Biomedical Research

Abstract

This is a retrospective study done on 170 children, aged 3 to 5 years, who were delivered in the third affiliated hospital of Zhengzhou university, Henan, China between Jan 2019 to Dec 2020. With the help of hospital records, a systematic detection of hypoglycemia (<2.2 mmol/L or 40 mg/dL) was carried out in the study population from birth to 28 days after birth. Main outcomes were a compiled neurological or neurodevelopmental outcome; any developmental delay; motor developmental delay; and cognitive developmental delay. For analysis, the study population was divided into two groups: one group consisted of children who suffered from 5 or more episodes of hypoglycemia in neonatal period (n=42) and the second group consisted those who suffered with less than 5 episodes (n=128). We noted that the group having 5 or more hypoglycemic episodes had a higher proportion of premature or small for date children than the other group (76.2% Vs 60.9%), and the difference is statistically significant. In adjusted regression analyses, the odds ratio (OR) of any neurological or neurodevelopmental outcome was 1.48 (95% confidence interval: 1.17–1.88) in group with 5 or more hypoglycemic episodes as compared to the other group. The adjusted risk of any developmental delay was more than doubled (OR 2.53 [1.71–3.73]), the adjusted risk of motor developmental delay was almost doubled (OR: 1.91 [1.06–3.44]) and the adjusted risk of cognitive developmental delay was almost tripled (OR 2.85 [1.70–4.76]) in the group that had more than 5 hypoglycemic episodes in neonatal period.

Keywords

Children, Blood glucose, Hypoglycemia, Neurological outcome, Developmental delay.

Introduction

Hypoglycemia may be caused by various defective pathways in the production and metabolism of glucose, as well as defective pathways to maintain euglycemia [1]. Plasma glucose levels are maintained at ~55–60 mg/dL after birth, and then increase to 70 mg/dL at approximately 2 days of life [2]. The newborn period is reflected by a plasma glucose requirement of approximately 6 mg/ kg/min, which changes relative to prematurity and increasing age [3]. Premature or growth restricted infants may have reduced ability to maintain euglycemia, due to reduced glycogen stores, increased metabolic needs, or poor counter-regulatory response to hypoglycaemia [4]. In children, conditions that cause hypoglycemia are often complex, diverse, and unique; therefore, evaluation and management of the hypoglycemic child requires a substantial knowledge of all physiologic mechanisms that maintain euglycemia [5].

Longstanding discussion and research continue in order to define clinical hypoglycemia. This can be defined as a plasma glucose level below 68 mg/dL, the cutoff glucose value for when counter-regulatory processes can occur [6]. However, other studies and guidelines have proposed various plasma glucose cutoff values which could be associated with increased risk for long-term adverse outcomes [7]. Official guidelines and others have noted that among infants who are symptomatic, plasma glucose level less than 50 mg/dL (<48 hours of life), and less than 60 mg/dL (>48 hours of life) should be evaluated [1].

Despite extensive literature on the subject, hypoglycemia in infants and children remains a puzzling yet urgent diagnostic and therapeutic challenge. Neonatal hypoglycemia is a common condition, and though many children do not develop sequelae, a few can develop severe neurological damage [8]. The neurological symptoms of neonatal hypoglycemia are non-specific. These symptoms may appear gradually, with irritability, tremor, jitteriness, eye rolling, seizures, hypotonia, exaggerated Moro reflex, and progression to seizures, and acute encephalopathy, lethargy and coma [8]. The most common clinical finding reported by many researchers is an altered level of alertness, characterized as a combination of jitteriness or stupor [9]. At follow up, neonatal hypoglycemia may lead to reduced head circumference, lower than expected psychomotor scores, motor deficit and mental retardation [8].

The aim of the study was to investigate the neurological effects of neonatal hypoglycemia in the third affiliated hospital of Zhengzhou university, Henan, China.

Materials and Methods

The current study is a retrospective study done on 170 children, aged 3 to 5 years, who were delivered in the third affiliated hospital of Zhengzhou university, Henan, China between Jan 2019 to Dec 2020. The inclusion criteria was a reported hypoglycemic episode or repeated episodes of hypoglycemia in these children in the neonatal period. With the help of hospital records, a systematic detection of hypoglycemia (<2.2 mmol/L or 40 mg/dL) was carried out in the study population from birth to 28 days after birth. The children who had incomplete hospital records were excluded from the study. Apart from that, children with congenital malformations, admitted in neonatal intensive care unit, born with inborn errors of metabolism and those with diabetic mothers were excluded. Exposure was neonatal moderate hypoglycemia. Main outcomes were the following (Table 1).

Table 1: Statistical Analyses.

A P value < 0.05 was considered statistically significant. For statistical analyses, SAS version 9.4 was used. The study was approved by the institutional ethical committee.

Results

Out of 170 children, 120 (70.6%) had recurring or multiple episodes of hypoglycemia in their neonatal period and rest 50 children had a single severe episode of hypoglycemia. It was seen that 68 (40.0%) children were diagnosed with hyperbilirubinemia and 18 (10.6%) with Hypoxic- Ischaemic Encephalopathy (HIE).

The mean age of children was 3.2 years (SD 0.5 years), with a mean birth weight of 1824 grams (SD 504 grams). One hundred and fifteen children (67.6%) were premature or small for date. Their mean blood glucose level at 28 days was 44 gm/dl (SD 13 gm/dl).

For analysis, the study population was divided into two groups: one group consisted of children who suffered from 5 or more episodes of hypoglycemia in neonatal period (n=42) and the second group consisted those who suffered with less than 5 episodes (n=128). This division, though arbitrary, was made as some of the outcomes were significantly different in the two groups. It was noted that children having 5 or more episodes had more complications and interest of outcome (any neurological outcome like intellectual disabilities, autism spectrum disorders, disorders of psychological development, attention deficit/ hyperactivity disorder, tics, stereotype behavior, stuttering, myoclonus, epilepsy and recurrent seizures, status epilepticus, abnormalities of gait and movement, other lack of coordination, dyslexia and alexia, other symbolic dysfunctions, seizures including febrile seizures, any motor/ cognitive developmental delay) as compared to the children with lower number of hypoglycemic episodes. Maternal, delivery and infant characteristics have been depicted in Table 2. It was noted that the group having 5 or more hypoglycemic episodes had a higher proportion of premature or small for date children as compared to the other group (76.2% Vs 60.9%), and the difference is statistically significant. The neurologic sequalae reported in study population has been depicted in Table 3, with seizures as presenting symptom to be the most common neurological finding in these children.

Table 2: Maternal, delivery and infant characteristics.

Table 3: Neurologic sequalae and hypoglycemic findings in 170 children.

The odds of developing an abnormal neurodevelopmental outcome was 3.5 times more in children who suffered from 5 or more episodes of hypoglycemia as compare to children who suffered from leaser or one episode of hypoglycemia. In adjusted regression analyses, the odds ratio (OR) of any neurological or neurodevelopmental outcome was 1.48 (95% confidence interval: 1.17–1.88) in group with 5 or more hypoglycemic episodes as compared to the other group. The adjusted risk of any developmental delay was more than doubled (OR 2.53 [1.71–3.73]), the adjusted risk of motor developmental delay was almost doubled (OR: 1.91 [1.06–3.44]) and the adjusted risk of cognitive developmental delay was almost tripled (OR 2.85 [1.70–4.76]) in the group that had more than 5 hypoglycemic episodes in neonatal period (Table 4).

Table 4: Risks of adverse neurodevelopmental outcomes in the two groups.

Discussion

The general assumption is that asymptomatic infants with transient hypoglycemia are at very low risk of neurologic complications [10,11] and this is supported by some studies [12,13]. However, there are indications that even moderate neonatal hypoglycemia may be associated with structural brain abnormalities [14,15], impaired neurodevelopment [16], impaired executive function and visual motor function [17] and poor school performances [18].

In the current study it was noted that the proportion of children manifesting any one or more adverse neurological outcomes (enlisted in methods section) was very high (70%). The proportion of children manifesting these outcomes were not that high in other studies [10,12,15]. The reason for the same is that our study was a hospital based study and consisted of children visiting the hospital due to some neurological adverse event or developmental delay. Children who did not develop any sequalae due to hypoglycemia are least likely to visit the hospital. It is also noteworthy that majority of the study sample was premature or small for date, which in itself is a predisposing factor for developmental delay. Also, the diagnostic criteria vary between studies that could lead to this incongruency.

However, in the current study we found that recurrent episodes of hypoglycemia were strongly correlated with persistent neurodevelopmental and physical growth deficits until 5 years of age. Other studies have also reported congruent findings to our study [12,19-22]. In our study, it was reported that prematurity or being small for date is associated with having 5 or more hypoglycemic episodes. In another study of moderately preterm infants, hypoglycemia was identified as the only neonatal morbidity that could predict an impaired neurodevelopment as reported by parents at 4 years of age [23]. The authors argued for a causal association and suggested intensified monitoring of glucose levels in moderately preterm infants. Two other studies have failed to associate moderate hypoglycemia to impaired neurodevelopmental outcomes [12,24].

In the current study it was found that 40% of the children had jaundice. Jaundice in neonates can be of various kinds: physiologic jaundice, breastfeeding failure jaundice, breast milk jaundice, jaundice from hemolysis, and jaundice caused by poor liver function. Also, genetic disorders or enzymatic deficiencies like galactose-1-phosphate uridyl transferase deficiency, 1-phosphofructaldolase deficiency (hereditary fructose intolerance), and fumaryl acetoacetate hydrolyase deficiency (Tyrosinemia) manifest as hyperbilirubinemia and many such neonates suffer from hypoglycemia. In this case, all the neonates had unconjugated hyperbilirubinemia. One of the main reasons is that the hepatobiliary system is immature. Hepatocytes haven’t yet expressed the genes related to the formation of glycosyltransferase with full power. (The hepatocytes have undersupplied the glycosyltransferase). Newborn babies have a little extra load of unconjugated bilirubin to the liver. There is a significant impairment of conjugating power of the newborn’s liver. However, in this study, the main problem identified was hypoglycemia and not hyperbilirubinemia. Discussion over the same is out of the scope in this paper.

Recurrent hypoglycemia also was a more predictable factor for long-term effects than the severity of a single hypoglycemic episode. Therefore repetitive blood glucose monitoring and rapid treatment even for mild hypoglycemia are recommended for small-for-gestationalage infants in the neonatal period.

In the current study, seizure was reported as the most common neurological sequalae in the study population. Seizures are usually the first presenting symptom of profound hypoglycemia (bgl<25 g/dl).[8] Seizures that are associated with hypoglycemia have a worse prognosis than hypoglycemia without seizures.[25] Visual impairment, another common symptom reported in the current study, is reportedly due to injury of the occipital lobes [8].

There are several limitations to the study. Firstly, due to lack of time and resources we conducted a retrospective study. However, a prospective cohort model is more suitable to these kinds of cause-effect studies. We excluded children whose hospital records did not show the desired outcome (hypoglycemia). Diagnosis status is a blunt instrument and there may be missed cases of moderate hypoglycemia where the diagnosis was not entered by the doctor at discharge. Like any other retrospective study, this study is susceptible to detection bias or selection bias (as is evidenced from the over representation of the outcome of interest in the study population). Despite of the limitations, our study contributes to the pool of evidence by providing data on a disputed and under-studied subject.

Conclusion

Hypoglycemia is a heterogeneous disorder with many possible etiologies, and a multidisciplinary approach is ideal in caring for these infants and children with this condition. We conclude that moderate neonatal hypoglycemia is associated with increased risks of impaired neurodevelopment in pre-school children. However, larger prospective studies are needed to substantiate the claims.

Acknowledgement

We would like to thank our study subjects for their consent and time.

References

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