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Per Neonatal Glycaemia and PDF
Per Neonatal Glycaemia and PDF
Per Neonatal Glycaemia and PDF
a Liggins Institute, University of Auckland, Auckland, New Zealand; b Department of Paediatrics: Child and Youth
Health, University of Auckland, Auckland, New Zealand; c Kidz First Neonatal Care, Counties Manukau Health,
Screening
Records screened Records excluded
(n = 1,517) (n = 1,456)
Quality of Evidence lowing title and abstract screening, and a further 49 were
We assessed the risk of bias for each study using a modified excluded following full-text review (Fig. 1). One cohort
version of the ROBINS-I tool for non-randomized studies of inter-
ventions, as previously described [11]. This included assessment of
study reported outcomes separately at 2 and 4.5 years of
the following domains for bias: recruitment and selection of par- age [3, 13]. Thus, a total of 11 studies (12 publications),
ticipants, confounding, ascertainment of exposures, measurement comprising 4,041 infants were included, of which 9 (10
of outcomes, missing data, and reporting of results. Two authors publications) provided data suitable for meta-analysis in
independently performed risk of bias assessments. Conflicts were early and mid-childhood. No studies reported outcomes
resolved by consensus or by consultation with a third author.
We evaluated the overall quality of evidence for each research
in adolescence.
question using the GRADE approach [12]. Seven outcomes were
selected for GRADE assessment: neurodevelopmental impair- Characteristics of the Selected Studies
ment, cognitive impairment, visual-motor impairment, low lan- All of the included studies were cohort studies; 3 were
guage/literacy, low numeracy, epilepsy, and executive dysfunction. prospective [13–15], 6 were retrospective [16–21], and
Two authors independently assessed the quality of evidence. Con-
flicts were resolved by consensus or by consultation with a third
for 2 it was unclear whether all data were collected pro-
author. spectively [22, 23] (Table 1). All studies were conducted
in developed countries, including Europe, the USA, Can-
ada, and New Zealand. Four studies were conducted in
the 1970s [14, 15, 20, 22], 2 in the 1990s [17, 21], 1 in the
Results 2000s [16] and 4 in the 2010s [13, 18, 19, 23]. In 10 stud-
ies the study population comprised infants at risk of hy-
Search Results poglycaemia; 1 study included all the infants born at the
Of 1,665 records identified through databases and hospital. Only 4 studies (5 publications) each had uncer-
hand searching, 148 were duplicates and were removed. tain or low risk of bias in one or more domains, and each
Of the remaining 1,517 studies, 1,456 were excluded fol- adjusted results for potential confounding [3, 13, 18, 19,
First author Study type Study population Sample size Definition of Glucose screening protocol Test method Target range Treatments Age at Neurodevelopmental tests Included Adjustment
and date hypoglycaemia for treatment follow-up in meta- for potential
analysis confounding
Griffiths Cohort Neonates admitted 41 exposed, 41 <1.11 mmol/ Single blood glucose measurement Capillary whole blood; Not specified Not specified 4.2 years Cognition: Stanford-Binet or Yes No
[22], 1971 to special care unexposed L (<20 mg/dL) within 24 h of admission; further modified Watson (mean) Griffiths
unit blood glucose measurement only if method Behavior: Stott Systemic
hypoglycaemic or if symptomatic Interview
Motor: Griffiths Locomotor
Koivisto Retro- At-risk or 151 exposed, 56 <1.7 mmol/L Blood glucose measured 3 times Capillary whole blood; Not specified 10–20% 1–4 years Cognitive, language and motor Yes No
Neurodevelopmental Outcomes
[20], 1972 spective symptomatic unexposed (<30 mg/dL) daily for 2–4 days in at-risk and laboratory-modified intravenous tests not specified
cohort neonates screened symptomatic infants, and Hultman or glucose glucose; Behavioural assessment not
for hypoglycaemia continued for 24 h after oxidase method hydrocortisone specified
euglycaemic or discontinuation of Ophthalmologic examination
treatment
Pildes Prospective At-risk or 39 exposed, 41 <1.11 mmol/L Daily blood glucose measurement Capillary whole blood; Not specified Oral dextrose; 1–7 years Cognitive: Cattell Infant Scale, Yes No
[15], cohort symptomatic unexposed (<20 mg/dL) for 1–4 days laboratory glucose 10–15% Stanford-Binet or Wechsler
1974 neonates screened oxidase method intravenous Intelligence Scale for Children
for hypoglycaemia dextrose; Social: Vineland Social
(mostly preterm or hydrocortisone Maturity Scale
SGA) or ACTH Electroencephalogram
Haworth Prospective Infants of diabetic 25 exposed, 12 ≤1.11 mmol/L 0.5, 1, 2, 3, 6,12, 24, 48 and 72 h, Capillary whole blood; Not specified Intravenous 4.5 years Yale Developmental Schedule Yes No
[14], 1976 cohort mothers unexposed (≤20 mg/dL) and more frequently if laboratory Huggett and glucose, (mean)
in low birth hypoglycaemic Nixon method long-acting
weight babies adrenalin or
(<2.5 kg) and both
≤1.65 mmol/L
(≤30 mg/dL)
in normal
weight babies
Stenninger Retro- Infants of diabetic 13 exposed 15 <1.5 mmol/L Glucose measurements for the first Capillary whole blood; Not specified Not specified 7–8 years Cognitive: Griffiths’ Yes No
[21], 1998 spective mothers unexposed (<27 mg/dL) 24 h, frequency not specified laboratory glucose Developmental Scales
cohort oxidase method Motor: Movement Assessment
Battery for Children
Behaviour: questionnaires
(not specified)
Validated neurological
screening test for evaluation of
minimal brain dysfunction
Electroencephalogram
DOI: 10.1159/000492859
Duvanel Retro- Preterm 62 exposed, 23 <2.6 mmol/L Blood glucose measured Dextrostix for screening; Not specified 10% intra- 6, 12, Cognitive: Griffith’s No No
[17], spective (≤34 weeks) and unexposed (47 mg/dL) approximately every 4–5 h for the if <2 mmol/L confirmed venous and 18 Developmental Scales,
Neonatology 2019;115:116–126
1999 cohort SGA first 24 h by laboratory venous dextrose months, McCarthy Scales of Aptitude
sample using glucose and 3.5
oxidase or hexokinase and 5 years
method
Brand Retro- Term and large 60 exposed, 15 <2.2 mmol/L 1, 3, and 5 h after birth and more Capillary whole blood; Not specified Additional 4 years Cognitive: Denver Yes No
[16], spective for gestational age unexposed (<40 mg/dL) frequently if hypoglycaemic laboratory glucose feeding or Developmental Scale,
2005 cohort oxidase method intravenous Snijders-Oomen non-verbal
dextrose intelligence test
Behaviour: Dutch version of
the Child Behaviour Check List
Kerstjens Cohort Moderate preterm 67 exposed, 765 <1.7 mmol/L Blood glucose measured several Bedside glucometer; Not specified Not specified 3.5–4 years Ages and Stages Questionnaire Yes Yes
[23], 2012 (32–35 weeks’ unexposed (<30 mg/dL) times during the first 24 h laboratory confirmation
gestation) if <3.0 mmol/L (54 mg/
dL) or <2.5 mmol/L
(45 mg/dL), depending
on site protocol
119
Table 1 (continued)
120
First author Study type Study population Sample size Definition of Glucose screening protocol Test method Target range Treatments Age at Neurodevelopmental tests Included Adjustment
and date hypoglycaemia for treatment follow-up in meta- for potential
analysis confounding
McKinlay Prospective Term and late- 216 exposed, <2.6 mmol/L 1 h, then before feeds 3–4 h for Capillary whole blood; ≥2.6 mmol/L Additional 2 years Cognitive: Bayley Scales of Yes Yes
2015 [3] cohort preterm neonates 188 unexposed (<47 mg/dL) first 24 h, then 6–8 h for next 24 h laboratory glucose (47 mg/dL) feeding, buccal Infant Development III.
born at risk for and until hypoglycaemia no longer oxidase method; masked dextrose gel, Executive: a battery of four
hypoglycaemia a clinical concern. More frequent continuous interstitial intravenous tasks, and Behavior Rating
if hypoglycaemic or receiving glucose monitoring dextrose Inventory of Executive Func-
intravenous dextrose tion (Preschool version)
Vision: visual screening using
four assessment categories and
random-dot kinematograms of
varying coherence
Hearing: audiologic screening
Kaiser Retro- All neonates 89 exposed, <1.94 mmol/L Universal newborn glucose Laboratory glucose Not specified Intravenous 10 years Fourth Grade Benchmark Yes Yes
[19], spective 1,306 unexposed (<35 mg/dL) screening at 1–3 h after birth; oxidase dextrose or Examination (literacy and
2015 cohort repeated after 1 h if hypoglycaemic additional mathematics)
feeding
DOI: 10.1159/000492859
Goode Retro- Preterm and low 461 exposed/ <2.49 mmol/L Not specified Dextrostix or plasma Not specified Not specified 5, 8, and Cognitive: Stanford-Binet, No Yes
[18], spective birth weight 282 unexposed (<45 mg/dL) glucose, method not 18 years Peabody Picture Vocabulary
2016 cohort specified Test, Wechsler Intelligence
Neonatology 2019;115:116–126
Scale for Children, Wechsler
Abbreviated Scale of Intelli-
gence. Academic: Woodcock-
Johnson Tests of Achievement
Behaviour: Child Behaviour
Checklist, Youth Report
Behaviour Surveillance System
McKinlay Prospective Term and 280 exposed, <2.6 mmol/L 1 h, then before feeds 3–4 h for Capillary whole blood; ≥2.6 mmol/L Additional 4.5 years Cognitive: Wechsler Preschool Yes Yes
[13], cohort moderate to late 197 unexposed (<47 mg/dL) first 24 h, then 6–8 h for next 24 h laboratory glucose (47 mg/dL) feeding, buccal and Primary Scale of Intelli-
2017 preterm infants and until hypoglycaemia no longer oxidase method; masked dextrose gel, gence (version 3)
born at risk of a clinical concern. More frequent continuous interstitial intravenous Executive: a battery of five
hypoglycaemia if hypoglycaemic or receiving glucose monitoring dextrose graded tasks, Behaviour Rating
intravenous dextrose Inventory of Executive Func-
tion
Motor: Movement Assessment
Battery for Children (version 2)
and Beery Buktenica Develop-
mental Test of Visual Motor
Integration (version 6) (BBV-
MI-6)
Vision: visual screening using
six assessment categories, visual
processing subscale of BBV-
MI-6, random dot kinetograms
of varying coherence
Auditory processing: auditory
subscale of the Phelps Kinder-
garten Readiness Scale
Emotional and behaviour:
Strengths and Difficulties
Questionnaire, Child Behav-
iour Checklist
Shah/Harding/Brown/McKinlay
Table 2. Risk of bias assessment
Assessed using a modified version of the ROBINS-I tool for non-randomized studies of interventions [11].
23]. No study was at low risk of bias across all domains. 15.4 vs. 15.9%; OR = 1.11, 95% CI = 0.73–1.69; p = 0.63;
Seven studies were small with fewer than 100 participants I2 = 28%), mild cognitive impairment (3 studies, 746 in-
and had very imprecise estimates of exposure effect. fants, 12.8 vs. 13.7%; OR = 0.86, 95% CI = 0.55–1.35; p =
0.52; I2 = 61%) and moderate-severe cognitive impair-
Early Childhood (2–5 Years) ment (3 studies, 746 infants, 2.6 vs. 2.1%; OR = 1.57, 95%
Primary Outcomes CI = 0.55–4.48; p = 0.40, I2 = 34%) [13, 20, 22]. Two of
The risk of neurodevelopmental impairment in early these 3 studies were at high risk of bias in one or more
childhood did not differ between those who were and domains. The risk of epilepsy in early childhood did not
were not exposed to neonatal hypoglycaemia (6 studies, differ between those exposed and not exposed to neonatal
1,657 infants; 25.8 vs. 16.6%; OR = 1.16, 95% CI = 0.86– hypoglycaemia (4 studies, 772 infants, 4.2 vs. 2.1%; OR =
1.57; p = 0.34; I2 = 16%) [3, 13–16, 20, 23]. Four out of the 1.93, 95% CI = 0.76–4.85; p = 0.16, I2 = 0%) [13, 14, 20,
6 studies contributing data to this meta-analysis were at 22]. Three of these 4 studies were at high risk of bias in
high risk of bias in one or more domains (Table 2). In 2 one or more domains. The risk of emotional-behavioural
studies, exposure to neonatal hypoglycaemia was associ- difficulty did not differ between those exposed and not
ated with increased risk of visual-motor impairment (508 exposed to neonatal hypoglycaemia (3 studies, 587 in-
infants; 4.6 vs. 1.5%; OR = 3.46, 95% CI = 1.13–10.57; p = fants, 18.9 vs. 19.0%; OR = 1.00, 95% CI = 0.66–1.53; p =
0.03; I2 = 0%) [13, 14]. One of these studies was at high 0.98, I2 = 0%) [13, 14, 22]. One of these studies was at low
risk of bias for confounding but contributed few data to or uncertain risk of bias while 2 were at high risk of bias
the meta-analysis [14]. In 1 study, there was an associa- in one or more domains. The risk of visual impairment in
tion between neonatal hypoglycaemia and executive dys- early childhood did not differ between those exposed or
function (463 infants; 10.6 vs. 4.7%; OR = 2.50, 95% CI = not exposed to neonatal hypoglycaemia (2 studies, 616
1.20–5.22; p = 0.01). This study had a low to uncertain risk infants, 5.0 vs. 1.7%; OR = 2.14, 95% CI = 0.70–6.53; p =
of bias [13]. There were insufficient data to undertake the 0.18, I2 = 0%) [13, 20]. One of these studies was at high
planned sensitivity analyses. risk of bias in one or more domains and contributed the
most data to the meta-analysis [20]. In 1 study, the rate of
Secondary Outcomes hearing impairment in early childhood did not differ be-
In early childhood, those exposed to neonatal hypogly- tween those exposed or not exposed to neonatal hypogly-
caemia compared with those not so exposed had similar caemia (477 infants, 0 vs. 0.5%; OR = 0.23, 95% CI = 0.01–
rates of any cognitive impairment (3 studies, 746 infants, 5.76; p = 0.37) [13]. This study had a low to uncertain risk
hands in a coordinated and efficient way, enabling, for is thought to occur within the ventral and dorsal cortical
example, one to perceive and copy shapes, letters, and visual streams. The ventral stream supports form pro-
numbers. Thus, visual-motor integration is important for cessing and object recognition, and includes the occipital
learning and academic achievement including reading, primary visual cortex and the inferior temporal lobe. The
writing, and mathematics [27, 28]. dorsal stream is responsible for motion perception and
The development of visual and motor systems is close- visually guided motor function and includes the occipital
ly related [29], and coordination of visual-motor function primary visual cortex, middle temporal lobe, and poste-
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