Do differences in diagnostic criteria for late fetal growth restriction matter?

BACKGROUND: Criteria for diagnosis of fetal growth restriction differ widely according to national and international guidelines, and further heterogeneity arises from the use of different biometric and Doppler reference charts, making the diagnosis of fetal growth restriction highly variable. OBJECTIVE: This study aimed to compare fetal growth restriction definitions between Delphi consensus and Society for Maternal-Fetal Medicine definitions, using different standards/charts for fetal biometry and different reference ranges for Doppler velocimetry parameters. STUDY DESIGN: From the TRUFFLE 2 feasibility study (856 women with singleton pregnancy at 32+0 to 36+6 weeks of gestation and at risk of fetal growth restriction), we selected 564 women with available mid-pregnancy biometry. For the comparison, we used standards/charts for estimated fetal weight and abdominal circumference from Hadlock, INTERGROWTH-21st, and GROW and Chitty. Percentiles for umbilical artery pulsatility index and its ratios with middle cerebral artery pulsatility index were calculated using Arduini and Ebbing reference charts. Sensitivity and specificity for low birthweight and adverse perinatal outcome were evaluated. RESULTS: Different combinations of definitions and reference charts identified substantially different proportions of fetuses within our population as having fetal growth restriction, varying from 38% (with Delphi consensus definition, INTERGROWTH-21st biometric standards, and Arduini Doppler reference ranges) to 93% (with Society for Maternal-Fetal Medicine definition and Hadlock biometric standards). None of the different combinations tested appeared effective, with relative risk for birthweight &lt;10th percentile between 1.4 and 2.1. Birthweight &lt;10th percentile was observed most frequently when selection was made with the GROW/Chitty charts, slightly less with the Hadlock standard, and least frequently with the INTERGROWTH-21st standard. Using the Ebbing Doppler reference ranges resulted in a far higher proportion identified as having fetal growth restriction compared with the Arduini Doppler reference ranges, whereas Delphi consensus definition with Ebbing Doppler reference ranges produced similar results to those of the Society for Maternal-Fetal Medicine definition. Application of Delphi consensus definition with Arduini Doppler reference ranges was significantly associated with adverse perinatal outcome, with any biometric standards/charts. The Society for Maternal-Fetal Medicine definition could not accurately detect adverse perinatal outcome irrespective of estimated fetal weight standard/chart used. CONCLUSION: Different combinations of fetal growth restriction definitions, biometry standards/charts, and Doppler reference ranges identify different proportions of fetuses with fetal growth restriction. The difference in adverse perinatal outcome may be modest, but can have a significant impact in terms of rate of intervention.</p

Do differences in diagnostic criteria for late fetal growth restriction matter?

BACKGROUND: Criteria for diagnosis of fetal growth restriction differ widely according to national and international guidelines, and further heterogeneity arises from the use of different biometric and Doppler reference charts, making the diagnosis of fetal growth restriction highly variable. OBJECTIVE: This study aimed to compare fetal growth restriction definitions between Delphi consensus and Society for Maternal-Fetal Medicine definitions, using different standards/charts for fetal biometry and different reference ranges for Doppler velocimetry parameters. STUDY DESIGN: From the TRUFFLE 2 feasibility study (856 women with singleton pregnancy at 32+0 to 36+6 weeks of gestation and at risk of fetal growth restriction), we selected 564 women with available mid-pregnancy biometry. For the comparison, we used standards/charts for estimated fetal weight and abdominal circumference from Hadlock, INTERGROWTH-21st, and GROW and Chitty. Percentiles for umbilical artery pulsatility index and its ratios with middle cerebral artery pulsatility index were calculated using Arduini and Ebbing reference charts. Sensitivity and specificity for low birthweight and adverse perinatal outcome were evaluated. RESULTS: Different combinations of definitions and reference charts identified substantially different proportions of fetuses within our population as having fetal growth restriction, varying from 38% (with Delphi consensus definition, INTERGROWTH-21st biometric standards, and Arduini Doppler reference ranges) to 93% (with Society for Maternal-Fetal Medicine definition and Hadlock biometric standards). None of the different combinations tested appeared effective, with relative risk for birthweight &lt;10th percentile between 1.4 and 2.1. Birthweight &lt;10th percentile was observed most frequently when selection was made with the GROW/Chitty charts, slightly less with the Hadlock standard, and least frequently with the INTERGROWTH-21st standard. Using the Ebbing Doppler reference ranges resulted in a far higher proportion identified as having fetal growth restriction compared with the Arduini Doppler reference ranges, whereas Delphi consensus definition with Ebbing Doppler reference ranges produced similar results to those of the Society for Maternal-Fetal Medicine definition. Application of Delphi consensus definition with Arduini Doppler reference ranges was significantly associated with adverse perinatal outcome, with any biometric standards/charts. The Society for Maternal-Fetal Medicine definition could not accurately detect adverse perinatal outcome irrespective of estimated fetal weight standard/chart used. CONCLUSION: Different combinations of fetal growth restriction definitions, biometry standards/charts, and Doppler reference ranges identify different proportions of fetuses with fetal growth restriction. The difference in adverse perinatal outcome may be modest, but can have a significant impact in terms of rate of intervention.</p

Reduced fetal growth velocity and weight loss are associated with adverse perinatal outcome in fetuses at risk of growth restriction.

BACKGROUND Although fetal size is associated with adverse perinatal outcome, the relationship between fetal growth velocity and adverse perinatal outcome is unclear. OBJECTIVE This study aimed to evaluate the relationship between fetal growth velocity and signs of cerebral blood flow redistribution, and their association with birthweight and adverse perinatal outcome. STUDY DESIGN This study was a secondary analysis of the TRUFFLE-2 multicenter observational prospective feasibility study of fetuses at risk of fetal growth restriction between 32+0 and 36+6 weeks of gestation (n=856), evaluated by ultrasound biometry and umbilical and middle cerebral artery Doppler. Individual fetal growth velocity was calculated from the difference of birthweight and estimated fetal weight at 3, 2, and 1 week before delivery, and by linear regression of all available estimated fetal weight measurements. Fetal estimated weight and birthweight were expressed as absolute value and as multiple of the median for statistical calculation. The coefficients of the individual linear regression of estimated fetal weight measurements (growth velocity; g/wk) were plotted against the last umbilical-cerebral ratio with subclassification for perinatal outcome. The association of these measurements with adverse perinatal outcome was assessed. The adverse perinatal outcome was a composite of abnormal condition at birth or major neonatal morbidity. RESULTS Adverse perinatal outcome was more frequent among fetuses whose antenatal growth was <100 g/wk, irrespective of signs of cerebral blood flow redistribution. Infants with birthweight <0.65 multiple of the median were enrolled earlier, had the lowest fetal growth velocity, higher umbilical-cerebral ratio, and were more likely to have adverse perinatal outcome. A decreasing fetal growth velocity was observed in 163 (19%) women in whom the estimated fetal weight multiple of the median regression coefficient was <-0.025, and who had higher umbilical-cerebral ratio values and more frequent adverse perinatal outcome; 67 (41%; 8% of total group) of these women had negative growth velocity. Estimated fetal weight and umbilical-cerebral ratio at admission and fetal growth velocity combined by logistic regression had a higher association with adverse perinatal outcome than any of those parameters separately (relative risk, 3.3; 95% confidence interval, 2.3-4.8). CONCLUSION In fetuses at risk of late preterm fetal growth restriction, reduced growth velocity is associated with an increased risk of adverse perinatal outcome, irrespective of signs of cerebral blood flow redistribution. Some fetuses showed negative growth velocity, suggesting catabolic metabolism

Trans-abdominal in vivo placental vessel occlusion using High Intensity Focused Ultrasound.

Pre-clinically, High Intensity Focused Ultrasound (HIFU) has been shown to safely and effectively occlude placental blood vessels in the acute setting, when applied through the uterus. However, further development of the technique to overcome the technical challenges of targeting and occluding blood vessels through intact skin remains essential to translation into human studies. So too does the assessment of fetal wellbeing following this procedure, and demonstration of the persistence of vascular occlusion. At 115 ± 10 d gestational age (term~147 days) 12 pregnant sheep were exposed to HIFU (n = 6), or to a sham (n = 6) therapy through intact abdominal skin (1.66 MHz, 5 s duration, in situ ISPTA 1.3-4.4 kW.cm-2). Treatment success was defined as undetectable colour Doppler signal in the target placental vessel following HIFU exposures. Pregnancies were monitored for 21 days using diagnostic ultrasound from one day before HIFU exposure until term, when post-mortem examination was performed. Placental vessels were examined histologically for evidence of persistent vascular occlusion. HIFU occluded 31/34 (91%) of placental vessels targeted, with persistent vascular occlusion evident on histological examination 20 days after treatment. The mean diameter of occluded vessels was 1.4 mm (range 0.3-3.3 mm). All pregnancies survived until post mortem without evidence of significant maternal or fetal iatrogenic harm, preterm labour, maternal or fetal haemorrhage or infection. Three of six ewes exposed to HIFU experienced abdominal skin burns, which healed without intervention within 21 days. Mean fetal weight, fetal growth velocity and other measures of fetal biometry were not affected by exposure to HIFU. Fetal Doppler studies indicated a transient increase in the umbilical artery pulsatility index (PI) and a decrease in middle cerebral artery PI as a result of general anaesthesia, which was not different between sham and treatment groups. We report the first successful application of fully non-invasive HIFU for occlusion of placental blood flow in a pregnant sheep model, with a low risk of significant complications. This proof of concept study demonstrates the potential of this technique for clinical translation

Noninvasive high-intensity focused ultrasound treatment of twin-twin transfusion syndrome: A preliminary in vivo study.

We investigated the efficacy, maternofetal responses, and safety of using high-intensity focused ultrasound (HIFU) for noninvasive occlusion of placental vasculature compared to sham treatment in anesthetized pregnant sheep. This technique for noninvasive occlusion of placental vasculature may be translatable to the treatment of conditions arising from abnormal placental vasculature, such as twin-twin transfusion syndrome (TTTS). Eleven pregnant sheep were instrumented with maternal and fetal arterial catheters and time-transit flow probes to monitor cardiovascular, acid-base, and metabolic status, and then exposed to HIFU (n = 5) or sham (n = 6) ablation of placental vasculature through the exposed uterine surface. Placental vascular flow was occluded in 28 of 30 targets, and histological examination confirmed occlusion in 24 of 30 targets. In both HIFU and sham exposures, uterine contact reduced maternal uterine artery flow, but delivery of oxygen and glucose to the fetal brain remained normal. HIFU can consistently occlude in vivo placental vessels and ablate blood flow in a pregnant sheep model. Cardiovascular and metabolic fetal responses suggest that the technique is safe in the short term and potentially translatable to human pregnancy

Maternal Cardiovascular Dysfunction is Associated with Hypoxic Cerebral and Umbilical Doppler Changes.

We investigate the relationship between maternal cardiovascular (CV) function and fetal Doppler changes in healthy pregnancies and those with pre-eclampsia (PE), small for gestational age (SGA) or fetal growth restriction (FGR). This was a three-centre prospective study, where CV assessment was performed using inert gas rebreathing, continuous Doppler or impedance cardiography. Maternal cardiac output (CO) and peripheral vascular resistance (PVR) were analysed in relation to the uterine artery, umbilical artery (UA) and middle cerebral artery (MCA) pulsatility indices (PI, expressed as z-scores by gestational week) using polynomial regression analyses, and in relation to the presence of absent/reversed end diastolic (ARED) flow in the UA. We included 81 healthy controls, 47 women with PE, 65 with SGA/FGR and 40 with PE + SGA/FGR. Maternal CO was inversely related to fetal UA PI and positively related to MCA PI; the opposite was observed for PVR, which was also positively associated with increased uterine artery impedance. CO was lower (z-score 97, p = 0.02) and PVR higher (z-score 2.88, p = 0.02) with UA ARED flow. We report that maternal CV dysfunction is associated with fetal vascular changes, namely raised impedance in the fetal-placental circulation and low impedance in the fetal cerebral vessels. These findings are most evident with critical UA Doppler changes and represent a potential mechanism for therapeutic intervention

Maternal and fetal cardiovascular and metabolic effects of intra-operative uterine handling under general anesthesia during pregnancy in sheep

Abstract: A cohort study of 6,500,000 human pregnancies showed an increased risk of adverse fetal outcomes following abdominal but not non-abdominal surgery under general anesthesia. This may be the consequence of uterine handling during abdominal surgery. However, there are no data on any effects on the cardiometabolic physiology of the fetus or mother in response to uterine manipulation in otherwise healthy pregnancy. Consequently, 9 sheep in late gestation were anesthetized with isofluorane and maternal and fetal catheters and flow probes were implanted to determine cardiovascular and metabolic changes during uterine handling. Uterine handling led to an acute increase in uterine artery vascular resistance, fetal peripheral vasoconstriction, a reduction in oxygen delivery to the femoral circulation, worsening fetal acidosis. There was no evidence of systemic fetal hypoxia, or changes in fetal heart rate, carotid blood flow or carotid oxygen delivery. Therefore, the data support that uterine handling during abdominal surgery under general anesthesia can impact adversely on fetal cardiometabolic health. This may provide a potential explanation linking adverse fetal outcomes in abdominal compared with non-abdominal surgery during pregnancy. The data have important implications for human fetal surgery where the uterus is handled, as operative procedures during late gestation under general maternal anesthesia become more prevalent

Maternal and fetal cardiovascular and metabolic effects of intra-operative uterine handling under general anesthesia during pregnancy in sheep

Abstract: A cohort study of 6,500,000 human pregnancies showed an increased risk of adverse fetal outcomes following abdominal but not non-abdominal surgery under general anesthesia. This may be the consequence of uterine handling during abdominal surgery. However, there are no data on any effects on the cardiometabolic physiology of the fetus or mother in response to uterine manipulation in otherwise healthy pregnancy. Consequently, 9 sheep in late gestation were anesthetized with isofluorane and maternal and fetal catheters and flow probes were implanted to determine cardiovascular and metabolic changes during uterine handling. Uterine handling led to an acute increase in uterine artery vascular resistance, fetal peripheral vasoconstriction, a reduction in oxygen delivery to the femoral circulation, worsening fetal acidosis. There was no evidence of systemic fetal hypoxia, or changes in fetal heart rate, carotid blood flow or carotid oxygen delivery. Therefore, the data support that uterine handling during abdominal surgery under general anesthesia can impact adversely on fetal cardiometabolic health. This may provide a potential explanation linking adverse fetal outcomes in abdominal compared with non-abdominal surgery during pregnancy. The data have important implications for human fetal surgery where the uterus is handled, as operative procedures during late gestation under general maternal anesthesia become more prevalent

Maternal and fetal cardiometabolic recovery following ultrasound-guided high-intensity focused ultrasound placental vascular occlusion.

High-intensity focused ultrasound (HIFU) is a non-invasive method of selective placental vascular occlusion, providing a potential therapy for conditions such as twin-twin transfusion syndrome. In order to translate this technique into human studies, evidence of prolonged fetal recovery and maintenance of a healthy fetal physiology following exposure to HIFU is essential. At 116 ± 2 days gestation, 12 pregnant ewes were assigned to control ( n = 6) or HIFU vascular occlusion ( n = 6) groups and anaesthetized. Placental blood vessels were identified using colour Doppler ultrasound; HIFU-mediated vascular occlusion was performed through intact maternal skin (1.66 MHz, 5 s duration, in situ ISPTA 1.8-3.9 kW cm-2). Unidentifiable colour Doppler signals in targeted vessels following HIFU exposure denoted successful occlusion. Ewes and fetuses were then surgically instrumented with vascular catheters and transonic flow probes and recovered from anaesthesia. A custom-made wireless data acquisition system, which records continuous maternal and fetal cardiovascular data, and daily blood sampling were used to assess wellbeing for 20 days, followed by post-mortem examination. Based on a comparison of pre- and post-treatment colour Doppler imaging, 100% (36/36) of placental vessels were occluded following HIFU, and occlusion persisted for 20 days. All fetuses survived. No differences in maternal or fetal blood pressure, heart rate, heart rate variability, metabolic status or oxygenation were observed between treatment groups. There was evidence of normal fetal maturation and no evidence of chronic fetal stress. There were no maternal injuries and no placental vascular haemorrhage. There was both a uterine and fetal burn, which did not result in any obstetric or fetal complications. This study demonstrates normal long-term recovery of fetal sheep from exposure to HIFU-mediated placental vascular occlusion and underlines the potential of HIFU as a potential non-invasive therapy in human pregnancy

The stroke oxygen pilot study: a randomized control trial of the effects of routine oxygen supplementation early after acute stroke--effect on key outcomes at six months

Introduction: Post-stroke hypoxia is common, and may adversely affect outcome. We have recently shown that oxygen supplementation may improve early neurological recovery. Here, we report the six-month outcomes of this pilot study. Methods: Patients with a clinical diagnosis of acute stroke were randomized within 24 h of admission to oxygen supplementation at 2 or 3 L/min for 72 h or to control treatment (room air). Outcomes (see below) were assessed by postal questionnaire at 6 months. Analysis was by intention-to-treat, and statistical significance was set at p#0.05. Results: Out of 301 patients randomized two refused/withdrew consent and 289 (148 in the oxygen and 141 in the control group) were included in the analysis: males 44%, 51%; mean (SD) age 73 (12), 71 (12); median (IQR) National Institutes of Health Stroke Scale score 6 (3, 10), 5 (3, 10) for the two groups respectively. At six months 22 (15%) patients in the oxygen group and 20 (14%) in the control group had died; mean survival in both groups was 162 days (p= 0.99). Median (IQR) scores for the primary outcome, the modified Rankin Scale, were 3 (1, 5) and 3 (1, 4) for the oxygen and control groups respectively. The covariate-adjusted odds ratio was 1.04 (95% CI 0.67, 1.60), indicating that the odds of a lower (i.e. better) score were non-significantly higher in the oxygen group (p= 0.86). The mean differences in the ability to perform basic (Barthel Index) and extended activities of daily living (NEADL), and quality of life (EuroQol) were also non-significant. Conclusions: None of the key outcomes differed at 6 months between the groups. Although not statistically significant and generally of small magnitude, the effects were predominantly in favour of the oxygen group; a larger trial, powered to show differences in longer-term functional outcomes, is now on-going. Trial Registration: Controlled-Trials.com ISRCTN12362720; Eudract.ema.europa.eu 2004-001866-4