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Background : Owing to inadequate supplies of donor blood for transfusion in sub-Saharan Africa (sSA) World Health Organization paediatric guidelines recommend restrictive transfusion practices, based on expert opinion. We examined whether survival amongst hospitalised children by admission haemoglobin and whether this was influenced by malaria infection and/or transfusion. Methods : A retrospective analysis of standardised clinical digital records in an unselected population of children admitted to a rural hospital in Kenya over an 8-year period. We describe baseline parameters with respect to categories of anaemia and outcome (in-hospital death) by haemoglobin (Hb), malaria and transfusion status. Results : Among 29,226 children, 1,143 (3.9%) had profound anaemia (Hb

Severe acute respiratory infections (SARI) remain one of the leading causes of mortality around the world in all age groups. There is large global variation in epidemiology, clinical management and outcomes, including mortality. We performed a short period observational data collection in critical care units distributed globally during regional peak SARI seasons from 1 January 2016 until 31 August 2017, using standardised data collection tools. Data were collected for 1 week on all admitted patients who met the inclusion criteria for SARI, with follow-up to hospital discharge. Proportions of patients across regions were compared for microbiology, management strategies and outcomes. Regions were divided geographically and economically according to World Bank definitions. Data were collected for 682 patients from 95 hospitals and 23 countries. The overall mortality was 9.5%. Of the patients, 21.7% were children, with case fatality proportions of 1% for those less than 5 years. The highest mortality was in those above 60 years, at 18.6%. Case fatality varied by region: East Asia and Pacific 10.2% (21 of 206), Sub-Saharan Africa 4.3% (8 of 188), South Asia 0% (0 of 35), North America 13.6% (25 of 184), and Europe and Central Asia 14.3% (9 of 63). Mortality in low-income and low-middle-income countries combined was 4% as compared with 14% in high-income countries. Organ dysfunction scores calculated on presentation in 560 patients where full data were available revealed Sequential Organ Failure Assessment (SOFA) scores on presentation were significantly associated with mortality and hospital length of stay. Patients in East Asia and Pacific (48%) and North America (24%) had the highest SOFA scores of >12. Multivariable analysis demonstrated that initial SOFA score and age were independent predictors of hospital survival. There was variability across regions and income groupings for the critical care management and outcomes of SARI. Intensive care unit-specific factors, geography and management features were less reliable than baseline severity for predicting ultimate outcome. These findings may help in planning future outbreak severity assessments, but more globally representative data are required.

Background Severe falciparum malaria can be compounded by bacterial sepsis, necessitating antibiotics in addition to anti-malarial treatment. The objective of this analysis was to develop a prognostic model to identify patients admitted with severe malaria at higher risk of developing bacterial sepsis. Methods A retrospective data analysis using trial data from the South East Asian Quinine Artesunate Malaria Trial. Variables correlating with development of clinically defined sepsis were identified by univariable analysis, and subsequently included into a multivariable logistic regression model. Internal validation was performed by bootstrapping. Discrimination and goodness-of-fit were assessed using the area under the curve (AUC) and a calibration plot, respectively. Results Of the 1187 adults with severe malaria, 86 (7.3%) developed clinical sepsis during admission. Predictors for developing sepsis were: female sex, high blood urea nitrogen, high plasma anion gap, respiratory distress, shock on admission, high parasitaemia, coma and jaundice. The AUC of the model was 0.789, signifying modest differentiation for identifying patients developing sepsis. The model was well-calibrated (Hosmer–Lemeshow Chi squared = 1.02). The 25th percentile of the distribution of risk scores among those who developed sepsis could identify a high-risk group with a sensitivity and specificity of 70.0 and 69.4%, respectively. Conclusions The proposed model identifies patients with severe malaria at risk of developing clinical sepsis, potentially benefiting from antibiotic treatment in addition to anti-malarials. The model will need further evaluation with more strictly defined bacterial sepsis as outcome measure. Electronic supplementary material The online version of this article (10.1186/s12936-018-2430-2) contains supplementary material, which is available to authorized users.

Summary Background Charts of size at birth are used to assess the postnatal growth of preterm babies on the assumption that extrauterine growth should mimic that in the uterus. Methods The INTERGROWTH-21 st Project assessed fetal, newborn, and postnatal growth in eight geographically defined populations, in which maternal health care and nutritional needs were met. From these populations, the Fetal Growth Longitudinal Study selected low-risk women starting antenatal care before 14 weeks' gestation and monitored fetal growth by ultrasonography. All preterm births from this cohort were eligible for the Preterm Postnatal Follow-up Study, which included standardised anthropometric measurements, feeding practices based on breastfeeding, and data on morbidity, treatments, and development. To construct the preterm postnatal growth standards, we selected all live singletons born between 26 and before 37 weeks' gestation without congenital malformations, fetal growth restriction, or severe postnatal morbidity. We did analyses with second-degree fractional polynomial regression models in a multilevel framework accounting for repeated measures. Fetal and neonatal data were pooled from study sites and stratified by postmenstrual age. For neonates, boys and girls were assessed separately. Findings From 4607 women enrolled in the study, there were 224 preterm singleton births, of which 201 (90%) were enrolled in the Preterm Postnatal Follow-up Study. Variance component analysis showed that only 0·2% and 4·0% of the total variability in postnatal length and head circumference, respectively, could be attributed to between-site differences, justifying pooling the data from all study sites. Preterm growth patterns differed from those for babies in the INTERGROWTH-21 st Newborn Size Standards. They overlapped with the WHO Child Growth Standards for term babies by 64 weeks' postmenstrual age. Interpretation Our data have yielded standards for postnatal growth in preterm infants. These standards should be used for the assessment of preterm infants until 64 weeks' postmenstrual age, after which the WHO Child Growth Standards are appropriate. Size-at-birth charts should not be used to measure postnatal growth of preterm infants. Funding Bill & Melinda Gates Foundation.

Human growth begins at conception and continues into adult life. Growth is usually classified as normal or abnormal using the expected attained size at a given age. The statistical analysis of growth data has been of interest to many academics from a wide range of disciplines over the last century. The study of fetal and neonatal growth is complex, and the many remaining clinical questions require complex statistical methodology. In this thesis, I have focused on growth in the prenatal period, namely fetal and newborn growth. The thesis highlights the potential pitfalls in methodology, statistical methods, and reporting of studies aimed at creating fetal charts. I propose a checklist for evaluating the methodological quality of studies that provides a rough guide of the minimum information that should be reported in these studies. This checklist is not intended to commend or discard studies, but rather to act as a consensus guideline to improve consistency and as a guide for evaluating similar studies for future research in human growth studies. The thesis assesses approaches for developing charts of attained size at a given age and the velocity gain (rate or speed of growth) of a fetus. It aims to address some of the statistical issues that relate to fetal and neonatal growth studies. The thesis also focuses on fetal velocity. This work is novel as there are currently no fetal velocity standards in existence. The methodologies discussed have previously been applied to child growth data, but not to fetal data, to the best of my knowledge. In this thesis, I construct the first fetal growth velocity standards. Such standards were not yet available largely due to lack of appropriate, good quality longitudinal fetal data. All of the work and research carried out as part of the thesis was embedded within the International Fetal and Newborn Growth Consortium for the 21st Century (INTERGROWTH-21st Project). The primary aims of the INTERGROWTH- 21st project were to produce international growth standards for practical clinical applications and to monitor trends in populations using three sets of data describing fetal growth (n=4,321 women), postnatal growth of preterm infants (n=201 preterm infants), and newborn size (weight, length, and head circumference) for gestational age (n=20,486 newborns). The design and conduct of these studies are detailed elsewhere and have already resulted in numerous publications, including four papers published in The Lancet. I was the responsible statistician for these publications and undertook all of the statistical analyses.

Background Adults born very preterm have increased cardiac mass and reduced function. We investigated whether a hypertrophic phenomenon occurs in later preterm infants and when this occurs during early development. Methods Cardiac ultrasound was performed on 392 infants (33% preterm at mean gestation 34+/-2 weeks). Scans were performed during fetal development in 137, at birth and three months postnatal age in 200 and during both fetal and postnatal development in 55. Cardiac morphology and function was quantified and computational models created to identify geometric changes. Results At birth, preterm offspring had reduced cardiac mass and volume relative to body size with a more globular heart. By three months, ventricular shape had normalised but both left and right ventricular mass relative to body size were significantly higher than expected for postmenstrual age (left 57.8±41.9 vs 27.3±29.4%, p Conclusions Preterm offspring, including those born in late gestation, have a disproportionate increase in ventricular mass from birth up to three months postnatal age. These differences were not present before birth. Early postnatal development may provide a window for interventions relevant to long-term cardiovascular health.

OBJECTIVE: Estimated fetal weight (EFW) and fetal biometry are complementary measures used to screen for fetal growth disturbances. Our aim was to provide international EFW standards to complement the INTERGROWTH-21st Fetal Growth Standards that are available for use worldwide. METHODS: Women with an accurate gestational-age assessment, who were enrolled in the prospective, international, multicenter, population-based Fetal Growth Longitudinal Study (FGLS) and INTERBIO-21st Fetal Study (FS), two components of the INTERGROWTH-21st Project, had ultrasound scans every 5 weeks from 9-14 weeks' until 40 weeks' gestation. At each visit, measurements of fetal head circumference (HC), biparietal diameter, occipitofrontal diameter, abdominal circumference (AC) and femur length (FL) were obtained blindly by dedicated research sonographers using standardized methods and identical ultrasound machines. Birth weight was measured within 12 h of delivery by dedicated research anthropometrists using standardized methods and identical electronic scales. Live babies without any congenital abnormality, who were born within 14 days of the last ultrasound scan, were selected for inclusion. As most births occurred at around 40 weeks' gestation, we constructed a bootstrap model selection and estimation procedure based on resampling of the complete dataset under an approximately uniform distribution of birth weight, thus enriching the sample size at extremes of fetal sizes, to achieve consistent estimates across the full range of fetal weight. We constructed reference centiles using second-degree fractional polynomial models. RESULTS: Of the overall population, 2404 babies were born within 14 days of the last ultrasound scan. Mean time between the last scan and birth was 7.7 (range, 0-14) days and was uniformly distributed. Birth weight was best estimated as a function of AC and HC (without FL) as log(EFW) = 5.084820 - 54.06633 × (AC/100)3 - 95.80076 × (AC/100)3 × log(AC/100) + 3.136370 × (HC/100), where EFW is in g and AC and HC are in cm. All other measures, gestational age, symphysis-fundus height, amniotic fluid indices and interactions between biometric measures and gestational age, were not retained in the selection process because they did not improve the prediction of EFW. Applying the formula to FGLS biometric data (n = 4231) enabled gestational age-specific EFW tables to be constructed. At term, the EFW centiles matched those of the INTERGROWTH-21st Newborn Size Standards but, at

Objective Accurate gestational‐age (GA) estimation, preferably by ultrasound measurement of fetal crown–rump length before 14 weeks' gestation, is an important component of high‐quality antenatal care. The objective of this study was to determine how GA can best be estimated by fetal ultrasound for women who present for the first time late in pregnancy with uncertain or unknown menstrual dates. Methods INTERGROWTH‐21st was a large, prospective, multicenter, population‐based project performed in eight geographically defined urban populations. One of its principal components, the Fetal Growth Longitudinal Study, aimed to develop international fetal growth standards. Each participant had their certain menstrual dates confirmed by first‐trimester ultrasound examination. Fetal head circumference (HC), biparietal diameter (BPD), occipitofrontal diameter (OFD), abdominal circumference (AC) and femur length (FL) were measured every 5 weeks from 14 weeks' gestation until delivery. For each participant, a single, randomly selected ultrasound examination was used to explore all candidate biometric variables and permutations to build models to predict GA. Regression equations were ranked based upon minimization of the mean prediction error, goodness of fit and model complexity. An automated machine learning algorithm, the Genetic Algorithm, was adapted to evaluate > 64 000 potential polynomial equations as predictors. Results Of the 4607 eligible women, 4321 (94%) had a pregnancy without major complications and delivered a live singleton without congenital malformations. After other exclusions (missing measurements in GA window and outliers), the final sample comprised 4229 women. Two skeletal measures, HC and FL, produced the best GA prediction, given by the equation loge(GA) = 0.03243 × (loge(HC))2 + 0.001644 × FL × loge(HC) + 3.813. When FL was not available, the best equation based on HC alone was loge(GA) = 0.05970 × (loge(HC))2 + 0.000000006409 × (HC)3 + 3.3258. The estimated uncertainty of GA prediction (half width 95% interval) was 6–7 days at 14 weeks' gestation, 12–14 days at 26 weeks' gestation and > 14 days in the third trimester. The addition of FL to the HC model led to improved prediction intervals compared with using HC alone, but no further improvement in prediction was afforded by adding AC, BPD or OFD. Equations that included other measurements (BPD, OFD and AC) did not perform better. Conclusions Among women initiating antenatal care late in pregnancy, a single set of ultrasound measurements combining HC and FL in the second trimester can be used to estimate GA with reasonable accuracy. We recommend this tool for underserved populations but considerable efforts should be implemented to improve early initiation of antenatal care worldwide. © 2016 Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology., Linked Comment: Ultrasound Obstet Gynecol 2016; 48: 693–693

Objective Estimated fetal weight (EFW) and fetal biometry are complementary measures used to screen for fetal growth disturbances. Our aim was to provide international EFW standards to complement the INTERGROWTH‐21st Fetal Growth Standards that are available for use worldwide. Methods Women with an accurate gestational‐age assessment, who were enrolled in the prospective, international, multicenter, population‐based Fetal Growth Longitudinal Study (FGLS) and INTERBIO‐21st Fetal Study (FS), two components of the INTERGROWTH‐21st Project, had ultrasound scans every 5 weeks from 9–14 weeks' until 40 weeks' gestation. At each visit, measurements of fetal head circumference (HC), biparietal diameter, occipitofrontal diameter, abdominal circumference (AC) and femur length (FL) were obtained blindly by dedicated research sonographers using standardized methods and identical ultrasound machines. Birth weight was measured within 12 h of delivery by dedicated research anthropometrists using standardized methods and identical electronic scales. Live babies without any congenital abnormality, who were born within 14 days of the last ultrasound scan, were selected for inclusion. As most births occurred at around 40 weeks' gestation, we constructed a bootstrap model selection and estimation procedure based on resampling of the complete dataset under an approximately uniform distribution of birth weight, thus enriching the sample size at extremes of fetal sizes, to achieve consistent estimates across the full range of fetal weight. We constructed reference centiles using second‐degree fractional polynomial models. Results Of the overall population, 2404 babies were born within 14 days of the last ultrasound scan. Mean time between the last scan and birth was 7.7 (range, 0–14) days and was uniformly distributed. Birth weight was best estimated as a function of AC and HC (without FL) as log(EFW) = 5.084820 − 54.06633 × (AC/100)3 − 95.80076 × (AC/100)3 × log(AC/100) + 3.136370 × (HC/100), where EFW is in g and AC and HC are in cm. All other measures, gestational age, symphysis–fundus height, amniotic fluid indices and interactions between biometric measures and gestational age, were not retained in the selection process because they did not improve the prediction of EFW. Applying the formula to FGLS biometric data (n = 4231) enabled gestational age‐specific EFW tables to be constructed. At term, the EFW centiles matched those of the INTERGROWTH‐21st Newborn Size Standards but, at

Debate continues over which morphological parameter is most important in selecting blastocysts for transfer. We aimed to investigate which parameter more accurately predicts the occurrence of a live birth by designing a retrospective cohort study of 1084 fresh elective single blastocyst transfers. Primary outcome was live birth rate (LBR) and secondary outcomes were implantation, clinical pregnancy and early pregnancy loss rates. Blastocyst expansion and inner cell mass (ICM), but not trophoectoderm, were associated with LBR in the definitive multivariable regression analysis. When ICM grade dropped from A to C the likelihood of achieving a live birth was reduced by 55% (OR=0.45, 95% CI 0.26-0.79, p = 0.005). These results were similar for clinical pregnancy rates. Early pregnancy loss rates of embryos with ICM grade C were more than double (38.0%) compared to those of grades A (15.95%) and B (17.17%, p = 0.002). The transfer of an embryo with an optimal inner cell mass reduces early pregnancy loss and increases the likelihood of a live birth. We did not find any significant association between trophectoderm and LBR in the multivariable analysis in contrast with recent studies.

Objectives To assess the feasibility, accuracy and reproducibility of manipulating three-dimensional (3D) volume sets in order to reconstruct optimal two-dimensional (2D) planes for fetal biometry throughout gestation and compare them with those derived from real-time 2D scanning. Methods Sixty-five fetuses were evaluated at a gestational age of 14-41 weeks. For each fetus a duplicate set of seven standard fetal measurements was taken by an experienced operator using 2D ultrasound and then 20 intentionally suboptimal 3D volumes from different predefined angles were captured and stored. These were manipulated and measured. The time taken to complete a full scan, with both 2D and 3D ultrasound, was recorded. All measurement differences were expressed as gestational age-specific Z-scores. For all comparisons Bland-Altman plots were used and limits of agreement were calculated. The means and variances of the measurements were tested with a paired t-test and Pitman's test for differences in variance, respectively. The difference between the time taken to perform a 2D and a 3D scan was tested using the Wilcoxon signed-ranks test. Results Mean agreement between 2D and 3D ultrasound measurements was good, with no statistically significant differences (i.e. no systematic error) unless the head was facing anteroposteriorly, or the long axis of the femur was at 60-90° to the transducer. The variance (random error) for 3D measurements was similar to that for 2D measurements. Planes from some volumes could not be extracted (7% for head circumference, 9% for abdominal circumference and 11% for femur length). The median time required to perform a full fetal biometric scan was significantly higher for 3D than for 2D (3:04 min vs 1:57 min, respectively; P < 0.001). Conclusions Fetal measurements derived from 3D volume acquisitions exhibited good agreement with those obtained by real-time 2D scanning, with no extra systematic or random error. However, they were slower to obtain, not all volumes were amenable to extraction of planes and measurements that came from a head facing anteroposteriorly or that were obtained with the long axis of the femur at 60-90°to the transducer were systematically smaller. Copyright © 2013 ISUOG. Published by John Wiley and Sons Ltd. Copyright © 2013 ISUOG. Published by John Wiley and Sons Ltd.

Objective: Fetal femur volume (FV) is a useful marker of skeletal growth. Our objective was to create a normal FV chart in a cohort of healthy pregnant women and to assess FV repeatability. Method: The method used was a prospective, observational study using 3D ultrasound. Low-risk pregnant women underwent serial scans from 14 to 42weeks. Strict inclusion and exclusion criteria were used in order to remove pathological conditions. Pregnancies were dated by last menstrual period and confirmed by crown-rump length. FV was measured using three linear measurements and a volume equation. Data were analyzed using multilevel modeling. Repeatability was assessed using within-subject coefficients of variation (CV), intraclass correlation coefficients (ICC), and Bland-Altman plots. Results: A total of 180 women underwent 868 scans, a median of five scans per participant. Median and centile values were presented in the form of curves, regression equations, and table of values per completed week. Intra-observer CV and ICC were 10.5% and 0.977, respectively; interobserver CV and ICC were 16.8% and 0.923. Conclusion: This normal FV chart can be used as a prescriptive standard in order to assess fetal skeletal growth. Measurement repeatability is satisfactory for clinical use, but FV has a larger random error than commonly seen with standard 2D biometry. What's already known about this topic? A validated method for femur volume measurement on 3D ultrasound uses three linear measurements and a volume equation. Fetal femur volume is correlated with maternal vitamin D concentration. What does this study add? A gestational femur volume chart is presented using serial ultrasound scans in healthy UK pregnancies. Measurement method repeatability is reported. © 2013 John Wiley and Sons, Ltd.