Comparative analysis of 2-year outcomes in GRIT and TRUFFLE trials

OBJECTIVE: To explore the effect on perinatal outcome of different fetal monitoring strategies for early-onset fetal growth restriction (FGR). METHODS: This was a cohort analysis of individual participant data from two European multicenter trials of fetal monitoring methods for FGR: the Growth Restriction Intervention Study (GRIT) and the Trial of Umbilical and Fetal Flow in Europe (TRUFFLE). All women from GRIT (n = 238) and TRUFFLE (n = 503) who were randomized between 26 and 32 weeks' gestation were included. The women were grouped according to intervention and monitoring method: immediate delivery (GRIT) or delayed delivery with monitoring by conventional cardiotocography (CTG) (GRIT), computerized CTG (cCTG) only (GRIT and TRUFFLE) or cCTG and ductus venosus (DV) Doppler (TRUFFLE). The primary outcome was survival without neurodevelopmental impairment at 2 years of age. RESULTS: Gestational age at delivery and birth weight were similar in both studies. Fetal death rate was similar between the GRIT and TRUFFLE groups, but neonatal and late death were more frequent in GRIT (18% vs 6%; P < 0.01). The rate of survival without impairment at 2 years was lowest in pregnancies that underwent immediate delivery (70% (95% CI, 61-78%)) or delayed delivery with monitoring by CTG (69% (95% CI, 57-82%)), increased in those monitored using cCTG only in both GRIT (80% (95% CI, 68-91%)) and TRUFFLE (77% (95% CI, 70-84%)), and was highest in pregnancies monitored using cCTG and DV Doppler (84% (95% CI, 80-89%)) (P < 0.01 for trend). CONCLUSIONS: This analysis supports the hypothesis that the optimal method for fetal monitoring in pregnancies complicated by early-onset FGR is a combination of cCTG and DV Doppler assessment. TRIAL REGISTRATION: GRIT ISRCTN41358726 and TRUFFLE ISRCTN56204499. © 2019 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of the International Society of Ultrasound in Obstetrics and Gynecology

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 (baseline 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

Fetal cerebral Doppler changes and outcome in late preterm fetal growth restriction: prospective cohort study

Peer reviewe

Perinatal and 2-year neurodevelopmental outcome in late preterm fetal compromise: The TRUFFLE 2 randomised trial protocol

Introduction Following the detection of fetal growth restriction, there is no consensus about the criteria that should trigger delivery in the late preterm period. The consequences of inappropriate early or late delivery are potentially important yet practice varies widely around the world, with abnormal findings from fetal heart rate monitoring invariably leading to delivery. Indices derived from fetal cerebral Doppler examination may guide such decisions although there are few studies in this area. We propose a randomised, controlled trial to establish the optimum method of timing delivery between 32 weeks and 36 weeks 6 days of gestation. We hypothesise that delivery on evidence of cerebral blood flow redistribution reduces a composite of perinatal poor outcome, death and short-term hypoxia-related morbidity, with no worsening of neurodevelopmental outcome at 2 years. Methods and analysis Women with non-anomalous singleton pregnancies 32+0 to 36+6 weeks of gestation in whom the estimated fetal weight or abdominal circumference i

Longitudinal Doppler Assessments in Late Preterm Fetal Growth Restriction

PURPOSE:  To assess the longitudinal variation of the ratio of umbilical and cerebral artery pulsatility index (UCR) in late preterm fetal growth restriction (FGR). MATERIALS AND METHODS:  A prospective European multicenter observational study included women with a singleton pregnancy, 32+ 0-36+ 6, at risk of FGR (estimated fetal weight [EFW] or abdominal circumference [AC]  40 percentile points). The primary outcome was a composite of abnormal condition at birth or major neonatal morbidity. UCR was categorized as normal (< 0.9) or abnormal (≥ 0.9). UCR was assessed by gestational age at measurement interval to delivery, and by individual linear regression coefficient in women with two or more measurements. RESULTS:  856 women had 2770 measurements; 696 (81 %) had more than one measurement (median 3 (IQR 2-4). At inclusion, 63 (7 %) a UCR ≥ 0.9. These delivered earlier and had a lower birth weight and higher incidence of adverse outcome (30 % vs. 9 %, relative risk 3.2; 95 %CI 2.1-5.0) than women with a normal UCR at inclusion. Repeated measurements after an abnormal UCR at inclusion were abnormal again in 67 % (95 %CI 55-80), but after a normal UCR the chance of finding an abnormal UCR was 6 % (95 %CI 5-7 %). The risk of composite adverse outcome was similar using the first or subsequent UCR values. CONCLUSION:  An abnormal UCR is likely to be abnormal again at a later measurement, while after a normal UCR the chance of an abnormal UCR is 5-7 % when repeated weekly. Repeated measurements do not predict outcome better than the first measurement, most likely due to the most compromised fetuses being delivered after an abnormal UCR

Comparative analysis of the 2-year outcomes in the GRIT and TRUFFLE trials

OBJECTIVE: To explore the influence on perinatal outcome of different fetal monitoring strategies for preterm fetal growth restriction (FGR). DESIGN: Cohort analysis of individual participant data from the Growth Restriction Intervention Study (GRIT) and Trial of Umbilical and Fetal Flow in Europe (TRUFFLE) studies. SETTING: European multi-centre trials. POPULATION: All women from GRIT (n=238) and TRUFFLE (n=503), randomized between 26 and 32 weeks. METHODS: Women were categorized according to their monitoring-intervention method: A. immediate delivery (from GRIT), B. delayed delivery using conventional cardiotocography (CTG, from GRIT), C. delayed delivery using computerized CTG only (cCTG, from GRIT), D delayed delivery using cCTG only (from TRUFFLE) and E. delayed delivery using cCTG and ductus venosus (DV) Doppler (from TRUFFLE). PRIMARY OUTCOME MEASURE: Survival without impairment at two years. RESULTS: Gestational age at delivery and birth weight were similar in both studies. Fetal death rate was similar between GRIT and TRUFFLE, but neonatal and late death were more frequent in GRIT (18% vs. 6%; p<0.01). The primary outcome was least common in groups A (70%; 95% confidence interval [CI] 61-78), and B (69%; 95% CI 57-82), and increased with more advanced monitoring in C (80%; 95% CI 68-91) and D (77%; 95% CI 70-84) and was highest in E (84%; 95% CI 80-89); (p trend <0.01). CONCLUSIONS: This analysis supports that fetal monitoring for early FGR can best be performed by the combination of cCTG and DV Doppler assessment. TRIAL REGISTRATION: GRIT ISRCTN41358726 and TRUFFLE ISRCTN56204499. This article is protected by copyright. All rights reserved

Fetal monitoring indications for delivery and 2‐year outcome in 310 infants with fetal growth restriction delivered before 32 weeks' gestation in the TRUFFLE study

Objective In the TRUFFLE (Trial of Randomized Umbilical and Fetal Flow in Europe) study on the outcome of early fetal growth restriction, women were allocated to one of three groups of indication for delivery according to the following monitoring strategies: (1) reduced fetal heart rate (FHR) short‐term variation (STV) on cardiotocography (CTG); (2) early changes in fetal ductus venosus (DV) waveform (DV‐p95); and (3) late changes in fetal DV waveform (DV‐no‐A). However, many infants per monitoring protocol were delivered because of safety‐net criteria, for maternal or other fetal indications, or after 32 weeks of gestation when the protocol was no longer applied. The objective of the present posthoc subanalysis was to investigate the indications for delivery in relation to 2‐year outcome in infants delivered before 32 weeks to further refine management proposals. Methods We included all 310 cases of the TRUFFLE study with known outcome at 2 years' corrected age and seven fetal deaths, excluding seven cases with inevitable perinatal death. Data were analyzed according to the allocated fetal monitoring strategy in combination with the indication for delivery. Results Overall, only 32% of liveborn infants were delivered according to the specified monitoring parameter for indication for delivery; 38% were delivered because of safety‐net criteria, 15% for other fetal reasons and 15% for maternal reasons. In the CTG‐STV group, 51% of infants were delivered because of reduced STV. In the DV‐p95 group, 34% of infants were delivered because of abnormal DV and, in the DV‐no‐A group, only 10% of infants were delivered accordingly. The majority of infants in the DV groups were delivered for the safety‐net criterion of spontaneous decelerations in FHR. Two‐year intact survival was highest in the DV groups combined compared with the CTG‐STV group (P = 0.05 for live births only, P = 0.21 including fetal death), with no difference between DV groups. A poorer outcome in the CTG‐STV group was restricted to infants delivered because of FHR decelerations in the safety‐net subgroup. Infants delivered because of maternal reasons had the highest birth weight and a non‐significantly higher intact survival. Conclusions In this subanalysis of infants delivered before 32 weeks, the majority were delivered for reasons other than the allocated monitoring strategy indication. Since, in the DV group, CTG‐STV criteria were used as a safety net but in the CTG‐STV group, no DV safety‐net criteria were applied, we speculate that the slightly poorer outcome in the CTG‐STV group might be explained by the absence of DV data. The optimal timing of delivery of fetuses with early intrauterine growth restriction may therefore be best determined by monitoring them longitudinally, with both DV and CTG monitoring

Domesticating domestication: reflections on the life of a concept

OBJECTIVES: Few data exist for counseling and perinatal management of women after an antenatal diagnosis of early-onset fetal growth restriction. Yet, the consequences of preterm delivery and its attendant morbidity for both mother and baby are far reaching. The objective of this study was to describe perinatal morbidity and mortality following early-onset fetal growth restriction based on time of antenatal diagnosis and delivery. METHODS: We report cohort outcomes for a prospective multicenter randomized management study of fetal growth restriction (Trial of Randomized Umbilical and Fetal Flow in Europe (TRUFFLE)) performed in 20 European perinatal centers between 2005 and 2010. Women with a singleton fetus at 26-32 weeks of gestation, with abdominal circumference 95(th) percentile, were recruited. The main outcome measure was a composite of fetal or neonatal death or severe morbidity: survival to discharge with severe brain injury, bronchopulmonary dysplasia, proven neonatal sepsis or necrotizing enterocolitis. RESULTS: Five-hundred and three of 542 eligible women formed the study group. Mean ± SD gestational age at diagnosis was 29 ± 1.6 weeks and mean ± SD estimated fetal weight was 881 ± 217 g; 12 (2.4%) babies died in utero. Gestational age at delivery was 30.7 ± 2.3 weeks, and birth weight was 1013 ± 321 g. Overall, 81% of deliveries were indicated by fetal condition and 97% were by Cesarean section. Of 491 liveborn babies, outcomes were available for 490 amongst whom there were 27 (5.5%) deaths and 118 (24%) babies suffered severe morbidity. These babies were smaller at birth (867 ± 251 g) and born earlier (29.6 ± 2.0 weeks). Death and severe morbidity were significantly related to gestational age, both at study entry and delivery and also with the presence of maternal hypertensive morbidity. The median time to delivery was 13 days for women without hypertension, 8 days for those with gestational hypertension, 4 days for pre-eclampsia and 3 days for HELLP syndrome. CONCLUSIONS: Fetal outcome in this study was better than expected from contemporary reports: perinatal death was uncommon (8%) and 70% survived without severe neonatal morbidity. The intervals to delivery, death and severe morbidity were related to the presence and severity of maternal hypertensive conditions