Long term respiratory consequences of intrauterine growth restriction

https://doi.org/10.1016/j.siny.2012.01.003Get rights and content

Summary

Epidemiological studies demonstrate that in-utero growth restriction and low birth weight are associated with impaired lung function and increased respiratory morbidity from infancy, throughout childhood and into adulthood. Chronic restriction of nutrients and/or oxygen during late pregnancy causes abnormalities in the airways and lungs of offspring, including smaller numbers of enlarged alveoli with thicker septal walls and basement membranes. The structural abnormalities and impaired lung function seen soon after birth persist or even progress with age. These changes are likely to cause lung symptomology through life and hasten lung aging.

Introduction

Next to preterm delivery, intrauterine growth restriction (IUGR) is one of the most important causes of perinatal morbidity and mortality.1 In its simplest form, IUGR occurs when the growth restriction is pathologic (i.e. not constitutional), indicating that the fetus has failed to achieve its full growth potential.1 Most commonly, IUGR results in an infant that is small for gestational age (SGA) with a birth weight less than the 10th centile at birth (for definitions see Box 1). However, as birth weight for any given gestation is largely normally distributed, an infant can be SGA without also having IUGR, whereas a small number of IUGR infants may have birth weights above the 10th centile, and therefore not be classified as SGA. The term ‘low birth weight’ (LBW), which refers to any infant with a birth weight <2500 g, is often used erroneously as a proxy for IUGR as this classification does not adjust for maturation and is predominantly populated by infants with appropriate growth for gestation. The confusion between these three terms confounds the interpretation of the literature. The use of customized centile calculators that consider maternal height, weight, ethnicity and parity and the fetal sex,2 can improve distinction of true IUGR from the constitutionally small infant.

IUGR is often described as symmetric or asymmetric; whereas the whole body of an infant with symmetric IUGR is proportionately small, the infant with asymmetric IUGR preserves growth of critical organs, such as the brain and the heart, at the expense of liver, gut and fat. However, the distinction between asymmetric and symmetric IUGR may be less clear as arguments that symmetric IUGR represents both an early3 and late form of asymmetric IUGR are proposed. The etiologic basis of IUGR may have maternal, placental, fetal or environmental origins (or a combination of any of these), as detailed in Fig. 1. Approximately 80–90% of all cases of IUGR amenable to preventive and therapeutic management involve impaired transplacental supply of oxygen and nutrients to the fetus.4 Pregnancy-induced hypertension and its associated pathological uteroplacental circulation is the single most contributory factor to the development of IUGR,3 whereas maternal smoking accounts for up to 40% of IUGR in developed countries.5

Interest in the long term effects of IUGR has gained momentum in recent years: signals related to poor placental nutrient transfer during critical periods of fetal development may promote adaptations to reduced nutrient transfer that are beneficial in the short term but which may lead to alterations of structure or function with adverse long term consequences. This process of ‘programming’6 is recognized as an important means by which perinatal events and the in utero environment contribute to disease susceptibility in later life.

Lung development occurs in several distinct stages: embryonic, pseudoglandular, canalicular, saccular and alveolar phases.7 Impaired fetal nutrient and oxygen availability can impact on any of these phases, potentially affecting long term lung function and respiratory morbidity. Placental insufficiency primarily occurs in late pregnancy in parallel with acinar and alveolar development: IUGR will thus most likely affect the structure and function of the distal lung.

This review examines the effects of nutritional and oxygen restriction on lung development in utero. It considers epidemiological evidence suggesting that changes in lung development not only impact on lung function and respiratory disease in early life, but also cause effects into late adulthood. Data from in-vivo animal models support and explain the observational studies.

Section snippets

Effects of IUGR on lung development

Much of our understanding of the effects of IUGR on lung development has arisen from studies using animal models. Most animal models of IUGR have restricted fetal growth using a nutritional approach (limitation of maternal energy and/or protein intake), interference with placental function and uterine blood flow (embolectomy), or placental insufficiency resulting from preconception carunclectomy, arterial ligation or chronic hypoxia.8 Other models have included exposure to tobacco smoke, late

Functional consequences of IUGR in the neonatal period

The impact of IUGR on the incidence of neonatal respiratory distress syndrome varies from an increased,29, 30, 31 decreased32 or equivocal33, 34 effect, most probably determined by the duration and nature of the insult causing IUGR. Similar variation in outcome can be observed in animal models.

A key feature of neonatal respiratory distress syndrome is endogenous surfactant deficiency. Several studies showed abnormalities of the surfactant system. In human infants, placental insufficiency is

Long term functional and clinical consequences of IUGR in animal models

The longer-term effects of IUGR on respiratory function and morbidity in later life are not yet fully understood. A small number of studies have characterized the changes in lung function into prepuberty and adulthood using animal models.

Growth restriction caused by late gestational umbilical–placental embolization results in persistent impairment of pulmonary function.43 Repeated measurements of the sheep in the 8 weeks following birth showed that, in comparison to controls, IUGR resulted in

Epidemiological evidence

Ecological studies conducted in the 1980s found that regions of the UK with a high rate of death due to coronary heart disease also had high infant mortality45; subsequent investigation identified that infants with the highest rates of death during infancy were those with the lowest birth weights and that surviving infants born at low birth weight went on to have the highest risk of cardiovascular disease in adulthood.46 These findings were closely followed by the discovery that size at one

Conclusion

Epidemiological studies using low birth weight as a proxy for IUGR demonstrate associations with reduced infant lung function and early respiratory morbidity, and also reveal that impaired lung function and respiratory disease persist into adulthood. IUGR can be caused by maternal, placental or fetal causes, and it is difficult in epidemiological studies to tease out the relative factors (such as tobacco exposure, infections or maternal vascular disease) and whether these are having a direct or

Conflict of interest statement

None declared.

Funding sources

Early life origins research has been funded by the Food Standards Agency UK (J.S.L., K.P.), British Lung Foundation (J.S.L., K.P.), SPARKS (Sport Aiding medical Research for Kids) (J.S.L., K.P., J.J.P.). J.S.L.’s early life origins research has also been supported by the infrastructure of Wellcome Trust Clinical Research Facility Southampton, NIHR Respiratory Biomedical Research Unit Southampton and Medical Research Council Epidemiology Resource Centre, University of Southampton. J.J.P.’s

References (88)

  • D.J. Barker et al.

    Weight in infancy and death from ischaemic heart disease

    Lancet

    (1989)
  • M.C. Williams et al.

    Persistent pulmonary hypertension of the neonate and asymmetric growth restriction

    Obstet Gynecol

    (1998)
  • Perinatal Institute. Gestation Network 2007. Centile Calculator http://www.gestation.net/birth weight_centiles/birth...
  • H.A. Wollmann

    Intrauterine growth restriction: definition and etiology

    Horm Res

    (1998)
  • M.S. Kramer

    Intrauterine growth and gestational duration determinants

    Pediatrics

    (1987)
  • K.C. Pike et al.

    Developmental mismatch: consequences for later cardiorespiratory health

    Br J Obstet Gynaecol

    (2008)
  • P.H. Burri

    Structural aspects of postnatal lung development – alveolar formation and growth

    Biol Neonate

    (2006)
  • P. Vuguin

    Animal models for assessing the consequences of intrauterine growth restriction on subsequent glucose metabolism of the offspring: a review

    J Matern Fetal Neonatal Med

    (2002)
  • J. Lipsett et al.

    Restricted fetal growth and lung development: a morphometric analysis of pulmonary structure

    Pediatr Pulmonol

    (2006)
  • C.M. Chen et al.

    Effects of maternal undernutrition during late gestation on the lung surfactant system and morphometry in rats

    Pediatr Res

    (2004)
  • Y. Lin et al.

    Surfactant content and type II cell development in fetal guinea pig lungs during prenatal starvation

    Pediatr Res

    (1991)
  • D.C. Curle et al.

    Retarded development of neonatal rat lung by maternal malnutrition

    J Histochem Cytochem

    (1978)
  • G.S. Maritz et al.

    Fetal growth restriction has long-term effects on postnatal lung structure in sheep

    Pediatr Res

    (2004)
  • R.M. Das

    The effects of intermittent starvation on lung development in suckling rats

    Am J Pathol

    (1984)
  • E.A. O’Brien et al.

    Uteroplacental insufficiency decreases p53 serine-15 phosphorylation in term IUGR rat lungs

    Am J Physiol

    (2007)
  • A. Karadag et al.

    Effect of maternal food restriction on fetal rat lung lipid differentiation program

    Pediatr Pulmonol

    (2009)
  • G.S. Maritz et al.

    Effects of fetal growth restriction on lung development before and after birth: a morphometric analysis

    Pediatr Pulmonol

    (2001)
  • L.A. Joss-Moore et al.

    IUGR decreases elastin mRNA expression in the developing rat lung and alters elastin content and lung compliance in the mature rat lung

    Physiol Genomics

    (2011)
  • J.L. Morrison et al.

    Antenatal glucocorticoid treatment of the growth-restricted fetus: benefit or cost?

    Reprod Sci

    (2009)
  • D. Wignarajah et al.

    Influence of intrauterine growth restriction on airway development in fetal and postnatal sheep

    Pediatr Res

    (2002)
  • R. Harding et al.

    Effects of intra-uterine growth restriction on the control of breathing and lung development after birth

    Clin Exp Pharmacol Physiol

    (2000)
  • P.J. Rozance et al.

    Intrauterine growth restriction decreases pulmonary alveolar and vessel growth and causes pulmonary artery endothelial cell dysfunction in vitro in fetal sheep

    Am J Physiol

    (2011)
  • W.M. Gilbert et al.

    Pregnancy outcomes associated with intrauterine growth restriction

    Am J Obstet Gynecol

    (2003)
  • D. Ley et al.

    Respiratory distress syndrome in infants with impaired intrauterine growth

    Acta Paediatr

    (1997)
  • J.E. Tyson et al.

    The small for gestational age infant: accelerated or delayed pulmonary maturation? Increased or decreased survival?

    Pediatrics

    (1995)
  • D.B. Bartels et al.

    Population based study on the outcome of small for gestational age newborns

    Arch Dis Child Fetal Neonatal Ed

    (2005)
  • L. Gortner et al.

    Neonatal outcome in small for gestational age infants: do they really better?

    J Perinat Med

    (1999)
  • M.J. Simchen et al.

    Neonatal outcome in growth-restricted versus appropriately grown preterm infants

    Am J Perinatol

    (2000)
  • A.J. Lechner et al.

    Lung mechanics, cellularity, and surfactant after prenatal starvation in guinea pigs

    J Appl Phys

    (1986)
  • G.A. Braems et al.

    Ovine surfactant protein cDNAs: use in studies on fetal lung growth and maturation after prolonged hypoxemia

    Am J Physiol

    (2000)
  • R. Gagnon et al.

    Changes in surfactant-associated protein mRNA profile in growth-restricted fetal sheep

    Am J Physiol

    (1999)
  • S. Orgeig et al.

    Intrauterine growth restriction delays surfactant protein maturation in the sheep fetus

    Am J Physiol

    (2010)
  • L. Gortner et al.

    Hypoxia-induced intrauterine growth retardation: effects on pulmonary development and surfactant protein transcription

    Biol Neonate

    (2005)
  • J.V. Been et al.

    Chorioamnionitis alters the response to surfactant in preterm infants

    J Pediatr

    (2010)
  • Cited by (0)

    View full text