National cohort of infants born before 24 gestational weeks showed increased survival rates but no improvement in neonatal morbidity

Aim: To describe survival and neonatal morbidities in infants born before 24\ua0weeks of gestation during a 12-year period. Methods: Data were retrieved from national registries and validated in medical files of infants born before 24\ua0weeks of gestation 2007–2018 in Sweden. Temporal changes were evaluated. Results: In 2007–2018, 282\ua0live births were recorded at 22\ua0weeks and 460 at 23\ua0weeks of gestation. Survival to discharge from hospital of infants born alive at 22 and 23\ua0weeks increased from 20% to 38% (p\ua0=\ua00.006) and from 45% to 67% (

Neonatal outcomes following early fetal growth restriction: a subgroup analysis of the EVERREST study

OBJECTIVE: To quantify the risks of mortality, morbidity and postnatal characteristics associated with extreme preterm fetal growth restriction (EP-FGR). DESIGN: The EVERREST (Do e s v ascular endothelial growth factor gene therapy saf e ly imp r ove outcome in seve r e e arly-onset fetal growth re st riction?) prospective multicentre study of women diagnosed with EP-FGR (singleton, estimated fetal weight (EFW) <3rd percentile, <600 g, 20+0-26+6 weeks of gestation). The UK subgroup of EP-FGR infants (<36 weeks) were sex-matched and gestation-matched to appropriate for age (AGA) infants born in University College London Hospital (1:2 design, EFW 25th-75th percentile). SETTING: Four tertiary perinatal units (UK, Germany, Spain, Sweden). MAIN OUTCOMES: Antenatal and postnatal mortality, bronchopulmonary dysplasia (BPD), sepsis, surgically treated necrotising enterocolitis (NEC), treated retinopathy of prematurity (ROP). RESULTS: Of 135 mothers recruited with EP-FGR, 42 had a stillbirth or termination of pregnancy (31%) and 93 had live births (69%). Postnatal genetic abnormalities were identified in 7/93 (8%) live births. Mean gestational age at birth was 31.4 weeks (SD 4.6). 54 UK-born preterm EP-FGR infants (<36 weeks) were matched to AGA controls. EP-FGR was associated with increased BPD (43% vs 26%, OR 3.6, 95% CI 1.4 to 9.4, p=0.01), surgical NEC (6% vs 0%, p=0.036) and ROP treatment (11% vs 0%, p=0.001). Mortality was probably higher among FGR infants (9% vs 2%, OR 5.0, 95% CI 1.0 to 25.8, p=0.054). FGR infants more frequently received invasive ventilation (65% vs 50%, OR 2.6, 95% CI 1.1 to 6.1, p=0.03), took longer to achieve full feeds and had longer neonatal stays (median difference 6.1 days, 95% CI 3.8 to 8.9 and 19 days, 95% CI 9 to 30 days, respectively, p<0.0001). CONCLUSIONS: Mortality following diagnosis of EP-FGR is high. Survivors experience increased neonatal morbidity compared with AGA preterm infants. TRIAL REGISTRATION NUMBER: NCT02097667

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

Development in children born very preterm after intrauterine growth restriction with abnormal fetal blood flow

Delivery of fetuses with intrauterine growth restriction (IUGR) with abnormal umbilical artery blood flow in the second trimester represents a clinical dilemma. So far, no evidence based management protocols are available adressing when to deliver these fetuses. The high risk of hypoxia and fetal death has to be balanced against that of extreme preterm birth with associated morbidity. The clinical routine in Lund has been a proactive management, that is to deliver on fetal indication before occurence of more severe hemodynamic changes. The aim of this study was to evaluate short and long-term consequences in very preterm IUGR fetuses (PT-IUGR) with abnormal blood flow in the umbilical artery. Study I: Mortality and neonatal morbidity did not differ between the PT-IUGR group and the very preterm background population, born before 30 gestational weeks (GW) in 1998-2004, with the exception of chronic lung disease (p <0.01). Survival without major neurological handicap at two years was equal between the two groups. Study II: At early school age, cognitive impairment was more prevalent in boys born very preterm with IUGR compared to a matched very preterm group with BW appropriate for gestational age (PT-AGA). Attention deficit disorders were more prevalent in children in both preterm groups compared to term children with birth weight AGA (T-AGA) (p <0.01). There was a trend towards more behavioral problems in the preterm groups. Study III: Lung function, assessed with spirometry in children at 6-10 years, was reduced in the PT-IUGR group compared to the T-AGA group. The PT-IUGR group had worse lung function when born after 26 GW in comparison to the PT-AGA group (p<0.05). Study IV: Cardiovascular measurements were assessed at 5-8 years. Systolic and mean blood pressure, adjusted for height, was higher in both preterm groups compared to the T-AGA group (p<0.05). Findings in the vascular measurements were different between the preterm groups; the PT-IUGR group had lower aortic stiffness (p<0.01) and lower endothelial-dependent vasodilation compared to the PT-AGA group (p<0.05), and thinner intima media thickness in the carotid artery compared to the T-AGA group (p<0.05). Conclusions: IUGR in very preterm birth did not have an impact on overall mortality or major handicaps. Impairment in lung function was only apparent in the preterm IUGR group after 26 GW, a period of gestation when delivery on fetal indication in general is considered acceptable. The adverse impact of IUGR on cognitive function was present at all gestational ages, but cognitive impairment was only significant in IUGR boys compared to preterm controls. The question whether the cognitive impairment in boys is transient or persistent remains unanswered. It is difficult to understand the implication of the outcomes of lower IMT and aortic stiffness seen in the preterm IUGR group on later cardiovascular health. Further studies have to be performed in older ages. The observed outcome would not seem to be sufficiently severe to refrain from delivery in these very preterm IUGR fetuses and we suggest that it is justified to deliver fetuses with IUGR and abnormal blood flow in the umbilical artery at early gestational age in order to prevent intrauterine death

Pre-eclampsia-An additional risk factor for cognitive impairment at school age after intrauterine growth restriction and very preterm birth.

To explore the possible influence of pre-eclampsia on cognitive outcome in children born very preterm after intrauterine growth restriction (IUGR) and abnormal umbilical artery blood flow

Reduced Prevalence of Severe Intraventricular Hemorrhage in Very Preterm Infants Delivered after Maternal Preeclampsia

Background: Very preterm (VPT) delivery after severe preeclampsia (PE) has been associated with adverse perinatal outcome. It is unclear whether fetal exposure to PE per se modifies the prevalence of neonatal morbidities associated with VPT birth. Objectives: To evaluate neonatal morbidity in VPT infants exposed to maternal PE compared to morbidity in nonexposed VPT infants. Methods: This retrospective study consisted of all inborn infants delivered before 30 gestational weeks admitted to a tertiary-level neonatal intensive care unit between 1998 and 2014: 195 infants exposed to maternal PE were compared to 957 infants without maternal PE (background group). Prevalence rates of neonatal morbidity, cerebral palsy (CP), and mortality at 2 years of age were obtained from patient records. Results: The PE group had a lower median (IQR) birth weight (795 [262] g) and a higher median gestational age (GA) (27 [3] weeks) at birth than the background group (890 [385] g and 26 [3] weeks, respectively; both p < 0.001). Exposure to maternal PE was associated with lower rates of severe intraventricular hemorrhage (IVH) (2 vs. 11%), retinopathy of prematurity requiring treatment (2 vs. 7%), mortality (9 vs. 15%), and CP (4 vs. 8%). Exposure to PE remained associated with a reduced prevalence of severe IVH (OR 0.17, 95% CI 0.05–0.57) after adjustment for GA, multiple birth, Apgar score, delivery mode, sex, and antenatal steroid treatment. Conclusion: Fetal exposure to PE is associated with a decreased rate of severe IVH following VPT birth. Studies on underlying mechanisms may provide a basis for prevention of IVH in the VPT infant

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

Neonatal clinical blood sampling led to major blood loss and was associated with bronchopulmonary dysplasia

Aim: Studies indicate that reduced foetal haemoglobin levels are related to increased neonatal morbidity rates. This study investigated the relationships between sampling-related blood loss and adult blood transfusions administered during postnatal days 1-14 and the development of severe neonatal morbidities in extremely preterm infants born before 28 weeks of gestation. Methods: The medical files of 149 extremely preterm infants born at two university hospitals in Sweden from 2013 to 2018 were investigated. Results: Blood sampling resulted in a 58% depletion of the endogenous blood volume postnatal days 1-14 (median 40.4 mL/kg, interquartile range 23.9-53.3 mL/kg) and correlated with the adult erythrocyte transfusion volume (rS = 0.870, P <.001). Sampling-related blood loss on postnatal days 1-7, adjusted for gestational age at birth and birth weight standard deviation score, was associated with the development of bronchopulmonary dysplasia (BPD) (odds ratio by a 10-unit increase 2.4, 95% confidence interval 1.1-5.4) (P =.03). No associations were found between blood sampling and intraventricular haemorrhage or necrotising enterocolitis in the full statistical model. The largest proportion of sampling-related blood was used for blood gas analyses (48.7%). Conclusion: Diagnostic blood sampling led to major endogenous blood loss replaced with adult blood components and was associated with the development of BPD