No abstract

Development of cortical interneurons continues until the end of human pregnancy. Premature birth deprives the newborns from the supply of maternal estrogen and a secure intrauterine environment. Indeed, preterm infants suffer from neurobehavioral disorders. This can result from both preterm birth and associated postnatal complications, which might disrupt recruitment and maturation of cortical interneurons. We hypothesized that interneuron subtypes, including parvalbumin-positive (PV), somatostatin-positive (SST), calretinin-positive (CalR), and neuropeptide Y-positive (NPY) interneurons, were recruited in the upper and lower cortical layers in a distinct manner with advancing gestational age. In addition, preterm birth would disrupt the heterogeneity of cortical interneurons, which might be reversed by estrogen treatment. These hypotheses were tested by analyzing autopsy samples from premature infants and evaluating the effect of estrogen supplementation in prematurely delivered rabbits. The PV and CalR neurons were abundant, whereas SST and NPY neurons were few in cortical layers of preterm human infants. Premature birth of infants reduced the density of PV or GAD67 neurons and increased SST interneurons in the upper cortical layers. Importantly, 17 β-estradiol treatment in preterm rabbits increased the number of PV neurons in the upper cortical layers relative to controls at postnatal day 14 (P14) and P21 and transiently reduced SST population at P14. Moreover, protein and mRNA levels of Arx, a key regulator of cortical interneuron maturation and migration, were higher in estrogen-treated rabbits relative to controls. Therefore, deficits in PV and excess of SST neurons in premature newborns are ameliorated by estrogen replacement, which can be attributed to elevated Arx levels. Estrogen replacement might enhance neurodevelopmental outcomes in extremely preterm infants. Premature birth often leads to neurodevelopmental delays and behavioral disorders, which may be ascribed to disturbances in the development and maturation of cortical interneurons. Here, we show that preterm birth in humans is associated with reduced population of parvalbumin-positive (PV) neurons and an excess of somatostatin-expressing interneurons in the cerebral cortex. More importantly, 17 β-estradiol treatment increased the number of PV neurons in preterm-born rabbits, which appears to be mediated by an elevation in the expression of Arx transcription factor. Hence the present study highlights prematurity-induced reduction in PV neurons in human infants and reversal in their population by estrogen replacement in preterm rabbits. Because preterm birth drops plasma estrogen level 100-fold, estrogen replacement in extremely preterm infants might improve their developmental outcome and minimize neurobehavioral disorders.

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Background Preterm birth or low birth weight is the single largest cause of death in newborns, however this mortality can be reduced through newborn care interventions, including Kangaroo Mother Care (KMC). Previously, a multi-country randomized controlled trial, coordinated by the World Health Organization (WHO), reported a significant survival advantage with initiation of continuous KMC immediately after birth compared with initiation of continuous KMC a few days after birth when the baby is considered clinically stable. Whether the survival advantage would lead to higher rates of neurodevelopmental morbidities, or the immediate KMC will also have a beneficial effect on cognitive development also, has not been investigated. We therefore propose to test the hypothesis that low-birth-weight infants exposed to immediate KMC will have lower rates of neurodevelopmental impairment in comparison to traditional KMC-treated infants, by prospectively following up infants already enrolled in the immediate KMC trial for the first 2 years of life, and assessing their growth and neurodevelopment. Methods This prospective cohort study will enroll surviving neonates from the main WHO immediate KMC trial. The main trial as well as this follow-up study are being conducted in five low- and middle-income countries in South Asia and sub-Saharan Africa. The estimated sample size for comparison of the risk of neurodevelopmental impairment is a total of 2200 children. The primary outcome will include rates of cerebral palsy, hearing impairment, vision impairment, mental and motor development, and epilepsy and will be assessed by the age of 3 years. The analysis will be by intention to treat. Discussion Immediate KMC can potentially reduce low-birth-weight-associated complications such as respiratory disease, hypothermia, hypoglycemia, and infection that can result in impaired neurocognitive development. Neuroprotection may also be mediated by improved physiological stabilization that may lead to better maturation of neural pathways, reduced risk of hypoxia, positive parental impact, improved sleep cycles, and improved stress responses. The present study will help in evaluating the overall impact of KMC by investigating the long-term effect on neurodevelopmental impairment in the survivors. Trial registration Clinical Trials Registry-India CTRI/2019/11/021899. Registered on 06 November 2019. Trials registration of parent trial: ACTRN12618001880235; Clinical Trials Registry-India: CTRI/2018/08/015369.

Background:Preterm birth or low birth weight is the single largest cause of death in newborns, but the mortality can be reduced through newborn care interventions, including Kangaroo Mother Care (KMC). Previously, a multi-country randomized controlled trial, coordinated by the World Health Organization reported a significant survival advantage with initiation of continuous KMC immediately after birth compared with initiation of continuous KMC a few days after birth when the baby is considered clinically stable.Whether the survival advantage would lead to higher rates of neurodevelopmental morbidity, or the immediate KMC will have a beneficial effect on cognitive development also, has not been investigated. We therefore propose to test the hypothesis that low-birth-weight infants exposed to immediate KMC will have lower rates of neurodevelopmental impairment in comparison to traditional KMC-treated infants, by prospectively following up infants already enrolled in the immediate KMC trial, for the first two years of life, and assessing their growth and neurodevelopment. Methods:This prospective cohort study will enroll surviving neonates from the main immediate KMC trial. The main trial as well as this follow-up study are being conducted in five low- and middle-income income countries in South Asia and sub-Saharan Africa. The sample size for comparison of risk of neurodevelopmental impairment is a total of about 2200 neonates. The primary outcomes will include rates of cerebral palsy, hearing impairment, vision impairment, mental and motor development, and epilepsy and will be assessed by the age of three years. The analysis will be by intention to treat.DiscussionImmediate KMC can potentially reduce low-birth-weight associated complications such as respiratory disease, hypothermia, hypoglycemia and infection that can result in impaired neurocognitive development. Neuroprotection may also be mediated by improved physiological stabilization that may lead to better maturation of neural pathways, reduced risk of hypoxia, positive parental impact, improved sleep cycles and improved stress responses. The present study will, therefore, help in evaluating the overall impact of KMC by investigating the long-term effect on neurodevelopmental impairment in the survivors.Trial registrationClinical Trials Registry-India: CTRI/2019/11/021899 on 06 November 2019