[Show abstract][Hide abstract] ABSTRACT: The INTERGROWTH-21 st Project aimed to produce international, prescriptive, postnatal growth standards for preterm infants born to healthy, well-nourished mothers receiving adequate antenatal care. There is little information available regarding optimal postnatal growth among uncomplicated preterm newborns. We describe how the preterm infants contributing to the standards followed evidence-based feeding recommendations.
In the Fetal Growth Longitudinal Study (FGLS), a component of the INTERGROWTH-21 st Project, fetal growth was monitored by ultrasound from <14 weeks’ gestation until birth in pregnancies at low risk of adverse outcomes. All preterms (≥26 +0 and <37 +0 weeks’ gestation) were followed up during infancy. Internationally-accepted feeding recommendations for preterms, agreed by the INTERGROWTH-21 st Neonatal Group, were implemented at each study site. Standardised questionnaires served to record information on their feeding practices.
Feeding data were collected from 201 eligible preterms. The median (interquartile range, IQR) gestational age at birth was 36.0 (35.0 – 36.6) weeks. The prevalence of any breastfeeding was 82 % within 72 h of birth, 96 % at 2 weeks, 82 % at 4 months and 70 % at 8 months postnatal age. The figures for exclusive breastfeeding were 51 % within 72 h of birth, 72 % at hospital discharge, 49 % at 4 months, 38 % at 5 months and 12 % at 6 months. Complementary foods were introduced at a median (IQR) postnatal age of 6.0 (5.1 – 6.8) months.
Most preterms were exclusively breastfed upon hospital discharge, and breastfeeding remained a substantial source of nutrition throughout the study. Recommendations, centred on breastfeeding, were adequately followed within the expected variation of such diverse settings.
[Show abstract][Hide abstract] ABSTRACT: Stunting (short length for age) and wasting (low body mass index [BMI] for age) are widely used to assess child nutrition. In contrast, newborns tend to be assessed solely based on their weight.
To use recent international standards for newborn size by gestational age to assess how stunted and wasted newborns differ in terms of risk factors and prognoses.
A cross-sectional study with follow-up until hospital discharge was conducted at urban sites in Brazil, China, India, Italy, Kenya, Oman, England, and the United States that are participating in the INTERGROWTH-21st Project. The study was conducted from April 27, 2009, to March 2, 2014, and the final dataset for analyses was locked on March 19, 2014.
Sociodemographic and behavioral maternal risk factors, previous pregnancy history, and maternal and fetal conditions during pregnancy were investigated as risk factors for stunting and wasting. Anthropometry at birth was used to predict for neonatal prognosis.
Newborn stunting and wasting were defined as birth length and BMI for gestational age below the third centiles of the INTERGROWTH-21st standards. Prognosis was assessed through mortality before hospital discharge, admission to neonatal intensive care units, and newborn complications.
From the 60 206 singleton live births during the study period, we selected all newborns between 33 weeks' and 42 weeks 6 days' gestation at birth (51 200 [85%]) with reliable ultrasound dating. Stunting affected 3.8% and wasting 3.4% of all newborns; both conditions were present in 0.7% of the sample. Of the 26 conditions studied, five were more strongly associated with stunting than with wasting (reported as odds ratios [OR]; 95% CI): short maternal height (6.7; 5.1-9.0), younger maternal age (0.7; 0.5-0.9), smoking (2.8; 2.3-3.3), illicit drug use (2.3; 1.5-3.6), and clinically suspected intrauterine growth restriction (5.2; 4.5-6.0). Wasting was more strongly related than stunting with 4 newborn outcomes (neonatal intensive care stay, 6.7 [5.5-8.1]; respiratory distress syndrome, 4.0 [3.3-4.9]; transient tachypnea, 2.1 [1.5-2.9]; and no oral feeding for >24 hours, 5.0 [3.9-6.5]). Maternal gestational diabetes mellitus was protective against wasting (0.6; 0.5-0.8) but not against stunting (0.9; 0.7-1.1).
Although newborn stunting and wasting share some common determinants, they are distinct phenotypes with their own risk factors and neonatal prognoses. To be consistent with the literature on infant and child nutrition, newborns should be classified using the 2 phenotypes of stunting and wasting. The distinction will help to prioritize preventive interventions and focus the management of fetal undernutrition.
[Show abstract][Hide abstract] ABSTRACT: Preterm birth has been difficult to study and prevent because of its complex syndromic nature.
To identify phenotypes of preterm delivery syndrome in the Newborn Cross-Sectional Study of the INTERGROWTH-21st Project.
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.
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.
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.
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.
[Show abstract][Hide abstract] ABSTRACT: Objectives
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.Methods
Urban areas in eight geographically diverse countries that met strict eligibility criteria were selected for the prospective, population-based recruitment, between 9+0 to 13+6 weeks of gestation, of healthy well-nourished women with singleton pregnancies at low risk of fetal growth impairment. GA was calculated on the basis of a certain LMP, regular menstrual cycle and lack of hormonal medication or breastfeeding in the preceding two months. CRL was measured using strict protocols and quality control measures. All women were followed up throughout pregnancy until delivery and hospital discharge. Neonatal and fetal deaths, severe pregnancy complications and congenital abnormalities were excluded.ResultsA total of 4,607 women were enrolled in the Fetal Growth Longitudinal Study (FGLS), one of the three main components of the INTERGROWTH-21st Project, of whom 4,321 women had a live singleton birth in the absence of severe maternal conditions or congenital abnormalities detected by ultrasound or at birth. The CRL was measured in 56 women at <9+0 weeks of gestation, resulting in 4,265 women who contributed data to the final analysis. The mean CRL and standard deviation (SD) increased with GA almost linearly. Their relationship to GA is defined by the two equations: Mean CRL (mm) = −50.6562 + 0.815118*GA + 0.00535302*GA2, and SD of CRL (mm) = −2.21626 + 0.0984894*GA, where GA is expressed in days. The formula for GA estimation is defined by the two equations: GA (days) = 40.9041 + 3.21585*CRL0.5 + 0.348956*CRL, and SD of GA (days) = 2.39102 + 0.0193474*CRL, where CRL is expressed in mm.Conclusions
We have produced international prescriptive standards for early fetal linear size and ultrasound dating of pregnancy in the first trimester that can be used throughout the world.
Full-text · Article · Dec 2014 · Ultrasound in Obstetrics and Gynecology
[Show abstract][Hide abstract] ABSTRACT: Large differences exist in size at birth and in rates of impaired fetal growth worldwide. The relative effects of nutrition, disease, the environment, and genetics on these differences are often debated. In clinical practice, various references are often used to assess fetal growth and newborn size across populations and ethnic origins, whereas international standards for assessing growth in infants and children have been established. In the INTERGROWTH-21st Project, our aim was to assess fetal growth and newborn size in eight geographically defined urban populations in which the health and nutrition needs of mothers were met and adequate antenatal care was provided.
Full-text · Article · Oct 2014 · The Lancet Diabetes & Endocrinology
[Show abstract][Hide abstract] ABSTRACT: SummaryBackground In 2006, WHO published international growth standards for children younger than 5 years, which are now accepted worldwide. In the INTERGROWTH-21st 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-21st 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-21st 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.
[Show abstract][Hide abstract] ABSTRACT: 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-21st Project, aimed to develop international growth and size standards for fetuses.
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.
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.
We recommend these international fetal growth standards for the clinical interpretation of routinely taken ultrasound measurements and for comparisons across populations.
Bill & Melinda Gates Foundation.
[Show abstract][Hide abstract] ABSTRACT: Impaired fetal growth and preterm birth are the leading causes of neonatal and infant mortality worldwide and there is a growing scientific literature suggesting that environmental exposures during pregnancy may play a causal role in these outcomes. Our purpose was to assess the environmental exposure of the Fetal Growth Longitudinal Study (FGLS) participants in the multinational INTERGROWTH-21(st) Project. First, we developed a tool that could be used internationally to screen pregnant women for such exposures and administered it in eight countries on a subsample (n = 987) of the FGLS participants. The FGLS is a study of fetal growth among healthy pregnant women living in relatively affluent areas, at low risk of adverse pregnancy outcomes and environmental exposures. We confirmed that most women were not exposed to major environmental hazards that could affect pregnancy outcomes according to the protocol's entry criteria. However, the instrument was able to identify some women that reported various environmental concerns in their homes such as peeling paint, high residential density (>1 person per room), presence of rodents or cockroaches (hence the use of pesticides), noise pollution and safety concerns. This screening tool was therefore useful for the purposes of the project and can be used to ascertain environmental exposures in studies in which the primary aim is not focused on environmental exposures. The instrument can be used to identify subpopulations for more in-depth assessment, (e.g. environmental and biological laboratory markers) to pinpoint areas requiring education, intervention or policy change.
Full-text · Article · Sep 2013 · BJOG An International Journal of Obstetrics & Gynaecology
[Show abstract][Hide abstract] ABSTRACT: Please cite this paper as: Villar J, Altman D, Purwar M, Noble J, Knight H, Ruyan P, Cheikh Ismail L, Barros F, Lambert A, Papageorghiou A, Carvalho M, Jaffer Y, Bertino E, Gravett M, Bhutta Z, Kennedy S, for the International Fetal and Newborn Growth Consortium for the 21st Century (INTERGROWTH-21st). The objectives, design and implementation of the INTERGROWTH-21st Project. BJOG 2013; 120 (Suppl. 2): 9–26. INTERGROWTH-21st is a multicentre, multiethnic, population-based project, being conducted in eight geographical areas (Brazil, China, India, Italy, Kenya, Oman, UK and USA), with technical support from four global specialised units, to study growth, health and nutrition from early pregnancy to infancy. It aims to produce prescriptive growth standards, which conceptually extend the World Health Organization (WHO) Multicentre Growth Reference Study (MGRS) to cover fetal and newborn life. The new international standards will describe: (1) fetal growth assessed by clinical and ultrasound measures; (2) postnatal growth of term and preterm infants up to 2 years of age; and (3) the relationship between birthweight, length and head circumference, gestational age and perinatal outcomes. As the project has selected healthy cohorts with no obvious risk factors for intrauterine growth restriction, these standards will describe how all fetuses and newborns should grow, as opposed to traditional charts that describe how some have grown at a given place and time. These growth patterns will be related to morbidity and mortality to identify levels of perinatal risk. Additional aims include phenotypic characterisation of the preterm and impaired fetal growth syndromes and development of a prediction model, based on multiple ultrasound measurements, to estimate gestational age for use in pregnant women without access to early/frequent antenatal care.
Full-text · Article · Sep 2013 · BJOG An International Journal of Obstetrics & Gynaecology
[Show abstract][Hide abstract] ABSTRACT: f Programa de P os-Graduac ß~ ao em Sa ude e Comportamento, Universidade Cat olica de Pelotas, g Programa de P os-Graduac ß~ ao em Epidemiologia, Universidade Federal de Pelotas, Pelotas, Brazil h Impaired fetal growth and preterm birth are the leading causes of neonatal and infant mortality worldwide and there is a growing scientific literature suggesting that environmental exposures during pregnancy may play a causal role in these outcomes. Our purpose was to assess the environmental exposure of the Fetal Growth Longitudinal Study (FGLS) participants in the multinational INTERGROWTH-21 st Project. First, we developed a tool that could be used internationally to screen pregnant women for such exposures and administered it in eight countries on a subsample (n = 987) of the FGLS participants. The FGLS is a study of fetal growth among healthy pregnant women living in relatively affluent areas, at low risk of adverse pregnancy outcomes and environmental exposures. We confirmed that most women were not exposed to major environmental hazards that could affect pregnancy outcomes according to the protocol's entry criteria. However, the instrument was able to identify some women that reported various environmental concerns in their homes such as peeling paint, high residential density (>1 person per room), presence of rodents or cockroaches (hence the use of pesticides), noise pollution and safety concerns. This screening tool was therefore useful for the purposes of the project and can be used to ascertain environmental exposures in studies in which the primary aim is not focused on environmental exposures. The instrument can be used to identify subpopulations for more in-depth assessment, (e.g. environmental and biological laboratory markers) to pinpoint areas requiring education, intervention or policy change., for the International Fetal and Newborn Growth Consortium for the 21 st Century (INTERGROWTH-21 st). A rapid questionnaire assessment of environmental exposures to pregnant women in the INTERGROWTH-21 st Project. BJOG 2013;120 (Suppl. 2): 129–138.
[Show abstract][Hide abstract] ABSTRACT: To refine a previously reported linkage peak for endometriosis on chromosome 10q26, and conduct follow-up analyses and a fine-mapping association study across the region to identify new candidate genes for endometriosis.
Cases=3,223 women with surgically confirmed endometriosis; controls=1,190 women without endometriosis and 7,060 population samples.
Analysis of 11,984 single nucleotide polymorphisms on chromosome 10.
Allele frequency differences between cases and controls.
Linkage analyses on families grouped by endometriosis symptoms (primarily subfertility) provided increased evidence for linkage (logarithm of odds score=3.62) near a previously reported linkage peak. Three independent association signals were found at 96.59 Mb (rs11592737), 105.63 Mb (rs1253130), and 124.25 Mb (rs2250804). Analyses including only samples from linkage families supported the association at all three regions. However, only rs11592737 in the cytochrome P450 subfamily C (CYP2C19) gene was replicated in an independent sample of 2,079 cases and 7,060 population controls.
The role of the CYP2C19 gene in conferring risk for endometriosis warrants further investigation.
Full-text · Article · Jun 2011 · Fertility and sterility
[Show abstract][Hide abstract] ABSTRACT: Endometriosis is a common gynecological disease associated with pelvic pain and subfertility. We conducted a genome-wide association study (GWAS) in 3,194 individuals with surgically confirmed endometriosis (cases) and 7,060 controls from Australia and the UK. Polygenic predictive modeling showed significantly increased genetic loading among 1,364 cases with moderate to severe endometriosis. The strongest association signal was on 7p15.2 (rs12700667) for 'all' endometriosis (P = 2.6 × 10⁻⁷, odds ratio (OR) = 1.22, 95% CI 1.13-1.32) and for moderate to severe disease (P = 1.5 × 10⁻⁹, OR = 1.38, 95% CI 1.24-1.53). We replicated rs12700667 in an independent cohort from the United States of 2,392 self-reported, surgically confirmed endometriosis cases and 2,271 controls (P = 1.2 × 10⁻³, OR = 1.17, 95% CI 1.06-1.28), resulting in a genome-wide significant P value of 1.4 × 10⁻⁹ (OR = 1.20, 95% CI 1.13-1.27) for 'all' endometriosis in our combined datasets of 5,586 cases and 9,331 controls. rs12700667 is located in an intergenic region upstream of the plausible candidate genes NFE2L3 and HOXA10.
[Show abstract][Hide abstract] ABSTRACT: To determine the relationship between disease severity and patient characteristics in endometriosis.
Cross-sectional study of self-reported survey data.
Academic research setting.
One thousand women in the Oxford Endometriosis Gene (OXEGENE) study.
Participants were assigned to one of two groups with predominantly revised AFS stage I-II (group I, n = 423) or III-IV disease (group II, n = 517). Their characteristics were compared by disease extent.
Most participants were white (96%) and of reproductive age (81%). Women in group I were significantly younger on entering the study (39.9 +/- 0.5 vs. 44.5 +/- 0.4 years). Overall time to diagnosis did not differ between groups. The most common symptoms leading to a diagnosis were dysmenorrhea (79%) and pelvic pain (69%). In group II, subfertility (21.5% vs. 30.0%) and an ovarian mass (7.3% vs. 29.4%) more commonly led to a diagnosis, whereas dyspareunia (51.1% vs. 39.5%) was significantly more common in group I. Subfertility (41.5% vs. 53.4%) remained more common in group II throughout reproductive life, although birth and miscarriage rates were similar.
Pelvic pain is common to all with endometriosis and those with more extensive disease report higher rates of subfertility. Remarkably, the time to diagnosis was similar among women.
Full-text · Article · Apr 2008 · Fertility and sterility
[Show abstract][Hide abstract] ABSTRACT: The aim of the International Endogene Study is to discover genes that influence susceptibility to endometriosis.
The study brings together two research groups based in Australia and the United Kingdom that independently have been collecting families for linkage analysis and candidate gene studies. Both groups used similar methods to recruit families, obtain clinical notes, assign disease status based on the operative records and available histology, and collect common clinical data including age at onset of symptoms, age at diagnosis, and symptoms experienced.
Recruitment has been mainly from Australia, the United Kingdom, and the United States.
All affected participants have surgically confirmed disease.
Clinical and epidemiological data.
To date, >1,100 families with affected sisters have been recruited, and >1,200 triads (affected women and both parents), for case-control studies.
We have created the largest resource yet assembled of clinical data and DNA for linkage and association studies in endometriosis. The increase in power to detect susceptibility genes vindicates the decision to merge the two studies and demonstrates the value of large-scale international collaboration.
Full-text · Article · Oct 2002 · Fertility and Sterility