妊娠早期阻断协同刺激分子诱导自然流产模型孕鼠脾脏细胞母-胎免疫耐受的研究

目的　探讨阻断协同刺激分子———CD80 和CD86对自然流产模型孕鼠妊娠结局及孕鼠脾脏免疫细胞对父系抗原免疫耐受状态的影响。方法　将雌性小鼠 (CBA/J)分别与BALB/c及DBA/2两种雄性小鼠合笼交配 ,分别建立正常妊娠模型CBA/J×BALB/c( 2 0只 ,对照组 )和自然流产模型CBA/J×DBA/2 ( 2 0只 ,研究组 )。CBA/J小鼠于妊娠第 4天 (着床期 )腹腔分别注射大鼠同型IgG 0 2mg( 10只 ) ,或大鼠抗小鼠CD80 和CD86单克隆抗体 ( 10只 )。妊娠第 9天 ,采用单向混合淋巴细胞反应 ,分析孕鼠脾脏免疫细胞对父系抗原的增殖能力 ,并测定细胞培养上清液中白细胞介素 2(IL 2 )水平 ,以研究脾脏细胞母 胎免疫耐受状态 ;妊娠第 14天观察两组的胚胎吸收率。结果　 ( 1)研究组中 ,腹腔注射大鼠IgG的孕鼠胚胎吸收率为 2 4 3% ,而注射大鼠抗小鼠CD80 和CD86单克隆抗体的孕鼠胚胎吸收率为 9 8% ,两者比较 ,差异有显著性 (P <0 0 5 )。 ( 2 )应用大鼠抗小鼠CD80 和CD86单克隆抗体 ,使妊娠 9d的孕鼠脾脏免疫细胞对父系抗原的增殖能力及IL 2水平显著下降(P <0 0 5 )。结论　孕早期阻断协同刺激分子 ,可诱导产生孕鼠脾脏免疫细胞对父系抗原的免疫耐受 ,从而使自然流产模型孕鼠的妊娠结局达到正常妊娠水平。     

Premature onset of labor, neonatal patent ductus arteriosus, and prostaglandin synthetase antagonists--a rat model of a human problem.

Premature labor and patent ductus arteriosus are two potentially fatal hazards of the human newborn infant. Prostaglandin synthetase antagonists have thus been used to suppress early labor and to close the ductus of the neonate. Indomethacin has been most effective but not free of significant complications. Neuronal necrosis may result from numerous systemic aberrations. A controlled rat model study was therefore devised to investigate fetal neuronal necrosis in relation to maternal indomethacin dose. Dams were given various treatments of 2 mg/kg of 4 mg/kg indomethacin within the last 3 days of gestation. Liquid chromatography was used to assess serum maternal and fetal drug levels. From light microscopy of more than 200 brains it was apparent that fetal neuronal necrosis correlates with maternal dose.     

Placental oxidative stress in a rat model of preeclampsia

The onset of preeclampsia is associated with increased maternal insult that could affect placental function. By increasing sodium intake (0.9% or 1.8% NaCl in drinking water) during the last week of gestation in the rat, we developed an animal model that shows many characteristics of preeclampsia such as increased blood pressure, decreased circulatory volume and diminished activity of the renin-angiotensin-aldosterone system. The aim of the present study was to determine in this model whether maternal perturbations in pregnancy lead to placental oxidative stress. Sprague-Dawley pregnant rats receiving salted-water were compared to not-supplemented pregnant rats. Markers of oxidative stress, ensuing cell death, and changes in the production of vasoactive substances (prostanoids: thromboxane, TxB(2); and prostacyclin, PGF(1alpha)) and the pro-inflammatory cytokine tumour necrosis factor-alpha (TNF-alpha) were measured in the placenta. In tissue from pregnant rats on 1.8% NaCl supplement, 8-iso-PGF(2alpha) levels, TxB(2)/6-keto-PGF(1alpha) ratios, total TNF-alpha RNA expression, as well as the apoptotic index (Bax/Bcl-2 ratio) and endothelial nitric oxide synthase protein expression increase while total glutathione content decreases. These findings demonstrate that maternal insult during gestation induced an imbalance in the oxidative environment in the placenta favouring oxidation. This was accompanied by an increased synthesis of vasoconstrictive substances and TNF-alpha by the placenta as well as the increased rate of placental cell apoptosis.     

Protective effects of pentoxifylline on lipopolysaccharide-induced white matter injury in a rat model of periventricular leukomalasia

Abstract

Objective: To investigate the potential neuroprotective effect of maternal pentoxifylline (PNTX) treatment in endotoxin-induced periventricular leukomalasia (PVL) in the developing rat brain.

Method: Intraperitoneal injection of lipopolysaccharide was administered on two of three Wistar pregnant rats to establish PVL. To obtain PNTX-treated group, one of the two dams were injected with PNTX. The control group was treated with saline. Rat pups were grouped as control, maternal LPS-treated group and PNTX?+?LPS-treated group. At 7th postnatal days, apoptosis and hypomyelination were evaluated. Apoptosis was evaluated by caspase-3 and terminal deoxynucleotidyl transferase [TdT] dUTP nick endlabelling reaction (TUNEL) immunostaining. To assess hypomyelination, myelin basic protein (MBP) staining, as a marker of myelination, was evaluated.

Results: MBP staining was significantly less and weaker in the brains of the LPS-treated group as compared with the PNTX-treated group. PNTX treatment significantly reduced the number of apoptotic cells in the periventricular WM shown on Tunel and caspase-3.

Conclusions: Presented study is first indicated that PNTX may provide protection against an LPS-induced inflammatory response and WMI in the developing rat brain. Our results also suggest that PNTX treatment in pregnant women with maternal or placental infection may minimize the risk of PVL and cerebral palsy.     

Erythropoietin attenuates lipopolysaccharide-induced white matter injury in the neonatal rat brain

Periventricular leukomalacia (PVL), a common neonatal brain white matter (WM) lesion, is frequently associated with cerebral palsy. Growing evidence has indicated that in addition to ischemia/reperfusion injury, cytokine-induced brain injury associated with maternal or fetal infection may also play an important role in the pathogenesis of PVL. Recent studies have shown that administration of lipopolysaccharide (LPS) to pregnant rats causes enhanced expression of the cytokines, i.e., IL-1 beta, TNF-alpha, and IL-6, in fetal brains. In recent years, it has been shown that erythropoietin (EPO) has a critical role in the development, maintenance, protection and repair of the nervous system. In the present study we investigated the effect of EPO on LPS-induced WM injury in Sprague-Dawley rats. LPS (500 microg/kg) suspension in pyrogen-free saline was administered intraperitoneally to pregnant rats at 18 and 19 days of gestation. The control group was treated with pyrogen-free saline. They were given 5,000 U/kg recombinant human EPO. Seven-day-old Sprague-Dawley rat pups were divided into four groups: control group, LPS-treated group, prenatal maternal EPO-treated group (5,000 U/kg, intraperitoneally given to pregnant rats at 18 and 19 days of gestation), and postnatal EPO-treated group (5,000 U/kg, intraperitoneally given to 1-day-old rat pups). Cytokine induction in the postnatal 7-day-old (P7) rat brain after maternal administration of LPS was determined by the ELISA method. The proinflammatory cytokine levels (IL-1 beta, TNF-alpha, and IL-6) in P7 rat pup brains were significantly increased in the LPS-treated group as compared with the control group. Prenatal maternal EPO treatment significantly reduced the concentration of TNF-alpha and IL-6 in the newborn rat brain following LPS injection. The concentration of IL-1 beta was decreased in the intrauterine EPO treatment group. Postnatal EPO treatment significantly decreased only the IL-6 concentration in the newborn rat brain following LPS injection. The concentration of cytokines, IL-1 beta and TNF-alpha, was reduced in the postnatal EPO treatment group. We demonstrated here that LPS administration in pregnant rats at gestational day 18 and 19 induced WM injury in P7 progeny characterized by apoptosis. Prenatal maternal and postnatal EPO treatment significantly reduced the number of apoptotic cells in the periventricular WM. Using immunohistochemistry techniques, we investigated the effects of maternal administration of LPS on myelin basic protein (MBP) staining, as a marker of myelination in the periventricular area in the neonatal rat brain. MBP staining was significantly less and weaker in the brains of the LPS-treated group as compared with the prenatal maternal EPO-treated group. However, the postnatal EPO treatment did not prevent LPS-stimulated loss of MBP-positive staining. In conclusion, especially prenatal maternal EPO treatment attenuates LPS-induced injury by reducing the expression of inflammatory cytokines and sparing MBP in the neonatal rat brain. While the postnatal EPO treatment prevented LPS-induced brain injury this effect was partial. To our knowledge, this is the first study that demonstrates a protective effect of EPO on LPS-induced WM injury in the developing brain. Regarding the wide use of EPO in premature newborns, this agent maybe potentially beneficial in treating LPS-induced brain injury in the perinatal period.     

Chemotherapy in a pregnant rat model. 1. Mitomycin-C: pregnancy-specific kinetics and placental transfer

Although cancer complicates pregnancy infrequently, its occurrence jeopardizes maternal and fetal well-being. Treatment with chemotherapeutic agents may adversely affect rapidly dividing fetal tissue, while physiologic changes in pregnancy may alter maternal drug disposition. Previous work on placental transfer and pregnancy-specific kinetics of antineoplastic agents is limited, making the establishment of treatment guidelines for the pregnant cancer patient difficult. Using a pregnant rat model and sensitive HPLC methodology we quantitated the placental transfer and resulting fetal exposure of mitomycin-C (MMC), an alkylating agent. Following maternal dosing, the relative fetal exposure was 6.4%, indicating that MMC does cross the placenta, although to a limited degree. Significant pregnancy-specific alterations in drug disposition, including higher plasma concentrations and decreased clearances in pregnant animals, highlight the need for drug-level monitoring and possible dosage modification when these agents are used in pregnancy.     

Predominance of L-dopa in fetal plasma and the amniotic fluid during late gestation in the rat

The purpose of this study was to reevaluate catecholamine distribution in fetal and maternal compartments during late gestation in the rat. Fetal and maternal plasma and amniotic fluid were collected from anesthetized rats on consecutive days from day 17 to day 22, the day of parturition. The fluid was analyzed for dihydroxyphenylalanine (L-dopa), dopamine, norepinephrine, and epinephrine by radioenzymatic assays. Amniotic fluid volume was determined by a direct weighing method. L-Dopa concentrations constituted approximately 50% of total fetal plasma catecholamines and were significantly higher in fetal than in maternal circulation. Dopamine concentrations in fetal plasma were tenfold lower than those of L-dopa but were also significantly higher in fetal than in maternal plasma; norepinephrine levels were similar in both. Maternal plasma epinephrine levels remained relatively constant, whereas fetal epinephrine levels increased fiftyfold from day 17 to day 22. L-Dopa concentrations in the amniotic fluid were tenfold higher than those of dopamine, and the concentrations of both increased markedly during the last 2 days of gestation. However, this apparent rise could be attributed to the concomitant fivefold reduction in the amniotic fluid volume observed at this time. It is concluded that L-dopa is the predominant catecholamine in both the fetal plasma and the amniotic fluid during late gestation in the rat. At the present time, neither the source nor the possible physiologic functions of L-dopa during fetal life are known.     

Placental dysfunction in Suramin-treated rats: impact of maternal diabetes and effects of antioxidative treatment

OBJECTIVE: The aim of the present study was to evaluate a rat model of placental dysfunction/preeclampsia in pregnancies complicated by maternal diabetes. A second objective was to evaluate the effects of vitamin E treatment in this model. METHODS: Normal and streptozotocin-induced diabetic rats of two different strains (U and H) were given intraperitoneal (IP) injections of the angiogenesis inhibitor Suramin (Sigma Chemical Co, St Louis, MO) or saline in early pregnancy, and fed standard or vitamin E-enriched food. The outcome of pregnancy was evaluated on gestational day 20. RESULTS: In both rat strains Suramin caused fetal growth retardation, decreased placental blood flow, and increased placental concentration of the isoprostane 8-iso-PGF(2alpha). In the U rats Suramin also caused increased fetal resorption rate, increased maternal blood pressure, decreased renal blood flow, and diminished maternal growth. Diabetes caused severe maternal and fetal growth retardation, increased resorption rate, and increased placental 8-iso-PGF(2alpha) concentration independent of Suramin administration. The maternal and fetal effects of Suramin and diabetes were more pronounced in the U strain than in the H strain. Vitamin E treatment improved the status of Suramin-injected diabetic rats: in U rats the blood pressure increase was normalized; and in both U and H rats the decreased placental blood flow was marginally enhanced, and the increase in placental 8-iso-PGF(2alpha) was partly normalized by vitamin E. CONCLUSION: Suramin injections to pregnant rats cause a state of placental insufficiency, which in U rats resembles human preeclampsia. The induction of this condition is at least partly mediated by oxidative stress, and antagonized by antioxidative treatment. Maternal diabetes involves increased oxidative stress, and causes both maternal and fetal morbidity, which are only marginally affected by additional Suramin treatment.     

No change in calreticulin with fetal growth restriction in human and rat pregnancies

Introduction

Calreticulin is a ubiquitously expressed protein that was detected in the circulation and is significantly increased in maternal blood during human pregnancy compared to the non-pregnant state. Calreticulin is further increased in the plasma of women with the pregnancy-related disorder pre-eclampsia compared to normotensive pregnancy. The aims of this study were to compare calreticulin in human pregnancy with calreticulin in rat pregnancy, and to compare calreticulin during fetal growth restriction with normal control pregnancies.

Methods

Women were recruited who either had normal pregnancies or had pregnancies complicated with fetal growth restriction; maternal blood samples and placentas were collected. Blood was also taken from women who were not-pregnant. Growth restriction was induced in pregnant rats by uterine vessel ligation; blood and placental samples were collected. Blood was also taken from non-pregnant rats. Western blot was used to quantify the placental expression of calreticulin and the concentrations of calreticulin in plasma.

Results

Although calreticulin was significantly increased in maternal plasma during human pregnancy compared to the non-pregnant state; it did not increase in plasma during rat pregnancy. These results suggest that there may be differences in the role of extracellular calreticulin in human compared to rat pregnancy. Calreticulin was not significantly altered in either placental extracts or maternal plasma in both the human and rat pregnancies complicated by fetal growth restriction compared to gestational matched control pregnancies.

Conclusion

This study found that there was no change in calreticulin during human pregnancy complicated with fetal growth restriction or when growth restriction is induced in rats.     

Exclusion of the fetal brain as the main source of rat and human amniotic fluid oxytocin

Summary. At term relatively high oxytocin concentrations are found in maternal plasma and in rat and human amniotic fluid. To determine the contribution of the fetal brain to these oxytocin levels, the peptide was measured in maternal rat plasma and amniotic fluid 2 days after intrauterine removal of the fetal brains, and in the amniotic fluid of 16 human anencephalics. After removal of the fetal rat brains and in human anencephalic pregnancies normal maternal plasma concentrations and amniotic fluid oxytocin contents were found. Consequently, both maternal plasma oxytocin and amniotic fluid oxytocin are not determined to any substantial degree by the fetal brain.     

Corticosterone transfer and metabolism in the dually perfused rat placenta: effect of 11beta-hydroxysteroid dehydrogenase type 2

Although rat is the most widely used model of glucocorticoid programming of the fetus, the role of rat placental 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2) in the transplacental pharmacokinetics of the naturally occurring glucocorticoid, corticosterone, has not yet been fully elucidated. In this study, expression of 11beta-HSD2 in the rat placenta on two different gestation days (16 and 22) was examined using quantitative RT-PCR and Western blotting, and dually perfused rat term placenta was employed to evaluate its functional capacity to transfer and metabolize corticosterone. Marked decrease in placental expression of 11beta-HSD2 toward term was observed on both mRNA and protein levels. In perfusion studies, increasing maternal corticosterone concentration from 3 to 200 nM resulted in the fall of 11beta-HSD2 conversion capacity from 64.3 to 16.3%, respectively. Enzyme saturation occurred at about 50 nM substrate concentration. When delivering corticosterone (3 or 100 nM) from the fetal side, a similar decline of 11beta-HSD2 conversion capacity was observed (66.5% and 48.5%, respectively). Addition of carbenoxolone (10 or 100 microM), a non-specific 11beta-HSD inhibitor, to maternal perfusate decreased conversion capacity from 66.7 to 12.6 or 8.1%, respectively. Similarly potent inhibitory effect was observed in feto-maternal studies. Neither saturation nor inhibition of 11beta-HSD2 was associated with transformation of corticosterone in metabolites other than 11-dehydrocorticosterone. These data suggest that 11beta-HSD2 is the principal enzyme controlling transplacental passage of corticosterone in rats and is able to eliminate corticosterone in both maternal and fetal circulations.     

Suramin-restricted blood volume in the placenta of normal and diabetic rats is normalized by vitamin E treatment

Previously maternal and fetal alterations resembling human pre-eclampsia were induced in pregnant rats by injections of the angiogenesis inhibitor Suramin. These alterations were aggravated by maternal diabetes and partly rectified by vitamin E supplementation. In the present study we evaluated the morphology of placentae and kidneys in this model. Non-diabetic and streptozotocin-induced diabetic pregnant rats of two rat strains (U and H) were treated with Suramin or saline, and given standard or vitamin E-enriched food. On gestational day 20 one placenta and the left kidney of the mother were collected for morphological and stereological analysis. In the placental trophospongium Suramin treatment caused cysts, which were further enhanced by maternal diabetes. Vitamin E treatment had no effect on the vacuolization. In the placental labyrinth of the non-diabetic rats Suramin treatment restricted maternal placental blood volume and increased the interface between maternal and fetal circulation. These changes were reversed by vitamin E treatment. Diabetes increased slightly the interface between the circulations in both rat strains. Suramin treatment decreased the interface, and vitamin E further decreased the interface in the diabetic U rats, whereas neither treatment affected the maternal-fetal interface in the diabetic H rats. The kidneys of Suramin-treated and diabetic rats were heavier compared to controls. Suramin treatment and maternal diabetes damaged renal glomeruli to a similar extent. Vitamin E treatment diminished the Suramin- and diabetes-induced glomerular damage in U rats, but not in H rats. The average cell count per glomerulus was decreased by Suramin in the U rats. Vitamin E treatment did not affect cell number per glomerulus in any group. We conclude that Suramin-injected pregnant rats constitute a valid animal model for placental dysfunction and pre-eclampsia, also from the histological perspective. The present work supports the notion that one important effect of untreated maternal diabetes may be impaired placentation, leading to oxidative stress, morphological damage, and compromised placental function.     

Excretion of foetal bilirubin by the rat placenta-maternal liver tandem

Using plasma membrane vesicles from human trophoblast, carrier-mediated transport of unconjugated bilirubin (UCBR) has been reported. In the present work, using the in situ perfused rat placenta-maternal liver tandem, the relevance of this pathway in vivo was investigated. After single-pass perfusion of rat placenta through the umbilical artery with 0.25 micromol [(3)H]-UCBR, approximately 15 per cent of it was taken up by the placenta, detected in maternal serum (>96 per cent was unconjugated) and subsequently secreted into maternal bile (approximately 15 per cent of administered dose; >88 per cent was glucuronidated bilirubin). Co-administration through the umbilical artery of 0.25 micromol [(3)H]-UCBR and 2.5 micromol unlabelled UCBR, bromosulfophthalein, cholic acid or biliverdin IXalpha, reduced [(3)H]-UCBR placenta uptake, and the amount of radioactivity found in the maternal serum and bile. Co-administration into maternal jugular vein of 0.1 micromol [(3)H]-UCBR-a dose 3-fold higher than that reaching the maternal compartment in placenta perfusion experiments-and 1.0 micromol bromosulfophthalein, cholic acid or biliverdin IXalpha, resulted in no marked inhibition of the amount of radioactivity bile output. When antipyrine and [(3)H]-UCBR were continuously co-infused to the mother, similar antipyrine concentrations in maternal and foetal serum were reached in approximately 15 min, while progressive increase in [(3)H]-bilirubin concentrations in maternal serum above 70 microM was accompanied by a very low transfer of this compound into foetal compartment where [(3)H]-bilirubin concentrations were always <10 microM. These results suggest that the transfer of UCBR across the rat placenta occurs, without biotransformation, via a foetal-to-maternal mainly unidirectional pathway that can be cis-inhibited by UCBR and other cholephilic organic anions.     

Effects of intra-amniotic meconium exposure on the fetal rat: development of a pathogenic model

OBJECTIVE: To develop an in vivo animal model for the study of the effects of intrauterine meconium exposure on the fetus. METHODS: Timed pregnant Long-Evans rats were purchased on gestational day (GD) 12 and allowed to acclimate for at least 48 h prior to surgery. Laparotomy was performed and both uterine horns were exteriorized through the abdominal incision. A 26-gauge needle was used to inject either 0.1-cm(3) sterile normal saline or a 20% meconium suspension into each individual gestational sac. The uterus was returned to the abdomen and the incision was closed. On GD 21 (term = 21 days) a cesarean section was completed and the number and viability of fetuses in each horn were recorded. RESULTS: A total of 14 animals were involved in this pilot study. One rat underwent sham surgery with only intra-amniotic saline injection and 13/15 fetuses survived to term. Two animals that underwent surgery on day 18 expired < 24 h postinjection. Eleven maternal animals were injected on GD 20 and underwent cesarean delivery at term; survival rates for saline-injected animals were 71.2% compared to 66.2% for meconium-exposed fetuses. CONCLUSION: We have established an in vivo animal model that allows for the examination of the effects of prolonged intrauterine meconium exposure on the fetus.     

Role of lipoprotein lipase activity on lipoprotein metabolism and the fate of circulating triglycerides in pregnancy

The mechanism that induces maternal hypertriglyceridemia in late normal pregnancy, and its physiologic significance are reviewed as a model of the effects of sex steroids on lipoprotein metabolism. In the pregnant rat, maternal carcass fat content progressively increases up to day 19 of gestation, then declines at day 21. The decline may be explained by the augmented lipolytic activity in adipose tissue that is seen in late pregnancy in the rat. This change causes maternal circulating free fatty acids and glycerol levels to rise. Although the liver is the main receptor organ for these metabolites, liver triglyceride content is reduced. Circulating triglycerides and very-low-density lipoprotein (VLDL)-triglyceride levels are highly augmented in the pregnant rat, indicating that liver-synthesized triglycerides are rapidly released into the circulation. Similar increments in circulating VLDL-triglycerides are seen in pregnant women during the third trimester of gestation. This increase is coincident with a decrease in plasma postheparin lipoprotein lipase activity, indicating a reduced removal of circulating triglycerides by maternal tissues or a redistribution in their use among the different tissues. During late gestation in the rat, tissue lipoprotein lipase activity varies in different directions; it decreases in adipose tissue, the liver, and to a smaller extent the heart, but increases in placental and mammary gland tissue. These changes play an important role in the fate of circulating triglycerides, which are diverted from uptake by adipose tissue to uptake by the mammary gland for milk synthesis, and probably by the placenta for hydrolysis and transfer of released nonesterified fatty acids to the fetus. After 24 hours of starvation, lipoprotein lipase activity in the liver greatly increases in the rat in late pregnancy; this change is not seen in virgin animals. This alteration is similar to that seen in liver triglyceride content and plasma ketone body concentration in the fasted pregnant rat. In the fasting condition during late gestation, heightened lipoprotein lipase activity is the proposed mechanism through which the liver becomes an acceptor of circulating triglycerides, allowing their use as ketogenic substrates, so that both maternal and fetal tissues may indirectly benefit from maternal hypertriglyceridemia. Changes in the magnitude and direction of lipoprotein lipase activity in different tissues during gestation actively contribute both to the development of hypertriglyceridemia and to the metabolic fate of circulating triglycerides. Any deviation in these metabolic adaptations occurring in the human mother may have consequences that modify her lipoprotein profile, even postpartum. Hormone-induced changes in pregnancy mirror those seen with oral contraceptive steroids and provide a teleologic rationale for the lipoprotein changes induced by sex steroids.     

Transfer and dynamics of uric acid in the pregnant rhesus monkey. II. A mathematical model.

The objective of the present study was to develop a mathematical model of the dynamics of uric acid between fetal and maternal compartments in the term pregnant rhesus monkey. In 3 different animals 14C-labeled uric acid was injected into the fetal circulation, the amniotic fluid and the maternal circulation, respectively. In one experiment no uric acid was administered and the fetus was deliberately killed at the beginning of the experiment. Samples of fetal and maternal blood, maternal urine and amniotic fluid were collected at regular intervals. Semilogarithmic time-activity curves were constructed and time constants were determined. An open four-compartment model (fetal-placental plasma, fetal-placental interstitial space, amniotic fluid and maternal plasma) was applied to describe the intercompartmental dynamics of uric acid. Transplacental clearance was approx. 1 ml X min-1 in both directions, maternal renal clearance was about 17 ml X min-1. These results and the calculated values of the other intercompartmental clearances support earlier results, obtained with the steady infusion method. Uric acid concentrations in amniotic fluid and fetal plasma appeared to increase significantly during the experiments. The rise in amniotic fluid levels can only be explained by accepting a yet undefined compartment in which uric acid is produced and cleared directly into the amniotic cavity. It is speculated that this additional compartment could be the fetal lung.     

The spontaneously hypertensive rat fetus, not the mother, is responsible for the reduced amniotic fluid PTHrP concentrations and growth restriction

Intrauterine parathyroid hormone-related protein (PTHrP) concentrations are reduced in association with growth restriction in the spontaneously hypertensive rat (SHR) compared to those of its normotensive control, the Wistar Kyoto (WKY) rat, implicating PTHrP as a pivotal fetal growth factor. The aim of this study was to examine, by embryo cross-transplanation between SHR and WKY, whether the mother, fetus, or both, are responsible for the suppressed SHR amniotic fluid PTHrP. One-day-old SHR embryos were gestated in either an SHR (SHR-in-SHR) or WKY (SHR-in-WKY) surrogate, similarly one-day-old WKY embryos were gestated in either an SHR (WKY-in-SHR) or WKY (WKY-in-WKY) mother. At 20 days gestation, maternal plasma and amniotic fluid samples were collected and assayed for PTHrP concentrations. Data were analysed by two-way ANOVA (mean+/-sem, n=5-9 mothers/group). There were no differences in litter number or maternal plasma PTHrP concentrations. Fetal weight (P< 0.009), fetal/placental weight ratio (P< 0.004) and amniotic fluid PTHrP concentrations (P< 0.001) were lower and amniotic fluid volume (P< 0.0001) was higher with an SHR fetus compared to the WKY fetus irrespective of maternal strain. Thus, the SHR fetus is growth restricted and has suppressed amniotic fluid PTHrP, which are largely determined by the fetus or gestational tissues and are independent of maternal hypertension or maternal PTHrP. We suggest that the low SHR amniotic fluid PTHrP may play a role in the development of SHR growth restriction.     

An integrated model for the prediction of preeclampsia using maternal factors and uterine artery Doppler velocimetry in unselected low-risk women

OBJECTIVE: The purpose of this study was to develop a predictive model for preeclampsia. STUDY DESIGN: This was a prospective screening study for preeclampsia using uterine artery Doppler ultrasound in unselected low-risk singleton pregnancies at community hospitals in the UK (n = 32,157). Logistic regression models were developed and their predictive ability assessed using the area under the receiver operator curve (AROC). RESULTS: Six hundred twelve (2.0%) women developed preeclampsia, and 144 (0.5%) required early delivery (<34 weeks). A model using both maternal and ultrasound factors had an AROC of 0.798, which was higher than ultrasound alone (0.729, P < .0001) or maternal factors alone (0.712, P < .0001). In early onset disease, the ROC of ultrasound alone (0.922) was not significantly improved by adding maternal predictors (0.945, P = .27). In contrast, late onset disease was better predicted by the combined model (AROC 0.798) than ultrasound alone (AROC 0.729, P < .0001) or maternal factors alone (AROC 0.712, P < .0001). CONCLUSION: The combination of uterine artery Doppler ultrasound and maternal factors provided the best estimate of risk.