The TRUFFLE study; fetal monitoring indications for delivery in 310 IUGR infants with 2 year's outcome delivered before 32 weeks of gestation.

OBJECTIVE: In the TRUFFLE study on outcome of early fetal growth restriction women were allocated to three timing of delivery plans according to antenatal monitoring strategies based on reduced computerized cardiotocographic heart rate short term variation (c-CTG STV) , early Ductus Venosus (DV p95) or late DV (DV noA) changes. However, many infants were per protocol delivered because of 'safety net' criteria, or for maternal indications, or 'other fetal indications' or after 32 weeks of gestation when the protocol was not applied anymore. It was the objective of the present post-hoc sub-analysis to investigate the indications for delivery in relation to outcome at 2 years in infants delivered before 32 weeks, to come to a further refinement of management proposals. METHODS: we included all 310 cases of the TRUFFLE study with known outcome at 2 years corrected age and 7 perinatal and infant deaths, apart from 7 cases with an inevitable death. Data were analyzed according to the randomization allocation and specified for the intervention indication. RESULTS: overall only 32% of fetuses born alive were delivered according to the specified monitoring parameter for indication for delivery. 38% were delivered because of safety net criteria, 15% because of other fetal reasons and 15% because of maternal reasons. In the c-CTG arm 51% of infants were delivered because of reduced STV. In the DV p95 arm 34% were delivered because of an abnormal DV and in the DV no A wave arm only 10% of cases were delivered accordingly. The majority of fetuses in the DV arms delivered for safety net criteria were delivered because of spontaneous decelerations. Two year's intact survival was highest in the combined DV arms as compared to the c-CTG arm (p = 0.05 when life born, p = 0.21 including fetal death), with no difference between the DV arms. Poorer outcome in the c-CTG arm was restricted to fetuses delivered because of decelerations in the safety net subgroup. Infants delivered because of maternal reasons had the highest birth weight and a non-significant higher intact survival. CONCLUSIONS: In this sub-analysis of fetuses delivered before 32 weeks the majority of infants were delivered for other reasons than according to the allocated CTG or DV monitoring strategy. Since in the DV arms CTG criteria were used as safety net criteria, but in the c-CTG arms no DV safety net criteria were applied, we speculate that the slightly poorer outcome in the CTG arm might be explained by absence of DV data. Optimal timing of delivery of the early IUGR fetus may therefore best be achieved by monitoring them longitudinally with DV and CTG monitoring

How to monitor pregnancies complicated by fetal growth restriction and delivery below 32 weeks: a post-hoc sensitivity analysis of the TRUFFLE-study.

OBJECTIVES: In the recent TRUFFLE study it appeared that, in pregnancies complicated by fetal growth restriction (FGR) between 26 and 32 weeks, monitoring of the ductus venosus (DV) combined with computerised cardiotocography (cCTG) as a trigger for delivery, increased the chance of infant survival without neurological impairment. However, concerns in interpretation were raised as DV monitoring appeared associated with a non-significant increase in fetal death, and part of the infants were delivered after 32 weeks, after which the study protocol was no longer applied. This secondary sensitivity analysis focuses on women who delivered before 32 completed weeks, and analyses fetal death cases in detail. METHODS: We analysed the monitoring data of 317 women who delivered before 32 weeks, excluding women with absent infant outcome data or inevitable perinatal death. The association of the last monitoring data before delivery and infant outcome was assessed by multivariable analysis. RESULTS: The primary outcome (two year survival without neurological impairment) occurred more often in the two DV groups (both 83%) than in the CTG-STV group (77%), however the difference was not statistically significant (p = 0.21). Nevertheless, in surviving infants 93% was free of neurological impairment in the DV groups versus 85% in the CTG-STV group (p = 0.049). All fetal deaths (n = 7) occurred in women allocated to DV monitoring, which explains this difference. Assessment of the monitoring parameters that were obtained shortly before fetal death in these 7 cases showed an abnormal CTG in only one. Multivariable regression analysis of factors at study entry demonstrated that higher gestational age, larger estimated fetal weight 50th percentile ratio and lower U/C ratio were significantly associated with the (normal) primary outcome. Allocation to the DV groups had a smaller effect, but remained in the model (p < 0.1). Assessment of the last monitoring data before delivery showed that in the CTG-STV group abnormal fetal arterial Doppler was significantly associated with adverse outcome. In contrast, in the DV groups an abnormal DV was the only fetal monitoring parameter that was associated with adverse infant outcome, while fetal arterial Doppler, STV below CTG-group cut-off or recurrent fetal heart rate decelerations were not. CONCLUSIONS: In accordance with the results of the overall TRUFFLE study of the monitoring-intervention management of very early severe FGR we found that the difference in the proportion of infants surviving without neuroimpairment (the primary endpoint) was non-significant when comparing timing of delivery with or without changes in the DV waveform. However, the uneven distribution of fetal deaths towards the DV groups was likely by chance, and among surviving children neurological outcomes were better. Before 32 weeks, delaying delivery until abnormalities in DVPI or STV and/or recurrent decelerations occur, as defined by the study protocol, is therefore probably safe and possibly benefits long-term outcome

Effects of antenatal betamethasone on fetal Doppler indices and short term fetal heart rate variation in early growth restricted fetuses

Purpose To investigate the effects of the antenatal administration of betamethasone on fetal Doppler and short term fetal heart rate variation (CTG-STV) in early growth restricted (FGR) fetuses.Materials and Methods Post hoc analysis of data derived from the TRUFFLE study, a prospective, multicenter, randomized management trial of severe early onset FGR. Repeat Doppler and CTG-STV measurements between the last recording within 48 hours before the first dose of betamethasone (base-line value) and for 10 days after were evaluated. Multilevel analysis was performed to analyze the longitudinal course of the umbilico-cerebral ratio (UC ratio), the ductus venosus pulsatility index (DVPIV) and CTG-STV.Results We included 115 fetuses. A significant increase from baseline in CTG-STV was found on day + 1 (p = 0.019) but no difference thereafter. The DVPIV was not significantly different from baseline in any of the 10 days following the first dose of betamethasone (p = 0.167). Multilevel analysis revealed that, over 10 days, the time elapsed from antenatal administration of betamethasone was significantly associated with a decrease in CTG-STV (p = 0.045) and an increase in the DVPIV (p = 0.001) and UC ratio (p < 0.001).Conclusion Although steroid administration in early FGR has a minimal effect on increasing CTG-STV one day afterwards, the effects on Doppler parameters were extremely slight with regression coefficients of small magnitude suggesting no clinical significance, and were most likely related to the deterioration with time in FGR. Hence, arterial and venous Doppler assessment of fetal health remains informative following antenatal steroid administration to accelerate fetal lung maturation.Developmen

Early neuromotor development of high risk infants - Gross motor function in preterm and full-term born infants

This thesis is the result of 20 years follow-up of preterm and full-term born ‘graduates’ of the neonatal intensive care unit of the Wilhelmina Children’s Hospital, Utrecht. The aim was to answer questions that arose during admission and follow-up assessments. Typical gross motor development of preterm infants Gross motor development of 800 preterm infants (gestational age [GA] <32 weeks) was assessed when the children were between 1 and 19 months corrected age (CA). The scores were significantly lower compared to norm-referenced values, most likely reflecting a variant of typical gross motor development. Prediction of neuromotor outcome based on brain imaging Sequential cranial ultrasonography (cUS) until term-equivalent age (TEA) combined with conventional magnetic resonance imaging (MRI) at TEA enables us to predict motor outcome in infants born preterm as long as experienced examiners interpret the images. Persistent normal cranial ultrasonography (cUS) is predictive of a normal outcome, whereas major brain injuries can accurately predict cerebral palsy (CP). Also in infants born full-term, cUS and MRI (including diffusion-weighted imaging) are effective tools to predict CP. Specific neuromotor developmental pathways We examined the association between PVL grade and gross motor functional abilities in 59 children with CP born preterm (GA ≤34 weeks) at four timepoints in their life (between a mean of 9.5 months CA and a median of 7.5 years). Infants’ gross motor abilities varied depending on the severity of PVL. Children with PVL grade I–II were able to walk independently, whereas most infants with c-PVL grade III–V did not achieve the potential to walk. Stability of gross motor function became more robust after the first year of age. In infants born preterm (G

Individual differences in developmental trajectories of A-not-B performance in infants born preterm

Because early executive functioning is a potentially important predictor of developmental delay and learning difficulties in infants born preterm, this study assessed the effect of several perinatal predictors on the development of A-not-B performance between 7 and 14 months corrected age in 76 infants born preterm, and its relationship to subsequent global cognitive functioning. Latent Growth Modeling showed that gestational age was a predictor of initial level, and that birth weight and gender were predictors of the rate of developmental change in A-not-B performance. Moreover, initial level and rate of developmental change in A-not-B performance were predictive of global cognitive functioning

Low Cerebral Oxygenation in Preterm Infants Is Associated with Adverse Neurodevelopmental Outcome

Objective To assess whether high and low levels of cerebral oxygenation (regional cerebral oxygenation [rScO(2)]) in infants born at <32 weeks of gestation were associated with adverse long-term outcome.Study design Observational cohort study including preterm infants born at <32 weeks of gestation at the Wilhelmina Children's Hospital, The Netherlands, between April 2006 and April 2013. The rScO(2) was continuously monitored for 72 hours after birth using near-infrared spectroscopy. Outcome was assessed at 15 and 24 months of corrected age by certified investigators. An unfavorable composite outcome was defined as an outcome score below -1 SD or death. Various rScO(2) thresholds were explored.Results In total, 734 infants were eligible for analysis, 60 of whom died. Associations with an unfavorable cognitive outcome in multivariable analysis were comparable for time spent with a rScO(2) below 55% and -1.5 SD (according to published reference values), with an OR of 1.4 (CI 1.1-1.7) for 20% of time below either threshold. Results at 15 months were comparable with results at 24 months. Results were not statistically significant for thresholds defining high values of rScO(2). The composite motor outcome was not significantly related to either low or high values or rScO(2).Conclusions Low, but not high, rScO(2) was associated with an unfavorable cognitive outcome. This suggests the use of a threshold of rScO(2) <55% for future clinical studies when using adult near-infrared sensors (rScO(2) <65% for neonatal sensors, approximately).Cardiolog

Prediction of cognitive and motor outcome of preterm infants based on automatic quantitative descriptors from neonatal MR brain images

This study investigates the predictive ability of automatic quantitative brain MRI descriptors for the identification of infants with low cognitive and/or motor outcome at 2-3 years chronological age. MR brain images of 173 patients were acquired at 30 weeks postmenstrual age (PMA) (n = 86) and 40 weeks PMA (n = 153) between 2008 and 2013. Eight tissue volumes and measures of cortical morphology were automatically computed. A support vector machine classifier was employed to identify infants who exhibit low cognitive and/or motor outcome (<85) at 2-3 years chronological age as assessed by the Bayley scales. Based on the images acquired at 30 weeks PMA, the automatic identification resulted in an area under the receiver operation characteristic curve (AUC) of 0.78 for low cognitive outcome, and an AUC of 0.80 for low motor outcome. Identification based on the change of the descriptors between 30 and 40 weeks PMA (n = 66) resulted in an AUC of 0.80 for low cognitive outcome and an AUC of 0.85 for low motor outcome. This study provides evidence of the feasibility of identification of preterm infants at risk of cognitive and motor impairments based on descriptors automatically computed from images acquired at 30 and 40 weeks PMA