Maternal PlGF and umbilical Dopplers predict pregnancy outcomes at diagnosis of early-onset fetal growth restriction.

BACKGROUNDSevere, early-onset fetal growth restriction (FGR) causes significant fetal and neonatal mortality and morbidity. Predicting the outcome of affected pregnancies at the time of diagnosis is difficult, thus preventing accurate patient counseling. We investigated the use of maternal serum protein and ultrasound measurements at diagnosis to predict fetal or neonatal death and 3 secondary outcomes: fetal death or delivery at or before 28+0 weeks, development of abnormal umbilical artery (UmA) Doppler velocimetry, and slow fetal growth.METHODSWomen with singleton pregnancies (n = 142, estimated fetal weights [EFWs] below the third centile, less than 600 g, 20+0 to 26+6 weeks of gestation, no known chromosomal, genetic, or major structural abnormalities) were recruited from 4 European centers. Maternal serum from the discovery set (n = 63) was analyzed for 7 proteins linked to angiogenesis, 90 additional proteins associated with cardiovascular disease, and 5 proteins identified through pooled liquid chromatography and tandem mass spectrometry. Patient and clinician stakeholder priorities were used to select models tested in the validation set (n = 60), with final models calculated from combined data.RESULTSThe most discriminative model for fetal or neonatal death included the EFW z score (Hadlock 3 formula/Marsal chart), gestational age, and UmA Doppler category (AUC, 0.91; 95% CI, 0.86-0.97) but was less well calibrated than the model containing only the EFW z score (Hadlock 3/Marsal). The most discriminative model for fetal death or delivery at or before 28+0 weeks included maternal serum placental growth factor (PlGF) concentration and UmA Doppler category (AUC, 0.89; 95% CI, 0.83-0.94).CONCLUSIONUltrasound measurements and maternal serum PlGF concentration at diagnosis of severe, early-onset FGR predicted pregnancy outcomes of importance to patients and clinicians.TRIAL REGISTRATIONClinicalTrials.gov NCT02097667.FUNDINGThe European Union, Rosetrees Trust, Mitchell Charitable Trust.

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 is <10th percentile or has decreased by 50 percentiles since 18-32 weeks will be included for observational data collection. Participants will be randomised if cerebral blood flow redistribution is identified, based on umbilical to middle cerebral artery pulsatility index ratio values. Computerised cardiotocography (cCTG) must show normal fetal heart rate short term variation (≥4.5 msec) and absence of decelerations at randomisation. Randomisation will be 1:1 to immediate delivery or delayed delivery (based on cCTG abnormalities or other worsening fetal condition). The primary outcome is poor condition at birth and/or fetal or neonatal death and/or major neonatal morbidity, the secondary non-inferiority outcome is 2-year infant general health and neurodevelopmental outcome based on the Parent Report of Children's Abilities-Revised questionnaire. ETHICS AND DISSEMINATION: The Study Coordination Centre has obtained approval from London-Riverside Research Ethics Committee (REC) and Health Regulatory Authority (HRA). Publication will be in line with NIHR Open Access policy. TRIAL REGISTRATION NUMBER: Main sponsor: Imperial College London, Reference: 19QC5491. Funders: NIHR HTA, Reference: 127 976. Study coordination centre: Imperial College Healthcare NHS Trust, Du Cane Road, London, W12 0HS with Centre for Trials Research, College of Biomedical & Life Sciences, Cardiff University. IRAS Project ID: 266 400. REC reference: 20/LO/0031. ISRCTN registry: 76 016 200.

Development of standard definitions and grading for Maternal and Fetal Adverse Event Terminology.

OBJECTIVE: Adverse event (AE) monitoring is central to assessing therapeutic safety. The lack of a comprehensive framework to define and grade maternal and fetal AEs in pregnancy trials severely limits understanding risks in pregnant women. We created AE terminology to improve safety monitoring for developing pregnancy drugs, devices and interventions. METHOD: Existing severity grading for pregnant AEs and definitions/indicators of 'severe' and 'life-threatening' conditions relevant to maternal and fetal clinical trials were identified through a literature search. An international multidisciplinary group identified and filled gaps in definitions and severity grading using Medical Dictionary for Regulatory Activities (MedDRA) terms and severity grading criteria based on Common Terminology Criteria for Adverse Event (CTCAE) generic structure. The draft criteria underwent two rounds of a modified Delphi process with international fetal therapy, obstetric, neonatal, industry experts, patients and patient representatives. RESULTS: Fetal AEs were defined as being diagnosable in utero with potential to harm the fetus, and were integrated into MedDRA. AE severity was graded independently for the pregnant woman and her fetus. Maternal (n = 12) and fetal (n = 19) AE definitions and severity grading criteria were developed and ratified by consensus. CONCLUSIONS: This Maternal and Fetal AE Terminology version 1.0 allows systematic consistent AE assessment in pregnancy trials to improve safety.

[High prenatal detection rates of complex congenital heart defects (CHD)]. / Fler medfödda hjärtfel upptäcks med utökad screening i tre steg.

AIM: To analyze prenatal detection rates of complex CHD after the implementation of an expanded three-tiered screening model at the Skane University Hospitals in Lund and Malmö in 2015.  Methods: Retrospective review of pregnancies screened from January 1, 2015 and being born by June 30, 2018. Complex CHD was defined as needing intervention in the first year of life.  Results: In 27675 screened pregnancies, 51 out of 65 (78 %) cases of complex CHD were detected prenatally. Exclusion of isolated ventricular septal defects yielded detection rates of 93 %. All patients needing surgery within 30 days, potential univentricular hearts and D-transposition of the great arteries were identified, whilst detection rates for tetralogy of Fallot, atrioventricular septal defect and coarctation were about 90 %. CONCLUSION: Our three-tiered model results in high detection rates of complex CHD with optimized resource utilization.

Cerebroplacental ratio as predictor of adverse perinatal outcome in the third trimester.

INTRODUCTION: Fetal growth restriction is associated with adverse perinatal outcome and the clinical management of these pregnancies is a challenge. The aim of this study was to investigate the potential of cerebroplacental ratio (CPR) to predict adverse perinatal outcome in high-risk pregnancies in the third trimester. Another aim was to study whether the CPR has better predictive value than its components, middle cerebral artery (MCA) pulsatility index (PI) and umbilical artery (UA) PI. MATERIAL AND METHODS: The study was a retrospective cohort study including 1573 singleton high-risk pregnancies with Doppler examinations performed at 32+0 to 40+6 gestational weeks at Lund University Hospital and the University Hospital of Malmö between 29 December 1994 and 31 December 2017. Receiver operating characteristics (ROC) curves were used to investigate the predictive value of the gestational age-specific z-scores for CPR, UA PI and MCA PI, respectively, for the primary outcome "perinatal asphyxia/mortality" and the secondary outcomes "birthweight small for gestational age (SGA)" and two composite outcomes: "appropriate for gestational age/large for gestational age liveborn infants with neonatal morbidity" and "SGA liveborn infants with neonatal morbidity." RESULTS: The performance in predicting perinatal asphyxia/mortality was poor for all three variables and did not differ significantly. The ROC area under curve (AUC) was 0.56, 0.55 and 0.53 for CPR, UA PI and MCA PI z-scores, respectively. The ROC AUC for CPR z-scores to predict SGA was 0.73, significantly higher than that for either UA PI or MCA PI (P < .001). The ability of CPR and the MCA PI to predict appropriate for gestational age/large for gestational age infant morbidity and SGA infant morbidity was similar and significantly better than UA PI (P < .001). CONCLUSIONS: In the present study, none of the three Doppler measures proved to be useful in predicting perinatal asphyxia and mortality. CPR and MCA PI were equally good in predicting neonatal morbidity, especially in SGA pregnancies, and both were significantly better predictors than the UA PI. CPR had a high predictive value for SGA at birth, better than that of its two components, UA PI and MCA PI.

Absence of GP130 cytokine receptor signaling causes extended Stüve-Wiedemann syndrome.

The gene IL6ST encodes GP130, the common signal transducer of the IL-6 cytokine family consisting of 10 cytokines. Previous studies have identified cytokine-selective IL6ST defects that preserve LIF signaling. We describe three unrelated families with at least five affected individuals who presented with lethal Stüve-Wiedemann-like syndrome characterized by skeletal dysplasia and neonatal lung dysfunction with additional features such as congenital thrombocytopenia, eczematoid dermatitis, renal abnormalities, and defective acute-phase response. We identified essential loss-of-function variants in IL6ST (a homozygous nonsense variant and a homozygous intronic splice variant with exon skipping). Functional tests showed absent cellular responses to GP130-dependent cytokines including IL-6, IL-11, IL-27, oncostatin M (OSM), and leukemia inhibitory factor (LIF). Genetic reconstitution of GP130 by lentiviral transduction in patient-derived cells reversed the signaling defect. This study identifies a new genetic syndrome caused by the complete lack of signaling of a whole family of GP130-dependent cytokines in humans and highlights the importance of the LIF signaling pathway in pre- and perinatal development.

Underlying maternal and pregnancy-related conditions account for a substantial proportion of neonatal morbidity in late preterm infants.

AIM: We studied the impact of maternal and pregnancy-related conditions and the effect of gestational age itself, on the health of infants born late preterm. METHODS: Singletons born in gestational weeks 34 + 0 to 41 + 6 in 1995-2013 in the southern region of Sweden were identified from a perinatal register. We found 14 030 infants born late preterm and 294 814 born at term. A hierarchical system was developed to examine the impact of pregnancy complications. The outcomes studied were as follows: neonatal death, central nervous system (CNS) or respiratory disease, infection, neonatal admission and respiratory support. Odds ratios (OR) and 95% confidence intervals (95% CI) were obtained using logistic regression analyses. RESULTS: Late preterm infants were at increased risk for all outcomes compared to term infants, with adjusted ORs from 13.1 (95% CI: 12.7-13.6) for neonatal admission to 2.3 (95% CI: 1.8-2.9) for infections. Late preterm birth after preterm prelabour rupture of membranes was associated with an overall lower risk compared to late preterm births due to other causes. Exposure to antepartum haemorrhage or maternal diabetes increased the risk for CNS and respiratory morbidity. CONCLUSION: Morbidity decreased in late preterm infants with increasing gestational age. Underlying conditions accounted for a substantial part of the morbidity.

EVERREST prospective study: a 6-year prospective study to define the clinical and biological characteristics of pregnancies affected by severe early onset fetal growth restriction.

BACKGROUND: Fetal growth restriction (FGR) is a serious obstetric condition for which there is currently no treatment. The EVERREST Prospective Study has been designed to characterise the natural history of pregnancies affected by severe early onset FGR and establish a well phenotyped bio-bank. The findings will provide up-to-date information for clinicians and patients and inform the design and conduct of the EVERREST Clinical Trial: a phase I/IIa trial to assess the safety and efficacy of maternal vascular endothelial growth factor (VEGF) gene therapy in severe early onset FGR. Data and samples from the EVERREST Prospective Study will be used to identify ultrasound and/or biochemical markers of prognosis in pregnancies with an estimated fetal weight (EFW) <3rd centile between 20+0 and 26+6 weeks of gestation. METHODS: This is a 6 year European multicentre prospective cohort study, recruiting women with a singleton pregnancy where the EFW is <3rd centile for gestational age and <600 g at 20+0 to 26+6 weeks of gestation. Detailed data are collected on: maternal history; antenatal, peripartum, and postnatal maternal complications; health economic impact; psychological impact; neonatal condition, progress and complications; and infant growth and neurodevelopment to 2 years of corrected age in surviving infants. Standardised longitudinal ultrasound measurements are performed, including: fetal biometry; uterine artery, umbilical artery, middle cerebral artery, and ductus venosus Doppler velocimetry; and uterine artery and umbilical vein volume blood flow. Samples of maternal blood and urine, amniotic fluid (if amniocentesis performed), placenta, umbilical cord blood, and placental bed (if caesarean delivery performed) are collected for bio-banking. An initial analysis of maternal blood samples at enrolment is planned to identify biochemical markers that are predictors for fetal or neonatal death. DISCUSSION: The findings of the EVERREST Prospective Study will support the development of a novel therapy for severe early onset FGR by describing in detail the natural history of the disease and by identifying women whose pregnancies have the poorest outcomes, in whom a therapy might be most advantageous. The findings will also enable better counselling of couples with affected pregnancies, and provide a valuable resource for future research into the causes of FGR. TRIAL REGISTRATION: NCT02097667 registered 31st October 2013.

Cardiovascular function in children born very preterm after intrauterine growth restriction with severely abnormal umbilical artery blood flow.

AIMS: Low birthweight has been linked to increased cardiovascular risk in adulthood. We evaluated the effect on cardiovascular outcome of intrauterine growth restriction (IUGR) with abnormal fetal blood flow in children born very preterm. METHODS: Blood pressure, cardiac function and size, diameters, distensibility, and stiffness of the abdominal aorta, carotid, and popliteal arteries, and endothelial function were assessed non-invasively in 7-year-old children (n = 32) born very preterm with IUGR, with birthweight (median, range) 650 g (395-976 g) and gestational age 27 weeks (24-29 weeks). In addition, intima-media thickness was measured in the carotid artery. Controls were matched for gender and age and had birthweight appropriate-for-gestational-age (AGA). The study included 32 preterm-AGA children with birthweight 1010 g (660-1790) g and 32 term-AGA children with birthweight 3530 g (3000-4390) g. RESULTS: Preterm-IUGR children had lower microvascular response to acetylcholine, lower aortic stiffness, and higher distensibility compared with the preterm-AGA group (p = 0.019, p = 0.001, and p < 0.001, respectively) and lower carotid intima-media thickness compared with the term-AGA group (p = 0.047). The highest aortic ß and lowest distensibility were found in the preterm-AGA group. Height-adjusted systolic blood pressure was higher in the preterm groups than in the term-AGA group (p = 0.018). Cardiac function and size did not differ between the groups. CONCLUSION: IUGR and preterm birth appear to be associated with structural changes in the arterial wall, whereas preterm birth seems to be associated with higher blood pressure. Using conventional echocardiography, we observed no effect of IUGR on cardiac size and function.

Lung function in children born after foetal growth restriction and very preterm birth.

AIMS: To assess lung function at early school age in children delivered at very early gestation owing to intrauterine growth restriction and abnormal foetal blood flow (IUGR). METHODS: Spirometry was performed at median age 8.4 (range 6.5-10.7) years in 31 children born preterm with IUGR (PT-IUGR) with a median (range) birth weight (BW) of 650 (395-976) g and median (range) gestational age 27 (24-29) weeks. Control groups were matched for gender and age and had BW appropriate for gestational age (AGA); 31 children born preterm (PT-AGA) with BW of 1010 (660-1790) g matched for gestational age at birth, and 31 children born at term (T-AGA) with BW of 3530 (3000-4390) g. RESULTS: The PT-IUGR group had lower mean (SD) values of z-scores for FEV(1), FEV(1)/FVC and forced mid-expiratory flow rate (FEF(25-75%)) compared to the T-AGA group, p = 0.003, p = 0.032 and p < 0.001, respectively, but did not differ from the PT-AGA group. PT-IUGR children delivered at ≥26 gestational weeks (GW) had lower FEF(25-75%) than PT-AGA children of corresponding GA, p = 0.014. CONCLUSION: Lung function was reduced in the PT-IUGR group at early school age compared to controls born at term. The influence of IUGR on later lung function was only apparent in children born preterm after 26 GW.

Volume blood flow estimation in the normal and growth-restricted fetus.

The objective was to compare volume blood flow (VBF) in the descending aorta (DAo) of gestational age and weight-matched growth restricted (GR) and normal (N) fetuses. A longitudinal study of 20 N was compared with 11 GR in two analyses matched for weight and gestation. DAo dimensions and flow velocity were measured simultaneously using a new technique combining an ultrasonic phase-locked echo-tracking system synchronized with a pulsed Doppler velocimeter. Cardiac output was estimated using standard echocardiographic views. DAo and semilunar valve diameters increased linearly in N and indexed cardiac output was similar in N and GR, although GR showed reduced DAo relative pulse amplitude, mean flow velocity and VBF. This synchronized technique permits calculation of VBF in human fetuses. Growth restriction is associated with reduced aortic wall pulsations and lower mean blood flow velocities and VBF in DAo secondary to increased placental impedance.