System for non-invasive evaluation of neonatal in-utero nutritional status and uses thereof

Abstract

The application provides a system for non-invasively evaluating the intrauterine nutrition condition of a newborn and application thereof, and the system is used for analyzing the change of compound components in meconium of the newborn. The application first proposes a novel system and method for non-invasively evaluating the intrauterine nutrition condition of the newborn, and the method can quickly and conveniently evaluate the intrauterine nutrition condition of the newborn in a non-invasive manner.

Description

[0001] This case is a divisional application of the invention patent filed on June 1, 2021, with application number 202110611164.8 and invention title "A non-invasive system for evaluating the intrauterine nutritional status of newborns and its application". Technical Field

[0002] This invention relates to the field of infant and toddler health, and more particularly to a non-invasive system for assessing the intrauterine nutritional status of newborns and its application. Background Technology

[0003] Currently, the World Health Organization (WHO) uses anthropometric Z-score system to assess neonatal growth in utero and evaluate child growth and nutrition. This system includes indicators such as neonatal weight, length, and head circumference, categorized by gestational age and sex. However, methods for assessing neonatal intrauterine nutrient accumulation are limited. Birth weight and length are known to be influenced by various factors, such as race, maternal body type, pre-pregnancy weight, parity, altitude, and others. Weight cannot distinguish between fat deposition and tissue water content. Furthermore, length cannot be measured precisely; the accuracy of length and head measurements is far lower than that of weight measurements and requires extensive training. While fetal nutrition may be significantly deficient in utero, weight, length, and head circumference may remain unaffected. Simultaneously, the CANS method, based on measuring neonatal subcutaneous fat and hair status, has not been widely adopted. Factors influencing hair growth, such as genetics, are numerous; and the formation of fetal subcutaneous tissue, especially fat, begins in late pregnancy, thus only reflecting nutritional status at that stage. Blood biochemical markers offer a "dynamic assessment" of neonatal nutrition, but they suffer from the drawbacks of being instantaneous and invasive. As mentioned above, the lack of simple, accurate, and non-invasive intrauterine neonatal nutrition assessment is one of the global public health challenges. This results in newborns, especially those in low-income countries, not receiving timely and accurate assessment, care, and intervention, which is detrimental to their infant and even adult health. In conclusion, current methods for assessing neonatal nutrition have limitations, and efforts are still needed to find accurate and non-invasive assessment methods. Summary of the Invention

[0004] To address the aforementioned problems, this invention provides a non-invasive system for evaluating the intrauterine nutritional status of newborns, the system being used to analyze changes in the composition of compounds in newborn meconium.

[0005] In one embodiment, the system is used to analyze changes in at least 10 compound components in the meconium of newborns.

[0006] In one embodiment, the analysis of at least 10 compounds in neonatal meconium is performed using markers selected from the following: arginine, glutamic acid, histidine, hydroxyproline, leucine, leucine-isoleucine, methionine, ornithine, phenylalanine, proline, tryptophan, tyrosine, valine, phosphoserine, betaine, indole-3-aldehyde, indole-3-propionic acid, indoline, piperic acid, pyrrolidine, 1,7-dimethylxanthine, 1-methylguanine, caffeine, cortisone, leucyl-proline, N-acetylglutamic acid, phenylacetyl-L-glutamine, propionyl-L-carnitine, uric acid, taurocholic acid, glycine-deoxycholic acid, butyrylcarnitine, carnitine C12-O, decylcarnitine, carnitine C16-O, hexanoylcarnitine, and valerate.

[0007] In one embodiment, the analysis of at least 10 compounds in neonatal meconium is selected from any one of the following groups of markers:

[0008] Serial Number Number of markers marker group 1 15 Glutamic acid; proline; tryptophan; tyrosine; valine; indole-3-aldehyde; 1,7-dimethylxanthine; cortisone; leucyl-proline; phenylacetyl-L-glutamine; glycine deoxycholic acid (GDCA); butyrylcarnitine; carnitine C16_O; hexanoylcarnitine; valeratecarnitine 2 14 Glutamic acid; Proline; Tryptophan; Tyrosine; Valine; 1,7-Dimethylxanthine; 1-Methylguanine; Cortisone; Leucyl-proline; Phenylacetyl-L-glutamine; Propionyl-L-carnitine; Butyryl-carnitine; Carnitine C16_O; Valoyl-carnitine 3 10 Glutamic acid, tryptophan, tyrosine, valine, 1,7-dimethylxanthine, cortisone, phenylacetyl-L-glutamine, butyrylcarnitine, valeratecarnitine, and hexanoylcarnitine 4 15 Glutamic acid; Leucine / Isoleucine; Proline; Tryptophan; Tyrosine; Valine; Indole-3-propionic acid; 1,7-Dimethylxanthine; 1-Methylguanine; Leucyl-proline; Phenylacetyl-L-glutamine; Glycine-deoxycholic acid (GDCA); Butyrylcarnitine; Decylcarnitine; Vanoylcarnitine 5 15 Glutamic acid; proline; tryptophan; tyrosine; valine; 1,7-dimethylxanthine; 1-methylguanine; cortisone; leucyl-proline; phenylacetyl-L-glutamine; glycine deoxycholic acid (GDCA); butyrylcarnitine; carnitine C16_O; hexanoylcarnitine; valerate carnitine 6 12 Glutamic acid; proline; tryptophan; tyrosine; valine; 1,7-dimethylxanthine; cortisone; leucyl-proline; phenylacetyl-L-glutamine; glycine deoxycholic acid (GDCA); butyrylcarnitine; hexanoylcarnitine 7 12 Glutamic acid; proline; tryptophan; tyrosine; valine; 1,7-dimethylxanthine; cortisone; leucyl-proline; phenylacetyl-L-glutamine; glycine deoxycholic acid (GDCA); butyrylcarnitine; carnitine C12_0 8 13 Glutamic acid; Leucine / Isoleucine; Proline; Tryptophan; Tyrosine; Valine; 1,7-Dimethylxanthine; Cortisone; Phenylacetyl-L-glutamine; Glycine-deoxycholic acid (GDCA); Butyrylcarnitine; Hexanoylcarnitine; Vanoylcarnitine 9 15 Glutamic acid; Histidine; Proline; Tryptophan; Tyrosine; Valine; 1,7-Dimethylxanthine; 1-Methylguanine; Cortisone; Leucyl-proline; Phenylacetyl-L-glutamine; Glycine-deoxycholic acid (GDCA); Butyrylcarnitine; Carnitine C16_O; Hexanoylcarnitine 10 13 Glutamic acid; Histidine; Proline; Tryptophan; Tyrosine; Valine; 1,7-Dimethylxanthine; Cortisone; Phenylacetyl-L-glutamine; Glycine-deoxycholic acid (GDCA); Butyrylcarnitine; Carnitine C16_O; Hexanoylcarnitine 11 14 Glutamic acid; Tryptophan; Tyrosine; Valine; Piperic acid; 1,7-Dimethylxanthine; Cortisone; Leucyl-proline; Phenylacetyl-L-glutamine; Glycine-deoxycholic acid (GDCA); Butyrylcarnitine; Carnitine C12-O; Hexanoylcarnitine; Vanoylcarnitine 12 14 Glutamic acid; proline; tryptophan; tyrosine; valine; 1,7-dimethylxanthine; 1-methylguanine; cortisone; leucyl-proline; phenylacetyl-L-glutamine; glycine deoxycholic acid (GDCA); butyrylcarnitine; carnitine C16_O; hexanoylcarnitine 13 12 Glutamic acid; Histidine; Tryptophan; Tyrosine; Valine; 1,7-Dimethylxanthine; 1-Methylguanine; Cortisone; Phenylacetyl-L-glutamine; Glycine-deoxycholic acid (GDCA); Butyrylcarnitine; Vanoylcarnitine 14 13 Proline; Tryptophan; Tyrosine; Valine; 1,7-Dimethylxanthine; Cortisone; Leucyl-proline; Phenylacetyl-L-glutamine; Glycine-deoxycholic acid (GDCA); Butyrylcarnitine; Carnitine C12_O; Carnitine C16_O; Hexanoylcarnitine 15 10 Glutamic acid; Tryptophan; Tyrosine; Valine; 1,7-Dimethylxanthine; Cortisone; Phenylacetyl-L-glutamine; Butyrylcarnitine; Hexanoylcarnitine; Valoylcarnitine 16 11 Glutamic acid; Proline; Tryptophan; Tyrosine; Valine; 1,7-Dimethylxanthine; Cortisone; Leucyl-proline; Phenylacetyl-L-glutamine; Butyrylcarnitine; Carnitine C16_0 17 15 Glutamic acid; proline; tryptophan; tyrosine; valine; piperic acid; 1,7-dimethylxanthine; 1-methylguanine; cortisone; leucyl-proline; phenylacetyl-L-glutamine; glycine deoxycholic acid (GDCA); butyrylcarnitine; decylcarnitine; carnitine C16_0 18 11 Glutamic acid; Tryptophan; Valine; Piperic acid; 1,7-Dimethylxanthine; Cortisone; Leucyl-proline; Phenylacetyl-L-glutamine; Glycine-deoxycholic acid (GDCA); Butyrylcarnitine; Carnitine C16_0

[0009] In one embodiment, at least 10 compounds in the meconium of a newborn are selected from the following group of markers:

[0010] Serial Number Number of markers marker group 1 14 Glutamic acid; Proline; Tryptophan; Tyrosine; Valine; 1,7-Dimethylxanthine; 1-Methylguanine; Cortisone; Leucyl-proline; Phenylacetyl-L-glutamine; Propionyl-L-carnitine; Butyryl-carnitine; Carnitine C16_O; Valoyl-carnitine 2 10 Glutamic acid; Tryptophan; Tyrosine; Valine; 1,7-Dimethylxanthine; Cortisone; Phenylacetyl-L-glutamine; Butyrylcarnitine; Hexanoylcarnitine; Valoylcarnitine

[0011] In one embodiment, the above system is provided for use in non-invasive evaluation of intrauterine nutritional status in newborns.

[0012] In one embodiment, the present invention provides a non-invasive method for evaluating the intrauterine nutritional status of newborns, the method evaluating the intrauterine nutritional status of newborns by analyzing changes in the composition of compounds in the meconium of newborns.

[0013] In one embodiment, the method evaluates the intrauterine nutritional status of a newborn by analyzing changes in at least 10 compounds in the newborn's meconium.

[0014] This invention presents for the first time a novel non-invasive system and method for evaluating the intrauterine nutritional status of newborns. This method allows for rapid and convenient evaluation of the newborn's intrauterine nutritional status in a non-invasive manner. This invention truly achieves non-invasive evaluation of newborns, overcoming the potential harm to newborns caused by existing methods for evaluating intrauterine nutritional status. More importantly, compared to current methods for evaluating newborn nutrition, this invention provides an objective and accurate assessment of the newborn's nutritional status, enabling more precise nutritional interventions for infants and young children. Detailed Implementation

[0015] To enable those skilled in the art to better understand the technical solutions in this application, the present invention will be further described below in conjunction with the embodiments. Obviously, the described embodiments are only a part of the embodiments of this application, and not all of them. Based on the embodiments in this application, all other embodiments obtained by those skilled in the art without creative effort should fall within the scope of protection of this application. The present invention will be further described below in conjunction with the embodiments.

[0016] Example 1: Participant Recruitment and Sample Collection

[0017] 1. Participant recruitment and sample collection

[0018] The preliminary selection criteria for infants to be included in the study are as follows: (1) Live-born singleton infants with a gestational age greater than or equal to 38 weeks and an Apgar score greater than 8; (2) Only infants hospitalized for more than 24 hours will be included; (3) Known gestational age (reliable ultrasound measurement of crown-rump length before 14 weeks of gestation or measurement of twin diameter at the start of prenatal care between 14 and 20 weeks of gestation). Each hospital has agreed to routinely use ultrasound to estimate gestational age through strict and standardized operating procedures. To ensure the accuracy of gestational age, in addition to ultrasound estimation, the last menstrual period is used as a reference. An estimated gestational age that differs from the gestational age calculated from the last menstrual period by 7 days or less is considered reliable; (4) No major congenital malformations; (5) No pregnancy-related diseases. Based on neonatal anthropometric parameters and the normal and low Z-scores of CANS (Conventional Nervous System), newborns were divided into a control group (≥38 weeks gestation, weight ≥2500g, Z-score > -1) and a case group (≥38 weeks gestation, weight <2500g, Z-score ≤ -2). There were 140 well-nourished newborns and 132 malnourished newborns. Physicochemical parameters of meconium, including weight, pH, and water content, were measured using analytical instruments. Meconium samples were collected immediately after the first excretion and immediately placed in liquid nitrogen, then stored at -80℃ for metabolomics analysis.

[0019] 2. Train operators

[0020] To ensure the quality of clinical data and samples, we conducted standardized meetings and rigorous training at local hospitals. Experienced physicians from Beijing Obstetrics and Gynecology Hospital provided rigorous clinical training to all staff members in all our clinical hospitals. Furthermore, the physicians provided clinical guidance to staff in all clinical hospitals. In addition, all sample collection and examination procedures were performed by highly experienced and trained personnel. Experts were also regularly organized to provide on-site guidance and supervision.

[0021] 3. Ethical review

[0022] All investigations and clinical procedures were discussed and approved by the Human Research Ethics Committee of the National Health Commission's Institute of Science and Technology. A Chinese informed consent form was drafted and revised based on the opinions of committee members, resulting in the final informed consent form.

[0023] 4. Clinical data of pregnant women

[0024] In the control group, the age of the pregnant women was 20-43 years, with a mean ± SD of 29.1 ± 4.51 years. In the case group, the age of the pregnant women was 19-42 years, with a mean ± SD of 29.5 ± 4.50 years. Factors affecting nutrition were investigated, including region, ethnicity, delivery method, pregnant woman's hair, spouse's hair, gestational hypertension, gestational diabetes, other endocrine disorders, pregnancy reactions, anemia, and umbilical cord attachment. Pregnant woman's hair, gestational hypertension, and spouse's hair were closely related to nutrition (P<0.05), while other investigated factors had no significant effect (P>0.05).

[0025] 5. Clinical data of newborns

[0026] 5.1. Gender and distribution of malnourished and well-nourished newborns.

[0027] The proportion of malnourished female newborns was 56.9%, while the proportion of malnourished male newborns was 39.1%, with the number of malnourished female newborns being significantly higher than that of male newborns (P<0.05).

[0028] 5.2 Anthropometry of Newborns

[0029] Anthropometry included weight, body length, head circumference, abdominal circumference, leg length, and chest circumference. The mean values ​​for these measurements in well-nourished individuals were 3255.0 g, 53.0 cm, 33.5 cm, 32.0 cm, 25.0 cm, and 34.0 cm, respectively, while the mean values ​​for the corresponding measurements in malnourished newborns were 2410.0 g, 49.0 cm, 31.5 cm, 28.0 cm, 22.0 cm, and 30.0 cm, respectively. Statistical analysis was performed using the independent samples Mann-Whitney U test. These measurements were significantly lower in malnourished newborns compared to well-nourished newborns (P < 0.05).

[0030] 5.3. CAN assessment for newborns

[0031] Neonatal subcutaneous fat assessment primarily measures subcutaneous fat in areas including the cheeks, chin, neck, chest, abdomen, arms, thighs, calves, back, and buttocks. The average subcutaneous fat measurements for well-nourished newborns were 32.0 mm, 12.9 mm, 11.0 mm, 19.9 mm, 13.3 mm, 12.0 mm, 9.3 mm, 10.5 mm, 8.6 mm, 10.1 mm, and 10.7 mm, respectively. For malnourished newborns, the average measurements for the corresponding body parts were 23.0 mm, 11.9 mm, 10.1 mm, 11.4 mm, 9.9 mm, 9.0 mm, 6.9 mm, 8.7 mm, 6.6 mm, 6.9 mm, and 8.4 mm, respectively. Statistical analysis was performed using the independent samples Mann-Whitney U test. Subcutaneous fat in malnourished newborns was significantly reduced in all body parts (cheeks, neck, chest, abdomen, arms, thighs, calves, back, and buttocks) compared to well-nourished newborns, except for the body parts examined and the chin (P<0.05).

[0032] Example 2. Assessing intrauterine nutrition accumulation in newborns using simple physical / chemical characteristics of meconium.

[0033] 1. Physical / chemical properties of meconium

[0034] The meconium weight of malnourished newborns ranged from 0.20g to 8.65g, with an average weight of 1.4g; while that of well-nourished newborns ranged from 0.12g to 20.81g, with an average weight of 1.6g. The pH value of meconium in well-nourished newborns ranged from 4.29 to 8.53, with an average of 5.9. The pH value of meconium in malnourished newborns ranged from 4.36 to 7.45. Furthermore, the water content of meconium in well-nourished newborns ranged from 41.67% to 93.67%, while that in malnourished newborns ranged from 4.28% to 92.53%.

[0035] 2. Physicochemical properties of meconium

[0036] 2.1 Statistical analysis of meconium color

[0037] The color of meconium was recorded according to the meconium grading standard card, and the statistical significance was analyzed using the chi-square test. There was no statistical significance between the two groups (P>0.05).

[0038] 2.2. Statistical Analysis of Meconium Color

[0039] The amount of meconium was recorded using a meconium color grading chart, and its statistical significance was analyzed using a t-test. The meconium chart grading is semi-quantitative; there was no statistically significant difference in meconium color between the well-nourished and malnourished groups (P>0.05), therefore meconium color cannot distinguish the nutritional status of these two groups.

[0040] 2.3. Statistical analysis of meconium viscosity

[0041] Meconium viscosity was recorded by stretching with a glass rod, and statistical significance was analyzed using the chi-square test. There was no statistically significant difference in meconium viscosity between the well-nourished and malnourished groups (P>0.05).

[0042] 2.4. Statistical analysis of meconium weight, pH and water content (%)

[0043] Statistical analysis of meconium weight, pH, and water content (%) was performed using a chi-square test. There were no statistically significant differences in these characteristics of meconium between the well-nourished and malnourished neonates (P>0.05).

[0044] Example 3. Evaluation of neonatal intrauterine nutrition through meconium metabolomics analysis

[0045] 1. Pretreatment of meconium

[0046] With the grinding beads in place, 150 μL of acetonitrile was added to 10 mg of meconium, and the mixture was then ground using microbeads (25 Hz × 1 min × 2 times). 120 μL of the homogenate was transferred to an EP tube and vortexed for 30 s. The mixture was then centrifuged at 14,000 rpm for 10 min at 4 °C. The supernatant was obtained, and the internal labeling solution was added to it. The mixture was then lyophilized for LC-MS analysis.

[0047] 2. Metabolomics analysis of meconium

[0048] Meconium metabolic profiles were obtained using a Waters Acquity ultra-high performance liquid chromatography (UPLC) system integrated with a Waters Q-TOF Premier mass spectrometer (Waters Corp., Milford, MA, USA). In cation mode, chromatographic separation was performed on a Waters BEHC8 column (50 mm × 2.1 mm, 1.7 μm) (Waters, Milford, MA). Mobile phase A was water containing 0.1% formic acid, while mobile phase B was acetonitrile containing 0.1% formic acid. The linear gradient increased from 5% B to 40% B within 2 min, from 40% B to 100% B within 6 min and held for 2 min, then decreased to 5% B within 10.1 min and held for 2 min to reach equilibrium. In negative ion mode, chromatographic separation was performed on an ACQUITY UPLC HSSST3 column (100 mm × 2.1 mm, 1.8 μm) (Waters, Milford, MA). Mobile phase A is water containing 6.5 mM NH4HCO3, while mobile phase B is acetonitrile containing 6.5 mM NH4HCO3. The linear gradient is 0% B within 1 minute, increases from 0% to 40% B within 2 minutes, then increases to 100% within 13 minutes and remains there for 5 minutes, decreases to 0% B at 22.1 minutes, and remains at equilibrium for 2.9 minutes.

[0049] 3. Quality Evaluation

[0050] In positive ion mode, 126 qualitative metabolites were detected. QC reproducibility was assessed, and the RSD (70.63%) of 89 metabolites was less than 30%. In negative ion mode, 50 qualitative metabolites were detected. QC reproducibility was assessed, and the RSD (94.34%) of the 50 metabolites was less than 30%. Therefore, this indicates good consistency in the measurements.

[0051] 4. Meconium metabolic profile between malnourished and well-nourished newborns

[0052] Meconium metabolism was analyzed using A-supervised analysis (PLS-DA). Fractional plots were used to analyze the distribution of metabolites in meconium. The results showed significant segregation, indicating that malnourished newborns exhibited marked metabolic disorders compared to well-nourished newborns.

[0053] 5. Analysis of differences in meconium metabolites between malnourished and well-nourished newborns.

[0054] 126 qualitative metabolites were detected in the meconium of both malnourished and well-nourished newborns using positive and negative assays. The specific analytical methods are as follows.

[0055] 5.1. Pretreatment of meconium samples

[0056] Weigh approximately 10 mg of meconium sample, add grinding beads, then add 150 L of acetonitrile, and grind using the beads (25 Hz × 1 min × 2 times). Transfer 120 μL of the homogenate to an EP tube and vortex for 30 s to mix. Centrifuge (14000 rpm × 10 min × 4°C). Collect the supernatant, add internal standard solution, and lyophilize. Reconstitute with 20% acetonitrile aqueous solution before analysis, and wait for LC-MS analysis. Mix well and load the sample.

[0057] 5.2. LC-MS Full Component Data Acquisition

[0058] Instrument: Vanquish UPLC-QExactive (Thermo Fisher Scientific, Rockford, IL, USA).

[0059] Before analyzing actual samples, the system is first balanced with blank samples. During the analysis of actual samples, a QC test is run every 10 actual samples to monitor the stability of pretreatment and instrument operation.

[0060] 5.2.1 Chromatographic separation conditions

[0061] Positive ion mode

[0062] Chromatographic column: Waters BEHC8 column (size: 50mm×2.1mm, 1.7μm) (Waters, Milford, MA), column temperature: 60℃, flow rate: 0.4ml / min.

[0063] Mobile phase: water with 0.1% formic acid (phase A) and acetonitrile with 0.1% formic acid (phase B).

[0064] Gradient: The initial gradient is 5%B, maintained for 0.5 min, then linearly increased to 40%B within 1.5 min, and then linearly increased to 100%B within 6 min and maintained for 2 min. At 10.1 min, it drops back to the initial gradient of 5%B and remains in equilibrium for 2 min.

[0065] Negative ion mode

[0066] Column: ACQUITYUPLCHSST3 (size: 100mm×2.1mm, 1.8μm) (Waters, Milford, MA), column temperature: 50℃, flow rate: 0.35ml / min.

[0067] Mobile phase: Phase A is water with 6.5 mM NH4HCO3 added; Phase B is an aqueous solution containing 95% methanol and 6.5 mM NH4HCO3.

[0068] Gradient: The initial gradient is 0%B, maintained for 1 minute, then increased to 40%B within 2 minutes, and then linearly increased to 100%B within 13 minutes and maintained for 5 minutes. At 22.1 minutes, it drops back to the initial gradient of 0%B and remains in equilibrium for 2.9 minutes.

[0069] 5.2.2 Mass Spectrometry Data Acquisition Parameters

[0070] MS full scan range: positive ions m / z 80-1200, spray voltage 3.50 kV; negative ions m / z 80-1200, spray voltage 3.00 kV. Capillary temperature 300°C, auxiliary heating gas temperature 350°C, sheath gas and auxiliary gas flow rates 45 and 10 (arbitrary units), respectively. Resolution set to 7e4.

[0071] 5.2.3 Data Processing Software

[0072] Metabolite peak extraction was performed using the data integration and processing software TraceFinder 3.2 (ThermoFisher Scientific, USA).

[0073] The Wilcoxon-Mann-Whitney test was used to analyze the differences in metabolites between the malnourished and well-nourished neonate groups. Compared with the control group, the malnourished neonate group showed a significant increase in 17 metabolites and a significant decrease in 19 metabolites (P<0.05), as shown in Table 1.

[0074] Metabolites Scanning mode p-value Arginine - 0.002 ↓ glutamic acid + 0.001 ↓ Histidine + 0.005 ↓ Hydroxyproline + 0.020 ↓ Leucine + 0.001 ↓ Leucine_Isoleucine + 0.001 ↓ Methionine + 0.003 ↓ ornithine + 0.026 ↓ Phenylalanine + 0.002 ↓ proline + 0.006 ↓ Tryptophan + 0.001 ↓ Tyrosine + 0.010 ↓ Valine + 0.000 ↓ Phosphoseserine - 0.010 ↓ betaine + 0.001 ↓ Indole-3-aldehyde + 0.002 ↓ Indole-3-propionic acid + 0.001 ↓ Indoline + 0.002 ↓ Piperic acid + 0.000 ↓ pyrrolidine + 0.002 ↓ 1,7-Dimethylxanthine - 0.000 ↑ 1-Methylguanine + 0.033 ↑ caffeine + 0.038 ↑ Cortisone + 0.011 ↑ Leucyl-proline (Leu-Pro) + 0.001 ↑ N-acetylglutamic acid - 0.000 ↑ Phenylacetyl-L-glutamine + 0.000 ↑ propionyl L-carnitine + 0.028 ↑ uric acid + 0.000 ↑ Taurocholic acid (TCA) - 0.043 ↑ Glycine deoxycholic acid (GDCA) - 0.019 ↑ Butyrylcarnitine + 0.040 ↑ Carnitine C12_0 + 0.004 ↑ Decyl carnitine + 0.029 ↑ Carnitine C16_0 + 0.001 ↑ Hexanoylcarnitine + 0.002 ↑ Vanoylcarnitine + 0.025 ↑

[0075] ↓The average value decreased (compared to well-nourished individuals with malnutrition).

[0076] ↑The average value increased (compared to good nutrition in malnourished individuals).

[0077] 6. Candidate markers for assessing neonatal nutrient accumulation in meconium

[0078] Receiver operating characteristic (ROC) curves play a central role in biomarker evaluation. ROC curve analysis was performed using SPSS 18. A training group was used to build the ROC model. The area under the ROC curve (AUC) was used as a measure of the biomarker's sensitivity and specificity. By searching for sensitivity and specificity, the optimal cutoff point for each biomarker was determined. The test group was then placed in the ROC model to assess its diagnostic capability. ROC analysis was performed on candidate metabolite biomarkers. 10-15 markers were randomly selected as candidate markers from differentially expressed metabolites. 69 marker groups were analyzed, and 13 marker groups had an AUC > 0.95 (see Table 2 for details).

[0079] 7. Identify a set of potential biomarkers in meconium to assess intrauterine nutrient accumulation in the newborn.

[0080] A random number table approach was used to analyze 130 newborns from 172 enrolled cohorts to prevent original grouping. Candidate biomarkers for metabolites were validated using targeted analysis to assess well-nourished and malnourished newborns. 69 biomarkers were selected and validated from the 130 newborns. ROC analysis was used to evaluate the value of the obtained metabolites. Among the 13 biomarkers with AUC > 0.95, the highest AUC was 0.88, indicating that this set of candidate biomarkers could be potential markers for highly accurate assessment of malnourished newborns. This potential set of biomarkers included 14 biomarkers: glutamate, proline, tryptophan, tyrosine, valine, 1,7-dimethylxanthine, 1-methylguanine, cortisone, leucyl-proline, phenylacetyl-L-glutamine, propionyl-L-carnitine, butyrylcarnitine, carnitine C16_O, and valerate carnitine. One candidate marker set comprised 10 markers with an AUC of 0.81, including glutamic acid, tryptophan, tyrosine, valine, 1,7-dimethylxanthine, cortisone, phenylacetyl-L-glutamine, butyrylcarnitine, valeratecarnitine, and hexanoylcarnitine. Of these 10 markers, 9 were identical to a set using a marker set with an AUC of 0.88, with only hexanoylcarnitine differing. This set of markers has one-third fewer markers than the set with an AUC of 0.88, and therefore may be a better choice with fewer markers and higher efficiency. See Table 2 for details.

[0081] Table 2. Results of different metabolite marker groups in neonatal meconium in assessing neonatal nutritional status

[0082] Serial Number AUC of the training set AUC of the test set Number of markers marker group 1 1 0.7 15 Glutamic acid; Leucine / Isoleucine; Proline; Tryptophan; Tyrosine; Valine; 1,7-Dimethylxanthine; 1-Methylguanine; Cortisone; Phenylacetyl-L-glutamine; Propionyl-L-carnitine; Glycine-deoxycholic acid (GDCA); Carnitine C12-O; Carnitine C16-O; Hexanoylcarnitine 2 0.99 0.81 15 Glutamic acid; proline; tryptophan; tyrosine; valine; indole-3-aldehyde; 1,7-dimethylxanthine; cortisone; leucyl-proline; phenylacetyl-L-glutamine; glycine deoxycholic acid (GDCA); butyrylcarnitine; carnitine C16_O; hexanoylcarnitine; valeratecarnitine 3 0.98 0.7 15 Glutamic acid; Proline; Tryptophan; Tyrosine; Valine; 1,7-Dimethylxanthine; 1-Methylguanine; Cortisone; Leucyl-proline; Phenylacetyl-L-glutamine; Glycine-deoxycholic acid (GDCA); Butyrylcarnitine; Carnitine C12-O; Decylcarnitine; Hexanoylcarnitine 4 0.97 0.74 14 Proline; Tryptophan; Tyrosine; Valine; Piperic acid; 1,7-Dimethylxanthine; Cortisone; Leucyl-proline; Phenylacetyl-L-glutamine; Propionyl-L-carnitine; Butyryl-carnitine; Carnitine C12_O; Carnitine C16_O; Hexanoylcarnitine 5 0.97 0.88 14 Glutamic acid; Proline; Tryptophan; Tyrosine; Valine; 1,7-Dimethylxanthine; 1-Methylguanine; Cortisone; Leucyl-proline; Phenylacetyl-L-glutamine; Propionyl-L-carnitine; Butyryl-carnitine; Carnitine C16_O; Valoyl-carnitine 6 0.97 0.81 10 Glutamic acid, tryptophan, tyrosine, valine, 1,7-dimethylxanthine, cortisone, phenylacetyl-L-glutamine, butyrylcarnitine, valeratecarnitine, and hexanoylcarnitine 7 0.96 0.76 15 Glutamic acid; Proline; Tryptophan; Tyrosine; Valine; Piperic acid; 1,7-Dimethylxanthine; Cortisone; Leucyl-proline; Phenylacetyl-L-glutamine; Propionyl-L-carnitine; Butyryl-carnitine; Carnitine C16_O; Hexanoylcarnitine; Valoylcarnitine 8 0.96 0.81 15 Glutamic acid; Leucine / Isoleucine; Proline; Tryptophan; Tyrosine; Valine; Indole-3-propionic acid; 1,7-Dimethylxanthine; 1-Methylguanine; Leucyl-proline; Phenylacetyl-L-glutamine; Glycine-deoxycholic acid (GDCA); Butyrylcarnitine; Decylcarnitine; Vanoylcarnitine 9 0.96 0.68 13 Glutamic acid; Histidine; Tryptophan; Piperic acid; 1,7-Dimethylxanthine; Cortisone; Phenylacetyl-L-glutamine; Glycine-deoxycholic acid (GDCA); Butyrylcarnitine; Carnitine C12_O; Carnitine C16_O; Hexanoylcarnitine; Vanoylcarnitine 10 0.95 0.77 14 Glutamic acid; Tryptophan; Tyrosine; Valine; Pyrrolidine; 1,7-Dimethylxanthine; Cortisone; Leucyl-proline; Phenylacetyl-L-glutamine; Propionyl-L-carnitine; Glycine-deoxycholic acid (GDCA); Butyrylcarnitine; Carnitine C16_O; Vanoylcarnitine 11 0.95 0.74 14 Glutamic acid; Tryptophan; Tyrosine; Valine; Piperic acid; 1,7-Dimethylxanthine; Cortisone; Leucyl-proline; Phenylacetyl-L-glutamine; Glycine-deoxycholic acid (GDCA); Butyrylcarnitine; Decylcarnitine; Carnitine C16_O; Vanoylcarnitine 12 0.95 0.72 13 Glutamic acid; proline; tryptophan; tyrosine; valine; 1,7-dimethylxanthine; 1-methylguanine; cortisone; leucyl-proline; phenylacetyl-L-glutamine; glycine deoxycholic acid (GDCA); butyrylcarnitine; carnitine C16_0 13 0.95 0.71 14 Glutamic acid; proline; tryptophan; tyrosine; valine; pyrrolidine; 1,7-dimethylxanthine; cortisone; leucyl-proline; phenylacetyl-L-glutamine; glycine deoxycholic acid (GDCA); butyrylcarnitine; carnitine C12_O; hexanoylcarnitine 14 0.94 0.74 15 Proline; Tryptophan; Tyrosine; Valine; Indole-3-propionic acid; Piperic acid; 1,7-Dimethylxanthine; 1-Methylguanine; Cortisone; Leucyl-proline; Phenylacetyl-L-glutamine; Glycine-deoxycholic acid (GDCA); Butyrylcarnitine; Carnitine C16_O; Vanoylcarnitine 15 0.94 0.72 12 Glutamic acid; Tryptophan; Valine; 1,7-Dimethylxanthine; 1-Methylguanine; Cortisone; Leucyl-proline; Phenylacetyl-L-glutamine; Glycine-deoxycholic acid (GDCA); Butyrylcarnitine; Carnitine C16_O; Hexanoylcarnitine 16 0.94 0.72 10 Glutamic acid; Proline; Tryptophan; 1,7-Dimethylxanthine; Cortisone; Leucyl-proline; Phenylacetyl-L-glutamine; Glycine-deoxycholic acid (GDCA); Butyrylcarnitine; Carnitine C16_0 17 0.94 0.78 14 Glutamic acid; Proline; Tryptophan; Tyrosine; Valine; 1,7-Dimethylxanthine; 1-Methylguanine; Cortisone; Leucyl-proline; Phenylacetyl-L-glutamine; Propionyl-L-carnitine; Butyryl-carnitine; Carnitine C12_O; Hexanoylcarnitine 18 0.94 0.82 15 Glutamic acid; proline; tryptophan; tyrosine; valine; 1,7-dimethylxanthine; 1-methylguanine; cortisone; leucyl-proline; phenylacetyl-L-glutamine; glycine deoxycholic acid (GDCA); butyrylcarnitine; carnitine C16_O; hexanoylcarnitine; valerate carnitine 19 0.94 0.74 14 Glutamic acid; Proline; Tryptophan; Tyrosine; Valine; 1,7-Dimethylxanthine; Cortisone; Leucyl-proline; Phenylacetyl-L-glutamine; Propionyl-L-carnitine; Butyryl-carnitine; Carnitine C16_O; Hexanoyl-carnitine; Valoyl-carnitine 20 0.94 0.81 12 Glutamic acid; proline; tryptophan; tyrosine; valine; 1,7-dimethylxanthine; cortisone; leucyl-proline; phenylacetyl-L-glutamine; glycine deoxycholic acid (GDCA); butyrylcarnitine; hexanoylcarnitine 21 0.94 0.74 15 Glutamic acid; proline; tryptophan; tyrosine; valine; piperic acid; 1,7-dimethylxanthine; 1-methylguanine; cortisone; leucyl-proline; phenylacetyl-L-glutamine; glycine deoxycholic acid (GDCA); butyrylcarnitine; decylcarnitine; carnitine C16_0 22 0.94 0.73 14 Glutamic acid; proline; tryptophan; tyrosine; valine; piperic acid; 1,7-dimethylxanthine; cortisone; leucyl-proline; phenylacetyl-L-glutamine; glycine deoxycholic acid (GDCA); butyrylcarnitine; hexanoylcarnitine; valeratecarnitine 23 0.94 0.68 14 Glutamic acid; Proline; Tryptophan; Tyrosine; Valine; Indole-3-propionic acid; 1,7-Dimethylxanthine; Cortisone; Leucyl-proline; Phenylacetyl-L-glutamine; Propionyl-L-carnitine; Glycine-deoxycholic acid (GDCA); Carnitine C16_O; Vanoylcarnitine 24 0.94 0.71 14 Glutamic acid; Histidine; Proline; Tryptophan; Valine; Piperic acid; 1,7-Dimethylxanthine; Cortisone; Leucyl-proline; Phenylacetyl-L-glutamine; Propionyl-L-carnitine; Glycine-deoxycholic acid (GDCA); Butyrylcarnitine; Carnitine C16_0 25 0.94 0.69 14 Glutamic acid; Histidine; Proline; Tryptophan; Tyrosine; Valine; Piperic acid; 1,7-Dimethylxanthine; Cortisone; Leucyl-proline; Phenylacetyl-L-glutamine; Propionyl-L-carnitine; Carnitine C16_O; Vanoyl-carnitine 26 0.93 0.68 12 Tryptophan; Valine; Piperic acid; 1,7-Dimethylxanthine; Cortisone; Leucyl-proline; Phenylacetyl-L-glutamine; Glycine-deoxycholic acid (GDCA); Butyrylcarnitine; Carnitine C12_O; Carnitine C16_O; Hexanoylcarnitine 27 0.93 0.76 15 Histidine; Tryptophan; Tyrosine; Valine; Indole-3-propionic acid; 1,7-Dimethylxanthine; 1-Methylguanine; Cortisone; Leucyl-proline; Phenylacetyl-L-glutamine; Propionyl-L-carnitine; Glycine-deoxycholic acid (GDCA); Butyrylcarnitine; Carnitine C16_O; Hexanoylcarnitine 28 0.93 0.7 15 Histidine; Proline; Tryptophan; Valine; Piperic acid; 1,7-Dimethylxanthine; Cortisone; Leucyl-proline; Phenylacetyl-L-glutamine; Glycine-deoxycholic acid (GDCA); Butyrylcarnitine; Carnitine C12_O; Decylcarnitine; Carnitine C16_O; Vanoylcarnitine 29 0.93 0.73 13 Glutamic acid; Valine; 1,7-Dimethylxanthine; 1-Methylguanine; Cortisone; Leucyl-proline; Phenylacetyl-L-glutamine; Propionyl-L-carnitine; Glycine-deoxycholic acid (GDCA); Butyrylcarnitine; Carnitine C12_O; Carnitine C16_O; Vanoylcarnitine 30 0.93 0.7 13 Glutamic acid; Tryptophan; Valine; Indole-3-propionic acid; 1,7-Dimethylxanthine; 1-Methylguanine; Cortisone; Phenylacetyl-L-glutamine; Glycine-deoxycholic acid (GDCA); Butyrylcarnitine; Carnitine C16_O; Hexanoylcarnitine; Vanoylcarnitine 31 0.93 0.6 10 Glutamic acid; Tryptophan; Piperic acid; 1,7-Dimethylxanthine; 1-Methylguanine; Cortisone; Leucyl-proline; Phenylacetyl-L-glutamine; Glycine-deoxycholic acid (GDCA); Butyrylcarnitine 32 0.93 0.62 10 Glutamic acid; Tryptophan; Piperic acid; 1,7-Dimethylxanthine; Cortisone; Phenylacetyl-L-glutamine; Glycine-deoxycholic acid (GDCA); Butyrylcarnitine; Carnitine C16_O; Hexanoylcarnitine 33 0.93 0.76 11 Glutamic acid; Proline; Tryptophan; Valine; 1,7-Dimethylxanthine; 1-Methylguanine; Cortisone; Phenylacetyl-L-glutamine; Glycine-deoxycholic acid (GDCA); Butyrylcarnitine; Carnitine C16_0 34 0.93 0.76 13 Glutamic acid; proline; tryptophan; tyrosine; valine; 1,7-dimethylxanthine; 1-methylguanine; cortisone; phenylacetyl-L-glutamine; glycine deoxycholic acid (GDCA); butyrylcarnitine; carnitine C12-O; hexanoylcarnitine 35 0.93 0.83 12 Glutamic acid; proline; tryptophan; tyrosine; valine; 1,7-dimethylxanthine; cortisone; leucyl-proline; phenylacetyl-L-glutamine; glycine deoxycholic acid (GDCA); butyrylcarnitine; carnitine C12_0 36 0.93 0.74 15 Glutamic acid; Histidine; Proline; Tryptophan; Tyrosine; Valine; Indole-3-propionic acid; 1,7-Dimethylxanthine; Cortisone; Leucyl-proline; Phenylacetyl-L-glutamine; Glycine-deoxycholic acid (GDCA); Butyrylcarnitine; Carnitine C16_O; Hexanoylcarnitine 37 0.92 0.77 13 Glutamic acid; proline; tryptophan; tyrosine; valine; pyrrolidine; 1,7-dimethylxanthine; cortisone; phenylacetyl-L-glutamine; propionyl-L-carnitine; glycine-deoxycholic acid (GDCA); butyrylcarnitine; decylcarnitine 38 0.92 0.61 15 Glutamic acid; proline; tryptophan; tyrosine; valine; piperic acid; 1-methylguanine; cortisone; leucyl-proline; glycine deoxycholic acid (GDCA); butyrylcarnitine; carnitine C12_O; carnitine C16_O; hexanoylcarnitine; valerate carnitine 39 0.92 0.85 13 Glutamic acid; Leucine / Isoleucine; Proline; Tryptophan; Tyrosine; Valine; 1,7-Dimethylxanthine; Cortisone; Phenylacetyl-L-glutamine; Glycine-deoxycholic acid (GDCA); Butyrylcarnitine; Hexanoylcarnitine; Vanoylcarnitine 40 0.92 0.87 15 Glutamic acid; Histidine; Proline; Tryptophan; Tyrosine; Valine; 1,7-Dimethylxanthine; 1-Methylguanine; Cortisone; Leucyl-proline; Phenylacetyl-L-glutamine; Glycine-deoxycholic acid (GDCA); Butyrylcarnitine; Carnitine C16_O; Hexanoylcarnitine 41 0.92 0.84 13 Glutamic acid; Histidine; Proline; Tryptophan; Tyrosine; Valine; 1,7-Dimethylxanthine; Cortisone; Phenylacetyl-L-glutamine; Glycine-deoxycholic acid (GDCA); Butyrylcarnitine; Carnitine C16_O; Hexanoylcarnitine 42 0.91 0.76 11 Tryptophan; Valine; Piperic acid; 1,7-Dimethylxanthine; Cortisone; Leucyl-proline; Phenylacetyl-L-glutamine; Propionyl-L-carnitine; Glycine-deoxycholic acid (GDCA); Butyrylcarnitine; Carnitine C16_0 43 0.91 0.71 13 Proline; Tryptophan; Tyrosine; Valine; Pyrrolidine; 1,7-Dimethylxanthine; Cortisone; Leucyl-proline; Phenylacetyl-L-glutamine; Glycine-deoxycholic acid (GDCA); Butyrylcarnitine; Carnitine C16_O; Hexanoylcarnitine 44 0.91 0.71 12 Histidine; Tryptophan; Valine; Piperic acid; 1,7-Dimethylxanthine; Cortisone; Phenylacetyl-L-glutamine; Propionyl-L-carnitine; Glycine-deoxycholic acid (GDCA); Butyrylcarnitine; Carnitine C12_O; Carnitine C16_O 45 0.91 0.7 12 Histidine; Proline; Tryptophan; Valine; Piperic acid; 1,7-Dimethylxanthine; Cortisone; Leucyl-proline; Phenylacetyl-L-glutamine; Glycine-deoxycholic acid (GDCA); Butyrylcarnitine; Carnitine C12_0 46 0.91 0.67 12 Glutamic acid; Tryptophan; Valine; 1,7-Dimethylxanthine; 1-Methylguanine; Cortisone; Phenylacetyl-L-glutamine; Propionyl-L-carnitine; Glycine-deoxycholic acid (GDCA); Butyrylcarnitine; Carnitine C12_O; Carnitine C16_O 0.91 0.74 14 Glutamic acid; Tryptophan; Valine; 1,7-Dimethylxanthine; 1-Methylguanine; Cortisone; Leucyl-proline; Phenylacetyl-L-glutamine; Propionyl-L-carnitine; Glycine-deoxycholic acid (GDCA); Butyrylcarnitine; Carnitine C16_O; Hexanoylcarnitine; Vanoylcarnitine 0.91 0.74 12 Glutamic acid; Tryptophan; Valine; Pyrrolidine; 1,7-Dimethylxanthine; Cortisone; Leucyl-proline; Phenylacetyl-L-glutamine; Glycine-deoxycholic acid (GDCA); Carnitine C12_O; Carnitine C16_O; Vanoylcarnitine 0.91 0.75 13 Glutamic acid; Tryptophan; Tyrosine; Valine; Piperic acid; 1,7-Dimethylxanthine; Leucyl-proline; Phenylacetyl-L-glutamine; Glycine-deoxycholic acid (GDCA); Carnitine C12_O; Carnitine C16_O; Hexanoylcarnitine; Vanoylcarnitine 0.91 0.82 14 Glutamic acid; Tryptophan; Tyrosine; Valine; Piperic acid; 1,7-Dimethylxanthine; Cortisone; Leucyl-proline; Phenylacetyl-L-glutamine; Glycine-deoxycholic acid (GDCA); Butyrylcarnitine; Carnitine C12-O; Hexanoylcarnitine; Vanoylcarnitine 0.91 0.66 11 Glutamic acid; Tryptophan; Piperic acid; 1,7-Dimethylxanthine; Cortisone; Leucyl-proline; Phenylacetyl-L-glutamine; Glycine-deoxycholic acid (GDCA); Butyrylcarnitine; Carnitine C16_O; Vanoylcarnitine 0.91 0.87 14 Glutamic acid; proline; tryptophan; tyrosine; valine; 1,7-dimethylxanthine; 1-methylguanine; cortisone; leucyl-proline; phenylacetyl-L-glutamine; glycine deoxycholic acid (GDCA); butyrylcarnitine; carnitine C16_O; hexanoylcarnitine 0.91 0.81 12 Glutamic acid; Histidine; Tryptophan; Tyrosine; Valine; 1,7-Dimethylxanthine; 1-Methylguanine; Cortisone; Phenylacetyl-L-glutamine; Glycine-deoxycholic acid (GDCA); Butyrylcarnitine; Vanoylcarnitine 0.9 0.82 13 Proline; Tryptophan; Tyrosine; Valine; 1,7-Dimethylxanthine; Cortisone; Leucyl-proline; Phenylacetyl-L-glutamine; Glycine-deoxycholic acid (GDCA); Butyrylcarnitine; Carnitine C12_O; Carnitine C16_O; Hexanoylcarnitine 0.9 0.75 10 Glutamic acid; Valine; 1,7-Dimethylxanthine; 1-Methylguanine; Cortisone; Phenylacetyl-L-glutamine; Glycine-deoxycholic acid (GDCA); Butyrylcarnitine; Carnitine C16_O; Vanoylcarnitine 0.9 0.7 10 Glutamic acid; Tryptophan; Valine; Piperic acid; 1,7-Dimethylxanthine; 1-Methylguanine; Cortisone; Phenylacetyl-L-glutamine; Glycine-deoxycholic acid (GDCA); Butyrylcarnitine 0.9 0.81 10 Glutamic acid; Tryptophan; Tyrosine; Valine; 1,7-Dimethylxanthine; Cortisone; Phenylacetyl-L-glutamine; Butyrylcarnitine; Hexanoylcarnitine; Valoylcarnitine 0.9 0.74 12 Glutamic acid; Tryptophan; Tyrosine; Valine; Pyrrolidine; 1,7-Dimethylxanthine; Cortisone; Leucyl-proline; Phenylacetyl-L-glutamine; Glycine-deoxycholic acid (GDCA); Butyrylcarnitine; Carnitine C16_0 0.9 0.83 11 Glutamic acid; Proline; Tryptophan; Tyrosine; Valine; 1,7-Dimethylxanthine; Cortisone; Leucyl-proline; Phenylacetyl-L-glutamine; Butyrylcarnitine; Carnitine C16_0 0.9 0.83 15 Glutamic acid; proline; tryptophan; tyrosine; valine; piperic acid; 1,7-dimethylxanthine; 1-methylguanine; cortisone; leucyl-proline; phenylacetyl-L-glutamine; glycine deoxycholic acid (GDCA); butyrylcarnitine; decylcarnitine; carnitine C16_0 0.9 0.72 14 Glutamic acid; Histidine; Proline; Tryptophan; Tyrosine; 1,7-Dimethylxanthine; Cortisone; Leucyl-proline; Phenylacetyl-L-glutamine; Propionyl-L-carnitine; Glycine-deoxycholic acid (GDCA); Butyrylcarnitine; Carnitine C16_O; Vanoylcarnitine 0.89 0.74 10 Glutamic acid; Tryptophan; Valine; 1,7-Dimethylxanthine; Cortisone; Phenylacetyl-L-glutamine; Glycine-deoxycholic acid (GDCA); Butyrylcarnitine; Carnitine C12_O; Carnitine C16_O 0.89 0.77 10 Glutamic acid; Histidine; Valine; Piperic acid; 1,7-Dimethylxanthine; Cortisone; Phenylacetyl-L-glutamine; Glycine-deoxycholic acid (GDCA); Butyrylcarnitine; Carnitine C16_0 0.88 0.77 11 Tryptophan; Valine; Piperic acid; 1,7-Dimethylxanthine; Cortisone; Phenylacetyl-L-glutamine; Glycine-deoxycholic acid (GDCA); Butyrylcarnitine; Carnitine C12-O; Decylcarnitine; Hexanoylcarnitine 0.88 0.75 10 Glutamic acid; Tryptophan; Valine; 1,7-Dimethylxanthine; Cortisone; Phenylacetyl-L-glutamine; Glycine-deoxycholic acid (GDCA); Butyrylcarnitine; Carnitine C16_O; Vanoylcarnitine 0.88 0.67 10 Glutamic acid; Tryptophan; Valine; Piperic acid; 1,7-Dimethylxanthine; Phenylacetyl-L-glutamine; Glycine-deoxycholic acid (GDCA); Decanoylcarnitine; Carnitine C16_O; Hexanoylcarnitine 0.88 0.8 11 Glutamic acid; Tryptophan; Valine; Piperic acid; 1,7-Dimethylxanthine; Cortisone; Leucyl-proline; Phenylacetyl-L-glutamine; Glycine-deoxycholic acid (GDCA); Butyrylcarnitine; Carnitine C16_0 0.86 0.77 12 Glutamic acid; Proline; Tryptophan; Valine; Piperic acid; 1,7-Dimethylxanthine; 1-Methylguanine; Cortisone; Leucyl-proline; Glycine-deoxycholic acid (GDCA); Carnitine C16_O; Vanoylcarnitine 0.85 0.77 10 Glutamic acid; Tryptophan; Valine; Piperic acid; 1,7-Dimethylxanthine; Cortisone; Phenylacetyl-L-glutamine; Glycine-deoxycholic acid (GDCA); Carnitine C12_O; Carnitine C16_O

[0083] 8. Conclusion

[0084] 1. In this invention, meconium was verified as a new non-invasive indicator for evaluating the nutritional status of newborns.

[0085] 2. This invention validates meconium as a novel, non-invasive indicator for assessing neonatal nutritional status. A group of 14 markers were identified in meconium: glutamate, proline, tryptophan, tyrosine, valine, 1,7-dimethylxanthine, 1-methylguanine, cortisone, leucyl-proline, phenylacetyl-L-glutamine, propionyl-L-carnitine, butyryl-carnitine, carnitine C16-O, and valerate-carnitine. Another group of 10 markers in meconium included glutamate, tryptophan, tyrosine, valine, 1,7-dimethylxanthine, cortisone, phenylacetyl-L-glutamine, butyryl-carnitine, valerate-carnitine, and hexanoyl-carnitine. These potential markers are primarily associated with fat and protein metabolism, which are essential nutrients for the human body. Therefore, we believe that these two groups of markers in meconium can effectively assess the accumulation of nutrients in newborns during utero.

[0086] It should be understood that the disclosed invention is not limited to the specific methods, schemes, and substances described, as these are all subject to variation. It should also be understood that the terminology used herein is for the purpose of describing specific embodiments only and is not intended to limit the scope of the invention, which is limited only by the appended claims.

[0087] Those skilled in the art will also recognize, or be able to identify, many equivalents of the specific embodiments of the invention described herein using no more than conventional experiments. These equivalents are also included in the appended claims.

Claims

1. A non-invasive method for evaluating the intrauterine nutritional status of newborns, characterized in that, The method assesses neonatal intrauterine nutritional status through meconium metabolomics analysis; the method determines changes in the composition of compounds in neonatal meconium through meconium metabolomics analysis, thereby assessing neonatal intrauterine nutritional status, wherein at least 10 compounds in neonatal meconium are selected from the following markers: Arginine, glutamic acid, histidine, hydroxyproline, leucine, leucine-isoleucine, methionine, ornithine, phenylalanine, proline, tryptophan, tyrosine, valine, phosphoserine, betaine, indole-3-aldehyde, indole-3-propionic acid, indoline, piperic acid, pyrrolidine, 1,7-dimethylxanthine, 1-methylguanine, caffeine, cortisone, leucyl-proline, N-acetylglutamic acid, phenylacetyl-L-glutamine, propionyl-L-carnitine, uric acid, taurocholic acid, glycine-deoxycholic acid, butyrylcarnitine, carnitine C12_O, decylcarnitine, carnitine C16_O, hexanoylcarnitine, and valerate carnitine; wherein at least 10 compounds in neonatal meconium are selected from any one of the following marker groups.