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.).
Objectives To describe the prevalence and co-occurrence of disabilities and their association with parental education in preterm children and term control subjects. Study design In a prospective ...study, preterm children (n = 104), born at <30 weeks’ gestation or birth weight <1000 g, and term children (n = 95) were assessed at corrected age 5 with an intelligence quotient (IQ) test, behavior questionnaires for parents and teachers, and motor and neurologic tests. A disability was defined as results in the mild abnormal range of each test or below. Associations of outcomes with parental education were studied. Results Of the preterm children, 75% had at least one disability and 50% more than one, compared with 27% and 8%, respectively, of term control subjects ( P < .01). The preterm-term difference in full scale IQ increased from 5 IQ points if parental education was high to 14 IQ points if it was low, favoring the term children in both groups. A similar pattern was found for behavior, but not for motor and neurologic outcome. Conclusions Disabilities occur frequently after very preterm birth and tend to aggregate. Neurologic and motor outcomes are mostly influenced by biologic risk, and social risks contribute to cognitive and behavioral outcome.
Aim
To elucidate the relation between motor impairment and other developmental deficits in very preterm‐born children without disabling cerebral palsy and term‐born comparison children at 5 years of ...(corrected) age.
Method
In a prospective cohort study, 165 children (81 very preterm‐born and 84 term‐born) were assessed with the Movement Assessment Battery for Children ‐ 2nd edition, Touwen's neurological examination, the Wechsler Preschool and Primary Scale of Intelligence, processing speed and visuomotor coordination tasks of the Amsterdam Neuropsychological Tasks, and the Strengths and Difficulties Questionnaire.
Results
Motor impairment (≤15th centile) occurred in 32% of the very preterm‐born children compared with 11% of their term‐born peers (p=0.001). Of the very preterm‐born children with motor impairment, 58% had complex minor neurological dysfunctions, 54% had low IQ, 69% had slow processing speed, 58% had visuomotor coordination problems, and 27%, 50%, and 46% had conduct, emotional, and hyperactivity problems respectively. Neurological outcome (odds ratio OR=41.7, 95% confidence intervals CI 7.5–232.5) and Full‐scale IQ (OR=7.3, 95% CI 1.9–27.3) were significantly and independently associated with motor impairment. Processing speed (OR=4.6, 95% CI 1.8–11.6) and attention (OR=3.2, 95% CI 1.3–7.9) were additional variables associated with impaired manual dexterity. These four developmental deficits mediated the relation between preterm birth and motor impairment.
Interpretation
Complex minor neurological dysfunctions, low IQ, slow processing speed, and hyperactivity/inattention should be taken into account when very preterm‐born children are referred for motor impairment.
What this paper adds
Very preterm children with motor impairment have more developmental deficits than very preterm children without motor impairment
Behaviour problems are comparable between these groups
MND, IQ, processing speed, and hyperactivity/inattention mediate between preterm birth and motor impairment.
Motor impairment in term‐born children is not associated with developmental deficits.
This article is commented on by Zwicker on pages 514–515 of this issue.
Abstract
STUDY QUESTION
Does Day-3 cleavage-stage PGS affect neurodevelopment of 9-year-old IVF offspring?
SUMMARY ANSWER
We did not find evidence of adverse consequences of Day-3 cleavage-stage PGS ...on neurodevelopment of 9-year-old IVF offspring, although children born after IVF with or without PGS often had a non-optimal neurological condition.
WHAT IS KNOWN ALREADY
Knowledge on long-term sequelae for development and health of children born following PGS is lacking. This is striking as evidence accumulates that IVF itself is associated with increased risk for impaired health and development in the offspring.
STUDY DESIGN SIZE, DURATION
This prospective, assessor-blinded, multicentre, follow-up study evaluated development and health of 9-year-old IVF children born to women who were randomly assigned to IVF with PGS (PGS group) or without PGS (control group). The follow-up examination at 9 years took place between March 2014 and May 2016.
PARTICIPANTS/MATERIALS, SETTING, METHODS
In total, 408 women were included and randomly assigned to IVF with or without Day-3 cleavage-stage PGS. This resulted in 52 ongoing pregnancies in the PGS group and 74 in the control group. In the PGS group, 59 children were born alive; in the control group, 85 children were born alive. At the age of 9 years, 43 children born after PGS and 56 control children participated in the study. Our primary outcome was the neurological optimality score, a sensitive measure of neurological condition assessed with a standardized, age-specific test (Touwen test). Secondary outcomes were adverse neurological condition (neurologically abnormal and the complex form of minor neurological dysfunction), cognitive development (intelligence quotient and specific domains), behaviour (parental and teacher's questionnaires), blood pressure and anthropometrics.
MAIN RESULTS AND THE ROLE OF CHANCE
Neurodevelopmental outcome of PGS children did not differ from that of controls; the neurological optimality scores (mean values (95% CI: PGS children 51.5 49.3; 53.7, control children 53.1 50.5; 55.7) were not significantly different. The prevalences of adverse neurological outcome (in all but one child implying the presence of the complex form of minor neurological dysfunction) did not differ between the groups (PGS group 17/43 40%, control group 19/56 34%), although the prevalence of complex minor neurological dysfunction in both groups was rather high. Also intelligence quotient scores of the two groups were not significantly different (PGS group 114 108; 120); control group 117 109; 125), and the behaviour, blood pressure and anthropometrics of both groups did not differ. Mean blood pressures of both groups were above the 60th percentile.
LIMITATIONS REASONS FOR CAUTION
The power analysis of the study was not based on the number of children needed for the follow-up study, but on the number of women who were needed to detect an increase in ongoing pregnancy rates after PGS. In addition, our study evaluated embryo biopsy in the form of PGS at cleavage stage (Day-3 embryo biopsy), while currently PGS at blastocyst stage (Day-5 embryo biopsy) is recommended and increasingly being used.
WIDER IMPLICATIONS OF THE FINDINGS
Our findings indicate that PGS in cleavage stage embryos is not associated with adverse effects on neurological, cognitive and behavioural development, blood pressure and anthropometrics of offspring at 9 years. This is a reassuring finding as embryo biopsy in the forms of PGS and PGD is increasingly applied. However, both groups of IVF offspring showed high prevalences of the clinically relevant form of minor neurological dysfunction, which is a point of concern for the IVF community. In addition, our study confirms findings of others that IVF offspring may be at risk of an unfavourable cardiovascular outcome. These findings are alarming and highlight the importance of research on the underlying mechanisms of unfavourable neurodevelopmental and cardiovascular outcomes in IVF offspring.
STUDY FUNDING/COMPETING INTEREST(S)
The randomized controlled trial was financially supported by the Organization for Health Research and Development (ZonMw), The Netherlands (Grant number 945-03-013). The follow-up was financially supported by the University Medical Center Groningen (Grant number: 754510), the Cornelia Foundation, and the graduate schools BCN and Share, Groningen, The Netherlands. The sponsors of the study had no role in study design, data collection, data analysis, data interpretation or writing of the report. There are no conflicts of interest.
TRIAL REGISTRATION NUMBER
ISRCTN76355836.
Post‐discharge preventive intervention programmes with involvement of the parent may support the resilience and developmental outcomes of infants born very preterm. Randomized controlled trials of ...home‐based family‐centred intervention programmes in very preterm infants that aimed to improve cognitive outcome, at least at age two, were selected and updated on the basis of a recent systematic review to compare their content and effect over time to form the basis of a narrative review. Six programmes were included in this narrative review. Four of the six programmes led to improved child cognitive and/or motor development. Two programmes, which focused primarily on responsive parenting and development, demonstrated improved cognitive outcome up till 5 years after completion of the programme. The programmes that also focused on maternal anxiety remediation led to improved maternal mental well‐being, along with improved child behaviour, in one study – even at 3 years after completion of the programme. The magnitude of the effects was modest. Family‐centred preventive intervention programmes that aim at improvement of child development should be continued after discharge home to improve the preterm child's resilience. Programmes may be most effective when they support the evolvement of a responsive parent–infant relationship over time, as well as the parent's well‐being.
What this paper adds
Responsive parenting is essential in post‐discharge interventions in preterm infants.
Responsive parenting can improve cognitive, motor, and behavioural outcomes in preterm infants.
Besides being one of the mechanisms responsible for ventilator-induced lung injury, atelectasis also seems to aggravate the course of experimental pneumonia. In this study, we examined the effect of ...reducing the degree of atelectasis by natural modified surfactant and/or open lung ventilation on bacterial growth and translocation in a piglet model of Group B streptococcal pneumonia. After creating surfactant deficiency by whole lung lavage, intratracheal instillation of bacteria induced severe pneumonia with bacterial translocation into the blood stream, resulting in a mortality rate of almost 80%. Treatment with 300 mg/kg of exogenous surfactant before instillation of streptococci attenuated both bacterial growth and translocation and prevented clinical deterioration. This goal was also achieved by reversing atelectasis in lavaged animals via open lung ventilation. Combining both exogenous surfactant and open lung ventilation prevented bacterial translocation completely, comparable to Group B streptococci instillation into healthy animals. We conclude that exogenous surfactant and open lung ventilation attenuate bacterial growth and translocation in experimental pneumonia and that this attenuation is at least in part mediated by a reduction in atelectasis. These findings suggest that minimizing alveolar collapse by exogenous surfactant and open lung ventilation may reduce the risk of pneumonia and subsequent sepsis in ventilated patients.
Late-onset neonatal sepsis (LOS) in preterm infants is an important cause of morbidity and mortality in preterm infants. Since presenting symptoms may be non-specific and subtle, early and correct ...diagnosis is challenging. We aimed to develop a nomogram based on clinical signs, to assess the likelihood of LOS in preterms with suspected infection without the use of laboratory investigations. We performed a prospective cohort study in 142 preterm infants <34 weeks admitted to the neonatal intensive care unit with suspected infection. During 187 episodes, 21 clinical signs were assessed. LOS was defined as blood culture-proven and/or clinical sepsis, occurring after 3 days of age. Logistic regression was used to develop a nomogram to estimate the probability of LOS being present in individual patients. LOS was found in 48 % of 187 suspected episodes. Clinical signs associated with LOS were: increased respiratory support (odds ratio (OR) 3.6; 95 % confidence interval (CI) 1.9–7.1), capillary refill (OR 2.2; 95 %CI 1.1–4.5), grey skin (OR 2.7; 95 %CI 1.4–5.5) and central venous catheter (OR 4.6; 95 %CI 2.2–10.0) (area under the curve of the receiver operating characteristic curve 0.828; 95 %CI 0.764–0.892).
Conclusion:
Increased respiratory support, capillary refill, grey skin and central venous catheter are the most important clinical signs suggestive of LOS in preterms. Clinical signs that are too non-specific to be useful in excluding or diagnosing LOS were temperature instability, apnoea, tachycardia, dyspnoea, hyper- and hypothermia, feeding difficulties and irritability.
Aim This study investigated prediction of separate cognitive abilities at the age of 5 years by cognitive development at the ages of both 2 and 3 years, and the agreement between these measurements, ...in very preterm children.
Methods Preterm children (n=102; 44 males; 58 females) with a gestational age less than 30 weeks and/or birthweight less than 1000g were assessed at the ages of 2 and 3 years using the second edition of the Bayley Scales of Infant Development, the Child Behaviour Checklist, and a neurological examination, and at the age of 5 years using the third edition of the Wechsler Preschool and Primary Scale of Intelligence.
Results Cognitive development at ages 2 and 3 years explained 44% and 57% respectively of full‐scale intelligence at the age of 5 years. Adding psychomotor, neurological, and behavioural outcomes to the regression model could not or only marginally improve the prediction; adding perinatal and sociodemographic characteristics to the regression model increased the explained variance to 57% and 64% respectively. These percentages were comparable for verbal intelligence. Processing speed quotient and especially performance intelligence were predicted less accurately.
Interpretation Not all aspects of intelligence are predicted sufficiently by the Mental Development Index at ages 2 and 3 years. Follow‐up of very preterm children until at least the age of 5 years is needed to distinguish between different aspects of cognitive development.
Objective To evaluate the effect of the Infant Behavioral Assessment and Intervention Program (IBAIP) in very low birth weight (VLBW) infants on cognitive, neuromotor, and behavioral development at ...5.5 years corrected age (CA). Study design In a randomized controlled trial, 86 VLBW infants received post discharge IBAIP intervention until 6 months CA, and 90 VLBW infants received standard care. At 5.5 years CA, cognitive and motor development, and visual-motor integration were assessed with the Wechsler Preschool and Primary Scale of Intelligence, third Dutch version , the Movement Assessment Battery for Children , second edition, and the Developmental Test of Visual Motor Integration. Neurologic conditions were assessed with the neurologic examination according to Touwen, and behavior with the Strengths and Difficulties Questionnaire. Results At 5.5 years CA, 69 children in the intervention and 67 children in the control group participated (response rate 77.3%). Verbal and performance IQ-scores <85 occurred significantly less often in the intervention than in the control group (17.9% vs 33.3%, P = .041, and 7.5% vs 21.2%, P = .023, respectively). However, after adjustment for differences, only the OR for performance IQ was significant: 0.24, 95% CI: 0.06-0.95. Adjusted mean scores on Wechsler Preschool and Primary Scale of Intelligence , third version subtasks block design and vocabulary, the Movement Assessment Battery for Children , second edition component aiming and catching, and the Developmental Test of Visual Motor Integration were significantly better in the intervention group. No intervention effect was found on the Strengths and Difficulties Questionnaire. Conclusion The IBAIP leads, 5 years after the early neurobehavioral intervention, to improvements on performance IQ, ball skills, and visual-motor integration at 5.5 years CA.
Aim This study aimed to compare a broad array of neurocognitive functions (processing speed, aspects of attention, executive functioning, visual–motor coordination, and both face and emotion ...recognition) in very preterm and term‐born children and to identify perinatal risk factors for neurocognitive dysfunctions.
Method Children who were born very preterm (n=102; 46 males, 56 females), defined as a gestational age of less than 30 weeks and/or birthweight under 1000g, and a comparison group of term‐born children (n=95; 40 males, 55 females) were assessed at age 5 with the Wechsler Preschool and Primary Scale of Intelligence, Stop Signal Task, several tasks of the Amsterdam Neuropsychological Tasks, and a Digit Span task.
Results When sociodemographic characteristics were taken into account, very preterm children scored worse than term‐born children on all neurocognitive functions, except on tasks measuring inhibition and sustained attention, for which results were inconclusive. Effect sizes for group effects were small to medium (r2 varying between 0.02 and 0.07). Principal component isolated four factors: visual–motor coordination, face/emotion recognition, reaction time/attention, and accuracy/attention. When sociodemographic and child characteristics at birth were accounted for, bronchopulmonary dysplasia was significantly negatively associated with all four components and also with working memory.
Interpretation Very preterm children are at risk for problems on a broad array of neurocognitive functions. Bronchopulmonary dysplasia is an independent risk factor for impaired neurocognitive functioning.
This article is commented on by Marlow on pages 105–106 of this issue.
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