Deep clinical and biological phenotyping of the preterm birth and small for gestational age syndromes: The INTERBIO-21st Newborn Case-Control Study protocol

Abstract

Background: INTERBIO-21st is Phase II of the INTERGROWTH-21st Project, the population-based, research initiative involving nearly 70,000 mothers and babies worldwide coordinated by Oxford University and performed by a multidisciplinary network of more than 400 healthcare professionals and scientists from 35 institutions in 21 countries worldwide. Phase I, conducted 2008-2015, consisted of nine complementary studies designed to describe optimal human growth and neurodevelopment, based conceptually on the WHO prescriptive approach. The studies generated a set of international standards for monitoring growth and neurodevelopment, which complement the existing WHO Child Growth Standards. Phase II aims to improve the functional classification of the highly heterogenous preterm birth and fetal growth restriction syndromes through a better understanding of how environmental exposures, clinical conditions and nutrition influence patterns of human growth from conception to childhood, as well as specific neurodevelopmental domains and associated behaviors at 2 years of age. Methods: In the INTERBIO-21st Newborn Case-Control Study, a major component of Phase II, our objective is to investigate the mechanisms potentially responsible for preterm birth and small for gestational age and their interactions, using deep phenotyping of clinical, growth and epidemiological data and associated nutritional, biochemical, omic and histological profiles. Here we describe the study sites, population characteristics, study design, methodology and standardization procedures for the collection of longitudinal clinical data and biological samples (maternal blood, umbilical cord blood, placental tissue, maternal feces and infant buccal swabs) for the study that was conducted between 2012 and 2018 in Brazil, Kenya, Pakistan, South Africa, Thailand and the UK. Discussion: Our study provides a unique resource for the planned analyses given the range of potentially disadvantageous exposures (including poor nutrition, pregnancy complications and infections) in geographically diverse populations worldwide. The study should enhance current medical knowledge and provide new insights into environmental influences on human growth and neurodevelopment.

Fetal cranial growth trajectories are associated with growth and neurodevelopment at 2 years of age: INTERBIO-21st Fetal Study

“…Detailed information about each study site was previously published 4 , 16 . In brief, Pelotas (Brazil) is the third most populous city in the state of Rio Grande do Sul, with 350,000 inhabitants and 4,000 births per year, nearly all of which take place in the city’s four maternity hospitals.…”

“… Many observational studies and some randomized trials demonstrate how fetal growth can be influenced by environmental insults (for example, maternal infections) 1 and preventive interventions (for example, multiple-micronutrient supplementation) 2 that can have a long-lasting effect on health, growth, neurodevelopment and even educational attainment and income in adulthood 3 . In a cohort of pregnant women ( n = 3,598), followed-up between 2012 and 2019 at six sites worldwide 4 , we studied the associations between ultrasound-derived fetal cranial growth trajectories, measured longitudinally from <14 weeks’ gestation, against international standards 5 , 6 , and growth and neurodevelopment up to 2 years of age 7 , 8 . We identified five trajectories associated with specific neurodevelopmental, behavioral, visual and growth outcomes, independent of fetal abdominal growth, postnatal morbidity and anthropometric measures at birth and age 2.…”

Association Between Preterm-Birth Phenotypes and Differential Morbidity, Growth, and Neurodevelopment at Age 2 Years

“…[2][3][4] Twelve preterm-birth phenotypes (ie, separate biological entities with specific risk factors, newborn anthropometry, and risk of neonatal morbidity and mortality) 5 have previously been identified. The present INTERBIO-21st Newborn Study 6 comprised phase 2 of the International Fetal and Newborn Growth Consortium for the 21st Century (INTERGROWTH-21st) Project, a populationbased research initiative involving almost 70 000 mothers and infants worldwide that was conducted from 2008 to 2015. In this study, we investigated whether preterm-birth phenotypes were associated with clinical, epidemiological, growth, and neurodevelopmental differences among preterm and term infants up to age 2 years.…”

Clinical phenotypes for risk stratification in small‐for‐gestational‐age fetuses

“…Despite important advances in research on the biological basis of IUGR [27][28][29] , the currently available information is complex and has not yet been translated into clinical practice. Some authors have suggested that we can improve characterization and phenotyping of pathologies, such as preterm birth 15 and IUGR 30 , based on maternal, fetal and placental clinical conditions. Accordingly, 12 preterm-birth phenotypes associated with differing neonatal outcome 17 and neurodevelopmental outcome up to 2 years of age 31 were identified recently.…”