Neurodevelopmental Impairment in Children After Group B Streptococcal Disease Worldwide: Systematic Review and Meta-analyses.

BACKGROUND: Survivors of infant group B streptococcal (GBS) disease are at risk of neurodevelopmental impairment (NDI), a burden not previously systematically quantified. This is the 10th of 11 articles estimating the burden of GBS disease. Here we aimed to estimate NDI in survivors of infant GBS disease. METHODS: We conducted systematic literature reviews (PubMed/Medline, Embase, Latin American and Caribbean Health Sciences Literature [LILACS], World Health Organization Library Information System [WHOLIS], and Scopus) and sought unpublished data on the risk of NDI after invasive GBS disease in infants <90 days of age. We did meta-analyses to derive pooled estimates of the percentage of infants with NDI following GBS meningitis. RESULTS: We identified 6127 studies, of which 18 met eligibility criteria, all from middle- or high-income contexts. All 18 studies followed up survivors of GBS meningitis; only 5 of these studies also followed up survivors of GBS sepsis and were too few to pool in a meta-analysis. Of meningitis survivors, 32% (95% CI, 25%-38%) had NDI at 18 months of follow-up, including 18% (95% CI, 13%-22%) with moderate to severe NDI. CONCLUSIONS: GBS meningitis is an important risk factor for moderate to severe NDI, affecting around 1 in 5 survivors. However, data are limited, and we were unable to estimate NDI after GBS sepsis. Comparability of studies is difficult due to methodological differences including variability in timing of clinical reviews and assessment tools. Follow-up of clinical cases and standardization of methods are essential to fully quantify the total burden of NDI associated with GBS disease, and inform program priorities

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

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

How to monitor pregnancies complicated by fetal growth restriction and delivery before 32 weeks : post-hoc analysis of TRUFFLE study

Objectives: In the recent TRUFFLE study, it appeared that, in pregnancies complicated by fetal growth restriction (FGR) between 26 and 32 weeks' gestation, monitoring of the fetal ductus venosus (DV) waveform combined with computed cardiotocography (CTG) to determine timing of delivery increased the chance of infant survival without neurological impairment. However, concerns with the interpretation were raised, as DV monitoring appeared to be associated with a non-significant increase in fetal death, and some infants were delivered after 32 weeks, at which time the study protocol no longer applied. This secondary sensitivity analysis of the TRUFFLE study focuses on women who delivered before 32 completed weeks' gestation and analyzes in detail the cases of fetal death. Methods: Monitoring data of 317 pregnancies with FGR that delivered before 32 weeks were analyzed, excluding those with absent outcome data or inevitable perinatal death. Women were allocated randomly to one of three groups of indication for delivery according to the following monitoring strategies: (1) reduced fetal heart rate short-term variation (STV) on CTG; (2) early changes in fetal DV waveform; and (3) late changes in fetal DV waveform. Primary outcome was 2-year survival without neurological impairment. The association of the last monitoring data before delivery and infant outcome was assessed by multivariable analysis. Results: 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). Among the surviving infants in the DV groups, 93% were free of neurological impairment vs 85% of surviving infants in the CTG-STV group (P = 0.049). All fetal deaths (n = 7) occurred in the groups with DV monitoring. Of the monitoring parameters obtained shortly before fetal death in these seven cases, an abnormal CTG was observed in only one case. Multivariable regression analysis of factors at study entry demonstrated that a later gestational age, higher estimated fetal weight-to-50th percentile ratio and lower umbilical artery pulsatility index (PI)/fetal middle cerebral artery-PI ratio were significantly associated with normal outcome. Allocation to DV monitoring had a smaller effect on outcome, but remained in the model (P < 0.1). Abnormal fetal arterial Doppler before delivery was significantly associated with adverse outcome in the CTG-STV group. In contrast, abnormal DV flow was the only monitoring parameter associated with adverse outcome in the DV groups, while fetal arterial Doppler, STV below the cut-off used in the CTG-STV group and recurrent decelerations in fetal heart rate were not. Conclusions: In accordance with the findings of the TRUFFLE study on monitoring and intervention management of very preterm FGR, we found that the proportion of infants surviving without neuroimpairment was not significantly different when the decision for delivery was based on changes in DV waveform vs reduced STV on CTG. The uneven distribution of fetal deaths towards the DV groups was probably a chance effect, and neurological outcome was better among surviving children in these groups. Before 32 weeks, delaying delivery until abnormalities in DV-PI or STV and/or recurrent decelerations in fetal heat rate occur, as defined by the study protocol, is likely to be safe and possibly benefits long-term outcome