Background: Hypoglycaemia is the most common metabolic problem in neonates but there is no universally accepted threshold for safe blood glucose concentrations due to uncertainty regarding effects on neurodevelopment. Objective: To systematically assess the association between neonatal hypoglycaemia on neurodevelopment outcomes in childhood and adolescence. Methods: We searched MEDLINE, EMBASE, CINAHL, and PsycINFO from inception until February 2018. We included studies that reported one or more prespecified outcomes and compared children exposed to neonatal hypoglycaemia with children not exposed. Studies of neonates with congenital malformations, inherited metabolic disorders and congenital hyperinsulinism were excluded. Two authors independently extracted data using a customized form. We used ROBINS-I to assess risk of bias, GRADE for quality of evidence, and REVMAN for meta-analysis (inverse variance, fixed effects). Results: 1,665 studies were screened, 61 reviewed in full, and 11 included (12 publications). In early childhood, exposure to neonatal hypoglycaemia was not associated with neurodevelopmental impairment (n = 1,657 infants; OR = 1.16, 95% CI = 0.86–1.57) but was associated with visual-motor impairment (n = 508; OR = 3.46, 95% CI = 1.13–10.57) and executive dysfunction (n = 463; OR = 2.50, 95% CI = 1.20–5.22). In mid-childhood, neonatal hypoglycaemia was associated with neurodevelopmental impairment (n = 54; OR = 3.62, 95% CI = 1.05–12.42) and low literacy (n = 1,395; OR = 2.04, 95% CI = 1.20–3.47) and numeracy (n = 1,395; OR = 2.04, 95% CI = 1.21–3.44). No data were available for adolescents. Conclusions: Neonatal hypoglycaemia may have important long-lasting adverse effects on neurodevelopment that may become apparent at later ages. Carefully designed randomized trials are required to determine the optimal management of neonates at risk of hypoglycaemia with long-term follow-up at least to school age.

Neonatal hypoglycaemia is the most common metabolic problem in newborn infants and a readily preventable cause of brain injury in infancy. However, clinical thresholds for diagnosis and treatment of neonatal hypoglycaemia are widely debated, with no universally accepted safe blood glucose concentration for newborns [1, 2]. This uncertainty is largely due to a lack of evidence regarding the effect of low neonatal glucose concentrations on neurodevelopmental outcomes. Further, recent studies have suggested that higher glucose concentrations after hypoglycaemia may also contribute to brain injury [3], thus adding complexity to this common clinical problem.

Key risk factors for neonatal hypoglycaemia include being born preterm, large for gestational age or high birth weight, small for gestational age or low birth weight, and being an infant of a diabetic mother. Approximately 30% of all neonates are considered at risk, of whom approximately 50% develop hypoglycaemia [4]. The most common definition of neonatal hypoglycaemia is a blood glucose concentration < 47 mg/dL (2.6 mmol/L), but lower and higher thresholds have been recommended. For example, the American Academy of Pediatrics advises that intravenous treatment is not needed until glucose concentrations are < 25 mg/dL (1.4 mmol/L) within the first 4 h after birth, or < 35 mg/dL (2.0 mmol/L) from 4 to 24 h [5]. However, the Pediatric Endocrine Society recommends that in babies at risk of hypoglycaemia, glucose concentrations should be maintained > 50 mg/dL (2.8 mmol/L), or > 60 mg/dL (3.3 mmol/L) if interventions beyond normal feeds are required [6]. This lack of consensus reflects the paucity of evidence about long-term outcomes after neonatal hypoglycaemia.

In 2006, Boluyt et al. [7] carried out a systematic review of the available studies on prognosis after neonatal hypoglycaemia. The review concluded that the extent of neurodevelopment impairment after neonatal hypoglycaemia in the first week of life was unclear, and thus the authors proposed an optimal study design to establish the relationship between neonatal hypoglycaemia and subsequent neurodevelopment. In 2008, the Eunice Kennedy Shriver National Institute of Child Health and Human Development Workshop on Neonatal Hypoglycaemia also identified major gaps in knowledge about neonatal hypoglycaemia and its clinical implications and prioritized it as a key area for research. Since then, although several review articles on the topic have appeared [8-10], no new systematic review has emerged.

This aim of this systematic review was to assess the association between neonatal hypoglycaemia on neurodevelopment outcomes at early childhood (2–5 years), mid-childhood (6–11 years), and adolescence (12–18 years).

This systematic review was conducted in accordance with the PRISMA statement, and was registered in PROSPERO (CRD42017073430, http://www.crd.york.ac.uk/PROSPERO/).

Search Strategy

We searched MEDLINE, EMBASE, CINAHL, and PsycINFO databases using the search terms infant, newborn, hypoglycaemia, neurodevelopmental disorders, neurological sequelae, neuroimaging, brain imaging, computed tomography scan, ultrasonography, and magnetic resonance imaging, including spelling variants (online suppl. material for full search strategy; see www.karger.com/doi/10.1159/000492859 for all online suppl. material). The search was restricted to studies involving humans and published in English. There was no limit on the year of publication. The search was last updated on February 12, 2018. We also hand-searched bibliographies of included studies, review papers and conference abstracts to identify additional items. One author conducted the search and initial title and abstract screening. Records identified for full-text screening were reviewed by two authors. Screening and eligibility assessments were performed using COVIDENCE (http://www.covidence.org/). Conflicts were resolved by consensus or after consultation with a third author.

Inclusion Criteria

We included all studies (trials, cohort, and case-control) that reported one or more of the primary or secondary outcomes and compared children or adolescents who were screened and found to be hypoglycaemic to those who were screened but were not hypoglycaemic. Studies were limited to neonates born at ≥32 weeks’ gestation and who were screened for hypoglycaemia in the first week after birth. We excluded case series, conference abstracts, and studies that reported outcomes in neonates with congenital malformations, inherited metabolic disorders or congenital hyperinsulinism.

Primary outcomes were neurodevelopmental impairment, visual-motor impairment, and executive dysfunction, as defined by authors. Secondary outcomes were cognitive impairment (as defined by authors), mild cognitive impairment (developmental or intelligence quotient from 2 to 1 standard deviation below the mean), moderate-severe cognitive impairment (developmental/intelligence quotient more than 2 standard deviations below the mean), epilepsy (afebrile seizures or as defined by authors), highest educational level (adolescence), death, measures of general health and health care utilization, emotional-behavioural difficulty, abnormal brain imaging findings, visual impairment, hearing impairment, motor impairment, low literacy and low numeracy (mid-childhood and early adolescence), all as defined by authors.

Data Extraction and Analysis

Data for primary and secondary outcomes were extracted independently by two authors using a customized data form. Conflicts were resolved by consensus or following consultation with a third author.

We planned meta-analysis using the inverse variance, fixed effects method in REVMAN (version 5.3), with the inclusion of adjusted analyses where possible. If there were data for more than one age within an age band, then the most recent data were used. We assessed statistical heterogeneity using the I2 statistic; values > 30% were regarded as evidence of substantial heterogeneity. Forest plots are provided in the online supplementary material. We planned sensitivity analysis of the primary outcomes including only studies at low risk of bias and only those that used accurate methods for measuring glucose concentrations.

Quality of Evidence

We assessed the risk of bias for each study using a modified version of the ROBINS-I tool for non-randomized studies of interventions, as previously described [11]. This included assessment of the following domains for bias: recruitment and selection of participants, confounding, ascertainment of exposures, measurement of outcomes, missing data, and reporting of results. Two authors independently performed risk of bias assessments. Conflicts were resolved by consensus or by consultation with a third author.

We evaluated the overall quality of evidence for each research question using the GRADE approach [12]. Seven outcomes were selected for GRADE assessment: neurodevelopmental impairment, cognitive impairment, visual-motor impairment, low language/literacy, low numeracy, epilepsy, and executive dysfunction. Two authors independently assessed the quality of evidence. Conflicts were resolved by consensus or by consultation with a third author.

Search Results

Of 1,665 records identified through databases and hand searching, 148 were duplicates and were removed. Of the remaining 1,517 studies, 1,456 were excluded following title and abstract screening, and a further 49 were excluded following full-text review (Fig. 1). One cohort study reported outcomes separately at 2 and 4.5 years of age [3, 13]. Thus, a total of 11 studies (12 publications), comprising 4,041 infants were included, of which 9 (10 publications) provided data suitable for meta-analysis in early and mid-childhood. No studies reported outcomes in adolescence.

Fig. 1.

Flow diagram of study identification and selection.

Fig. 1.

Flow diagram of study identification and selection.

Close modal

Characteristics of the Selected Studies

All of the included studies were cohort studies; 3 were prospective [13-15], 6 were retrospective [16-21], and for 2 it was unclear whether all data were collected prospectively [22, 23] (Table 1). All studies were conducted in developed countries, including Europe, the USA, Canada, and New Zealand. Four studies were conducted in the 1970s [14, 15, 20, 22], 2 in the 1990s [17, 21], 1 in the 2000s [16] and 4 in the 2010s [13, 18, 19, 23]. In 10 studies the study population comprised infants at risk of hypoglycaemia; 1 study included all the infants born at the hospital. Only 4 studies (5 publications) each had uncertain or low risk of bias in one or more domains, and each adjusted results for potential confounding [3, 13, 18, 19, 23]. No study was at low risk of bias across all domains. Seven studies were small with fewer than 100 participants and had very imprecise estimates of exposure effect.

Table 1.

Characteristics of included studies

Characteristics of included studies
Characteristics of included studies

Early Childhood (2–5 Years)

Primary Outcomes

The risk of neurodevelopmental impairment in early childhood did not differ between those who were and were not exposed to neonatal hypoglycaemia (6 studies, 1,657 infants; 25.8 vs. 16.6%; OR = 1.16, 95% CI = 0.86–1.57; p = 0.34; I2 = 16%) [3, 13-16, 20, 23]. Four out of the 6 studies contributing data to this meta-analysis were at high risk of bias in one or more domains (Table 2). In 2 studies, exposure to neonatal hypoglycaemia was associated with increased risk of visual-motor impairment (508 infants; 4.6 vs. 1.5%; OR = 3.46, 95% CI = 1.13–10.57; p = 0.03; I2 = 0%) [13, 14]. One of these studies was at high risk of bias for confounding but contributed few data to the meta-analysis [14]. In 1 study, there was an association between neonatal hypoglycaemia and executive dysfunction (463 infants; 10.6 vs. 4.7%; OR = 2.50, 95% CI = 1.20–5.22; p = 0.01). This study had a low to uncertain risk of bias [13]. There were insufficient data to undertake the planned sensitivity analyses.

Table 2.

Risk of bias assessment

Risk of bias assessment
Risk of bias assessment

Secondary Outcomes

In early childhood, those exposed to neonatal hypoglycaemia compared with those not so exposed had similar rates of any cognitive impairment (3 studies, 746 infants, 15.4 vs. 15.9%; OR = 1.11, 95% CI = 0.73–1.69; p = 0.63; I2 = 28%), mild cognitive impairment (3 studies, 746 infants, 12.8 vs. 13.7%; OR = 0.86, 95% CI = 0.55–1.35; p = 0.52; I2 = 61%) and moderate-severe cognitive impairment (3 studies, 746 infants, 2.6 vs. 2.1%; OR = 1.57, 95% CI = 0.55–4.48; p = 0.40, I2 = 34%) [13, 20, 22]. Two of these 3 studies were at high risk of bias in one or more domains. The risk of epilepsy in early childhood did not differ between those exposed and not exposed to neonatal hypoglycaemia (4 studies, 772 infants, 4.2 vs. 2.1%; OR = 1.93, 95% CI = 0.76–4.85; p = 0.16, I2 = 0%) [13, 14, 20, 22]. Three of these 4 studies were at high risk of bias in one or more domains. The risk of emotional-behavioural difficulty did not differ between those exposed and not exposed to neonatal hypoglycaemia (3 studies, 587 infants, 18.9 vs. 19.0%; OR = 1.00, 95% CI = 0.66–1.53; p = 0.98, I2 = 0%) [13, 14, 22]. One of these studies was at low or uncertain risk of bias while 2 were at high risk of bias in one or more domains. The risk of visual impairment in early childhood did not differ between those exposed or not exposed to neonatal hypoglycaemia (2 studies, 616 infants, 5.0 vs. 1.7%; OR = 2.14, 95% CI = 0.70–6.53; p = 0.18, I2 = 0%) [13, 20]. One of these studies was at high risk of bias in one or more domains and contributed the most data to the meta-analysis [20]. In 1 study, the rate of hearing impairment in early childhood did not differ between those exposed or not exposed to neonatal hypoglycaemia (477 infants, 0 vs. 0.5%; OR = 0.23, 95% CI = 0.01–5.76; p = 0.37) [13]. This study had a low to uncertain risk of bias. The risk of motor impairment in early childhood did not differ between those who were and were not exposed to neonatal hypoglycaemia (4 studies, 777 infants, 17.5 vs. 17.8%; OR = 1.06, 95% CI = 0.70–1.60; p = 0.79, I2 = 6%) [13, 14, 20, 22]. Three out of 4 of these studies were at high risk of bias in one or more domains. One study reported higher rates of low language/literacy in those exposed to neonatal hypoglycaemia compared with those not so exposed but results were imprecise and not statistically significant (37 infants, 16 vs. 0%; OR = 5.23, 95% CI = 0.26–105.50; p = 0.28) [14]. This study had an uncertain to high risk of bias. One study reported on rates of cerebral palsy and found no difference between those exposed and not exposed to neonatal hypoglycaemia (401 infants, 0.9 vs. 1.1%; OR = 0.81, 95% CI = 0.11–6.07; p = 0.84) [3]. This study was at a low to uncertain risk of bias. None of the included studies reported on abnormal brain imaging, highest education level, death or measures of general health and health care utilization in early childhood.

Quality of Evidence

For the primary outcomes in early childhood, the quality of evidence was either low or very low (Table 3). For the selected secondary outcomes of any cognitive impairment, epilepsy, and low language/literacy, the quality of evidence was also very low (Table 3).

Table 3.

GRADE summary of quality of evidence for effect of neonatal hypoglycaemia on neurodevelopmental outcomes

GRADE summary of quality of evidence for effect of neonatal hypoglycaemia on neurodevelopmental outcomes
GRADE summary of quality of evidence for effect of neonatal hypoglycaemia on neurodevelopmental outcomes

Mid-Childhood (6–11 Years)

Primary Outcomes

In 2 small studies, those exposed to neonatal hypoglycaemia compared with those not so exposed had a higher risk of neurodevelopmental impairment (54 infants, 47.8 vs. 22.6%; OR = 3.62, 95% CI = 1.05–12.42; p = 0.04, I2 = 0%) [15, 21]. Both of these studies were at an uncertain to high risk of bias in one or more domains. None of the included studies reported on visual-motor impairment or executive dysfunction in mid-childhood. There were insufficient data to undertake the planned sensitivity analyses.

Secondary Outcomes

In 1 study, the risk of emotional-behavioural difficulty in mid-childhood was non-significantly increased in those exposed to neonatal hypoglycaemia than those not so exposed (28 infants, 30.8 vs. 6.7%; OR = 6.22, 95% CI = 0.60–64.97; p = 0.13) but rates of motor impairment were similar (28 infants, 15.4 vs. 13.3%; OR = 1.18, 95% CI = 0.14–9.83; p = 0.88) [21]. This study had an uncertain to high risk of bias in one or more domains. In another study, those exposed to neonatal hypoglycaemia compared with those not so exposed had an increased risk of low language/literacy (1,395 infants, 67.4 vs. 43.0%; OR = 2.04, 95% CI = 1.20–3.47; p = 0.008) [19] and low numeracy (1,395 infants, 53.9 vs. 34.0%; OR = 2.04, 95% CI = 1.21–3.44; p = 0.007) in mid-childhood [19]. This study had a low to uncertain risk of bias.

None of the included studies reported on any cognitive impairment, mild cognitive impairment, moderate-severe cognitive impairment, epilepsy, abnormal brain imaging, visual impairment, hearing impairment, highest educational level, death, and measures of general health and health care utilization in mid-childhood.

Quality of Evidence

For the primary outcome of neurodevelopmental impairment in mid-childhood the quality of the evidence was very low (Table 3). For the selected secondary outcomes of low language/literacy and low numeracy, the quality of the evidence was low (Table 3).

Adolescence (12–18 Years)

None of the included studies reported on primary or secondary outcomes in adolescence.

Neonatal hypoglycaemia is the most common metabolic condition in newborn infants [4] and has been associated with widespread changes in the developing brain [24], yet the impact of neonatal hypoglycaemia on long-term neurodevelopment is widely debated [25]. We undertook this systematic review to determine the relationship between neonatal hypoglycaemia and neurodevelopment throughout childhood. We found low-quality evidence that in early childhood (2–5 years) neonatal hypoglycaemia is associated with specific cognitive deficits, including a two- to threefold increased risk of visual-motor impairment and executive dysfunction. In later childhood (6–11 years), we found low-quality evidence that neonatal hypoglycaemia is associated with a twofold increased risk of literacy and numeracy problems, and very low-quality evidence of an increased risk of general cognitive impairment. No data were available on outcomes in adolescence.

Visual-motor integration is the coordination of visual perception, the ability to extract and organize visual information from the environment, and motor skills, especially fine motor ones [26]. It allows the use of eyes and hands in a coordinated and efficient way, enabling, for example, one to perceive and copy shapes, letters, and numbers. Thus, visual-motor integration is important for learning and academic achievement including reading, writing, and mathematics [27, 28].

The development of visual and motor systems is closely related [29], and coordination of visual-motor function is thought to occur within the ventral and dorsal cortical visual streams. The ventral stream supports form processing and object recognition, and includes the occipital primary visual cortex and the inferior temporal lobe. The dorsal stream is responsible for motion perception and visually guided motor function and includes the occipital primary visual cortex, middle temporal lobe, and posterior parietal lobe. In the neonatal period, these cortical areas appear to be particularly susceptible to injury from neuroglycopenia, possibly because of higher metabolic activity [9, 30-32]. This provides a possible pathophysiological basis for the association between neonatal hypoglycaemia and impaired visual-motor integration in early childhood.

Executive function is the collective capacity for problem-solving, planning, attention control, and goal-directed behaviour [33]. Children with impaired executive control have difficulty remembering and carrying out instructions, staying focused, and planning and monitoring progress with a specific task, which can affect not only daily activities but also learning. The prefrontal cortex is responsible for the proper development of executive function, and increased activation of this region is associated with better performance on executive function tasks, as well as academic outcomes [34, 35]. The development of the prefrontal cortex and executive capacity is continuous from childhood through adolescence and into early adulthood [36, 37], and any abnormality in this region can result in executive function difficulties. Although neonatal hypoglycaemia has traditionally been associated with posterior brain injury, recent studies have suggested that its effects on the brain may be more widespread and include the frontal cortex [24, 38], potentially interfering with the normal development of executive capacity.

Demands on visual-motor and executive function increase with age, but we could not determine whether the changes seen in early childhood after neonatal hypoglycaemia persist or worsen over time due to the lack of longer-term outcome data. However, the finding of a twofold increased risk of literacy and numeracy problems in mid-childhood suggests a trajectory of worsening function in skills that are important for learning [39, 40]. The fact that neonatal hypoglycaemia was associated with general cognitive impairment in mid-childhood but not in early childhood supports this hypothesis. Importantly, this systematic review shows that tests of general development in infancy are unlikely to adequately assess the effects of neonatal hypoglycaemia on brain development. Thus, intervention studies will require longer-term end points, at least into mid-childhood, including specific tests of visual-motor and executive function.

It is more than a decade since Boluyt et al. [7] conducted the first systematic review of neurodevelopmental outcomes after neonatal hypoglycaemia. They concluded that there were insufficient data to quantify the effect of neonatal hypoglycaemia on neurodevelopment and provided recommendations about an optimal study design. Our systematic review identified 3 subsequent studies, but only 1 that followed these recommendations [3, 13], including prospective cohort design, nested randomized trial of treatment, gold standard glucose measurements, standardized neurodevelopmental assessment and sufficient sample size [7]. This is somewhat surprising given the recognition of neonatal hypoglycaemia as a priority research area and calls from the National Institute of Child Health and Human Development for further high-quality studies [1].

There are several differences between our systematic review and that of Boluyt et al. [7]. We excluded case series because without contemporaneous controls it is not possible to account for confounding, especially relating to the reasons that babies were considered at risk of hypoglycaemia and socio-economic factors. We also excluded studies that assessed outcomes at less than 2 years of age, due to the limited predictive value of very early developmental assessment [41], and studies that primarily included infants with congenital hyperinsulinism. We assessed not only the methodological quality of individual studies, but also the overall strength of the evidence for key outcomes using the GRADE approach.

Even with optimal study design, several challenges remain in determining the effect of neonatal hypoglycaemia on later neurodevelopment. As with any cohort study, the possibility of residual confounding cannot be excluded. Although neuroglycopenia can cause irreversible brain injury, other mechanisms may underlie associations between episodes of hypoglycaemia and neurodevelopmental impairment. For example, genetic polymorphisms of ATP-dependent potassium channels could affect both pancreatic β-cells and neuronal function [42].

In addition, the relationship between the severity, frequency, and duration of neonatal hypoglycaemic episodes and cerebral energy supply and utilization remains unclear [43], and thus the best measure of exposure for use in analyses is uncertain [25]. This is complicated by different approaches to screening, diagnosis, and treatment of hypoglycaemia, making characterization of the degree of exposure challenging. Further, masked continuous interstitial glucose monitoring has shown that the burden of hypoglycaemia in the early newborn period may be substantially greater than is detected by serial glucose measurements, even with frequent screening [3]. These undetected and thus untreated episodes may have an important influence on long-term outcomes [13]. However, there are few data on the effect of different approaches to treatment on glucose concentrations after hypoglycaemia [44].

Limitations

A key limitation of this systematic review is that only a limited number of studies were identified that met the inclusion criteria, leading to imprecise estimates of effect, and that data were not available for all prespecified outcomes at each epoch. There are several possible reasons for this including the difficulty of recruiting large cohorts around the time of birth, and the cost and complexity of long-term neurodevelopmental follow-up throughout childhood. Of note, only 3 of the included studies contributed data beyond 5 years of age [18, 21, 23]. Another limitation is the lack of adjustment for potential confounding factors, with only half of the included studies attempting to control for this potential source of bias. Finally, the description of hypoglycaemic management and treatment targets was generally poor. This may be important, as there is emerging evidence both in animals and humans that glucose reperfusion injury may exacerbate oxidative stress associated with hypoglycaemia if the correction is too rapid or too high, even within the normal glucose range [3, 45, 46].

Recommendations for Research

Studies are needed to determine the efficacy and cost-effectiveness of different strategies for improving long-term outcomes in neonates born at risk of hypoglycaemia. Future studies should involve large prospective cohorts with nested randomized trials of different approaches to treatment, or large randomized trials of different approaches to prevention or screening and diagnosis of hypoglycaemia in neonates considered at risk. All studies require the use of gold standard glucose assay methods [25, 47] and long-term follow-up at least to school age, with attention to visual-motor and executive function, and educational achievement. Consideration should be given to the use of masked continuous glucose monitoring to aid in the interpretation of study results, although retrospective point-to-point recalibration against all laboratory blood glucose values is important for accurate interstitial measurements in babies [48].

This systematic review found that neonatal hypoglycaemia is associated with a two- to threefold increased risk of specific cognitive deficits in early childhood (2–5 years), including visual-motor impairment and executive dysfunction, and general cognitive impairment and literacy and numeracy problems in later childhood (6–11 years). Although the overall quality of evidence was low to very low, this review nevertheless suggests that neonatal hypoglycaemia may have important long-lasting adverse effects on neurodevelopment. Carefully designed intervention trials are needed to determine the optimal management of neonates at risk of hypoglycaemia to improve long-term outcomes.

The authors have no conflicts of interest to declare.

1.
Hay
WW
 Jr
,
Raju
TN
,
Higgins
RD
,
Kalhan
SC
,
Devaskar
SU
.
Knowledge gaps and research needs for understanding and treating neonatal hypoglycemia: workshop report from Eunice Kennedy Shriver National Institute of Child Health and Human Development
.
J Pediatr
.
2009
Nov
;
155
(
5
):
612
7
.
[PubMed]
0022-3476
2.
Rozance
PJ
,
Hay
WW
.
Hypoglycemia in newborn infants: features associated with adverse outcomes
.
Biol Neonate
.
2006
;
90
(
2
):
74
86
.
[PubMed]
0006-3126
3.
McKinlay
CJ
,
Alsweiler
JM
,
Ansell
JM
,
Anstice
NS
,
Chase
JG
,
Gamble
GD
, et al;
CHYLD Study Group
.
Neonatal glycemia and neurodevelopmental outcomes at 2 years
.
N Engl J Med
.
2015
Oct
;
373
(
16
):
1507
18
.
[PubMed]
0028-4793
4.
Harris
DL
,
Weston
PJ
,
Harding
JE
.
Incidence of neonatal hypoglycemia in babies identified as at risk
.
J Pediatr
.
2012
Nov
;
161
(
5
):
787
91
.
[PubMed]
0022-3476
5.
Adamkin
DH
.
Clinical report – postnatal glucose homeostasis in late-term and preterm infants
.
Pediatrics
.
2011
;
127
:
575
9
.
[PubMed]
0031-4005
6.
Thornton
PS
,
Stanley
CA
,
De Leon
DD
,
Harris
D
,
Haymond
MW
,
Hussain
K
, et al;
Pediatric Endocrine Society
.
Recommendations from the pediatric endocrine society for evaluation and management of persistent hypoglycemia in neonates, infants, and children
.
J Pediatr
.
2015
Aug
;
167
(
2
):
238
45
.
[PubMed]
0022-3476
7.
Boluyt
N
,
van Kempen
A
,
Offringa
M
.
Neurodevelopment after neonatal hypoglycemia: a systematic review and design of an optimal future study
.
Pediatrics
.
2006
Jun
;
117
(
6
):
2231
43
.
[PubMed]
0031-4005
8.
Adamkin
DH
.
Neonatal hypoglycemia
.
Semin Fetal Neonatal Med
.
2017
Feb
;
22
(
1
):
36
41
.
[PubMed]
1744-165X
9.
Paudel
N
,
Chakraborty
A
,
Anstice
N
,
Jacobs
RJ
,
Hegarty
JE
,
Harding
JE
, et al;
CHYLD Study Group
.
Neonatal hypoglycaemia and visual development: a review
.
Neonatology
.
2017
;
112
(
1
):
47
52
.
[PubMed]
1661-7800
10.
Rozance
PJ
.
Update on neonatal hypoglycemia
.
Curr Opin Endocrinol Diabetes Obes
.
2014
Feb
;
21
(
1
):
45
50
.
[PubMed]
1752-296X
11.
Bradford
BF
,
Thompson
JM
,
Heazell
AE
,
Mccowan
LM
,
McKinlay
CJ
.
Understanding the associations and significance of fetal movements in overweight or obese pregnant women: a systematic review
.
Acta Obstet Gynecol Scand
.
2018
Jan
;
97
(
1
):
13
24
.
[PubMed]
0001-6349
12.
Balshem
H
,
Helfand
M
,
Schünemann
HJ
,
Oxman
AD
,
Kunz
R
,
Brozek
J
, et al
GRADE guidelines: 3. Rating the quality of evidence
.
J Clin Epidemiol
.
2011
Apr
;
64
(
4
):
401
6
.
[PubMed]
0895-4356
13.
McKinlay
CJ
,
Alsweiler
JM
,
Anstice
NS
,
Burakevych
N
,
Chakraborty
A
,
Chase
JG
, et al;
Children With Hypoglycemia and Their Later Development (CHYLD) Study Team
.
Association of neonatal glycemia with neurodevelopmental outcomes at 4.5 years
.
JAMA Pediatr
.
2017
Oct
;
171
(
10
):
972
83
.
[PubMed]
2168-6203
14.
Haworth
JC
,
McRae
KN
,
Dilling
LA
.
Prognosis of infants of diabetic mothers in relation to neonatal hypoglycaemia
.
Dev Med Child Neurol
.
1976
Aug
;
18
(
4
):
471
9
.
[PubMed]
0012-1622
15.
Pildes
RS
,
Cornblath
M
,
Warren
I
,
Page-El
E
,
Di Menza
S
,
Merritt
DM
, et al
A prospective controlled study of neonatal hypoglycemia
.
Pediatrics
.
1974
Jul
;
54
(
1
):
5
14
.
[PubMed]
0031-4005
16.
Brand
PL
,
Molenaar
NL
,
Kaaijk
C
,
Wierenga
WS
.
Neurodevelopmental outcome of hypoglycaemia in healthy, large for gestational age, term newborns
.
Arch Dis Child
.
2005
Jan
;
90
(
1
):
78
81
.
[PubMed]
0003-9888
17.
Duvanel
CB
,
Fawer
CL
,
Cotting
J
,
Hohlfeld
P
,
Matthieu
JM
.
Long-term effects of neonatal hypoglycemia on brain growth and psychomotor development in small-for-gestational-age preterm infants
.
J Pediatr
.
1999
Apr
;
134
(
4
):
492
8
.
[PubMed]
0022-3476
18.
Goode
RH
,
Rettiganti
M
,
Li
J
,
Lyle
RE
,
Whiteside-Mansell
L
,
Barrett
KW
, et al
Developmental outcomes of preterm infants with neonatal hypoglycemia
.
Pediatrics
.
2016
Dec
;
138
(
6
):
55
55
.
[PubMed]
0031-4005
19.
Kaiser
JR
,
Bai
S
,
Gibson
N
,
Holland
G
,
Lin
TM
,
Swearingen
CJ
, et al
Association between transient newborn hypoglycemia and fourth-grade achievement test proficiency: a population-based study
.
JAMA Pediatr
.
2015
Oct
;
169
(
10
):
913
21
.
[PubMed]
2168-6203
20.
Koivisto
M
,
Blanco-Sequeiros
M
,
Krause
U
.
Neonatal symptomatic and asymptomatic hypoglycaemia: a follow-up study of 151 children
.
Dev Med Child Neurol
.
1972
Oct
;
14
(
5
):
603
14
.
[PubMed]
0012-1622
21.
Stenninger
E
,
Flink
R
,
Eriksson
B
,
Sahlèn
C
.
Long-term neurological dysfunction and neonatal hypoglycaemia after diabetic pregnancy
.
Arch Dis Child Fetal Neonatal Ed
.
1998
Nov
;
79
(
3
):
F174
9
.
[PubMed]
1359-2998
22.
Griffiths
AD
,
Bryant
GM
.
Assessment of effects of neonatal hypoglycaemia. A study of 41 cases with matched controls
.
Arch Dis Child
.
1971
Dec
;
46
(
250
):
819
27
.
[PubMed]
0003-9888
23.
Kerstjens
JM
,
Bocca-Tjeertes
IF
,
de Winter
AF
,
Reijneveld
SA
,
Bos
AF
.
Neonatal morbidities and developmental delay in moderately preterm-born children
.
Pediatrics
.
2012
Aug
;
130
(
2
):
e265
72
.
[PubMed]
0031-4005
24.
Burns
CM
,
Rutherford
MA
,
Boardman
JP
,
Cowan
FM
.
Patterns of cerebral injury and neurodevelopmental outcomes after symptomatic neonatal hypoglycemia
.
Pediatrics
.
2008
Jul
;
122
(
1
):
65
74
.
[PubMed]
0031-4005
25.
Harding
JE
,
Harris
DL
,
Hegarty
JE
,
Alsweiler
JM
,
McKinlay
CJ
.
An emerging evidence base for the management of neonatal hypoglycaemia
.
Early Hum Dev
.
2017
Jan
;
104
:
51
6
.
[PubMed]
0378-3782
26.
Beery
KE
.
The Beery-Buktenica developmental test of visual-motor integration: Beery VMI, with supplemental developmental tests of visual perception and motor coordination, and stepping stones age norms from birth to age six
.
MN
:
NCS Pearson Minneapolis
;
2004
.
27.
Barnhardt
C
,
Borsting
E
,
Deland
P
,
Pham
N
,
Vu
T
.
Relationship between visual-motor integration and spatial organization of written language and math
.
Optom Vis Sci
.
2005
Feb
;
82
(
2
):
138
43
.
[PubMed]
1040-5488
28.
Taylor Kulp
M
.
Relationship between visual motor integration skill and academic performance in kindergarten through third grade
.
Optom Vis Sci
.
1999
Mar
;
76
(
3
):
159
63
.
[PubMed]
1040-5488
29.
Thompson
B
,
McKinlay
CJ
,
Chakraborty
A
,
Anstice
NS
,
Jacobs
RJ
,
Paudel
N
, et al;
CHYLD Study Team
.
Global motion perception is associated with motor function in 2-year-old children
.
Neurosci Lett
.
2017
Sep
;
658
:
177
81
.
[PubMed]
0304-3940
30.
Aslan
Y
,
Dinc
H
.
MR findings of neonatal hypoglycemia
.
AJNR Am J Neuroradiol
.
1997
May
;
18
(
5
):
994
6
.
[PubMed]
0195-6108
31.
Barkovich
AJ
,
Ali
FA
,
Rowley
HA
,
Bass
N
.
Imaging patterns of neonatal hypoglycemia
.
AJNR Am J Neuroradiol
.
1998
Mar
;
19
(
3
):
523
8
.
[PubMed]
0195-6108
32.
Spar
JA
,
Lewine
JD
,
Orrison
WW
 Jr
.
Neonatal hypoglycemia: CT and MR findings
.
AJNR Am J Neuroradiol
.
1994
Sep
;
15
(
8
):
1477
8
.
[PubMed]
0195-6108
33.
Anderson
P
.
Assessment and development of executive function (EF) during childhood
.
Child Neuropsychol
.
2002
Jun
;
8
(
2
):
71
82
.
[PubMed]
0929-7049
34.
Shaw
P
,
Greenstein
D
,
Lerch
J
,
Clasen
L
,
Lenroot
R
,
Gogtay
N
, et al
Intellectual ability and cortical development in children and adolescents
.
Nature
.
2006
Mar
;
440
(
7084
):
676
9
.
[PubMed]
0028-0836
35.
Tamnes
CK
,
Østby
Y
,
Walhovd
KB
,
Westlye
LT
,
Due-Tønnessen
P
,
Fjell
AM
.
Neuroanatomical correlates of executive functions in children and adolescents: a magnetic resonance imaging (MRI) study of cortical thickness
.
Neuropsychologia
.
2010
Jul
;
48
(
9
):
2496
508
.
[PubMed]
0028-3932
36.
Lebel
C
,
Walker
L
,
Leemans
A
,
Phillips
L
,
Beaulieu
C
.
Microstructural maturation of the human brain from childhood to adulthood
.
Neuroimage
.
2008
Apr
;
40
(
3
):
1044
55
.
[PubMed]
1053-8119
37.
Tamnes
CK
,
Østby
Y
,
Fjell
AM
,
Westlye
LT
,
Due-Tønnessen
P
,
Walhovd
KB
.
Brain maturation in adolescence and young adulthood: regional age-related changes in cortical thickness and white matter volume and microstructure
.
Cereb Cortex
.
2010
Mar
;
20
(
3
):
534
48
.
[PubMed]
1047-3211
38.
Cakmakci
H
,
Usal
C
,
Karabay
N
,
Kovanlikaya
A
.
Transient neonatal hypoglycemia: cranial US and MRI findings
.
Eur Radiol
.
2001
;
11
(
12
):
2585
8
.
[PubMed]
0938-7994
39.
Bull
R
,
Espy
KA
,
Wiebe
SA
.
Short-term memory, working memory, and executive functioning in preschoolers: longitudinal predictors of mathematical achievement at age 7 years
.
Dev Neuropsychol
.
2008
;
33
(
3
):
205
28
.
[PubMed]
8756-5641
40.
Sortor
JM
,
Kulp
MT
.
Are the results of the Beery-Buktenica Developmental Test of Visual-Motor Integration and its subtests related to achievement test scores?
Optom Vis Sci
.
2003
Nov
;
80
(
11
):
758
63
.
[PubMed]
1040-5488
41.
Harris
SR
,
Langkamp
DL
.
Predictive value of the Bayley mental scale in the early detection of cognitive delays in high-risk infants
.
J Perinatol
.
1994
Jul-Aug
;
14
(
4
):
275
9
.
[PubMed]
0743-8346
42.
Hattersley
AT
,
Ashcroft
FM
.
Activating mutations in Kir6.2 and neonatal diabetes: new clinical syndromes, new scientific insights, and new therapy
.
Diabetes
.
2005
Sep
;
54
(
9
):
2503
13
.
[PubMed]
0012-1797
43.
Mujsce
DJ
,
Christensen
MA
,
Vannucci
RC
.
Regional cerebral blood flow and glucose utilization during hypoglycemia in newborn dogs
.
Am J Physiol
.
1989
Jun
;
256
(
6 Pt 2
):
H1659
66
.
[PubMed]
0002-9513
44.
Harris
DL
,
Gamble
GD
,
Weston
PJ
,
Harding
JE
.
What happens to blood glucose concentrations after oral treatment for neonatal hypoglycemia?
J Pediatr
.
2017
Nov
;
190
:
136
41
.
[PubMed]
0022-3476
45.
Ennis
K
,
Dotterman
H
,
Stein
A
,
Rao
R
.
Hyperglycemia accentuates and ketonemia attenuates hypoglycemia-induced neuronal injury in the developing rat brain
.
Pediatr Res
.
2015
Jan
;
77
(
1-1
):
84
90
.
[PubMed]
0031-3998
46.
Suh
SW
,
Gum
ET
,
Hamby
AM
,
Chan
PH
,
Swanson
RA
.
Hypoglycemic neuronal death is triggered by glucose reperfusion and activation of neuronal NADPH oxidase
.
J Clin Invest
.
2007
Apr
;
117
(
4
):
910
8
.
[PubMed]
0021-9738
47.
Glasgow
MJ
,
Harding
JE
,
Edlin
R
;
for the CHYLD Study Team
.
Cost analysis of cot-side screening methods for neonatal hypoglycaemia
.
Neonatology
.
2018
;
114
(
2
):
155
62
.
[PubMed]
1661-7800
48.
McKinlay
CJ
,
Chase
JG
,
Dickson
J
,
Harris
DL
,
Alsweiler
JM
,
Harding
JE
.
Continuous glucose monitoring in neonates: a review
.
Matern Health Neonatol Perinatol
.
2017
Oct
;
3
(
1
):
18
.
[PubMed]
2054-958X
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.