JP7342121B2 - Method for determining the risk of malnutrition and/or low birth weight in a subject - Google Patents

Description

The present invention relates to a method for determining the risk of malnutrition and/or the risk of giving birth to a low birth weight baby in a subject.

It is known that infants weighing less than 2,500 g at birth (low birth weight infants) are at high risk of diabetes, hypertension, coronary artery disease, enhancement of stress response pathways, and disorders of neuropsychiatric development. In Japan, birth weights for both men and women have continued to decline since peaking in the 1970s. In Japan, the proportion of low birth weight infants has been increasing for both males and females since the 1970s, and has remained high at around 10% of births since the beginning of the 2010s, which is extremely high among OECD member countries. It has been pointed out that underweight and malnourished young women are behind this, and it has become a social issue.

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

Serum albumin levels or plasma albumin levels are widely used as nutritional markers (Non-Patent Document 1).

Albumin takes two forms: reduced and oxidized. In healthy humans, the ratio of the amount of reduced albumin to the total amount of albumin (total amount of reduced albumin and oxidized albumin) in serum 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, disease, intense exercise, etc. (Non-Patent Document 2). Oxidative stress is thought to be 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 favor the oxidized type (Non-Patent Document 3). This shift in the redox balance of albumin correlates with a decrease in the synthesis rate of albumin in the liver (Non-Patent Document 3).

International publication 2016/024627

Quinlan (2005) HEPATOLOGY, 41, 1211-1219 Karl Oettl (2010) Methods in Enzymology, 474, 181-195 Wada(2017) Nutr Res, 37, 46-57

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

As a result of intensive research, the present inventors discovered that the redox state of albumin in the blood of a pregnant woman is correlated with the nutritional status of the pregnant woman and/or the birth weight of the child of the same pregnant woman, and completed the present invention. I let it happen.

That is, the present invention can be exemplified as follows.
[1]
A method for determining the risk of undernutrition and/or low birth weight baby birth in a female subject, the method comprising:
A method comprising the step of determining the risk of malnutrition and/or the risk of giving birth to a low birth weight baby in the subject using data reflecting the redox state of albumin in a blood sample separated from the subject as an index.
[2]
The method further includes a step of measuring the data before 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 between 24 and 30 weeks of gestation.
[6]
The method described above, wherein when the value of the data converted to the ratio of the amount of reduced albumin to the total amount of albumin is low, it is determined that the risk of malnutrition and/or the risk of giving birth to a low birth weight baby is high.
[7]
The method described above, wherein the risk of malnutrition and/or the risk of giving birth to a low birth weight baby 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 described above, wherein the risk of malnutrition and/or the risk of giving birth to a low birth weight baby 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 described above, wherein the risk of malnutrition and/or the risk of giving birth to a low birth weight baby 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 described above, wherein the risk of malnutrition and/or the risk of giving birth to a low birth weight baby 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 described above, wherein the risk of malnutrition and/or the risk of giving birth to a low birth weight baby 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 decreasing.
[12]
If 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 giving birth to a low birth weight baby is high,
Data in which the past value reflects the redox status of albumin in the blood sample isolated from the subject during the period from before pregnancy to 16 weeks of gestation, converted into a ratio of the amount of reduced albumin to the total amount of albumin. The above method, wherein the value of .
[13]
If the value of the data converted into the ratio of the reduced albumin amount to the total albumin amount is 3 percentage points or more lower than the past value, it is determined that the risk of malnutrition and/or the risk of giving birth to a low birth weight baby is high. The method described above.
[14]
If the value of the data converted into the ratio of the reduced albumin amount to the total albumin amount is lower than the past value by 7 percentage points or more, the risk of malnutrition and/or low birth weight baby is determined to be high. The method described above.
[15]
If the value of the data converted into the ratio of the reduced albumin amount to the total albumin amount is 10 percentage points or more lower than the past value, it is determined that the risk of malnutrition and/or the risk of giving birth to a low birth weight baby is high. The method described above.
[16]
The method, wherein the value of the data is a value corrected according to the length of storage period and storage temperature of the blood sample.
[17]
The method, wherein the subject has risk factors for undernutrition and/or low birth weight.
[18]
The risk factors include multiple pregnancy, experience of premature birth, experience of miscarriage, lack of prenatal care, undernutrition, underweight, obesity, poor weight gain, excessive weight gain, stress, pregnancy at a young age, pregnancy at an older age, anemia, and smoking. , alcohol consumption, diabetes, hypertension, infection, inflammation, placental insufficiency, placental hypoplasia, uterine disorder, and cervical disorder.
[19]
A kit for determining the risk of malnutrition and/or the risk of giving birth to a low birth weight baby in a female subject, comprising a reagent for measuring data reflecting the redox state of albumin in a blood sample isolated from the female subject.
[20]
Use of data reflecting the redox status of albumin in a blood sample isolated from a female subject as a marker of risk of malnutrition and/or risk of low birth weight in a female subject.
[21]
A nutritional composition for reducing the risk of malnutrition in women and/or the risk of giving birth to low birth weight babies, which has the function of increasing the ratio of reduced albumin to the total amount of albumin in women's blood.
[22]
A method for reducing the risk of malnutrition and/or the risk of giving birth to a low birth weight baby in a woman, the method comprising administering the nutritional composition to the woman.

FIG. 3 is a diagram showing a chromatogram obtained by HPLC analysis of reduced albumin and oxidized albumin. FIG. 2 is a diagram showing the effect of calorie restriction on serum albumin concentration in rats. FIG. 2 is a diagram showing the effect of calorie restriction on serum reduced albumin ratio in rats. FIG. 2 is a diagram showing the correlation between the reduced albumin ratio of maternal serum and the birth weight of offspring in rats. FIG. 3 is a diagram showing the correlation between the amount of decrease in the ratio of reduced albumin in maternal serum and the birth weight of offspring in rats. FIG. 2 is a diagram showing changes in reduced albumin ratio when human plasma is stored at 4°C. FIG. 3 is a diagram showing the rate of decrease in reduced albumin ratio when human plasma is stored at 4°C. FIG. 2 is a diagram showing changes in reduced albumin ratio when human plasma is stored at -25°C. FIG. 3 is a diagram showing the rate of decrease in reduced albumin ratio when human plasma is stored at -25°C.

The present invention will be explained in detail below.

<1> Method of the present invention In the present invention, the redox state of albumin in the blood can be used to determine the risk of malnutrition and/or the risk of giving birth to a low birth weight baby in a subject. In the present invention, the redox state of albumin in blood can be used particularly to determine the risk of low birth weight. That is, the risk of malnutrition and/or the risk of giving birth to a low birth weight baby in a subject can be determined using the redox state of albumin in the blood as an index. Specifically, the risk of malnutrition and/or the risk of giving birth to a low birth weight baby in a subject can be determined using data reflecting the redox state of albumin in a blood sample isolated from the subject as an indicator. . In other words, the redox status of albumin in the blood (specifically, data that reflects the redox status of albumin in a blood sample isolated from a subject) is a measure of the risk of malnutrition and/or low risk of malnutrition in a subject. It can be used as a marker to determine the risk of birth weight.

That is, the present invention is a method for determining the risk of malnutrition and/or the risk of giving birth to a low birth weight baby in a subject, which uses data reflecting the redox state of albumin in a blood sample isolated from the subject as an indicator. Provided is a method comprising the step of determining the risk of malnutrition and/or the risk of giving birth to a low birth weight baby 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 "measuring process." That is, the method is a method for determining the risk of malnutrition and/or the risk of giving birth to a low birth weight baby in a subject, and includes measuring data reflecting the redox state of albumin in a blood sample isolated from the subject. and determining the risk of malnutrition and/or the risk of giving birth to a low birth weight baby in the subject using the data as an index.

The present invention also provides a method for acquiring data used as an index for determining the risk of malnutrition and/or the risk of giving birth to a low birth weight baby in a subject, the method comprising: A method is provided that includes the step of measuring data reflecting the redox state of. Regarding this process, the description regarding the measurement process can be applied mutatis mutandis. In this method, data reflecting the measured redox state of albumin may be regarded as data used as an index for determining the risk of malnutrition and/or the risk of giving birth to a low birth weight baby in the subject. In other words, by performing the measurement step, it is possible to obtain data used as an index for determining the risk of malnutrition and/or the risk of giving birth to a low birth weight baby in the subject. “Data measurement” or “data acquisition” may be read as “data production”.

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

"Subject" means a human individual who is the subject of determination of malnutrition risk and/or low birth weight baby risk. The subject referred to herein is also referred to as a "target subject" to distinguish it from a control subject described later. The subject is a female subject. The subject may or may not be pregnant. The subject may be an individual before pregnancy. A "pre-pregnant individual" may mean an individual who is not pregnant and who may become pregnant in the future. The subject may in particular be 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 and/or will not develop IUGR (intrauterine growth retardation). The subject may or may not have risk factors for undernutrition and/or low birth weight. The subject may have risk factors for undernutrition and/or low birth weight, among other things. Such risk factors include, for example, multiple pregnancy, previous preterm birth, previous miscarriage, lack of prenatal care, undernutrition, underweight, obesity, poor weight gain, excessive weight gain, stress, early pregnancy, and advanced age. These include pregnancy, anemia, smoking, alcohol use, diabetes, high blood pressure, infections, inflammation, placental insufficiency, placenta formation failure, uterine disorders, and cervical disorders. A subject may have one or more risk factors.

"Blood sample" means a sample containing blood albumin. Examples of blood samples include processed whole blood such as serum and plasma, and whole blood. Blood samples include serum and plasma, among others. Serum or plasma can be obtained, for example, by standing or centrifuging whole blood. The blood sample may be used in the measurement step as it is, or may be used in the measurement step after being subjected to appropriate pretreatment. The blood sample may be used in the measurement step, for example, after being diluted or concentrated as appropriate. The blood sample may or may not be used in the measurement process immediately after being separated from the subject. For example, the blood sample may be used in the measurement step after a predetermined period of time has elapsed after being separated from the subject. The passage of a predetermined period of time is also referred to as "storage of blood sample." Further, the predetermined period is also referred to as a "retention period."

There are no particular restrictions on when the blood sample is separated from the subject. The time at which the blood sample is separated from the subject can be appropriately set depending on various conditions such as the purpose of determining the risk of malnutrition and/or the risk of giving birth to a low birth weight baby in the subject. The time when the blood sample is separated from the subject includes the period before pregnancy and during pregnancy. The period during pregnancy includes, for example, after the start of pregnancy, after 4 weeks of gestation, after 8 weeks of gestation, after 12 weeks of gestation, after 16 weeks of gestation, after 20 weeks of gestation, after 24 weeks of gestation, The period may be after 28 weeks of gestation, or after 32 weeks of gestation, until birth, up to 40 weeks of gestation, up to 34 weeks of gestation, up to 30 weeks of gestation, up to 26 weeks of gestation, 22 weeks of gestation or up to 18 weeks of gestation, or a combination thereof. The period during pregnancy includes in particular the period from 24 weeks to 30 weeks of gestation. Note that "the blood sample is separated from the subject during a certain period" may mean that the blood sample is separated from the subject at some point during the certain period. "Pre-pregnancy period" may mean a period during which pregnancy is not occurring and there is a possibility of pregnancy in the future. "Pre-pregnancy period" is, for example, 5 years before the start of pregnancy, 4 years before, 2 years before, 1 year before, before September, before 6 months, before April, before 3 months, before 2 months, or The period may be from before January to the start of pregnancy.

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

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

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

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

For example, the ratio of the amounts of components as exemplified above can be calculated by measuring the amounts of at least two components selected from the amount of oxidized albumin, the amount of reduced albumin, and the total amount of albumin. Note that the total albumin amount can be calculated as the total amount of reduced albumin amount and 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 depending on the type of component. The amount of each component can be measured, for example, by a known method for quantifying compounds. Such techniques include HPLC, UPLC, LC/MS, GC/MS, MALDI-TOF/MS, CE/MS, NMR, and the like. These methods can be used alone or in appropriate combinations. When measuring the amounts of a plurality of components, the amounts of these components may be measured separately or may be measured all at once. Note that "measuring the amount of a certain component" means obtaining data that reflects the amount of a certain component in any format that can be used to calculate data that reflects the redox state of albumin. You may do so. Examples of data reflecting the amount of a certain component include raw data obtained by the method of measuring the amount of each component as exemplified above, and data processed from the raw data.

If the blood sample is used in the measurement process after a predetermined period of time has passed after it has been separated from the subject, for example, depending on various conditions such as the length of the predetermined period (length of storage period) and storage temperature, etc. Accordingly, 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 may decrease during storage of a blood sample. In other words, the reduced albumin ratio depends on the number of days (X1) of storage after the blood sample is separated from the subject, for example, when the storage temperature is a refrigerated temperature such as 0 to 10°C (for example, 4°C). may indicate the reduction rate (Y1) of the reduced albumin ratio calculated by the following formula (I). In addition, for example, if the storage temperature is a freezing temperature such as -35°C to -15°C (for example, -25°C), the following will be applied depending 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 formula (II) may be shown. Furthermore, if the storage temperature changes during storage of the blood sample, the reduced albumin ratio can be calculated as appropriate based on the number of storage days at each temperature. For example, a blood sample stored at a refrigerated temperature of 0 to 10°C (for example, 4°C) for X1 days to obtain a reduction rate of Y1 reduced albumin ratio is -35°C to -15°C (for example, -25°C). The number of days (referred to as X2') required to obtain the rate of decrease in the reduced albumin ratio of Y1 at a freezing temperature such as ℃) is equivalent to the number of days stored in the blood sample. Thus, for example, a blood sample may be stored for X1 days at a refrigerated temperature such as 0 to 10°C (e.g., 4°C) and then stored at a freezing temperature of -35°C to -15°C (e.g., -25°C) for X2. 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 rate of decrease Y in the reduced albumin ratio of the blood sample in this case can be calculated by substituting the number of storage days (X2'+X2) for X2 in equation (II). "Reduction rate of reduced albumin ratio" means the ratio of the reduction value of reduced albumin ratio due to storage to the value of reduced albumin ratio at the time when the blood sample is separated from the subject. For other storage temperatures as well, the reduction rate (Y) of the reduced albumin ratio can be calculated by creating a relational expression between the number of storage days (X) and the reduction rate (Y). Further, the reduced albumin ratio may show a 28% decrease rate, for example, when the storage temperature is above -70°C (eg, 0 to 10°C) and the storage period is 19 days or more. Further, the reduced albumin ratio may show a 28% decrease rate, for example, when the storage temperature is above -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 0% decrease rate regardless of the number of days of storage (that is, no correction may be necessary) when the storage temperature is −70° C. or lower, for example. Therefore, by correcting the measured value of the reduced albumin ratio by the reduction rate, the corrected value of the reduced albumin ratio (i.e., the reduced albumin ratio at the time the blood sample is separated from the subject) can be used in the prediction process. Albumin ratio) can be calculated. In other words, the corrected value of the reduced albumin ratio that can be used in the prediction process (i.e., the reduced albumin ratio at the time the blood sample is separated from the subject) is based on the actual value of the reduced albumin ratio and the reduced albumin ratio. It can be calculated using the following formula (III) based on the ratio reduction rate (Y). 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 (e.g., number of storage days and storage temperature) is unknown, the blood sample should be stored at a storage temperature above -70°C (e.g., 0 to 10°C) until the reduced albumin ratio stops decreasing. The sample can be further stored and correction can be carried out by setting the reduction rate at 28% at the time when the reduced albumin ratio stops decreasing. In addition, for blood samples whose storage history (e.g., number of storage days and storage temperature) is unknown, it is important to note that even if the blood sample is further stored at a storage temperature higher than -70°C (e.g., 0 to 10°C), reduced albumin will not be present. If no decrease in the ratio is observed, it is determined that the reduction in the reduced albumin ratio has been completed, and correction can be carried out with the reduction rate set at 28%. Specifically, for example, at a storage temperature above -70°C (for example, 0 to 10°C) for 1 or more days, 2 or more days, 3 or more days, 4 or more days, 5 or more days, 6 or more days, or 7 days. If a decrease in the reduced albumin ratio is not observed even after storing the blood sample as described above, it may be determined that the reduction in the reduced albumin ratio has been 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 = Actual value * 100/(100-Y)...(III)

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

The "risk of malnutrition in the subject" includes the presence or absence and degree of the possibility of malnutrition in the subject, and the degree of malnutrition.

"The subject is at risk of malnutrition" means, for example, that the subject may currently be undernourished and/or that the subject may be at risk of malnutrition in the future. It can mean "There is no risk of malnutrition in the subject" means, for example, that there is no possibility that the subject is currently suffering from malnutrition and/or that there is no possibility that the subject will suffer from malnutrition in the future. It can mean "The subject is at high risk of malnutrition" means, for example, that there is a high possibility that the subject is currently suffering from malnutrition, that there is a high possibility that the subject will suffer from malnutrition in the future, and/or Alternatively, it may mean that the severity of malnutrition is high when the subject suffers from malnutrition. "The risk of malnutrition in the subject is low" means, for example, that the probability that the subject is currently suffering from undernutrition is low, that the subject is unlikely to suffer from malnutrition in the future, and/ Alternatively, it may mean that the severity of malnutrition is small when the subject suffers from malnutrition. ``Subjects who will suffer from malnutrition in the future'' include cases where a test subject who is not currently pregnant will suffer from malnutrition if she becomes pregnant in the future, or if a test subject who is currently pregnant continues to become pregnant. This can lead to malnutrition.

The "risk of giving birth to a low birth weight child in a subject" includes the presence or absence and degree of the possibility that the child of the test subject will be born with a low birth weight, and the degree of low birth weight.

"The subject is at risk of giving birth to a low birth weight baby" may mean, for example, that there is a possibility that the subject's child will be born with a low birth weight. "There is no risk of giving birth to a low birth weight child in the subject" may mean, for example, that there is no possibility that the child of the test subject will be born with a low birth weight. "The test subject has a high risk of giving birth to a low birth weight baby" means, for example, that there is a high possibility that the test subject's child will be born with a low birth weight, and/or that the test subject's child is likely to be born with a low birth weight. It may mean that the severity of underweight is greater. "The subject has a low risk of having a low birth weight" means, for example, that there is a low possibility that the subject's child will be born with a low birth weight, and/or that the subject's child will be born with a low birth weight. It may mean that the severity of underweight is less. The child of the test subject includes a child that the test subject is currently pregnant with and a child that the test subject will become pregnant with in the future.

"Currently" may mean the time the blood sample was isolated from the subject.

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

In the method of the present invention, for example, the risk of giving birth to a low birth weight baby that does not correspond to IUGR may be determined.

The determination step can be performed using, for example, the level of the 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 data reflecting the redox state of albumin with a threshold value. That is, "the value of data reflecting the redox state of albumin is high" may mean, for example, that the value of data reflecting the redox state of albumin is high compared to a 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 greater than or equal to the threshold value, or that the value of the data reflecting the redox state of albumin is higher than the threshold value. It may mean that the value of data reflecting the redox state of albumin is above a threshold value, or that the value of data reflecting the redox state of albumin is statistically significantly higher than the threshold value. Specifically, "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 1.01 times or more than 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 can also mean that. Furthermore, "the value of data reflecting the redox state of albumin is low" may mean, for example, that the value of data reflecting the redox state of albumin is low compared to a 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, or that the value of the data reflecting the redox state of albumin is low compared to the threshold. It may mean that the value of the data reflecting the redox state of albumin is less than the threshold value, or that the value of the data reflecting the redox state of albumin is statistically significantly lower than the threshold value. Specifically, "the value of the data reflecting the redox state of albumin is low compared to the threshold value" 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 can also mean that.

The value of data reflecting the redox state of albumin may be classified into a dangerous range based on a threshold value, for example. The value of data reflecting the redox state of albumin may be classified into a non-hazardous range based on a threshold value, for example. Specifically, the value of data reflecting the redox state of albumin may be classified into a dangerous range and a non-dangerous range, for example, based on a threshold value. The "risk range" refers to a range in which there is a high possibility that there is a risk of malnutrition and/or a risk of giving birth to a low birth weight baby in the subject regarding the value of data reflecting the redox state of albumin. The "non-dangerous range" refers to a range in which there is a high possibility that there is no risk of malnutrition in the subject and/or risk of giving birth to a low birth weight child, regarding the value of data reflecting the redox state of albumin. That is, if the value of the data reflecting the redox state of albumin is within the dangerous range, it may be determined that there is a high possibility that the subject has a risk of malnutrition and/or a risk of giving birth to a low birth weight baby. On the other hand, if the value of the data reflecting the redox state of albumin is within the non-dangerous range, it may be determined that there is a high possibility that there is no risk of malnutrition and/or low birth weight baby birth in the subject.

For example, if the value of the data reflecting the redox state of albumin converted to the ratio selected from the ratios (A) above is low, there is a risk of malnutrition in the subject and/or a risk of giving birth to a low birth weight baby, or It can be judged as high. For example, if the value of data reflecting the redox status of albumin converted to the ratio selected from the ratios (A) above is lower than the threshold value, the risk of undernutrition in the subject and/or the birth of a low birth weight baby is determined. It may be determined that there is a risk or that the risk is high. In this case, a range that is considered low compared to the threshold may be a dangerous range. Specifically, for example, the value of data reflecting the redox state of albumin converted to the reduced albumin ratio is 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 It may be determined that there is a risk of malnutrition and/or a low birth weight baby, or that the risk is high. In particular, if the value of data reflecting the redox state of albumin converted to reduced albumin ratio is below 85%, below 82%, below 78%, or below 75%, the risk of malnutrition in the subject and/or may be determined to have a high or high risk of giving birth to a low birth weight baby. Furthermore, the lower the value of the data reflecting the redox state of albumin converted into the ratio selected from the ratios (A) above, the higher the risk of undernutrition and/or low birth weight baby in the subject. It's okay.

For example, if the value of the data reflecting the redox status of albumin converted to the ratio selected from the ratios (A) above is high, there is no risk of malnutrition and/or low birth weight baby birth in the subject, or It can be judged as low. For example, if the value of the data reflecting the redox state of albumin converted to the ratio selected from the ratios (A) above is higher than the threshold value, the risk of undernutrition in the subject and/or the birth of a low birth weight baby is determined. It may be determined that there is no or low risk. In this case, a range that is considered high compared to the threshold may be a non-hazardous range. In addition, the higher the value of the data reflecting the redox state of albumin converted into the ratio selected from the ratios (A) above, the lower the risk of malnutrition and/or the risk of giving birth to a low birth weight baby in the subject. It's okay.

For example, if the value of the data reflecting the redox state of albumin converted to the ratio selected from the ratios (B) above is high, there is a risk of malnutrition in the subject and/or a risk of giving birth to a low birth weight baby, or It can be judged as high. For example, if the value of data reflecting the redox state of albumin converted to the ratio selected from the ratio (B) above is higher than the threshold value, the risk of malnutrition in the subject and/or the risk of giving birth to a low birth weight baby. It may be determined that there is or is high. In this case, a range that is considered high compared to the threshold may be a dangerous range. Furthermore, the higher the value of the data reflecting the redox state of albumin converted into the ratio selected from the ratios (B) above, the higher the risk of malnutrition and/or low birth weight baby birth in the subject. It's okay.

For example, if the value of the data reflecting the redox state of albumin converted to the ratio selected from the ratios (B) above is low, there is no risk of malnutrition and/or low birth weight baby birth in the subject, or It can be judged as low. For example, if the value of data reflecting the redox state of albumin converted to the ratio selected from the ratio (B) above is lower than the threshold value, the risk of malnutrition in the subject and/or the risk of giving birth to a low birth weight baby. It may be determined that there is no or low level. In this case, a range that is considered low compared to the threshold may be a non-hazardous range. Furthermore, the lower the value of the data reflecting the redox status of albumin converted into the ratio selected from the ratios (B) above, the lower the risk of malnutrition and/or the risk of giving birth to a low birth weight baby in the subject. It's okay.

In addition, "the ratio of a certain component amount satisfies a certain standard (for example, low or high, low or high compared to a threshold value, is in a certain range)" or "albumin converted to the ratio of a certain component amount" ``The value of the data that reflects the redox state of albumin satisfies a certain criterion (e.g., low or high, low or high compared to a threshold value, is in a certain range)'' means that the value of the data reflects the redox state of albumin. It means that the value of the data is within a range where the ratio of the amount of the certain component is considered to satisfy the certain criterion (for example, low or high, low or high compared to a threshold, within a certain range). However, it is not required that the ratio of the amount of a certain component is actually used in the determination.

That is, for example, ``the reduced albumin ratio satisfies a certain criterion (e.g., low or high, low or high compared to a threshold value, is in a certain range)'' or ``the oxidation of albumin in terms of the reduced albumin ratio "The value of the data reflecting the redox state of albumin satisfies a certain criterion (e.g., low or high, low or high compared to a threshold value, within a certain range)" means that the value of the data reflecting the redox state of albumin The value means that the reduced albumin ratio is in a range that is considered to meet the certain criteria (e.g., low or high, low or high compared to a threshold, in a certain range), and that the reduced albumin ratio is actually reduced. There is no requirement that type albumin ratios be used in the determination.

In addition, "a certain index (for example, a ratio of a certain component amount, a value of data reflecting the redox state of albumin converted to a ratio of a certain amount of a component, or a value of data reflecting the redox state of albumin)" There is or is not a risk of undernutrition and/or low birth weight in a subject if the criteria are met (e.g., low or high, low or high compared to a threshold, within a certain range). "Determined to be high or low" means that it is determined that there is, no, high, or low risk of undernutrition and/or low birth weight infants in the subject at least to the extent that the relevant criteria are met. does not require that the risk of malnutrition and/or the risk of giving birth to a low birth weight baby be determined in a subject to the extent that the criteria are not met. However, in one aspect, "a certain index (e.g., a ratio of a certain component amount, a value of data reflecting the redox state of albumin converted to a ratio of a certain component amount, or a value reflecting the redox state of albumin The risk of undernutrition and/or low birth weight in a subject if the value of the data that If the risk of malnutrition and/or low birth weight of a child is determined to be absent, present, low, or high, the risk of undernutrition and/or low birth weight in the subject is determined to be absent, present, low, or high, respectively, to the extent that the criteria are not met. You may judge.

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

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

Control subjects include positive controls and negative controls. A "positive control" may refer to a subject who can be determined to be at risk of malnutrition and/or to have a low birth weight baby. A "negative control" may refer to a subject who can be determined to have no or low risk of malnutrition and/or low birth weight. Positive controls include individuals with a history of malnutrition before the blood sample was isolated, individuals with malnutrition at the time the blood sample was isolated, and individuals with a history of malnutrition after the blood sample was isolated. An individual who has been malnourished, an individual who has given birth to a low birth weight baby before the blood sample is isolated, an individual who has given birth to a low birth weight baby after the blood sample is isolated, or a combination thereof. can be mentioned. Negative controls include individuals with no history of malnutrition before the blood sample was isolated, individuals with no history of malnutrition at the time the blood sample was isolated, and individuals after the blood sample was isolated. The nature of individuals who did not suffer from undernutrition, individuals who had not given birth to a low birth weight infant before the blood sample was isolated, individuals who had not given birth to a low birth weight infant after the blood sample was isolated, and the combination thereof. An example is an individual having the following. The threshold value may be determined based solely on the value of the data reflecting the albumin redox state measured for the positive control and based only on the value of the data reflecting the albumin redox state measured for the negative control. The determination may be based on the value of the data reflecting the redox state of albumin measured for both the positive and negative controls. The threshold value may typically be determined based on the value of data reflecting the redox status of albumin measured for both positive and negative controls. The number of positive controls and negative controls is not particularly limited as long as a threshold value that allows determination of the risk of undernutrition and/or low birth weight baby with desired accuracy is obtained. The number of positive controls and negative controls may be one, two or more. The number of positive controls and negative controls may usually be two or more. The number of positive controls and negative controls may be, for example, 5 or more, 10 or more, 20 or more, or 50 or more. The number of positive controls and negative controls may be, for example, 10,000 or less, 1,000 or less, or 100 or less, respectively.

When determining the threshold based only on the value of data reflecting the albumin redox state measured for the positive control, for example, the value of the data reflecting the albumin redox state measured in multiple positive controls A value selected from a range from the upper limit to the lower limit, for example, an average value, may be set as the threshold value. Further, for example, in the distribution of values of data reflecting the redox state of albumin measured in a plurality of positive controls, a threshold value may be determined such that a predetermined proportion of the positive controls is included in the dangerous 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 value based only on the value of data reflecting the albumin redox state measured for the negative control, for example, the value of the data reflecting the albumin redox state measured in multiple negative controls A value selected from a range from the upper limit to the lower limit, for example, an average value, may be set as the threshold value. Furthermore, for example, in the distribution of values of data reflecting the redox state of albumin measured in multiple negative control individuals, a threshold value may be determined such that a predetermined proportion of negative controls 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%.

If the threshold is determined 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, e.g. The threshold value may be determined such that a predetermined percentage of the positive control is included in the dangerous range and a predetermined percentage of the negative control is included in the non-dangerous range. It is preferable that the proportion of positive controls falling within the dangerous range and the proportion of negative controls falling within the non-hazardous range are both higher. These percentages may be, for example, 70% or more, 80% or more, 90% or more, 95% or more, 97% or more, or 100%, respectively. If it is difficult to increase both of these ratios, for example, a threshold value can be set so that one of the ratios becomes higher preferentially, depending on various conditions such as the purpose of use of the determination result by the method of the present invention. It's okay. For example, if the aim is to implement risk reduction measures as thoroughly as possible in subjects with or at high risk of malnutrition and/or low birth weight, positive controls should be used to reduce the false negative rate. The threshold value may be set so that the proportion of those included in the dangerous range becomes higher preferentially.

The determination of the threshold value may be performed using software, for example. For example, statistical analysis software may be used to determine a threshold value that can statistically most appropriately discriminate between a negative control and a positive control. Such software includes statistical analysis software such as "R".

The control subject also includes the target subject itself. That is, for example, the risk of malnutrition and/or the risk of giving birth to a low birth weight baby in a subject may be determined using changes in the redox state of albumin in the subject's blood as an index. "The value of data reflecting the redox state of albumin is high" may include a case where the value of data reflecting the redox state of albumin increases. Specifically, "the value of data reflecting the redox state of albumin has increased" may mean that the value of data reflecting the redox state of albumin is higher compared to past values. . Furthermore, "the value of data reflecting the redox state of albumin is low" may include a case where the value of data reflecting the redox state of albumin is decreased. Specifically, "the value of data reflecting the redox state of albumin has decreased" may mean that the value of data reflecting the redox state of albumin is low compared to past values. . That is, the threshold value may also be a past value.

For example, if the value of the data reflecting the redox state of albumin converted to the ratio selected from the ratio (A) above decreases, there is a risk of malnutrition in the subject and/or a risk of giving birth to a low birth weight baby. Or it may be determined to be high. For example, if the value of data reflecting the redox state of albumin converted into the ratio selected from the ratios (A) above is low compared to past values, the risk of undernutrition and/or low body weight in the subject It may be determined that there is a risk of giving birth to a child or that the risk is high. In addition, the greater the degree of decrease in the value of the data reflecting the redox state of albumin converted into the ratio selected from the ratio (A) above, the greater the risk of undernutrition in the subject and/or the risk of giving birth to a low birth weight baby. 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 ratio (B) increases, there is a risk of malnutrition in the subject and/or a risk of giving birth to a low birth weight baby. Or it may be determined to be high. For example, if the value of data reflecting the redox state of albumin converted into the ratio selected from the ratio (B) above is high compared to past values, the risk of undernutrition and/or low body weight in the subject It may be determined that there is a risk of giving birth to a child or that the risk is high. Furthermore, the greater the degree of increase in the value of the data reflecting the redox state of albumin converted into the ratio selected from the ratio (B) above, the greater the risk of undernutrition and/or the risk of giving birth to a low birth weight baby in the subject. It may be determined that it is high.

By "historical value" is meant a value of data that reflects the redox state of albumin in a blood sample previously isolated (ie, at some point in the past) from a target subject. A certain point in the past can be set as appropriate depending on various conditions such as the separation time of the blood sample used in the measurement process. The measurement interval of data reflecting the redox state of albumin (i.e., the interval between the separation of the blood sample to measure the past value and the separation of the blood sample to measure the current value) 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, up to 5 years, up to 4 years, 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 any combination thereof that is not contradictory. Good too. A certain point in the past includes a period before pregnancy and a period during pregnancy. Periods during pregnancy that are taken as a certain point in the past include, for example, after the start of pregnancy, after 4 weeks of gestation, after 8 weeks of gestation, after 12 weeks of gestation, after 16 weeks of gestation, after 20 weeks of gestation , or after 24 weeks of gestation, up to 28 weeks of gestation, up to 24 weeks of gestation, up to 20 weeks of gestation, up to 16 weeks of gestation, up to 12 weeks of gestation, or up to 8 weeks of gestation It may be a period up to or a combination thereof. A period during pregnancy taken as a point in time in the past includes, in particular, the period from the beginning of pregnancy to the 16th week of gestation. A point in time in the past includes, inter alia, the period from before conception to 16 weeks of gestation. Specifically, for example, data values (past values) reflecting the redox state of albumin in blood samples separated from subjects during the period from before pregnancy to 16 weeks of gestation and from 24 weeks to 30 weeks of gestation. can be compared with the value of data reflecting the redox state of albumin in blood samples separated from the subject during the period (current value). A 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 percentage points or more, 4 percentage points or more, 5 percentage points or more, 6 percentage points or more, 7 percentage points or more, 8 percentage points or more, 9 percentage points or more compared to past values. , or is lower by 10 percentage points or more, it may be determined that the subject has a risk of malnutrition and/or a low birth weight baby risk or is high.

When a change in the redox state of albumin in the blood of a subject is used as an index, an increase or decrease in the risk of malnutrition and/or the risk of giving birth to a low birth weight baby in the subject may be determined. "There is or is a high risk of undernutrition and/or birth of a low birth weight baby" may include cases where the risk of undernutrition and/or the risk of birth of a low birth weight baby increases. "The risk of undernutrition and/or the risk of giving birth to a low birth weight has increased" specifically means that the risk of undernutrition and/or the risk of giving birth to a low birth weight is higher than at a certain point in the past. It's fine. Furthermore, "no or low risk of undernutrition and/or low birth weight baby" may include cases where the risk of undernutrition and/or low birth weight baby birth risk is reduced. “The risk of undernutrition and/or the risk of giving birth to a low birth weight has decreased” specifically means that the risk of undernutrition and/or the risk of giving birth to a low birth weight child is lower compared to a certain point in the past. It's fine.

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

The determination result obtained by the method of the present invention determines whether to implement a treatment for reducing the risk of malnutrition and/or the risk of giving birth to a low birth weight baby (hereinafter also referred to as "risk reduction treatment") for the subject. It can be used as an indicator for In other words, by implementing the method of the present invention, an index for determining whether to perform risk reduction treatment on a subject can be obtained. That is, for example, when it is determined by the method of the present invention that there is a risk of malnutrition and/or a low birth weight baby in a subject, or that the risk of giving birth to a low birth weight baby is high, it is decided to implement risk reduction measures for the subject. It's fine. For pre-pregnant subjects, risk reduction, e.g. in preparation for future pregnancies (i.e. to reduce the risk of malnutrition and/or low birth weight in future pregnancies) Treatment may be performed. For pregnant subjects, risk reduction treatments may be implemented, for example, to reduce the risk of malnutrition and/or low birth weight in the current pregnancy. Furthermore, for example, if it is determined by the method of the present invention that there is no or low risk of malnutrition and/or low birth weight birth in the subject, it is determined not to implement risk reduction measures for the subject. You may do so. Risk reduction measures may be medical or non-medical. Risk reduction treatments include nutritional interventions. Nutritional intervention can be carried out, for example, using the compositions of the 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 below can be applied mutatis mutandis.

The methods of the invention may be performed before performing a risk reduction action, during the performance of a risk reduction action, or after performance of a risk reduction action. The methods of the invention may in particular be carried out prior to the implementation of risk reduction measures. By carrying out the method of the invention before performing a risk reduction procedure, for example, an indicator is obtained for deciding whether to initiate a risk reduction procedure. Further, by implementing the method of the present invention during implementation of a risk reduction treatment, for example, an index for determining whether to continue the risk reduction treatment can be obtained. Further, by implementing the method of the present invention after implementing the risk reduction treatment, for example, an index for determining whether to perform the risk reduction treatment again can be obtained. That is, for example, when it is determined by the method of the present invention that there is a risk of malnutrition and/or a low birth weight baby in a subject, or that the risk of low birth weight is high, it is determined to start, continue, or reimplement risk reduction treatment. It's fine. For example, if it is determined by the method of the present invention that there is no or low risk of malnutrition and/or low birth weight birth in the subject, it may be determined not to start, continue, or re-implement risk reduction measures. You may do so.

<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. This kit is also referred to as the "kit of the present invention."

The kit of the present invention includes a kit for determining the risk of malnutrition and/or the risk of giving birth to a low birth weight baby in a subject, and a kit for determining the risk of malnutrition and/or the risk of giving birth to a low birth weight baby in a patient. 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 isolated from a subject (for example, to calculate data reflecting the redox state of albumin). may be configured such that the data used can be measured). That is, the kit of the present invention is specifically used, for example, for measuring data reflecting the redox state of albumin in a blood sample isolated from a subject (e.g. The kit may include components (for measuring data used in calculating data). Data used to calculate data reflecting the redox state of albumin include data reflecting the amount of oxidized albumin, the amount of reduced albumin, and the total amount of albumin. Such components include reagents and equipment. Specific examples of such components include sample preparation reagents and detection reagents. The sample preparation reagent includes 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. Specifically, the sample preparation reagent includes 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. Specifically, the detection reagent includes a liquid used as a mobile phase in HPLC. Such constituent elements can be appropriately set depending on various conditions such as the means for measuring data reflecting the redox state of albumin.

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

That is, in the present invention, a computer may execute the steps included in the method of the present invention. A computer may perform some or all of the steps involved in the method of the invention. A computer may, for example, carry out the measuring step and/or the determining step.

Specifically, for example, medical personnel 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 components such as oxidized albumin amount, reduced albumin amount, total albumin amount, etc.), and determines the amount of albumin. data values reflecting the redox state) can be used to obtain measurement results. The computer can further determine the risk of malnutrition and/or the risk of giving birth to a low birth weight baby in the subject based on the measurement results. The computer can further output the determination results obtained in this way, so that medical personnel can obtain the determination results.

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

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

The fact that the composition of the present invention has a function of increasing the reduced albumin ratio in the blood of a subject can be confirmed by, for example, administering the composition of the present invention to a subject, measuring the reduced albumin ratio in the subject's blood, and determining the same ratio. This can be confirmed by checking whether the amount has increased compared to 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 malnutrition and/or the risk of giving birth to a low birth weight baby can be reduced in the subject. That is, the composition of the present invention may be a composition for reducing the risk of malnutrition and/or the risk of giving birth to a low birth weight baby.

Regarding the subject to whom the composition of the present invention is administered, the description of the subject in the method of the present invention can be applied mutatis mutandis. The subject to whom the composition of the present invention is administered may or may not be a subject who is at risk of malnutrition and/or low birth weight baby, or who can be determined to be at high risk. In particular, the subject to whom the composition of the present invention is administered may be a subject who can be determined to have or be at high risk of malnutrition and/or low birth weight.

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

The composition of the present invention (for example, a food/beverage composition or a pharmaceutical composition) may specifically be a nutritional composition. "Nutritional composition" may refer to a composition effective for nutritional intake. The composition of the present invention may be nutritionally balanced, for example. Specifically, the composition of the present invention may contain, for example, a well-balanced combination of nutrients necessary during pregnancy and/or lactation. The compositions of the invention may also be fortified with nutrients, for example. The compositions of the invention may be specifically fortified with nutrients necessary during pregnancy and/or lactation, for example. Nutritional enrichment may also include caloric enrichment. Nutrients include protein, sugar, and fat. For example, the nutritional status of the subject may be improved by adjusting the nutritional balance or fortifying the nutrition, thereby reducing the risk of malnutrition and/or the risk of giving birth to a low birth weight baby in the subject.

The food/beverage composition may be, for example, the food/drink itself, or may be a material used in the production of the food/beverage. Examples of the raw materials include seasonings, food additives, and other food and drink materials. Food and beverage compositions include, specifically, flour products, instant foods, processed agricultural products, processed marine products, processed livestock products, dairy products (fermented milk, cheese, infant formula, etc.), oils and fats, and basic seasonings. , complex seasonings, frozen foods, confectionery, beverages, and other commercially available food and beverages. Food and drink compositions include, specifically, health foods, functional foods, enteral nutrition foods, special purpose foods, health claims foods (foods for specified health uses, foods with nutritional function claims, foods with functional claims, etc.), and nutritional supplements. Also included are foods and quasi-drugs. The food/drink composition may be a supplement, for example, and specifically may be a tablet-shaped supplement. Specifically, the food and drink compositions include formula milk containing a well-balanced combination of nutrients necessary for pregnancy and/or lactation, and formula formula milk enriched with nutrients such as protein, sugar, fat, and calories. Can be mentioned. In the component-adjusted milk, the nutrition may be fortified to, for example, 1.25 times or more of the normal amount.

The food/drink composition can be provided and sold as a food/beverage product labeled with uses (including health uses) such as reducing the risk of malnutrition and/or the risk of giving birth to a low birth weight baby. Furthermore, the food and drink compositions can be provided and sold with indications such as "pregnant women" and "lactating women" for consumption.

"Display" includes all acts to inform consumers of the above-mentioned use, and if the expression is such that it may recall or infer the above-mentioned use, the purpose of the display, the contents of the display, and the display Regardless of the object or medium, all fall under the category of "display." It is particularly preferable that the display be made using expressions that allow the consumer to directly recognize the use.

Specifically, the display includes acts of transferring, handing over, displaying for transfer or delivery, importing products related to food and drink compositions or products with the above-mentioned usage written on their packaging, advertisements related to products, and prices. Examples of such acts include displaying or distributing the above-mentioned use on a table or transaction document, or stating the above-mentioned use on information containing these and providing it by electromagnetic (Internet, etc.) method. Examples of the display include, in particular, displays on packaging, containers, catalogs, pamphlets, promotional materials at sales sites such as POP, and other documents.

In addition, the display is preferably a display approved by the government (for example, a display that is approved based on various systems established by the government and performed in a manner based on such approval). In addition, the labeling includes health foods, functional foods, enteral nutrition foods, special purpose foods, foods with health claims (e.g., foods for specified health uses, foods with nutritional function claims, foods with functional claims), nutritional supplements, and pharmaceutical products. An example of this is displaying it as a foreign product. Displays approved by the government include those approved by the Consumer Affairs Agency. Labeling approved by the Consumer Affairs Agency includes food for specified health uses and labeling approved under similar systems. Specifically, the labeling approved by the Consumer Affairs Agency includes labeling as a food for specified health uses, labeling as a food for specified health uses with conditions, labeling that it affects the structure or function of the body, and reducing disease risk. This includes labeling, functional labeling based on scientific evidence, etc. More specifically, Cabinet Office Ordinance on Permission of Special Purpose Labeling as stipulated in the Health Promotion Act (August 31, 2009) This includes labeling as food for specified health uses (especially labeling for health uses) as stipulated in Japan Cabinet Office Ordinance No. 57) and similar labeling.

<5> Risk reduction method of the present invention The risk reduction method of the present invention is a method for reducing the risk of malnutrition and/or the risk of giving birth to a low birth weight baby in a subject, which includes the step of administering the composition of the present invention to the subject. . This process is also referred to as the "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 malnutrition and/or the risk of giving birth to a low birth weight baby can be reduced in the subject.

Note that "administering the composition of the present invention to a subject" may be synonymous with "making a subject ingest the composition of the present invention". The intake may be voluntary (free intake) or forced (forced intake). Specifically, the administration step may be a step of supplying the composition of the present invention to a subject and allowing the subject to freely ingest the composition of the present invention. Administration may be oral or parenteral. Examples of parenteral administration include tube administration and intrarectal administration.

The mode of administration of the composition of the present invention (e.g., administration subject, administration timing, administration period, administration frequency, administration amount, and other conditions related to administration) may include the effect of reducing the risk of malnutrition and/or the risk of giving birth to a low birth weight baby, etc. There is no particular restriction as long as the desired effect can be obtained. The mode of administration of the composition of the present invention can be appropriately determined depending on various conditions such as the type of the composition of the present invention, the type, age, and health condition of the subject to be administered.

Regarding the subject to whom the composition of the present invention is administered, the description of the subject in the method of the present invention can be applied mutatis mutandis. The subject to whom the composition of the present invention is administered may or may not be a subject who is at risk of malnutrition and/or low birth weight baby, or who can be determined to be at high risk. In particular, the subject to whom the composition of the present invention is administered may be a subject who can be determined to have or be at high risk of malnutrition and/or low birth weight.

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 less than 5 years, less than 4 years, less than 2 years, less than 1 year, less than 40 weeks, less than 36 weeks, less than 32 weeks, less than 28 weeks, less than 24 weeks, less than 20 weeks, or less than 16 weeks. or a non-contradictory combination thereof. The composition of the present invention may be administered, for example, once per day or divided into multiple doses per day. Further, the composition of the present invention may be administered, for example, daily or once every few days. Compositions of the invention may, in particular, be administered daily. The dose of the composition of the invention at each administration may or may not be constant.

The present invention will now be described in more detail with reference to non-limiting examples.

<Example 1> Evaluation of the relationship between maternal albumin redox balance and offspring birth weight in rats Wistar rats on the first day of pregnancy were purchased from Japan SLC. The animals were divided into the following three groups to ensure uniform body weights, fed with AIN-93G, a normal purified sample, and maintained until the day of delivery.
A: Ad libitum 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, which is the early stage of pregnancy, the 16th day of pregnancy, which is the middle stage, and the 19th day, which is the second stage of pregnancy, and the blood obtained was centrifuged to obtain serum. The obtained serum was stored at -80°C until analysis. The dams gave birth to pups on the 21st or 22nd day of gestation. The weight of the newborn pups was measured immediately after birth and was taken as the birth weight.

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

2 μL of the stored 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 K.K.)
Column temperature: 37℃
Detection wavelength: excitation wavelength 280 nm, fluorescence wavelength 340 nm
Mobile phase: Solution A (0.4 M sodium sulfate, 50 mM sodium acetate (pH4.85))
Solution B (0.4 M sodium sulfate, 50 mM sodium acetate (pH4.85), 10% ethanol)
Mobile phase conditions: The mixing ratio of liquid A/liquid B was changed from 100/0 to 20/80 in 80 minutes.
Flow rate: 0.5 mL/min Sample injection volume: 15 μL
Standard sample: Prepared by mixing rat serum albumin (manufactured by Sigma-Aldrich Co.) and glutathione (manufactured by Fuji Film Wako Pure Chemical Industries, Ltd.) at a weight ratio of 1:10. The sample was subjected to HPLC analysis under the above conditions, and the retention times of reduced albumin and oxidized albumin were determined (Figure 1).

For each sample, divide the peaks by drawing a perpendicular line at the position of the minimum value between the peak of reduced albumin and the peak of oxidized albumin in the HPLC chromatogram, and calculate the area of reduced albumin relative to the total peak area of albumin. The ratio of the values was calculated and used as the reduced albumin ratio.

On day 19 of pregnancy, maternal serum albumin levels were significantly lower in the 40% calorie restriction group than in the control group (Figure 2). On the other hand, the maternal reduced albumin ratio was lower in the 20% and 40% calorie restriction groups than in the control group on both the 16th and 19th day of pregnancy (Figure 3). A positive correlation was observed between the mother's reduced albumin ratio on the 19th day of pregnancy and the birth weight of the offspring (Figure 4). A negative correlation was observed between the decrease in the mother's reduced albumin ratio from day 9 to day 19 of pregnancy and the birth weight of the offspring (Figure 5).

<Example 2> Changes in albumin redox balance over time during storage of blood samples Reduced albumin is stable below -70°C, but depending on the storage conditions of the blood sample, natural oxidation of reduced albumin progresses, causing reduction of the blood sample. type albumin ratio decreases. For example, in clinical tests, plasma or serum after blood collection may be temporarily stored in a refrigerator and then frozen at -30 to -20°C. Therefore, we investigated changes in the reduced albumin ratio when plasma was stored refrigerated at 4°C.

Plasma from six adult women in their 20s to 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 to examine changes over time in the plasma 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 K.K.)
Column temperature: 35℃
Detection wavelength: excitation wavelength 280 nm, fluorescence wavelength 340 nm
Mobile phase: Solution A (0.4 M sodium sulfate, 50 mM sodium acetate (pH4.85))
Solution B (0.4 M sodium sulfate, 50 mM sodium acetate (pH4.85), 10% ethanol)
Mobile phase conditions: The mixing ratio of liquid A/B was kept at 100/0 for 0 to 5 minutes, and the mixing ratio of liquid A/B was changed from 100/0 to 40/60 for 5 to 25 minutes. The mixing ratio of liquid A/B was maintained at 40/60 for ~30 minutes.
Flow rate: 1.0 mL/min Sample injection volume: 15 μL

The reduced albumin ratio decreased over time until the 18th day of storage, and became almost constant after the 19th day of storage (Figure 6). That is, the rate of decrease in the reduced albumin ratio remained almost constant after the 19th day of storage. The reduction rate of the reduced albumin ratio after the 19th day of storage was approximately 28% (Table 1). The rate of decrease in reduced albumin ratio was calculated using the following formula:
Decrease rate of reduced albumin ratio = 100-100× (reduced albumin ratio after storage/reduced albumin ratio before storage)

A relationship expressed by the following formula (I) was observed between the number of days of storage at 4°C (X) and the rate of decrease in reduced albumin ratio (Y) (FIG. 7). Therefore, the reduced albumin ratio before storage can be calculated by correcting the measured value of the reduced albumin ratio of a blood sample stored at 4° C. with the reduction rate calculated by formula (I). Note that formula (I) is not limited to the case where the blood sample is stored at 4°C, but can also be applied when the blood sample is stored at surrounding temperature (for example, 0 to 10°C).

Y (%) = 4.9694ln(X) + 13.918 (R ² = 0.9556) ...Formula (I)

Furthermore, since the reduction rate (Y) of the reduced albumin ratio due to natural oxidation is approximately constant at approximately 28%, the reduced albumin ratio of a blood sample that has undergone sufficient natural oxidation is corrected by assuming a reduction rate of 28%. be able to.

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

Plasma from three adult men in their 30s to 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 to examine changes over time in the plasma 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 K.K.)
Column temperature: 35℃
Detection wavelength: excitation wavelength 280 nm, fluorescence wavelength 340 nm
Mobile phase: Solution A (0.4 M sodium sulfate, 50 mM sodium acetate (pH4.85))
Solution B (0.4 M sodium sulfate, 50 mM sodium acetate (pH4.85), 10% ethanol)
Mobile phase conditions: The mixing ratio of liquid A/B was kept at 100/0 for 0 to 5 minutes, and the mixing ratio of liquid A/B was changed from 100/0 to 40/60 for 5 to 25 minutes. The mixing ratio of liquid A/B was maintained at 40/60 for ~30 minutes.
Flow rate: 1.0 mL/min Sample injection volume: 15 μL

The reduced albumin ratio decreased over time until the 56th day of storage, and became almost constant after the 56th day of storage (Figure 8). That is, the rate of decrease in the reduced albumin ratio remained almost constant after the 56th day of storage. The reduction rate of the reduced albumin ratio after the 56th day of storage was approximately 28% (Table 2). The rate of decrease in reduced albumin ratio was calculated using the following formula:
Decrease rate of reduced albumin ratio = 100-100× (reduced albumin ratio after storage/reduced albumin ratio before storage)

A relationship expressed by the following formula (II) was observed between the number of days of storage at -25°C (X) and the rate of decrease in the reduced albumin ratio (Y) (FIG. 9). Therefore, the reduced albumin ratio before storage can be calculated by correcting the measured value of the reduced albumin ratio of a blood sample stored at -25°C with the reduction rate calculated by formula (II). Note that formula (II) is not limited to the case where the blood sample is stored at -25°C, but can also be applied when the blood sample is stored at surrounding temperatures (for example, -15 to -35°C).

Y (%) = 6.1728ln(X) + 2.1133 (R ² = 0.962)...Formula (II)

Furthermore, since the reduction rate (Y) of the reduced albumin ratio due to natural oxidation is approximately constant at approximately 28%, the reduced albumin ratio of a blood sample that has undergone sufficient natural oxidation is corrected by assuming a reduction rate of 28%. be able to.

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

Serum albumin levels in serum were 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 determined that natural oxidation of reduced albumin had progressed sufficiently in the serum used in this example, and the actual value of reduced albumin ratio was corrected by setting the reduction rate to 28%, and the serum was tested. The reduced albumin ratio (hereinafter also referred to as "corrected value of reduced albumin ratio") at the time of separation from the subject was calculated. The serum albumin value was 4.4 ± 0.3 g/dL, the actual 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 adult female plasma before storage obtained in Example 2.

The subjects (i.e., 54 pregnant women) were divided into quartiles based on the birth weight of their babies, and those below 25%tile were classified as the low birth weight group (2617.0 ± 77.4 g; n = 14), and the rest were in the control group (3236.4 ± 45.8 g; n=40). Between-group comparisons were made for subject demographic factors (i.e., age, height, non-pregnant weight, and non-pregnant BMI), serum albumin levels, and reduced albumin ratio. Significant differences between the 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 there is no multicollinearity between the height and the corrected value of reduced albumin ratio, the birth weight should be 25% tile or less using multiple logistic regression analysis (stepwise variable increase/decrease method). We created a model to predict. The corrected values for height and reduced albumin ratio are each significant and independent dependent variables, and the unit odds ratios for each factor are height 0.79 (95% confidence interval 0.65-0.92) and adjusted value for reduced albumin ratio 0.79 (95%). The confidence interval was 0.63-0.94)).

Using this model, we performed an ROC (recover operating characteristics) analysis and found a height of 158 cm and a corrected reduced albumin ratio of 85.4% as the cutoff values for predicting birth weight to be below the 25% tile. It was done.

In this way, it has become clear that the risk of malnutrition and/or the risk of giving birth to a low birth weight baby in a subject can be determined sensitively by using the redox state of albumin in the blood as an index. In particular, in the case of pregnant women, the risk of malnutrition and/or the risk of giving birth to a low birth weight baby can be determined sensitively using known nutritional markers such as serum albumin or plasma albumin levels due to factors such as increased blood volume. On the other hand, if the redox state of albumin in the blood is used as an indicator, the risk of malnutrition in a subject and/or the risk of giving birth to a low birth weight baby can be determined sensitively.

<Example 5>
Multiple pregnancy, experience of premature birth, experience of miscarriage, lack of prenatal care, undernutrition, underweight, obesity, poor weight gain, excessive weight gain, stress, pregnancy at a young age, pregnancy at an advanced age, anemia, smoking, alcohol consumption, diabetes, Examples based on blood collected during prenatal checkups for pregnant women between 24 and 30 weeks of pregnancy who have hypertension, infection, inflammation, placental insufficiency, placental hypoplasia, uterine disorders, or cervical disorders. The reduced albumin ratio is measured using the method described in 2, and the risk of giving birth to a low birth weight baby is diagnosed. For pregnant women whose reduced albumin ratio was 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 formula milk with a well-balanced combination of nutrients necessary for lactation), modified milk with nutritional content such as protein, sugar, fat, and calories (e.g., nutritionally fortified 1.25 times or more), Reduce the risk of low birth weight babies by administering nutritionally-adjusted foods such as adult formula or nutritional supplements.

According to the present invention, it is possible to determine the risk of malnutrition and/or the risk of giving birth to a low birth weight baby in a subject.

Claims (15)

A method for determining the risk of undernutrition and/or low birth weight baby birth in a female subject, the method comprising:
Determining the risk of malnutrition and/or the risk of giving birth to a low birth weight baby in the subject using data reflecting the redox state of albumin in the blood sample separated from the subject as an indicator.
(i) the value of the above data converted into the ratio of the amount of reduced albumin to the total amount of albumin is 85% or less; or (ii) 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; , compared with the values of data reflecting the redox status of albumin in blood samples isolated from said subject during the period from before pregnancy to 16 weeks of gestation, converted to the ratio of the amount of reduced albumin to the amount of total albumin. The risk of undernutrition and/or low birth weight birth is determined to be high if the
At least the risk of giving birth to a low birth weight baby is determined,
However, methods excluding methods for determining the risk of giving birth to a low birth weight baby due to ischemia. 2. The method of claim 1, further comprising the step of measuring said data before said 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. 5. A method according to any one of claims 1 to 4, wherein the blood sample is isolated from the subject between 24 and 30 weeks of gestation. Claims 1 to 5 , wherein the risk of undernutrition and/or the risk of giving birth to a low birth weight baby 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. The method described in any one of the above. Claims 1 to 5 , wherein the risk of malnutrition and/or the risk of giving birth to a low birth weight baby 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. The method described in any one of the above. Claims 1 to 5 , wherein the risk of undernutrition and/or the risk of giving birth to a low birth weight baby 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. The method described in any one of the above. If the value of the data converted into the ratio of the reduced albumin amount to the total albumin amount is lower than the past value by 7 percentage points or more, the risk of malnutrition and/or low birth weight baby is determined to be high. The method according to any one of claims 1 to 5 . If the value of the data converted into the ratio of the reduced albumin amount to the total albumin amount is 10 percentage points or more lower than the past value, it is determined that the risk of malnutrition and/or the risk of giving birth to a low birth weight baby is high. The method according to any one of claims 1 to 5 . The method according to any one of claims 1 to 10 , wherein the data value is a value corrected according to the length of storage period and storage temperature of the blood sample. The method according to any one of claims 1 to 11 , wherein the subject has risk factors for undernutrition and/or low birth weight. The risk factors include multiple pregnancy, experience of premature birth, experience of miscarriage, lack of prenatal care, undernutrition, underweight, obesity, poor weight gain, excessive weight gain, stress, pregnancy at a young age, pregnancy at an older age, anemia, and smoking. 13. The method according to claim 12 , wherein the factor is one or more factors selected from , alcohol consumption, diabetes, hypertension, infection, inflammation, placental insufficiency, placental hypoplasia, uterine disorder, and cervix disorder. . 14. The method according to any one of claims 1 to 13 , wherein the risk of malnutrition and the risk of giving birth to a low birth weight baby are determined. Use of data reflecting the redox status of albumin in a blood sample isolated from a female subject as a marker of malnutrition risk and/or low birth weight risk in a female subject, comprising:
At the very least, its use as a marker of low birth weight risk;
However, the use does not include use as a marker for the risk of giving birth to a low birth weight baby due to ischemia.

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