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Triglyceride (TG) hydrolases in the placental microvillous plasma membrane (MVM) release fatty acids from circulating lipoproteins and represent the critical initial step in transplacental fatty acid transfer. We investigated the activity of two TG hydrolases in MVM isolated from placentas of appropriately grown for gestational age pregnancies and pregnancies complicated by intrauterine growth restriction (IUGR), insulin-dependent diabetes mellitus (IDDM) or gestational diabetes mellitus (GDM). In addition, we measured protein expression of lipoprotein lipase (LPL) in MVM and two fatty acid binding proteins (L- and C-FABP) in placental homogenates. The TG hydrolase activities were assessed by measuring hydrolysis of (3)H-trioleic acid incorporated into intralipid micelles after incubation with MVM. The placenta-specific TG hydrolase activity (optimum at pH 6) did not differ in the patient groups studied. MVM LPL activity (optimum at pH 8) was reduced by 47% in preterm IUGR (n = 8, P < 0.05), compared with gestational age-matched controls. The LPL activity in placentas of IDDM pregnancies was increased by 39% (n = 8, P < 0.05), compared with controls. No significant differences were observed in cases of GDM. We found no alteration in protein expression of LPL or C-FABP. The expression of L-FABP was increased by 112% (n = 8, P < 0.05) in IDDM and 64% (n = 8, P < 0.05) in GDM. These results indicate that alterations in MVM LPL activity and expression of L-FABP may contribute to the altered lipid deposition and metabolism in IUGR and diabetic pregnancies.

Many fetuses suffering from intrauterine growth restriction (IUGR) are hypoglycaemic. However, the underlying mechanisms are not well established. An increased placental glucose consumption in IUGR could impair glucose transfer across the placenta. In this study we used two different approaches to investigate glucose metabolism in preterm and term placentae of IUGR fetuses. We determined activity and protein expression of the three rate-limiting glycolytic enzymes phosphofructo kinase (PFK), pyruvate kinase (PK) and hexokinase (HXK) in a cytoplasmic fraction of homogenates of placentae obtained from IUGR and appropriate for gestational age (AGA) pregnancies. Protein expression was assessed using Western blot and enzyme activities were determined in a spectrophotometer by measuring the rate of NADH oxidation (PFK and PK) or NADP reduction (HXK) in enzyme reactions coupled to the respective enzyme. To determine the distribution of the glycolytic enzymes immunocytochemistry was performed. We also measured glucose consumption and lactate production in fresh placental villous tissue using a perifusion system. The expression of PFK, PK and HXK as well as the activity of PK and HXK was unaltered in IUGR placentae. The activity of PFK on the other hand was 32 per cent lower in IUGR placentae (n=24, P<0.05). Immunocytochemistry confirmed the distribution of the enzymes to the cytoplasm of the syncytiotrophoblast. Placental glucose consumption in IUGR [0.06+/-0.01 micromol/(min*g), n=5] was not different from AGA [0.06+/-0.005 micromol/(min*g), n=12], whereas lactate production was decreased by 28 per cent in IUGR. These results do not support the hypothesis of increased placental glucose consumption but suggest an altered glycolytic pathway in the IUGR placenta.

The reduced fetal growth in intrauterine growth restriction (IUGR) has been attributed to decreased placental blood flow whereas maternal hyperglycemia is believed to represent the primary cause of accelerated fetal growth in pregnancies complicated by diabetes. However, recent research has demonstrated specific changes in placental transport function in association to these pregnancy complications that are likely to contribute to the altered fetal growth patterns. For example, in IUGR the activity of certain key amino acid transporters is reduced in the placental barrier and accelerated fetal growth in diabetes is associated with an increased activity of placental glucose and amino acid transporters. Therefore, placental insufficiency in IUGR is not just a question of reduced placental blood flow and up-regulation of placental nutrient transporters in diabetes may explain the high incidence of accelerated fetal growth despite rigorous maternal glycemic control.

In contrast to classical transporting epithelia, the Na(+)/K(+) ATPase is distributed to both the microvillous membrane (MVM) and the basal membrane (BM) of the placental syncytiotrophoblast. Na(+)/K(+) ATPase is important in maintaining the electrochemical gradient for Na(+), which represents the driving force for Na(+)-coupled transport of nutrients. We hypothesized that syncytiotrophoblast Na(+)/K(+)-ATPase activity is reduced in intrauterine growth restriction (IUGR). We isolated MVM and BM from control (n = 10) and IUGR placentas (n = 11). The protein expression of Na(+)/K(+)-ATPase alpha(1)-subunit was determined by Western blotting and found to be slightly reduced in MVM isolated from IUGR (-10%; P < 0.05) placentas. Na(+)/K(+) ATPase activity was measured as the ouabain-sensitive, K(+)-dependent cleavage of the fluorescent pseudosubstrate 3-O-methylfluorescein phosphate and was reduced by 35% in MVM obtained from IUGR placentas (P < 0.02). To assess the transcriptional levels of Na(+)/K(+)-ATPase mRNA, real time PCR was used. No significant changes in steady state mRNA levels for Na(+)/K(+)-ATPase were detected. The expression of the Na(+)/K(+)-ATPase alpha(1)-subunit and Na(+)/K(+)-ATPase activity in the BM were unaffected in cases of IUGR. These data suggest that Na(+)/K(+)-ATPase activity is reduced in the MVM of placentas from IUGR pregnancies. These changes might impair the function of Na(+)-coupled transporters and contribute to the reduced growth of these fetuses.

Neonates born after pregnancies complicated by diabetes or intrauterine growth restriction (IUGR) have increased incidence of hypocalcaemia. Furthermore, IUGR is associated with reduced bone mineralization in infancy and osteoporosis in adult life. We tested the hypothesis that placental calcium transport is altered in these pregnancy complications. Transport of calcium into syncytiotrophoblast basal plasma membrane (BM) vesicles was studied by rapid filtration and protein expression of Ca(2+) ATPase by Western blot. In IUGR Ca(2+) ATPase activity was increased by 48 per cent (n=13; P< 0.05) whereas protein expression was 15 per cent lower (n=13; P< 0.05) than in controls (n=16). Basal membrane ATP dependent calcium transport was unaltered in gestational diabetes (GDM) but increased by 54 per cent in insulin dependent diabetes (IDDM) compared to controls (P< 0.05; n =14). Diabetes did not affect Ca(2+) ATPase expression in BM. We have previously shown that the mid-molecular fragment of parathyroid hormone related peptide (PTHrP midmolecule) stimulates BM Ca(2+) ATPase in vitro. PTHrP midmolecule concentrations in umbilical cord plasma were measured using radioimmunoassay. The concentrations in umbilical cord plasma were increased in IUGR, but unaltered in diabetes. In conclusion, placental calcium pump is activated in IUGR and IDDM, which may be secondary to increased foetal calcium demand. We speculate that PTHrP midmolecule may be one mechanism for activating BM Ca(2+) ATPase in IUGR.

The mechanisms underlying the reduced fetal plasma concentrations of amino acids and glucose associated with intrauterine growth restriction (IUGR) remain to be fully established. The activity of the amino acid transporter system A has been shown to be reduced in the syncytiotrophoblast microvillous membrane (MVM) in IUGR, however the impact of these changes on transplacental transport is difficult to assess without information on system A activity in the basal plasma membrane (BM). In this study we measured system A activity and mediated D-glucose uptake using radiolabelled substrates and rapid filtration techniques, and glucose transporter isoform 1 (GLUT 1) protein expression using Western blots in MVM and BM isolated from human placentas. In term IUGR (n=11) MVM system A activity was unaltered compared to controls (n=9). In contrast, system A activity in MVM was reduced by 50 per cent (P< 0.05) in preterm IUGR (n=8, gestational age 28-36 weeks) as compared to controls (n=8, gestational age 28-35 weeks). BM system A activity was unaltered in both IUGR groups. Similarly, MVM and BM GLUT 1 expression and mediated D-glucose uptake was not affected by IUGR. In all preterm IUGR pregnancies signs of severe fetal compromise were present whereas term IUGR fetuses were less affected. These data support the view that MVM system A activity is related to the severity of compromise in IUGR. The markedly reduced system A activity in MVM in preterm IUGR together with the unaltered activity in BM is consistent with a decreased transplacental transport of neutral amino acids in this pregnancy complication. The hypoglycemia present in utero in some IUGR fetuses is not caused by a decreased glucose transport capacity across the syncytiotrophoblast plasma membranes., (Copyright 2002 Elsevier Science Ltd. All rights reserved.)

During normal pregnancy, a predominance of Th2 type cytokines prevails and is considered to protect the fetus. Animal experiments suggest that an increase of Th1 type cytokines may instead have deleterious effects. We have studied with the reverse transcription PCR technique mRNA for IL-1alpha, IL-1beta, IL-6, IL-8, IL-10, transforming growth factor-beta, tumor necrosis factor-alpha, and interferon-gamma in placentas from full-term appropriately grown newborns, newborns with intrauterine growth retardation (IUGR) and newborns who were only small for gestational age. The mRNA for IL-10 was significantly reduced in the IUGR placentas (p < 0.05), whereas the mRNA for IL-8 was significantly higher (p < 0.05) for the IUGR cases compared with the full-term neonates. It might be that reduced IL-10 in the placenta is involved in the pathogenesis of IUGR.

The objective of this study was to determine placental membrane permeabilities to water, urea and mannitol in intrauterine growth restriction (IUGR) and compare them to normal gestational age matched controls. Further, we wished to investigate whether potential changes in permeability were related to changes in membrane fluidity, cholesterol or phospholipid fatty acid content of the membranes. Syncytiotrophoblast microvillous (MVM) and basal membranes (BM) were isolated from normal and IUGR placentas at term. Passive permeability to water, urea, and mannitol showed no significant alterations in IUGR compared to controls. Cholesterol content in BM, but not in MVM, was lower in placentas from pregnancies complicated by IUGR. However, membrane fluidity did not change in these pregnancies. The phospholipid fatty acid composition of the plasma membranes isolated from all placentas showed a predominance of unsaturated fatty acid species in the BM and saturated species in the MVM. In the MVM from IUGR, mead acid (20:3), behenic acid (22:0) and nervonic acid (24:1) constituted higher percentages of the total when compared to normally grown controls. In the BM from IUGR, mead acid (20:3) was increased relative to the total phospholipid fatty acid content. In conclusion, the syncytiotrophoblast membranes exhibit only minor changes in passive permeability and composition when the pregnancy is complicated by IUGR.

Intrauterine growth retardation (IUGR) was studied both after experimental induction in rats and spontaneously occurring in man. The growth-retarded rat pups were compared to appropriately grown litter mates with developmental and behavioural tests at 50 and 90 days of age. Female rats exhibited no differences between growth-retarded and control rats but growth-retarded male rats had poor performance at 50 but not at 90 days compared to male controls. In the patient study 25 growth-retarded babies were compared with 21 appropriately grown controls. The growth-retarded babies had delayed latency periods of the visual evoked potentials at term and 6 weeks later, and at follow-up (18 months) demonstrated significantly more developmental and behavioural problems than the control group.

Despite the importance of glucose for fetal growth, gestational development of placental glucose transport capacity has not been studied in the human. Furthermore, inadequate glucose transport has been implicated as a pathophysiological mechanism in intrauterine growth retardation (IUGR). We studied glucose transporter (GLUT) protein expression in sections of normal term placental tissue (immunocytochemistry) and in syncytiotrophoblast microvillous (MVM) and basal membranes (BM) isolated from normal term, preterm, and IUGR placentas (immunoblotting). GLUT 1, but not GLUT 3, protein was abundantly present in syncytiotrophoblast membranes. MVM had approximately 3-fold higher GLUT 1 density than BM at term. MVM GLUT 1 density was maintained from 16 weeks of gestation to term. BM GLUT 1 density increased 2-fold in late second trimester and remained unaltered thereafter to term. GLUT 1 densities in term and preterm IUGR placentas were unaltered. Net D-glucose uptake rates corresponded to the GLUT 1 densities. These data suggest that 1) GLUT 1 is the main glucose transporter protein isoform in human syncytiotrophoblast; 2) the glucose transport capacity for MVM is potentially approximately 20-fold higher than that of BM; 3) GLUT 1 densities may be regulated independently in MVM and BM; 4) the increase in surface area and the maintenance of a high GLUT 1 density can account for the increase in placental glucose transport in the latter part of pregnancy; and 5) fetal hypoglycemia in IUGR is not due to a decrease in placental glucose transporter density.

Perinatal morbidity and mortality are still high in cases of intra-uterine growth retardation. Present screening methods select large risk groups and have a low positive predictive value. Instruments which could be used as indicators for those cases within the risk group needing close fetal monitoring would be valuable. The aim of this prospective study was to evaluate fetal ponderal index with respect to signs of fetal distress and neonatal outcome. By means of a risk scoring system, 73 pregnancies with increased risks of intra-uterine growth retardation were compared with 61 controls. By means of ultrasound, fetal weight was estimated and the fetal femur measured. The fetal ponderal index was calculated by dividing the estimated fetal weight in grams by the third power of the femur length. In the control group, 5/61 showed signs of distress and in the risk group, 43/73. The mean fetal ponderal index of the controls was 8.60 (SD 0.84) and in the risk group 7.72. The groups were compared with each other with respect to signs of distress. The fetuses showing signs of distress had a mean FePI of 7.45 (p less than 0.001). Those (30/73) in the risk group not showing signs of fetal distress had a mean value of 8.14 and differed significantly (p less than 0.001) from the distress group. Fetal ponderal index would seem to be a valuable adjunct for the differentiation of the more susceptible fetuses in an intra-uterine growth retardation risk group.

Antenatal risk factors in combination with symphysis-fundus distance can identify pregnancies with small infants, who can be divided in genetically small, malformed, and malnourished infants. Only the last category benefit from fetal surveillance. Maternal diseases, pregnancy complications (hypertension), and environmental factors (smoking) are connected to malnourished small infants.

Intrauterine growth retardation is associated with increased risks for permanent neurological disabilities. A series of studies was undertaken to elucidate whether fetal growth retardation causes a primary perturbation of brain function and development and whether an increased vulnerability for periods of oxygen lack exists. In two groups of neonates who were small for gestational age (SGA) evoked potentials were investigated. A high frequency of abnormal recordings were obtained in SGA babies. SGA babies had significantly longer latency periods for the primary evoked potentials than appropriately grown controls. In guinea pigs and rats growth retardation was induced by reducing the placental blood flow during late gestation. Growth retarded guinea pups demonstrated a considerable reduction of the ability to retain normal somatosensory evoked response during hypoxia compared to appropriately grown littermates. Growth retarded rat fetuses exhibited marked changes of the monoamine metabolism in the brain inasmuch as basal levels of serotonin and its main metabolite were low while an inappropriate acceleration of the serotonin synthesis rate took place during hypoxia. The tissue concentrations of aspartate were also significantly lower in growth retarded fetuses than normally grown littermates. Finally, lipid peroxidation was assessed. During adequate oxygenation no difference was observed when lipid peroxidation was assessed. During adequate oxygenation no difference was observed when lipid peroxidation in brain tissue of growth retarded and appropriately grown fetuses was compared but during mild-moderate hypoxia lipid peroxidation was significantly more intense in the growth retarded group.(ABSTRACT TRUNCATED AT 250 WORDS)

The relative fatty acid composition of lecithin was measured in maternal and cord blood serum in human pregnancies at risk for intrauterine growth retardation (IUGR) (n = 28) as compared to controls (n = 20). In the IUGR cases (n = 13) linoleic acid was lower in maternal samples but higher in cord blood, oleic acid was elevated in both whereas docosohexaenoic acid was lower. Essential fatty acid composition of lecithin was found to be different in IUGR.

To examine the impact of intrauterine growth retardation (IUGR) on essential fatty acids in human placenta, fatty acid composition in total acylglycerol and in the major phosphoglycerides phosphatidylcholine (PC) and phosphatidylethanolamine (PE), of 15 placentas from small for gestational age (SGA) births was compared with that of 7 control placentas. The acylglycerol fatty acid content was similar between the two groups, but the proportion of fatty acids of the linoleic acid series, including arachidonic acid, was significantly lower in SGA placentas. When the fatty acid composition in PC was studied, the reduction in fatty acids of the linoleic acid series was even more striking, and fatty acids of the linolenic acid series was also significantly less in the SGA group. These fatty acid changes in placenta membrane phospholipids can affect the transport of important nutrients to the fetal compartment. The decreased level of arachidonic acid and docosahexanoic acid might also lead to a disturbed formation of fetal thromboxane and prostacyclin. However, cord plasma PC fatty acid patterns were nearly identical in the two groups suggesting that in IUGR, the essential fatty acids will be transported to the fetus at the expense of the placenta.

A scoring system for selection of pregnancies at risk of intrauterine growth retardation (IUGR) is presented. It is based on eight weighted items which include information from previous pregnancies and from the current one including the increment of fundal height and of maternal weight. With a risk population of 7% all IUGR infants were included. The IUGR infants constituted 34% of the risk group.

Intrauterine growth retardation (IUGR) and neonatal respiratory disorders (RD) are two dominating problems in perinatal medicine. The aims of this study were to analyze the possibilities of selecting groups of pregnant women with increased risk of either problem, to analyze the relationship between IUGR and neonatal respiratory disorders and to evaluate the influence on neonatal respiratory adaptation of different events during delivery. For these purposes epidemiological methods were mainly used but in paper V an animal model was applied. In the whole population of pregnant women attending the antenatal clinic of the department during a six month period the items which had the best discriminating power between normal and IUGR pregnancies were selected. These eight items (previous infants less than or equal to 2,500 g, hypertension, kidney diseases, smoking, bleeding with or without uterine contractions, insufficient increase of weight, girth or fundal height) were used as a scoring system. With a risk population of 7%, all IUGR cases were included. The IUGR infants constituted 34% of the risk group. For one year all newborns of mothers living in Göteborg were screened prospectively for signs of respiratory disorders. It was not possible to indicate antenatally pregnancies with increased risks of neonatal respiratory disturbances. Preterm small for gestational age (SGA) infants were found to have the same risk of RD as non-SGA infants. Full term SGA infants had a higher incidence of RD, which could not be explained by their higher incidence of cesarean sections (CS) and low Apgar scores. In preterm infants and in full term infants after CS the relation between rupture-delivery interval and risk for RD was "u-shaped". There was a higher incidence of RD if delivery was immediately at rupture than a few hours up to 36 h later. After more than 36 h the risk increased again. Consequently there seems to be no advantage in postponing delivery more than 36 h after ROM. The impact of CTG (cardiotocography) pattern on RD during delivery, was analyzed in two subgroups of infants (greater than or equal to 37 weeks, delivered by CS). Infants with ominous CTG patterns were unexpectedly found to have a reduced incidence of RD, 6% compared to 21% in infants with normal patterns. A possible explanation could be that "intrauterine stress" might exert a positive effect on neonatal respiratory adaptation.(ABSTRACT TRUNCATED AT 400 WORDS)

Obstetric and neonatal performance were analyzed in an ultrasound-dated small for gestational age (SGA) population from 1982-1985. Eighty-three percent of 160 SGA infants were identified antenatally by means of intrauterine growth retardation (IUGR) risk scoring, and the pregnancies were supervised at a high-risk clinic. Fifty percent were delivered electively, predominantly in gestational weeks 38-39. Thirty percent were born preterm. The cesarean section rate was 40%. Perinatal mortality was 6%, or 4% when lethal malformations were excluded, ten times higher than the corresponding total population figures. Eleven percent of the fetuses had severe malformations. In the remaining SGA population, one infant died after experiencing severe perinatal asphyxia and another developed cerebral palsy; no other major sequelae were found before the age of 18 months. Hypoglycemia and hypothermia occurred frequently, but these problems were managed satisfactorily. The mean hospital stay for term infants was twice that of appropriate for gestational age infants. We conclude that the extra attention paid to the SGA population is well motivated. Future efforts should be directed toward improving the diagnostic techniques for IUGR, as most of the perinatal mortality occurred among SGA infants not identified before birth.