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N Engl J Med. 2020 Feb 6;382(6):534-544. doi: 10.1056/NEJMoa1905593.

Lower versus Traditional Treatment Threshold for Neonatal Hypoglycemia.

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From OLVG, Department of Pediatrics (A.A.M.W.K., N.R.V.), and Academic Medical Center, Emma Children's Hospital, Department of Neonatology (D.H.G.M.N., J.H.K.), the University of Amsterdam, Pediatric Clinical Research Office (J.H.L.) and the VU Medical Center, Vrije Universiteit, Department of Neonatology (R.C.J.J.), Amsterdam UMC, Amsterdam, Meander Medical Center, Department of Pediatrics, Amersfoort (P.F.E.), St. Antonius Hospital, Departments of Research and Epidemiology (L.M.D.) and Pediatrics (M.D.-B), Nieuwegein, Zaans Medical Center, Department of Pediatrics, Zaandam (F.J.P.C.M.H.), Zuyderland Medical Center Heerlen, Department of Pediatrics, Sittard-Geleen (R.M.J.M.), Maastricht University Medical Center, Department of Pediatrics-Neonatology, Schools of Oncology and Developmental Biology (GROW) and NUTRIM, Maastricht (L.J.I.Z.), Erasmus MC-Sophia, Department of Neonatology (E.P.V.), Maasstad Hospital, Department of Pediatrics (H.G.S.), and St. Franciscus Gasthuis, Department of Pediatrics (M.W.A.H.), Rotterdam, Canisius-Wilhelmina Hospital, Department of Pediatrics, Nijmegen (B.A.S.), Amphia Hospital, Department of Pediatrics, Breda (R.H.T.B.), Rijnstate Hospital, Department of Pediatrics, Arnhem (J.J.V.), the University of Groningen, University Medical Center Groningen, Beatrix Children's Hospital, Department of Neonatology, Groningen (P.H.D.), University Medical Center Utrecht, Wilhelmina Children's Hospital, Department of Neonatology, Utrecht (J.U.M.T.), Albert Schweitzer Hospital, Department of Pediatrics, Dordrecht (A.C.M.), and the National Health Care Institute (ZINL), Diemen (N.B.) - all in the Netherlands; and the Hospital for Sick Children, Division of Neonatology/Child Health Evaluative Sciences, University of Toronto, Toronto (M.O.).



Worldwide, many newborns who are preterm, small or large for gestational age, or born to mothers with diabetes are screened for hypoglycemia, with a goal of preventing brain injury. However, there is no consensus on a treatment threshold that is safe but also avoids overtreatment.


In a multicenter, randomized, noninferiority trial involving 689 otherwise healthy newborns born at 35 weeks of gestation or later and identified as being at risk for hypoglycemia, we compared two threshold values for treatment of asymptomatic moderate hypoglycemia. We sought to determine whether a management strategy that used a lower threshold (treatment administered at a glucose concentration of <36 mg per deciliter [2.0 mmol per liter]) would be noninferior to a traditional threshold (treatment at a glucose concentration of <47 mg per deciliter [2.6 mmol per liter]) with respect to psychomotor development at 18 months, assessed with the Bayley Scales of Infant and Toddler Development, third edition, Dutch version (Bayley-III-NL; scores range from 50 to 150 [mean {±SD}, 100±15]), with higher scores indicating more advanced development and 7.5 points (one half the SD) representing a clinically important difference). The lower threshold would be considered noninferior if scores were less than 7.5 points lower than scores in the traditional-threshold group.


Bayley-III-NL scores were assessed in 287 of the 348 children (82.5%) in the lower-threshold group and in 295 of the 341 children (86.5%) in the traditional-threshold group. Cognitive and motor outcome scores were similar in the two groups (mean scores [±SE], 102.9±0.7 [cognitive] and 104.6±0.7 [motor] in the lower-threshold group and 102.2±0.7 [cognitive] and 104.9±0.7 [motor] in the traditional-threshold group). The prespecified inferiority limit was not crossed. The mean glucose concentration was 57±0.4 mg per deciliter (3.2±0.02 mmol per liter) in the lower-threshold group and 61±0.5 mg per deciliter (3.4±0.03 mmol per liter) in the traditional-threshold group. Fewer and less severe hypoglycemic episodes occurred in the traditional-threshold group, but that group had more invasive diagnostic and treatment interventions. Serious adverse events in the lower-threshold group included convulsions (during normoglycemia) in one newborn and one death.


In otherwise healthy newborns with asymptomatic moderate hypoglycemia, a lower glucose treatment threshold (36 mg per deciliter) was noninferior to a traditional threshold (47 mg per deciliter) with regard to psychomotor development at 18 months. (Funded by the Netherlands Organization for Health Research and Development; HypoEXIT Current Controlled Trials number, ISRCTN79705768.).

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