If you don't remember your password, you can reset it by entering your email address and clicking the Reset Password button. You will then receive an email that contains a secure link for resetting your password
If the address matches a valid account an email will be sent to __email__ with instructions for resetting your password
Department of Neonatology, Maternal and Child Health Hospital of Hubei Province, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaDepartment of Neonatology, Xianning Central Hospital, First Affiliated Hospital of Hubei University of Science and Technology, Xianning, ChinaSchool of Medicine, Wuhan University of Science and Technology, Wuhan, China
Department of Neonatology, Maternal and Child Health Hospital of Hubei Province, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
Department of Neonatology, Maternal and Child Health Hospital of Hubei Province, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
Corresponding author. Department of Neonatology, Maternal and Child Health Hospital of Hubei Province, No. 745 Wuluo Road, Hongshan District, Wuhan 430070, China.
Department of Neonatology, Maternal and Child Health Hospital of Hubei Province, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
Birth asphyxia causes hypoxia or inadequate perfusion to the organs of newborns, leading to metabolism dysfunctions including blood glucose disorders.
Methods
Neonates with and without birth asphyxia were retrospectively recruited from 53 hospitals in Hubei Province from January 1 to December 31, 2018. In summary, 875, 1139, and 180 cases in the control group, the mild asphyxia group, and the severe asphyxia group were recruited, respectively. Neonatal blood glucose values at postnatal 1, 2, 6, and 12 h (time error within 0.5 h was allowed) were gathered from the medical records.
Results
The incidence rates of hyperglycemia in the control group, the mild asphyxia group and the severe asphyxia group were 2.97%, 7.90%, and 23.33%, respectively (p < 0.001). Additionally, the incidence rates of hypoglycemia in the three groups above were 3.66%, 4.13%, and 7.78%, respectively (p = 0.042). The blood glucose values of neonates with hypoglycemia in the asphyxia group were lower than in the control group (p = 0.003). Furthermore, the blood glucose values of neonates with hyperglycemia were highest in the severe asphyxia group (p < 0.001). There were 778 and 117 cases with blood glucose records at four predefined time points in the mild and severe asphyxia group, respectively. The incidence of blood glucose disorders in the mild asphyxia group significantly decreased from postnatal 6 h (p＜0.05). However, we found no obvious changes of the incidence of glucose disorders within postnatal 12 h in the severe asphyxia group (p = 0.589).
Conclusion
Birth asphyxia is likely to cause neonatal blood glucose disorders, both hypoglycemia and hyperglycemia, during the early postnatal life. The neonates with severe asphyxia have higher incidence, worse severity and longer duration of blood glucose disorders than neonates with mild asphyxia.
The neonatal mortality rate in China in 2019 is 3.5 deaths per 1000 live births, and birth asphyxia is the second leading cause of death in neonates, constituting more than one fifth of neonatal mortality, second only to preterm birth complications.
Global, regional, and national causes of under-5 mortality in 2000-15: an updated systematic analysis with implications for the Sustainable Development Goals.
Global, regional, and national causes of under-5 mortality in 2000-15: an updated systematic analysis with implications for the Sustainable Development Goals.
Birth asphyxia is a combination of hypoxia, hypercarbia, and metabolic acidosis, in which newborns cannot initiate or sustain spontaneous breathing after birth due to various perinatal events.
It is a damage to the fetus or neonate either in the antepartum or intrapartum period, with high short-term mortality and adverse long-term outcomes such as cerebral palsy and cognitive impairment.
Birth asphyxia causes hypoxia or inadequate perfusion to various organs of newborns, leading to a variety of metabolism dysfunction including blood glucose disorders.
Previous researches reported that neonatal blood glucose disorders are more likely to occur during the first 12 h of life, and both birth asphyxia and blood glucose disorders are associated to the brain injury of the neonates.
Hypoglycaemia and hyperglycaemia are associated with unfavourable outcome in infants with hypoxic ischaemic encephalopathy: a post hoc analysis of the CoolCap study.
Hypoglycaemia and hyperglycaemia are associated with unfavourable outcome in infants with hypoxic ischaemic encephalopathy: a post hoc analysis of the CoolCap study.
In our preliminary study, 134 neonates with birth asphyxia were enrolled, and the neonatal blood glucose values within postnatal 30 min before any nutritional support were analyzed.
We found that neonates with severe asphyxia had a higher incidence of blood glucose disorders, especially hyperglycemia, than neonates with mild asphyxia. However, dynamic monitoring data of the neonatal blood glucose in the early postnatal life is rarely reported, and the association between the severity of birth asphyxia and the duration of the neonatal blood glucose disorders is unclear at present.
This study aimed to clarify the profiles of the blood glucose of neonates with birth asphyxia within the first 12 h of life to provide evidence for individual clinical management. We enrolled 53 neonatal intensive care units (NICUs) in Hubei Province and conducted a multi-center retrospective study to know the incidence of hypoglycemia and hyperglycemia within the first 12 h of life. Additionally, the dynamic changes of neonatal blood glucose values at postnatal 1, 2, 6, and 12 h were analyzed to evaluate the duration of the blood glucose disorders.
2. Methods
2.1 Study design and population
Participants were recruited from a multi-center study on Epidemiological Investigation and Quality Improvement of Birth Asphyxia in Hubei Province. The retrospective study was conducted at 53 NICUs in 12 cities of Hubei Province from January 1 to December 31, 2018. Inclusion criteria were as follows: (1) neonates with birth asphyxia; (2) a random sampling method was used for the selection of neonates in the control group, from neonates who were admitted for other diseases (e.g., prematurity, hyperbilirubinemia, neonatal amniotic fluid aspiration syndrome, neonatal respiratory distress syndrome) except for birth asphyxia in the same NICUs as the asphyxia group and matched by gestational age; (3) neonates with complete medical records; and (4) presence of at least once blood glucose value at predefined time points (postnatal 1, 2, 6, and 12 h), and the time error within half an hour was allowed. Exclusion criteria included the following
: (1) neonates with APGAR score 1 min or 5min ≤7 caused by other disease (except for birth asphyxia), such as congenital heart disease, central nervous system malformation, neuromuscular disease, fetal hemorrhagic shock, fetal edema, or passive drug poisoning of the fetus caused by the use of large doses of anesthetics by the mother; (2) accidental asphyxia after birth; (3) neonates of mothers with diabetes; and (4) no blood glucose value at predefined time points.
Neonates were usually infused with a glucose-containing fluid at an initial glucose infusion rate of 4 mg/kg/min. Hypoglycemia was treated with intravenous dextrose, increasing glucose infusion rates or glucagon. Hyperglycemia was managed by reducing glucose infusion rate or giving insulin infusion. Feeding was initiated as soon as possible, if tolerable.
2.2 Data collection
Blood glucose values were collected at predefined time points. Neonatal clinical data (sex, gestational age, birth weight, type of delivery, twins or multiples, gestational complications, severity of asphyxia, etc.) were collected from medical records. The study was led by the Maternal and Child Health Hospital of Hubei Province. Data collectors from 53 NICUs were trained through on-site meeting, WeChat, E-mail and telephone. Data were collected by EpiData software (version 3.1). Data collection was supervised by 12 supervisors.
2.3 Definitions
Mild birth asphyxia was diagnosed when a newborn with APGAR score 1 min or 5 min ≤7, accompanied by umbilical artery blood pH < 7.2; severe birth asphyxia was diagnosed when a newborn with APGAR score of 1min ≤3 or 5 min ≤5, accompanied by umbilical arterial blood pH < 7.0. Where NICUs were not equipped for umbilical arterial blood gas analysis, birth asphyxia was diagnosed according to the APGAR score.
Blood glucose disorders: hypoglycemia was defined as blood glucose <2.2 mmol/L (40 mg/dL), and hyperglycemia was defined as blood glucose >7.0 mmol/L (125 mg/dL).
Maternal prenatal infections: these included maternal chorioamnionitis, group B streptococcal infection, sexually transmitted diseases, and respiratory tract infections in this study.
Fetal distress: fetal heart rate <100 bpm, lasting for over 5 min and/or amniotic fluid grade III pollution.
The effects of monotherapy with erythropoietin in neonatal hypoxic-ischemic encephalopathy on neurobehavioral development: a systematic review and meta-analysis.
This study was in accordance with the Helsinki Declaration and was approved by the Medical Ethics Committee of the Maternal and Child Health Hospital of Hubei Province (ref no: [2020]IECXM027).
2.5 Statistical analyses
IBM SPSS Statistics software (version 22.0, Chicago, IL, USA) was used for statistical analysis. The continuous numerical variables were expressed as mean ± standard deviation. One-way ANOVA was used to compare the data of the three groups, followed by Least Significant Difference t post hoc tests or Tamhane post hoc test according to whether data conformed to normality of variance or not, respectively. Repeated measures ANOVA was used to compare the neonatal blood glucose values at different time points. The categorical variables were expressed as numbers and proportions (%), and Chi-square test or Fisher test was used to compare the proportions of the groups, if applicable. P values < 0.05 were considered statistically significant.
3. Results
3.1 Demographics of the enrolled neonates
A total of 4940 neonates were recruited in the retrospective study, and 2194 neonates finally enrolled in this study according to the protocol (Fig. 1). Among them, 1139 cases were in the mild asphyxia group, 180 cases were in the severe asphyxia group, and 875 cases were in the control group. The gestational age of the neonates ranged from 25 to 42 weeks. There were no statistical differences among the three groups in gestational age, birth weight, premature rupture of membranes, twins or multiples, small/large for gestational age, gestational hypertension, prenatal infections, and prenatal corticosteroids (all p > 0.05; Table 1). More than half of the newborns were from tertiary NICUs, especially in the severe asphyxia group. The proportion of fetal distress and caesarean delivery in the asphyxia group was significantly higher than that in the control group. Additionally, males had a higher incidence of birth asphyxia (Table 1).
P values < 0.05 were statistically significant; a defined as p < 0.05 compared with the control group; b defined as p < 0.05 compared with the mild asphyxia group.
3.2 The incidence and severity of blood glucose disorders in three groups
Within the first 12 h of life, the incidence rates of hyperglycemia of the neonates in the control group, mild asphyxia group, and severe asphyxia group were 2.97%, 7.90%, and 23.33%, respectively (p < 0.001). The incidence rates of hypoglycemia in the control group, mild asphyxia group, and severe asphyxia group were 3.66%, 4.13%, and 7.78%, respectively (p = 0.042). Additionally, the incidence rates of both hypoglycemia and hyperglycemia in the three groups above were 0.11%, 0.53%, and 1.11%, respectively, without significant difference (p = 0.110).
Further, the blood glucose values among the three groups were compared to analyze the severity of blood glucose disorders. There were 2859 samples, 3745 samples, and 597 samples in the control, the mild asphyxia and the severe asphyxia group, respectively (Table 2). The blood glucose values of hypoglycemia were lower in the severe asphyxia group (1.64 ± 0.32 mmol/L) and the mild asphyxia group (1.74 ± 0.28 mmol/L) than in the control group (1.88 ± 0.24 mmol/L) (p = 0.003; Table 2), which indicates a more severe degree of hypoglycemia. Additionally, the blood glucose values of hyperglycemia were higher (8.91 ± 1.60 mmol/L) in the severe asphyxia group than in the control group (7.92 ± 0.94 mmol/L) and mild asphyxia group (8.33 ± 1.30 mmol/L) (p < 0.001), which also indicates a more severe degree of hyperglycemia.
Table 2The blood glucose values of neonates in the three groups.
Control group
Mild asphyxia group
Severe asphyxia group
P value
n = 2859
n = 3745
n = 597
Normoglycemia n (%)
2754 (96.33%)
3511 (93.75%)a
506 (84.76%)a,b
<0.001
mmol/L
4.48 ± 0.91
4.55 ± 0.98a
4.67 ± 1.07a
<0.001
Hypoglycemia n (%)
52 (1.82%)
71 (1.90%)
16 (2.68%)
0.371
mmol/L
1.88 ± 0.24
1.74 ± 0.28a
1.64 ± 0.32a
0.003
Hyperglycemia n (%)
53 (1.86%)
163 (4.35%)a
75 (12.56%)a,b
<0.001
mmol/L
7.92 ± 0.94
8.33 ± 1.30a
8.91 ± 1.60a,b
<0.001
P values < 0.05 were statistically significant; a defined as p < 0.05 compared with the control group; b defined as p < 0.05 compared with the mild asphyxia group.
Neonates with four blood glucose values at the predefined time points were enrolled to analyze the blood glucose profile during the first 12 h of life, and 615, 778, and 117 neonates were enrolled in the control group, mild asphyxia group, and severe asphyxia group, respectively (Table 3). The blood glucose values of the three groups increased gradually at 1, 2, 6, and 12 h (p < 0.001). Neonates in the severe group had higher blood glucose values at all predefined time points (p < 0.001).
Table 3The changes of blood glucose during the first 12 h.
3.4 Duration of blood glucose disorders of asphyxiated neonates
At each predefined time point, the incidence of blood glucose disorders in the severe asphyxia group was higher than that in the mild group at the same time (all p < 0.05; Fig. 2A). In the mild asphyxia group, the incidence of blood glucose disorders was highest at postnatal 1 h, followed by postnatal 2 h, and significantly decreased from postnatal 6 h. However, there was no significant decrease of the incidence of blood glucose disorders within the first 12 h in the severe group (p = 0.589; Fig. 2B). In the mild asphyxia group, 60 cases had abnormal blood glucose at postnatal 1 h, and the blood glucose gradually recovered at 2, 6, and 12 h. Eighteen cases had abnormal blood glucose at postnatal 1 h in the severe asphyxia group, of which half had recovered at 2 h (p < 0.05); however, there was no further recovery at 6 h and 12 h (p = 0.310 and p = 0.083, respectively; Fig. 2C).
Fig. 2Distribution of blood glucose values at each time point during the first 12 h. (A) Y-axis depicts incidence of neonates with normoglycemia and blood glucose disorders at each time point. At each predefined time point, the incidence of blood glucose disorders in the severe asphyxia group was higher than that in the mild asphyxia group (all p＜0.05). (B) The incidence of blood glucose disorders in the mild asphyxia group was highest at postnatal 1 h (7.71%, n = 60/778), followed by postnatal 2 h (6.81%, n = 53/778). The incidence of blood glucose disorders was 5.14% (40/778) and 3.86% (30/778) at postnatal 6 and 12 h, respectively, which significantly decreased from that at 1 and 2 h (both p＜0.05). The incidence of blood glucose disorders in the severe asphyxia group at four predefined time points was 15.38% (18/117), 12.82% (15/117), 12.82% (15/117), and 9.40% (11/117), respectively (p = 0.589). (C) In the mild asphyxia group, 60 cases had abnormal blood glucose at postnatal 1 h. Twenty-six (43.33%), 13 (21.67%), and 5 (8.33%) neonates sustained glucose disorders at 2, 6, and 12 h, respectively. Of the 18 cases with abnormal glucose at 1 h in the severe asphyxia group, 9 (50%), 6 (33.33%), and 4 (22.22%) sustained glucose disorders at 2, 6, and 12 h, respectively. M: Mild asphyxia group; S: Severe asphyxia group. ∗ were statistically significant (p < 0.05).
Our study showed that birth asphyxia was more likely to cause neonatal blood glucose disorders (both hypoglycemia and hyperglycemia) within the first 12 h of life. Moreover, neonates with severe asphyxia seemed to have worse and longer blood glucose disorders than neonates with mild asphyxia. Neonatal asphyxia is often the extension of fetal distress. In our study, the proportion of fetal distress in the asphyxia group was significantly higher than that in the control group. In addition, newborns with severe asphyxia were more likely to be born by caesarean section. Because they were more likely to have fetal distress and need to deliver as soon as possible,
Abnormal blood glucose is an important effect of hypoxia ischemia on body metabolism, and its effect as well as mechanism is complex and debated. Newborns do not have sufficient storage of liver glycogen, but their requirement of energy is relatively high.
At the early stage of neonatal birth asphyxia, anaerobic glycolysis predominates along with the high metabolic rate and the increase of oxygen and glucose consumption.
Moreover, the blood of asphyxiated newborns is redistributed to ensure the blood supply to important organs such as brain and heart, which causes reduction of the blood and oxygen supply to gastrointestinal canal and affects the absorption of glucose.
All of the abovementioned factors can cause hypoglycemia. In our study, incidence of hypoglycemia is higher in the severe asphyxia group (7.78%) than in the mild asphyxia group (4.13%) and the control group (3.66%). In addition, this study also indicated that the degree of hypoglycemia in asphyxiated neonates was more serious than that in the control group. Previous studies also demonstrated incidence of hypoglycemia in asphyxiated neonates to be higher, and the degree of hypoglycemia in neonates with severe asphyxia to be more serious.
Both relative insulin resistance and defective islet beta-cell processing of proinsulin are responsible for transient hyperglycemia in extremely preterm infants.
Another mechanism responsible for asphyxia-related hyperglycemia is the increased secretion of stress-induced hormones (i.e., glucagon, catecholamine, corticosteroids and other glucose-raising substances) which enhance the gluconeogenesis.
In this study, the incidence of hyperglycemia is higher in the severe asphyxia group (23.33%) than in the mild asphyxia group (7.90%). A multi-center study involving 25 perinatal centers in the UK, the USA, and New Zealand consistently reported an incidence of 48% (102/214) of hyperglycemia in newborns with moderate-to-severe hypoxic ischemic encephalopathy.
Hypoglycaemia and hyperglycaemia are associated with unfavourable outcome in infants with hypoxic ischaemic encephalopathy: a post hoc analysis of the CoolCap study.
Furthermore, our study also indicated a more severe degree of hyperglycemia in neonates with severe asphyxia, which is consistent with the previous studious.
The occurrence and recovery time of multiple organ damage after asphyxia are correlated with the severity of the disease. Nadeem et al. reported that 90% of blood glucose disorders (particularly hyperglycemia) occurred within the first 6 h after birth asphyxia, and some persisted up to 72 h after birth.
In our study, the incidence of blood glucose disorders in the mild asphyxia group was highest at 1 h and then decreased gradually, but the blood glucose disorders in the severe asphyxia group did not significantly decrease within 12 h of life. These results suggested that the severely asphyxiated newborns had a longer duration of blood glucose disorders.
Additionally, this study explored the trend of blood glucose values of three groups during the early postnatal life and showed that the average blood glucose values of each group was lowest at postnatal 1 h and then gradually increased during the first 12 h. These results are consistent with the studies of Yoon et al. and Srinivasan et al.
The variation of blood glucose during the early life, also known as “transitional neonatal hypoglycemia,” is associated with the termination of maternal glucose supply, the insufficient storage of neonatal liver glycogen, and the increased energy consumption by cold and neonatal activity after birth.
Subsequently, blood glucose gradually increased with the initiation of feeding, intravenous infusion of glucose and maturation of gluconeogenesis.
In this study, the factors (i.e., gestational age, weight, small/large for gestational age, infections, prenatal corticosteroids, etc.) that may affect the neonatal blood glucose showed no significant differences between the control group and asphyxia group. In addition, all the newborns in the three groups were given homogeneous medical intervention to maintain normal blood glucose so that their blood glucose values were comparable. Although the neonatal blood glucose disorders cannot completely exclude the interference of treatments, they were mainly caused by birth asphyxia.
Several limitations of this study should be taken into consideration. As a retrospective study, the blood glucose values of the study are incomplete and discontinuous, which led to the undervaluation of the true incidence and duration of blood glucose disorders. Moreover, the retrospective study did not set the standardized treatment thresholds and interventions. The blood glucose disorders gradually recovered over time, but it was not possible to distinguish whether this recovery was due to the elimination of the effects of birth asphyxia or the response to treatments. Additionally, even though blood samples from arterial, capillary or venous may independently affect blood glucose values,
unified blood sampling was not available in this study. Therefore, further prospective studies are needed which set up standardized measurement and intervention, and which follow up long-term neurodevelopmental outcomes.
5. Conclusions
Birth asphyxia is more likely to cause blood glucose disorders, both of hypoglycemia and hyperglycemia, during the early postnatal life. Neonates with severe asphyxia have higher incidence, worse severity and longer duration of blood glucose disorders than neonates with mild asphyxia. In addition, blood glucose should be closely monitored and appropriately treated in neonates with birth asphyxia, especially severe cases. Meanwhile, reasonable monitoring and management in blood glucose will bring these vulnerable newborns closer to receiving precision fluid management.
Fund program
1.
Research Projects of the Maternal and Child Health Hospital of Hubei Province (Multi-center Epidemiological Investigation and Quality Improvement of Birth Asphyxia in Hubei Province)
2.
Public Health Leading Talents Training Program of Hubei Province (NO. 1020013003)
Declaration of competing interest
The authors have no conflicts of interest to declare.
Acknowledgments
The authors would like to thank Ms. Jun-Fang Xu of Hubei Minzu University for designing EpiData software package. Thanks also to the following clinical team who collected data for this study: Gucheng County Second People's Hospital; Gucheng Maternal and Child Health Hospital; Macheng People's Hospital; Songzi Maternal and Child Health Hospital; Xiaonan District Maternal and Child Health Hospital; Shiyan Renmin Hospital; Xiangzhou District People's Hospital; Fangxian Maternal and Child Health Hospital; Laohekou First Hospital; People's Hospital of Yicheng City; Jingzhou Maternal and Child Health Hospital; Tongshan People's Hospital; Yunxi People's Hospital; Shiyan Maternal and Child Health Hospital; Xian'an District Maternal and Child Health Hospital; Luotian People's Hospital; Yingcheng Maternal and Child Health Hospital; NanZhang People's Hospital; Zaoyang First People's Hospital; Fangxian People's Hospital; Xiaochang First People's Hospital; Dongfeng General Hospital of Sinopharm; Xishui Maternal and Child Health Hospital; Nanzhang Maternal and Child Health Hospital; Songzi People's Hospital; Yunyang District Maternal and Child Health Hospital; Nanzhang Hospital of Traditional Chinese Medicine; Tianmen Hospital of Traditional Chinese Medicine; Xianning maternal and child health care hospital; Xiaogan First People's Hospital; Baokang County People's Hospital; Xiangyang Central Hospital; Chibi General Hospital; Yinshan Maternal and Child Health Hospital.
References
Qiao J.
Wang Y.
Li X.
Jiang F.
Zhang Y.
Ma J.
et al.
A Lancet Commission on 70 years of women's reproductive, maternal, newborn, child, and adolescent health in China.
Global, regional, and national causes of under-5 mortality in 2000-15: an updated systematic analysis with implications for the Sustainable Development Goals.
Hypoglycaemia and hyperglycaemia are associated with unfavourable outcome in infants with hypoxic ischaemic encephalopathy: a post hoc analysis of the CoolCap study.
The effects of monotherapy with erythropoietin in neonatal hypoxic-ischemic encephalopathy on neurobehavioral development: a systematic review and meta-analysis.
Both relative insulin resistance and defective islet beta-cell processing of proinsulin are responsible for transient hyperglycemia in extremely preterm infants.
00056-6&id=gr1.jpg){kind=link}
00056-6&id=gr2.jpg){kind=link}