Fetal cerebellar growth and Sylvian fissure maturation: international standards from Fetal Growth Longitudinal Study of INTERGROWTH-21st Project.

OBJECTIVE: To construct international ultrasound-based standards for fetal cerebellar growth and Sylvian fissure maturation. METHODS: Healthy, well nourished pregnant women, enrolled at < 14 weeks' gestation in the Fetal Growth Longitudinal Study (FGLS) of INTERGROWTH-21st , an international multicenter, population-based project, underwent serial three-dimensional (3D) fetal ultrasound scans every 5 ± 1 weeks until delivery in study sites located in Brazil, India, Italy, Kenya and the UK. In the present analysis, only those fetuses that underwent developmental assessment at 2 years of age were included. We measured the transcerebellar diameter and assessed Sylvian fissure maturation using two-dimensional ultrasound images extracted from available 3D fetal head volumes. The appropriateness of pooling data from the five sites was assessed using variance component analysis and standardized site differences. For each Sylvian fissure maturation score (left or right side), mean gestational age and 95% CI were calculated. Transcerebellar diameter was modeled using fractional polynomial regression, and goodness of fit was assessed. RESULTS: Of those children in the original FGLS cohort who had developmental assessment at 2 years of age, 1130 also had an available 3D ultrasound fetal head volume. The sociodemographic characteristics and pregnancy/perinatal outcomes of the study sample confirmed the health and low-risk status of the population studied. In addition, the fetuses had low morbidity and adequate growth and development at 2 years of age. In total, 3016 and 2359 individual volumes were available for transcerebellar-diameter and Sylvian-fissure analysis, respectively. Variance component analysis and standardized site differences showed that the five study populations were sufficiently similar on the basis of predefined criteria for the data to be pooled to produce international standards. A second-degree fractional polynomial provided the best fit for modeling transcerebellar diameter; we then estimated gestational-age-specific 3rd , 50th and 97th smoothed centiles. Goodness-of-fit analysis comparing empirical centiles with smoothed centile curves showed good agreement. The Sylvian fissure increased in maturation with advancing gestation, with complete overlap of the mean gestational age and 95% CIs between the sexes for each development score. No differences in Sylvian fissure maturation between the right and left hemispheres were observed. CONCLUSION: We present, for the first time, international standards for fetal cerebellar growth and Sylvian fissure maturation throughout pregnancy based on a healthy fetal population that exhibited adequate growth and development at 2 years of age. © 2020 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

International standards for fetal brain structures based on serial ultrasound measurements from Fetal Growth Longitudinal Study of INTERGROWTH-21st Project.

OBJECTIVE: To create prescriptive growth standards for five fetal brain structures, measured using ultrasound, in healthy, well-nourished women at low risk of impaired fetal growth and poor perinatal outcome, taking part in the Fetal Growth Longitudinal Study (FGLS) of the INTERGROWTH-21st Project. METHODS: This was a complementary analysis of a large, population-based, multicenter, longitudinal study. The sample analyzed was selected randomly from the overall FGLS population, ensuring an equal distribution among the eight diverse participating sites and of three-dimensional (3D) ultrasound volumes across pregnancy (range: 15-36 weeks' gestation). We measured, in planes reconstructed from 3D ultrasound volumes of the fetal head at different timepoints in pregnancy, the size of the parieto-occipital fissure (POF), Sylvian fissure (SF), anterior horn of the lateral ventricle, atrium of the posterior horn of the lateral ventricle (PV) and cisterna magna (CM). Fractional polynomials were used to construct the standards. Growth and development of the infants were assessed at 1 and 2 years of age to confirm their adequacy for constructing international standards. RESULTS: From the entire FGLS cohort of 4321 women, 451 (10.4%) were selected at random. After exclusions, 3D ultrasound volumes from 442 fetuses born without a congenital malformation were used to create the charts. The fetal brain structures of interest were identified in 90% of cases. All structures, except the PV, showed increasing size with gestational age, and the size of the POF, SF, PV and CM showed increasing variability. The 3rd , 5th , 50th , 95th and 97th smoothed centiles are presented. The 5th centiles for the POF and SF were 3.1 mm and 4.7 mm at 22 weeks' gestation and 4.6 mm and 9.9 mm at 32 weeks, respectively. The 95th centiles for the PV and CM were 8.5 mm and 7.5 mm at 22 weeks and 8.6 mm and 9.5 mm at 32 weeks, respectively. CONCLUSIONS: We have produced prescriptive size standards for fetal brain structures based on prospectively enrolled pregnancies at low risk of abnormal outcome. We recommend these as international standards for the assessment of measurements obtained using ultrasound from fetal brain structures. © 2020 Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

The antepartum stillbirth syndrome: risk factors and pregnancy conditions identified from the INTERGROWTH-21st Project.

OBJECTIVES: To identify risk factors for antepartum stillbirth, including fetal growth restriction, among women with well-dated pregnancies and access to antenatal care. DESIGN: Population-based, prospective, observational study. SETTING: Eight international urban populations. POPULATION: Pregnant women and their babies enrolled in the Newborn Cross-Sectional Study of the INTERGROWTH-21st Project. METHODS: Cox proportional hazard models were used to compare risks among antepartum stillborn and liveborn babies. MAIN OUTCOME MEASURES: Antepartum stillbirth was defined as any fetal death after 16 weeks' gestation before the onset of labour. RESULTS: Of 60 121 babies, 553 were stillborn (9.2 per 1000 births), of which 445 were antepartum deaths (7.4 per 1000 births). After adjustment for site, risk factors were low socio-economic status, hazard ratio (HR): 1.6 (95% CI, 1.2-2.1); single marital status, HR 2.0 (95% CI, 1.4-2.8); age ≥40 years, HR 2.2 (95% CI, 1.4-3.7); essential hypertension, HR 4.0 (95% CI, 2.7-5.9); HIV/AIDS, HR 4.3 (95% CI, 2.0-9.1); pre-eclampsia, HR 1.6 (95% CI, 1.1-3.8); multiple pregnancy, HR 3.3 (95% CI, 2.0-5.6); and antepartum haemorrhage, HR 3.3 (95% CI, 2.5-4.5). Birth weight <3rd centile was associated with antepartum stillbirth [HR, 4.6 (95% CI, 3.4-6.2)]. The greatest risk was seen in babies not suspected to have been growth restricted antenatally, with an HR of 5.0 (95% CI, 3.6-7.0). The population-attributable risk of antepartum death associated with small-for-gestational-age neonates diagnosed at birth was 11%. CONCLUSIONS: Antepartum stillbirth is a complex syndrome associated with several risk factors. Although small babies are at higher risk, current growth restriction detection strategies only modestly reduced the rate of stillbirth. TWEETABLE ABSTRACT: International stillbirth study finds individual risks poor predictors of death but combinations promising.

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

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 < 37 weeks' gestation, the EFW centiles were, as expected, higher than those of babies born preterm. Comparing EFW cross-sectional values with the INTERGROWTH-21st Preterm Postnatal Growth Standards confirmed that preterm postnatal growth is a different biological process from intrauterine growth. CONCLUSIONS: We provide an assessment of EFW, as an adjunct to routine ultrasound biometry, from 22 to 40 weeks' gestation. However, we strongly encourage clinicians to evaluate fetal growth using separate biometric measures such as HC and AC, as well as EFW, to avoid the minimalist approach of focusing on a single value. © 2016 Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Ultrasound-based gestational-age estimation in late pregnancy.

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.

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

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-21(st) 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 and 13 + 6 weeks' 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 last menstrual period, regular menstrual cycle and lack of hormonal medication or breastfeeding in the preceding 2 months. CRL was measured using strict protocols and quality-control measures. All women were followed up throughout pregnancy until delivery and hospital discharge. Cases of neonatal and fetal death, severe pregnancy complications and congenital abnormalities were excluded from the study. RESULTS: A total of 4607 women were enrolled in the Fetal Growth Longitudinal Study, one of the three main components of the INTERGROWTH-21(st) Project, of whom 4321 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' gestation; these were excluded, resulting in 4265 women who contributed data to the final analysis. The mean CRL and SD increased with GA almost linearly, and their relationship to GA is given by the following two equations (in which GA is in days and CRL in mm): mean CRL = -50.6562 + (0.815118 × GA) + (0.00535302 × GA(2) ); and SD of CRL = -2.21626 + (0.0984894 × GA). GA estimation is carried out according to the two equations: GA = 40.9041 + (3.21585 × CRL(0.5) ) + (0.348956 × CRL); and SD of GA = 2.39102 + (0.0193474 × CRL). 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.

A rapid questionnaire assessment of environmental exposures to pregnant women in the INTERGROWTH-21st Project.

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.

Translating research into practice: the introduction of the INTERGROWTH-21st package of clinical standards, tools and guidelines into policies, programmes and services.

The INTERGROWTH-21(st) Project has generated a package of international clinical standards, tools and guidelines. It is now necessary to plan for the next phase of the project: the translation of the research findings into practice through its global dissemination. The plan is to pre-empt barriers to implementation by drawing from the published literature; gathering views and perspectives from policy makers, programmers and practitioners; incorporating input from local 'champions', and collecting and analysing data generated by a monitoring and evaluation system. Working at the global, regional, national and local levels will enable wide dissemination of the package, as well as increase the scope for adaptation and integration in diverse clinical contexts. We seek maximum uptake of the package in policies, guidelines and clinical practice to improve the quality of care offered to mothers and newborns. The strategy will also enhance our understanding of the effectiveness of different approaches to the translation of evidence into practice.

Implementation of the INTERGROWTH-21st Project in Italy.

Turin, Italy, was one of the two European sites for the INTERGROWTH-21(st) Project. The sample for the Newborn Cross-Sectional Study (NCSS) was drawn from two obstetric hospitals that together account for 79% of the city's approximately 12,000 births per year. Women were recruited for the Fetal Growth Longitudinal Study (FGLS) from ten antenatal clinics serving the city's largest obstetric hospital, Azienda Ospedaliera OIRM-S. Anna. Special activities to encourage participation and raise awareness of the project in this population included obtaining an endorsement from the coordinator of the city's antenatal care service, and disseminating information about the project to women through posters and leaflets in antenatal clinics. One of the major challenges at this site was the low recruitment rate in the early phase of FGLS because of the high prevalence of smoking and of women >35 years old in the population. The addition of six extra recruiting clinics served to increase the pool of potentially eligible women who could be screened and led to a marked improvement in the recruitment rate.

Anthropometric protocols for the construction of new international fetal and newborn growth standards: the INTERGROWTH-21st Project.

The primary aim of the INTERGROWTH-21(st) Project is to construct new, prescriptive standards describing optimal fetal and preterm postnatal growth. The anthropometric measurements include the head circumference, recumbent length and weight of the infants, and the stature and weight of the parents. In such a large, international, multicentre project, it is critical that all study sites follow standardised protocols to ensure maximal validity of the growth and nutrition indicators used. This paper describes, in detail, the selection of anthropometric personnel, equipment, and measurement and calibration protocols used to construct the new standards. Implementing these protocols at each study site ensures that the anthropometric data are of the highest quality to construct the international standards.

Implementation of the INTERGROWTH-21st Project in the United States.

The North American site in the INTERGROWTH-21(st) Project was North Seattle, Washington State, USA. The majority of the data were collected from within Seattle City, which has approximately 12 300 births per year. The sample for the Newborn Cross-Sectional Study (NCSS) was drawn from two hospitals (Swedish Medical Center and the University of Washington) covering almost 80% of deliveries within the target population. The Fetal Growth Longitudinal Study (FGLS) sample was recruited from several antenatal clinics serving the University of Washington Medical Center and Providence Everett Medical Center. Special activities to encourage participation and raise awareness of the studies included furnishing the recruitment sites with fliers designed by the Project Coordinating Unit, and presenting the studies to clinical staff to encourage providers to refer appropriate patients. One of the major challenges at this site was the low recruitment rate in the early phase of the FGLS because of the high rates of smoking, maternal age >35 years and body mass index >30 years. This was remedied by the inclusion of other ancillary clinics, as well as increased advertising among the general public.

Anthropometric standardisation and quality control protocols for the construction of new, international, fetal and newborn growth standards: the INTERGROWTH-21st Project.

The primary aim of the INTERGROWTH-21(st) Project is to construct new, prescriptive standards describing optimal fetal and preterm postnatal growth. The anthropometric measurements include the head circumference, recumbent length and weight of the infants, and the stature and weight of the parents. In such a large, international, multicentre project, it is critical that all study sites follow standardised protocols to ensure maximal validity of the growth and nutrition indicators used. This paper describes in detail the anthropometric training, standardisation and quality control procedures used to collect data for these new standards. The initial standardisation session was in Nairobi, Kenya, using newborns, which was followed by similar sessions in the eight participating study sites in Brazil, China, India, Italy, Kenya, Oman, UK and USA. The intraobserver and inter-observer technical error of measurement values for head circumference range from 0.3 to 0.4 cm, and for recumbent length from 0.3 to 0.5 cm. These standardisation protocols implemented at each study site worldwide ensure that the anthropometric data collected are of the highest quality to construct international growth standards.

Standardisation of neonatal clinical practice.

The International Fetal and Newborn Growth Consortium for the 21(st) Century (INTERGROWTH-21(st) ) is a large-scale, population-based, multicentre project involving health institutions from eight geographically diverse countries, which aims to assess fetal, newborn and preterm growth under optimal conditions. Given the multicentre nature of the project and the expected number of preterm births, it is vital that all centres follow the same standardised clinical care protocols to assess and manage preterm infants, so as to ensure maximum validity of the resulting standards as indicators of growth and nutrition with minimal confounding. Moreover, it is well known that evidence-based clinical practice guidelines can reduce the delivery of inappropriate care and support the introduction of new knowledge into clinical practice. The INTERGROWTH-21(st) Neonatal Group produced an operations manual, which reflects the consensus reached by members of the group regarding standardised definitions of neonatal morbidities and the minimum standards of care to be provided by all centres taking part in the project. The operational definitions and summary management protocols were developed by consensus through a Delphi process based on systematic reviews of relevant guidelines and management protocols by authoritative bodies. This paper describes the process of developing the Basic Neonatal Care Manual, as well as the morbidity definitions and standardised neonatal care protocols applied across all the INTERGROWTH-21(st) participating centres. Finally, thoughts about implementation strategies are presented.

The objectives, design and implementation of the INTERGROWTH-21st Project.

INTERGROWTH-21(st) 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.

Implementation of the INTERGROWTH-21st Project in India.

The South Asian site in the INTERGROWTH-21(st) Project was the city of Nagpur, in Maharashtra State, India, with approximately 4500 births per year among the target population with middle to high socio-economic status. These deliveries are mainly concentrated in 20 small private hospitals, most of which are in the city centre. The sample for the Newborn Cross-Sectional Study (NCSS) was drawn from ten of these hospitals, covering 76% of the target low-risk pregnant population. The Fetal Growth Longitudinal Study (FGLS) sample was recruited from the largest of these institutions, Ketkar Hospital, as well as several ancillary antenatal care clinics. Special activities to encourage participation and raise awareness of the study at this site included translating patient information leaflets into local languages and securing local media interest. Among the unique challenges of the Indian site was the coordination of the large number of hospitals involved in NCSS, a task that required careful planning and organisation by the field teams.

Managing data for the international, multicentre INTERGROWTH-21st Project.

The INTERGROWTH-21(st) Project data management was structured incorporating both a centralised and decentralised system for the eight study centres, which all used the same database and standardised data collection instruments, manuals and processes. Each centre was responsible for the entry and validation of their country-specific data, which were entered onto a centralised system maintained by the Data Coordinating Unit in Oxford. A comprehensive data management system was designed to handle the very large volumes of data. It contained internal validations to prevent incorrect and inconsistent values being captured, and allowed online data entry by local Data Management Units, as well as real-time management of recruitment and data collection by the Data Coordinating Unit in Oxford. To maintain data integrity, only the Data Coordinating Unit in Oxford had access to all the eight centres' data, which were continually monitored. All queries identified were raised with the relevant local data manager for verification and correction, if necessary. The system automatically logged an audit trail of all updates to the database with the date and name of the person who made the changes. These rigorous processes ensured that the data collected in the INTERGROWTH-21(st) Project were of exceptionally high quality.

Implementation of the INTERGROWTH-21st Project in the UK.

There are approximately 10,000 births per year in the county of Oxfordshire in the UK, which is one of the two European sites for the International Fetal and Newborn Growth Consortium for the 21(st) Century (INTERGROWTH-21(st) ) Project. The samples for both components of the project--the Fetal Growth Longitudinal Study (FGLS) and Newborn Cross-Sectional Study (NCSS)--were drawn from the John Radcliffe Hospital, a major university hospital with a large regional role that covers more than 75% of deliveries in the county. Special activities to encourage participation in this population included the formation of a research coalition to streamline recruitment in the Maternity Unit and the distribution of study information leaflets to women using the hospital's antenatal care service. This was a demanding project and several challenges were overcome to reach recruitment targets and to maintain high standards of data quality. Amongst the major challenges for FGLS at this study site was the level of ineligibility because of maternal age, smoking and body mass index (BMI) ≥ 30. The major challenge for the NCSS field teams was to ensure that all anthropometric data were collected before the early discharge of uncomplicated deliveries, often within 6 hours of birth. It is evident from our experience in implementing this project that, when large-scale clinical studies are meticulously planned and avoid major disruption to routine clinical care, they are well received by hospital staff and can contribute to the improvement of the overall standard of clinical care.

Implementation of the INTERGROWTH-21st Project in Oman.

The Middle Eastern site in the INTERGROWTH-21(st) Project was Muscat, the capital city of Oman, with approximately 10,500 births per year. The sample for the Newborn Cross-Sectional Study (NCSS) was drawn from two hospitals covering 96% of the region's births. The Fetal Growth Longitudinal Study (FGLS) sample was recruited from four primary health facilities serving Khoula Hospital, using the eligibility criteria in the INTERGROWTH-21(st) protocol. Special activities to encourage participation in this population included local advocacy campaigns to encourage early antenatal booking and ultrasound dating in the population. The major challenges at the site were the recruitment of sufficient numbers of women at an early gestational age, and the timely measurement of all newborns within 12 hours of birth. Many individuals and institutions collaborated effectively over a period of several years on these studies, which required careful planning and close monitoring for their successful implementation.

Implementation of the INTERGROWTH-21st Project in China.

The East Asian site in the INTERGROWTH-21(st) Project was Shunyi County, Beijing, China, which is an affluent suburb of north Beijing delivering approximately 7000 women annually. The Newborn Cross-Sectional Study (NCSS) sample was drawn from two hospitals, covering >85% of births in the county. The Fetal Growth Longitudinal Study sample (FGLS) was recruited from the antenatal clinic of Shunyi Maternal & Child Health Hospital, the larger of the two institutions. Special activities to promote the study in this population included: (1) the distribution of health education materials about the importance of antenatal care and (2) the organisation of seminars by the study team to brief key stakeholders at the two hospitals about the goals of the research. One of the major challenges at this site in the early stages of the study was a reluctance to have an early ultrasound dating scan (<14(+0) weeks of gestation). This challenge was overcome after a thorough evaluation of the literature regarding the benefits of an early ultrasound scan for dating purposes, as a result of which there was a formal change in hospital policy.

Implementation of the INTERGROWTH-21st Project in Kenya.

The African site in the INTERGROWTH-21(st) Project was Parklands, a wealthy suburb of Nairobi, Kenya, with a largely middle-to-high socio-economic status population. There are three hospitals with obstetric units in Parklands, with approximately 4300 births per year. The Newborn Cross-Sectional Study (NCSS) sample was drawn from all three hospitals, covering 100% of births in this target population. The Fetal Growth Longitudinal Study (FGLS) sample was recruited from antenatal clinics serving these hospitals, using the eligibility criteria in the INTERGROWTH-21(st) protocol. Special activities to raise awareness of the study included securing media coverage and distributing leaflets in antenatal clinic waiting rooms. FGLS required women to be recruited in the first trimester; therefore, a major challenge at this study site was the high background frequency of first antenatal consultations in the second trimester. The problem was overcome by the study awareness campaign, as a result of which more women started attending antenatal care earlier in pregnancy.