pre-pregnancy to 16 weeks gestation, in which the past value was converted into the ratio of the amount of reduced albumin to the total amount of albumin. The method according to any one of claims 1 to 11, which is the value of.
When the value of the data converted to the ratio of the amount of reduced albumin to the total amount of albumin is lower than the past value by 3 percentage points or more, it is determined that the risk of undernutrition and / or the risk of birth of a low-weight infant is high. The method according to claim 12.
When the value of the data converted to the ratio of the amount of reduced albumin to the total amount of albumin is lower than the past value by 7 percentage points or more, it is determined that the risk of undernutrition and / or the risk of birth of a low-weight infant is high. The method according to claim 12.
When the value of the data converted to the ratio of the amount of reduced albumin to the total amount of albumin is 10 percentage points or more lower than the past value, it is determined that the risk of undernutrition and / or the risk of birth of a low-weight infant is high. The method according to claim 12.
The method according to any one of claims 1 to 15, wherein the value of the data is a value corrected according to the length of the storage period and the storage temperature of the blood sample.
The method according to any one of claims 1 to 16, wherein the subject has a risk factor for undernutrition and / or birth of a low weight infant.
The risk factors are multiple pregnancies, preterm birth experience, miscarriage experience, lack of prenatal management, undernutrition, leanness, obesity, poor weight gain, overweight, stress, younger pregnancy, older pregnancy, anemia, smoking. The method of claim 17, wherein the method is one or more factors selected from drinking, diabetes, hypertension, infection, inflammation, placental dysfunction, placental dysplasia, uterine disorders, and cervical disorders. ..
A kit for determining the risk of malnutrition and / or the risk of birth of a low-weight infant in a female subject, which contains a reagent for measuring data reflecting the redox state of albumin in a blood sample isolated from a female subject.
Use of data reflecting the redox status of albumin in blood samples isolated from said subjects as markers of malnutrition risk and / or low birth weight infant risk in female subjects.
A nutritional composition for reducing the risk of undernutrition and / or the risk of birth of a low birth weight infant, which has a function of increasing the ratio of reduced albumin to the total amount of albumin in the blood of women.
A method for reducing the risk of undernutrition and / or the risk of birth of a low birth weight infant in a woman, which comprises administering the nutritional composition according to claim 21 to the woman.