Elsevier

Sleep Medicine Reviews

Volume 18, Issue 4, August 2014, Pages 299-310
Sleep Medicine Reviews

Clinical review
The development of cardiovascular and cerebral vascular control in preterm infants

https://doi.org/10.1016/j.smrv.2013.06.002Get rights and content

Summary

Over the past three decades there has been a steady increase in the incidence of preterm birth. The worldwide rate of preterm birth is estimated to be 9.6% of all births, a total of almost 13 million births annually. Preterm birth is associated with a range of adverse cardiovascular and central nervous system outcomes, which may be attributed to altered development of these systems following preterm birth. Preterm birth has a considerable impact on cardiovascular parameters with preterm infants displaying higher heart rates and reduced blood pressure when compared to term born infants at matched ages. Furthermore, premature infants have altered autonomic control of cardiovascular parameters which manifests as abnormalities in heart rate variability and baroreflex mediated control of heart rate and blood pressure. As a result, systemic cardiovascular parameters can be unstable following preterm birth which may place stress on the neonatal brain. The brain of a preterm infant is particularly vulnerable to these fluctuations due to immature cerebral haemodynamics. Preterm infants, particularly those who are very preterm or unwell, display fluctuating pressure-passivity between systemic blood pressure and cerebral blood flow representing a considerably increased risk of cerebral haemorrhage or hypoxia. This is further compounded by immaturity of cerebral blood flow–metabolism coupling, which means increased metabolic demand cannot adequately be met by increased cerebral blood flow. It has been suggested that adverse long-term outcomes following preterm birth may occur as a result of exposure to physiological stress either in-utero or early in infancy.

Introduction

Preterm birth, defined as birth prior to 37 wk of gestation, has been steadily increasing in recent years and now accounts for 9.6% of births worldwide, a total of approximately 13 million births annually [1]. The rate of preterm birth is rising due in part to advances in assisted reproduction technology leading to an increase in the number of multiple births and an increase in the number of medically indicated preterm births [2].

Increasing rates of preterm birth are being accompanied by increasing survival rates in infants born prematurely, particularly those born very prematurely. Prior to the introduction of assisted ventilation, antenatal corticosteroids and artificial surfactant, survival rates of infants born prior to 28 wk gestational age (GA) were low. Currently, survival rates for infants born at 22 wk vary from 0 to 12%, increasing to 53–88% at 26 wk GA [3].

However, despite improved survival, prematurity is associated with a range of both short and long-term poor outcomes. At the time of birth, preterm infants are more likely to be growth restricted, exposed to intrauterine inflammation in the form of chorioamnionitis or to have experienced foetal distress, as these are common reasons for preterm labour or early delivery [2]. In the immediate neonatal period, preterm infants are at an increased risk of short-term complications including respiratory distress syndrome, necrotising enterocolitis and intracranial haemorrhage. As a consequence, poor long-term outcomes including neurodevelopmental delay and chronic lung disease are also common in preterm infants [3]. The risk of major medical disability as a result of preterm birth increases significantly with decreasing GA, with one in nine infants born at 23–27 wk GA receiving a disability pension at 19–35 y compared with one in 42 for those born at 34–36 wk GA [4].

Although the major morbidities associated with preterm birth are well documented, the more subtle effects of premature birth on development are largely unexplored. It has been suggested that cardiovascular and central nervous system (CNS) disease may develop later in life as a result of disrupted development following preterm birth [5]. The exact mechanisms resulting in disrupted development remain unclear but are likely to be complex and multifactorial; we suggest impaired vascular control may play a role. As such, this review aims to investigate the influence of premature birth on the development of cardiovascular and cerebral vascular control early in infancy.

Section snippets

Development and control of the cardiovascular system

At term the cardiovascular system is not yet fully mature and maturation continues for several weeks after birth. Mitotic divisions of the myocardium have been found to continue for several weeks after birth and the mechanical performance of the myocardium shows improvement with increasing postnatal age [6]. An additional challenge during this period of rapid cardiovascular development is the transition from intrauterine to extrauterine life which occurs at birth and requires significant

Heart rate

Preterm birth has a considerable effect on cardiovascular parameters including HR and BP. Preterm infants at term-equivalent age have higher resting HRs than infants born at term and this persists up until seven months of age [18], [19]. It has been suggested that while HR is primarily dependent on post-conceptional age, fluctuations in HR are also influenced by postnatal age, with HR in both preterm and term infants peaking between 4 and 10 wk postnatal age [18]. Similar studies have also

Cerebrovascular control

The brain is a highly metabolically active organ, requiring 3.5 ml of oxygen per 100 g of brain tissue per minute which accounts for approximately 15% of the total resting cardiac output. Approximately 60% of the total energy usage of the brain is for generation of continuous electrical activity by neurons. The remaining 40% of energy usage is responsible for homeostatic cellular functions undertaken largely by the supporting cells within the brain. The neuronal component of cerebral energy

Cerebral autoregulation in preterm infants

With the preterm brain being particularly susceptible to haemorrhage and ischaemia, which may be due to fluctuations in CBF, there has been much interest in the ability of preterm infants to regulate their cerebral haemodynamics (Table 1). A number of studies have found that cerebral autoregulation is impaired in preterm infants *[76], [77], [78]. Tsuji et al., found that in 32 infants with gestational ages ranging from 23 to 31 wk, 17 exhibited a high correlation between MAP and HbD, a measure

Long-term cardiovascular outcomes

It is becoming increasingly apparent that infants born preterm are at increased risk of developing cardiovascular disease in adulthood. The theory “foetal origins of adult disease” was first described more the 20 years ago by Barker et al., who found an increased risk of death from ischaemic heart disease amongst adult men who had been born with a low birth weight [108]. They suggested that an adverse intrauterine environment results in increased cardiovascular risk in adulthood due to the

Conclusions

The rate of preterm birth across the world is increasing and due to significant improvements in neonatal intensive care, the survival rates for infants born preterm have increased dramatically. However, despite improved mortality, preterm infants still experience considerable morbidity and are at increased risk for a range of adverse outcomes later in life. Preterm birth is associated with impaired cardiovascular control largely due to immaturity of the ANS which manifests as higher HRs,

Acknowledgements

The authors have no conflicts of interest to declare. Karinna Fyfe is supported by an Australian Postgraduate Award. Stephanie Yiallourou is supported by a project grant from the National Health and Medical Research Council of Australia. Flora Wong is a National Health and Medical Research Council of Australia Health Professional Research Fellow. Rosemary Horne is a National Health and Medical Research Council of Australia Senior Research Fellow. All of the research was supported by the

References (111)

  • J.E. Mazursky et al.

    Development of baroreflex influences on heart rate variability in preterm infants

    Early Hum Dev

    (1998)
  • J.S. Soul et al.

    Near-infrared spectroscopy

    Sem Pediatr Neurol

    (1999)
  • M. Wolf et al.

    Advances in near-infrared spectroscopy to study the brain of the preterm and term neonate

    Clin Perinatol

    (2009)
  • A.D. Edwards et al.

    Cotside measurement of cerebral blood flow in ill newborn infants by near infrared spectroscopy

    Lancet

    (1988)
  • D.A. Goff et al.

    Noninvasive cerebral perfusion imaging in high-risk neonates

    Semin Perinatol

    (2010)
  • G. Greisen

    Autoregulation of cerebral blood flow in newborn babies

    Early Hum Dev

    (2005)
  • D.M. Munger et al.

    Sleep state changes associated with cerebral blood volume changes in healthy term newborn infants

    Early Hum Dev

    (1998)
  • O. Pryds et al.

    Vasoparalysis associated with brain damage in asphyxiated term infants

    J Pediatr

    (1990)
  • D.W.A. Milligan

    Failure of autoregulation and intraventricular haemorrhage in preterm infants

    Lancet

    (1980)
  • O. Pryds et al.

    Heterogeneity of cerebral vasoreactivity in preterm infants supported by mechanical ventilation

    J Pediatr

    (1989)
  • F. Mosca et al.

    Cerebral vasoreactivity to arterial carbon dioxide tension in preterm infants: the effect of ibuprofen

    J Pediatr

    (1999)
  • A.M. Muller et al.

    Loss of CO2 reactivity of cerebral blood flow is associated with severe brain damage in mechanically ventilated very low birth weight infants

    Europ J Paediatr Neurol

    (1997)
  • S. Beck et al.

    Worldwide incidence of preterm birth: a systematic review of maternal mortality and morbidity

    Bull WHO

    (2010)
  • D. Moster et al.

    Long-term medical and social consequences of preterm birth

    N Engl J Med

    (2008)
  • D.J. Barker et al.

    Fetal origins of adult disease: strength of effects and biological basis

    Int J Epidemiol

    (2002)
  • R.A. Polin et al.

    Fetal and neonatal physiology: expert consult

    (2011)
  • K. Saladin

    Anatomy & physiology: the unity of form and function

    (2011)
  • R.M. Harper et al.

    Polygraphic studies of normal infants during the first six months of life. I. Heart rate and variability as a function of state

    Pediatr Res

    (1976)
  • M. Malik

    Heart rate variability

    Ann Noninvasive Electrocardiol

    (1996)
  • A. Malliani et al.

    Cardiovascular neural regulation explored in the frequency domain

    Circulation

    (1991)
  • M. Pagani et al.

    Power spectral analysis of heart rate and arterial pressure variabilities as a marker of sympatho-vagal interaction in man and conscious dog

    Circ Res

    (1986)
  • N.A. de Beer et al.

    Customized spectral band analysis compared with conventional Fourier analysis of heart rate variability in neonates

    Physiol Meas

    (2004)
  • J. Ardura et al.

    Development of sleep-wakefulness rhythm in premature babies

    Acta Paediatr

    (1995)
  • S.R. Yiallourou et al.

    Maturation of heart rate and blood pressure variability during sleep in term-born infants

    Sleep

    (2012)
  • R. Tuladhar et al.

    Comparison of postnatal development of heart rate responses to trigeminal stimulation in sleeping preterm and term infants

    J Sleep Res

    (2005)
  • N.B. Witcombe et al.

    Blood pressure and heart rate patterns during sleep are altered in preterm-born infants: implications for sudden infant death syndrome

    Pediatrics

    (2008)
  • A. Greenough et al.

    Blood pressure levels of preterm infants in the first year of life

    Acta Paediatr

    (1993)
  • M.K. Georgieff et al.

    Rate of change of blood pressure in premature and full term infants from birth to 4 months

    Pediatr Nephrol

    (1996)
  • E. Longin et al.

    Maturation of the autonomic nervous system: differences in heart rate variability in premature vs. term infants

    J Perinat Med

    (2006)
  • H. Patural et al.

    Birth prematurity determines prolonged autonomic nervous system immaturity

    Clin Auton Res

    (2004)
  • J.L. Segar

    Fetal and neonatal cardiovascular physiology

  • C. Borst et al.

    Mechanisms of initial heart rate response to postural change

    Am J Physiol

    (1982)
  • N. Montano et al.

    Power spectrum analysis of heart rate variability to assess the changes in sympathovagal balance during graded orthostatic tilt

    Circulation

    (1994)
  • S.R. Yiallourou et al.

    Prone sleeping impairs circulatory control during sleep in healthy term infants: implications for SIDS

    Sleep

    (2008)
  • C. Harrington et al.

    Cardiovascular responses to three simple, provocative tests of autonomic activity in sleeping infants

    J Appl Physiol

    (2001)
  • G. Cohen et al.

    Cardiovascular stress hyperreactivity in babies of smokers and in babies born preterm

    Circulation

    (2008)
  • S. Waldman et al.

    Baroreceptors in preterm infants: their relationship to maturity and disease

    Dev Med Child Neurol

    (1979)
  • K. Holden et al.

    Incomplete baroreceptor responses in newborn infants

    Am J Perinatol

    (1985)
  • H. Lagercrantz et al.

    Autonomic reflexes in preterm infants

    Acta Paediatr Scand

    (1990)
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