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.

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.

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).

Deficits in vision and visual attention associated with motor performance of very preterm/very low birth weight children.

AIM: To extend understanding of impaired motor functioning of very preterm (VP)/very low birth weight (VLBW) children by investigating its relationship with visual attention, visual and visual-motor functioning. METHODS: Motor functioning (Movement Assessment Battery for Children, MABC-2; Manual Dexterity, Aiming & Catching, and Balance component), as well as visual attention (attention network and visual search tests), vision (oculomotor, visual sensory and perceptive functioning), visual-motor integration (Beery Visual Motor Integration), and neurological status (Touwen examination) were comprehensively assessed in a sample of 106 5.5-year-old VP/VLBW children. Stepwise linear regression analyses were conducted to investigate multivariate associations between deficits in visual attention, oculomotor, visual sensory, perceptive and visual-motor integration functioning, abnormal neurological status, neonatal risk factors, and MABC-2 scores. RESULTS: Abnormal MABC-2 Total or component scores occurred in 23-36% of VP/VLBW children. Visual and visual-motor functioning accounted for 9-11% of variance in MABC-2 Total, Manual Dexterity and Balance scores. Visual perceptive deficits only were associated with Aiming & Catching. Abnormal neurological status accounted for an additional 19-30% of variance in MABC-2 Total, Manual Dexterity and Balance scores, and 5% of variance in Aiming & Catching, and neonatal risk factors for 3-6% of variance in MABC-2 Total, Manual Dexterity and Balance scores. CONCLUSION: Motor functioning is weakly associated with visual and visual-motor integration deficits and moderately associated with abnormal neurological status, indicating that motor performance reflects long term vulnerability following very preterm birth, and that visual deficits are of minor importance in understanding motor functioning of VP/VLBW children.

Fetal fibronectin status and cervical length in women with threatened preterm labor and the effectiveness of maintenance tocolysis.

OBJECTIVE: To assess the effect of maintenance tocolysis in women who are at high or low risk for preterm delivery according to fetal fibronectin (fFN) status and cervical length (CL). STUDY DESIGN: We compared the risk of preterm delivery in fFN pos and fFN neg women and in women with a CL <15 mm and ≥15 mm, by using the Cox regression. Differences between the effectiveness of maintenance tocolysis in high- and low-risk women were assessed by using an interaction term. RESULTS: 122 fFN tests were taken, of which 50 were fFN pos. CL was measured in 236 women, of whom 52 women had a CL <15 mm. The median gestational age at delivery was lower in fFN pos women; fFN pos women had a higher hazard for preterm delivery at any point of time (HR 4.7; 95% CI 2.9 to 7.6). Comparable results were seen for CL. Neither fFN status nor CL did alter the effect of maintenance tocolysis, which was ineffective in the total randomized group, on the risk of preterm delivery (p for interaction = 0.87 for fFN and 0.18 for CL). CONCLUSION: Maintenance tocolytic therapy with nifedipine is ineffective and not dependent on fFN or CL status.

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.

Predictive Factors for Delivery within 7 Days after Successful 48-Hour Treatment of Threatened Preterm Labor.

Objective The aim of this study was to assess which characteristics and results of vaginal examination are predictive for delivery within 7 days, in women with threatened preterm labor after initial treatment. Study Design A secondary analysis of a randomized controlled trial on maintenance nifedipine includes women who remained undelivered after threatened preterm labor for 48 hours. We developed one model for women with premature prelabor rupture of membranes (PPROM) and one without PPROM. The predictors were identified by backward selection. We assessed calibration and discrimination and used bootstrapping techniques to correct for potential overfitting. Results For women with PPROM (model 1), nulliparity, history of preterm birth, and vaginal bleeding were included in the multivariable analysis. For women without PPROM (model 2), maternal age, vaginal bleeding, cervical length, and fetal fibronectin (fFN) status were in the multivariable analysis. Discriminative capability was moderate to good (c-statistic 0.68; 95% confidence interval [CI] 0.60-0.77 for model 1 and 0.89; 95% CI, 0.84-0.93 for model 2). Conclusion PPROM and vaginal bleeding in the current pregnancy are relevant predictive factors in all women, as are maternal age, cervical length, and fFN in women without PPROM and nulliparity, history of preterm birth in women with PPROM.

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.

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.

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.

Reliability of reagent strips for semi-quantitative measurement of glucosuria in a neonatal intensive care setting.

BACKGROUND: Glucosuria in preterm infants is often measured using a visually readable reagent strip, e.g., when monitoring total parenteral nutrition or during sepsis or when treating with corticosteroids. However, the specific circumstances in a neonatal intensive care unit (NICU), such as the use of diapers and the high temperature in incubators, could affect its reliability. OBJECTIVES: To evaluate the reliability of the semi-quantitative measurement of glucosuria under the specific circumstances of a NICU setting. METHODS: Nine hundred assessments of artificially supplemented (contrived) urine samples, intended to simulate pathological specimens, were performed under the following varying conditions: environmental temperature (21°C and 34°C); different times of contact of the urine with the diaper; and using two different methods of collecting urine from the diaper. Each reagent strip was read independently by three observers. The test strips scores were categorized as 0, 1+, 2+, 3+, or 4+ in ascending degree of glucosuria. RESULTS: Agreement was excellent under all the different conditions (temperature, weighted kappa (κ(w)) = 0.92; method of urine collection, κ(w) = 0.88; time, p = 0.266). Inter-observer reliability was very good (multi-rater κ = 0.81). The deviation between the different conditions was seldom larger than one category (2.9%). The reagent strip readings were concordant with the true urinary glucose concentrations in 79.0% of assessments. The discordance was never larger than one category. CONCLUSION: The reliability of the semi-quantitative measurement of glucosuria in newborn infants using reagent strips is good, even under the conditions of a NICU. Changes in the rating of reagent strips of more than one category are most likely to be beyond measurement error.

Thyroid hormone supplementation in preterm infants born before 28 weeks gestational age and neurodevelopmental outcome at age 36 months.

BACKGROUND: Thyroid hormones are required for normal brain maturation, and neonatal plasma thyroid hormone concentrations are low in infants less than 28 weeks gestation. It is not known whether treatment of such infants with thyroid hormone improves neurodevelopmental outcome. METHODS: At three years corrected age, mental, motor, and neurological development was assessed in infants born at less than 28 weeks gestational age who had participated in a phase 1 trial of differing doses and modes of administration of thyroid hormone. The trial's endpoints were thyroid hormone (thyroxine, T4) and thyotropin plasma concentrations in eight study arms: six treated with T4 [4, 8, and 16 µg/(kg · day)], bolus or continuous], one treated with iodine only, and one treated with placebo. Follow-up at three years was not part of the original study goals. Developmental index scores, rates of cerebral palsy (CP), and rates of adverse outcome (death or moderate to severe delay in development and/or disabling CP) were compared between the eight study groups and between groups combined by dosage level, and between infants with and without T4 supplementation. RESULTS: Of 166 randomized infants, 32 (19%) died in the neonatal period. Of the 134 survivors, follow-up results were available for 89 children (66%). Mental and motor development and rates of cerebral palsy did not differ in any of the comparisons made. CONCLUSION: In this study, no differences in neurodevelopment were found in relation to thyroid hormone treatment, but power was insufficient to detect any but very large differences.

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.

The relationship between multiple developmental difficulties in very low birth weight children at 3½ years of age and the need for learning support at 5 years of age.

This study investigated whether multiple developmental difficulties are more frequent in very low birth weight (VLBW) children than in those born full term. The association between multiple developmental difficulties assessed at 3½ years of age and educational provision for the child at 5½ years was also investigated, with 'educational provision' referring to the curriculum, school placement and the level of learning support. There were 143 VLBW children without cerebral palsy (CP) and 41 term-born peers assessed at 3½ years of age. The assessment included 6 measures of development: word comprehension, visual motor integration, visual perception, motor coordination, executive functioning and behaviour. Educational provision was determined at age 5½ years. A mildly abnormal score (score <1 standard deviation) was considered to indicate developmental difficulty. Scores from the six measures of development were analysed to determine the difficulty frequency and the presence of multiple difficulties (>1 difficulty score) in each child. This study showed that at 3½ years of age, the VLBW children had significantly more difficulty with motor coordination than their term-born peers. In addition, 27% of the VLBW children had multiple difficulties compared to 10% in the term-born group. Multiple logistic regression analyses showed that of the difficulties, impaired motor coordination was most strongly associated with the requirement for learning support two years later. Regression analyses showed that having multiple difficulties was significantly associated with the need for learning support (Odds Ratio of 3.4 (95% CI: 1.5-7.8). These results show that the presence of multiple difficulties in a VLBW child of preschool age, can impact the child's educational provision two years later.

Visual search and attention in five-year-old very preterm/very low birth weight children.

INTRODUCTION: This study aimed to establish visual search performance and attention functioning in very preterm/very low birth weight (VP/VLBW) children using novel and well established measures, and to study their contribution to intellectual functioning. METHODS: Visual search and attention network efficiency were assessed in 108 VP/VLBW children and 72 age matched term controls at 5.5 years corrected age. Visual search performance was investigated with a newly developed paradigm manipulating stimulus density and stimulus organization. Attention functioning was studied using the Attention Network Test (ANT). Intellectual functioning was measured by a short form of the Wechsler Preschool and Primary Scale of Intelligence. Data were analyzed using ANOVAs and multiple regression analyses. RESULTS: Visual search was less efficient in VP/VLBW children as compared to term controls, as indicated by increased search time (0.31 SD, p = .04) and increased error rate (0.36 SD, p = .02). In addition, VP/VLBW children demonstrated poorer executive attention as indicated by lower accuracy for the executive attention measure of the ANT (0.61 SD, p < .001). No differences were found for the alerting (0.06 SD, p = .68) and orienting attention measures (0.13 SD, p = .42). Visual search time and error rate, and executive attention, collectively, accounted for 14% explained variance in full scale IQ (R(2) = .14, p < .001). DISCUSSION: VP/VLBW children were characterized by less efficient visual search ability and reduced executive attention. Visual attention dysfunctions contributed to intelligence, suggesting the opportunity to improve intellectual functioning by using interventions programs that may enhance attention capacities.

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.

Comparing two motor assessment tools to evaluate neurobehavioral intervention effects in infants with very low birth weight at 1 year.

BACKGROUND: Infants with very low birth weight (VLBW) are at increased risk for motor deficits, which may be reduced by early intervention programs. For detection of motor deficits and to monitor intervention, different assessment tools are available. It is important to choose tools that are sensitive to evaluate the efficacy of intervention on motor outcome. OBJECTIVE: The purpose of this study was to compare the Alberta Infant Motor Scale (AIMS) and the Psychomotor Developmental Index (PDI) of the Bayley Scales of Infant Development-Dutch Second Edition (BSID-II-NL) in their ability to evaluate effects of an early intervention, provided by pediatric physical therapists, on motor development in infants with VLBW at 12 months corrected age (CA). DESIGN: This was a secondary study in which data collected from a randomized controlled trial (RCT) were used. METHODS: At 12 months CA, 116 of 176 infants with VLBW participating in an RCT on the effect of the Infant Behavioral Assessment and Intervention Program were assessed with both the AIMS and the PDI. Intervention effects on the AIMS and PDI were compared. RESULTS: Corrected for baseline differences, significant intervention effects were found for AIMS and PDI scores. The highest effect size was for the AIMS subscale sit. A significant reduction of abnormal motor development in the intervention group was found only with the AIMS. LIMITATIONS: No Dutch norms are available for the AIMS. CONCLUSIONS: The responsiveness of the AIMS to detect intervention effects was better than that of the PDI. Therefore, caution is recommended in monitoring infants with VLBW only with the PDI, and the use of both the AIMS and the Bayley Scales of Infant Development is advised when evaluating intervention effects on motor development at 12 months CA.

Assessing independency in daily activities in very preterm children at preschool age.

This study investigates whether very low birth weight (VLBW) preschoolers experience disability in daily activities and what the risk factors for disability in daily activities are. The Dutch Pediatric Evaluation of Disability Inventory (PEDI-NL) was used to detect disability in daily activities in 143 VLBW children without cerebral palsy (CP) at 44 months of corrected age (CA). Data from the psychomotor-developmental index (PDI) and the mental developmental index (MDI) of the Bayley Scales of Infant Development II (BSID II) at 24 months CA, and data relating to perinatal and socio-economic status were available. Disability in daily activities was found in 27 (19%) VLBW children without CP. High frequencies of disability were found in 19 (13%) children on the mobility domain and in 12 (8%) children on the social functioning domain. The multiple logistic regression analyses showed that low BSID II outcomes (<2 SD) were risk factors for disability in the mobility domain, but not for disability in the social functioning domain. The predictive value of the BSID II outcomes is moderate, 46% of the VLBW children with a low PDI and 44% with a low MDI developed a disability in the mobility domain. This study showed a higher frequency of disability in daily activities in VLBW preschoolers compared to term born peers. Therefore, it is suggested to assess VLBW children's performance of daily activities before they start school.