Fetal Growth Restriction Has Long-Term Effects on Postnatal Lung Structure in Sheep

Abstract

We have previously shown that fetal growth restriction (FGR) during late gestation in sheep affects lung development in the near-term fetus and at 8 wk after birth. In the present study, our aim was to determine the effects of FGR on the structure of the lungs at 2 y after birth; our hypothesis was that changes observed at 8 wk after birth would persist until maturity. FGR was induced in sheep by umbilicoplacental embolization, which was maintained from 120 d until delivery at term (approximately 147 d); birth weights of FGR lambs were 41% lower than in controls. At 2 y after birth, body and lung weights were not different, but there were 28% fewer alveoli and alveoli were significantly larger than in controls; hence there was a 10% reduction in the internal surface area relative to lung volume in FGR sheep compared with controls. The lungs of FGR sheep, compared with controls, had thicker interalveolar septa as a result of increased extracellular matrix deposition; the alveolar blood-air barrier was also thicker, largely because of an 82% increase in basement membrane thickness. These changes are qualitatively similar to those observed at 8 wk. Our data show that structural alterations in the lungs induced by FGR that were apparent at 8 wk were still evident at 2 y after birth, indicating that FGR may result in permanent changes in the structure of the lungs of the offspring and may affect respiratory health and lung aging later in life. Low birth weight as a result of FGR has been associated with an increased risk of morbidity and mortality during infancy (1, 2). It is likely that altered lung development may be a contributing factor as it has been shown that the risk of respiratory illness and the requirement for ventilatory support is increased in FGR infants (3, 4). Respiratory impairments may persist into later life because low birth weight children who were growth-restricted in utero (5, 6), as well as adults having low birth weights (7,8), have evidence of impaired lung function. At present, however, the structural basis for a relationship between FGR and later pulmonary dysfunction is poorly understood.The sheep is a suitable animal model in which to study the effects of FGR on lung development; it is a long-gestation species in which alveolar formation begins before birth (9), as in the human (10), and which reaches sexual maturity 6 mo after birth. Recently we found, in developing sheep, that fundamental aspects of respiratory function were impaired after FGR; FGR lambs were hypoxemic and hypercapnic soon after birth and had reduced pulmonary diffusing capacity and lung compliance up to 8 wk (11). In addition to these functional alterations, we found that FGR induced structural changes in lung parenchyma that were evident in the near-term fetus and became more pronounced at 8 wk after birth (12). In particular, the blood-air barrier and structure of interalveolar septa were affected after FGR. It is possible that structural

The effects of intrauterine growth restriction and antenatal glucocorticoids on ovine fetal lung development

“…Following 20 d of umbilicoplacental embolization, tissue density and alveolar size and number were unaffected. However when these animals were studied postnatally, tissue density was increased at 8 wk of age whereas at 2 years of age the IUGR lung had fewer, larger alveoli (10,11). This suggests that while no structural changes are present in fetal tissue, experimental IUGR may induce morphological changes later in life.…”

“…In experimental studies, structural changes in the IUGR fetal lung have been reported that may underlie impaired lung function. For example, studies in sheep have found that IUGR results in fewer, larger alveoli with thicker alveolar septa, and therefore impaired blood-gas exchange, which persists into adulthood (10,11). Functionally, these structural lung effects in IUGR sheep are reflected by reduced lung compliance and increased chest wall compliance in sheep-changes that may compromise respiratory function (12).…”

Respiratory morbidity at follow-up of small-for-gestational-age infants born very prematurely

“…Other studies have demonstrated that normal lung development is critically dependent on the presence of appropriate oxygen tensions and nutrition (34), which are reduced in SGA fetuses. In both sheep (35) and rats (36), the reduced number of alveoli associated with IUGR at birth persisted into adulthood with no evidence of catch-up growth. Those data are in line with the finding that lung function at school age was reduced in prematurely born infants who had experienced IUGR as compared with genderand age-matched children born at term (37).…”

Retard de croissance intra-utérin et dysplasie bronchopulmonaire

“…G.S. Maritz a montré, chez l'agneau de 8 semaines ayant souffert d'un RCIU, une diminution du nombre d'alvéoles avec un élargis-sement de celles-ci, persistant chez l'animal adulte [8]. D'autres études chez l'agneau ont également montré des anomalies des voies aériennes (trachée et bronches) chez les animaux porteurs d'un RCIU [9].…”