Our aim was to determine the effects of fetal growth restriction (FGR) during late gestation on the structure of the lungs in the fetus near term and at 8 weeks after birth. The studies were performed using two groups of pregnant sheep and their offspring. In both groups, FGR was induced by umbilico-placental embolisation (UPE); for fetal studies, UPE was performed from 120 days of gestation until 140 days (term, approximately 146 days), when fetuses were killed for tissue analysis. For postnatal studies, UPE continued from 120 days until delivery at term; postnatal lambs were killed at 8 weeks after birth for tissue analysis. UPE led to a thicker pulmonary blood-air barrier at 140 days of gestation and this difference, which was due to a thickened basement membrane, was still present at 8 weeks after birth. At 8 weeks, we also observed a smaller number of alveoli per respiratory unit, thicker interalveolar septa, and a greater volume density of lung tissue in FGR lambs compared to controls. These changes would be expected to impair gas exchange and alter the mechanical properties of the lungs. Our data show that structural alterations in the lungs induced by placental insufficiency were more evident at 8 weeks of postnatal age than near term, indicating that the effects of FGR on the lung may become more serious with age and may affect respiratory health later in life.

Epidemiologic studies have shown persistent effects of low birth weight on respiratory function and lung health, but underlying mechanisms are not understood. Our aim was to determine the effects of intrauterine growth restriction (IUGR), a major cause of low birth weight, on postnatal respiratory function. IUGR was induced by umbilico-placental embolization during late gestation in chronically catheterized sheep. Umbilicoplacental embolization was performed between 120 d of gestation and term (~146 d) during which fetuses were hypoxemic and hypoglycemic relative to controls. Umbilico-placental embolization led to a 48% reduction in birth weight compared with controls, and throughout the postnatal study period IUGR lambs (n ϭ 8) remained lighter than controls (n ϭ 8). Respiratory function was repeatedly studied in lambs for 8 wk after birth; during this period, IUGR lambs were mildly hypoxemic and tended to be hypercapnic compared with controls. In IUGR lambs, relative to controls, O 2 consumption (mL/min/kg) and minute ventilation (mL/kg) were increased and pulmonary diffusing capacity (adjusted for functional residual capacity) was decreased. Functional residual capacity, measured by helium dilution, and total lung capacity (measured at 30 cm H 2 O) were smaller in IUGR lambs than in controls. When adjusted for functional residual capacity, static lung compliance was reduced and chest wall compliance was increased in IUGR lambs. Restricted fetal growth, resulting in low birth weight, has been associated with altered lung development and impaired respiratory function after birth. Recent studies of neonates and infants who have been growth restricted in utero indicate that they have an increased risk of mortality and morbidity (1), including respiratory distress (2, 3). Respiratory compromise may persist during postnatal development as it has been shown that children with evidence of growth restriction in utero have reduced forced expiratory flow rates (4, 5) indicative of impaired airway function. In addition, adults who were of low birth weight and, therefore, likely to have been growth restricted in utero, have reduced expiratory flow rates and an increased risk of respiratory morbidity and mortality (6, 7). Thus, a number of epidemiologic studies suggest that pulmonary gas exchange and airway function after birth may be affected by IUGR.Placental insufficiency and IUGR are common causes of low birth weight, and are associated with pregnancy-induced hypertension, maternal tobacco smoking, and placental pathology (8, 9). Fetuses identified as being growth restricted have been found to be hypoxemic, hypoglycemic, and to have elevated

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SUMMARY1. Epidemiological studies of infants, children and adults indicate that prenatal compromises that restrict fetal growth and cause low birthweight increase the risk of respiratory deficiencies after birth.2. It is apparent that the lung has a limited ability to recover from early developmental compromises and that altered development can permanently impair lung architecture.3. Lung development in utero can be adversely affected by factors associated with fetal growth restriction, namely fetal hypoxaemia, reduced substrate supply and hypercortisolaemia.4. We have conducted a series of studies of respiratory development in chronically catheterized ovine fetuses and postnatal lambs in which growth restriction was induced during late gestation by embolizing the umbilico-placental vascular bed, a technique that replicates key aspects of human placental insufficiency.5. During late gestation, restricting the growth of the ovine fetus did not alter lung weight or lung liquid secretion or volume when each factor was related to bodyweight, but it did lead to increased lung DNA concentrations and an increased thickness of the air-blood barrier. Expression of pulmonary surfactant proteins A, B and C were not altered and, hence, it was unlikely that surfactant protein synthesis had been impaired by growth restriction.6. When growth restriction continued to term, lambs were born with a low birthweight and remained small compared with controls for 8 weeks after birth. Low-birthweight lambs were mildy hypoxaemic and compliances of their lungs and chest wall were, respectively, decreased and increased relative to controls. Pulmonary surfactant proteins A, B and C were not deficient, indicating that decreased lung compliance most likely had a structural basis.7. Morphometric analysis of lungs at 8 weeks after birth indicated that low-birthweight lambs had increased alveolar wall thicknesses, less 'air-space' and thicker blood-air barriers. These properties would be expected to restrict pulmonary gas exchange and decrease pulmonary compliance.8. We conclude that growth restriction during early development can have lasting adverse effects on the lungs and chest wall and that these may be sufficient to affect respiratory function throughout later life as well as advancing ageing of the lungs.