Umbilical Artery Cord Blood Glucose Predicted neonatal hypoglycemia in Gestational Diabetes Mellitus and Other at-risk Newborns after Vaginal Delivery

doi:10.21203/rs.3.rs-1958011/v1

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Umbilical Artery Cord Blood Glucose Predicted neonatal hypoglycemia in Gestational Diabetes Mellitus and Other at-risk Newborns after Vaginal Delivery

https://doi.org/10.21203/rs.3.rs-1958011/v1

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Purpose

To explore the value of umbilical artery cord blood glucose (UACBG) in predicting hypoglycemia in gestational diabetes mellitus (GDM) and other at-risk newborns, and to provide a cut-off UACBG value for predicting hypoglycemia occurrence.

Methods

In this prospective study, we enrolled at-risk infants delivered vaginally, including neonates born to mothers with GDM, premature, macrosomia, and low birth weight. We separated the infants into GDM group and other at-risk group. All subjects underwent UACBG measurement during delivery. Neonatal peripheral blood glucose measurement was performed at 0.5 h and 2 h after birth. The predictive performance of UACBG for neonatal hypoglycemia was assessed using receiver operating characteristic curve (ROC), area under curve (AUC), sensitivity and specificity.

Results

916 newborns were included, 538 in GDM group and 378 in other at-risk group. For hypoglycemia prediction within 2 h, the best cut-off of UACBG was 4.150 mmol/L, yielding an AUC of 0.688 (95% CI 0.625–0.751). UACBG had a better performance at 0.5 h (AUC 0.757; 95% CI 0.690–0.824). In detail, the AUC was 0.703 in GDM group (95% CI 0.594–0.811), with the optimal cut-off of 4.550 mmol/L. In other at-risk group, the AUC was 0.797(95% CI 0.716–0.877), and the best threshold was 4.350 mmol/L. No significant differences were observed between GDM group and other at-risk group in AUC at 0.5 h, 2 h and within 2 h.

Conclusions

UACBG may be an efficient, non-invasive approach to predicting neonatal hypoglycemia within 2 h after birth.

umbilical cord blood

glucose

hypoglycemia

newborn

● We found that UACBG was efficient in predicting neonatal hypoglycemia within 2 h after delivery, especially at 0.5 h after birth.

What is new:

● This novel measure provides a different, non-invasive approach to assessing the risk of neonatal hypoglycemia after birth, potentially contributing to more targeted application of prophylactic interventions in time.

Neonatal hypoglycemia is defined as blood glucose concentration <47 mg/dL (<2.6 mmol/L)[1], which usually occurs within 2 h after delivery[2, 3]. Constant hypoglycemia is likely to lead to brain cell death and even irreversible cranial nerve injury in newborns[4, 5], having an adverse effect on the intelligence development of newborns. Hypoglycemia affected about 15% of newborns[6], especially those born premature, macrosomia, low birth weight or to mothers with gestational diabetes mellitus (GDM)[7].

GDM is the most prevalent disorder during pregnancies, influencing up to 15–25% of women worldwide[8]. The rate of neonatal hypoglycemia in pregnancies with GDM is 8–30%[9]. Fetal hyperinsulinemia caused by the hyperglycemia in utero increases the incidence of neonatal hypoglycemia in gestations with GDM[10, 11].

Other at-risk newborns, including premature, macrosomia and low birth weight newborns, are also likely to be diagnosed with neonatal hypoglycemia, of which the incidence was approximately 50%[7]. Lower storage of glycogen, increased free insulin, absence of substrate source for gluconeogenesis, and increased insulin sensitivity in these at-risk infants are related to neonatal hypoglycemia[12-18].

Maintaining blood glucose dynamic stability is an important step in the fetal to neonatal transition. Clinically, neonatal hypoglycemia usually shows no obvious symptoms, and the diagnosis mainly depends on neonatal blood glucose monitoring. This raises the question of the possibility of more accurately diagnosing neonates at the greatest risk of hypoglycemia. It has been suggested by Daria Turner et al. that the screening of neonatal hypoglycemia should be performed within one hour of birth ideally[19]. Additionally, the infections and pain resulting from the invasive nature of glucose monitoring have encouraged researchers to explore non-invasive methods for predicting blood glucose. It has been reported that umbilical cord blood glucose level was associated with neonatal blood glucose[20, 21]. A recent study also revealed that immediate cord blood sampling for blood glucose evaluation among at-risk newborns would be an alternative method for early diagnosis of perinatal asphyxia and hypoglycemia[22]. However, the predictive value of umbilical artery cord blood glucose (UACBG) on neonatal hypoglycemia in pregnancies remains unclear.

We supposed that at-risk neonates would be at the highest risk of hypoglycemia within 2 h of age. Since the mechanism of hypoglycemia in GDM infants is different from that in other at-risk ones (premature, macrosomia and low birth weight newborns), this study separated modeling of GDM and other at-risk infants to explore the value of UACBG in predicting neonatal hypoglycemia within 2 h after delivery.

Subjects

This prospective study was conducted between January 2021 and February 2022 on at-risk newborns delivered vaginally at Affiliated Maternal and Child Health Care Hospital of Nantong University. This research was approved by the Hospital Ethics Committee (Ethics No: Y 2020039). Inclusion criteria were infants delivered vaginally in singleton gestations, who born premature (<37 week), macrosomia (>4000 g), low birth weight (<2500 g) or to mothers with GDM. Fetal malformation and stillbirth were excluded.

Grouping

GDM group: All newborns delivered by mothers with GDM were included, regardless of whether they were born premature (<37 week), macrosomia (>4000 g), or low birth weight (<2500 g). Due to the low incidence of pre-pregnancy diabetes mellitus, the risk of neonatal hypoglycemia in pregnancies with pre-pregnancy diabetes mellitus differs greatly from that of GDM. In order to maintain consistency of the research, we excluded infants born to women with pre-pregnancy diabetes mellitus. According to The International Association of Diabetes in Pregnancy Study Group (IADPSG)[23], with a 75 g oral glucose tolerance test (OGTT) performed during 24-28 gestational weeks, GDM is diagnosed if at least one value is abnormal (fasting: ≥ 5.1 mmol/L, 60 min: ≥ 10.0 mmol/L and 120 min: ≥ 8.5 mmol/L).

The other at-risk group: Except newborns delivered by women with GDM, other at-risk infants requiring close monitoring of blood glucose, including premature, macrosomia, and low birth weight were included. At-risk newborns were defined by the American Academy of Pediatrics (AAP) Committee on Fetus and Newborn[24], including those born premature (<37 week), macrosomia (>4000 g), or low birth weight (full-term infants born <2500 g).

Routine management of blood glucose after vaginal delivery

1. Diet

On the day of labor, mothers took nutritious and digestible food to replenish strength in the morning, such as chicken soup, wonton, noodles, cake, bread or dessert. After entering labor, midwives in the delivery room conducted diet management on parturients. During the intervals of contractions, midwives instructed parturients to properly take sports drinks or liquid food, normally containing carbohydrate of 45-60 mg/mL and energy of 850-1100 kj/mL. The types of food were selected according to the maternal wishes.

2. Maternal management of blood glucose during labor

For women diagnosed with GDM, the blood glucose level during labor was aimed to maintain at 3.9−6.1 mmol/L (70−110 mg/dL). Blood glucose was measured every 2 hours during labor. If the blood glucose level was higher than 5.6 mmol/L (100 mg/ dL), insulin was administered. Blood glucose monitoring during delivery wasn’t performed on parturients without GDM.

3. Management of at-risk newborns after delivery

After the birth of at-risk newborns, delayed umbilical cord clamping and radiation body rewarming were performed. Within 2 h after delivery, rooming-in was adopted in the delivery room, with room temperature at 26℃. We performed the first sucking within 30 min and skin to skin contact for 30 min. We extracted the heel blood of all at-risk infants at 0.5 h and 2 h after delivery for rapid bedside blood glucose monitoring. After performing the 30 min routine measurement of the peripheral blood glucose, if the blood glucose was <2.6 mmol/L, breast feeding support was provided by midwives to prolong sucking time.; if the blood glucose was <2.3 mmol/L, liquid milk was provided. Intravenous glucose infusion of 10% dextrose water of 200 mg /kg was conducted on newborns with constant hypoglycemia to make the blood glucose concentration rise to 2.2- 2.8 mmol /L.

Measurement

1. UACBG measurement.

After vaginal delivery, as the umbilical cord pulse ceased (1-3 min after birth), 1ml blood was extracted in umbilical artery with heparinized blood gas needle before ligation. GEM Premier 4000 automatic blood gas analyzer (manufacturer: Instrumentation Laboratory Co.; Country: America) was used for immediate measurement in delivery room, acquiring the level of cord blood glucose by the electrode method. Laboratory professionals conducted the blood glucose measurement.

2. Neonatal peripheral blood glucose measurement

Given the ethics of monitoring blood glucose with venous blood, blood glucose measurement was performed with rapid blood glucose meter. Studies have confirmed that there is a good correlation between the actual blood glucose concentration and the results of the dipstick test, which can be used to discriminate hypoglycemia. Midwives conducted peripheral blood glucose tests. At 0.5 h and 2 h after birth, a needle was used to puncture the medial heel of the newborn, and the first drop of blood was discarded. Then one drop of plantar peripheral blood was collected from all newborns. Blood glucose measurement was performed quickly using Roche Accu-Chek micro blood glucose meter (manufacturer: Instrumentation Laboratory Co.; Country: America). When the heel blood was measured <2.6 mmol/L with rapid blood glucose meter, blood would be extracted from the radial artery again. Whole blood glucose concentration was measured with glucose oxidase method to diagnose hypoglycemia.

3. Data collection

The electronic medical record system of the hospital was used to collect basic clinical data such as age, gestational age, parity, BMI, length of labor, labor analgesia, newborn birth weight, Apgar score, and the test values of OGTT measured at 24−28 weeks, and blood glucose at birth.

Statistical analyses

The sample size was calculated using Power Analysis and Sample Size (PASS) software to detect an area under the receiver operating characteristic curve (AUROC) of 0.70 given a null hypothesis of an AUROC of 0.5. Considering that the neonatal hypoglycemia rate was approximately 10%, we determined that a minimum of 341 infants (including 31 hypoglycemia neonatal and 310 normal glucose neonatal) were needed in each group to obtain a study power of 80% with an α error of 0.05. Subjects with missing data were not included in the current study.

With data entered by two persons, consistency check was performed. All statistical analyses were conducted with SPSS statistics version 25.0. In terms of continuous variables, the Student’s t-test was applied to compare normal distribution data, which were described as means and standard deviations (SD). Mann-Whitney U test was used to compare non-normal distribution data, which were described with median and interquartile range. In the case of categorical variables, we used Chi-square test. The correlation between UACBG and neonatal blood glucose was analyzed by Pearson linear correlation analysis. Receiver Operating Characteristic curve (ROC) curve and area under curve (AUC) were used to assess the discrimination of cord blood glucose predicting neonatal hypoglycemia.

Clinical characteristics of infants

A total of 916 newborns were included in our research, 538 in GDM group and 378 in the other at-risk group. Of the newborns in the other at-risk group, 116 (30.69%) were premature, 218 (57.67%) were macrosomia and 44 (11.64%) were low birth weight. Supplementary Information 1 demonstrated that 103 cases lost data of umbilical cord blood glucose, 42 cases lost data of 0.5-h peripheral blood glucose and 76 cases lost data of 2-h peripheral blood glucose. Among the GDM group, maternal ages were older (29.31±3.93 year Vs. 28.43±3.61 year), pre-pregnancy BMI was higher (22.48±4.26 kg/m² Vs. 21.90±3.11 kg/m²), the proportion of primipara (70.45% Vs. 62.43%) and female newborns (49.44% Vs. 41.27%) were higher, more patients had a 1 min Apgar score <7 (1.86% Vs. 0.26%), and the labor process was longer (389.22±180.48 min Vs. 365.20±166.71 min). (Table 1)

The value of UACBG in GDM group was higher than that in the other at-risk group(5.06±1.23 mmol/L Vs. 4.68±1.08 mmol/L), and their peripheral blood glucose at 0.5 h (4.12±0.94 mmol/L Vs. 3.81±0.92 mmol/L) and 2 h (3.72±0.71 mmol/L Vs. 3.48±0.65 mmol/L ) postnatal was also higher. The risk of neonatal hypoglycemia was higher in the other at-risk group, among which the total incidence of hypoglycemia within 2 h is 14.33% (n=49), while 7.27% (n=36) in the GDM one. The incidence of 0.5-h neonatal hypoglycemia is 9.02% (n=33) in the other at-risk group and 4.13% (n=21) in the GDM group respectively. Among the other at-risk group, there are 14 infants born premature (12.07% of all premature birth), 15 born macrosomia (9.09% of all macrosomia infants), and 4 born low birth weight (6.88% of all infants with low birth weight). In the GDM group, 1 case was complicated with premature and 3 were with macrosomia. Regarding 2-h neonatal hypoglycemia, the risk is 8.99% (n=31) in pregnancies with the other at-risk newborns, among which there are 18 born premature (15.52% of all premature birth), 9 born macrosomia (9.09% of all macrosomia infants), and 4 born low birth weight (6.88% of all infants with low birth weight), and 3.84% (n=19) in those with GDM, of which one case was complicated with premature and another one was with macrosomia. (Table 2)

Correlation between UACBG and postpartum peripheral blood glucose

UACBG was more significantly related to 0.5-h peripheral blood glucose (r=0.574) [GDM group (r=0.540) and the other at-risk group (r=0.606)]. However, the correlation declined when it comes to 2-h peripheral blood glucose (r=0.166) [GDM group (r=0.138) and the other at-risk group (r=0.154)]. (Table 3)

UACBG predicting neonatal hypoglycemia

Using ROC analyses, for total hypoglycemia within 2 h, we found that the best cut-off point was 4.150 mmol/L, yielding a sensitivity of 0.756, a specificity of 0.532, and an AUC of 0.688 (95% CI 0.625-0.751, p=0.000). UACBG has a better performance for hypoglycemia at 0.5 h (AUC 0.757; 95% CI 0.690-0.824, p=0.000), and the optimal threshlod was 4.550 mmol/L, with a sensitivity of 0.604 and a specificity of 0.813. Regarding hypoglycemia at 2 h, we obtained an optimal cut-off of 3.950 mmol/L, yielding a sensitivity of 0.805, a specificity of 0.432, and an AUC of 0.637 (95% CI 0.550-0.725, p=0.002). (Figure 1a-c)

Figure 1d-f showed the comparison of ROC curves between the GDM group and other at-risk group. For hypoglycemia prediction within 2 h (Figure 1d), the AUC was 0.680 (95% CI 0.589-0.771, p=0.000) in GDM group, with a best cut-off of 4.150 mmol/L, and 0.678 (95% CI 0.586-0.771, p=0.000) in the other at-risk one, with a best threshold of 3.950 mmol/L. UACBG had a better predictive ability at 0.5 h (Figure 1e), the AUC was 0.703 in GDM group (95% CI 0.594-0.811, p=0.002), and the optimal cut-off point was 4.550 mmol/L, with sensitivity at 0.648 and specificity at 0.714. In the other at-risk group, the sensitivity was 0.654, the specificity was 0.815, and the AUC was 0.797(95% CI 0.716-0.877, p=0.000), with the best threshold of 4.350 mmol/L. ROC curves for detection of neonatal hyperglycemia at 2 h were presented in Figure 1f. The AUC were 0.628 (95% CI 0.496-0.761, p=0.066) in GDM group and 0.620（95% 0.496-0.744, p=0.043）in the other at-risk group, with the optimal cut-offs of 4.750 mmol/L and 3.550 mmol/L. No significant differences were observed between GDM group and the other at-risk group for prediction of neonatal hyperglycemia within 2 h (Z=0.023, P=0.982), at 0.5 h (Z=1.340, P=0.180) and at 2 h (Z=0.0871, P=0.931) after delivery.

To our knowledge, this research is the first to explore the value of UACBG in predicting neonatal hypoglycemia in pregnancies with GDM and those with at-risk newborns separately within 2 h after delivery. We found that UACBG was efficient in predicting neonatal hypoglycemia within 2 h after delivery, especially at 0.5 h after birth. No differences were observed between GDM group and the other at-risk group in UACBG prediction.

Here are some possible theories explaining the pathogenesis of UACBG predicting neonatal hypoglycemia. The newborns are dependent on placenta glucose transfer[25]. Emerging data reveal that the newborns themselves, such as fetal glucose consumption, may significantly affect placental glucose supply[21]. A healthy, term infant consumes about 10% of available glucose flowing in fetal–placental circulation, which would likely be higher in gestations with infants born premature, macrosomia, low birth weight or to mothers with GDM[20, 21]. Thus, determining the glucose extraction of fetus may be a more accurate approach to identifying neonates at the highest risk of hypoglycemia. Glucose extraction, calculated from umbilical cord arterial blood samples, represents the utilisation of blood glucose in fetal–placental unit. Thus, we hypothesize that this measure could predict the incidence of hypoglycemia. Studies regarding the genes and cells of umbilical cord blood and neonatal blood also supported our hypothesis. A recent study pointed out that DNA methylation (DNAm) from umbilical cord blood and neonatal blood demonstrated a high overall agreement, with 70% of CpGs having similar mean DNAm concentrations[26]. Zhang et al. found that the frequencies of cobblestone area-forming cells and long-term culture-initiating cells in mononuclear cells of umbilical cord blood and neonatal blood were similar[27]. These findings implied that umbilical cord blood and neonatal blood come from the same source, therefore, it is possible for umbilical cord blood to be used as an alternative to neonatal blood to predict neonatal hypoglycemia. What’s more, some studies proposed that Slit-2/Robo1 signaling might be involved in the pathogenesis of UACBG predicting neonatal hypoglycemia[28]. After studying the relationship between Slit-2 and neonatal blood glucose, it has been revealed that cord artery blood could well reflect the neonatal metabolic concentrations[29]. However, these theories need further experimental evidence.

As to why UACBG extraction at 2 h showed worse performance in predicting neonatal hypoglycemia, it may be due to the treatments targeted at transient hypoglycemia, such as feeding of formula or breast milk, intravenous dextrose performed when glucose levels are <18–25 mg/dL.[30] In addition, with the first sucking and skin to skin contact performed, the result was more greatly influenced by external environment at 2 h after birth.

ROC analyses showed that there were no significant differences in the ability of UACBG predicting neonatal hypoglycemia within 2 h after delivery between GDM group and the other at-risk group, which may be ascribed to diet management on vaginal parturients, early post-delivery breast feeding and optimal maternal glucose management during the antepartum and intrapartum period[31].

However, the umbilical cord blood glucose level is higher in GDM group and the incidence of neonatal hypoglycemia was different between these two groups, which can be explained by the differences in the pathophysiology of hypoglycemia.

The mechanisms of neonatal hypoglycemia in GDM pregnancies are complex. Above all, according to the modified Pedersen hypothesis[32], which has also been verified by the Pediatric Endocrine Society committee on hypoglycemia[10], the steeper glucose gradient leads to excess glucose crossing the placenta, creating a fetal hyperinsulinemia environment, in which the prime mover is the pancreatic beta-cell. Increased glucose uptake, improper suppression of lipolysis and ketogenesis, and inappropriately huge glycemic response to epinephrine or glucagon facilitate a state of neonatal hypoglycemia[33]. Excess glucose crossing the placenta during this process explains why the umbilical cord blood glucose level is higher in GDM group. Recent studies implicated that impaired KATP channel transition in response to fetal hypoxemia and low cerebro-placental ratio were another two possible underlying mechanisms[34-36]. Moreover, for women with GDM, given that hyperglycemia might stimulate the secretion of fetal insulin, efforts are generally made to control maternal blood glucose during labor and delivery, which in turn may increase the incidence of neonatal hypoglycemia[37].

Among the other at-risk group, term neonates maintain self-sufficient glucose homeostasis with the stored glycogen. In comparison, premature newborns have lower storage of glycogen and employ them more quickly, increasing the incidence of hypoglycemia after birth[17, 18], which explains why the risk of neonatal hypoglycemia turned out to be the highest in premature birth and increased within 2 h after delivery. In terms of macrosomia infants, neonatal hypoglycemia may be ascribed to their excessive growth, improper response to hypoglycemia antenatally, abnormal neonatal fat mass and weight distribution[16, 38]. Infants born with low birth weight have low glycogen and fat stores or inferior ability in mobilizing the stores, absence of substrate source for gluconeogenesis, inappropriate secretion of insulin, increased insulin sensitivity, and decreased counter-regulatory hormones, leading to increased incidence of neonatal hypoglycemia[12, 13, 15]. Low birth weight has also been reported to be associated with transient hyperinsulinism, irrespective of maternal blood glucose status[14].

According to the results, we should perform UACBG extraction at 0.5 h after delivery, with an umbilical blood glucose less than 4.35 mmol/L as the threshlod for treatment in infants born premature, macrosomia, or low birth weight, and GDM group using less than 4.55 mmol/L. Glucose concentration should be maintained above the threshold to treat neonatal hypoglycemia.

Further assessing the risk of neonatal hypoglycemia in these two groups, which was the highest in premature birth, and increased within 2 h after delivery, suggesting that we should pay more attention to preterm birth. We speculated that this novel measure may show better accuracy in predicting neonatal hypoglycemia in premature delivery, which warrants further investigation in a larger cohort.

This research has some limitations. The generalizability of our findings may be limited owing to infants born in a single hospital and lack of follow-up. In addition, we acknowledge that intervention cut-offs for the management of hypoglycemia are different among institutions, so the definition of ≤2.6 mmol/L may cause a bias in the conclusion. Premature interventions could lead to excess treatment of more neonates than would be necessary. Thus, our findings should be cautiously interpreted.

Nevertheless, in contrast with other studies on the identification of neonatal hypoglycemia, our research has advantages. First, in current invasive neonatal glucose monitoring methods, the glucose meters used could lead to breaking of skin, pain and the potential for infection[39]. However, we met the call for the development of a measurement non-invasively and painlessly evaluating glucose levels accurately in neonates. Second, considering the effect of cesarean delivery on the odds of neonatal hypoglycemia[40], only vaginal delivery was included, which also increases the reliabiliy of our findings. Third, given the differences in post-delivery breast feeding, formula milk supplementation, and early skin to skin contact among newborns in different medical institutions, we explored the predictive value of at 0.5 h and 2 h respectively, making it possible to diagnose neonatal hypoglycemia and take interventions in time to avoid later neurodevelopmental disorders. Last, we separated modeling of GDM and other at-risk infants, further determining the application scope of UACBG in predicting neonatal hypoglycemia.

UACBG could help predict neonatal hypoglycemia within 2 h after delivery, especially at 0.5 h. No significant differences were observed in the ability of UACBG in predicting neonatal hypoglycemia within 2 h after delivery between GDM group and the other at-risk group. This novel measure provides a different approach to assessing the risk of neonatal hypoglycemia after birth, potentially contributing to more targeted application of prophylactic interventions in time, although more studies are warranted to confirm the predictive value of UACBG.

AAP American Academy of Pediatrics

AUC area under curve

AUROC area under the receiver operating characteristic curve

DNAm DNA methylation

GDM gestational diabetes mellitus

IADPSG International Association of Diabetes in Pregnancy Study Group

OGTT oral glucose tolerance test

PASS Power Analysis and Sample Size

ROC receiver operating characteristic curve

SD standard deviations

UACBG umbilical artery cord blood glucose

Funding

This work was supported by the Funding of Science and Technology Program of Nantong City [MS12020036&MS12021040].

Competing interests

None.

Authors’ contributions

Yuan Wang: Data analysis, interpretation of results, and drafted the initial manuscript

Huahua Liu: Study design and data collection

Leilei Zhang, Xin Wang, and Mingbo Wang: Data collection and analysis

Zhifang Chen and Feng Zhang: Data analysis and finalized the manuscript

All authors critically reviewed the manuscript, and approved the final manuscript as submitted.

Ethics approval

This research was approved by the Ethics Committee (Ethics No: Y 2020039) of Affiliated Maternal and Child Health Care Hospital of Nantong University.

Consent to participate

The written consent to participate was obtained from the parents of the children.

Consent for publication

We obtained informed consent from all individual participants included in this study.

Dixon KC, Ferris RL, Marikar D, Chong M, Mittal A, Manikam L et al (2017) Definition and monitoring of neonatal hypoglycaemia: a nationwide survey of NHS England Neonatal Units. Arch Dis Child Fetal Neonatal Ed, 102(1):F92-F93.
Begum S, Dey SK, Fatema K (2018) Neonatal Glycemic Status of Infants of Diabetic Mothers in a Tertiary Care Hospital. Indian J Endocrinol Metab, 22(5):621–626.
Xinxin Huang XJ, Yan lin, Xianlin Zhou (2017) Dynamic changes of blood glucose in newborns with gestational diabetes mellitus within 48 hours after birth and the influencing factors of hypoglycemia. Chinese Journal of Evidence Based Pediatrics, 12(5):342–346.
McKinlay CJD, Alsweiler JM, Anstice NS, Burakevych N, Chakraborty A, Chase JG et al (2017) Association of Neonatal Glycemia With Neurodevelopmental Outcomes at 4.5 Years. JAMA Pediatr, 171(10):972–983.
Shah R, Harding J, Brown J, McKinlay C (2019) Neonatal Glycaemia and Neurodevelopmental Outcomes: A Systematic Review and Meta-Analysis. Neonatology, 115(2):116–126.
Harding JE, Harris DL, Hegarty JE, Alsweiler JM, McKinlay CJ (2017) An emerging evidence base for the management of neonatal hypoglycaemia. Early Hum Dev, 104:51–56.
Harris DL, Weston PJ, Harding JE (2012) Incidence of neonatal hypoglycemia in babies identified as at risk. J Pediatr, 161(5):787–791.
Choudhury AA, Devi Rajeswari V (2021) Gestational diabetes mellitus - A metabolic and reproductive disorder. Biomed Pharmacother, 143:112183.
Maayan-Metzger A, Lubin D, Kuint J (2009) Hypoglycemia rates in the first days of life among term infants born to diabetic mothers. Neonatology, 96(2):80–85.
Stanley CA, Rozance PJ, Thornton PS, De Leon DD, Harris D, Haymond MW et al (2015) Re-evaluating "transitional neonatal hypoglycemia": mechanism and implications for management. J Pediatr, 166(6):1520–1525 e1521.
Kc K, Shakya S, Zhang H (2015) Gestational diabetes mellitus and macrosomia: a literature review. Ann Nutr Metab, 66 Suppl 2:14–20.
Thornton PS, Stanley CA, De Leon DD, Harris D, Haymond MW, Hussain K et al (2015) Recommendations from the Pediatric Endocrine Society for Evaluation and Management of Persistent Hypoglycemia in Neonates, Infants, and Children. J Pediatr, 167(2):238–245.
Thompson-Branch A, Havranek T (2017) Neonatal Hypoglycemia. Pediatr Rev, 38(4):147–157.
Hawdon JM (2011) Babies born after diabetes in pregnancy: what are the short- and long-term risks and how can we minimise them? Best Pract Res Clin Obstet Gynaecol, 25(1):91–104.
Sharma D, Farahbakhsh N, Shastri S, Sharma P (2016) Intrauterine growth restriction - part 2. J Matern Fetal Neonatal Med, 29(24):4037–4048.
Guemes M, Hussain K (2015) Hyperinsulinemic Hypoglycemia. Pediatr Clin North Am, 62(4):1017–1036.
Staffler A, Klemme M, Mola-Schenzle E, Mittal R, Schulze A, Flemmer AW (2013) Very low birth weight preterm infants are at risk for hypoglycemia once on total enteral nutrition. J Matern Fetal Neonatal Med, 26(13):1337–1341.
Mitanchez D (2007) Glucose regulation in preterm newborn infants. Horm Res, 68(6):265–271.
Turner D, Monthe-Dreze C, Cherkerzian S, Gregory K, Sen S (2019) Maternal obesity and cesarean section delivery: additional risk factors for neonatal hypoglycemia? J Perinatol, 39(8):1057–1064.
Hay WW, Jr. (2006) Placental-fetal glucose exchange and fetal glucose metabolism. Trans Am Clin Climatol Assoc, 117:321–339; discussion 339–340.
Holme AM, Roland MC, Lorentzen B, Michelsen TM, Henriksen T (2015) Placental glucose transfer: a human in vivo study. PLoS One, 10(2):e0117084.
Aundhakar CD, Bahatkar K (2021) Electrolyte status and plasma glucose levels in birth asphyxia: A case–control study. Journal of Medical Sciences, 41(1).
Weinert LS (2010) International Association of Diabetes and Pregnancy Study Groups recommendations on the diagnosis and classification of hyperglycemia in pregnancy: comment to the International Association of Diabetes and Pregnancy Study Groups Consensus Panel. Diabetes Care, 33(7):e97; author reply e98.
Committee on F, Newborn, Adamkin DH (2011) Postnatal glucose homeostasis in late-preterm and term infants. Pediatrics, 127(3):575–579.
Kalhan S, Parimi P (2000) Gluconeogenesis in the fetus and neonate. Semin Perinatol, 24(2):94–106.
Jiang Y, Wei J, Zhang H, Ewart S, Rezwan FI, Holloway JW et al (2020) Epigenome wide comparison of DNA methylation profile between paired umbilical cord blood and neonatal blood on Guthrie cards. Epigenetics, 15(5):454–461.
Zhang XB, Li K, Fok TF, Li CK, James AE, Lam AC et al (2002) Cobblestone area-forming cells, long-term culture-initiating cells and NOD/SCID repopulating cells in human neonatal blood: a comparison with umbilical cord blood. Bone Marrow Transplant, 30(9):557–564.
Li P, Shi Y, Shuai H, Cai Y, Lu W, Wang G et al (2017) Alterted SLIT2/ROBO1 signalling is linked to impaired placentation of missed and threatened miscarriage in early pregnancy. Histopathology, 71(4):543–552.
Wang Y, Zhao S, Peng W, Chen Y, Chi J, Che K et al (2022) The Role of Slit-2 in Gestational Diabetes Mellitus and Its Effect on Pregnancy Outcome. Front Endocrinol (Lausanne), 13:889505.
Hawdon JM (2019) Identification and Management of Neonatal Hypoglycemia in the Full-Term Infant. British Association of Perinatal Medicine Framework for Practice, 2017. J Hum Lact, 35(3):521–523.
Ogunyemi D, Friedman P, Betcher K, Whitten A, Sugiyama N, Qu L et al (2017) Obstetrical correlates and perinatal consequences of neonatal hypoglycemia in term infants. J Matern Fetal Neonatal Med, 30(11):1372–1377.
Pedersen J, Bojsen-Moller B, Poulsen H (1954) Blood sugar in newborn infants of diabetic mothers. Acta Endocrinol (Copenh), 15(1):33–52.
Hoe FM, Thornton PS, Wanner LA, Steinkrauss L, Simmons RA, Stanley CA (2006) Clinical features and insulin regulation in infants with a syndrome of prolonged neonatal hyperinsulinism. J Pediatr, 148(2):207–212.
Stanescu DL, Stanley CA (2022) Advances in Understanding the Mechanism of Transitional Neonatal Hypoglycemia and Implications for Management. Clin Perinatol, 49(1):55–72.
Yang J, Hammoud B, Li C, Ridler A, Yau D, Kim J et al (2021) Decreased KATP Channel Activity Contributes to the Low Glucose Threshold for Insulin Secretion of Rat Neonatal Islets. Endocrinology, 162(9).
Ganor Paz Y, Barzilay E, Saied Idriss S, Murray-Davis B, Melamed N, Ray J et al (2022) Association of the Cerebro-Placental Ratio with Adverse Outcomes in Pregnancies Affected by Gestational Diabetes Mellitus. J Ultrasound Med.
Kitzmiller JL, Block JM, Brown FM, Catalano PM, Conway DL, Coustan DR et al (2008) Managing preexisting diabetes for pregnancy: summary of evidence and consensus recommendations for care. Diabetes Care, 31(5):1060–1079.
Bouchghoul H, Mokhtari DM, Letourneau A, Bouyer J, Senat MV (2022) Risk of hypoglycemia by anthropometric measurements in neonates of mothers with diabetes. Eur J Pediatr.
Woo HC, Tolosa L, El-Metwally D, Viscardi RM (2014) Glucose monitoring in neonates: need for accurate and non-invasive methods. Arch Dis Child Fetal Neonatal Ed, 99(2):F153-157.
Ruiz NM, Garcia Iniguez JP, Rite Gracia S, Samper Villagrasa MP (2022) Prospective study on influence of perinatal factors on the development of early neonatal hypoglycemia in late preterm and term infants. An Pediatr (Engl Ed), 96(3):230–241.

Table 1 Characteristics of the study population.
	GDM group (N=538)	Other at−risk group (N=378)	F/t	p
Age (years), mean±SD	29.31±3.93	28.43±3.61	-3.527	0.000
Residence, n (%) City Country Migrant population Rural population	344(64.18) 131(24.44) 24(4.48) 37(6.90)	229(60.58) 94(24.87) 27(7.14) 28(7.41)	3.375	0.337
BMI (kg/m²), mean±SD
Pre-pregnancy	22.48±4.26	21.90±3.11	-2.274	0.023
Antepartum	27.37±3.87	27.51±3.56	0.559	0.577
Times of pregnancy, n (%) 1 2 ≥3	379(70.45) 138(25.65) 21(3.90)	236(62.43) 132(34.92) 10(2.65)	9.633	0.008
Gestational age (weeks), mean±SD	38.55±2.06	38.96±1.60	-3.283	0.001
Premature delivery, n (%) Yes No	38(7.06) 500(92.94)	116(30.69) 262(69.31)	88.598	0.000
Neonatal gender, n (%) Male Female	272(50.56) 266(49.44)	222(58.73) 156(41.27)	5.968	0.015
Neonatal weight (g), n (%) <2500 2501~3999 ≥4000	21(3.91) 488(90.88) 28(5.21)	78(20.64) 82(21.69) 218(57.67)	454.858	0.000
Apgar score 1min, n (%) ≤7 ≥8	10(1.86) 538(98.14)	1(0.26) 377(99.74)	4.756	0.032
Apgar score 5min, n (%) ≤7 ≥8	1(0.19) 537(99.81)	0(0) 378(100)	-	1.000
Length of labor (min), mean±SD	389.22±180.48	365.20±166.71	-2.047	0.041
Transferred to NICU, n (%) Yes No	30(5.58) 508(94.42)	11(2.91) 367(97.09)	3.691	0.055
Complications, n (%) 0 1 ≥2	339(63.01) 182(33.83) 17(2.96)	231(61.27) 138(36.60) 8(2.13)	1.910	0.591
pH of cord blood, mean±SD	7.23±0.90	7.23±0.83	-0.008	0.994
Two cases are absent of information on residence, Apgar score 1 min was modified by fisher exact test. In addition to GDM, complications included premature rupture of membrane，gestational hypertension, hyperthyroidism, hypothyroidism, oligoamnios, polyhydramnios, ICP, anaemia, and placental abruption. GDM, gestational diabetes mellitus

Table 2 Umbilical cord blood glucose, and 0.5-h and 2-h peripheral blood glucose in the two groups.
	GDM group (N=538)	Other at−risk group (N=378)		F/t	p
Umbilical cord blood glucose (mmol/L)	5.06±1.23	4.68±1.08	-4.567		0.000
0.5-h peripheral blood glucose (mmol/L)	4.12±0.94	3.81±0.92	-4.79		0.000
2-h peripheral blood glucose (mmol/L)	3.72±0.71	3.48±0.65	-5.018		0.000
Difference value of change in blood glucose	0.39±1.01	0.35±0.97	-0.548		0.584
0.5-h hypoglycemia	21(4.13)	33(9.02)	8.749		0.003
2-h hypoglycemia	19(3.84)	31(8.99)	9.621		0.002
Total hypoglycemia within 2h	36(7.27)	49(14.33)	11.033		0.001
Umbilical cord blood glucose: GDM group (n=478), Other at-risk group (n=335); 0.5-h peripheral blood glucose: GDM group (n=508), Other at-risk group (n=366); 2-h peripheral blood glucose: GDM group (n=495), Other at-risk group (n=345). GDM, gestational diabetes mellitus.

Table 3 The correlation between umbilical cord blood glucose and peripheral blood glucose.
	umbilical cord blood glucose in GDM group		umbilical cord blood glucose in other at-risk group		Total umbilical cord blood glucose
	r	p	r	p	r	p
0.5-h peripheral blood glucose in GDM group	0.540	0.000	-	-	-
0.5-h peripheral blood glucose in other at-risk group	-	-	0.606	0.000	-	-
Total 0.5-h peripheral blood glucose	-	-	-	-	0.574	0.000
2-h peripheral blood glucose in GDM group	0.138	0.004			-	-
2-h peripheral blood glucose in other at-risk group	-	-	0.154	0.007	-	-
Total 2-h peripheral blood glucose	-	-	-	-	0.166	0.000
GDM, gestational diabetes mellitus.

No competing interests reported.

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Umbilical Artery Cord Blood Glucose Predicted neonatal hypoglycemia in Gestational Diabetes Mellitus and Other at-risk Newborns after Vaginal Delivery

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