Antenatal therapies and the developing brain

This chapter presents a review of basic science and human studies of two commonly used pharmacologic agents (antenatal steroids and magnesium sulfate), in pregnancies at risk of preterm delivery, and examines the effects of these therapies on the developing brain. Very low birthweight (VLBW) infants are known to be at risk of both short-term and long-term neurodevelopmental sequelae; therefore, an understanding of the mechanisms contributing to both neuroprotective and neurotoxic effects of antenatal therapies on the immature brain and potential effects on long-term outcome are critical. Although the short-term beneficial effects of a single course of antenatal steroids are well documented, the experimental animal literature suggests detrimental effects on neurodevelopment of multiple doses. In addition, clinical studies of repeat doses suggest a negative impact on head and brain growth. The animal and human data on the effects of MgSO₄are also mixed with both beneficial effects or no effects on neurodevelopment. This review will discuss the potential impact of single versus multiple doses and timing of doses on the brain.     

Antenatal glucocorticoids and the developing brain: mechanisms of action

Glucocorticoids are critical for normal brain development. There is no doubt that prenatal treatment with synthetic glucocorticoid affords great benefit to the preterm infant. However, animal studies, now carried out in many species, indicate that there may be some long-term physiological costs of early exposure to excess glucocorticoid, and that these appear sex-dependant. Further, the effects may not become apparent until later life. Given the dynamics of corticosteroid receptor systems in late gestation, it is likely that there are critical windows of development when specific regions of the brain are more sensitive to the influence of synthetic glucocorticoid. Once such windows have been identified it will be possible to target prenatal treatments, so as to maximize benefit and reduce risk of long-term effects. Notwithstanding, the data reviewed below indicate that caution should be exercised in the use of multiple course glucocorticoid therapy during pregnancy.     

Antenatal glucocorticoids and programming of the developing CNS

Glucocorticoids (GCs) are essential for many aspects of normal brain development. However, there is growing evidence from a number of species that exposure of the fetal brain to excess GC, at critical stages of development, can have life-long effects on behavior and neuroendocrine function. The hypothalamo-pituitary-adrenal axis, which is central to the integration of the individual's endocrine and behavioral response to stress, appears highly sensitive to excess GC exposure during development. A number of animal studies have shown that exposure to synthetic GCs in utero results in adult offspring that exhibit hyperactivity of the hypothalamo-pituitary-adrenal axis. This will have a long-term impact on health, inasmuch as increased life-long exposure to endogenous GC has been linked to the premature onset of diseases associated with aging. The mechanisms involved in the permanent programming of hypothalamo-pituitary-adrenal function and behavior are not well understood. Synthetic GCs are used extensively to promote pulmonary maturation in fetuses at risk of being delivered before term. Therefore, it is important that we understand the potential long-term consequences of prenatal GC exposure on brain development as well as the underlying mechanisms involved. This review will explore the current state of knowledge in this rapidly expanding field.     

Antenatal steroids: Miracle drug for preemies

Antenatal corticosteroid administration has been unequivocally demonstrated to reduce neonatal morbidity and mortality. In addition to its well-documented role in reducing respiratory distress syndrome, evidence is accumulating indicating the global maturational effect of this therapy in the growing fetus. New data demonstrates, the hitherto relatively not well known, beneficial effects of this mode of therapy on renal, cardiovascular, gastrointestinal, endocrinal and cerebral maturation. Despite its well proven efficacy and safety, this therapy is used only in a small fraction of eligible mothers. In this article, biological basis of antenatal steroids use, clinical benefits including those to extremely premature infants, indications for their administration, treatment regimens, practice variations in their administration, cost analysis, and some directions for future research are reviewed. It is hoped that given the evidence reviewed in this article, the use of antenatal steroids administration in proper clinical settings will increase with a significant impact in reducing the neonatal morbidity and mortality.     

Antenatal steroids and fluid balance in very low birthweight infants

OBJECTIVES: To determine if insensible water loss (IWL) differed between infants exposed or not exposed antenatally to corticosteroids and to explore possible mechanisms for the early postnatal diuresis associated with antenatal steroid exposure. DESIGN: Retrospective analysis of prospectively collected data. SETTING: Level three neonatal intensive care unit. PATIENTS: Ninety six infants, median gestational age 27.5 weeks (range 23-33). MAIN OUTCOME MEASURES: Comparison of the IWL, urine output and osmolality, fluid input, electrolyte imbalance, respiratory illness severity (as assessed by surfactant requirement, maximum peak inspiratory pressure, and inspired oxygen concentration), and cardiovascular status (as assessed by inotrope requirement) between infants with antenatal corticosteroid exposure and gestational age matched controls. RESULTS: The infants exposed to antenatal steroids differed significantly from the controls in having both a lower IWL (p = 0.0135) and a higher urine output (p = 0.0036) on day 1, and fewer developed hyponatraemia (p = 0.027) on day 2. Fewer of those exposed to antenatal steroids required inotropes (p = 0.06), but their respiratory status was similar to that of the controls. CONCLUSIONS: Infants exposed to antenatal corticosteroids have a lower IWL. The results suggest that greater skin maturation, but also better perfusion rather than less severe respiratory status, explains the early diuresis in infants exposed to antenatal steroids.     

Antenatal care in developing countries: the need for a tailored model

In developed countries, 98% of all women receive prenatal care and 94% give birth under the supervision of skilled healthcare practitioners with timely access to appropriate emergency treatment if complications arise. In contrast, large numbers of pregnant women in Africa and Asia do not receive adequate prenatal care and lack skilled attendance at birth. In developing countries quality of prenatal care is often scarce: models of care adopted in the western world and exported to the developing world have not been monitored early enough to discover their weak points promptly. This blind attitude has transformed antenatal care into an empty and useless ritual, and explains why antenatal care programmes continue to be unsuccessful, being inappropriate to the specific situation. A mix of educational and cultural factors together with persistent lack of resources in a global critical situation all contribute to the poor results of antenatal care programmes. Antenatal care services should be free of charge, planned and implemented within the community, cost-effective, and should yield evidence-based quality care. They should also include information for the patient and family members, provide affordable treatment of existing conditions, and warrant referral for complications.     

Connecting the developing preterm brain

White matter injury and abnormal maturation are thought to be major contributors to the neurodevelopmental disabilities observed in children and adolescents who were born preterm. Early detection of abnormal white matter maturation is important in the design of preventive, protective, and rehabilitative strategies for the management of the preterm infant. Diffusion Tensor Imaging (DTI) allows non-invasive, in vivo visualization and quantification of white matter tracts and has become a valuable tool in assessing white matter maturation in children born preterm. We will review the use of DTI to study white matter maturation and injury in the preterm brain.     

Sex steroids and the brain: lessons from animal studies

Gonadal steroid hormones have multiple effects throughout development on steroid responsive tissues in the brain. The belief that the cellular morphology of the adult brain cannot be modulated or that the synaptic connectivity is "hard-wired" is being rapidly refuted by abundant and growing evidence. Indeed, the brain is capable of undergoing many morphological changes throughout life and gonadal steroids play an important role in many of these processes. Gonadal steroids are implicated in the development of sexually dimorphic structures in the brain, in the control of physiological behaviors and functions and the brain's response to physiological or harmful substances. The effect of sex steroids on neuroprotection and neuroregeneration is an important and expanding area of investigation. Astroglia are targets for estrogen and testosterone and are apparently involved in the actions of sex steroids on the central nervous system. Sex hormones induce changes in the expression of glial fibrillary acidic protein, the growth of astrocytic processes and the extent to which neuronal membranes are covered by astroglial processes. These changes are linked to modifications in the number of synaptic inputs to neurons and suggest that astrocytes may participate in the genesis of gonadal steroid-induced sex differences in synaptic connectivity and synaptic plasticity in the adult brain. Astrocytes and tanycytes may also participate in the cellular effects of sex steroids by releasing neuroactive substances and by regulating the local accumulation of specific growth factors, such as insulin-like growth factor-I, that are involved in estrogen-induced synaptic plasticity and estrogen-mediated neuroendocrine control. Astroglia may also be involved in the regenerative and neuroprotective effects of sex steroids since astroglial activation after brain injury or after peripheral nerve axotomy is regulated by sex hormones.     

Antenatal steroids may reduce adverse neurological outcome following chorioamnionitis: neurodevelopmental outcome and chorioamnionitis in premature infants

OBJECTIVE: To examine the effect of antenatal steroid exposure and in utero inflammation on the development of severe intraventricular haemorrhage, periventricular leukomalacia and long-term neurological outcome in infants less than 30 completed weeks gestation. METHOD: Infants less than 30 completed weeks gestation from January 1996 to July 2001 were identified from a prospectively managed database. Placental pathology was reviewed for the presence or absence of chorioamnionitis and funisitis. Infants were divided into three groups depending on the degree of exposure to fetal inflammation (no inflammation, chorioamnionitis only and chorioamnionitis and funisitis). Data relating to gestational age, birthweight, sex, antenatal steroid exposure, surfactant treatment, days of positive pressure ventilation and days of oxygen requirement were collected. Cerebral ultrasound studies were examined for evidence of intraventricular or intraparenchymal echodensity and periventricular leukomalacia. Long-term neurological outcome was assessed by neurological examination for cerebral palsy and by Griffiths Mental Developmental Assessment for general developmental quotient. RESULTS: Two hundred and twenty infants were identified. The mean gestational age was 27.7 weeks and the mean birthweight 1092 g. Seventy-two per cent of mothers had received a complete course of antenatal steroids. The risk of Grade III intraventricular haemorrhage or intraparenchymal echodensity was associated with exposure to in utero inflammation if a complete course of antenatal steroids had not been received (P = 0.002). This association did not exist if a complete course of antenatal steroids was given (P = 0.62). Fourteen infants had cerebral palsy (7%). The presence of cerebral palsy was also associated with in utero inflammation in the absence of complete antenatal steroid cover (P = 0.03) and not in the presence of complete cover (P = 0.59). The mean general developmental quotient on Griffiths Mental Developmental Assessment at 12 months or 3 years was not affected by exposure to in utero inflammation regardless of antenatal steroid exposure. CONCLUSION: Risk of intraventricular haemorrhage or intraparenchymal echodensity and cerebral palsy was associated with in utero inflammation in the absence of a complete course of antenatal steroids. A complete course of antenatal steroids appeared to extinguish any association between in utero inflammation and adverse neurological outcome.