Lower versus Traditional Treatment Threshold for Neonatal Hypoglycemia.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.).

Developmental outcome of 9-year-old children born after PGS: follow-up of a randomized trial.

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.

Nifedipine versus atosiban for threatened preterm birth (APOSTEL III): a multicentre, randomised controlled trial.

BACKGROUND: In women with threatened preterm birth, delay of delivery by 48 h allows antenatal corticosteroids to improve neonatal outcomes. For this reason, tocolytics are often administered for 48 h; however, there is no consensus about which drug results in the best maternal and neonatal outcomes. In the APOSTEL III trial we aimed to compare the effectiveness and safety of the calcium-channel blocker nifedipine and the oxytocin inhibitor atosiban in women with threatened preterm birth. METHODS: We did this multicentre, randomised controlled trial in ten tertiary and nine teaching hospitals in the Netherlands and Belgium. Women with threatened preterm birth (gestational age 25-34 weeks) were randomly assigned (1:1) to either oral nifedipine or intravenous atosiban for 48 h. An independent data manager used a web-based computerised programme to randomly assign women in permuted block sizes of four, with groups stratified by centre. Clinicians, outcome assessors, and women were not masked to treatment group. The primary outcome was a composite of adverse perinatal outcomes, which included perinatal mortality, bronchopulmonary dysplasia, sepsis, intraventricular haemorrhage, periventricular leukomalacia, and necrotising enterocolitis. Analysis was done in all women and babies with follow-up data. The study is registered at the Dutch Clinical Trial Registry, number NTR2947. FINDINGS: Between July 6, 2011, and July 7, 2014, we randomly assigned 254 women to nifedipine and 256 to atosiban. Primary outcome data were available for 248 women and 297 babies in the nifedipine group and 255 women and 294 babies in the atosiban group. The primary outcome occurred in 42 babies (14%) in the nifedipine group and in 45 (15%) in the atosiban group (relative risk [RR] 0·91, 95% CI 0·61-1·37). 16 (5%) babies died in the nifedipine group and seven (2%) died in the atosiban group (RR 2·20, 95% CI 0·91-5·33); all deaths were deemed unlikely to be related to the study drug. Maternal adverse events did not differ between groups. INTERPRETATION: In women with threatened preterm birth, 48 h of tocolysis with nifedipine or atosiban results in similar perinatal outcomes. Future clinical research should focus on large placebo-controlled trials, powered for perinatal outcomes. FUNDING: ZonMw (the Netherlands Organisation for Health Research and Development).

Rethinking preventive post-discharge intervention programmes for very preterm infants and their parents.

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.

Attention in 3-Year-Old Children with VLBW and Relationships with Early School Outcomes.

AIM: To compare attention skills of children with a very low birth weight (VLBW) with children with a normal birth weight (NBW) when entering primary school, and explore the association of attention skills with school career 2 years later. METHODS: Participants were 151 children with VLBW and 41 with NBW. Attention was assessed at 3 years and 8 months of corrected age (CA) and school career at 5½ years of CA. Children performed two tests, parents completed three questionnaires, and an assessor systematically observed children's attention. RESULTS: Children with VLBW had significantly lower mean scores on five of the six measures. Significantly more children with VLBW had scores in the clinical range on the Child Behavior Checklist completed by the parents (13% versus 0%) and scores representing dysfunction on assessor observations (19% versus 2%). At 5½ years of age, 36% of the children with VLBW followed special education or had grade retention. Dysfunctional attention as observed by the assessor was most strongly associated with need for learning support at 5½ years of age. CONCLUSIONS: At preschool age, children with VLBW have attention difficulties. Attentive behavior at preschool age is a predictor of school career 2 years later.

A functional approach to cerebral visual impairments in very preterm/very-low-birth-weight children.

BACKGROUND: Cerebral visual impairment (CVI) is a major cause of visual impairment, with very preterm birth/very low birth weight (VP/VLBW) being a major risk factor. There is no generally accepted definition of CVI. This study aims to investigate the usefulness of an empirically-based functional definition of CVI. METHODS: One-hundred-five VP/VLBW children and 67 controls participated. CVI was defined after comprehensive oculomotor, visual sensory and perceptive assessment, and validated against vision problems in daily life and in terms of intellectual, behavioral, emotional and social functioning, as well as use of therapeutic services. RESULTS: Twenty-four per cent of the VP/VLBW children met criteria for CVI, compared to 7% of controls (P = 0.006, OR: 3.86, 95% CI: 1.40-10.70). VP/VLBW children with CVI had lower performance IQ, but not verbal IQ, than those without CVI. Visual problems in daily life were confirmed in VP/VLBW children classified with CVI. Additionally, difficulties in behavioral and social functioning were most prominent among VP/VLBW children with CVI. CONCLUSION: In VP/VLBW children, CVI defined in terms of visual function deficits is accompanied by intellectual, behavioral, and social impairments, validating our operational definition of CVI. CVI might act as a marker for developmental problems in VP/VLBW children.

Glucosuria as an early marker of late-onset sepsis in preterms: a prospective cohort study.

BACKGROUND: Early and accurate diagnosis of late-onset sepsis (LONS) in preterm infants is difficult since presenting signs are subtle and non-specific. Because neonatal sepsis may be accompanied by glucose intolerance and glucosuria, we hypothesized that glucosuria may be associated with LONS in preterms, in an early stage. We aim to evaluate the association of glucosuria and late-onset neonatal sepsis (LONS) in preterm infants, in an attempt to improve early and accurate diagnosis of LONS. METHODS: We performed a prospective observational cohort study in 316 preterms (<34 weeks). We daily measured glucosuria and followed patients for occurrence of LONS, defined as clinical and blood culture-proven sepsis occurring after 72 h. Attending physicians were blinded to glucosuria results. We assessed the diagnostic value of glucosuria for clinical and blood culture-proven LONS using logistic regression analysis. RESULTS: Glucosuria was found in 65.8% of 316 preterm patients, and sepsis was suspected 157 times in 123 patients. LONS was found in 47.1% of 157 suspected episodes. The presence of glucosuria was associated with LONS (OR 2.59, 95% CI 1.24-5.43, p = 0.012) with sensitivity 69.0% and specificity 53.8% (Likelihoodratio 1.49). After adjustment for gestational age, birth weight, and postnatal age, this association weakened and was no longer significant (adjusted OR 2.16; 95% CI 0.99-1.85, p = 0.055). An increase in glucosuria 48-24 h before onset of symptoms was not associated with LONS. CONCLUSION: In preterms glucosuria is associated with LONS within 24 h, however this association is too weak to be of diagnostic value.

Motor impairment in very preterm-born children: links with other developmental deficits at 5 years of age.

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] 7.5­232.5) and Full-scale IQ(OR=7.3, 95% CI 1.9­27.3) were significantly and independently associated with motor impairment. Processing speed (OR=4.6, 95% CI 1.8­11.6) and attention (OR=3.2, 95% CI1.3­7.9) 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.

Visual sensory and perceptive functioning in 5-year-old very preterm/very-low-birthweight children.

AIM: To examine visual sensory and perceptive functions, study their interrelations, and explore associations between visual dysfunctions and intelligence in very preterm/very-low-birthweight (VP/VLBW) children. METHOD: One-hundred and sixteen VP/VLBW children (57 males, 59 females; mean gestational age 30.1 wks, SD 2.3; mean corrected age 5 y 6 mo, SD 1 mo) and 73 term-born children (40 males, 33 females; mean gestational age 39.9 wks, SD 1.3; mean age 5 y 6 mo, SD 3 mo) completed visual sensory (acuity, visual field, contrast-, color-, and stereovision), perceptive (visual coherence, and Developmental Test of Visual Perception non-motor scale), and intelligence assessments. RESULTS: Compared with term-born children, VP/VLBW children had reduced acuity (d=0.70, p<0.001), inferior visual field (d=0.67, p<0.001), and stereovision (v=0.19, p=0.008). VP/VBLW children showed weaker static coherence (d=0.49, p=0.001) and Position in Space (d=0.41, p=0.006) performance, independent of visual sensory deficits, and showed lower Verbal IQ (VIQ) and Performance IQ (PIQ; p<0.001). Visual perceptive functioning accounted for 13% of variance in VIQ, and for 35% of variance in PIQ. INTERPRETATION: Visual sensory and perceptive dysfunctions are present in VP/VLBW children and occur largely independently of each other. Visual perceptive dysfunctions are moderately associated with PIQ, and weakly with VIQ.

Nifedipine versus atosiban in the treatment of threatened preterm labour (Assessment of Perinatal Outcome after Specific Tocolysis in Early Labour: APOSTEL III-Trial).

BACKGROUND: Preterm birth is the most common cause of neonatal morbidity and mortality. Postponing delivery for 48 hours with tocolytics to allow for maternal steroid administration and antenatal transportation to a centre with neonatal intensive care unit facilities is the standard treatment for women with threatening preterm delivery in most centres. However, there is controversy as to which tocolytic agent is the drug of first choice. Previous trials have focused on tocolytic efficacy and side effects, and are probably underpowered to detect clinically meaningfull differences in neonatal outcome. Thus, the current evidence is inconclusive to support a balanced recommendation for clinical practice. This multicenter randomised clinical trial aims to compare nifedipine and atosiban in terms of neonatal outcome, duration of pregnancy and maternal side effects. METHODS/DESIGN: The Apostel III trial is a nationwide multicenter randomised controlled study. Women with threatened preterm labour (gestational age 25 - 34 weeks) defined as at least 3 contractions per 30 minutes, and 1) a cervical length of ≤ 10 mm or 2) a cervical length of 11-30 mm and a positive Fibronectin test or 3) ruptured membranes will be randomly allocated to treatment with nifedipine or atosiban. Primary outcome is a composite measure of severe neonatal morbidity and mortality. Secondary outcomes will be time to delivery, gestational age at delivery, days on ventilation support, neonatal intensive care (NICU) admittance, length admission in neonatal intensive care, total days in hospital until 3 months corrected age, convulsions, apnoea, asphyxia, proven meningitis, pneumothorax, maternal side effects and costs. Furthermore, an economic evaluation of the treatment will be performed. Analysis will be by intention to treat principle. The power calculation is based on an expected 10% difference in the prevalence of adverse neonatal outcome. This implies that 500 women have to be randomised (two sided test, ß 0.2 at alpha 0.05). DISCUSSION: This trial will provide evidence on the optimal drug of choice in acute tocolysis in threatening preterm labour. CLINICAL TRIAL REGISTRATION: NTR2947, date of registration: June 20th 2011.

Sustained developmental effects of the infant behavioral assessment and intervention program in very low birth weight infants at 5.5 years corrected age.

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.

Blood pressure and anthropometrics of 4-y-old children born after preimplantation genetic screening: follow-up of a unique, moderately sized, randomized controlled trial.

BACKGROUND: Recent studies suggest that in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI) are associated with suboptimal cardiometabolic outcome in offspring. It is unknown whether preimplantation genetic screening (PGS), which involves embryo biopsy, affects blood pressure (BP), anthropometrics, and the frequency of received medical care. METHODS: In this prospective multicenter follow-up study, we assessed BP, anthropometrics, and received medical care of 4-y-old children born to women who were randomly assigned to IVF/ICSI with PGS (n = 49) or without PGS (controls; n = 64). We applied linear and generalized linear mixed-effects models to investigate possible effects of PGS. RESULTS: BP in the PGS and control groups was similar: 102/64 and 100/64 mm Hg, respectively. Main anthropometric outcomes in the PGS vs. control group were: BMI: 16.1 vs. 15.8; triceps skinfold: 108 vs. 98 mm; and subscapular skinfold: 54 vs. 53 mm (all P values > 0.05). More PGS children than controls had received paramedical care (speech, physical, or occupational therapy: 14 (29%) vs. 9 (14%); P = 0.03 in multivariable analysis). The frequency of medicial treatment was comparable. CONCLUSION: PGS does not seem to affect BP or anthropometrics in 4-y-old children. The higher frequency of received paramedical care after PGS may suggest an effect of PGS on subtle developmental parameters.

Perinatal risk factors for neurocognitive impairments in preschool children born very preterm.

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 1000 g, 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 (r(2) 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.

Clinical signs to identify late-onset sepsis in preterm infants.

UNLABELLED: 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.

Effect of maintenance tocolysis with nifedipine in threatened preterm labor on perinatal outcomes: a randomized controlled trial.

IMPORTANCE: In threatened preterm labor, maintenance tocolysis with nifedipine, after an initial course of tocolysis and corticosteroids for 48 hours, may improve perinatal outcome. OBJECTIVE: To determine whether maintenance tocolysis with nifedipine will reduce adverse perinatal outcomes due to premature birth. DESIGN, SETTING, AND PARTICIPANTS: APOSTEL-II (Assessment of Perinatal Outcome with Sustained Tocolysis in Early Labor) is a double-blind, placebo-controlled trial performed in 11 perinatal units including all tertiary centers in The Netherlands. From June 2008 to February 2010, women with threatened preterm labor between 26 weeks (plus 0 days) and 32 weeks (plus 2 days) gestation, who had not delivered after 48 hours of tocolysis and a completed course of corticosteroids, were enrolled. Surviving infants were followed up until 6 months after birth (ended August 2010). INTERVENTION: Randomization assigned 406 women to maintenance tocolysis with nifedipine orally (80 mg/d; n = 201) or placebo (n = 205) for 12 days. Assigned treatment was masked from investigators, participants, clinicians, and research nurses. MAIN OUTCOME MEASURES: Primary outcome was a composite of adverse perinatal outcomes (perinatal death, chronic lung disease, neonatal sepsis, intraventricular hemorrhage >grade 2, periventricular leukomalacia >grade 1, or necrotizing enterocolitis). Analyses were completed on an intention-to-treat basis. RESULTS: Mean (SD) gestational age at randomization was 29.2 (1.7) weeks for both groups. Adverse perinatal outcome was not significantly different between groups: 11.9% (24/201; 95% CI, 7.5%-16.4%) for nifedipine vs 13.7% (28/205; 95% CI, 9.0%-18.4%) for placebo (relative risk, 0.87; 95% CI, 0.53-1.45). CONCLUSIONS AND RELEVANCE: In patients with threatened preterm labor, nifedipine-maintained tocolysis did not result in a statistically significant reduction in adverse perinatal outcomes when compared with placebo. Although the lower than anticipated rate of adverse perinatal outcomes in the control group indicates that a benefit of nifedipine cannot completely be excluded, its use for maintenance tocolysis does not appear beneficial at this time. TRIAL REGISTRATION: trialregister.nl Identifier: NTR1336.

Prediction of cognitive abilities at the age of 5 years using developmental follow-up assessments at the age of 2 and 3 years in very preterm children.

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.

Difference in mother-child interaction between preterm- and term-born preschoolers with and without disabilities.

AIM: To investigate differences in the quality of mother-child interaction between preterm- and term-born children at age 5, and to study the association of mother-child interaction with sociodemographic characteristics and child disability. METHODS: Preterm children (n = 94), born at <30 weeks' gestation and/or birth weight <1000 g, and term children (n = 84) were assessed at corrected age of 5 using a mother-child interaction observation. Disabilities were assessed using an intelligence test, behaviour questionnaires for parents and teachers, and motor and neurological examinations. RESULTS: Mothers of preterm-born children were less supportive of and more interfering with their children's autonomy than mothers of term-born children. This difference was only partly explained by sociodemographic factors. Dyads showed a lower quality of mother-child interaction if children had a severe disability, especially when mothers had a lower level of education. CONCLUSION: Five years after birth, mother-child interaction of very premature children and their mothers compared unfavourably with term children and their mothers. Mothers with sociodemographic disadvantages, raising a preterm child with severe disabilities, struggle most with giving adequate sensitive support for the autonomy development of their child. Focused specialized support for these at risk groups is warranted.

Infant behavioral assessment and intervention program in very low birth weight infants improves independency in mobility at preschool age.

OBJECTIVE: To evaluate the effects of the Infant Behavioral Assessment and Intervention Program(©) (IBAIP) in very low birth weight infants on sensory processing and daily activities at preschool age. STUDY DESIGN: Follow-up of children included in a randomized controlled trial. Eighty-six infants were enrolled in post-discharge IBAIP until 6 months corrected age, and 90 infants received standard care. At 3.5 years of age, the Sensory Profile-Dutch version (SP-NL) and Pediatric Evaluation of Disability Inventory-Dutch version (PEDI-NL) were administered. For comparison, parents of 41 term-born children also completed the SP-NL. RESULTS: Seventy-six children (88%) in the IBAIP group and 75 children (83%) children in the control group were examined at 44 months corrected age. After adjustment for pre-randomization differences in perinatal characteristics, the IBAIP group outperformed the control group significantly on SP-NL domains of oral sensory processing and sensory processing related to endurance/tone and PEDI-NL domains of mobility. The control group only scored significantly lower than the term group on the SP-NL domain endurance/tone. The very low birth weight groups performed significantly below the PEDI-NL's norm. CONCLUSION: In line with the positive developmental effects of the IBAIP until 24 months corrected age, independency in mobility in daily activities was improved at 3.5 years.

High incidence of multi-domain disabilities in very preterm children at five years of age.

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.

A neurobehavioral intervention and assessment program in very low birth weight infants: outcome at 24 months.

OBJECTIVE: To determine whether the Infant Behavioral Assessment and Intervention Program (IBAIP) improves development and behavior in very low birth weight (VLBW) infants at 24-month corrected age. STUDY DESIGN: In a multicenter, randomized, controlled trial 86 infants received postdischarge intervention until 6-month corrected age. The intervention consisted of supporting infants' self-regulation and development, and facilitating sensitive parent-infant interactions; 90 control infants received regular care. At 6 months, positive intervention effects were found. At 24 months, development and behavior were evaluated with the Bayley Scales of Infant Development-II (BSID-II) and the Child Behavior Check List (CBCL). RESULTS: Eighty-three intervention and 78 control infants were available for follow-up. After adjustment for differences in perinatal characteristics, an intervention effect of 6.4 points (+/- standard error, 2.4) on the Psychomotor Developmental Index favored the intervention infants. Groups did not differ on the Mental Developmental Index, the Behavioral Rating Scale of the BSID-II, or on the CBCL. Subgroup analyses revealed improved motor as well as improved mental outcomes in intervention infants with bronchopulmonary dysplasia and with combined biological and social risk factors. CONCLUSIONS: The IBAIP shows sustained motor improvement in VLBW infants until 2-year corrected age.