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Original Article Neonatal Glycemia and Neurodevelopmental Outcomes at 2 Years Christopher J.D. McKinlay, Ph.D., Jane M. Alsweiler, Ph.D., Judith M. Ansell, Ph.D., Nicola S.

Anstice, Ph.D., J. Geoffrey Chase, Ph.D., Gregory D. Gamble, M.Sc., Deborah L. Harris, Ph.D., Robert J. Jacobs, Ph.D., Yannan Jiang, Ph.D., Nabin Paudel, B.Optom., Matthew Signal, Ph.D., Benjamin Thompson, D.Phil., Trecia A. Wouldes, Ph.D., Tzu-Ying Yu, Ph.D., and Jane E.

Harding, D.Phil., for the CHYLD Study Group N Engl J Med 2015; 373:1507-1518 DOI: 10.1056/NEJMoa1504909. Methods We performed a prospective cohort study involving 528 neonates with a gestational age of at least 35 weeks who were considered to be at risk for hypoglycemia; all were treated to maintain a blood glucose concentration of at least 47 mg per deciliter (2.6 mmol per liter).

We intermittently measured blood glucose for up to 7 days. We continuously monitored interstitial glucose concentrations, which were masked to clinical staff. Assessment at 2 years included Bayley Scales of Infant Development III and tests of executive and visual function. Results Of 614 children, 528 were eligible, and 404 (77% of eligible children) were assessed; 216 children (53%) had neonatal hypoglycemia (blood glucose concentration. Figure 2 Effect of Hypoglycemia on the Primary Outcome and Relation between Continuous Glycemic Exposure and the Primary Outcome. Panel A shows the effect of hypoglycemia on the risk of the primary outcome.

A hypoglycemic episode was defined as a blood glucose concentration of less than 47 mg per deciliter (2.6 mmol per liter) on a single measurement or consecutive measurements; severe hypoglycemia was defined as a blood glucose concentration of less than 36 mg per deciliter (2.0 mmol per liter). Results were adjusted for socioeconomic decile, sex, and primary risk factor for neonatal hypoglycemia. Panel B shows the relationship between continuous glycemic exposure and the primary outcome. Logistic regression was used to compare the risk of an adverse outcome according to the quintile of the continuous glycemic variable in the first 48 hours. Results were adjusted for socioeconomic decile, sex, and primary risk factor for neonatal hypoglycemia. Diamonds denote quintile 1, upward-pointing triangles quintile 2, circles quintile 3 (reference), squares quintile 4, and downward-pointing triangles quintile 5.

Values for quintiles 1 through 5 (Q1–5) represent the lowest value for each quintile. The central band was defined as a blood glucose or an interstitial glucose concentration of 54 to 72 mg per deciliter. To convert the values for glucose to millimoles per liter, multiply by 0.05551.

Neonatal hypoglycemia is a common and readily treatable risk factor for neurologic impairment in children. Although associations between prolonged symptomatic neonatal hypoglycemia and brain injury are well established, the effect of milder hypoglycemia on neurologic development is uncertain. Consequently, large numbers of newborns are screened and treated for low blood glucose concentrations, which involves heel-stick blood tests, substantial costs, and the possibility of iatrogenic harm.

Under current guidelines, up to 30% of neonates are considered to be at risk for hypoglycemia, 15% receive a diagnosis of hypoglycemia, and approximately 10% require admission to a neonatal intensive care unit, costing an estimated $2.1 billion annually in the United States alone. Associated formula feeding and possible separation of mother and baby reduce breast-feeding rates, with potentially adverse effects on broader infant health and development. In addition, pain-induced stress in neonates, such as repeated heel sticks, may itself impair brain development. Thus, to determine appropriate glycemic thresholds for treatment, there have been repeated calls for studies of the effect of neonatal hypoglycemia on long-term development.

We report the results of the Children with Hypoglycaemia and Their Later Development (CHYLD) study, a large prospective cohort study of term and late-preterm neonates born at risk for hypoglycemia. The study investigated the relation between the duration, frequency, and severity of low glucose concentrations in the neonatal period and neuropsychological development at 2 years. Study Design and Participants Eligible infants were those at risk for neonatal hypoglycemia primarily on the basis of maternal diabetes, preterm birth (gestational age of 90th percentile or >4500 g). Infants were enrolled before or shortly after birth in one of two parallel studies: the Babies and Blood Sugar’s Influence on EEG Study (BABIES) (102 infants) and the Sugar Babies study (514 infants), conducted from 2006 to 2010 at Waikato Hospital, in Hamilton, New Zealand, a regional public hospital with 5500 births annually. Infants with serious congenital malformations or terminal conditions were excluded. Cohort characteristics, glycemic management, and neonatal outcomes have been reported previously.

Infants underwent regular measurement of blood glucose concentrations by means of the glucose oxidase method (ABL800 FLEX, Radiometer) for 24 to 48 hours or until there were no ongoing clinical concerns. Masked continuous interstitial glucose monitoring (CGMS Gold, Medtronic MiniMed) was performed as previously described. Hypoglycemia, defined as a blood glucose concentration of less than 47 mg per deciliter (2.6 mmol per liter), was treated with any combination of additional feeding, buccal dextrose gel, and intravenous dextrose to maintain a blood glucose concentration of at least 47 mg per deciliter. Approximately one third of the infants (237) were enrolled in a randomized, placebo-controlled trial of buccal dextrose gel.

Both neonatal studies and the follow-up study were approved by the regional ethics committee. Written informed consent was obtained from a parent or guardian of each infant at study entry and at follow-up. Statistical Analysis Analysis was performed with SAS software, version 9.4 (SAS Institute). Primary analyses compared primary and secondary outcomes between children with and those without hypoglycemic episodes in the first week after birth (any episode, ≥3 episodes, episodes on ≥3 days, and any severe episode), with the use of generalized linear models adjusted for prespecified potential confounders (socioeconomic decile, sex, and primary risk factor for neonatal hypoglycemia). A hypoglycemic episode was defined as a blood glucose concentration of less than 47 mg per deciliter on a single measurement or consecutive measurements, with a severe episode defined as a blood glucose concentration of less than 36 mg per deciliter (2.0 mmol per liter). Interstitial episodes were defined as periods of interstitial glucose concentrations that were below those thresholds for at least 10 minutes.

Results are presented as risk ratios and mean differences with 95% confidence intervals. A two-tailed alpha level of less than 0.05 was considered to indicate statistical significance, with no adjustment for multiple comparisons. Sample size was limited by the size of the inception cohorts, but we estimated that this study would have 80% power to detect between-group differences in BSID-III scores of 5 points or more.

Secondary analyses related continuous measures of hypoglycemic exposure to primary outcomes, with the use of receiver-operating-characteristic (ROC) curves. To explore the predictive value of different glycemic thresholds for adverse neurodevelopmental outcomes, the negative interstitial increment was used, calculated as the area above the interstitial glucose concentration curve and below a given threshold. Repeated-measures mixed models explored trend over time. Logistic regression was used to estimate the likelihood of the primary outcomes according to quantile of continuous glycemic variables. Study Cohort The cohort comprised 614 infants (2 infants participated in both neonatal studies) ( Figure 1 Cohort of Children Followed up at 2 Years. BABIES denotes Babies and Blood Sugar’s Influence on EEG Study, BRIEF-P Behavior Rating Inventory of Executive Function–preschool version, and BSID-III Bayley Scales of Infant Development III. Pediatric assessment included history taking and physical examination (including neurologic examination) by a pediatrician.

Because follow-up started after some children were older than 2 years of age and those born before 35 weeks’ gestation were excluded, 528 children were eligible, of whom 404 (77% of eligible infants) were assessed at a mean (±SD) corrected age of 24.3±1.9 months. Eligible children who did not participate in the study were more likely to be of Maori or other non-European ethnic origin, and their mothers had a slightly lower body-mass index but were similar with respect to other baseline variables ( Table 1 Maternal and Neonatal Characteristics of the Study Participants and Nonparticipants. Neonatal Hypoglycemia Although neonatal hypoglycemia was common (observed in 216 children [53%]), regular measurement of blood glucose concentrations and early treatment meant that recurrent hypoglycemia was infrequent ( ). Nevertheless, continuous interstitial glucose monitoring showed that nearly one quarter of the infants had low glucose concentrations that were not detected by intermittent blood glucose monitoring. Even with treatment, many infants had prolonged periods of low interstitial glucose concentrations. Thus, 25% of those treated for neonatal hypoglycemia had at least 5 hours of low interstitial glucose concentrations during the first week ( ).

Discussion After reports of altered somatosensory evoked potentials and an increased incidence of developmental delay in infants with glucose concentrations of less than 47 mg per deciliter, a glucose concentration of 47 mg per deciliter became a well-accepted glycemic threshold for treatment in newborns, despite the lack of evidence that intervention at this threshold is safe or effective. The use of this threshold in newborns is perhaps surprising, given that blood glucose concentrations below 60 mg per deciliter (3.3 mmol per liter) are considered low in children and adults. In this large prospective study of at-risk term and late-preterm infants, we found that with a treatment threshold of 47 mg of glucose per deciliter, neonatal hypoglycemia was not associated with adverse neurodevelopmental outcomes at 2 years.

Our study suggests that a protocol of regular blood glucose monitoring in the first 48 hours after birth and intervention aimed at maintaining a blood glucose concentration of at least 47 mg per deciliter is effective in preventing neuronal injury in at-risk term and late-preterm newborns. It is important to distinguish between thresholds for intervention that can be safely applied to all infants and the lowest glucose concentration at which clinically significant neuroglycopenia is avoided. It is unlikely that neuroglycopenia can be defined by a single numerical value, since the relationships among glycemic exposure, alternative cerebral fuels, other perinatal stressors, and neuronal function are complex and may be highly infant-specific. At present, there are no reliable tools to assess the neurologic state in relation to the blood glucose concentration in infants. Hexcmp2 2 34 Serial Number there. Therefore, clinicians need a pragmatic threshold for providing treatment that ensures an adequate supply of metabolic fuels for the developing brain during the neonatal transition.

In our study, continuous interstitial glucose monitoring showed that episodes of low glucose concentrations were common, even in infants thought to have normal blood glucose concentrations and those receiving treatment for hypoglycemia. Although these data could be interpreted as evidence that a lower glycemic threshold for treatment might be safe, they also highlight the need for a considerable margin of safety in setting such a threshold. We were not able to establish an association between the degree of hypoglycemia and neurologic outcomes, most likely because treatment was effective and the infants were monitored closely, so that recurrent or severe hypoglycemia was rare. However, a recent retrospective study showed a graded association between hypoglycemic thresholds of less than 40 mg per deciliter (2.2 mmol per liter) and neurodevelopmental impairment in late-preterm infants, an observation that provides grounds for caution, particularly since the infants were followed for longer than 2 years in that study. Furthermore, whereas a lower threshold may reduce the need for intervention, it may not reduce the requirement for screening and associated costs, since hypoglycemia can occur at any stage in the first few days after birth, even in infants with normal initial glucose concentrations. Therefore, if lower intervention and treatment thresholds are to be considered, it seems reasonable that they should be evaluated in randomized trials. A strength of our study is the comprehensive neuropsychometric assessment undertaken, including advanced testing of executive function, vision, and visual processing — skills thought to be particularly affected by neonatal hypoglycemia.

Therefore, we are confident that our results are robust and that we would have detected clinically significant effects of hypoglycemia on neurocognitive processing. Nevertheless, the possibility remains that hypoglycemia affects skills that do not emerge until later phases of development, and repeat assessment at 4.5 years of age is ongoing. Another strength of our study is the use of continuous interstitial glucose monitoring, which provides recordings every 5 minutes, allowing detailed characterization of glucose profiles over time. Although continuous interstitial glucose monitoring remains an important research tool, our study suggests that at a treatment threshold of 47 mg of glucose per deciliter, screening by means of intermittent blood glucose measurement with the use of a reference method is sufficient. However, this may not be the case at lower glucose thresholds. A surprising finding of our study is the association of neurosensory impairment, especially cognitive delay, with higher glucose concentrations and less glucose stability, indicated by a larger proportion of time outside the central range of 54 to 72 mg per deciliter in the first 48 hours. Hyperglycemia (a blood glucose concentration of >180 mg per deciliter [10.0 mmol per liter]) is associated with neurodevelopmental impairment in very preterm infants, but an association has not previously been reported in more mature infants, especially at glucose concentrations typically regarded as being within the normal range.

Furthermore, the estimated effect sizes in our study were relatively large, particularly given the brief glycemic exposure, with increases in the risk of neurosensory impairment ranging from 40 to 77%, and even higher for infants in the uppermost quintiles. Of concern is the suggestion in our data that rapid correction of hypoglycemia to higher blood glucose concentrations may be associated with a poorer outcome.

This finding, in an exploratory analysis, was unexpected and must be interpreted with caution, since the study was observational and unknown confounders cannot be excluded in such studies. Furthermore, the association was seen only in tests of general development (BSID-III), not in tests of processing ability. However, this finding is consistent with evidence from animal models that higher blood glucose concentrations during recovery from hypoglycemia can worsen neurologic damage, at least in part because of increased generation of reactive oxygen species. Similarly, in both children and adults in the intensive care unit, the combination of hypoglycemia and highly variable glucose concentrations is strongly associated with mortality. Thus, the manner in which hypoglycemia is treated and the subsequent stability of blood glucose concentrations may be important in newborns. We are currently undertaking a randomized trial () to assess the long-term effects of different doses and frequencies of dextrose gel administration.

In the present cohort study, neonatal hypoglycemia was not associated with adverse neurologic outcomes when infants were treated with the aim of maintaining a blood glucose concentration of at least 47 mg per deciliter (2.6 mmol per liter), even though transient low glucose concentrations remained common. The possibility that blood glucose concentrations at the high end of the normal range or unstable blood glucose concentrations and rapid correction of hypoglycemia may be harmful requires further investigation.

Supported by grants from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD069622), the Health Research Council of New Zealand (10-399), and the Auckland Medical Research Foundation (1110009). Provided by the authors are available with the full text of this article at NEJM.org.

The views expressed in this article are those of the authors and do not necessarily represent the official views of the Eunice Kennedy Shriver National Institute of Child Health and Human Development or the National Institutes of Health. We thank the children and families who participated in this study, as well as the members of the International Advisory Group: Heidi Feldman, Stanford University School of Medicine; William Hay, University of Colorado School of Medicine; Darrell Wilson, Stanford University School of Medicine; and Robert Hess, McGill Vision Research Unit, Department of Ophthalmology, McGill University.

Source Information From the Liggins Institute (C.J.D.M., J.M. Alsweiler, J.M. Ansell, G.D.G., D.L.H., Y.J., J.E.H.), the Department of Paediatrics (J.M. Alsweiler), the School of Optometry and Vision Science (N.S.A., R.J.J., N.P., B.T., T.-Y.Y.), and the Department of Psychological Medicine (T.A.W.), University of Auckland, Auckland, the Department of Mechanical Engineering, University of Canterbury, Christchurch (J.G.C., M.S.), and the Neonatal Intensive Care Unit, Waikato District Health Board, Hamilton (D.L.H.) — all in New Zealand; and the School of Optometry and Vision Science, University of Waterloo, Waterloo, ON, Canada (B.T.). Address reprint requests to Dr. Harding at the Liggins Institute, University of Auckland, Private Bag 92019, Victoria St. W., Auckland 1142, New Zealand,.

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