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] < 10th percentile, abnormal arterial Doppler or fall in AC from 20-week scan of > 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.

Child outcomes after amnioinfusion compared with no intervention in women with second-trimester rupture of membranes: a long-term follow-up study of the PROMEXIL-III trial.

OBJECTIVE: To assess the effect of transabdominal amnioinfusion or no intervention on long-term outcomes in children born after second-trimester prelabour rupture of the membranes (PROM between 16+0/7 -24+0/7  weeks) and oligohydramnios. POPULATION: Follow up of infants of women who participated in the randomised controlled trial: PPROMEXIL-III (NTR3492). METHODS: Surviving infants were invited for neurodevelopmental assessment up to 5 years of corrected age using a Bayley Scales of Infant and Toddler Development or a Wechsler Preschool and Primary Scale of Intelligence. Parents were asked to complete several questionnaires. MAIN OUTCOME MEASURES: Neurodevelopmental outcomes were measured. Mild delay was defined as -1 standard deviation (SD), severe delay as -2 SD. Healthy long-term survival was defined as survival without neurodevelopmental delay or respiratory problems. RESULTS: In the amnioinfusion group, 18/28 children (64%) died versus 21/28 (75%) in the no intervention group (relative risk 0.86; 95% confidence interval [CI] 0.60-1.22). Follow-up data were obtained from 14/17 (82%) children (10 amnioinfusion, 4 no intervention). In both groups, 2/28 (7.1%) had a mild neurodevelopmental delay. No severe delay was seen. Healthy long-term survival occurred in 5/28 children (17.9%) after amnioinfusion versus 2/28 (7.1%) after no intervention (odds ratio 2.50; 95% CI 0.53-11.83). When analysing data for all assessed survivors, 10/14 (71.4%) survived without mild neurodevelopmental delay and 7/14 (50%) were classified healthy long-term survivor. CONCLUSIONS: In this small sample of women suffering second-trimester PROM and oligohydramnios, amnioinfusion did not improve long-term outcomes. Overall, 71% of survivors had no neurodevelopmental delay. TWEETABLE ABSTRACT: Healthy long-term survival was comparable for children born after second-trimester PROM and treatment with amnioinfusion or no intervention.

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

OBJECTIVES: To explore the association between fetal umbilical and middle cerebral artery (MCA) Doppler abnormalities and outcome in late preterm pregnancies at risk of fetal growth restriction. METHODS: This was a prospective cohort study of singleton pregnancies at risk of fetal growth restriction at 32 + 0 to 36 + 6 weeks of gestation, enrolled in 33 European centers between 2017 and 2018, in which umbilical and fetal MCA Doppler velocimetry was performed. Pregnancies were considered at risk of fetal growth restriction if they had estimated fetal weight and/or abdominal circumference (AC) < 10th percentile, abnormal arterial Doppler and/or a fall in AC growth velocity of more than 40 percentile points from the 20-week scan. Composite adverse outcome comprised both immediate adverse birth outcome and major neonatal morbidity. Using a range of cut-off values, the association of MCA pulsatility index and umbilicocerebral ratio (UCR) with composite adverse outcome was explored. RESULTS: The study population comprised 856 women. There were two (0.2%) intrauterine deaths. Median gestational age at delivery was 38 (interquartile range (IQR), 37-39) weeks and birth weight was 2478 (IQR, 2140-2790) g. Compared with infants with normal outcome, those with composite adverse outcome (n = 93; 11%) were delivered at an earlier gestational age (36 vs 38 weeks) and had a lower birth weight (1900 vs 2540 g). The first Doppler observation of MCA pulsatility index < 5th percentile and UCR Z-score above gestational-age-specific thresholds (1.5 at 32-33 weeks and 1.0 at 34-36 weeks) had the highest relative risks (RR) for composite adverse outcome (RR 2.2 (95% CI, 1.5-3.2) and RR 2.0 (95% CI, 1.4-3.0), respectively). After adjustment for confounders, the association between UCR Z-score and composite adverse outcome remained significant, although gestational age at delivery and birth-weight Z-score had a stronger association. CONCLUSION: In this prospective multicenter study, signs of cerebral blood flow redistribution were found to be associated with adverse outcome in late preterm singleton pregnancies at risk of fetal growth restriction. Whether cerebral redistribution is a marker describing the severity of fetal growth restriction or an independent risk factor for adverse outcome remains unclear, and whether it is useful for clinical management can be answered only in a randomized trial. © 2020 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of the International Society of Ultrasound in Obstetrics and Gynecology.

Can nature conservation and wood production be reconciled in managed forests? A review of driving factors for integrated forest management in Europe.

Integrated forest management (IFM) can help reconcile critical trade-offs between goals in forest management, such as nature conservation and biomass production. The challenge of IFM is dealing with these trade-offs at the level of practical forest management, such as striving for compromises between biomass extraction and habitat retention. This paper reviews some of the driving factors that influence the integration of nature conservation into forest management. The review was conducted in three steps - a literature review, an expert workshop and an expert-based cooperative analysis. Of 38 driving factors identified, three were prioritised by more of the participants than any of the others: two are socio-cultural factors, identity (how people identify with forest) as well as outreach and education, and one is economic - competitiveness in forest value chains. These driving factors correspond to what are considered in the literature as enablers for IFM. The results reveal that targeted, group-oriented, adaptive and innovative policy designs are needed to integrate nature conservation into forest management. Further, the results reveal that a "one-size-fits-all" governance approach would be ineffective, implying that policy instruments need to consider contextually specific driving factors. Understanding the main driving factors and their overall directions can help to better manage trade-offs between biodiversity conservation and biomass production in European forests.

Vaginal delivery in women with a low-lying placenta: a systematic review and meta-analysis.

BACKGROUND: Low-lying placentas are positioned close to the internal os of the cervix. The preferred way of delivery within this group is unclear. OBJECTIVES: To review the literature on the success of a vaginal delivery with a low-lying placenta. SEARCH STRATEGY: We searched OVID EMBASE and MEDLINE for studies on vaginal delivery with a low-lying placenta. DATA COLLECTION AND ANALYSES: Data was extracted on successful vaginal delivery and emergency caesarean section due to haemorrhage. We distinguished between different distances between the cervical os and the placenta (internal os distance, IOD); 0-10, 11-20, and >20 mm. A meta-analysis of proportions was made for successful vaginal delivery and emergency caesarean section at every cut-off value. Maternal morbidity (i.e. antepartum blood loss, postpartum haemorrhage and blood transfusion) at different cut-off values was evaluated. MAIN RESULTS: Of the 999 articles retrieved, 10 articles met our inclusion criteria. A vaginal delivery was successful at an IOD of 0-10 mm in 43%, at an IOD of 11-20 mm in 85%, and at an IOD of >20 mm in 82%. A shorter IOD had a higher chance of antepartum haemorrhage, whereas a larger IOD needed postpartum blood transfusion more often. Postpartum haemorrhage did not depend on IOD. CONCLUSION: A low-lying placenta is not a contraindication for a trial of labour, and the morbidity in these women is not increased. However, women with a low-lying placenta have a higher chance of an emergency caesarean section compared with women with a placenta outside the lower uterine segment. Therefore, shared decision-making is mandatory in case of a trial of labour. TWEETABLE ABSTRACT: This systematic review demonstrates the possibility of a vaginal delivery in women with a low-lying placenta within 20 mm of the cervix.

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. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd.

Longitudinal study of computerized cardiotocography in early fetal growth restriction.

OBJECTIVES: To explore whether, in early fetal growth restriction (FGR), the longitudinal pattern of fetal heart rate (FHR) short-term variation (STV) can be used to identify imminent fetal distress and whether abnormalities of FHR recordings are associated with 2-year infant outcome. METHODS: The original TRUFFLE study assessed whether, in early FGR, delivery based on ductus venosus (DV) Doppler pulsatility index (PI), in combination with safety-net criteria of very low STV on cardiotocography (CTG) and/or recurrent FHR decelerations, could improve 2-year infant survival without neurological impairment in comparison with delivery based on CTG monitoring only. This was a secondary analysis of women who delivered before 32 weeks and had consecutive STV data recorded > 3 days before delivery and known infant outcome at 2 years of age. Women who received corticosteroids within 3 days of delivery were excluded. Individual regression line algorithms of all STV values, except the last one before delivery, were calculated. Life tables and Cox regression analysis were used to calculate the daily risk for low STV or very low STV and/or FHR decelerations (below DV group safety-net criteria) and to assess which parameters were associated with this risk. Furthermore, it was assessed whether STV pattern, last STV value or recurrent FHR decelerations were associated with 2-year infant outcome. RESULTS: One hundred and forty-nine women from the original TRUFFLE study met the inclusion criteria. Using the individual STV regression lines, prediction of a last STV below the cut-off used by the CTG monitoring group had sensitivity of 42% and specificity of 91%. For each day after study inclusion, the median risk for low STV (CTG group cut-off) was 4% (interquartile range (IQR), 2-7%) and for very low STV and/or recurrent FHR decelerations (below DV group safety-net criteria) was 5% (IQR, 4-7%). Measures of STV pattern, fetal Doppler (arterial or venous), birth-weight multiples of the median and gestational age did not usefully improve daily risk prediction. There was no association of STV regression coefficients, a low last STV and/or recurrent FHR decelerations with short- or long-term infant outcomes. CONCLUSION: The TRUFFLE study showed that a strategy of DV monitoring with safety-net criteria of very low STV and/or recurrent FHR decelerations for delivery indication could increase 2-year infant survival without neurological impairment. This post-hoc analysis demonstrates that, in early FGR, the daily risk of abnormal CTG, as defined by the DV group safety-net criteria, is 5%, and that prediction is not possible. This supports the rationale for CTG monitoring more often than daily in these high-risk fetuses. Low STV and/or recurrent FHR decelerations were not associated with adverse infant outcome and it appears safe to delay intervention until such abnormalities occur, as long as DV-PI is within normal range. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd.

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. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.

Incidence of and risk indicators for vasa praevia: a systematic review.

BACKGROUND: Vasa praevia (VP) is a rare phenomenon that is assumed to increase the risk of severe complications, including fetal death. Critical data on its incidence are lacking, so there is no rational basis for prenatal screening. OBJECTIVES: To review the literature on the incidence and risk indicators for VP. SEARCH STRATEGY: We searched OVID MEDLINE, OVID EMBASE, the Cochrane Library and PubMed for case-control and cohort studies on incidence and risk indicators for VP. SELECTION CRITERIA: Two reviewers selected studies and scored their methodological quality. DATA COLLECTION AND ANALYSIS: We calculated the mean incidence of VP. We constructed 2 × 2 tables cross-classifying potential risk indicators against the incidence of VP to calculate common odds ratios and 95% confidence intervals, using the Mantel-Haenszel method. MAIN RESULTS: We included 13 studies (two prospective cohort studies, ten retrospective cohort studies and one case-control study) reporting on 569 410 patients with 325 cases of VP. Based on ten included cohort studies providing information on the incidence, the mean incidence of VP was 0.60 per 1000 pregnancies. We identified five different risk indicators and markers for VP: second-trimester placenta praevia, conception by assisted reproductive technologies, a bilobed or succenturiate placenta, umbilical cord insertion in the lower third part of the uterus at first-trimester ultrasound and velamentous cord insertion. Almost 83% of the cases of VP had one or more risk indicators. AUTHORS' CONCLUSIONS: In view of the low incidence, screening for VP in an unselected population is not advised. Targeted screening of women with one or more risk indicators as a part of routine mid-gestation scanning should be considered. TWEETABLE ABSTRACT: Vasa praevia is more common in placenta praevia, conception by ART, velamentous cord insertion and bilobed placenta.

Planning the mode of delivery for twin pregnancies: A web-based questionnaire.

Using orthogonal design, we created a questionnaire containing 16 cases of twin pregnancies. For each case, respondents indicated whether they would plan a vaginal delivery (VD) or a caesarean section (CS). We assessed the association between each variable (maternal age, parity, mode of conception, gestational age, chorionicity, body mass index, foetal growth, foetal presentation and wish for additional children) and the planned mode of delivery. A VD was planned mostly for vertex presentation of twin A (vertex-vertex vs. non-vertex-vertex, odds ratio [OR]: 0.002, 95% confidence interval [CI]: 0.001-0.003, p < 0.001). For vertex- non-vertex (vs. vertex-vertex) presentation, chances on planning a VD decreased threefold (OR: 0.29, 95% CI: 0.018-0.46, p < 0.001), although the majority of respondents would still plan a VD. In multiparous (vs. nulliparous) women, VD was chosen more often (OR: 3.24, 95% CI: 2.50-4.18, p < 0.001).Vertex presentation of twin A and multiparity were the main reasons for planning a VD.

Remifentanil PCIA during labor and delivery: can we improve maternal monitoring?.

BACKGROUND: Remifentanil patient controlled intravenous analgesia (PCIA) during labor has rapidly gained popularity. Its pharmacological profile makes it suitable for this indication. However, remifentanil is a potent respiratory depressant that might cause serious maternal hypoventilation, respiratory arrest and desaturation. METHODS: In the present study we compared standard monitoring of parturients (saturation measurements and visual respiratory rate measurements at set times) with continuous monitoring. Data of patients in the standard monitoring group were collected from handwritten charts containing oxygen saturation and respiratory rate. The patients in the continuous monitoring group were connected to a device that measures the oxygen saturation and respiratory rate every two seconds and automatically saves the data. These data were analyzed retrospectively. RESULTS: In the standard monitoring group 1 patient (1%) had severe desaturation SpO2 < 80%, 22 patients (25%) had SpO2 < 94% and in no patient a respiratory rate (RR) < 8/min was recorded. In the continuous monitoring group 20 patients (33%) showed SpO2 < 80%, 58 patients (97%) SpO2 < 94% and 38 patients (63%) had bradypnea (RR < 8/min). The analysis of the data of the continuous monitoring group showed severe desaturations and serious respiratory depression. CONCLUSION: The standard intermittent monitoring strategy dramatically underestimated the incidence of both bradypnea and oxygen desaturations with undetected hypoxemia and possible complications as a consequence. During use of remifentanil PCIA one-to-one midwifery care is advised. When obstetric caregivers are not present in the immediate vicinity of the parturient, high quality continuous monitoring, remote alarm notification and readiness for immediate corrective intervention are essential for safe use of this analgesic strategy.

Systematic review of accuracy of ultrasound in the diagnosis of vasa previa.

OBJECTIVE: Vasa previa is an obstetric complication in which the fetal blood vessels lie outside the chorionic plate in close proximity to the internal cervical os. In women with vasa previa, the risk of rupture of these vessels is increased, thus potentially causing fetal death or serious morbidity. Our objective was to assess the accuracy of ultrasound in the prenatal diagnosis of vasa previa. METHODS: We searched MEDLINE, EMBASE, the Cochrane Library and PubMed for studies on vasa previa. Two reviewers independently selected studies on the accuracy of ultrasound in the diagnosis of vasa previa. The studies were scored on methodological quality using the Quality Assessment of Diagnostic Accuracy Studies tool (QUADAS-2). Data on sensitivity and specificity were subsequently extracted. RESULTS: The literature search revealed 583 articles, of which two prospective and six retrospective cohort studies were eligible for inclusion in the qualitative analysis. All studies documented methods suitable for the prenatal diagnosis of vasa previa. Four out of the eight studies used transvaginal ultrasound (TVS) for primary evaluation, while the remaining four studies used transabdominal ultrasound and performed a subsequent TVS when vasa previa was suspected. The QUADAS-2 tool reflected poor methodology in six of the eight included studies, and prenatal detection rates varied from 53% (10/19) to 100% (total of 442,633 patients, including 138 cases of vasa previa). In the two prospective studies (n = 33,795, including 11 cases of vasa previa), transvaginal color Doppler performed during the second trimester detected all cases of vasa previa (sensitivity, 100%) with a specificity of 99.0-99.8%. CONCLUSION: The accuracy of ultrasound in the diagnosis of vasa previa is high when performed transvaginally in combination with color Doppler.

Ultrasonographic prediction of birth weight discordance in twin pregnancies.

OBJECTIVE: This study aimed to assess the accuracy of the ultrasonographic prediction of intertwin birth weight discordance based on crown-rump length, estimated fetal weight (EFW) and abdominal circumference. METHOD: We retrospectively studied variables of prenatal surveillance of 281 twin pregnancies at the University Medical Centre Utrecht, between 2008 and 2011. RESULTS: Fifteen per cent of twins had a birth weight discordance of ≥20%. One twin more commonly had intrauterine growth restriction in the birth weight discordance group compared with the concordantly grown group (69% vs 20%, respectively). Sonographically, EFW discrepancy and increased abdominal circumference ratio were significantly correlated with birth weight discordance. The negative predictive values were high (92% and 87%, respectively). The best prediction of weight discordance was given by EFW discordance at the last ultrasound before delivery. CONCLUSION: Intertwin birth weight discordance is best predicted by an intertwin EFW discordance at the last ultrasound. If discordance is not suspected by ultrasound, the vast majority had no birth weight discordance. In case of birth weight discordance, the presence of at least one growth-restricted twin is very likely. However, because around 20% of concordantly grown twin pairs comprise at least one intrauterine growth restriction infant, one cannot rely on weight discordance alone.

Assessment of the current and emerging criteria for the histopathological classification of lung neuroendocrine tumours in the lungNENomics project.

BACKGROUND: Six thoracic pathologists reviewed 259 lung neuroendocrine tumours (LNETs) from the lungNENomics project, with 171 of them having associated survival data. This cohort presents a unique opportunity to assess the strengths and limitations of current World Health Organization (WHO) classification criteria and to evaluate the utility of emerging markers. PATIENTS AND METHODS: Patients were diagnosed based on the 2021 WHO criteria, with atypical carcinoids (ACs) defined by the presence of focal necrosis and/or 2-10 mitoses per 2 mm2. We investigated two markers of tumour proliferation: the Ki-67 index and phospho-histone H3 (PHH3) protein expression, quantified by pathologists and automatically via deep learning. Additionally, an unsupervised deep learning algorithm was trained to uncover previously unnoticed morphological features with diagnostic value. RESULTS: The accuracy in distinguishing typical from ACs is hampered by interobserver variability in mitotic counting and the limitations of morphological criteria in identifying aggressive cases. Our study reveals that different Ki-67 cut-offs can categorise LNETs similarly to current WHO criteria. Counting mitoses in PHH3+ areas does not improve diagnosis, while providing a similar prognostic value to the current criteria. With the advantage of being time efficient, automated assessment of these markers leads to similar conclusions. Lastly, state-of-the-art deep learning modelling does not uncover undisclosed morphological features with diagnostic value. CONCLUSIONS: This study suggests that the mitotic criteria can be complemented by manual or automated assessment of Ki-67 or PHH3 protein expression, but these markers do not significantly improve the prognostic value of the current classification, as the AC group remains highly unspecific for aggressive cases. Therefore, we may have exhausted the potential of morphological features in classifying and prognosticating LNETs. Our study suggests that it might be time to shift the research focus towards investigating molecular markers that could contribute to a more clinically relevant morpho-molecular classification.

Perinatal morbidity and mortality in early-onset fetal growth restriction: cohort outcomes of the trial of randomized umbilical and fetal flow in Europe (TRUFFLE).

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 < 10(th) percentile and umbilical artery Doppler pulsatility index > 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.

Perinatal mortality and mode of delivery in monochorionic diamniotic twin pregnancies ≥ 32 weeks of gestation: a multicentre retrospective cohort study.

OBJECTIVE: To study perinatal mortality rates in a cohort of 465 monochorionic (MC) twins without twin-twin transfusion syndrome (TTS) born at 32 weeks of gestation or later since reported interauterine fetal death (IUFD) rates >32 weeks of gestations in the literature vary, leading to varying recommendations on the optimal timing of delivery, and to investigate the relation between perinatal mortality and mode of delivery. DESIGN: Multicentre retrospective cohort study. SETTING: Ten perinatal referral centres in the Netherlands. POPULATION: All MC twin pregnancies without TTTS delivered at ≥ 32 weeks of gestation between January 2000 and December 2005. METHODS: The medical records of all MC twin pregnancies without TTTS delivered at the ten perinatal referral centres in the Netherlands between January 2000 and December 2005 were reviewed. MAIN OUTCOME MEASURES: Perinatal mortality in relation to gestational age and mode of delivery at ≥ 32 weeks of gestation. RESULTS: After 32 weeks of gestation, five out of 930 fetuses died in utero and there were six neonatal deaths (6 per 1000 infants). In women who delivered ≥ 37 weeks, perinatal mortality was 7 per 1000 infants. Trial of labour was attempted in 376 women and was successful in 77%. There were three deaths in deliveries with a trial of labour (8 per 1000 deliveries), of which two were related to mode of delivery. Infants born by caesarean section without labour had an increased risk of neonatal morbidity and respiratory distress syndrome. CONCLUSIONS: In MC twin pregnancies the incidence of intrauterine fetal death is low ≥ 32 weeks of gestation. Therefore, planned preterm delivery before 36 weeks does not seem to be justified. The risk of intrapartum death is also low, at least in tertiary centres.

Non-invasively measured brain activity and radiological progression in diffuse glioma.

Non-invasively measured brain activity is related to progression-free survival in glioma patients, suggesting its potential as a marker of glioma progression. We therefore assessed the relationship between brain activity and increasing tumor volumes on routine clinical magnetic resonance imaging (MRI) in glioma patients. Postoperative magnetoencephalography (MEG) was recorded in 45 diffuse glioma patients. Brain activity was estimated using three measures (absolute broadband power, offset and slope) calculated at three spatial levels: global average, averaged across the peritumoral areas, and averaged across the homologues of these peritumoral areas in the contralateral hemisphere. Tumors were segmented on MRI. Changes in tumor volume between the two scans surrounding the MEG were calculated and correlated with brain activity. Brain activity was compared between patient groups classified into having increasing or stable tumor volume. Results show that brain activity was significantly increased in the tumor hemisphere in general, and in peritumoral regions specifically. However, none of the measures and spatial levels of brain activity correlated with changes in tumor volume, nor did they differ between patients with increasing versus stable tumor volumes. Longitudinal studies in more homogeneous subgroups of glioma patients are necessary to further explore the clinical potential of non-invasively measured brain activity.

Predictors of outcome at 2 years of age after early intrauterine growth restriction.

OBJECTIVE: To examine the relative importance of antenatal and perinatal variables on short- and long-term outcome of preterm growth restricted fetuses with umbilical artery (UA) Doppler abnormalities. METHODS: This was a cohort study of 180 neonates with birth weight < 10(th) percentile, gestational age at delivery < 34 weeks and abnormal Doppler ultrasound examination of the UA. Various antenatal and perinatal variables were studied in relation to short- and long-term outcome. RESULTS: Neonatal and overall mortality (up to 2 years of age) were predicted by low gestational age at delivery. Neonatal mortality was additionally predicted by absent or reversed UA end-diastolic flow, while the presence of severe neonatal complications and placental villitis were additional predictors of both infant (between 28 days and 1 year of postnatal life) and overall mortality. Placental villitis was found to be the only predictor of necrotizing enterocolitis. Low gestational age at delivery, male sex, abnormal cardiotocography, absent or reversed UA end-diastolic flow and the HELLP syndrome predicted respiratory distress syndrome. Abnormal neurodevelopmental outcome at 2 years was predicted by low birth weight (< 2.3(rd) percentile), fetal acidosis (UA pH < 7.00), and placental villitis. CONCLUSION: Less advanced gestation at delivery remains an important predictor of short-term outcome in growth-restricted fetuses. In addition, the presence of placental villitis may aid neonatologists in the early identification of infants at increased risk of necrotizing enterocolitis, death and abnormal neurodevelopment at 2 years of age. Abnormal neurodevelopment was related to low weight and acidosis at birth, indicating that the severity of malnutrition and fetal acidosis affect long-term outcome.

Pulmonary neuroendocrine neoplasms with well differentiated morphology and high proliferative activity: illustrated by a case series and review of the literature.

OBJECTIVES: Pulmonary neuroendocrine neoplasms (NENs) are subdivided in carcinoids and neuroendocrine carcinomas (small cell lung carcinoma and large cell neuroendocrine carcinoma (LCNEC)), based on the presence of necrosis and mitotic index (MI). However, it is unclear if tumors with well differentiated morphology but high proliferation rate should be regarded as LCNEC or as high grade carcinoids. In previous case series, a longer overall survival then expected in LCNEC has been suggested. We describe 7 of those cases analyzed for pRb expression and overall survival. MATERIAL AND METHODS: Cases with well differentiated morphology, but MI > 10/2mm2 and/or Ki-67 proliferation index >20% were selected based on pathology reports of consecutive NENs in our university medical center (Maastricht UMC+, 2007-2018) and confirmed by pathological review. Immunohistochemistry was performed to assess pRb expression. RESULTS: Seven stage IV cases were included in this study. Median overall survival was 8 months (95% confidence interval 5-11 months). Cases with well differentiated morphology and preserved pRb expression (4/7) had a median overall survival of 45 months. CONCLUSION: A subgroup of pulmonary NENs with well differentiated morphology but high proliferation rate likely exists. pRb staining might be helpful to predict prognosis, but clinical relevance remains to be studied.