Monitoring human growth and development: a continuum from the womb to the classroom

A comprehensive set of fully integrated anthropometric measures is needed to evaluate human growth from conception to infancy so that consistent judgments can be made about the appropriateness of fetal and infant growth. At present, there are 2 barriers to this strategy. First, descriptive reference charts, which are derived from local, unselected samples with inadequate methods and poor characterization of their putatively healthy populations, commonly are used rather than prescriptive standards. The use of prescriptive standards is justified by the extensive biologic, genetic, and epidemiologic evidence that skeletal growth is similar from conception to childhood across geographic populations, when health, nutrition, environmental, and health care needs are met. Second, clinicians currently screen fetuses, newborn infants, and infants at all levels of care with a wide range of charts and cutoff points, often with limited appreciation of the underlying population or quality of the study that generated the charts. Adding to the confusion, infants are evaluated after birth with a single prescriptive tool: the World Health Organization Child Growth Standards, which were derived from healthy, breastfed newborn infants, infants, and young children from populations that have been exposed to few growth-restricting factors. The International Fetal and Newborn Growth Consortium for the 21st Century Project addressed these issues by providing international standards for gestational age estimation, first-trimester fetal size, fetal growth, newborn size for gestational age, and postnatal growth of preterm infants, all of which complement the World Health Organization Child Growth Standards conceptually, methodologically, and analytically. Hence, growth and development can now, for the first time, be monitored globally across the vital first 1000 days and all the way to 5 years of age. It is clear that an integrative approach to monitoring growth and development from pregnancy to school age is desirable, scientifically supported, and likely to improve care, referral patterns, and reporting systems. Such integration can be achieved only through the use of international growth standards, especially in increasingly diverse, mixed ancestry populations. Resistance to new scientific developments has been hugely problematic in medicine; however, we are confident that the obstetric and neonatal communities will join their pediatric colleagues worldwide in the adoption of this integrative strategy

Achieving accurate estimates of fetal gestational age and personalised predictions of fetal growth based on data from an international prospective cohort study: a population-based machine learning study.

Background: Preterm birth is a major global health challenge, the leading cause of death in children under 5 years of age, and a key measure of a population's general health and nutritional status. Current clinical methods of estimating fetal gestational age are often inaccurate. For example, between 20 and 30 weeks of gestation, the width of the 95% prediction interval around the actual gestational age is estimated to be 18-36 days, even when the best ultrasound estimates are used. The aims of this study are to improve estimates of fetal gestational age and provide personalised predictions of future growth. Methods: Using ultrasound-derived, fetal biometric data, we developed a machine learning approach to accurately estimate gestational age. The accuracy of the method is determined by reference to exactly known facts pertaining to each fetus-specifically, intervals between ultrasound visits-rather than the date of the mother's last menstrual period. The data stem from a sample of healthy, well-nourished participants in a large, multicentre, population-based study, the International Fetal and Newborn Growth Consortium for the 21st Century (INTERGROWTH-21st). The generalisability of the algorithm is shown with data from a different and more heterogeneous population (INTERBIO-21st Fetal Study). Findings: In the context of two large datasets, we estimated gestational age between 20 and 30 weeks of gestation with 95% confidence to within 3 days, using measurements made in a 10-week window spanning the second and third trimesters. Fetal gestational age can thus be estimated in the 20-30 weeks gestational age window with a prediction interval 3-5 times better than with any previous algorithm. This will enable improved management of individual pregnancies. 6-week forecasts of the growth trajectory for a given fetus are accurate to within 7 days. This will help identify at-risk fetuses more accurately than currently possible. At population level, the higher accuracy is expected to improve fetal growth charts and population health assessments. Interpretation: Machine learning can circumvent long-standing limitations in determining fetal gestational age and future growth trajectory, without recourse to often inaccurately known information, such as the date of the mother's last menstrual period. Using this algorithm in clinical practice could facilitate the management of individual pregnancies and improve population-level health. Upon publication of this study, the algorithm for gestational age estimates will be provided for research purposes free of charge via a web portal. Funding: Bill & Melinda Gates Foundation, Office of Science (US Department of Energy), US National Science Foundation, and National Institute for Health Research Oxford Biomedical Research Centre

International values for haemoglobin distributions in healthy pregnant women.

BACKGROUND: Anaemia in pregnancy is a global health problem with associated morbidity and mortality. METHODS: A secondary analysis of prospective, population-based study from 2009 to 2016 to generate maternal haemoglobin normative centiles in uncomplicated pregnancies in women receiving optimal antenatal care. Pregnant women were enrolled <14 weeks' gestation in the Fetal Growth Longitudinal Study (FGLS) of the INTERGROWTH-21st Project which involved eight geographically diverse urban areas in Brazil, China, India, Italy, Kenya, Oman, United Kingdom and United States. At each 5 ± 1 weekly visit until delivery, information was collected about the pregnancy, as well as the results of blood tests taken as part of routine antenatal care that complemented the study's requirements, including haemoglobin values. FINDINGS: A total of 3502 (81%) of 4321 women who delivered a live, singleton newborn with no visible congenital anomalies, contributed at least one haemoglobin value. Median haemoglobin concentrations ranged from 114.6 to 121.4 g/L, 94 to 103 g/L at the 3rd centile, and from 135 to 141 g/L at the 97th centile. The lowest values were seen between 31 and 32 weeks' gestation, representing a mean drop of 6.8 g/L compared to 14 weeks' gestation. The percentage variation in maternal haemoglobin within-site was 47% of the total variance compared to 13% between sites. INTERPRETATION: We have generated International, gestational age-specific, smoothed centiles for maternal haemoglobin concentration compatible with better pregnancy outcomes, as well as adequate neonatal and early childhood morbidity, growth and development up to 2 years of age. FUNDING: Bill & Melinda Gates Foundation Grant number 49038

Body composition at birth and its relationship with neonatal anthropometric ratios: the newborn body composition study of the INTERGROWTH-21(st) project.

Background We aimed to describe newborn body composition and identify which anthropometric ratio (weight/length; BMI; or ponderal index, PI) best predicts fat mass (FM) and fat-free mass (FFM). Methods Air-displacement plethysmography (PEA POD) was used to estimate FM, FFM, and body fat percentage (BF%). Associations between FFM, FM, and BF% and weight/length, BMI, and PI were evaluated in 1,019 newborns using multivariate regression analysis. Charts for FM, FFM, and BF% were generated using a prescriptive subsample (n=247). Standards for the best-predicting anthropometric ratio were calculated utilizing the same population used for the INTERGROWTH-21(st) Newborn Size Standards (n=20,479). Results FFM and FM increased consistently during late pregnancy. Differential FM, BF%, and FFM patterns were observed for those born preterm (34(+0)-36(+6) weeks' gestation) and with impaired intrauterine growth. Weight/length by gestational age (GA) was a better predictor of FFM and FM (adjusted R(2)=0.92 and 0.71, respectively) than BMI or PI, independent of sex, GA, and timing of measurement. Results were almost identical when only preterm newborns were studied. We present sex-specific centiles for weight/length ratio for GA. Conclusions Weight/length best predicts newborn FFM and FM. There are differential FM, FFM, and BF% patterns by sex, GA, and size at birth

The satisfactory growth and development at 2 years of age of the INTERGROWTH-21st Fetal Growth Standards cohort support its appropriateness for constructing international standards.

BACKGROUND: The World Health Organization recommends that human growth should be monitored with the use of international standards. However, in obstetric practice, we continue to monitor fetal growth using numerous local charts or equations that are based on different populations for each body structure. Consistent with World Health Organization recommendations, the INTERGROWTH-21st Project has produced the first set of international standards to date pregnancies; to monitor fetal growth, estimated fetal weight, Doppler measures, and brain structures; to measure uterine growth, maternal nutrition, newborn infant size, and body composition; and to assess the postnatal growth of preterm babies. All these standards are based on the same healthy pregnancy cohort. Recognizing the importance of demonstrating that, postnatally, this cohort still adhered to the World Health Organization prescriptive approach, we followed their growth and development to the key milestone of 2 years of age. OBJECTIVE: The purpose of this study was to determine whether the babies in the INTERGROWTH-21st Project maintained optimal growth and development in childhood. STUDY DESIGN: In the Infant Follow-up Study of the INTERGROWTH-21st Project, we evaluated postnatal growth, nutrition, morbidity, and motor development up to 2 years of age in the children who contributed data to the construction of the international fetal growth, newborn infant size and body composition at birth, and preterm postnatal growth standards. Clinical care, feeding practices, anthropometric measures, and assessment of morbidity were standardized across study sites and documented at 1 and 2 years of age. Weight, length, and head circumference age- and sex-specific z-scores and percentiles and motor development milestones were estimated with the use of the World Health Organization Child Growth Standards and World Health Organization milestone distributions, respectively. For the preterm infants, corrected age was used. Variance components analysis was used to estimate the percentage variability among individuals within a study site compared with that among study sites. RESULTS: There were 3711 eligible singleton live births; 3042 children (82%) were evaluated at 2 years of age. There were no substantive differences between the included group and the lost-to-follow up group. Infant mortality rate was 3 per 1000; neonatal mortality rate was 1.6 per 1000. At the 2-year visit, the children included in the INTERGROWTH-21st Fetal Growth Standards were at the 49th percentile for length, 50th percentile for head circumference, and 58th percentile for weight of the World Health Organization Child Growth Standards. Similar results were seen for the preterm subgroup that was included in the INTERGROWTH-21st Preterm Postnatal Growth Standards. The cohort overlapped between the 3rd and 97th percentiles of the World Health Organization motor development milestones. We estimated that the variance among study sites explains only 5.5% of the total variability in the length of the children between birth and 2 years of age, although the variance among individuals within a study site explains 42.9% (ie, 8 times the amount explained by the variation among sites). An increase of 8.9 cm in adult height over mean parental height is estimated to occur in the cohort from low-middle income countries, provided that children continue to have adequate health, environmental, and nutritional conditions. CONCLUSION: The cohort enrolled in the INTERGROWTH-21st standards remained healthy with adequate growth and motor development up to 2 years of age, which supports its appropriateness for the construction of international fetal and preterm postnatal growth standards

The likeness of fetal growth and newborn size across non-isolated populations in the INTERGROWTH-21st Project: the Fetal Growth Longitudinal Study and Newborn Cross-Sectional Study

Background: 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. Methods: For this study, fetal growth and newborn size were measured in two INTERGROWTH-21st component studies using prespecified markers and the same methods, equipment, and selection criteria. In the Fetal Growth Longitudinal Study (FGLS), we studied educated, affluent, healthy women, with adequate nutritional status who were at low risk of intrauterine growth restriction. The primary markers of fetal growth were ultrasound measurements of fetal crown-rump length at less than 14 weeks and 0 days of gestation and fetal head circumference from 14 weeks and 0 days to 40 weeks and 0 days of gestation, and birthlength for newborn size. In the concomitant, population-based Newborn Cross-Sectional Study (NCSS), we measured birthlength in all newborn babies from the eight geographically defined urban populations with the same methods, instruments, and staff as in FGLS. From this large NCSS cohort, we selected an FGLS-like subpopulation to match FGLS with the same eligibility criteria. Findings: Between May 14, 2009, and Aug 2, 2013, we enrolled 4607 women in FGLS and 59 137 women in NCSS. From NCSS, 20 486 (34•6%) women met the FGLS eligibility criteria, and constituted the FGLS-like subpopulation. With variance component analysis, only between 1•9% and 3•5% of the total variability in crown-rump length, fetal head circumference, and newborn birthlength could be attributed to between-site differences. With standardised site effect analysis in 16 gestational age windows from 9 weeks and 0 days of gestation to birth for the three measures (128 comparisons), only one was marginally higher than 0•5 SD of the standardised site difference range. Sensitivity analyses, excluding individual populations in turn from the pooling of all-site centiles across gestational ages, showed no noticeable effect on the 3rd, 50th, and 97th centiles derived from the remaining populations. Our populations were consistent at birth with those in the WHO Multicentre Growth Reference Study (MGRS). The mean birthlength for term newborn babies in that study was 49•5 cm (SD 1•9), which was very similar to that in the FGLS cohort (49•4 cm [1•9]) and the NCSS derived FGLS-like subpopulation (49•3 cm [1•8]). Interpretation: Fetal growth and newborn length are similar across diverse geographical settings when mothers\u27 nutritional and health needs are met, and environmental constraints on growth are low. The findings for birthlength are in strong agreement with those of the WHO MGRS. These results provide the conceptual frame to create international standards for growth from conception to newborn baby, which will extend the present infant to childhood WHO MGRS standards. Funding: Bill & Melinda Gates Foundation

Anthropometric Characterization of Impaired Fetal Growth: Risk Factors for and Prognosis of Newborns With Stunting or Wasting

Importance: 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. Objective: 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. Design, Setting, and Participants: 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. Exposures: 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. Main Outcomes and Measures: 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. Results: From the 60 206 singleton live births during the study period, we selected all newborns between 33 weeks\u27 and 42 weeks 6 days\u27 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 \u3e24 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). Conclusions and Relevance: 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

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

Objectives: We aimed to identify risk factors for antepartum stillbirth including fetal growth restriction, amongst 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 amongst antepartum stillborn and liveborn babies. Main outcome measures: Antepartum stillbirth was defined as any fetal death after 16 weeks of 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, 2·0 (1·4-2·8); age 40 years, 2·2 (1·4-3·7); essential hypertension 4·0 (2·7-5·9); HIV/AIDS 4·3 (2·0-9·1); preeclampsia 1·6 (1·1-3·8), multiple pregnancy 3·3 (2.0-5·6) and antepartum haemorrhage 3.3 (2.5-4.5). Birth weight < 3rd centile was associated with antepartum stillbirth, 4.6 (3.4-6.2). The greatest risk was in babies not suspected to have been growth restricted antenatally, 5.0 (3.6-7.0). The population attributable risk of antepartum death associated with SGA 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