Complex Perinatal Syndromes Affecting Early Human Growth and Development: Issues to Consider to Understand Their Aetiology and Postnatal Effects

Abstract

Complex perinatal syndromes (CPS) affecting pregnancy and childhood, such as preterm birth, and intra- and extra-uterine growth restriction, have multiple, diverse contexts of complexity and interaction that determine the short- and long-term growth, health and development of all human beings. Early in life, genetically-guided somatic and cerebral development occurs alongside a psychism "in statu nascendi," with the neural structures subjected to the effects of the intra- and extra-uterine environments in preparation for optimal postnatal functioning. Different trajectories of fetal cranial and abdominal growth have been identified before 25 weeks' gestation, tracking differential growth and neurodevelopment at 2 years of age. Similarly, critical time-windows exist in the first 5-8 months of postnatal life because of interactions between the newborn and their environment, mother/care-givers and feeding practices. Understanding these complex relational processes requires abandoning classical, linear and mechanistic interpretations that are placed in rigid, artificial biological silos. Instead, we need to conduct longitudinal, interdisciplinary research and integrate the resulting new knowledge into clinical practice. An ecological-systemic approach is required to understand early human growth and development, based on a dynamic multidimensional process from the molecular or genomic level to the socio-economic-environmental context. For this, we need theoretical and methodological tools that permit a global understanding of CPS, delineating temporal trajectories and their conditioning factors, updated by the incorporation of new scientific discoveries. The potential to optimize human growth and development across chronological age and geographical locations - by implementing interventions or "treatments" during periods of greatest instability or vulnerability - should be recognized. Hence, it is imperative to take a holistic view of reproductive and perinatal issues, acknowledging at all levels the complexity and interactions of CPS and their sensitive periods, laying the foundations for further improvements in growth and development of populations, to maximize global human potential. We discuss here conceptual issues that should be considered for the development and implementation of such a strategy aimed at addressing the perinatal health problems of the new millenium.

Keywords: complex perinatal syndromes; extra-uterine growth restriction; human growth and development; intra-uterine growth restriction; pregnancy and childhood; preterm birth.

FIGURE 1

Preterm phenotypes and the complex interaction amongst their aetiological factors. Size of the circles represent the prevalence of the phenotype (%) in a recent multi-country population (Villar et al., 2021b). Links across phenotypes adapted from Barros et al. (2015).

FIGURE 2

Preterm phenotypes and the association with early childhood language and cognitive development expressed as odds ratios (OR) and 95% confidence intervals, using term newborns as the reference group (Villar et al., 2021b). The different sizes of the circles represent the strength of the associations.

FIGURE 3

Variance components analysis of 16 neurodevelopmental domains evaluated in the present study (Upper) and variance components analysis of 7 measures of fetal, newborn, infant, and child growth (Lower). Red bars are the % of total variance explained by between sites variability (Villar et al., 2019).

FIGURE 4

Schematic representation of the interaction between environmental factors and clinical phenotypes.

FIGURE 5

The Severe Neonatal Morbidity Index (SNMI) according to the eight preterm birth phenotypes. SNMI includes bronchopulmonary dysplasia, hypoxic-ischemic encephalopathy, sepsis, neonatal anemia (requiring transfusion), periventricular hemorrhage or leukomalacia, retinopathy of prematurity, necrotizing enterocolitis (Bell Stage 2 or higher), and patent ductus arteriosus (requiring pharmacological treatment or surgery). There were no cases of severe neonatal morbidity in newborns with the severe maternal disease phenotype. Odds ratios estimated in comparison with the preterm phenotype “No main condition detected”. The 95% Cls were based on robust SEs. IUGR refers to fetal growth restriction (Villar et al., 2021b).

FIGURE 6

Fetal cranial growth trajectories in the INTERBIO-21st study (Villar et al., 2021a).

FIGURE 7

INTERGROWTH-21st growth, developmental standards, clinical and data collection tools.