E O Ohuma

International standards for newborn weight, length, and head circumference by gestational age and sex: the Newborn Cross-Sectional Study of the INTERGROWTH-21st Project

BACKGROUND In 2006, WHO published international growth standards for children younger than 5 years, which are now accepted worldwide. In the INTERGROWTH-21(st) Project, our aim was to complement them by developing international standards for fetuses, newborn infants, and the postnatal growth period of preterm infants. METHODS INTERGROWTH-21(st) is a population-based project that assessed fetal growth and newborn size in eight geographically defined urban populations. These groups were selected because most of the health and nutrition needs of mothers were met, adequate antenatal care was provided, and there were no major environmental constraints on growth. As part of the Newborn Cross-Sectional Study (NCSS), a component of INTERGROWTH-21(st) Project, we measured weight, length, and head circumference in all newborn infants, in addition to collecting data prospectively for pregnancy and the perinatal period. To construct the newborn standards, we selected all pregnancies in women meeting (in addition to the underlying population characteristics) strict individual eligibility criteria for a population at low risk of impaired fetal growth (labelled the NCSS prescriptive subpopulation). Women had a reliable ultrasound estimate of gestational age using crown-rump length before 14 weeks of gestation or biparietal diameter if antenatal care started between 14 weeks and 24 weeks or less of gestation. Newborn anthropometric measures were obtained within 12 h of birth by identically trained anthropometric teams using the same equipment at all sites. Fractional polynomials assuming a skewed t distribution were used to estimate the fitted centiles. FINDINGS We identified 20,486 (35%) eligible women from the 59,137 pregnant women enrolled in NCSS between May 14, 2009, and Aug 2, 2013. We calculated sex-specific observed and smoothed centiles for weight, length, and head circumference for gestational age at birth. The observed and smoothed centiles were almost identical. We present the 3rd, 10th, 50th, 90th, and 97th centile curves according to gestational age and sex. INTERPRETATION We have developed, for routine clinical practice, international anthropometric standards to assess newborn size that are intended to complement the WHO Child Growth Standards and allow comparisons across multiethnic populations. FUNDING Bill & Melinda Gates Foundation.

International standards for fetal growth based on serial ultrasound measurements: the Fetal Growth Longitudinal Study of the INTERGROWTH-21st Project

BACKGROUND In 2006, WHO produced international growth standards for infants and children up to age 5 years on the basis of recommendations from a WHO expert committee. Using the same methods and conceptual approach, the Fetal Growth Longitudinal Study (FGLS), part of the INTERGROWTH-21(st) Project, aimed to develop international growth and size standards for fetuses. METHODS The multicentre, population-based FGLS assessed fetal growth in geographically defined urban populations in eight countries, in which most of the health and nutritional needs of mothers were met and adequate antenatal care was provided. We used ultrasound to take fetal anthropometric measurements prospectively from 14 weeks and 0 days of gestation until birth in a cohort of women with adequate health and nutritional status who were at low risk of intrauterine growth restriction. All women had a reliable estimate of gestational age confirmed by ultrasound measurement of fetal crown-rump length in the first trimester. The five primary ultrasound measures of fetal growth--head circumference, biparietal diameter, occipitofrontal diameter, abdominal circumference, and femur length--were obtained every 5 weeks (within 1 week either side) from 14 weeks to 42 weeks of gestation. The best fitting curves for the five measures were selected using second-degree fractional polynomials and further modelled in a multilevel framework to account for the longitudinal design of the study. FINDINGS We screened 13,108 women commencing antenatal care at less than 14 weeks and 0 days of gestation, of whom 4607 (35%) were eligible. 4321 (94%) eligible women had pregnancies without major complications and delivered live singletons without congenital malformations (the analysis population). We documented very low maternal and perinatal mortality and morbidity, confirming that the participants were at low risk of adverse outcomes. For each of the five fetal growth measures, the mean differences between the observed and smoothed centiles for the 3rd, 50th, and 97th centiles, respectively, were small: 2·25 mm (SD 3·0), 0·02 mm (3·0), and -2·69 mm (3·2) for head circumference; 0·83 mm (0·9), -0·05 mm (0·8), and -0·84 mm (1·0) for biparietal diameter; 0·63 mm (1·2), 0·04 mm (1·1), and -1·05 mm (1·3) for occipitofrontal diameter; 2·99 mm (3·1), 0·25 mm (3·2), and -4·22 mm (3·7) for abdominal circumference; and 0·62 mm (0·8), 0·03 mm (0·8), and -0·65 mm (0·8) for femur length. We calculated the 3rd, 5th 10th, 50th, 90th, 95th and 97th centile curves according to gestational age for these ultrasound measures, representing the international standards for fetal growth. INTERPRETATION We recommend these international fetal growth standards for the clinical interpretation of routinely taken ultrasound measurements and for comparisons across populations. FUNDING Bill & Melinda Gates Foundation.

Systematic review of methodology used in ultrasound studies aimed at creating charts of fetal size.

Please cite this paper as: Ioannou C, Talbot K, Ohuma E, Sarris I, Villar J, Conde‐Agudelo A, Papageorghiou A. Systematic review of methodology used in ultrasound studies aimed at creating charts of fetal size. BJOG 2012;119:1425–1439.

Diarrhoea Complicating Severe Acute Malnutrition in Kenyan Children: A Prospective Descriptive Study of Risk Factors and Outcome

Background Severe acute malnutrition (SAM) accounts for two million deaths worldwide annually. In those hospitalised with SAM, concomitant infections and diarrhoea are frequent complications resulting in adverse outcome. We examined the clinical and laboratory features on admission and outcome of children with SAM and diarrhoea at a Kenyan district hospital. Methods A 4-year prospective descriptive study involving 1,206 children aged 6 months to 12 years, hospitalized with SAM and managed in accordance with WHO guidelines. Data on clinical features, haematological, biochemical and microbiological findings for children with diarrhoea (≥3 watery stools/day) were systematically collected and analyzed to identify risk factors associated with poor outcome. Results At admission 592 children (49%) had diarrhoea of which 122 (21%) died compared to 72/614 (12%) deaths in those without diarrhoea at admission (Χ2 = 17.6 p<0.001). A further 187 (16%) children developed diarrhoea after 48 hours of admission and 33 died (18%). Any diarrhoea during admission resulted in a significantly higher mortality 161/852 (19%) than those uncomplicated by diarrhoea 33/351 (9%) (Χ2 = 16.6 p<0.001). Features associated with a fatal outcome in children presenting with diarrhoea included bacteraemia, hyponatraemia, low mid-upper arm circumference <10 cm, hypoxia, hypokalaemia and oedema. Bacteraemia had the highest risk of death (adjusted OR 6.1; 95% C.I 2.3, 16.3 p<0.001); and complicated 24 (20%) of fatalities. Positive HIV antibody status was more frequent in cases with diarrhoea at admission (23%) than those without (15%, Χ2 = 12.0 p = 0.001) but did not increase the risk of death in diarrhoea cases. Conclusion Children with SAM complicated by diarrhoea had a higher risk of death than those who did not have diarrhoea during their hospital stay. Further operational and clinical research is needed to reduce mortality in children with SAM in the given setting.

Intra- and interobserver variability in fetal ultrasound measurements

To assess intra‐ and interobserver variability of fetal biometry measurements throughout pregnancy.

International standards for early fetal size and pregnancy dating based on ultrasound measurement of crown-rump length in the first trimester of pregnancy.

There are no international standards for relating fetal crown–rump length (CRL) to gestational age (GA), and most existing charts have considerable methodological limitations. The INTERGROWTH‐21st Project aimed to produce the first international standards for early fetal size and ultrasound dating of pregnancy based on CRL measurement.

International estimated fetal weight standards of the INTERGROWTH-21st Project.

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.

In Vitro Activities of Quinine and Other Antimalarials and pfnhe Polymorphisms in Plasmodium Isolates from Kenya

ABSTRACT Resistance to the amino alcohol quinine has been associated with polymorphisms in pfnhe, a sodium hydrogen exchanger. We investigated the role of this gene in quinine resistance in vitro in isolates from Kenya. We analyzed pfnhe whole-gene polymorphisms, using capillary sequencing, and pfcrt at codon 76 (pfcrt-76) and pfmdr1 at codon 86 (pfmdr1-86), using PCR-enzyme restriction methodology, in 29 isolates from Kilifi, Kenya, for association with the in vitro activities of quinine and 2 amino alcohols, mefloquine and halofantrine. In vitro activity was assessed as the drug concentration that inhibits 50% of parasite growth (IC50). The median IC50s of quinine, halofantrine, and mefloquine were 92, 22, and 18 nM, respectively. The presence of 2 DNNND repeats in microsatellite ms4760 of pfnhe was associated with reduced susceptibility to quinine (60 versus 227 nM for 1 and 2 repeats, respectively; P < 0.05), while 3 repeats were associated with restoration of susceptibility. The decrease in susceptibility conferred by the 2 DNNND repeats was more pronounced in parasites harboring the pfmdr1-86 mutation. No association was found between susceptibility to quinine and the pfcrt-76 mutation or between susceptibility to mefloquine or halofantrine and the pfnhe gene and the pfcrt-76 and pfmdr1-86 mutations. Using previously published data on the in vitro activities of chloroquine, lumefantrine, piperaquine, and dihydroartemisinin, we investigated the association of their activities with pfnhe polymorphism. With the exception of a modulation of the activity of lumefantrine by a mutation at position 1437, pfnhe did not modulate their activities. Two DNNND repeats combined with the pfmdr1-86 mutation could be used as an indicator of reduced susceptibility to quinine.

INTERGROWTH-21st very preterm size at birth reference charts

844 www.thelancet.com Vol 387 February 27, 2016 malformations, or ultrasound evidence of FGR, and 37 because of implausible anthropometric measurements or gestational age estimates. As expected, perinatal events (eg, higher pre-eclampsia, caesarean section, and neonatal mortality rates) for these very preterm babies diff ered from the Newborn Size Standards (appendix). The third, 10th, 50th, 90th, and 97th smoothed centile curves for weight, length, and head circumference at birth according to gestational age and sex, superimposed on the individual data, are shown in the appendix (actual centile values and corresponding equations are provided in the appendix and at the INTERGROWTH-21st website). Values for birthweight and head circumference at 33 weeks’ gestation overlapped perfectly with the original Newborn Size Standards; values for length were complementary at the median level, but less so at the extreme centiles because of the diff erently shaped curves in early and late pregnancy (fi gure). We present very preterm reference charts for newborn baby size at birth using the same underlying population, methods, instruments, standardisation protocols, and statistical analyses as for the Newborn Size Standards, which they complement well. They provide neonatologists with a single way to assess and screen newborn babies from 24 to 42 weeks’ gestation. The head circumference charts are particularly important in view of the urgent need, in the midst of the Zika virus outbreak, to assess the head size of newborn babies with a set of standardised, gestational-age specifi c charts, to avoid over-reporting of cases of microcephaly across all aff ected regions.

The Distribution of Clinical Phenotypes of Preterm Birth Syndrome Implications for Prevention

IMPORTANCE Preterm birth has been difficult to study and prevent because of its complex syndromic nature. OBJECTIVE To identify phenotypes of preterm delivery syndrome in the Newborn Cross-Sectional Study of the INTERGROWTH-21st Project. DESIGN, SETTING, AND PARTICIPANTS A population-based, multiethnic, cross-sectional study conducted at 8 geographically demarcated sites in Brazil, China, India, Italy, Kenya, Oman, the United Kingdom, and the United States. A total of 60,058 births over a 12-month fixed period between April 27, 2009, and March 2, 2014. Of these, 53,871 had an ultrasonography estimate of gestational age, among which 5828 were preterm births (10.8%). Pregnancies were prospectively studied using a standardized data collection and online data management system. Newborns had anthropometric and clinical examinations using standardized methods and identical equipment and were followed up until hospital discharge. MAIN OUTCOMES AND MEASURES The main study outcomes were clusters of preterm phenotypes and for each cluster, we analyzed signs of presentation at hospital admission, admission rates for neonatal intensive care for 7 days or more, and neonatal mortality rates. RESULTS Twelve preterm birth clusters were identified using our conceptual framework. Eleven consisted of combinations of conditions known to be associated with preterm birth, 10 of which were dominated by a single condition. However, the most common single cluster (30.0% of the total preterm cases; n = 1747) was not associated with any severe maternal, fetal, or placental condition that was clinically detectable based on the information available; within this cluster, many cases were caregiver initiated. Only 22% (n = 1284) of all the preterm births occurred spontaneously without any of these severe conditions. Maternal presentation on hospital admission, newborn anthropometry, and risk for death before hospital discharge or admission for 7 or more days to a neonatal intensive care unit, none of which were used to construct the clusters, also differed according to the identified phenotypes. The prevalence of preterm birth ranged from 8.2% in Muscat, Oman, and Oxford, England, to 16.6% in Seattle, Washington. CONCLUSIONS AND RELEVANCE We identified 12 preterm birth phenotypes associated with different patterns of neonatal outcomes. In 22% of all preterm births, parturition started spontaneously and was not associated with any of the phenotypic conditions considered. We believe these results contribute to an improved understanding of this complex syndrome and provide an empirical basis to focus research on a more homogenous set of phenotypes.