a positive relationship between longer breastfeeding duration of healthy full-term infants and higher receptive language and verbal and nonverbal intelligence later in life (JAMA Pediatr. 2013 Sep;167(9):836-44.). Mandy Brown Belfort, MD, MPH Neonatologist, Department of Pediatric Newborn Medicine, Brigham and Women’s Hospital Neonatologist Mandy Brown Belfort, MD, MPH, is leading a pilot study that utilizes specialized equipment to assess breastmilk composition, including macronutrients like protein and fat that are important for growth and neurodevelopment. Neuroscience meets nurture: challenges of prematurity and the critical role of family-centred and developmental care as a key part of the neuroprotection care bundle Roopali Soni ,1,2 Charlotte Tscherning Wel-Wel ,1,3 Nicola J Robertson 4,5 To cite: Soni R, Tscherning Wel-Wel C, Robertson NJ. Arch Dis Child Fetal Neonatal Ed Epub ahead of print: [please include Day Month Year]. doi:10.1136/ archdischild-2020-319450 1 Neonatology, Sidra Medical and Research Center, Doha, Ad Dawhah, Qatar 2 Department of Neonatology, Mediclinic Parkview Hospital, Dubai, UAE 3 Center of Physiopathology Toulouse-Purpan(CPTP), University of Toulouse, Toulouse, France 4 Institute for Women’s Health, University College London, London, UK 5 Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK Correspondence to Dr Roopali Soni, Neonatology, Sidra Medical and Research Center, Doha PO Box 26999, Qatar; roopali.soni@gmail.com Received 3 October 2020 Revised 1 April 2021 Accepted 13 April 2021 © Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ. ABSTRACT Advances in neonatal–perinatal medicine have resulted in increased survival at lower gestations. Although the incidence of germinal matrix haemorrhageintraventricular haemorrhage and cystic periventricular leucomalacia is reducing, a new phenotype of preterm brain injury has emerged consisting of a combination of destructive and dysmaturational effects. Consequently, severe neurological disability is reported at a lower rate than previously, but the overall morbidity associated with premature birth continues to present a large global burden and contributes significantly to increased financial costs to health systems and families. In this review, we examine the developmental milestones of fetal brain development and how preterm birth can disrupt this trajectory. We review common morbidities associated with premature birth today. Although drugbased and cell-based neuroprotective therapies for the preterm brain are under intense study, we outline basic, sustainable and effective non-medical, family-centred and developmental care strategies which have the potential to improve neurodevelopmental outcomes for this population and need to be considered part of the future neuroprotection care bundle. INTRODUCTION Despite advances in medical knowledge and techniques, prematurity and its sequelae continue to present a significant global challenge. Here we review the burden of prematurity, preterm brain development and injury, commonly associated neurodevelopmental morbidities, and focus on the evidence in support of developmental and familycentred care practices to enhance preterm brain development and neurodevelopmental outcomes. PRETERM BIRTH AND SURVIVAL Nearly 15 million babies are born preterm every year (WHO definition <37 completed weeks’ gestation). The 10 countries with the highest rates of prematurity (mainly sub-Saharan Africa and South Asia) account for 60% of all preterm births worldwide. Although rates are highest on average for low-income countries (11.8%), followed by lower middle-income countries (11.3%) and lowest for upper middle-income and high-income countries (9.4% and 9.3%), relatively high preterm birth rates are seen in many individual high-income countries where they contribute substantially to neonatal mortality and morbidity1 (figure 1). For infants born at 22+0–25+6 weeks in the UK, survival to discharge has continued to improve over the decades from 40% in 1995, to 66% in 2014.2 Several international studies have similarly indicated an incremental improvement in survival for the most premature babies over the last one to two decades.3–5 The largest changes in outcome are at the lowest gestational ages (GAs). At 22 weeks’ GA, recent cohort studies from the USA, UK, Sweden and Germany indicate that approximately 30% of live-born babies who receive active treatment survive to discharge.5 PRETERM BRAIN DEVELOPMENT The human central nervous system (CNS) develops with a pattern similar to all mammals, beginning as a simple neural tube and gradually developing features through hugely complex and strictly regulated processes. The growth rate in the human CNS is higher than any other organ from the 4th postconceptional week (PCW) to the 3rd postnatal year.6 The association areas of the cerebral neocortex develop more slowly, and the gestation period and childhood are much longer compared with other mammals. This period of dependency and the prolonged developmental course allows, more than any other species, the environment to shape the development of cognition, social and emotional factors. In addition, the developing human brain has larger proliferative areas and diverse subtypes of neural and progenitor cells that lead to increased brain expansion, especially of the neocortex.6 Fetal development is the most important period for neurogenetic events, with regard to number of neurons (proliferation), their molecular diversity (molecular specification), allocation in the cortex (migration), phenotype differentiation (dendritogenesis), and is a time for the growth of axons (axonogenesis) and functional contacts (synaptogenesis).7 The subplate zone of the telencephalon plays a pivotal role in the development of the human brain and is the most prominent transient compartment of the fetal cortex. It is the major site of synaptogenesis and neuron maturation and is a site for increasing the number of associative and thalamocortical pathways in the human neocortex.7 Most developmental processes extend into the postnatal period, especially processes associated Sciences Library. Protected by copyright. on May 17, 2021 at CU Anschutz Strauss Health http://fn.bmj.com/ Arch Dis Child Fetal Neonatal Ed: first published as 10.1136/archdischild-2020-319450 on 10 May 2021. Downloaded from F2 Soni R, et al. Arch Dis Child Fetal Neonatal Ed 2021;0:F1–F8. doi:10.1136/archdischild-2020-319450 Review with interneuron connectivity.8 Each of these cellular processes may be vulnerable to environmental influences, and their impairment may disrupt brain growth9 (figure 2). The third trimester is a critical period during which global and regional brain volume increases three to fourfold. The general architecture of the human brain is achieved during the first 6 months of fetal life, mostly driven by genetic influences, which are then silenced in the third trimester,10 when environmental factors, uterine or in the neonatal intensive care unit (NICU)11 12 strongly influence the last phases of prenatal and early postnatal brain development.13 Prematurity is one of many biological or environmental insults that can push the trajectory of the developing brain to an atypical path, with the resultant increased prevalence of neurodevelopmental and neuropsychiatric disorders.8 SENSORY DEVELOPMENT OF THE FETUS The sensory systems of the fetus become functional in the following sequence during early development: tactile>>visual histories at the time of birth.14 The basic structure of the eyes, ears and olfactory bulb develops early in gestation. Some of the primary receptors for touch, position and motion also develop early. The development of touch starts at around 8 PCW, initially beginning with sensory receptor development in the face, mostly on the lips and nose. Taste buds begin to emerge at 8 PCW, and at 13–15 PCW, the fetus has similar taste buds to adults. Smell develops around the same time that the fetus has taste function. Figure 1 Estimated preterm birth rates by country for the year 2010. Source: Blencowe et al, Lancet 2012. Figure 2 Figure summarising some key cellular processes in the developing prefrontal cortex and functional milestones. Illustrations in the top panel show the gross anatomical features of the developing prenatal brain. The schematic below details the approximate timing and sequence of key cellular processes and developmental milestones, indicating the peak developmental period in which each feature is acquired. Note the predominance of axonal growth, dendritic differentiation and synaptogenesis during mid-fetal and beginning of the late fetal period. Proliferation of neurons within the subplate is hypothetical during this period, but proliferation of glia continues. Note that after 34 PCW, there is dissolution of the subplate with presence of subplate remnant in the neonatal period. The period of highest risk for WMI between 23 and 32 weeks’ gestation coincides with the predominance of pre-oligodendrocytes in the WM and constitutes a developmental window of enhanced susceptibility. Risk of GMH-IVH-HPI decreases by 32 weeks but abnormal cortical maturation continues until term age. The lower half of the figure shows development of functional milestones and acquisition of key sensorimotor responses. Figure adapted from Silbereis and Kostovic. GMH-