Newborns are at relatively high risk for developing hypoglycaemia in the first 24 h after birth. Well-known risk factors are prematurity, small for gestational age (SGA) or large for gestational age (LGA), and maternal pre-existent or gestational diabetes mellitus. Prolonged hypoglycaemia is associated with poor neurodevelopmental outcomes; hence, prevention through proper monitoring and treatment is important. Given the ongoing debate concerning frequency and duration of screening for neonatal hypoglycaemia, therefore, we investigated the frequency and duration of glucose monitoring safe to discover neonatal hypoglycaemia in different risk groups. Data of newborns at risk for hypoglycaemia were retrospectively collected and analysed. Blood glucose concentrations were measured 1, 3, 6, 12, and 24 h after birth. Moderate hypoglycaemia was defined as a blood glucose concentration of < 2.2 mM and severe hypoglycaemia as a concentration of < 1.5 mM. Of 1570 newborns, 762 (48.5%) had at least one episode of hypoglycaemia in the first 24 h after birth; 30.6% of them had severe hypoglycaemia (all in the first 9 h after birth). Only three SGA and two LGA newborns had a first moderate asymptomatic hypoglycaemic episode beyond 12 h after birth. The incidence of hypoglycaemia increased with accumulation of multiple risk factors. Conclusion: Safety of limiting the monitoring to 12 h still has to be carefully evaluated in the presence of SGA or LGA newborns; however, our results suggest that 12 h is enough for late preterm newborns (> 34 weeks) and maternal diabetes. What is Known: � Newborns are at relatively high risk for developing hypoglycaemia and such hypoglycaemia is associated with adverse neurodevelopmental outcomes. � Proper glucose monitoring and prompt treatment in case of neonatal hypoglycaemia are necessary. What is New: � Glucose monitoring 12 h after birth is proficient for most newborns at risk. � Maternal diabetes leads to the highest risk of early neonatal hypoglycaemia and newborns with more than one risk factor are at increased risk of hypoglycaemia. . . . Keywords Glucose monitoring Neonatal hypoglycaemia Newborns Screening Abbreviations LGA Large for gestational age CGM Continuous glucose monitoring mM Millimolar (1 mmol/litre) DM Diabetes mellitus POC Point-of-care GC Glucose concentration SD Standard deviation GDM Gestational diabetes mellitus SGA Large for gestational age Communicated by Patrick Van Reempts * Marije Hogeveen Department of Electrical Engineering (Signal Processing firstname.lastname@example.org Systems), Eindhoven Technical University, Flux, Groene loper 19, Postbus 513, 5600 MB Eindhoven, Celine Blank the Netherlands Celineblank@Icloud.com Department of Obstetrics and Gynaecology, Radboudumc, Jeroen van Dillen Geert Grooteplein Zuid 10, 6525 GA Nijmegen, the J.email@example.com Netherlands Division of Neonatology, Department of Paediatrics, Radboudumc, Department of Obstetrics and Gynaecology, Catharina Hospital, Amalia Children’s Hospital, Geert Grooteplein Zuid 10, 6525 Michelangelolaan 2, 5623 EJ Eindhoven, the Netherlands GA Nijmegen, the Netherlands Eur J Pediatr T1DM Diabetes mellitus type 1 Amalia Children’s Hospital Nijmegen, the Netherlands, from T2DM Diabetes mellitus type 2 a four-year period (2010–2013). Inclusion criteria were gesta- tional age (GA) ≥ 34 weeks and screening indication accord- ing to our local guideline: prematurity (< 37 weeks of gesta- Introduction tion), SGA, LGA, and maternal diabetes of any kind (identical to recommendations by the American Academy of Pediatrics To date, there is still little evidence and consensus regard- (AAP)) [3, 4]. Exclusion criteria were severe asphyxia (Apgar ing definition, indication, and frequency of screening for 5 min after birth ≤ 3)  and death within the first 24 h after neonatal hypoglycaemia, one of the most frequently en- birth. In the first 24 h after birth, moderate hypoglycaemia and countered problems in neonatology. Newborns are at rel- severe hypoglycaemia were defined as a blood glucose con- atively high risk for developing hypoglycaemia in the first centration (GC) between 1.5–2.1 mM and below 1.5 mM, 24 h after birth . The incidence of hypoglycaemia in respectively, moderate and severe reflecting therapy in this apparently healthy newborns varies widely (between 4 case. Blood glucose concentrations were measured on capil- and 40%) depending amongst others on definition of lary blood samples taken by several point-of-care (POC) glu- hypoglycaemia, timing of glucose monitoring after deliv- cose meters during this period (HemoCue Glu201DM, Nova ery, and population studied [16, 21]. StatStrip GluCard memory PC, Roche OMNI-56 blood gas Risk factors for neonatal hypoglycaemia are prematurity analyser and Siemens Rapid lab 1265). In case of (< 37 weeks of gestation), being small for gestational age hypoglycaemia (GC < 2.2 mM), capillary blood was sent to (SGA) (birth weight ≤ 10th percentile for GA), large for ges- the laboratory for confirmation. tational age (LGA) (birth weight ≥ 90th percentile for GA), Blood glucose samples were taken 1, 3, 6, 12, and 24 h and pre-existent maternal diabetes (diabetes mellitus type 1, after birth according to local guidelines . In case of any type 2 (T1DM, T2DM)) or gestational diabetes mellitus clinical signs of hypoglycaemia, such as twitching and drows- (GDM) [2, 3, 11, 26]. iness, additional glucose samples were taken. In apparently healthy infants, glucose concentrations tend Feeding was initiated in the first hour after birth. to decrease after birth, reach a nadir 1 h after birth, increase Breastfeeding was encouraged throughout pregnancy, but again, and stabilise after one day [2, 16]. The majority of first the ultimate choice between breastfeeding and formula feed- hypoglycaemic episodes occur in the first 24 h after birth ing was made by the parents. In our hospital (as in the (81%), from which 48% within 6 h . Netherlands), approximately 80% of women start with exclu- Recurrent severe hypoglycaemia is associated with poor sive breastfeeding post-delivery . Feeding is continued at neurodevelopmental outcomes; however, duration and se- least every 3 h, with breastfeeding sometimes more often. verity of hypoglycaemia to cause injury are unknown. Newborns with moderate hypoglycaemia were treated with The management of the asymptomatic infant at risk for increased enteral carbohydrate intake, either through more low glucose remains controversial. Despite this, preven- frequent breast feedings or (additional) formula feeding. In tion of (prolonged) hypoglycaemia by screening and case of repeated moderate hypoglycaemia (≥ 3×), continuous treatment seems rational [3, 13, 19]. intravenous glucose 10% was started after administration of Existing guidelines for screening and treatment recom- 2 ml/kg bolus. Newborns with severe hypoglycaemia were mend glucose monitoring in newborns at risk but vary in immediately treated with continuous intravenous glucose (1) definition of hypoglycaemia (between 2.2 and 10% and a bolus. 2.6 mM), (2) total monitoring time (12–48hafter birth), Birth percentiles, SGA (< 10th percentile) or LGA (> 90th and (3) time intervals (between 1 and 8 h). This is illus- percentile), were calculated using Dutch birth weight curves trating the lack of consensus regarding the frequency and (https://www.perined.nl/producten/geboortegewichtcurven). duration of glucose monitoring deemed necessary and Relevant maternal and neonatal information and GC were safe to discover neonatal hypoglycaemia [2, 7, 12, 15, extracted from patient files. Our primary outcome was time of 18]. Furthermore, different risk factors may prompt a dif- first hypoglycaemia, which we studied in all risk factors sep- ferent strategy. Therefore, we studied the onset of the first arately. When hypoglycaemia was described in discharge cor- hypoglycaemic episode in newborns at risk according to respondence but data on timing of blood glucose concentra- their risk factors. tions were missing of more than two standardised sample moments, cases were only used for overall analysis. For statistical analysis, SPSS software version 20 was used. Materials and methods Normally, distributed data were expressed as percentage and mean (SD). Median (range) was used for skewed distributed This is a retrospective observational cohort study. We enrolled data. For 2 × 2 tables, chi-square test was performed. Multivariate logistic regression analyses were used to examine all eligible newborns born and admitted at Radboudumc Eur J Pediatr the association between (severe) hypoglycaemia and possible mother (19.1%) (Table 1). Most newborns had one risk factor risk factors, including screening indications, background in- (87.1%), 12.1% two risk factors, and 0.7% three risk factors formation, and other complications. A p value < 0.05 was (Fig. 1). In the first hour after birth, GCs for this cohort reach considered statistically significant. their lowest values. After that, blood GCs remain stable at a This study was exempt from Regional Ethics Review value of 3.1–3.4 mM (Fig. 2). Board approval, under the legal requirements for clinical re- Of 1570 patients at risk, 762 (48.5%) suffered from at least search in the Netherlands. one episode of hypoglycaemia. One-third of hypoglycaemic episodes were severe (< 1.5 mM), with maternal pre-existing diabetes as the main risk factor (54.5%) (Table 1). The prev- Results alence of hypoglycaemia is similar in different birth weight groups (p > 0.05) (Table 1). Pre-existent maternal diabetes led We enrolled 1628 newborns with risk factors for to early hypoglycaemia (first hour after birth) in 21 cases (75%) (Table 2). hypoglycaemia of which 1573 met our inclusion and exclu- sion criteria. Data of three newborns were unavailable. The In GDM, the majority of newborns (100/113; 88.5%) had a final analysis was performed on data from 1570 newborns. In hypoglycaemia within 3 h after birth. Hypoglycaemia occur- 327 cases, data of more than two sample moments were miss- ring more than 12 h after birth for the first time was seen in ing. These cases were only used for the overall analysis only five newborns (Table 2). One SGA newborn had a GC of (hypoglycaemia 125/327). Newborns at risk were premature 2.1 mM 15 h after birth, and three LGA newborns and one (33.5%), SGA (32.4%), LGA (27.6%), or born to a diabetic SGA newborn had moderate hypoglycaemias (GC 1.7, 1.9, Table 1 Maternal, gestational, and newborn characteristics Overall Glucose < 2.2 mM ‘hypoglycaemia’ Glucose < 1.5 mM ‘severe hypoglycaemia’ Total number of newborns 1570 762/1570 (48.5%) 271/1570 (17.2%) Gestational age, weeks* 38.29 (36.43–39.86) 37.86 (36.29–39.43) 37.49 (36.14–38.86) Birth weight, g** 3106 ± 814 3043 ± 819 2980 ± 783 Sex Male 804/1570 (51.2%) 395/804 (49.1%) 133/804 (16.5%) Females 766/1570 (48.8%) 367/766 (47.9%) 138/766 (18.0%) Single/multiple birth Singleton 1385/1570 (88%) 657/1385 (47.4%) 238/1385 (17.2%) Twin 164/1570 (10.4%) 72/165 (43.9%) 27/165 (16.4%) Triplet 20/1570 (1.3%) 8/20 (40.0%) 6/20 (30.0%) Preterm delivery Total preterm deliveries 526/1570 (33.5%) 298/526 (56.7%) 115/526 (21.9%) 34–35 weeks 102/526 (19.4%) 51/102 (50.0%) 22/102 (21.6%) 35–36 weeks 163/526 (31.0%) 85/163 (52.1%) 36/163 (22.1%) 36–37 weeks 261/526 (49.6%) 162/261 (62.1%) 57/261 (21.8%) Weight LGA (p > 90) 433/1570 (27.6%) 198/433 (45.7%) 61/433 (14.1%) Extremely LGA (p > 97.7) 114/1570 (7.4%) 52/114 (45.6%) 17/114 (14.9%) SGA (p < 10) 508/1570 (32.4%) 233/508 (45.9%) 115/508 (22.6%) Extremely SGA (p < 2.3) 131/1570 (8.3%) 69/131 (52.7%) 22/131 (16.8%) Diabetes Total 300/1570 (19.1%) 154/300 (51.3%) 66/300 (22.0%) T1DM/ T2DM 41/300 (13.7%) 33/41 (80.5%) 18/41 (43.9%) GDM 259/300 (86.3%) 121/259 (46.7%) 48/259 (18.5%) Data are number (percentage). Percentages are of total number of newborns or of individual and overall numbers of newborns in the different groups *Median (25th–75th percentile) **Mean (SD) Eur J Pediatr Preterm 216/396 (55%) 11/19 46/81 (58%) (57%) SGA LGA 16/19 176/412 (43%) 1/2 (50%) 8/9 (84%) 150/348 (43%) (84%) 10/13 29/57 (77%) (51%) 90/200 (45%) Newborn of a Diabec mother Numerator = number of newborns with hypoglycaemia in diﬀerent risk group(s) Denominator = total number of newborns of diﬀerent risk group(s) Percentage = number of newborns with hypoglycaemia of the total numbers of newborns in the speciﬁcally risk group Fig. 1 Neonatal hypoglycaemia with different combinations of risk factors 2.1, and 2.1 mM respectively) 24 h after birth. These new- comparing to the group with two risk factors (51–84%, p = borns were all treated with additional feedings only. 0.011) and the group with three risk factors (50–89%, p = In the group with other complications, e.g. congenital 0.004)) (Fig. 1). abnormalities, respiratory distress, or (risk for) infection, Multivariate logistic regression analysis including all po- significantly less newborns developed a hypoglycaemic tential risk factors, sex, single/multiple birth, and other com- episode (p =0.04). plications (congenital abnormalities, respiratory distress and The overall prevalence of hypoglycaemia increased with (risk for) infection) showed that hypoglycaemia was signifi- increasing number of risk factors (one risk factor (43–55%), cant associated with prematurity (OR = 1.545, 95% CI 1.00– 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 1 h 3 h 6 h 12 h 24 h Time aer birth (hour) Fig. 2 Median blood glucose concentration of total newborns (median, 25th and 75th percentile) Blood glucose concentraon (mM) Eur J Pediatr Table 2 Timing of first hypoglycaemia according to screening indication Timing of first hypoglycaemia All newborns T1DM, T2DM GDM Preterm SGA LGA N = 1570* N =41 N =259 N =526 N =508 N =433 0–1 h after birth 512/1428 21/34 83/237 207/457 135/454 134/386 >1–2 h after birth 19/60 0/2 5/11 8/27 3/16 6/16 >2–3 h after birth 102/888 5/13 12/149 33/238 45/317 16/240 >3–5 h after birth 3/22 0/0 1/5 1/7 0/6 1/6 >5–9 h after birth 71/797 1/9 8/136 14/210 32/279 24/224 >9–12 h after birth 19/768 1/8 4/135 7/206 3/257 4/218 >12–15 h after birth 1/33 0/0 0/4 0/11 0/11 1/10 >15–18 h after birth 0/65 0/1 0/9 0/26 0/17 0/17 >18–24 h after birth 4/667 0/7 0/119 0/177 3/223 1/191 *There are newborns with more than one risk factor 2.02, p < 0.05), pre-existent DM (T1DM and T2DM com- risk groups . Different studies suggest that LGA newborns bined) (OR = 4.23, 95% CI 1.81–10.32, p =0.001), and other and newborns of diabetic mothers should have their monitor- complications (OR = 0.70, 95% CI 0.53–0.94, p =0.018). ing discontinued 12 h after birth (if GC is ≥ 2.6 mM) [2, 7]and Also, in case of severe hypoglycaemia, significant association SGA newborns and late preterm newborns after 24 h , 36 h was found with newborns born to mothers with pre-existent , or 48 h . DM (OR = 4.74, 95% CI 2.44–9.20, p < 0.001) and prematu- The high incidence of hypoglycaemia in offspring of rity (OR = 1.84, 95% CI 1.24–2.73, p =0.002). mothers with pre-existent DM (81%) was comparable to the incidence seen in the study of Maayan Metzger et al. (54% GC < 2.6 mM and 83% GC < 2.2 mM)  but rather high com- Discussion pared to the study of Harris et al. (49%) . However, in the latter study, no distinction between maternal pre-existent DM The overall incidence of hypoglycaemia in our cohort of ne- and GDM was defined. onates at risk was 48.5%. For most newborns at risk, it is safe More than one risk factor resulted in higher incidence (Fig. to stop monitoring GCs 12 h after birth. The highest incidence 2) which is in contrast to the study of Harris et al. in which no of hypoglycaemia was related to maternal diabetes and significant difference was found . This might be due to the there is an increasing risk of hypoglycaemia with in- relative small sample size in their study. creasing number of risk factors. The majority of first The nadir 1–2 h after birth in blood GC is also observed in hypoglycaemias occurred within 3 h after birth, compa- apparently health newborns and is considered part of normal rable to other studies [14, 16]. adaptation to postnatal life by several authors, although it is The overall incidence of hypoglycaemia in our cohort is not consistently described [2, 14, 16]. rather high; other studies report 6.8–51% [6, 12, 20, 23]. This Our data illustrate that 96.7% (710/734) of all newborns might be due to our selection criteria for newborns at risk for who developed hypoglycaemia had the first hypoglycaemia hypoglycaemia although our screening indications are identi- within 6 h after birth. Since there were only five cases of mild cal to those recommended by the AAP . Other possible asymptomatic hypoglycaemia beyond 12 h, all treated with explanations are our standardised and frequent monitoring additional feeding only, one could argue to stop glucose mon- and difference in GC cut-off point to define hypoglycaemia. itoring after 12 h for all risk groups. Safety of limiting the Hypoglycaemia was defined as a GC < 2.6 mM by Harris et al. monitoring to 12 h still has to be carefully evaluated in the  (overall incidence 51%) and a GC < 1.6 mM by Schaefer- presence of SGA or LGA newborns. Graf et al.  (overall incidence 25.2%); by means of this, Some limitations of this study should be addressed. Due to incidence of hypoglycaemia might be influenced. Our lowest the retrospective design, it was not possible to obtain the exact level of action is 2.2 mM in the first 24 h which is comparable glucose concentrations in 327 cases. Since the introduction of to the actionable range recommended by the AAP (4–24 h the electronic patient files, values of blood glucose concentra- after birth, 1.9–2.5 mM) . tions are directly stored in these files. Furthermore, not all A wide range of policies regarding duration of glucose samples were obtained at the exact prescribed time points, concentration monitoring exists [2, 7, 12, 15]. Some authors which was mainly due to breastfeeding on demand and sam- state that the same screening strategy should be applied to pling just prior to intake (recommended clinical practice). each risk group while others suggest to differentiate between Also, in this time period, several blood glucose meters and Eur J Pediatr creativecommons.org/licenses/by/4.0/), which permits unrestricted use, analysers were used. It is known that results of POC glucose distribution, and reproduction in any medium, provided you give appro- meters in the critical range may be unreliable . To mini- priate credit to the original author(s) and the source, provide a link to the mise misdiagnosis, blood samples, which showed a GC below Creative Commons license, and indicate if changes were made. 2.2 mM, were retested in the clinical laboratory. Moreover, variance in reliability of POC glucose meters is depending on variability in instrument analytical performance and References interaction between users and POC glucose meters . Continuous glucose monitoring (CGM) has been studied in 1. ACOG Committee Opinion (2006) The Apgar score. Obstet Gynecol 107:1209–1212 neonates and results are promising. CGM could potentially 2. Adamkin DH (2011) Postnatal glucose homeostasis in late-preterm decrease number of blood samples and the exposure to and term infants. Pediatrics 127:575–579. https://doi.org/10.1542/ hypoglycaemia. Furthermore, it is feasible, calibration can peds.2010-3851 be as low as 12 hourly, and it has limited side effects even in 3. 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European Journal of Pediatrics – Springer Journals
Published: May 30, 2018
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