Umbilicoplacental Embolization Research Articles

Intrauterine growth restriction elevates circulating acylcarnitines and suppresses fatty acid metabolism genes in the fetal sheep heart.

At birth, the mammalian myocardium switches from using carbohydrates as the primary energy substrate to free fatty acids as the primary fuel. Thus, a compromised switch could jeopardize normal heart function in the neonate. Placental embolization in sheep is a reliable model of intrauterine growth restriction (IUGR). It leads to suppression of both proliferation and terminal differentiation of cardiomyocytes. We hypothesized that the expression of genes regulating cardiac fatty acid metabolism would be similarly suppressed in IUGR, leading to compromised processing of lipids. Following 10 days of umbilicoplacental embolization in fetal sheep, IUGR fetuses had elevated circulating long-chain fatty acylcarnitines compared with controls (C14: CTRL 0.012 ± 0.005nmol/ml vs. IUGR 0.018 ± 0.005nmol/ml, P < 0.05; C18: CTRL 0.027 ± 0.009nmol/mol vs. IUGR 0.043 ± 0.024nmol/mol, P < 0.05, n = 12 control, n = 12 IUGR) indicative of impaired fatty acid metabolism. Uptake studies using fluorescently tagged BODIPY-C12-saturated free fatty acid in live, isolated cardiomyocytes showed lipid droplet area and number were not different between control and IUGR cells. mRNA levels of sarcolemmal fatty acid transporters (CD36, FATP6), acylation enzymes (ACSL1, ACSL3), mitochondrial transporter (CPT1), β-oxidation enzymes (LCAD, HADH, ACAT1), tricarboxylic acid cycle enzyme (IDH), esterification enzymes (PAP, DGAT) and regulator of the lipid droplet formation (BSCL2) gene were all suppressed in IUGR myocardium (P < 0.05). However, protein levels for these regulatory genes were not different between groups. This discordance between mRNA and protein levels in the stressed myocardium suggests an adaptive protection of key myocardial enzymes under conditions of placental insufficiency. KEY POINTS: The fetal heart relies on carbohydrates in utero and must be prepared to metabolize fatty acids after birth but the effects of compromised fetal growth on the maturation of this metabolic system are unknown. Plasma fatty acylcarnitines are elevated in intrauterine growth-restricted (IUGR) fetuses compared with control fetuses, indicative of impaired fatty acid metabolism in fetal organs. Fatty acid uptake and storage are not different in IUGR cardiomyocytes compared with controls. mRNA levels of genes regulating fatty acid transporter and metabolic enzymes are suppressed in the IUGR myocardium compared with controls, while protein levels remain unchanged. Mismatches in gene and protein expression, and increased circulating fatty acylcarnitines may have long-term implications for offspring heart metabolism and adult health in IUGR individuals. This requires further investigation.

Placental insufficiency decreases cell cycle activity and terminal maturation in fetal sheep cardiomyocytes

Umbilicoplacental embolization (UPE) in sheep has been used to investigate the effects of placental insufficiency on fetal development. However, its specific effects on the heart have been little studied. The aim of this study was to determine the effects of placental insufficiency, induced by UPE, on cardiomyocyte size, maturation and proliferation. Instrumented fetal sheep underwent UPE for either 10 or 20 days. Hearts were collected at 125 +/- 1 days (10 day group) or 136 +/- 1 days (20 day group) of gestation (term approximately 145 days). Cell size, maturational state (as measured by the proportion of binucleated myocytes) and cell cycle activity (as measured by positive staining of cells for Ki-67) were determined in dissociated cardiomyocytes. UPE fetuses were hypoxaemic, but mean arterial pressures were not different from controls. UPE fetuses were lighter than control fetuses (10 days: -21%, P < 0.05; 20 days: -27%, P < 0.01) and had smaller hearts, but heart weight was appropriate for body weight. Neither lengths nor widths were different between control and UPE cardiomyocytes at either age. Ten days of UPE did not significantly alter the proportion of binucleated myocytes or cell cycle activity in either ventricle. However, 20 days of UPE reduced cell cycle activity in both ventricles by approximately 70% (P < 0.05); the proportion of binucleated myocytes was also lower in UPE fetuses at this age (left ventricle: 31.1 +/- 12.0 versus 46.0 +/- 6.6%, P < 0.05; right ventricle: 29.4 +/- 12.3 versus 46.3 +/- 5.3%, P < 0.05). It is concluded that in the absence of fetal arterial hypertension, placental insufficiency is associated with substantially depressed growth of the heart through suppressed proliferation and maturation of cardiomyocytes.

Fetal Growth Restriction Induced by Chronic Placental Insufficiency Has Long-Term Effects on the Retina but Not the Optic Nerve

Reduced birth weight is associated with an increased risk of visual impairments. This study was undertaken to determine whether prenatal exposure to a chronic compromise sufficient to cause fetal growth restriction (FGR) results in long-term alterations to the retina and optic nerve. FGR was induced by umbilicoplacental embolization (UPE) in two cohorts of pregnant ewes from (1) 120 days of gestation (dg) until 140 dg and (2) 120 dg until term ( approximately 147 dg). Control fetuses were not subjected to UPE. The structure and neurochemistry of the retina and number and structure of ganglion cell axons were assessed in near-term (140 dg) and adult animals (2.3 years). In near-term FGR fetuses compared with control fetuses there were significant reductions (P < 0.05) in the outer plexiform layer (OPL), the photoreceptor inner and outer segment layers, the inner nuclear layer (INL) in the central retina and the outer nuclear layer (ONL) in the peripheral retina, and the diameter of ganglion cell axons in the optic nerve, with a proportional reduction in the thickness of myelin sheaths. In FGR animals compared with the control at 2.3 years, there were significant reductions (P < 0.05) in the total thickness of the retina, the thickness of the photoreceptor outer segment layer and the INL and the number of tyrosine hydroxylase-immunoreactive (TH-IR) dopaminergic amacrine cells. Axonal diameter and myelin sheath thickness in the optic nerve were not different (P > 0.05) between groups. Chronic placental insufficiency in late gestation results in long-lasting effects on specific retinal components, including photoreceptor outer segments and TH-IR amacrine cells. Other alterations observed at term, including reductions in growth and myelination of optic nerve axons, do not persist, suggesting delayed rather than permanently compromised development. Alterations persisting into adulthood could affect visual function.

Changes in aquaporin 1 expression affect amniotic fluid volume

STEPHANIE MANN, NATALIA DVORAK, ROBERT TAYLOR, Phoenix Integrated Residency in Ob/Gyn, Obstetrics and Gynecology, Phoenix, Arizona, University of California, San Francisco, Obstetrics, Gynecology and Reproductive Sciences, San Francisco, California OBJECTIVE: Recent work from our laboratory has demonstrated the presence of aquaporin (AQP) water channels in fetal membranes from pregnancies with normal amniotic fluid (AF) volume. The objective of this study was to investigate changes in AQP 1 mRNA expression from fetal membranes of pregnancies with polyhydramnios and oligohydramnios. STUDY DESIGN: Placentas from term pregnancies (37-40 wks) were collected from women who presented with intact membranes and one of the following: (1) idiopathic oligohydramnios (AFI !5.0 cm); (2) polyhydramnios (AFI >24.0 cm); and (3) normal amount AF (AFI >5.0 cm and!24.0 cm). The membranes (amnion and chorion) directly overlying the placenta and the free floating reflected membranes were sampled (total of four samples from each placenta). RNA was isolated from the amnion and chorion of each region. Quantitative RT-PCR was used to compare expression of AQP1 mRNA in the membranes collected from the above pregnancies. Statistical analysis was performed with a t test. P ! .05 was considered signficant. RESULTS: As shown in the figure, AQP1 mRNA expression is increased in the reflected amnion from pregnancies with idiopathic polyhydramnios and decreased in the reflected amnion and chorion from pregnancies with oligohydramnios. CONCLUSION: The expression of the water channel AQP1 is altered in the reflected fetal membranes. These results suggests that there is an adaptive response by the fetal membranes in situations of either decreased or increased AF volume to prevent excessive loss or accumulation of fluid, respectively. We speculate that therapies focused on regulating AQP1 expression may be useful for treating oligohydramnios and polyhydramnios. 458 PERINATAL GLUCOSE TOLERANCE AFTER INTRAUTERINE GROWTH RESTRICTION IN THE LATE-GESTATION OVINE FETUS PHILIPPE DERUELLE, IVA GUEORGUIEVA, BERENGERE SICOT DE JENLIS, SOPHIE JAILLARD, JACQUES WEILL, VERONIQUE DEBARGE, LAURENT STORME, CHRU de Lille, Lille, France, CHRU de Lille, Pediatric endocrinology unit, Lille, France, CHRU de Lille, Department of perinatology, Lille, France, CHRU de Lille, France, Department of perinatology, Lille, France OBJECTIVE: Newborns with Intrauterine-Growth Restriction (IUGR) are at increased risk to develop a metabolic syndrome later in life, namely obesity, cardiovascular disease, impaired glucose tolerance. Whereas these facts have been largely studied during childhood or adult life, little is known about the consequences of IUGR on glucose tolerance during the perinatal period. The purpose of this study was to determine whether chronic placental embolization in the late gestation ovine fetus induce insulin resistance during the perinatal period. STUDY DESIGN: IUGR was induced by umbilico-placental embolization during late gestation in chronically catheterized sheep. Umbilico-placental embolization was performed between 130 and 140 d of gestation (terme = 147 d) during which fetuses were hypoxemic relative to controls. Euglycemic, hyperinsulinemic glucose clamp experiments were performed in utero and during the first three weeks after birth in order to measure the effect of fetal insulin concentration on fetal glucose uptake at a constant glucose concentration. Fetal coricotropin, cortisol and catecholamines concentrations were measured daily. RESULTS: Chronic placental embolization produced asymmetrically IUGR fetuses and increased vascular resistance in umbilical artery (P ! .05). The exogenous glucose infusion rate necessary to maintain constant glycemia was significantly lower in IUGR relative to control fetuses at 140 d of gestation (IUGR vs. control, 2.5 G .5 mg/kg/min and 5.0 G 0.5 mg/kg/min, P ! .05) and 7 days after birth (IUGR vs. control, 3.5 G .7 mg/kg/min and 5.7 G 1.4 mg/kg/ min, P ! .05). Glucose clamps were similar between groups at 2 and 3 weeks after birth. Cortisol levels were similar between the two groups. In response to chronic fetal hypoxemia, there was a progressive increased in baseline fetal plasma epinephrine, norepinephrine and dopamine concentrations (P ! .01). CONCLUSION: We concluded that chronic fetal hypoxemia induces insulin resistance during the perinatal period. We speculate that this change could be related to an increase in fetal catecholamines levels.

Effects of Exposure to Chronic Placental Insufficiency on the Postnatal Brain and Retina in Sheep

Chronic placental insufficiency (CPI) has the potential to affect fetal brain development and to cause brain injury. Our aim was to determine the effects of exposure to CPI during late gestation on brain and retinal structure and brain neurotrophin expression 8 weeks after birth. Six fetal sheep were exposed to CPI, induced by umbilico-placental embolization, from 120 days of gestation until term (approximately 147 days) such that fetal arterial oxygen saturation (SaO2) was reduced by approximately 50%. Nine untreated animals served as controls. During CPI, fetal arterial PO2, SaO2, pH, and growth were reduced (p < 0.05); these animals remained small at 8 weeks after birth. Structural abnormalities were present in the brains and retinae of all CPI-exposed lambs. There was a reduction in retinal width and in the number of retinal tyrosine hydroxylase-immunoreactive dopaminergic amacrine cells (p < 0.05). In the dorsal hippocampus the combined width of strata oriens and pyramidale was significantly reduced (p < 0.05). In the cerebellum there was a significant reduction (p = 0.05) in cerebellar cross-sectional area, most notably in the inner granule cell layer, and a reduction (p < 0.05) in immunoreactivity for the cytoskeletal protein neurofilament-200 in the white matter. Gliosis was present in either the cerebral white matter or cerebellum in all animals and degeneration was seen around blood vessels in 4/6 umbilico-placental embolization animals. There were reductions in brain-derived neurotrophic factor immunoreactivity in the hippocampus (p < 0.05) and tyrosine kinase B immunoreactivity in the cerebellum (p < 0.05). This study shows that late gestational CPI affects morphology and neurotrophin expression of the postnatal brain. These alterations in the brain can apparently persist from fetal life or become established after birth; some changes that were present in the fetus at term did not persist into postnatal life.

Neurotrophin expression in the hippocampus and cerebellum is affected by chronic placental insufficiency in the late gestational ovine fetus

Our aim was to determine the effects of chronic placental insufficiency (CPI) during late gestation on the expression of neurotrophic factors and their receptors in the hippocampus and cerebellum in the near-term fetus. Structural alterations were also assessed in these brain regions. CPI was induced in eight fetal sheep by umbilicoplacental embolization (UPE) from 120 to 140 days of gestation (term ∼147d) such that fetal arterial O 2 saturation (SaO 2) was maintained at ∼50% of pre-UPE values. Five non-UPE fetuses served as controls. UPE resulted in fetal hypoxemia, hypoglycaemia, and growth restriction. In hippocampi from UPE fetuses, there were reductions in the optical density (OD) of the immunoreactivity (IR) of brain-derived neurotrophic factor (BDNF) protein within the mossy fibre collaterals of the polymorphic layer and in stratum lucidum ( p<0.05); there was no consistent effect on tyrosine-related kinase (Trk) B receptor or neurotrophin-3 (NT-3) expression. Within the cerebellum, there was an increase in BDNF-IR ( p<0.05) in the molecular layer; however, Trk B-IR and NT-3-IR were unaltered. There were no significant alterations to the structural parameters measured in the hippocampus. We conclude that CPI in late gestation affects the expression of BDNF in the fetal hippocampus and cerebellum, but these changes do not have a well-defined relationship to structural outcome.

Nephron endowment and filtration surface area in the kidney after growth restriction of fetal sheep.

Low birth weight is associated with adult-onset diseases including hypertension and renal disease; altered renal development after intrauterine growth restriction (IUGR) may underlie such prenatal programming. Our aim was to investigate nephron endowment and renal filtration surface area in fetal sheep in which IUGR resulted from late gestational umbilico-placental embolization (UPE) or natural twinning. UPE was performed between 120 and 140 d of gestation (term approximately 147 d). At autopsy (140 d), body weights of UPE and twin fetuses were, respectively, 34% and 28% lower than controls. Kidneys were sampled using a smooth fractionator approach and glomerular number was estimated using a physical disector/fractionator technique. Glomerular capillary length and filtration surface area were estimated using unbiased stereological techniques. Although relative kidney weights (grams per kilogram body weight) were not different between groups, nephron endowment was 40% lower in twin fetuses compared with controls (34.3 +/- 10.6 x 10(4) and 55.9 +/- 19.8 x 10(4), respectively; p < 0.05); UPE did not alter nephron number (50.7 +/- 13.2 x 10(4)). There was no difference in the glomerular capillary length or surface area between the UPE and control fetuses. IUGR due to twinning leads to reduced nephron endowment whereas late gestational IUGR does not, suggesting that reduced nephron endowment is dependent on the timing of the growth restriction. Our findings demonstrate that reduced birth weight per se does not necessarily imply reduced nephron endowment.

PULMONARY ELASTIN SYNTHESIS AND DEPOSITION IN DEVELOPING AND MATURE SHEEP: EFFECTS OF INTRAUTERINE GROWTH RESTRICTION

Hypoxia and nutrient restriction during gestation restrict fetal growth and alter lung development. As elastin is intimately involved in lung development, our aim was to assess pulmonary elastin synthesis and deposition following intrauterine growth restriction (IUGR) induced by umbilicoplacental embolization (UPE). Pulmonary tropoelastin expression and elastin content were examined at 128 days (5 days UPE) and 140 days (20 days UPE) of the 147- days gestation and at 8 weeks and 2.3 years after birth (both ∼27 days UPE) in sheep. UPE induced hypoxemia, hypoglycemia, and fetal growth restriction but did not affect pulmonary tropoelastin mRNA levels or elastin deposition at any age; furthermore, elastin content was unaltered apart from being lower at 140 days. The authors conclude that hypoxemia and undernutrition associated with IUGR do not affect elastin synthesis and deposition in fetal lungs; alterations in lung structure following IUGR must have other causes.

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

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.

Changes in 5alpha-pregnane steroids and neurosteroidogenic enzyme expression in fetal sheep with umbilicoplacental embolization.

Pregnane steroids have sedative and neuroprotective effects on the brain, due to interactions with the steroid-binding site of the GABAA receptor. In the adult brain, synthesis of the pregnane steroids is increased in response to stress. Therefore, we have used umbilicoplacental embolization to mimic chronic placental insufficiency during late gestation in sheep, to investigate the expression of the steroidogenic enzymes p450scc, 5alpha-reductase type I (5alphaRI), 5alpha-reductase type II (5alphaRII), and allopregnanolone (AP) content in the fetal brain. Umbilicoplacental embolization was induced from 114 d gestation (term approximately 147 d) by daily injection of inert microspheres into the umbilical artery and continued for 17-23 d. Fetal arterial oxygen saturation was reduced to approximately 60% of the preembolization value in each fetus, with a significant reduction in blood arterial Po2, pH, and plasma glucose concentrations (p < 0.05) and a significant increase in blood arterial Pco2 and plasma lactate concentrations (p < 0.05). At postmortem at 131-137 d gestation, embolized fetuses were growth-restricted (2.10 +/- 0.14 kg, n = 5) compared with age-matched controls (4.43 +/- 0.56 kg, n = 7, p < 0.05). Umbilicoplacental embolized fetuses showed increased P450scc expression in the primary motor cortex; 5alphaRI expression was not changed in any of the regions examined, whereas 5alphaRII expression was markedly increased in all brain regions. Brain AP content did not significantly change, whereas plasma concentrations were increased. These findings suggest that the increased expression of p450scc and 5alphaRII may be a response that maintains AP concentration in the fetal brain after compromised placental function and/or intrauterine stress.

Chronic placental insufficiency and foetal growth restriction lead to long-term effects on postnatal retinal structure.

The aim of this study was to determine the effects of foetal growth restriction on the retina after birth. Foetal growth restriction (FGR) was induced via umbilico-placental embolization (UPE) in ewes from 120 days of pregnancy until term (term approximately 147 days); controls were not exposed to UPE. Lambs were delivered and raised until 2 years of age when retinas were collected and processed for structural and neurochemical analysis. The foetuses exposed to UPE were hypoxemic and at birth were growth restricted. In 2-year-old FGR sheep, the total thickness of the retina and the number of tyrosine hydroxylase immunoreactive dopaminergic amacrine cells were reduced compared to controls (P < 0.05). It is concluded that restricted foetal growth leads to long-term structural and neurochemical changes in the retina. Of particular interest are the alterations to dopaminergic amacrine cell numbers, as alterations in this population may affect contrast sensitivity and have implications for the alterations in vision observed in very low birthweight infants.

Postnatal outcomes in term and preterm lambs following fetal growth restriction.

1. Epidemiological evidence indicates that low birthweight increases the risk of a number of adult-onset diseases. It is now apparent that many babies with a low birthweight may have been subjected to a combination of reduced growth rates in utero as well as preterm birth. However, the long-term effects of preterm birth following intra-uterine growth restriction (IUGR) are unknown. Thus, our objectives were: (i) to identify prenatal factors associated with preterm birth in IUGR fetuses; and (ii) to characterize postnatal effects of preterm birth following IUGR. 2. We studied pregnant sheep and their offspring, in which fetal growth was restricted by umbilico-placental embolization during late gestation. Some of these animals were born at term (146 +/- 1 days) and some were born prematurely (139 +/- 1 days). In both groups, we have conducted longitudinal studies of postnatal respiratory function, cardiovascular function and learning ability up to 6-8 weeks of age. 3. Before birth, IUGR fetuses born prematurely (P-IUGR) were more hypoxaemic and acidaemic and had higher haemoglobin concentrations than both control fetuses and IUGR fetuses born at term (T-IUGR). In P-IUGR fetuses, plasma cortisol concentrations increased earlier than in the two other groups. The P-IUGR lambs had lower birthweights than T-IUGR lambs and both groups of IUGR lambs remained lighter than controls for 8 weeks. 4. After birth, P-IUGR lambs were hypoxaemic compared with T-IUGR and control lambs. Pulmonary diffusing capacity (adjusted for lung volume) was significantly lower in both groups of IUGR lambs than in controls, with P-IUGR lambs having lower values than T-IUGR lambs. Lung compliance (adjusted for lung volume), was not different between P-IUGR and control lambs, but values were higher in T-IUGR lambs than in control and P-IUGR lambs. Chest wall compliance (adjusted for lung volume) was higher in both groups of IUGR lambs than in controls. 5. During the 8 week postnatal study period, both groups of IUGR lambs had lower mean arterial pressures than control lambs; this relative hypotension was greatest in P-IUGR lambs. 6. In tests of learning ability, P-IUGR lambs took longer to complete a simple maze task at all ages and, in the second postnatal week, made a greater number of errors compared with controls. In an obstacle course, P-IUGR lambs recorded longer trial durations; they also made more errors than control lambs. 7. We conclude that preterm birth in the presence of late- gestational placental insufficiency and IUGR can result in specific effects on respiratory and cardiovascular development after birth, in addition to the effects of IUGR alone.

Compromised respiratory function in postnatal lambs after placental insufficiency and intrauterine growth restriction.

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. Umbilico-placental embolization was performed between 120 d of gestation and term ( approximately 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 = 8) remained lighter than controls (n = 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. At 8 wk, pulmonary DNA and protein concentrations were decreased in IUGR lambs relative to controls. We conclude that restriction of fetal growth by placental insufficiency induces alterations in the lungs and chest wall that result in persistent impairments in respiratory function during early postnatal life.

Effects of intrauterine growth restriction on lung liquid dynamics and lung development in fetal sheep

Objective: The aim of this study was to determine the effects of intrauterine growth restriction on fetal lung liquid and lung development. Study Design: Intrauterine growth restriction was induced in 7 fetal sheep from 120 to 140 days' gestation (term, approximately 147 days' gestation) by umbilicoplacental embolization. We used 6 control fetuses. Volumes and production rates of fetal lung liquid were measured, and lungs were removed post mortem (140 days' gestation) for analysis of concentrations of deoxyribonucleic acid, protein, and messenger ribonucleic acid for surfactant proteins A, B, and C. Results: Umbilicoplacental embolization induced fetal hypoxemia, hypoglycemia, and intrauterine growth restriction. At 140 days' gestation lung weight was reduced by 34%, and the fetal lung liquid production rate (15.9 ± 1.8 mL/h for intrauterine growth restriction vs 24.8 ± 3.9 mL/h for control) and volume (110.9 ± 16.3 mL for intrauterine growth restriction vs 178.1 ± 11.9 mL for control) were reduced in the intrauterine growth restriction group. After adjustment for body weight, however, values were not different from those in the control group. Pulmonary deoxyribonucleic acid and plasma cortisol concentrations were elevated by intrauterine growth restriction, but levels of messenger ribonucleic acid for surfactant proteins were unchanged. Conclusion: In intrauterine growth restriction, lung liquid and lung growth were proportionate to body weight, and surfactant protein expression was unaffected. Alterations in lung deoxyribonucleic acid concentrations suggest that the lungs may be structurally immature. (Am J Obstet Gynecol 2001;184:209-16.)

Placental insufficiency and fetal growth restriction lead to postnatal hypotension and altered postnatal growth in sheep.

Low birth weight has been associated with elevated arterial pressure in later life but mechanisms are unknown. Our aim was to determine the effects of low birth weight resulting from intrauterine growth restriction (IUGR) on fetal and postnatal arterial pressures and the potential roles of circulating cortisol and renin. We induced IUGR by umbilico-placental embolization (UPE) in fetal sheep from 120 d of gestation until birth (approximately 147 d); postnatal lambs (8 IUGR, 8 controls) were studied for 8 wk. Fetal and postnatal arterial pressures were measured and blood samples taken for measurement of gas tensions, cortisol concentrations and renin activity. In IUGR fetuses, mean arterial pressure (MAP) initially increased with UPE, but near term was not different to values in controls. IUGR lambs weighed 33% less than controls at birth and remained lighter than controls during the 8 postnatal weeks; their growth pattern was different to that of controls. IUGR lambs had lower MAP than controls, and this relative hypotension (-4 mm Hg) persisted throughout the 8 postnatal weeks. Covariate analysis showed that the relative hypotension of IUGR lambs could have resulted from their smaller size. Plasma cortisol concentrations were not different between IUGR and control animals before or after birth. Plasma renin activity was not different in postnatal IUGR lambs compared with controls. Thus, postnatal cortisol and renin levels were not consistent with the development of hypotension or hypertension. We conclude that late gestational IUGR in sheep leads to relative hypotension in the early postnatal period, probably a result of reduced body size.

Relation between damage to the placenta and the fetal brain after late-gestation placental embolization and fetal growth restriction in sheep

Objective: Our aim was to determine the effects of 30 days of placental insufficiency on fetal brain development and to relate placental damage to the degree of fetal brain injury. Study Design: Umbilicoplacental embolization was induced from 110 to 140 days of gestation (term, 147 days) in 7 fetal sheep, such that fetal arterial oxygen saturation was maintained at 50% of pre–umbilicoplacental embolization values. Six control fetuses were used. At 140 days the fetal brains and placentas were subjected to structural and histochemical analysis. Results: During umbilicoplacental embolization, fetal arterial oxygen saturation, PaO 2, and pH were reduced ( P < .05). Thirty days of umbilicoplacental embolization caused a decrease in cross-sectional area of the placentome ( P < .05), with 20% of tissue showing damage. All umbilicoplacental embolization fetuses were growth restricted and had brain damage, most prominently in the cerebral white matter. There was no relation between the extent of placental damage and the severity of fetal brain damage. Conclusions: The absence of a correlation between damage to the placenta and fetal brain is likely to be caused by variations between individuals in (1) the amount of placenta that is required to be functionally damaged to achieve the prescribed level of hypoxemia and (2) the response of the fetal brain to that level of hypoxemia. (Am J Obstet Gynecol 2000;183:1013-22.)

Renal and amniotic fluid responses to umbilicoplacental embolization for 20 days in fetal sheep.

We determined the effects of placental insufficiency induced by umbilicoplacental embolization on fetal renal function and amniotic fluid volume and composition. Pregnant ewes underwent surgery at 115 +/- 2 days after mating (term approximately 147 days) for implantation of fetal vascular, bladder, and amniotic sac catheters. We studied five fetuses from 120 to 140 days during umbilicoplacental embolization and six control fetuses. Umbilicoplacental embolization reduced fetal arterial partial pressure of oxygen from 24.1 +/- 0.5 mmHg (pretreatment) to 14.6 +/- 0.2 mmHg. Fetal body weights were reduced to 80% of control values. Urine production and glomerular filtration rate in treated fetuses were significantly lower than in controls at 135 days of gestation. Amniotic fluid volume was not different between embolized and control animals. Fetal urine production in treated fetuses, when adjusted for body weight, was not different from that in control fetuses. We conclude that, in fetal growth restriction, reduced kidney weight, rather than hypoxemia per se is responsible for reduced urine production, which, if severe and prolonged, may contribute to oligohydramnios.