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Circulatory changes during gestational development of the human fetus have been considered to be similar to those noted in studies of the lamb fetus. Blood flow measurements derived by Doppler ultrasound and magnetic resonance imaging techniques in human fetuses at various stages of gestation have been compared with those in the lamb. Combined ventricular output relative to fetal body weight does not change significantly with growth in the lamb or human. However, the proportion of cardiac output to the brain increases markedly in the human, but only slightly in the lamb fetus in the latter half of gestation. Cardiac output distribution to other organs also changes little in the lamb, but in the human, there is a marked decrease in the proportion distributed to the placenta and an increase in pulmonary flow. The developmental changes in the distribution of combined ventricular output in the human fetus may modify the responses to circulatory disturbances, such as congenital cardiovascular malformations, dependent on gestation.

Obstruction of the fetal trachea is a potent stimulus for fetal lung growth and may have therapeutic potential in human fetuses with lung hypoplasia. However, the effects of increased lung expansion on lung development near midgestation, which is the preferred timing for fetal intervention, have not been well studied. Our aim was to determine the effects of increased lung expansion on lung development at 75-90 d of gestation in fetal sheep. In three groups of fetuses (n = 4 for each), the trachea was occluded for either 10 [10-d tracheal occlusion (TO) group] or 15 d (15-d TO group) or left intact (control fetuses). TO for both 10 and 15 d caused fetal hydrops, resulting in significantly increased fetal body weights. Both periods of TO significantly increased total lung DNA contents from 99.8 +/- 10.1 to 246.0 +/- 5.3 and 246.9 +/- 48.7 mg in 10- and 15-d TO fetuses, respectively. TO for 10 and 15 d also increased airspace diameter, although the percentage of lung occupied by airspace was not increased in 10-d TO fetuses due to large increases in interairway distances; this resulted from a large increase in mesenchymal tissue. The interairway distances at 15 d of TO were reduced compared with the 10-d value but were still approximately 30% larger than control values. We conclude that TO at

Prenatal growth deficiencies as well as gender have been associated with cardiovascular disease in later life. It is also known that the duration of fetal cardiac time intervals (CTI) are dependent on fetal development. The aim of this work was to examine the relationship between fetal CTI in healthy and intrauterine growth retardation (IUGR) fetuses, taking gender into account. A total of 269 magnetocardiograms (MCG) were obtained in 47 healthy and 27 IUGR pregnancies. In each signal-averaged MCG, durations of CTI were determined. Age- and heart rate-corrected values were compared between normal and IUGR fetuses separately with respect to gender. Overall, there was an association between atrial and ventricular conduction times and estimated fetal body weight. In female fetuses, IUGR was associated with shorter P WAVE, PQ segment, PR interval, and QRS complex and longer STT and QT intervals. For males, this was so only for P wave, QRS complex, and STT interval. The shortening of conduction times in IUGR may be explained by reduced cardiac muscle mass associated with lower body weight. On the other hand, the gender-specific differences, particularly in the IUGR fetuses may be due to hormonal factors.

Chronic reduction in substrate delivery to the fetus may induce redistribution of fetal cardiac output to maintain nutrient delivery to vital organs, including the brain. Reduced vasoconstriction, in conjunction with increased local synthesis of nitric oxide may contribute to “brain sparing.” The authors hypothesized that maternal undernutrition would reduce vasoconstrictor responses in fetal carotid arteries due to increased nitric oxide. Timed pregnant Sprague-Dawley rats were randomized on day 0 of pregnancy to control (C) or nutrient restricted (NR) diet. Dams were killed on day 20 of pregnancy. Fetal carotid artery responses were assessed using a pressurized myograph system. Fetal body weight was reduced by NR diet. In NR fetuses, liver, lung, kidney, and heart weights were lower, whereas proportional brain weight was greater. Carotid artery constriction to endothelin-1 was similar in both groups; however, phenylephrine-induced constriction was decreased in NR arteries. Arteries from control fetuses constricted in response to increasing concentrations of L-NAME, whereas arteries from NR did not. There was also no effect of L-NAME on constriction to phenylephrine in arteries from NR fetuses. Our study indicates that the reduced carotid artery vasoconstriction to phenylephrine in NR fetuses, which is consistent with the maintenance of fetal brain blood flow, was not mediated by enhanced nitric oxide. Reduced phenylephrine but not endothelin-1–induced constriction suggests specific effects on adrenergic carotid artery function, which may implicate this pathway in the vascular adaptation to fetal undernutrition.

Fetal growth retardation, a common end point for a variety of conditions affecting mother and fetus, is associated with reduced liver mass. We have performed studies to determine the mechanism for decreased liver mass in a maternal starvation model of fetal growth restriction in the rat. Pregnant dams were deprived of food for 48 h before delivery on embryonic day 19 (E19). Fetal body weight was not affected. However, fetal liver weight was reduced by approximately 15%. Immunostaining of fetal liver for proliferating cell nuclear antigen and flow cytometry on isolated fetal hepatocytes showed G1 cell cycle arrest in samples from starved dams. Based on our prior studies showing attenuated hepatic insulin signaling in the late gestation fetal rat, we tested the hypothesis that G1 arrest in our model might be due to altered nutrient signaling. Fetal plasma amino acid analyses showed no decrease in branched-chain amino acids, but arginine concentrations were decreased in fetuses of fasted mothers. Reduced arginine in E19 fetal hepatocyte culture media was associated with decreased DNA synthesis. Whereas levels of cyclins D and E were unchanged in fetal hepatocytes exposed to low arginine, cyclin E-dependent kinase activity was reduced. Low arginine also induced changes in the translational machinery, indicative of impaired signaling through the nutrient sensing kinase mammalian target of rapamycin. Our results are consistent with the hypothesis that restricted nutrient availability signals to the hepatocyte cell cycle in fetuses of fasted mothers, thereby accounting for decreased hepatocyte proliferation and liver mass.

Top of pageAbstract ABSTRACT: We investigated pituitary regulation of late-gestation fetal growth in the spontaneous dwarf rat, a strain with an autosomal recessive mutation (gene symbol dr) in the growth hormone (GH) gene resulting in complete isolated GH deficiency. GH-normal/GH-deficient (Dr/dr) females were crossed with Dr/dr or dr/dr males, producing both GH-deficient and GH-normal fetuses within the same litter. Pups were killed within 3 h after birth to approximate the developmental state of a late-gestation fetus. The body weight of GH-deficient fetuses was inhibited by 14% in comparison to GH-normal animals, but tail length remained unaffected. The brain and lungs were the only organs whose growth appeared to be pituitary-independent. Other organs showed moderate pituitary dependence in proportion to body weight. Serum IGF-I and IGF-II were reduced by 73% and 52%, respectively, in the absence of GH. The major IGF-binding proteins (IGFBP) were analyzed by Western ligand blot. The predominant 26- to 30-kD IGFBP band normally seen in neonatal rat serum was greatly increased in GH-deficient sera, to 250% of GH-normal sera as measured by densitometry. However, addition of α-Hec 1 antibody to IGFBP-2, which has been used to identify IGFBP-2 as the major neonatal IGFBP, resulted in immunoprecipitation of only a small amount of the 26- to 30-kD band from the GH-deficient fetuses, suggesting the presence of an additional IGFBP. Northern analysis of GH-deficient livers did not reveal any visible increase in IGFBP-1, IGFBP-2, or IGFBP-4 mRNA. We conclude that pituitary GH exerts a modest, but significant, selective effect on fetal body weight and organ growth. Serum levels of both IGF-I and IGF-II, as well as their binding proteins, were shown to be pituitary-GH–dependent in the fetal period. The increase of low-molecular-weight binding proteins in the GH-deficient fetus, which we were unable to attribute to IGFBP-1, -2, -3, or -4, may indicate the presence of unique fetal binding protein(s). The spontaneous dwarf rat may be an important model for further investigation of the development of pituitary dependence in fetal growth.

Maturation of the glucose reabsorptive process by the fetal kidney was studied in 9 chronic fetal lamb preparations (0.66 to 3.72 kg) and values compared to data obtained from 4 nonpregnant ewes. Blood and urine control values showed a close relationship between fetal glomerular filtration rate (GFR ml/min) and fetal body weight (r=0.78, p

Summary: Smoking during pregnancy results in offspring with an average birth weight 200 g less than those of non-smoking mothers. The pathogenesis of this effect is still unknown and there is no general agreement about the causal relationship between maternal smoking and subsequent fetal growth retardation. In the present study, a model of maternal smoking during pregnancy in the rat was established using the P & I Walton Exposure Machine. The study consisted of three groups: control, pair-fed, and smokeexposed. Smoke-exposed animals were exposed continuously to tobacco smoke for cycles of 7 min, 16 times a day from d 5 to d 20 of gestation. On d 21 of gestation, fetuses from all groups were removed by cesarean section, weighed, and dissected. The fetal brain, liver, and lungs as well as the placentas were weighed and analyzed for nucleic acid content. Fetal weight was found to be significantly reduced in both pair-fed and smoke-exposed groups compared with the control group. There was also a significant reduction in fetal body weight of the animals in the smoke-exposed group in comparison to those in the pair-fed group. Exposing the mother to smoke affected neither fetal brain weight nor nucleic acid content whereas fetal liver and lungs showed a significant decrease in both weight and nucleic acid content. These results indicate that the fetal growth retardation associated with maternal exposure to tobacco smoke in the rat corresponds to a disproportionate type. In addition, the present results indicate that the maternal tobacco smoke exposure induced fetal growth retardation without placental growth retardation.

Protein turnover in fetal diaphragm, heart, liver, and brain was determined at 21 days gestation in fetal rats whose mothers had received a protein-restricted diet (6% protein) throughout gestation. This diet resulted in severe combined protein-calorie malnutrition. Fetal body weight was significantly decreased at days 19–22 gestation versus controls (27% protein diet) when pregnant animals were protein-restricted (e.g. 40% decrease in body weight at day 22 gestation versus controls). Protein synthesis was determined by intravenous injection of “massive” amounts of [3H]phenylalanine to pregnant animals and measuring free and protein-bound specific radioactivities in fetal tissues. Rate constants for protein degradation were calculated by subtracting fractional growth rate from protein synthesis. Fractional protein synthesis was reduced in diaphragm (0.26 versus 0.41 days-1), heart (0.41 versus 0.52 days-1), and liver (0.35 versus 0.89 days-1) in fetuses from malnourished mothers relative to controls. Similarly, fractional protein degradation was decreased in these fetal tissues – diaphragm (0.03 versus 0.06 days-1), heart (0.14 versus 0.18 days-1), and liver (0.25 versus 0.80 days-1). Reduced protein accretion during maternal malnutrition in these fetal tissues is secondary to decreased protein synthesis out of proportion to the concurrent reduction in protein degradation. Protein synthesis and degradation in fetal brain from malnourished mothers were not altered versus controls. These effects of malnutrition on protein turnover in fetal tissues throughout pregnancy in the rat correspond closely with the effect of protein restriction in young adult rats and the effect of protein-calorie malnutrition on whole body protein turnover in human infants.

The hormonal and metabolic factors which contribute to fetal growth are poorly understood. In the present experiments pregnant rats were continously infused from day 18 to 20 post conception with saline (S) or amino acids (AA: 2.5g/kg/day). After an overnight fast of 14 hours fetal body weight, fetal serum somatomedin (SM, porcine cartilage bioassay) and the "endogenous" fetal cartilage bioactivity were determined (=incorporation of 35SO4 into the fetal costal cartilage in response to 0, 5 or 10 per cent normal rat serum). Results: AA-compared to S-infusions increased fetal body weight (S:4.0±0.5*g, n=9; AA: 4.9±0.3*g, n=6; p

It is unknown why fetal rats of diabetic mothers are smaller than normal. Therefore, pregnant rats were infused i.v. from day 19 to 21 with saline (S) or 40% Glucose (G). Fetal body weight and the thymidine incorporation into fetal a) rib cartilage in vivo and b) isolated chondrocytes in response to normal fetal or maternal rat serum were determined. Bodyweights were lower in G: 4.17 ± 0.17 g, n=18 than in S: 4.32 ± 0.14g, n=24, < 0.05. In S thymidine incorporation in vivo was higher in small compared to big fetuses: r= -0.531, n=55, < 0.001. Opposite results were obtained in group G: r= +0.542, n=54, < 0.001. The results of the thymidine incorporation into isolated chondrocytes are shown in the table (cpm/105 cells). (M ± SEM; n=12, a< 0.05; b < 0.001 versus 0% serum) Chondrocytes of hyperglycemic fetuses did not respond to maternal serum, which suggests that both adult and fetal growth factors are needed for appropriate fetal growth.