Long term respiratory consequences of intrauterine growth restriction
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
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