- Email: [email protected]
Retrospective evaluation of a national guideline to prevent neonatal hypoglycemia
Accepted Manuscript Retrospective evaluation of a national guideline to prevent neonatal hypoglycemia A.H. Rasmussen, MD., S. Biostatistician Wehberg, PhD, J. Fenger-Grøn, MD., H.T. Christesen, MD, PhD, Professor PII:
S1875-9572(17)30021-9
DOI:
10.1016/j.pedneo.2016.12.002
Reference:
PEDN 635
To appear in:
Pediatrics & Neonatology
Received Date: 18 August 2016 Revised Date:
10 November 2016
Accepted Date: 4 December 2016
Please cite this article as: Rasmussen A, Wehberg SB, Fenger-Grøn J, Christesen H, Retrospective evaluation of a national guideline to prevent neonatal hypoglycemia, Pediatrics and Neonatology (2017), doi: 10.1016/j.pedneo.2016.12.002. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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This material is original research.
Title:
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Retrospective evaluation of a national guideline to prevent neonatal
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hypoglycemia
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Running title:
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Neonatal hypoglycemia
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Rasmussen, AH. MD. Hans Christian Andersen Children´s Hospital, Odense University Hospital, Denmark and Institute of Clinical Research, University of Southern Denmark, Odense, Denmark.
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Wehberg, S. Biostatistician, PhD., Odense University Hospital, Odense, Denmark.
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Fenger-Grøn, J. MD. Dept. of Pediatrics, Lillebaelt Hospital, Kolding, Denmark.
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Christesen, HT. Professor, MD, PhD, Hans Christian Andersen Children´s Hospital, Odense University
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Hospital and Institute of Clinical Research, University of Southern Denmark, Odense, Denmark.
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Corresponding author:
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Henrik T Christesen. Professor, MD, PhD, Hans Christian Andersen Children´s Hospital, Odense University
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Hospital and Institute of Clinically Research, University of Southern Denmark, Odense, Denmark.
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Telephone: +45 2137 0888
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Email: [email protected]
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This material is original research. No related papers from the authors have been published or are under
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consideration for publication elsewhere, and this paper has not been submitted elsewhere.
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Retrospective evaluation of a national guideline to prevent neonatal hypoglycemia
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under consideration for publication elsewhere, and this paper has not been submitted elsewhere.
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Keywords: Hypoglycemia; Neonate; Prevention.
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Abstract
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Background. Hypoglycemia is common in neonates and may cause adverse neurological
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outcomes. Guidelines should aim to prevent repeated hypoglycemic episodes in risk groups,
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but they are not usually stratified according to the severity of hypoglycemia risk, which may
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lead to the implementation of inappropriate and redundant interventions.
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Aim. To evaluate the effect of a national prevention guideline stratified according to mild,
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moderate, and severe risks of hypoglycemia.
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Methods. From national registers, a population cohort of 22,725 neonates was identified
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retrospectively before and after implementation of a national guideline. Of these, 1900 had
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World Health Organization International Classification of Diseases 10 discharge diagnoses of
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hypoglycemia. Diagnoses indicating hypoglycemia risk [small/large for gestational age
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(SGA/LGA), asphyxia, prematurity, maternal insulin-treated diabetes mellitus (mIDM)] were
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recorded. Neonatal ward files were evaluated to validate hypoglycemia diagnoses. Adjusted
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odds ratios (aORs) were calculated, adjusting for sex, parity, SGA, LGA, preterm birth, and
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asphyxia, where relevant.
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ACCEPTED MANUSCRIPT Results. Primiparity and male sex were associated independently with hypoglycemia
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diagnosis [aORs, 1.29 (1.17–1.42) and 1.14 (1.03–1.26), respectively]. The overall incidence of
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hypoglycemia diagnosis at discharge decreased from 9.4% to 5.5% after guideline
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implementation [aORchange, 0.57 (0.50–0.64)]. The overall incidence of validated hypoglycemia
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decreased from 2.1% to 1.2% [aOR 0.59 (0.46–0.77), p<0.001]. By risk group, the
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hypoglycemia incidence decreased from 30.5% to 18.6% [aOR 0.52 (0.36–0.75)] among SGA
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neonates, from 25.8% to 16.4% [aOR 0.57 (0.42–0.76)] among preterm infants, and from
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27.4% to 16.6% [aOR 0.63 (0.34–0.83)] among those with asphyxia. LGA neonates showed a
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decreased incidence in obstetric wards only. No significant change was observed for the
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mIDM group.
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Conclusion. Stratification of hypoglycemia risk in a hypoglycemia prevention guideline was
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followed by decreased estimated hypoglycemia incidences, but no causative conclusion could
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be drawn. Prospective studies with risk stratification for hypoglycemia prevention are
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encouraged.
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Glucose is an essential fuel for brain metabolism and, depending on its severity and duration,
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hypoglycemia may result in adverse neurological outcomes.(1-4) The key to hypoglycemia
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prevention is to identify neonates at risk, as this condition may be difficult to detect clinically.
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(1, 5-8)
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The threshold for intervention in neonatal hypoglycemia remains controversial.(1, 9) After
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the physiological nadir, the mean plasma glucose level in 3–47-h-old, healthy, non-exclusively
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breastfed term neonates is 3.5–3.7 mmol/L, with a fifth percentile of 2.2–2.3 mmol/L.(10)
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This value is lower in healthy, exclusively breastfed term neonates (11), but higher ketone
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bodies provide alternative fuel in this group.(5)
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In risk groups, the clinical cut-off value for treatment of hypoglycemia is usually set around
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2.5 mmol/L (45 mg/dL) after the first hours of life. This threshold is used widely in clinical
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practice, despite differences in the methods and devices used for determination of the glucose
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concentration (12), and is supported by the recent guideline from The American Academy of
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Pediatrics.(13) Others have stated that asymptomatic neonates at risk should not maintain
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glucose levels < 2.0 mmol/L after feeding (1, 14), and treatment thresholds of 1.8 mmol/L on
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one occasion and 2.6 mmol/L on multiple occasions have been proposed.(15)
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The incidence of neonatal hypoglycemia ranges from 5% to 15% (1, 16, 17), possibly
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reflecting differences in study populations, preventive measures, and hypoglycemia
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definitions and measuring techniques (18), in addition to normal biological variation.
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According to the Institute of Medicine’s definition, clinical guidelines are “ systematically
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developed statements to assist practitioner and patient decisions about appropriate health
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care for specific clinical circumstances” (19) , and guidelines intend to improve efficiency and
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quality of care and reduce inappropriate practice.(20, 21) Hypoglycemia prevention protocols
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can improve the standard of care for neonates with hypoglycemia.(23) Although guidelines
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have the potential to have harmful effects as well as benefits if not evaluated, (20, 21) the
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consequences of guideline implementation have not been well studied. We are not aware of
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any previous study evaluating the effects of the implementation of a systematic, stratified
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guideline on the prevention and treatment of neonatal hypoglycemia.
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In Denmark, a national guideline for the prevention of neonatal hypoglycemia was introduced
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in 2010 with the primary aims of avoiding repeated hypoglycemic episodes in risk groups and
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enhancing the quality of care. The guideline stratified hypoglycemia risk as mild, moderate,
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and severe, allowing for the differentiation of preventive actions according to severity.
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In this study, we aimed to evaluate the prevention effect of the national prevention guideline
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by estimating the incidence proportions of neonatal hypoglycemia overall and for major risk
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groups, before and after the guideline implementation.
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Methods
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Data sources and uptake area
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This retrospective, observational cohort study was based on data from the Danish National
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Patient Registry (DNPR) and the Danish Medical Birth Registry (DMBR). The DNPR contains
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data for all hospitalized patients and newborns in Denmark. The DMBR has more detailed
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information on pregnancies and deliveries; it contains highly reliable and valid data on 99.8%
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of all Danish deliveries. (24) The following data were extracted from the DNPR and DMBR for
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each subject included in the study: personal identification number, postal code, parity,
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gestational age (GA), sex, birth weight, hospital/department, and all discharge diagnoses
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according to the World Health Organization’s International Classification of Diseases 10
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ACCEPTED MANUSCRIPT (ICD10). Additional data were collected from the medical records of three hospitals in the
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Region of Southern Denmark: Odense University Hospital (OUH; Department of Obstetrics
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and Hans Christian Andersen Children’s Hospital) and the two adjacent regional hospitals
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Lillebaelt Hospital, Kolding (Departments of Obstetrics and Pediatrics) and Svendborg
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Hospital (Department of Obstetrics). The OUH receives at-risk and high-risk mothers and
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neonates from the Svendborg and Kolding uptake areas, including all mothers with insulin-
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treated diabetes mellitus (mIDM). After delivery, all mother–infant pairs with mIDM were
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referred to the neonatal ward.
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Guideline
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Before 2010, no uniform hypoglycemia prevention program was established in Denmark. The
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national guideline was introduced in 2010 (Supplementary Table 1). In brief, infants were
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classified into no-, low-, moderate-, and high-risk groups at birth, depending on the risk
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factors present. Prevention measures ranged from breast contact to intravenous glucose
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administration within the first 30 min of life. If the first two glucose measurements were ≥2.5
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mmol/L, no further glucose determination was required.
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Time periods
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The pre-guideline period extended from August 1, 2006 to July 31, 2008; the post-guideline
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period extended from January 1, 2011 to December 31, 2011, or from July 1, 2012 to
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December 31, 2012 (for Lillebaelt Hospital, Kolding). Data collected between these periods
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were not included due to use of pilot versions of the guideline, and the difference in the post-
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guideline period is due to a delay in guideline implementation at Lillebaelt Hospital, Kolding.
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The risk groups were defined retrospectively according to small for gestational age (SGA) or
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large for gestational age (LGA) status [birth weight exceeding ±2 standard deviations (SDs) of
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the reference value], prematurity (GA<37+0 weeks), asphyxia (umbilical cord pH<7.1 and/or
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base excess≤10), and mIDM. Neonates with ICD10 diagnoses of hypoglycemia (P70.0–70.9)
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were identified. Mothers with mIDM attending the neonatal ward of OUH could be identified,
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but maternal ICD10 diabetes diagnosis codes were generally not available in the national
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registries used for the present study. Neonates with more than one hypoglycemia risk factor
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were assigned to more than one risk group.
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156 Blood glucose measurement
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Glucose concentrations were measured using different devices. In the neonatal ward of OUH,
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capillary blood glucose was tested using the HemoCue 201/201+ point-of-care testing (POCT)
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device until mid-April 2011, where after the HemoCue 201 DM RT and 201 DM were used.
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The Roche Accu-Chek Inform II system was used in the neonatal ward of Lillebaelt Hospital,
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Kolding, and Radiometer ABL 800 flex analyzers were used in the obstetric departments
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throughout the study period.
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All HemoCue devices measured glucose concentrations in whole blood, but the HemoCue 201
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RT/201 DM device automatically presented calculated plasma glucose values after
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multiplying by 1.11.
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Populations and outcome measures
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We studied the incidence proportions of neonatal hypoglycemia in the hospitals’ uptake area
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for each of the two time periods in four different patient populations, overall and separately
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denominator was the total birth count extracted from the DNPR/DMBR for the uptake area,
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and the numerator (count of neonates with hypoglycemia within the denominator group) was
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based on ICD10 diagnoses of hypoglycemia (P70.0–70.9) from the DNPR/DMBR in the
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neonatal period. For obstetric ward neonatal data, the denominator consisted of all neonates
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discharged from one of the three obstetric wards to home, and the numerator was based on
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recording of P70.0–70.9 diagnoses in the medical records. Bedside blood glucose values were
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not recorded systematically in the medical records of the obstetric departments, disallowing
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blood sample–based validation of neonatal hypoglycemia diagnoses in this population. For
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neonatal ward data, the denominator consisted of all neonates referred to one of the two
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neonatal wards. The numerator was based on recording of P70.0–70.9 diagnoses in the
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medical records. For neonatal ward data on validated hypoglycemia, the denominator was the
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same and the numerator was based on recording of P70.0–70.9 diagnoses in the medical
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records in cases for which data on blood glucose level and age (in hours) at the time of blood
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glucose determination were also available. These data were analyzed to validate diagnoses of
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hypoglycemia. Hypoglycemia was defined as glucose value <1.7 mmol/L at 0–2 h of life and
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<2.5 mmol/L after 2 h of life.
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Methodological bias (sensitivity analysis)
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We reviewed a random sample of data from 400 neonates without ICD10 hypoglycemia
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diagnoses in the neonatal ward of OUH within the asphyxia and SGA hypoglycemia risk factor
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groups. Hypoglycemic neonates identified by this search, but not identified through the
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original registry data search, were not included in the incidence estimates.
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First, odds ratios (ORs) for hypoglycemia diagnosis with 95% confidence intervals (CIs) were
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calculated based on logistic regression models for the following risk factors: SGA, LGA,
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preterm birth, asphyxia, and mIDM (where relevant), as well as parity and sex. This analysis
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was conducted for the overall patient population, across both time periods. Second, neonatal
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characteristics were compared between neonates with and without hypoglycemia diagnoses
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for each time period using the Mann–Whitney U, Student’s t, and chi-squared tests, where
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appropriate. Third, incidence proportions of hypoglycemia with 95% CIs were calculated for
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five patient populations (overall and separately according to risk groups). In addition, ORs for
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change with 95% CIs were calculated based on logistic regression models (univariate and
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adjusted for sex, parity, SGA, LGA, preterm birth, and asphyxia, where relevant). No
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adjustment for multiple testing was performed. Data were analyzed using Stata software
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(StataCorp, College Station, TX, USA).
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Ethics
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The regional ethics committee approved the study (protocol no. S-20120119).
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Results
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Overall, the study population included 22,725 neonates (48.4% girls, 51.6% boys). The mean
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(±SD) birth weights were 3400 (±600) g for girls and 3506 (±644) g for boys. The mean GA
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was 39 (±2.2) weeks. Prematurity was seen in 1693 (7.4%), asphyxia in 902 (3.9%), SGA in
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848 (3.7%), LGA in 822 (3.6%), and mIDM in 245 (1.1%) neonates. In total, 3949 (17.3%)
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neonates fell into risk groups, of which 406 (10.3%) had more than one risk factor.
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strongly with increased odds of hypoglycemia diagnosis (Table 1). Surprisingly, primiparity
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status and male sex were also associated strongly with increased adjusted odds ratios (aORs)
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for hypoglycemia. Neonates belonging to the risk groups defined in this study accounted for
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1289/1900 (67.8%) of all neonates with hypoglycemia diagnoses. Accordingly, almost one-
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third of neonates with such diagnoses could not be assigned to any risk group.
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The baseline characteristics of all neonates and those with hypoglycemia, defined by
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discharge diagnoses, in the two study periods are shown in Figure 1.
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The estimated incidence proportion of hypoglycemia by discharge diagnosis was 8.4% (Table
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2).
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National registry data showed that the incidence of hypoglycemia diagnoses in the SGA, LGA,
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preterm, and asphyxia risk groups was 26.2% (22.7–27.0%), with no significant difference
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among risk group estimates. In the neonatal ward, the incidence of validated hypoglycemia
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ranged from 5.5% to 10.5% among risk groups, but was much higher (32.2%) in the mIDM
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group.
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The implementation of the hypoglycemia guideline was associated with a highly significant
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decrease in the incidence proportion of this condition in the overall population in all analyses
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(Table 2).
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For neonates in the neonatal ward, the incidence of validated hypoglycemia also decreased,
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from 2.1% to 1.2% [crude OR for change, 0.55 (0.43–0.71), p<0.001; aOR, 0.59 (0.46–0.77)].
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All analyses showed decreased incidence proportions in the SGA and preterm birth groups.
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For the asphyxia group, a highly significant decrease was seen in the national registry and in
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the obstetric wards, but no change was observed in the neonatal wards. For the mIDM and
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LGA risk groups, no significant change was observed in any analysis.
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have affected the incidence of mild hypoglycemia (2.3–2.4 mmol/L) diagnoses within the
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post-implementation period. To compensate for this bias, we conducted a subanalysis
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including only OUH neonatal ward patients with validated hypoglycemia (<2.3 mmol/L)
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through April 15, 2011. This methodological bias correction did not change the incidence
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estimates.
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In the review of 400 neonatal ward files with ICD10 codes for asphyxia and SGA, without
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discharge diagnosis codes for hypoglycemia, we identified unreported hypoglycemia in 16.5%
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of neonates. Underreporting showed a decreasing trend between the pre- and post-
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implementation periods, especially for SGA (overall, from 20% to 13%, p=0.18; asphyxia, from
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16% to 12%, p=0.42; SGA, from 24% to 14%, p=0.07).
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253 Discussion
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In Danish neonatal departments, various initiatives to prevent and treat neonatal
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hypoglycemia have existed for decades. Until the introduction of the national guideline,
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however, practices were heterogeneous, differing within as well as between departments. The
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implementation of the national guideline instituted a homogenous, consistent, and systematic
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approach, and the current study was conducted to evaluate its effect on the risk of
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hypoglycemia. The retrospective design of our study and methodological constraints,
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including the lack of a uniform blood glucose recording protocol and the quality dependence
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of discharge diagnoses, except for the validation substudy that was conducted using data from
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the neonatal ward, do not allow the calculation of exact incidence estimates or drawing of
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definitive conclusions on the causes of changes. However, the estimated overall hypoglycemia
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incidence fell significantly between the two study periods; this effect was most pronounced in
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hypoglycemia discharge diagnoses. No evidence of an increase in hypoglycemia was observed
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after the guideline introduction, suggesting that the uniform incidence decrease was not due
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to methodological bias.
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The overall population incidence of neonatal hypoglycemia, according to discharge diagnosis,
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was 8.4%, which was within previously reported incidences of 5–15%. (2, 7, 8, 16, 17, 25, 26)
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Our estimate had the advantage of being based on a large population birth cohort, but the
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disadvantage of being based predominantly on discharge diagnoses and glucose
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measurements obtained with different methods. Validation exercises for these diagnoses
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showed both overreporting and underreporting of hypoglycemia compared with medical
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records reviews.
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In a multivariable analysis, we identified SGA, LGA, preterm birth, and asphyxia as
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independent risk factors for hypoglycemia. These risk groups, as well as the risk faced by
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infants of diabetic mothers, are well known.(5, 7, 25, 27) Almost one-third of our neonates
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with hypoglycemia diagnoses were not assigned to a risk group. One explanation for this
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finding could be missing discharge diagnoses of gestational diabetes, which in the absence of
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hypoglycemia could have been reported in the mothers’ hospital records only, and hence not
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included in the current study. Surprisingly, the analysis based on the identified risk groups
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showed that primiparity and male sex were independent risk factors for hypoglycemia.
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Explanatory factors may include delayed onset of lactogenesis in breastfeeding primipara
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(28) and increased male representation in neonates below the LGA cut-offs, but >4000 g,
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above which the risk of hypoglycemia also may be increased.(29)
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The overall incidence of hypoglycemia according to discharge diagnosis among the risk
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groups of SGA, LGA, preterm birth, and asphyxia was 26.2%. Others have reported
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restricted to neonatal ward data for newborns with validated hypoglycemia, the incidence
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was at the lower end of this reported range (12.4%).
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The estimated incidence of hypoglycemia diagnosis fell significantly after the implementation
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of the prevention guideline. This change may be attributed to a preventive effect of the
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guideline, but the contribution of methodological bias, including errors in discharge diagnoses
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and variations in blood glucose measurement counts and methods, cannot be ruled out. In
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support of a true decrease in the incidence of hypoglycemia, a decreased incidence was also
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seen in the validation exercise. Moreover, our subanalysis of neonatal ward cases of glucose
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values <2.3 mmol/L also showed a highly significant decrease in the incidence.
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Decreases in the estimated incidence of hypoglycemia were seen in the SGA and preterm risk
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groups, regardless of data source. The decrease in preterm neonates occurred despite a
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decrease in the mean GA and birth weight, which would tend to increase the risk of
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hypoglycemia, among all such neonates in the post-guideline period.
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For neonates with asphyxia, a decrease was seen only in the obstetric ward, suggesting that
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hypoglycemia prevention in the neonatal wards was effective before guideline
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implementation, or that detection of hypoglycemia among those with milder asphyxia in the
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obstetric ward who were not referred to the neonatal ward was more complete after
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guideline implementation.
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The LGA and mIDM risk groups showed no decrease in hypoglycemia, regardless of the data
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source. The unchanged incidence in the LGA group may reflect the ease of hypoglycemia
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prevention in this group by early feeding, a prevention strategy which was carried out before
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guideline implementation. For mIDM, the avoidance of hypoglycemia in this patient group
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received much attention before guideline implementation.
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methodological problems associated with POCT device use, raises open questions about the
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appropriateness of the prevention strategy examined here and others. At the least, the
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national prevention program introduced less-intrusive interventions for low-risk neonates
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without increasing the incidence of hypoglycemia in any risk group.
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The strengths of our study included the examination of a large, population-based birth cohort;
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the inclusion of data from several sources; the validation of hypoglycemia diagnoses; and the
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adjustment of analyses of incidence changes in risk groups. Limitations included the
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retrospective design, with the risk of inaccuracy of discharge diagnoses and medical records;
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the methodological problems associated with glucose measurement using different POCT
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devices; the non-inclusion of neonates with diet-treated maternal diabetes; and potential
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undiscovered reporting bias from unidentified changes in practice.
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We conclude that the introduction of a standardized, stratified hypoglycemia prevention
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program was followed by the use of a more systematic and consistent prevention strategy for
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hypoglycemia. The stratification of risk as mild, moderate, and severe, which enables the
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implementation of differentiated prevention initiatives, was met not by an increased
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hypoglycemia incidence, but by strong suggestions of a decrease. These findings encourage
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the further use of a stratified approach, which should be studied in other settings using a
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prospective design.
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Table 1. Factors associated with hypoglycemia diagnosis (ICD10 discharge diagnosis). Odds ratios with 95% confidence intervals based on logistic regression analysis of 22,725 neonates in the national registry database are presented. Both time periods are included.
Factor
P-value <0.001 <0.001 < 0.001 < 0.001 <0.001 0.001
Adjusted* OR (95% CI) 3.39 (2.86-4.03) 4.10 (3.43-4.90) 3.41 (3.04-3.96) 4.20 (3.56-4.95) 1.29 (1.17-1.42) 1.14 (1.03-1.26)
P-value <0.001 <0.001 <0.001 <0.001 <0.001 0.008
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*OR adjusted for sex, parity, and SGA, LGA, preterm birth, and asphyxia, where relevant. Abbreviations: OR, odds ratio; CI, confidence interval; SGA, small for gestational age; LGA, large for gestational age; AGA, appropriate for gestational age.
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SGA vs. AGA LGA vs. AGA Preterm Asphyxia Parity 1 vs. >1 Male vs. female
Crude OR (95% CI) 4.88 (4.15-5.72) 3.88 (3.27-4.61) 4.12 (3.54-4.54) 4.10 (3.50-4.81) 1.47 (1.34-1.62) 1.17 (1.06-1.28)
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Table 2. Incidence proportions of hypoglycemia before and after national guideline implementation, and odds ratios for change.
Incidence proportions (95% CI) in relation to guideline implementation Both periods Before After
Crude OR
Odds ratio (95% CI) for change p Adjusted* OR
p
0.57 (0.50-0.64) 0.52 (0.36-0.75) 0.96 (0.65-1.41) 0.57 (0.42-0.76) 0.53 (0.34-0.83)
<0.001 <0.001 0.839 <0.001 0.006
0.51 (0.43-0.59) 0.55 (0.34-0.90) 0.66 (0.38-1.18) 0.61 (0.48-0.78) 0.37 (0.21-0.65)
<0.001 0.018 0.167 0.016 0.001
0.76 (0.63-0.77) 0.55 (0.28-0.87) 1.30 (0.81-2.11) 0.59 (0.40-0.88) 1.27 (0.65-2.46)
0.001 0.018 0.286 0.009 0.482
0.59 (0.46-0.77) 0.56 (0.34-0.94) 0.72 (0.33-1.55) 0.28 (0.15-0.52) 1.33 (0.65-2.73) 0.83 (0.45-1.53)
<0.001 0.021 0.406 <0.001 0.430 0.559
0.43 (0.31-0.58)
<0.001
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National registry Overall 8.4% (8.0-8.8) 9.4% (9.0-9.9) 5.5% (4.9-6.1) 0.55 (0.49-0.62) <0.001 SGA 27.0% (24.0-30.1) 30.5% (26.9-34.5) 18.6% (13.9-23.9) 0.51 (0.36-0.74) <0.001 LGA 23.6% (19.9-25.7) 25.3% (19.9-26.7) 21.1% (15.8-27.3) 0.89 (0.60-1.30) 0.554 Preterm 23.6% (21.6-25.7) 25.8% (23.4-28.2) 16.4% (12.9-20.0) 0.56 (0.42-0.75) <0.001 Asphyxia 25.3% (22.6-28.3) 27.4% (24.2-30.8) 16.6% (11.3-23.0) 0.52 (0.34-0.81) 0.004 Obstetric ward neonates Overall 5.3% (5.0-5.6) 6.1% (5.8-6.5) 3.0% (2.7-3.5) 0.48 (0.41-0.56) <0.001 SGA 13.2% (11.0-15.6) 15.0% (12.8-18.8) 9.1% (5.8-13.3) 0.56 (0.35-0.92) 0.022 LGA 10.3% (8.3-12.6) 11.2% (8.8-13.9) 7.7% (4.5-12.1) 0.66 (0.38-1.17) 0.156 Preterm 11.1% (9.6-12.7) 12.2% (10.4-14.1) 7.7% (5.3-10.7) 0.60 (.040-0.90) 0.014 Asphyxia 18.2% (15.7-20.8) 20.3% (17.4-23.4) 8.9% (5.1-14.2) 0.38 (0.22-0.67) 0.001 Neonatal ward neonates Overall 3.0% (2.8-3.3) 3.3% (3.0-3.6) 2.4% (2.0-2.8) 0.72 (0.60-0.86) 0.001 SGA 13.7% (11.5-16.3) 15.6% (0.13-0.19) 9.3% (6.2-13.8) 0.56 (0.35-0.91) 0.019 LGA 12.4% (10.2-14.8) 12.0% (9.6-14.8) 13.5% (9.1-18.8) 1.14 (0.71-1.80) 0.573 Preterm 12.5% (10.9-14.1) 13.6% (11.8-15.6) 8.7% (6.1-11.9) 0.60 (0.41-0.88) 0.010 Asphyxia 7.2% (5.6-9.0) 7.1% (5.3-9.1) 7.7% (4.1-12.7) 1.09 (0.58-2.10) 0.579 Neonatal ward, validated hypoglycemia Overall 1.8% (1.7-2.0) 2.1% (1.9-2.3) 1.2% (0.1-0.2) 0.55 (0.43-0.71) <0.001 SGA 10.5% (8.5-12.7) 11.9% (9.4-14.8) 7.1% (4.2-11.0) 0.62 (0.31-0.93) 0.003 LGA 6.2% (4.6-8.1) 6.8% (5.0-9.1) 4.3% (2.0-8.0) 0.62 (0.29-1.29) 0.204 Preterm 7.9% (6.7-9.3) 9.4% (7.9-11.2) 2.9% (1.6-5.2) 0.29 (0.16-0.54) <0.001 Asphyxia 5.5% (4.2-7.4) 5.4% (3.9-7.4) 6.5% (3.3-11.3) 1.20 (0.61-2.40) 0.594 Maternal diabetes, 32.2% (26.4-38.4) 34.5% (27.3-42.3) 27.5% (18.1-38.6) 1.2 (0.40- (1.29) 0.270 insulin-treated Bias-corrected 1.8% (1.6-1.9) 2.1 (1.9-2.3) 1.1% (0.8-1.4) 0.44 (0.30-0.55) <0.001 hypoglycemia 350 *Adjusted for sex, parity, SGA, LGA, preterm birth, and asphyxia, where relevant. 351 Abbreviations: CI, confidence interval; OR, odds ratio; SGA, small for gestational age; LGA, large for gestational age.
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Figure 1. Baseline characteristics for all neonates, and neonates at risk of hypoglycemia, defined by discharge diagnosis, before and after
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implementation of a national guideline for the prevention of hypoglycemia.
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SGA, small for gestational age; LGA, large for gestational age; DM, diabetes mellitus.
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COI statement
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The authors have no conflict of interest relevant to this article.
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1.Cornblath M, Hawdon JM, Williams AF, Aynsley-Green A, Ward-Platt MP, Schwartz R, et al.
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Controversies regarding definition of neonatal hypoglycemia: suggested operational
367
thresholds. Pediatrics. 2000;105(5):1141-5.
368
2.Lucas A, Morley R, Cole TJ. Adverse neurodevelopmental outcome of moderate neonatal
369
hypoglycaemia. BMJ (Clinical research ed). 1988;297(6659):1304-8.
370
3.Arya VB, Senniappan S, Guemes M, Hussain K. Neonatal Hypoglycemia. Indian J Pediatr.
371
2013.
372
4.McKinlay CJ, Alsweiler JM, Ansell JM, Anstice NS, Chase JG, Gamble GD, et al. Neonatal
373
Glycemia and Neurodevelopmental Outcomes at 2 Years. The New England journal of
374
medicine. 2015;373(16):1507-18.
375
5.Hawdon JM, Ward Platt MP, Aynsley-Green A. Patterns of metabolic adaptation for preterm
376
and term infants in the first neonatal week. Arch Dis Child. 1992;67(4 Spec No):357-65.
377
6.Altman M, Vanpee M, Cnattingius S, Norman M. Neonatal morbidity in moderately preterm
378
infants: a Swedish national population-based study. The Journal of pediatrics.
379
2011;158(2):239-44.e1.
380
7.Agrawal RK, Lui K, Gupta JM. Neonatal hypoglycaemia in infants of diabetic mothers. Journal
381
of paediatrics and child health. 2000;36(4):354-6.
382
8.Maayan-Metzger A, Lubin D, Kuint J. Hypoglycemia rates in the first days of life among term
383
infants born to diabetic mothers. Neonatology. 2009;96(2):80-5.
384
9.Guemes M, Rahman SA, Hussain K. What is a normal blood glucose? Arch Dis Child. 2015.
385
10.Alkalay AL, Sarnat HB, Flores-Sarnat L, Elashoff JD, Farber SJ, Simmons CF. Population
386
meta-analysis of low plasma glucose thresholds in full-term normal newborns. Am J Perinatol.
387
2006;23(2):115-9.
AC C
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ACCEPTED MANUSCRIPT 11.Swenne I, Ewald U, Gustafsson J, Sandberg E, Ostenson CG. Inter-relationship between
389
serum concentrations of glucose, glucagon and insulin during the first two days of life in
390
healthy newborns. Acta Paediatr. 1994;83(9):915-9.
391
12.D'Orazio P, Burnett RW, Fogh-Andersen N, Jacobs E, Kuwa K, Kulpmann WR, et al.
392
Approved IFCC recommendation on reporting results for blood glucose (abbreviated). Clinical
393
chemistry. 2005;51(9):1573-6.
394
13.Adamkin DH. Postnatal glucose homeostasis in late-preterm and term infants. Pediatrics.
395
2011;127(3):575-9.
396
14.Hawdon JM. Definition of neonatal hypoglycaemia: time for a rethink? Archives of disease
397
in childhood Fetal and neonatal edition. 2013;98(5):F382-3.
398
15.Screening guidelines for newborns at risk for low blood glucose. Paediatr Child Health.
399
2004;9(10):723-40.
400
16.Merenstein GB, Gardner SL. Handbook of neonatal intensive care. 5 ed. St. Louis, Mo.:
401
Mosby; 2002. xx, 863 s., illustreret (pbk) p.
402
17.Hay WW, Jr., Raju TN, Higgins RD, Kalhan SC, Devaskar SU. Knowledge gaps and research
403
needs for understanding and treating neonatal hypoglycemia: workshop report from Eunice
404
Kennedy Shriver National Institute of Child Health and Human Development. The Journal of
405
pediatrics. 2009;155(5):612-7.
406
18.Harris DL, Weston PJ, Harding JE. Incidence of neonatal hypoglycemia in babies identified
407
as at risk. The Journal of pediatrics. 2012;161(5):787-91.
408
19.Institute of Medicine Committee to Advise the Public Health Service on Clinical Practice G.
409
In: Field MJ, Lohr KN, editors. Clinical Practice Guidelines: Directions for a New Program.
410
Washington (DC): National Academies Press (US)
411
Copyright (c) National Academy of Sciences.; 1990.
AC C
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22
ACCEPTED MANUSCRIPT 20.Grimshaw JM, Russell IT. Effect of clinical guidelines on medical practice: a systematic
413
review of rigorous evaluations. Lancet (London, England). 1993;342(8883):1317-22.
414
21.Woolf SH, Grol R, Hutchinson A, Eccles M, Grimshaw J. Clinical guidelines: potential
415
benefits, limitations, and harms of clinical guidelines. BMJ (Clinical research ed).
416
1999;318(7182):527-30.
417
22.Rozance PJ, Hay WW, Jr. Describing hypoglycemia--definition or operational threshold?
418
Early Hum Dev. 2010;86(5):275-80.
419
23.Stewart CE, Sage EL, Reynolds P. Supporting 'Baby Friendly': a quality improvement
420
initiative for the management of transitional neonatal hypoglycaemia. Archives of disease in
421
childhood Fetal and neonatal edition. 2015.
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24.Knudsen LB, Olsen J. The Danish Medical Birth Registry. Dan Med Bull. 1998;45(3):320-3.
423
25.Hume R, McGeechan A, Burchell A. Failure to detect preterm infants at risk of
424
hypoglycemia before discharge. The Journal of pediatrics. 1999;134(4):499-502.
425
26.Sexson WR. Incidence of neonatal hypoglycemia: a matter of definition. The Journal of
426
pediatrics. 1984;105(1):149-50.
427
27.Rozance PJ. Update on neonatal hypoglycemia. Curr Opin Endocrinol Diabetes Obes.
428
2014;21(1):45-50.
429
28.Nommsen-Rivers LA, Chantry CJ, Peerson JM, Cohen RJ, Dewey KG. Delayed onset of
430
lactogenesis among first-time mothers is related to maternal obesity and factors associated
431
with ineffective breastfeeding. Am J Clin Nutr. 2010;92(3):574-84.
432
29.Linder N, Lahat Y, Kogan A, Fridman E, Kouadio F, Melamed N, et al. Macrosomic newborns
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of non-diabetic mothers: anthropometric measurements and neonatal complications.
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Archives of disease in childhood Fetal and neonatal edition. 2014;99(5):F353-8.
AC C
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30.Jonas D, Dietz W, Simma B. Hypoglycemia in Newborn Infants at Risk. Klinische Padiatrie.
436
2014.
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S1875-9572(17)30021-9
DOI:
10.1016/j.pedneo.2016.12.002
Reference:
PEDN 635
To appear in:
Pediatrics & Neonatology
Received Date: 18 August 2016 Revised Date:
10 November 2016
Accepted Date: 4 December 2016
Please cite this article as: Rasmussen A, Wehberg SB, Fenger-Grøn J, Christesen H, Retrospective evaluation of a national guideline to prevent neonatal hypoglycemia, Pediatrics and Neonatology (2017), doi: 10.1016/j.pedneo.2016.12.002. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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This material is original research.
Title:
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Retrospective evaluation of a national guideline to prevent neonatal
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hypoglycemia
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Running title:
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Neonatal hypoglycemia
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Rasmussen, AH. MD. Hans Christian Andersen Children´s Hospital, Odense University Hospital, Denmark and Institute of Clinical Research, University of Southern Denmark, Odense, Denmark.
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Wehberg, S. Biostatistician, PhD., Odense University Hospital, Odense, Denmark.
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Fenger-Grøn, J. MD. Dept. of Pediatrics, Lillebaelt Hospital, Kolding, Denmark.
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Christesen, HT. Professor, MD, PhD, Hans Christian Andersen Children´s Hospital, Odense University
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Hospital and Institute of Clinical Research, University of Southern Denmark, Odense, Denmark.
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Corresponding author:
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Henrik T Christesen. Professor, MD, PhD, Hans Christian Andersen Children´s Hospital, Odense University
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Hospital and Institute of Clinically Research, University of Southern Denmark, Odense, Denmark.
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Telephone: +45 2137 0888
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Email: [email protected]
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This material is original research. No related papers from the authors have been published or are under
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consideration for publication elsewhere, and this paper has not been submitted elsewhere.
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Retrospective evaluation of a national guideline to prevent neonatal hypoglycemia
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under consideration for publication elsewhere, and this paper has not been submitted elsewhere.
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Keywords: Hypoglycemia; Neonate; Prevention.
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Abstract
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Background. Hypoglycemia is common in neonates and may cause adverse neurological
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outcomes. Guidelines should aim to prevent repeated hypoglycemic episodes in risk groups,
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but they are not usually stratified according to the severity of hypoglycemia risk, which may
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lead to the implementation of inappropriate and redundant interventions.
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Aim. To evaluate the effect of a national prevention guideline stratified according to mild,
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moderate, and severe risks of hypoglycemia.
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Methods. From national registers, a population cohort of 22,725 neonates was identified
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retrospectively before and after implementation of a national guideline. Of these, 1900 had
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World Health Organization International Classification of Diseases 10 discharge diagnoses of
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hypoglycemia. Diagnoses indicating hypoglycemia risk [small/large for gestational age
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(SGA/LGA), asphyxia, prematurity, maternal insulin-treated diabetes mellitus (mIDM)] were
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recorded. Neonatal ward files were evaluated to validate hypoglycemia diagnoses. Adjusted
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odds ratios (aORs) were calculated, adjusting for sex, parity, SGA, LGA, preterm birth, and
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asphyxia, where relevant.
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ACCEPTED MANUSCRIPT Results. Primiparity and male sex were associated independently with hypoglycemia
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diagnosis [aORs, 1.29 (1.17–1.42) and 1.14 (1.03–1.26), respectively]. The overall incidence of
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hypoglycemia diagnosis at discharge decreased from 9.4% to 5.5% after guideline
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implementation [aORchange, 0.57 (0.50–0.64)]. The overall incidence of validated hypoglycemia
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decreased from 2.1% to 1.2% [aOR 0.59 (0.46–0.77), p<0.001]. By risk group, the
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hypoglycemia incidence decreased from 30.5% to 18.6% [aOR 0.52 (0.36–0.75)] among SGA
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neonates, from 25.8% to 16.4% [aOR 0.57 (0.42–0.76)] among preterm infants, and from
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27.4% to 16.6% [aOR 0.63 (0.34–0.83)] among those with asphyxia. LGA neonates showed a
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decreased incidence in obstetric wards only. No significant change was observed for the
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mIDM group.
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Conclusion. Stratification of hypoglycemia risk in a hypoglycemia prevention guideline was
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followed by decreased estimated hypoglycemia incidences, but no causative conclusion could
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be drawn. Prospective studies with risk stratification for hypoglycemia prevention are
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encouraged.
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Glucose is an essential fuel for brain metabolism and, depending on its severity and duration,
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hypoglycemia may result in adverse neurological outcomes.(1-4) The key to hypoglycemia
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prevention is to identify neonates at risk, as this condition may be difficult to detect clinically.
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(1, 5-8)
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The threshold for intervention in neonatal hypoglycemia remains controversial.(1, 9) After
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the physiological nadir, the mean plasma glucose level in 3–47-h-old, healthy, non-exclusively
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breastfed term neonates is 3.5–3.7 mmol/L, with a fifth percentile of 2.2–2.3 mmol/L.(10)
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This value is lower in healthy, exclusively breastfed term neonates (11), but higher ketone
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bodies provide alternative fuel in this group.(5)
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In risk groups, the clinical cut-off value for treatment of hypoglycemia is usually set around
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2.5 mmol/L (45 mg/dL) after the first hours of life. This threshold is used widely in clinical
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practice, despite differences in the methods and devices used for determination of the glucose
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concentration (12), and is supported by the recent guideline from The American Academy of
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Pediatrics.(13) Others have stated that asymptomatic neonates at risk should not maintain
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glucose levels < 2.0 mmol/L after feeding (1, 14), and treatment thresholds of 1.8 mmol/L on
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one occasion and 2.6 mmol/L on multiple occasions have been proposed.(15)
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The incidence of neonatal hypoglycemia ranges from 5% to 15% (1, 16, 17), possibly
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reflecting differences in study populations, preventive measures, and hypoglycemia
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definitions and measuring techniques (18), in addition to normal biological variation.
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According to the Institute of Medicine’s definition, clinical guidelines are “ systematically
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developed statements to assist practitioner and patient decisions about appropriate health
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care for specific clinical circumstances” (19) , and guidelines intend to improve efficiency and
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quality of care and reduce inappropriate practice.(20, 21) Hypoglycemia prevention protocols
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can improve the standard of care for neonates with hypoglycemia.(23) Although guidelines
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have the potential to have harmful effects as well as benefits if not evaluated, (20, 21) the
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consequences of guideline implementation have not been well studied. We are not aware of
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any previous study evaluating the effects of the implementation of a systematic, stratified
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guideline on the prevention and treatment of neonatal hypoglycemia.
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In Denmark, a national guideline for the prevention of neonatal hypoglycemia was introduced
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in 2010 with the primary aims of avoiding repeated hypoglycemic episodes in risk groups and
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enhancing the quality of care. The guideline stratified hypoglycemia risk as mild, moderate,
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and severe, allowing for the differentiation of preventive actions according to severity.
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In this study, we aimed to evaluate the prevention effect of the national prevention guideline
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by estimating the incidence proportions of neonatal hypoglycemia overall and for major risk
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groups, before and after the guideline implementation.
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Methods
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Data sources and uptake area
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This retrospective, observational cohort study was based on data from the Danish National
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Patient Registry (DNPR) and the Danish Medical Birth Registry (DMBR). The DNPR contains
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data for all hospitalized patients and newborns in Denmark. The DMBR has more detailed
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information on pregnancies and deliveries; it contains highly reliable and valid data on 99.8%
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of all Danish deliveries. (24) The following data were extracted from the DNPR and DMBR for
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each subject included in the study: personal identification number, postal code, parity,
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gestational age (GA), sex, birth weight, hospital/department, and all discharge diagnoses
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according to the World Health Organization’s International Classification of Diseases 10
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Region of Southern Denmark: Odense University Hospital (OUH; Department of Obstetrics
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and Hans Christian Andersen Children’s Hospital) and the two adjacent regional hospitals
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Lillebaelt Hospital, Kolding (Departments of Obstetrics and Pediatrics) and Svendborg
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Hospital (Department of Obstetrics). The OUH receives at-risk and high-risk mothers and
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neonates from the Svendborg and Kolding uptake areas, including all mothers with insulin-
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treated diabetes mellitus (mIDM). After delivery, all mother–infant pairs with mIDM were
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referred to the neonatal ward.
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Guideline
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Before 2010, no uniform hypoglycemia prevention program was established in Denmark. The
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national guideline was introduced in 2010 (Supplementary Table 1). In brief, infants were
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classified into no-, low-, moderate-, and high-risk groups at birth, depending on the risk
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factors present. Prevention measures ranged from breast contact to intravenous glucose
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administration within the first 30 min of life. If the first two glucose measurements were ≥2.5
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mmol/L, no further glucose determination was required.
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Time periods
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The pre-guideline period extended from August 1, 2006 to July 31, 2008; the post-guideline
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period extended from January 1, 2011 to December 31, 2011, or from July 1, 2012 to
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December 31, 2012 (for Lillebaelt Hospital, Kolding). Data collected between these periods
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were not included due to use of pilot versions of the guideline, and the difference in the post-
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guideline period is due to a delay in guideline implementation at Lillebaelt Hospital, Kolding.
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The risk groups were defined retrospectively according to small for gestational age (SGA) or
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large for gestational age (LGA) status [birth weight exceeding ±2 standard deviations (SDs) of
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the reference value], prematurity (GA<37+0 weeks), asphyxia (umbilical cord pH<7.1 and/or
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base excess≤10), and mIDM. Neonates with ICD10 diagnoses of hypoglycemia (P70.0–70.9)
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were identified. Mothers with mIDM attending the neonatal ward of OUH could be identified,
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but maternal ICD10 diabetes diagnosis codes were generally not available in the national
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registries used for the present study. Neonates with more than one hypoglycemia risk factor
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were assigned to more than one risk group.
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Glucose concentrations were measured using different devices. In the neonatal ward of OUH,
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capillary blood glucose was tested using the HemoCue 201/201+ point-of-care testing (POCT)
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device until mid-April 2011, where after the HemoCue 201 DM RT and 201 DM were used.
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The Roche Accu-Chek Inform II system was used in the neonatal ward of Lillebaelt Hospital,
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Kolding, and Radiometer ABL 800 flex analyzers were used in the obstetric departments
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throughout the study period.
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All HemoCue devices measured glucose concentrations in whole blood, but the HemoCue 201
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RT/201 DM device automatically presented calculated plasma glucose values after
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multiplying by 1.11.
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Populations and outcome measures
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We studied the incidence proportions of neonatal hypoglycemia in the hospitals’ uptake area
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for each of the two time periods in four different patient populations, overall and separately
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denominator was the total birth count extracted from the DNPR/DMBR for the uptake area,
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and the numerator (count of neonates with hypoglycemia within the denominator group) was
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based on ICD10 diagnoses of hypoglycemia (P70.0–70.9) from the DNPR/DMBR in the
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neonatal period. For obstetric ward neonatal data, the denominator consisted of all neonates
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discharged from one of the three obstetric wards to home, and the numerator was based on
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recording of P70.0–70.9 diagnoses in the medical records. Bedside blood glucose values were
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not recorded systematically in the medical records of the obstetric departments, disallowing
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blood sample–based validation of neonatal hypoglycemia diagnoses in this population. For
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neonatal ward data, the denominator consisted of all neonates referred to one of the two
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neonatal wards. The numerator was based on recording of P70.0–70.9 diagnoses in the
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medical records. For neonatal ward data on validated hypoglycemia, the denominator was the
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same and the numerator was based on recording of P70.0–70.9 diagnoses in the medical
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records in cases for which data on blood glucose level and age (in hours) at the time of blood
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glucose determination were also available. These data were analyzed to validate diagnoses of
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hypoglycemia. Hypoglycemia was defined as glucose value <1.7 mmol/L at 0–2 h of life and
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<2.5 mmol/L after 2 h of life.
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Methodological bias (sensitivity analysis)
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We reviewed a random sample of data from 400 neonates without ICD10 hypoglycemia
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diagnoses in the neonatal ward of OUH within the asphyxia and SGA hypoglycemia risk factor
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groups. Hypoglycemic neonates identified by this search, but not identified through the
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original registry data search, were not included in the incidence estimates.
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First, odds ratios (ORs) for hypoglycemia diagnosis with 95% confidence intervals (CIs) were
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calculated based on logistic regression models for the following risk factors: SGA, LGA,
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preterm birth, asphyxia, and mIDM (where relevant), as well as parity and sex. This analysis
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was conducted for the overall patient population, across both time periods. Second, neonatal
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characteristics were compared between neonates with and without hypoglycemia diagnoses
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for each time period using the Mann–Whitney U, Student’s t, and chi-squared tests, where
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appropriate. Third, incidence proportions of hypoglycemia with 95% CIs were calculated for
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five patient populations (overall and separately according to risk groups). In addition, ORs for
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change with 95% CIs were calculated based on logistic regression models (univariate and
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adjusted for sex, parity, SGA, LGA, preterm birth, and asphyxia, where relevant). No
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adjustment for multiple testing was performed. Data were analyzed using Stata software
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(StataCorp, College Station, TX, USA).
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Ethics
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The regional ethics committee approved the study (protocol no. S-20120119).
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Results
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Overall, the study population included 22,725 neonates (48.4% girls, 51.6% boys). The mean
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(±SD) birth weights were 3400 (±600) g for girls and 3506 (±644) g for boys. The mean GA
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was 39 (±2.2) weeks. Prematurity was seen in 1693 (7.4%), asphyxia in 902 (3.9%), SGA in
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848 (3.7%), LGA in 822 (3.6%), and mIDM in 245 (1.1%) neonates. In total, 3949 (17.3%)
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neonates fell into risk groups, of which 406 (10.3%) had more than one risk factor.
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strongly with increased odds of hypoglycemia diagnosis (Table 1). Surprisingly, primiparity
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status and male sex were also associated strongly with increased adjusted odds ratios (aORs)
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for hypoglycemia. Neonates belonging to the risk groups defined in this study accounted for
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1289/1900 (67.8%) of all neonates with hypoglycemia diagnoses. Accordingly, almost one-
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third of neonates with such diagnoses could not be assigned to any risk group.
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The baseline characteristics of all neonates and those with hypoglycemia, defined by
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discharge diagnoses, in the two study periods are shown in Figure 1.
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The estimated incidence proportion of hypoglycemia by discharge diagnosis was 8.4% (Table
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2).
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National registry data showed that the incidence of hypoglycemia diagnoses in the SGA, LGA,
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preterm, and asphyxia risk groups was 26.2% (22.7–27.0%), with no significant difference
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among risk group estimates. In the neonatal ward, the incidence of validated hypoglycemia
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ranged from 5.5% to 10.5% among risk groups, but was much higher (32.2%) in the mIDM
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group.
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The implementation of the hypoglycemia guideline was associated with a highly significant
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decrease in the incidence proportion of this condition in the overall population in all analyses
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(Table 2).
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For neonates in the neonatal ward, the incidence of validated hypoglycemia also decreased,
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from 2.1% to 1.2% [crude OR for change, 0.55 (0.43–0.71), p<0.001; aOR, 0.59 (0.46–0.77)].
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All analyses showed decreased incidence proportions in the SGA and preterm birth groups.
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For the asphyxia group, a highly significant decrease was seen in the national registry and in
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the obstetric wards, but no change was observed in the neonatal wards. For the mIDM and
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LGA risk groups, no significant change was observed in any analysis.
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have affected the incidence of mild hypoglycemia (2.3–2.4 mmol/L) diagnoses within the
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post-implementation period. To compensate for this bias, we conducted a subanalysis
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including only OUH neonatal ward patients with validated hypoglycemia (<2.3 mmol/L)
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through April 15, 2011. This methodological bias correction did not change the incidence
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estimates.
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In the review of 400 neonatal ward files with ICD10 codes for asphyxia and SGA, without
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discharge diagnosis codes for hypoglycemia, we identified unreported hypoglycemia in 16.5%
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of neonates. Underreporting showed a decreasing trend between the pre- and post-
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implementation periods, especially for SGA (overall, from 20% to 13%, p=0.18; asphyxia, from
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16% to 12%, p=0.42; SGA, from 24% to 14%, p=0.07).
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253 Discussion
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In Danish neonatal departments, various initiatives to prevent and treat neonatal
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hypoglycemia have existed for decades. Until the introduction of the national guideline,
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however, practices were heterogeneous, differing within as well as between departments. The
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implementation of the national guideline instituted a homogenous, consistent, and systematic
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approach, and the current study was conducted to evaluate its effect on the risk of
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hypoglycemia. The retrospective design of our study and methodological constraints,
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including the lack of a uniform blood glucose recording protocol and the quality dependence
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of discharge diagnoses, except for the validation substudy that was conducted using data from
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the neonatal ward, do not allow the calculation of exact incidence estimates or drawing of
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definitive conclusions on the causes of changes. However, the estimated overall hypoglycemia
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incidence fell significantly between the two study periods; this effect was most pronounced in
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hypoglycemia discharge diagnoses. No evidence of an increase in hypoglycemia was observed
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after the guideline introduction, suggesting that the uniform incidence decrease was not due
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to methodological bias.
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The overall population incidence of neonatal hypoglycemia, according to discharge diagnosis,
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was 8.4%, which was within previously reported incidences of 5–15%. (2, 7, 8, 16, 17, 25, 26)
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Our estimate had the advantage of being based on a large population birth cohort, but the
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disadvantage of being based predominantly on discharge diagnoses and glucose
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measurements obtained with different methods. Validation exercises for these diagnoses
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showed both overreporting and underreporting of hypoglycemia compared with medical
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records reviews.
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In a multivariable analysis, we identified SGA, LGA, preterm birth, and asphyxia as
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independent risk factors for hypoglycemia. These risk groups, as well as the risk faced by
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infants of diabetic mothers, are well known.(5, 7, 25, 27) Almost one-third of our neonates
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with hypoglycemia diagnoses were not assigned to a risk group. One explanation for this
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finding could be missing discharge diagnoses of gestational diabetes, which in the absence of
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hypoglycemia could have been reported in the mothers’ hospital records only, and hence not
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included in the current study. Surprisingly, the analysis based on the identified risk groups
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showed that primiparity and male sex were independent risk factors for hypoglycemia.
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Explanatory factors may include delayed onset of lactogenesis in breastfeeding primipara
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(28) and increased male representation in neonates below the LGA cut-offs, but >4000 g,
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above which the risk of hypoglycemia also may be increased.(29)
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The overall incidence of hypoglycemia according to discharge diagnosis among the risk
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groups of SGA, LGA, preterm birth, and asphyxia was 26.2%. Others have reported
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restricted to neonatal ward data for newborns with validated hypoglycemia, the incidence
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was at the lower end of this reported range (12.4%).
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The estimated incidence of hypoglycemia diagnosis fell significantly after the implementation
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of the prevention guideline. This change may be attributed to a preventive effect of the
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guideline, but the contribution of methodological bias, including errors in discharge diagnoses
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and variations in blood glucose measurement counts and methods, cannot be ruled out. In
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support of a true decrease in the incidence of hypoglycemia, a decreased incidence was also
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seen in the validation exercise. Moreover, our subanalysis of neonatal ward cases of glucose
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values <2.3 mmol/L also showed a highly significant decrease in the incidence.
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Decreases in the estimated incidence of hypoglycemia were seen in the SGA and preterm risk
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groups, regardless of data source. The decrease in preterm neonates occurred despite a
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decrease in the mean GA and birth weight, which would tend to increase the risk of
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hypoglycemia, among all such neonates in the post-guideline period.
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For neonates with asphyxia, a decrease was seen only in the obstetric ward, suggesting that
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hypoglycemia prevention in the neonatal wards was effective before guideline
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implementation, or that detection of hypoglycemia among those with milder asphyxia in the
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obstetric ward who were not referred to the neonatal ward was more complete after
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guideline implementation.
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The LGA and mIDM risk groups showed no decrease in hypoglycemia, regardless of the data
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source. The unchanged incidence in the LGA group may reflect the ease of hypoglycemia
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prevention in this group by early feeding, a prevention strategy which was carried out before
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guideline implementation. For mIDM, the avoidance of hypoglycemia in this patient group
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received much attention before guideline implementation.
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methodological problems associated with POCT device use, raises open questions about the
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appropriateness of the prevention strategy examined here and others. At the least, the
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national prevention program introduced less-intrusive interventions for low-risk neonates
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without increasing the incidence of hypoglycemia in any risk group.
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The strengths of our study included the examination of a large, population-based birth cohort;
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the inclusion of data from several sources; the validation of hypoglycemia diagnoses; and the
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adjustment of analyses of incidence changes in risk groups. Limitations included the
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retrospective design, with the risk of inaccuracy of discharge diagnoses and medical records;
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the methodological problems associated with glucose measurement using different POCT
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devices; the non-inclusion of neonates with diet-treated maternal diabetes; and potential
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undiscovered reporting bias from unidentified changes in practice.
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We conclude that the introduction of a standardized, stratified hypoglycemia prevention
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program was followed by the use of a more systematic and consistent prevention strategy for
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hypoglycemia. The stratification of risk as mild, moderate, and severe, which enables the
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implementation of differentiated prevention initiatives, was met not by an increased
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hypoglycemia incidence, but by strong suggestions of a decrease. These findings encourage
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the further use of a stratified approach, which should be studied in other settings using a
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prospective design.
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Table 1. Factors associated with hypoglycemia diagnosis (ICD10 discharge diagnosis). Odds ratios with 95% confidence intervals based on logistic regression analysis of 22,725 neonates in the national registry database are presented. Both time periods are included.
Factor
P-value <0.001 <0.001 < 0.001 < 0.001 <0.001 0.001
Adjusted* OR (95% CI) 3.39 (2.86-4.03) 4.10 (3.43-4.90) 3.41 (3.04-3.96) 4.20 (3.56-4.95) 1.29 (1.17-1.42) 1.14 (1.03-1.26)
P-value <0.001 <0.001 <0.001 <0.001 <0.001 0.008
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*OR adjusted for sex, parity, and SGA, LGA, preterm birth, and asphyxia, where relevant. Abbreviations: OR, odds ratio; CI, confidence interval; SGA, small for gestational age; LGA, large for gestational age; AGA, appropriate for gestational age.
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SGA vs. AGA LGA vs. AGA Preterm Asphyxia Parity 1 vs. >1 Male vs. female
Crude OR (95% CI) 4.88 (4.15-5.72) 3.88 (3.27-4.61) 4.12 (3.54-4.54) 4.10 (3.50-4.81) 1.47 (1.34-1.62) 1.17 (1.06-1.28)
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Table 2. Incidence proportions of hypoglycemia before and after national guideline implementation, and odds ratios for change.
Incidence proportions (95% CI) in relation to guideline implementation Both periods Before After
Crude OR
Odds ratio (95% CI) for change p Adjusted* OR
p
0.57 (0.50-0.64) 0.52 (0.36-0.75) 0.96 (0.65-1.41) 0.57 (0.42-0.76) 0.53 (0.34-0.83)
<0.001 <0.001 0.839 <0.001 0.006
0.51 (0.43-0.59) 0.55 (0.34-0.90) 0.66 (0.38-1.18) 0.61 (0.48-0.78) 0.37 (0.21-0.65)
<0.001 0.018 0.167 0.016 0.001
0.76 (0.63-0.77) 0.55 (0.28-0.87) 1.30 (0.81-2.11) 0.59 (0.40-0.88) 1.27 (0.65-2.46)
0.001 0.018 0.286 0.009 0.482
0.59 (0.46-0.77) 0.56 (0.34-0.94) 0.72 (0.33-1.55) 0.28 (0.15-0.52) 1.33 (0.65-2.73) 0.83 (0.45-1.53)
<0.001 0.021 0.406 <0.001 0.430 0.559
0.43 (0.31-0.58)
<0.001
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National registry Overall 8.4% (8.0-8.8) 9.4% (9.0-9.9) 5.5% (4.9-6.1) 0.55 (0.49-0.62) <0.001 SGA 27.0% (24.0-30.1) 30.5% (26.9-34.5) 18.6% (13.9-23.9) 0.51 (0.36-0.74) <0.001 LGA 23.6% (19.9-25.7) 25.3% (19.9-26.7) 21.1% (15.8-27.3) 0.89 (0.60-1.30) 0.554 Preterm 23.6% (21.6-25.7) 25.8% (23.4-28.2) 16.4% (12.9-20.0) 0.56 (0.42-0.75) <0.001 Asphyxia 25.3% (22.6-28.3) 27.4% (24.2-30.8) 16.6% (11.3-23.0) 0.52 (0.34-0.81) 0.004 Obstetric ward neonates Overall 5.3% (5.0-5.6) 6.1% (5.8-6.5) 3.0% (2.7-3.5) 0.48 (0.41-0.56) <0.001 SGA 13.2% (11.0-15.6) 15.0% (12.8-18.8) 9.1% (5.8-13.3) 0.56 (0.35-0.92) 0.022 LGA 10.3% (8.3-12.6) 11.2% (8.8-13.9) 7.7% (4.5-12.1) 0.66 (0.38-1.17) 0.156 Preterm 11.1% (9.6-12.7) 12.2% (10.4-14.1) 7.7% (5.3-10.7) 0.60 (.040-0.90) 0.014 Asphyxia 18.2% (15.7-20.8) 20.3% (17.4-23.4) 8.9% (5.1-14.2) 0.38 (0.22-0.67) 0.001 Neonatal ward neonates Overall 3.0% (2.8-3.3) 3.3% (3.0-3.6) 2.4% (2.0-2.8) 0.72 (0.60-0.86) 0.001 SGA 13.7% (11.5-16.3) 15.6% (0.13-0.19) 9.3% (6.2-13.8) 0.56 (0.35-0.91) 0.019 LGA 12.4% (10.2-14.8) 12.0% (9.6-14.8) 13.5% (9.1-18.8) 1.14 (0.71-1.80) 0.573 Preterm 12.5% (10.9-14.1) 13.6% (11.8-15.6) 8.7% (6.1-11.9) 0.60 (0.41-0.88) 0.010 Asphyxia 7.2% (5.6-9.0) 7.1% (5.3-9.1) 7.7% (4.1-12.7) 1.09 (0.58-2.10) 0.579 Neonatal ward, validated hypoglycemia Overall 1.8% (1.7-2.0) 2.1% (1.9-2.3) 1.2% (0.1-0.2) 0.55 (0.43-0.71) <0.001 SGA 10.5% (8.5-12.7) 11.9% (9.4-14.8) 7.1% (4.2-11.0) 0.62 (0.31-0.93) 0.003 LGA 6.2% (4.6-8.1) 6.8% (5.0-9.1) 4.3% (2.0-8.0) 0.62 (0.29-1.29) 0.204 Preterm 7.9% (6.7-9.3) 9.4% (7.9-11.2) 2.9% (1.6-5.2) 0.29 (0.16-0.54) <0.001 Asphyxia 5.5% (4.2-7.4) 5.4% (3.9-7.4) 6.5% (3.3-11.3) 1.20 (0.61-2.40) 0.594 Maternal diabetes, 32.2% (26.4-38.4) 34.5% (27.3-42.3) 27.5% (18.1-38.6) 1.2 (0.40- (1.29) 0.270 insulin-treated Bias-corrected 1.8% (1.6-1.9) 2.1 (1.9-2.3) 1.1% (0.8-1.4) 0.44 (0.30-0.55) <0.001 hypoglycemia 350 *Adjusted for sex, parity, SGA, LGA, preterm birth, and asphyxia, where relevant. 351 Abbreviations: CI, confidence interval; OR, odds ratio; SGA, small for gestational age; LGA, large for gestational age.
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Figure 1. Baseline characteristics for all neonates, and neonates at risk of hypoglycemia, defined by discharge diagnosis, before and after
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implementation of a national guideline for the prevention of hypoglycemia.
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SGA, small for gestational age; LGA, large for gestational age; DM, diabetes mellitus.
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COI statement
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The authors have no conflict of interest relevant to this article.
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ACCEPTED MANUSCRIPT References
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1.Cornblath M, Hawdon JM, Williams AF, Aynsley-Green A, Ward-Platt MP, Schwartz R, et al.
366
Controversies regarding definition of neonatal hypoglycemia: suggested operational
367
thresholds. Pediatrics. 2000;105(5):1141-5.
368
2.Lucas A, Morley R, Cole TJ. Adverse neurodevelopmental outcome of moderate neonatal
369
hypoglycaemia. BMJ (Clinical research ed). 1988;297(6659):1304-8.
370
3.Arya VB, Senniappan S, Guemes M, Hussain K. Neonatal Hypoglycemia. Indian J Pediatr.
371
2013.
372
4.McKinlay CJ, Alsweiler JM, Ansell JM, Anstice NS, Chase JG, Gamble GD, et al. Neonatal
373
Glycemia and Neurodevelopmental Outcomes at 2 Years. The New England journal of
374
medicine. 2015;373(16):1507-18.
375
5.Hawdon JM, Ward Platt MP, Aynsley-Green A. Patterns of metabolic adaptation for preterm
376
and term infants in the first neonatal week. Arch Dis Child. 1992;67(4 Spec No):357-65.
377
6.Altman M, Vanpee M, Cnattingius S, Norman M. Neonatal morbidity in moderately preterm
378
infants: a Swedish national population-based study. The Journal of pediatrics.
379
2011;158(2):239-44.e1.
380
7.Agrawal RK, Lui K, Gupta JM. Neonatal hypoglycaemia in infants of diabetic mothers. Journal
381
of paediatrics and child health. 2000;36(4):354-6.
382
8.Maayan-Metzger A, Lubin D, Kuint J. Hypoglycemia rates in the first days of life among term
383
infants born to diabetic mothers. Neonatology. 2009;96(2):80-5.
384
9.Guemes M, Rahman SA, Hussain K. What is a normal blood glucose? Arch Dis Child. 2015.
385
10.Alkalay AL, Sarnat HB, Flores-Sarnat L, Elashoff JD, Farber SJ, Simmons CF. Population
386
meta-analysis of low plasma glucose thresholds in full-term normal newborns. Am J Perinatol.
387
2006;23(2):115-9.
AC C
EP
TE D
M AN U
SC
RI PT
364
21
ACCEPTED MANUSCRIPT 11.Swenne I, Ewald U, Gustafsson J, Sandberg E, Ostenson CG. Inter-relationship between
389
serum concentrations of glucose, glucagon and insulin during the first two days of life in
390
healthy newborns. Acta Paediatr. 1994;83(9):915-9.
391
12.D'Orazio P, Burnett RW, Fogh-Andersen N, Jacobs E, Kuwa K, Kulpmann WR, et al.
392
Approved IFCC recommendation on reporting results for blood glucose (abbreviated). Clinical
393
chemistry. 2005;51(9):1573-6.
394
13.Adamkin DH. Postnatal glucose homeostasis in late-preterm and term infants. Pediatrics.
395
2011;127(3):575-9.
396
14.Hawdon JM. Definition of neonatal hypoglycaemia: time for a rethink? Archives of disease
397
in childhood Fetal and neonatal edition. 2013;98(5):F382-3.
398
15.Screening guidelines for newborns at risk for low blood glucose. Paediatr Child Health.
399
2004;9(10):723-40.
400
16.Merenstein GB, Gardner SL. Handbook of neonatal intensive care. 5 ed. St. Louis, Mo.:
401
Mosby; 2002. xx, 863 s., illustreret (pbk) p.
402
17.Hay WW, Jr., Raju TN, Higgins RD, Kalhan SC, Devaskar SU. Knowledge gaps and research
403
needs for understanding and treating neonatal hypoglycemia: workshop report from Eunice
404
Kennedy Shriver National Institute of Child Health and Human Development. The Journal of
405
pediatrics. 2009;155(5):612-7.
406
18.Harris DL, Weston PJ, Harding JE. Incidence of neonatal hypoglycemia in babies identified
407
as at risk. The Journal of pediatrics. 2012;161(5):787-91.
408
19.Institute of Medicine Committee to Advise the Public Health Service on Clinical Practice G.
409
In: Field MJ, Lohr KN, editors. Clinical Practice Guidelines: Directions for a New Program.
410
Washington (DC): National Academies Press (US)
411
Copyright (c) National Academy of Sciences.; 1990.
AC C
EP
TE D
M AN U
SC
RI PT
388
22
ACCEPTED MANUSCRIPT 20.Grimshaw JM, Russell IT. Effect of clinical guidelines on medical practice: a systematic
413
review of rigorous evaluations. Lancet (London, England). 1993;342(8883):1317-22.
414
21.Woolf SH, Grol R, Hutchinson A, Eccles M, Grimshaw J. Clinical guidelines: potential
415
benefits, limitations, and harms of clinical guidelines. BMJ (Clinical research ed).
416
1999;318(7182):527-30.
417
22.Rozance PJ, Hay WW, Jr. Describing hypoglycemia--definition or operational threshold?
418
Early Hum Dev. 2010;86(5):275-80.
419
23.Stewart CE, Sage EL, Reynolds P. Supporting 'Baby Friendly': a quality improvement
420
initiative for the management of transitional neonatal hypoglycaemia. Archives of disease in
421
childhood Fetal and neonatal edition. 2015.
422
24.Knudsen LB, Olsen J. The Danish Medical Birth Registry. Dan Med Bull. 1998;45(3):320-3.
423
25.Hume R, McGeechan A, Burchell A. Failure to detect preterm infants at risk of
424
hypoglycemia before discharge. The Journal of pediatrics. 1999;134(4):499-502.
425
26.Sexson WR. Incidence of neonatal hypoglycemia: a matter of definition. The Journal of
426
pediatrics. 1984;105(1):149-50.
427
27.Rozance PJ. Update on neonatal hypoglycemia. Curr Opin Endocrinol Diabetes Obes.
428
2014;21(1):45-50.
429
28.Nommsen-Rivers LA, Chantry CJ, Peerson JM, Cohen RJ, Dewey KG. Delayed onset of
430
lactogenesis among first-time mothers is related to maternal obesity and factors associated
431
with ineffective breastfeeding. Am J Clin Nutr. 2010;92(3):574-84.
432
29.Linder N, Lahat Y, Kogan A, Fridman E, Kouadio F, Melamed N, et al. Macrosomic newborns
433
of non-diabetic mothers: anthropometric measurements and neonatal complications.
434
Archives of disease in childhood Fetal and neonatal edition. 2014;99(5):F353-8.
AC C
EP
TE D
M AN U
SC
RI PT
412
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30.Jonas D, Dietz W, Simma B. Hypoglycemia in Newborn Infants at Risk. Klinische Padiatrie.
436
2014.
AC C
EP
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M AN U
SC
RI PT
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