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We report a 13-week-old female fetus with early onset fetal akinesia deformation sequence (FADS) and hydranencephaly. In a previous pregnancy, the same ultrasonographic findings were noted at 13 weeks. Fetopathological examination of both female fetuses confirmed FADS with severe arthogryposis, multiple pterygia, and muscular hypoplasia. Neuropathological examination showed massive cystic dilatation of the cerebral ventricles (hydranencephaly) with calcification of the basal ganglion and brain stem and a proliferative vasculopathy throughout the central nervous system. The findings in the two female siblings document the earliest echographic diagnosis of hydranencephaly, Fowler type, and this observation further supports autosomal recessive inheritance of this distinct type of hydranencephaly., (Copyright 2002 Wiley-Liss, Inc.)

We report the second trimester prenatal diagnosis of severe symmetrical limb deficiencies with posterior fossa cyst and cardiac anomaly in a female fetus. Fetopathological examination revealed additional anomalies: renal-hepatic-pancreatic dysplasia, cleft palate, and Müllerian duct anomaly. The spectrum of congenital malformations in the present observation is difficult to classify into a single syndrome entity and presents an overlap with several syndromes: Roberts syndrome, Goldston syndrome, and renal-hepatic-pancreatic dysplasia., (Copyright 2001 Wiley-Liss, Inc.)

In this report we describe a 17 weeks old female fetus with a lumbosacral meningocoele, multicystic renal dysplasia (Potter type IIb) and postaxial polydactyly type A at the left hand and left foot. There was no hepatic fibrosis. Although multicystic renal dysplasia and postaxial polydactyly are often present in the Meckel syndrome, a lumbosacral neural tube defect is not a typical finding in this syndrome.

Objectives: This was a retrospective study on the results of interphase fluorescence in situ hybridization (FISH), performed routinely for chromosome 21 and on ultrasonographic indications for chromosomes 13, 18, X and Y in a series of 5049 amniotic fluid samples., Methods: Interphase FISH for chromosome 21 was performed in 5049 consecutive amniotic fluid samples for the rapid prenatal diagnosis of Down syndrome. Aneuploidy for four other chromosomes (13, 18, X and Y) was tested following ultrasonographic indications. Karyotypes from standard cytogenetic analysis were compared to the FISH results., Results: Using conventional cytogenetics 3.6% (183/5049) chromosomal anomalies were detected. After exclusion of familial chromosome rearrangements, i.e. balanced autosomal reciprocal or Robertsonian translocations (30/5049) and inversions (19/5049), 2.65% chromosomal anomalies (134/5049) were diagnosed. Of this group 0.18% (9/5049) were chromosomal rearrangements not detectable by FISH and 2.47% (125/5049) were numerical chromosomal anomalies detectable by interphase FISH for chromosomes 13, 18, 21, X and Y. With routine interphase FISH for chromosome 21 and FISH on echographic indication for the other four chromosomes we detected 107/125 of these numerical chromosomal anomalies, i.e. 85.6%. All 70 cases of trisomy 21 were detected by FISH and confirmed with conventional cytogenetics (sensitivity=100%) and there were no false-positive results (specificity=100%). Maternal cell contamination of amniotic fluid samples occurred in 1.27% (64/5049) of samples; 0.26% (13/5049) of these samples were uninformative by FISH due to maternal cell contamination (12/5049) or absence of nuclei in one sample (1/5049)., Conclusion: In this group of 5049 samples we found that FISH is a reliable technique for the rapid prenatal diagnosis of trisomy 21. The number of uninformative cases due to maternal cell contamination was low. The strategy to perform FISH for chromosome 21 in all samples and only on ultrasonographic indication for the four other chromosomes (13, 18, X and Y) followed by standard cytogenetics is effective., (Copyright 2002 John Wiley & Sons, Ltd.)

Taurine, a non-protein sulfur amino-acid, is the most abundant free amino-acid in the body and plays an important role in several essential biological processes. Apart from its role in cholesterol degradation, it acts as neurotransmitter, and has a function as osmoregulator and antioxidant in most body tissues. During pregnancy, taurine accumulates in the maternal tissues, to be released in the perinatal period to the fetus via the placenta and to the newborn via the maternal milk. It is accumulated especially in the fetal and neonatal brain. Low maternal taurine levels result in low fetal taurine levels. Taurine-deficiency in the mother leads to growth retardation of the offspring, and to impaired perinatal development of the central nervous system and of the endocrine pancreas. The adult offspring of taurine-deficient mothers display signs of impaired neurological function, impaired glucose tolerance and vascular dysfunction; they may develop gestational diabetes and transmit the effects to the next generation. This transgeneration effect of taurine-deficiency in the perinatal period fits into the concept of fetal origin of adult disease.

A retrospective review of obstetric anaesthesia charts was performed for all parturients receiving regional anaesthesia over a 22-month period. The incidence of headache, post dural puncture headache (PDPH) and various other complications of regional anaesthesia that had been prospectively assessed were noted, as was the anaesthetic technique used (epidural or combined spinal epidural (CSE)). PDPH was rare (0.44%) and occurred with similar frequency in those managed with either epidural or CSE anaesthesia or analgesia. The pencil-point spinal needle gauge (27 or 29) did not influence the incidence of PDPH. Following a CSE technique, the epidural catheter more reliably produced effective analgesia/anaesthesia as compared with a standard epidural technique (1.49% versus 3.18% incidence of replaced catheters respectively). We conclude, based on the results of this retrospective review, that CSE is acceptable with respect to the occurrence of PDPH and that it is possible it is advantageous in relation to the correct placement of the epidural catheter

We report the prenatal diagnosis at 16 weeks' gestation of bilateral split-hand/split-foot malformation (SHSFM) with severe lobster claw deformity of hands and feet in a male fetus without associated malformations. A minor manifestation of SHSFM was present in the father with only mild bilateral foot involvement (syndactyly I-II; cleft II-III; left cutaneous syndactyly III-IV). Mutation analysis of the p63 gene on chromosome 3q27 showed a missense mutation 577A-->G (predicting amino acid substitution K193E) in the father. This mutation has not been reported so far in SHSFM but resembles the previously reported 580A-->G (predicting amino acid substitution K194E) in a family with SHSFM., (Copyright 2001 John Wiley & Sons, Ltd.)

Development of placentation and successful pregnancy depend on co-ordinated interactions between the maternal decidua and myometrium, and the invasive properties of the fetal trophoblast. Syncytin, a protein encoded by the envelope gene of a recently identified human endogenous defective retrovirus, HERV-W, is highly expressed in placental tissue. Previously, we have shown that the major site of syncytin expression is the placental syncytiotrophoblast, a fused multinuclear syncytium originating from cytotrophoblast cells. Here we present the first evidence that in pre-eclampsia, syncytin gene expression levels are dramatically reduced. Additionally, immunohistochemical examination of normal placentae and placentae from women with pre-eclampsia reveals that the syncytin protein in placental tissue from women with pre-eclampsia is localized improperly to the apical syncytiotrophoblast microvillous membrane as opposed to its normal location on the basal syncytiotrophoblast cytoplasmic membrane. Our previous results suggest that syncytin may mediate placental cytotrophoblast fusion in vivo and may play an important role in human placental morphogenesis. The present study suggests that altered expression of the syncytin gene, and altered cellular location of its protein product, may contribute to the aetiology of pre-eclampsia., (Copyright 2001 Harcourt Publishers Ltd.)

We present a retrospective study of the frequency and type of associated malformations and chromosomal anomalies in 42 consecutive cases of congenital diaphragmatic hernia (CDH) diagnosed in utero during the period from 1985 to 1999. In 26% (11/42) of the cases, associated malformations were detected. Chromosomal anomalies were present in 9.5% (4/42). In this group of 15 cases (15/42 = 36%) with associated malformations or chromosomal anomalies, all cases, except one, had prenatal sonographic evidence of additional problems. The survival rate of fetuses with CDH and associated malformations or chromosomal anomalies was poor (1/15). Therefore, the overall survival rate of in utero-diagnosed CDH was only 31% (13/42), while isolated left CDH had a survival rate of 52% (12/23). The in utero diagnosis of CDH implies a detailed echographic examination to exclude additional anomalies. The risk for a syndromal or chromosomal malformation becomes small when no additional anomalies are seen on ultrasound.

We report the prenatal echographic diagnosis of holoprosencephaly (HPE) at 11 weeks' gestation. Fetopathological examination revealed an unusual variant of semilobar HPE with middle interhemispheric fusion associated with sex-reversal: 46,XY normal male karyotype, normal external and internal female genitalia and streak gonads., (Copyright 2001 John Wiley & Sons, Ltd.)

We report the second trimester prenatal echographic diagnosis of an epignathus teratoma in a female fetus with ring X chromosome mosaicism. The ring X chromosome mosaicism was present in the amniotic cell culture and in the teratoma and the ring X was inactive (X-inactive specific transcript (XIST) locus expressed). Hypoplastic left heart with valvular aortic stenosis and non-immune hydrops were additional findings, and are well-documented in Turner syndrome. The occurrence of epignathus teratoma in Turner syndrome has not been documented sofar.

Exposure to a diabetic intrauterine environment leads to diabetogenic disturbances throughout later life in rats. This is accompanied by a fetally acquired dysplasia of the ventromedial hypothalamic nucleus (VMN) which is decisively involved in the regulation of metabolism. We investigated whether malformation of the VMN is preventable by normalization of gestational hyperglycaemia. Correction of hyperglycaemia in pregnant streptozotocin-diabetic rats was achieved by pancreatic islet transplantation. The number of neurons in the VMN was significantly reduced in adult offspring of non-treated, sham-transplanted mother rats (P<0.05), but did not differ between offspring of islet-transplanted mother rats and offspring of control mothers. In conclusion, prevention of VMN malformation in offspring of islet-transplanted diabetic mothers might be co-responsible for normalization of their glucose homeostasis during life.

We report first trimester cystic hygroma colli with subsequent resolution and development of a fetal akinesia deformation sequence. Neuropathological examination of the brain showed intra- and extracellular white matter edema while spinal cord, peripheral nerves and muscles were normal. Hygroma colli as the first echographic sign of subsequent severe fetal akinesia sequence without muscular dystrophy as seen in the Lethal Multiple Pterygium syndrome has not been previously reported.

There is evidence that the diabetic intra-uterine environment has consequences for later life. Maternal diabetes mainly results in asymmetric macrosomia. This macrosomia is associated with an increased insulin secretion and overstimulation of the insulin producing B-cells during fetal life. In later life, a reduced insulin secretion is found. Intra-uterine growth restriction is present in severe maternal diabetes associated with vasculopathy. Intra-uterine growth restriction is associated with low insulin secretion and reduced development of the insulin receptors. In later life, these alterations can induce insulin resistance. The long-term consequences of an abnormal intra-uterine environment are of primary importance world-wide. Concentrated efforts are needed to explore how these long-term effects can be prevented.

Gestational diabetes compromises fetal development and induces a diabetogenic effect in the offspring, including the development of gestational diabetes and the transmission of the effect to the next generation. Changes are not limited to glucose and insulin metabolism, and appear to be modulated by alterations at the hypothalamo-hypophyseal axis. In the present work, serum concentrations are given for the non-protein amino-acids taurine and gamma-aminobutyric acid (GABA), both neurotransmitters essential for normal brain development, and for the endogenous neuroprotector carnosine, a known anti-oxydans. Taurine levels are significantly below normal values in mildly diabetic mothers, in their fetal and adult offspring, virgin and pregnant, and in the fetuses of these pregnant offspring. GABA and carnosine levels are at the limit of detection in the diabetic mothers and their offspring at every stage. It is concluded that the low taurine, GABA and carnosine levels in diabetic mothers and their fetuses might compromise the normal structural and functional development of the fetal brain. When adult, these offspring present a deficiency of the circulating levels of these neurotransmitters involved in the hypothalamo-hypophyseal regulation of insulin secretion. This might contribute to the development of impaired glucose tolerance and gestational diabetes, thereby transmitting the effect to the next generation.

Guinea-pig fetuses at term are mineralized to a degree comparable with human fetuses, which makes the guinea-pig an attractive animal model to study maternal-fetal interactions with regard to Ca and phosphate (P) homeostasis. We studied non-pregnant and pregnant (day 57) vitamin D-replete guinea-pigs, fed either a normal guinea-pig chow with 9.6 g Ca/kg and 4.9 g P/kg or a study diet with 2 g Ca/kg and 1 g P/kg (low-Ca-P diet) for 7-8 weeks. Both pregnancy and the low-Ca-P diet decreased plasma concentrations of 25-hydroxycholecalciferol (25(OH)D3), but increased total and free 1 alpha,25-dihydroxycholecalciferol (1,25(OH)2D3), strongly suggesting an additive stimulation of 1 alpha-hydroxylase activity. Maternal and fetal 25(OH)D3 and 1,25(OH)2D3 levels were highly correlated (r 0.82 and 0.92 respectively, P < 0.001). Dual-energy absorption X-ray absorptiometry (DXA) showed that both pregnancy and the low-Ca-P diet decreased bone mineral density (BMD) of the maternal femur, particularly at the distal metaphysis. Despite higher 1,25(OH)2D3 concentrations and lower BMD, pregnant animals on the low-Ca-P diet were hypocalcaemic; blood Ca2+ levels were inversely correlated with the number of fetuses in this group (r -0.93, P < 0.001). Fetal growth as well as mineralization (assessed by whole-body and femoral DXA, bone histomorphometry and plasma-bone osteocalcin measurements) were unaltered in the low-Ca-P group. In conclusion, fetal mineralization proceeds normally but induces maternal hypocalcaemia in guinea-pigs with dietary restriction of Ca and P.

Objective: Pregnancy complicated by diabetes is associated with maternal complications and fetal abnormalities. Animal models of diabetes suggest that heightened free radical production may be implicated in the pathogenesis of this condition. The purpose of this investigation was to evaluate oxidative stress in plasma from diabetic rats and their fetuses through measurement of concentrations of 8-isoprostaglandin F(2alpha), a stable marker of lipid peroxidation., Study Design: Diabetes was induced in virgin and pregnant rats with streptozotocin. Blood samples were collected after 20 days of diabetes. Adult and fetal plasma 8-isoprostaglandin F(2alpha) concentrations were determined by gas chromatography-mass spectroscopy., Results: Significantly higher plasma 8-isoprostaglandin F(2alpha) concentrations were observed in the virgin rats with diabetes and in both the pregnant dams with diabetes and their fetuses when compared with their respective control groups without diabetes (P <.001)., Conclusion: Oxidative stress was induced in both mother and fetus in rodent pregnancy complicated by diabetes. This finding may have implications for fetal dysmorphogenesis and in fetal programming for adulthood disease.

Adult offspring of severely diabetic pregnant rats are insulin resistant and display cardiovascular dysfunction. When pregnant they develop mild hyperglycaemia. Diets high in saturated fat have been implicated in the development of cardiovascular disease and vascular dysfunction. In the present study we have determined vascular function in small mesenteric arteries from offspring of normal (OC) and diabetic (OD) rats fed standard chow and offspring of diabetic rats fed a diet high in saturated fats (OD-HF) from weaning to adulthood, and throughout their subsequent pregnancies. OD rats displayed an increased sensitivity to noradrenaline (P < 0.05) and impaired sensitivity to the endothelium-dependent vasodilator, acetylcholine. The component of acetylcholine-induced relaxation attributable to endothelium-derived hyperpolarizing factor was reduced in OD-HF rats. Pregnant OD rats also demonstrated impaired maximum relaxation to acetylcholine (pregnant OD rats v. pregnant OC rats P < 0.05). In pregnant OD-HF rats noradrenaline sensitivity was enhanced and endothelium-dependent relaxation further reduced (pregnant OD-HF rats v. pregnant OC rats P < 0.001). The isoprostane, 8-epi-prostaglandin F2alpha, a marker of oxidative stress, was increased in pregnant OD rats (pregnant OD rats v. pregnant OC rats P

Aims/hypothesis: To investigate the outgrowth of the ectoplacental cone in diabetic rats in vivo and in vitro., Methods: Female Wistar rats were injected intraperitoneally with streptozotocin (75 mg/kg body weight, n = 15), or with control buffer (n = 27) 3 days before mating. On day 9 (day 1 = copulation plug) decidual swellings were weighed and the volume and mitotic index of the embryo and ectoplacental cone were estimated. Also, ectoplacental cones were cultured either in the presence of decidual cells from pseudopregnant diabetic rats or in high glucose concentration media. Cultures were evaluated by the daily outgrowth and by the proportion of giant cells and proliferating cells on day 5., Results: In diabetic rats on day 9, the weight of the decidual swellings and the mitotic index in the ectoplacental cone were lower compared with controls (p < 0.0001 and p < 0.05, respectively). In vitro, control ectoplacental cones in the presence of decidual cells from diabetic rats showed a slight reduction in outgrowth on day 3 and 5 of culture. Outgrowth of diabetic ectoplacental cones in high glucose concentration medium was impaired on day 1 (p < 0.0005) compared with control ectoplacental cones in control medium, and on day 1 and 2 (both p < 0.005) compared with control ectoplacental cones in high glucose concentration medium. In control medium, the outgrowth of diabetic ectoplacental cones was impaired on day 1 (p < 0.05), compared with control ectoplacental cones. Proliferation was stimulated in diabetic ectoplacental cone cultures., Conclusion/interpretation: These data suggest that the outgrowth of diabetic ectoplacental cones is impaired by high glucose concentrations.

Tumour necrosis factor (TNF)-alpha and interferon (IFN)-gamma, produced by maternal inflammatory cells, may compromise trophoblast survival at the trophoblast-maternal interface and notably in the placental bed which is invaded by trophoblast. Extracellular matrix components, e.g. fibronectin, may enhance trophoblast survival. A possible protective effect of fibronectin against toxic effects of TNF-alpha and IFN-gamma was investigated in cultured trophoblasts isolated from six human term placentas, grown on uncoated and fibronectin-coated plastics. IFN-gamma and increasing doses of TNF-alpha resulted in decreasing viability of trophoblast on uncoated as well as fibronectin-coated dishes, as shown by 3-[4, 5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide (MTT) assays, but for each TNF/IFN treatment condition viability on fibronectin was higher (P < 0.001). Epidermal growth factor (EGF), a growth factor reported to protect against TNF-alpha/IFN-gamma induced toxicity, resulted in further increased viability, but not if IFN-gamma was included in the treatment. EGF caused increased fibronectin secretion into the medium (P < 0.001), and double cytokeratin/fibronectin immunostaining confirmed the trophoblastic nature of fibronectin secreting cells. We conclude that fibronectin increases viability, but does not completely abolish the cytotoxic action of TNF-alpha and IFN-gamma on trophoblast. The protective effect of EGF may be related to stimulation of fibronectin secretion by trophoblast.

Objective: The aim of this study was the measurement of maternal serum levels of M-CSF throughout pregnancy, in a low risk obstetrical population, to examine the relationship of M-CSF and pregnancy outcome., Study Design: Maternal serum was obtained at various stages of pregnancy and post partum, M-CSF levels were measured by ELISA, pertinent clinical data tabulated, and pregnancy outcome was determined., Results: In 564 pregnancies studied, 22% of 260 nulliparous pregnancies and 10% of 304 multiparous pregnancies were hypertensive. Preeclampsia occurred in 1.5% of nulliparous and in 1% of the multiparous women. In apparently normal pregnancies with good outcome, M-CSF levels rose throughout pregnancy. No cases of preeclampsia occurred if maternal serum M-CSF levels increased more than 100% throughout pregnancy., Conclusions: This study suggests that absolute levels and relative changes in maternal serum M-CSF levels during pregnancy are associated with adverse pregnancy outcomes.

Maternal diabetes induces fetal alterations, resulting in lasting consequences for the glucose tolerance of the offspring over several generations. In our experimental rat model, circulating prolactin, oestradiol, progesterone and corticosterone levels, known to influence insulin secretion and action, are determined in plasma of female adult offspring of mildly and severely diabetic mothers. Prolactin and progesterone levels are equally low in both groups as compared to controls, stressing the involvement of the CNS in the transgeneration effect; oestradiol and corticosterone levels are normal. No correlation is found between these hormonal alterations and the known differences in glucose tolerance.

Objective: To compare the efficacy and side effects of misoprostol, compared with methylergometrine, for the prevention of postpartum haemorrhage., Design: A double-blind, randomised clinical trial of 200 women with apparently normal pregnancies., Setting: University teaching hospital., Participants: Two hundred women with apparently normal pregnancies., Methods: After the baby had been born, all women received two capsules by mouth and the contents of an ampule by intravenous injection. Each woman only received one active product. The capsules contained either a total of 600 microg misoprostol or placebo, and the ampule 200 microg of methylergometrine or placebo., Main Outcome Measures: Need for further oxytocic drugs, blood pressure, the presence of side effects, mean haemoglobin and haematocrit three days after delivery., Results: Two hundred women completed the study (100 received methylergometrine and 100 misoprostol). Postpartum haemorrhage occurred in 4.3% of the methylergometrine group and 8.3% of the misoprostol group (P = 0.57). The need for further oxytocic drugs was 4.4% and 12.8% after methylergometrine and misoprostol, respectively (P = 0.065). One hour after the birth of the baby there was no difference in the mean systolic blood pressure (117 +/- 12 mmHg versus 115 +/- 11 mmHg) (P = 0.26) or the mean diastolic blood pressure (72 +/- 10 mmHg versus 71 +/- 11 mmHg for the groups receiving methylergometrine or misoprostol, respectively) (P = 0.97). The mean temperature in the misoprostol group rose to 37.4 degrees C, compared with 37 degrees C in the methylergometrine group (P < 0.0001). In the misoprostol group 34% developed fever (> 38 degrees C) compared with 3% in the methylergometrine group (P < 0.0001). Shivering (visual analogue score > or = 8) also occurred more often after misoprostol (42%) than after methylergometrine (8.5%) (P < 0.0001). The haemoglobin level (g/dL) on the third postpartum day was similar for both groups ( 11.0 and 11.2 for methylergometrine and misoprostol, respectively) (P = 0.39)., Conclusions: This study suggests that although protection from postpartum haemorrhage using parenteral methylergometrine and oral misoprostol is nearly equal, misoprostol is associated with more side effects.

1. Western diets high in saturated fat are associated with an increased incidence of cardiovascular diseases. In this study we have evaluated vascular endothelial function and oxidative stress in virgin rats fed a normal (VC) or high in saturated fat diet (VHF) (20 % lard and corn oil w/w) from weaning until adulthood, and throughout subsequent pregnancy (PC and PHF, respectively). 2. The saturated fat diet was associated with enhanced noradrenaline sensitivity in small mesenteric arteries from VHF rats (VHF vs. VC, P < 0.05) and blunted endothelium-dependent relaxation in VHF and PHF rats (VHF vs. VC, P < 0.001; PHF vs. PC, P < 0.05). Endothelial dysfunction was attributable to a reduced nitric oxide component of relaxation in VHF rats, and blunted prostacyclin and endothelium-derived hyperpolarizing factor components in PHF rats. 3. Other than plasma cholesterol, which was reduced in VHF and PHF rats, plasma lipids were normal. Fasting plasma insulin and glucose concentrations were raised in VHF rats (P < 0.05) and the plasma marker of oxidative stress, 8-iso PGF2alpha, was increased in PHF animals (P < 0.01). 4. These findings suggest that endothelial dysfunction induced by a saturated fat diet is cholesterol independent and likely to be of different mechanistic origin in virgin and pregnant rats.

Food restriction during pregnancy in rats induces intrauterine growth retardation with consequences persisting into adulthood. In the present study we have investigated the hypothesis that malnutrition in pregnant rats may lead to altered cardiovascular function in adult female offspring. Perinatal growth retardation was induced by a 50% reduction of normal dietary intake in rats during the second half of pregnancy. Systolic and diastolic blood pressure values and heart rate were recorded in conscious female offspring (100 d old) using a femoral artery probe. No significant differences in heart rate, or in systolic and diastolic blood pressures were recorded between control offspring and offspring of nutritionally deprived rats. In order to ascertain whether cardiovascular variables in the offspring were influenced by lactation, subgroups of offspring from food-restricted dams were fostered with lactating dams fed on a normal diet. Blood pressure and heart rate were also found to be normal in these offspring. The rise in blood pressure associated with NO inhibition was similar in all groups. Isolated resistance artery function was assessed in vitro in offspring (100-120 d old) of a second group of semi-starved dams. Small mesenteric arteries from these animals showed reduced endothelium-dependent relaxation (to acetylcholine and bradykinin), but enhanced sensitivity to exogenous NO (sodium nitroprusside). We conclude that food restriction during the second half of pregnancy and/or lactation does not induce hypertension in adult offspring, but may effect subtle changes in vascular function.

Severe diabetes in pregnant rats produces persistent metabolic consequences in adult offspring. This study investigated whether diabetes in pregnant rats could also lead to cardiovascular abnormalities in the adult offspring. Blood pressure, heart rate and in vitro vascular reactivity of small arteries were evaluated in female adult offspring of control rats and of rats rendered diabetic with streptozotocin. Rise in blood pressures were similar in both groups of offspring but heart rate was lower in the diabetic offspring (p < 0.05). The rise in blood pressure associated with infusion of a nitric oxide synthase inhibitor was similar in both groups, but the associated decrease in heart rate was more pronounced in diabetic offspring (p < 0.01). Small mesenteric arteries from this group showed enhanced sensitivity to noradrenaline (p < 0.05) and abnormal endothelium-dependent relaxation to acetylcholine (p < 0.01) and bradykinin (p < 0.05). Reduction in acetylcholine induced relaxation, reflected reduced synthesis of nitric oxide or a cyclooxygenase product and was not attributable to an endothelium-derived hyperpolarizing factor. Sensitivity to exogenous nitric oxide was normal. A subgroup of pups born to diabetic dams were suckled by control maternal dams and a subgroup of those born to controls by diabetic dams. Suckling was an important determinant of impaired growth; offspring of diabetic rats suckled by their own mother and those of control rats by diabetic dams showed impaired growth rates whereas growth of offspring of diabetic rats suckled by control dams paralleled those of control rats suckled by their own mother.

Aims: To assess the outcome of preterm prelabor rupture of the membranes (PPROM) before 26 weeks of gestation and to develop a prediction model for survival., Methods: 148 consecutive cases of PPROM before 26 weeks of gestation, collected between 1988 and 1996, were retrospectively analyzed. A multivariate analysis (generalized estimating equations) of 21 process and 5 short and long term outcome variables was performed., Results: 40 out of 148 children (27%) died before or during birth, 57 (38.5%) of the children survived more than 28 days, from which still 5 died after one month. Amongst the 52 survivors (35.1%), the Bayley Mental Development Index and Psychomotor Development Index at a corrected age of 7 months was normal in respectively 85.7% and 75.5% of the cases. At 6-7 years of age, 24 out of 33 children (73%) performed adequately at school. Sex, gestational age at PPROM, birth weight, the administration of steroids and interactions of steroid administration with sex and with gestational age at the time of PPROM largely determined the chances of survival., Conclusions: Overall fetal survival after PPROM before 26 weeks of gestation was 35.1%. Survival can be predicted with an accuracy of 75%, a sensitivity of 85% and a specificity of 60%. More than 70% of the survivors behaved and performed adequately at school age, but 27% require special long-term attention and care.

Objectives: (1) To identify the distribution of renin-like immunoreactivity in placental bed, placenta-free uterine wall, placenta, fetal membranes, and intertwin membranes obtained from normal pregnancies and (2) to compare the findings in normal pregnancies with those in pregnancies complicated by various hypertensive disorders., Study Design: Biopsies were taken from 31 normotensive pregnant women, eight of whom had twin pregnancies, and from 28 women with various hypertensive disorders of pregnancy. The anti-human renal renin monoclonal antibody, F37.1A1, was used for immunostaining. Histological structures were identified with standard H&E and PAS techniques, supplemented with immunostaining using the specific cell markers CD68 and cytokeratin., Results: Renin-like immunoreactivity was found in cytokeratin immunolabelled placental syncytiotrophoblast, amnionic and glandular epithelium, but most consistently in CD68 immunolabelled maternal and fetal macrophages. The distribution of renin-like immunoreactivity throughout the pregnant uterus roughly parallelled reported renin concentrations in the various tissues, while its localization conforms also with that of cathepsin D. There were no obvious differences in renin-like immunolabelling between normotensive or hypertensive women. Renin-like immunoreactivity was particularly common in the atherotic lesions that are observed more often in pregnancies complicated with hypertensive disorders of pregnancy and/or intra-uterine growth restriction., Conclusions: The data complement earlier findings showing that only two of four anti-renal renin monoclonal antibodies, both of which cross-react with cathepsin D, give a positive immunostaining in placental tissue. They question whether classical concepts on renin localisation in uteroplacental tissues all relate to one and the same enzyme. The demonstration of renin-like enzymes in different cell types, including macrophages, may explain the diversity of functions that has been attributed to uterine renin. There were no differences between tissues obtained from normotensive and hypertensive pregnancies, except for the consistent presence of renin-like immunoreactivity in atherotic lesions.

Perturbations of the maternal environment involve an abnormal intrauterine milieu for the developing fetus. The altered fuel supply (depends on substrate availability, placental transport of nutrients and uteroplacental blood flow) from mother to fetus induces alterations in the development of the fetal endocrine pancreas and adaptations of the fetal metabolism to the altered intrauterine environment, resulting in intrauterine growth retardation. The alterations induced by maternal diabetes or maternal malnutrition (protein-calorie or protein deprivation) have consequences for the offspring, persisting into adulthood and into the next generation.

Objective: Assessment of the appearance, distribution and numerical density of immune cell populations in the normal human uterine cervix., Setting: University Hospital Gasthuisberg., Subjects: 29 healthy women undergoing total hysterectomy for non-cervical benign uterine disease., Analysis: Immunohistochemistry and morphometrical analysis on histological sections containing ectocervix, transformation zone and endocervix, using antibodies against the following antigens: HLA-DR, CD4, CD22, CD1a and CD8., Statistical Analysis: Wilcoxon rank sum test., Results: Lymphocytes in the epithelial and stromal compartments are predominantly T-lymphocytes. Intraepithelial T-lymphocyte and Langerhans' cell densities and their distribution are not influenced by the menstrual cycle and are the same in both ectocervix and transformation zone., Conclusion: The wide variation of T lymphocyte subpopulations and Langerhans' cell densities in the normal epithelium of the uterine cervix is stressed. We are the first to present a large and well-defined control series, which is indispensable to study the effect of smoking and other factors on the cervical immune system.

While endovascular trophoblast invasion of the human placental bed spiral arteries has been studied extensively, no information is available on the interaction between interstitially invading trophoblast and uterine capillaries and venules. Placental bed biopsies of eight normotensive and 15 pre-eclamptic patients were double-immunostained for cytokeratin and the endothelial marker CD31, providing satisfactory staining results in six and 10 biopsies, respectively. Interstitial trophoblast tissue density did not differ between the two series of biopsies, implying that this pathway of invasion is not impaired in pre-eclampsia. Both groups showed a similar incidence of approach of non-arterial vascular structures by perivascular trophoblast. Differences in CD31 staining intensity were noticed in different vascular cross-sections. Lower staining intensity was related to the presence of perivascular trophoblast. Because of the identity of CD31 with the platelet-endothelial cell adhesion molecule (PECAM)-1, the trophoblast-dependent downregulation of CD31 may play a role in the control of leukocytic traffic within the placental bed. The phenomena described in this paper did not show any difference between the normotensive and pre-eclamptic patients, implying that interaction of interstitial trophoblast with venous and capillary structures is not related to the pathogenesis of pre-eclampsia.

Adult offspring of diabetic rat mothers display a disturbed glucose tolerance and gestational diabetes. The amount of endocrine pancreas and of B-cells is largely sufficient in these non-pregnant and pregnant youngsters. The present work aims a morphometric evaluation of B-cell activity in adult youngsters from control, mildly and severely diabetic mothers, in basal condition and in their adaptation to pregnancy. B-cells are divided, on basis of the ultrastructural morphology of their organelles, in dark non-activated B-cells and pale activated B-cells. These data are related to the concepts of functional B-cell heterogeneity and dose-dependent recruitment of pancreatic B-cells on stimulation. The recruitment of B-cells in each of the groups is evaluated from the proportion pale/dark B-cells. In control animals this is about 50/50, in both experimental groups there is a marked predominance of pale B-cells. During normal pregnancy, a shift occurs towards a majority of pale B-cells. In the offspring of diabetic mothers, the ratio does not further change during gestation. It can be concluded that the disturbance in B-cell stimulation and the development of gestational diabetes in offspring of diabetic mothers is associated with a maximal recruitment of the B-cells already in basal non-pregnant condition.

To identify tumour necrosis factor (TNF)-alpha immunopositive cells, third trimester human placental bed biopsies were selected from nine normotensive control women, 16 severely pre-eclamptic patients and seven patients with pre-existing hypertension with superimposed pre-eclampsia. In addition, five first and early second trimester specimens were included in the study. Immunostaining was performed with a mouse IgG1 monoclonal antibody (J1D9) reactive specifically with human TNF-alpha (1:300 ascitic fluid), using a biotin-streptavidin-peroxidase technique. Variable staining of stromal cells was noted in all biopsies. Specimens of early pregnancy showed marked immunostaining for TNF-alpha on proliferating tips of anchoring villi, invasive interstitial cytotrophoblast (but not the multinuclear giant cells), and endovascular trophoblast invading the spiral arteries. At term, weak staining was found in trophoblast incorporated within spiral artery walls. In biopsies from pre-eclamptic patients, spiral arteries without physiological change showed very little staining except in atherotic vessels where the infiltrated lipophages often showed intense immunolabelling. The marked presence of TNF-alpha in extravillous cytotrophoblast of young specimens is suggestive of a role in early invasion. Immunostaining of foam cells in non-invaded spiral arteries in pre-eclampsia at or near-term indicates a potential role of this cytokine in the development of atherotic lesions.

Nd: YAG laser coagulation is used to treat severe twin-to-twin transfusion syndrome (TTS). Success of the technique depends on visualization of the placenta, the fetal membranes and the targeted vessels, as well as obtaining an optimal inclination angle for laser coagulation. In the rare case of an extensive anterior placenta, it may be difficult to achieve these conditions using the percutaneous approach. Here, we propose an alternative to the percutaneous procedure. Modifications involve an open access and the use of a flexible cannula and bent scope. An extraplacental area, usually at the fundus, is identified by B-mode and color Doppler imaging. A mini-laparotomy is made under general anesthesia. The viscera are retracted and the cannula is inserted under direct view and ultrasound control by the Seldinger technique. The curved fiberscope is passed through the flexible cannula, allowing adequate inspection of the placenta, and target vessels can be coagulated at an angle close to 90 degrees. After the procedure, the uterus is closed primarily to prevent postoperative leakage of amniotic fluid or hemorrhage. This technique has been successfully used in six patients with TTS and a completely anterior placenta, with a gestational age between 18.5 and 22.0 weeks. In all patients, the amniotic cavity was accessed without hemorrhage. The outcomes are similar to those published previously for laser coagulation. The mean interval from intervention until delivery was 10.5 weeks. All 12 fetuses were live born but four died from complications of extreme prematurity. No maternal complications occurred.

There is evidence that an abnormal intrauterine environment has consequences for later life. Intrauterine growth retardation is associated with low insulin secretion during fetal life and probably a reduced development of insulin receptors. In later life these alterations can induce insulin resistance. Macrosomia is associated with an increased insulin secretion during fetal life and exhaustion of the insulin producing B cells. In later life a reduced insulin secretion is found. The working mechanisms have been explored in experimental studies. Normalisation of the diabetic intrauterine milieu can prevent consequences in later life. There are also indications that vascular changes in later life can be reduced by anti-oxidantia. In the human intrauterine growth retardation is related in later life with insulin resistance, vascular diseases and preeclampsia; macrosomia is related with gestational diabetes and breastcarcinoma.

The foetal growth is, for the greater part, determined genetically. There are, however, favouring and inhibiting factors, which influence this growth. In such a matter, the mother, the placenta and the foetus play an important part. The mother shows as well metabolic as vascular adaptations. The placenta must let through nutrients and oxygen; the uteroplacental circulation is characterized by a high flow, together with a low vascular resistance. The foetus itself plays an important part owing to its own growth factors. The principal growth factors are insulin and the growth factors analogous to insulin. The slowing up of the intra-uterine growth is the consequence of genetic factors or of the decrease of the growth-potential. The real cause is, however, mostly a decrease of the vascular adaptation in the mother or a diminution of the uteroplacental circulation. The vascular causes usually induce an asymmetrical delay in the growth; foetal causes induce a symmetrical retardation. An exaggerated growth of the foetus--or macrosomy--is mostly due to an excessive inflow of nutrients: this is the case when a pregnant woman is suffering from diabetes. During the former years, it has become evident that abnormalities of the foetal growth influence the later life of people.

Diabetes of the mother during pregnancy induces structural and functional adaptations in the fetal endocrine pancreas. We have previously shown in our experimental rat model, that the impact of this abnormal intra-uterine milieu leads, in the adult offspring, to a disturbance of the glucose homeostasis and to the development of gestational diabetes. The aim of the present work is to investigate wether these functional differences can be explained by structural differences at the level of the endocrine pancreas. Therefore the size and the structure of the endocrine pancreas, as well as the contribution of the insulin-, glucagon-, somatostatin- and PP-cells, were investigated morphometrically in the adult youngsters of mildly and of severely diabetic mothers, since both display a disturbed glucose tolerance but with divergent characteristics. Also the adaptation of their endocrine pancreas to pregnancy was measured and compared to that of a control pregnancy. In the offspring of mildly diabetic mothers, the size of the endocrine pancreas and the distribution of the islets of Langerhans are normal. Also the doubling of the endocrine mass during pregnancy is similar to controls. The high proportion of A-cells, especially in relation to a normal B-cell mass and the low amount of PP-cells, might play a role in the impairment of the insulin response in these animals and in the development of gestational diabetes. In the offspring of severely diabetic mothers a clear hypertrophy of the endocrine pancreas is noted, which is mainly due to the presence of numerous small islets and which does not increase further during pregnancy. In these animals, the size of the endocrine pancreas and of the B-cell mass have reached 'pregnant' values without pregnancy, which coincides with an exaggerated insulin output and peripheral insulin resistance, as during normal pregnancy. No further increase in islet mass is seen during pregnancy, which is associated with gestational diabetes.

Objective: The goal was to study the effects on uterine contractility, blood pressure, and heart rate of thyrotropin-releasing hormone given antenatally in combination with glucocorticoids to accelerate fetal maturation., Study Design: A placebo-controlled, randomized, double-blind study was performed involving 30 women whose pregnancies were followed up at the University Hospital Gasthuisberg in 1994 and 1995., Results: Thyrotropin-releasing hormone induced a significant mean increase of nearly 6 mm Hg in systolic blood pressure and approximately 5 mm Hg in diastolic blood pressure. The duration of this raise was < 20 minutes. Thyrotropin-releasing hormone had no significant effect on maternal heart rate or uterine contractility: 4.2 +/- 1.6 contractions per hour before versus 4.7 +/- 1.7 contractions per hour after treatment., Conclusions: Thyrotropin-releasing hormone induces a small (mean < 6 mm Hg) and brief mean (< 20 minutes) increase in blood pressure but appears to have no clinically detectable effect on uterine contractility.

Previous work in humans and rats has revealed a link between perinatal growth retardation and glucose intolerance in adulthood. Both maternal semistarvation and severe diabetes are accompanied by perinatal growth retardation in rats. In this study, we compared the effect of these conditions on tissue glucose uptake in their female offspring. Glucose uptake was measured as glucose metabolic index (GMI), using 2-deoxy-[1-3H]-glucose, in the postabsorptive state and during euglycemic hyperinsulinemia. The GMI was measured in insulin-sensitive tissues (5 skeletal muscles, diaphragm and white adipose tissue) and in two noninsulin-sensitive tissues (duodenum and brain) of adult offspring of normal dams, dams rendered diabetic with streptozotocin on d 11 of pregnancy, and dams fed half normal rations from d 11 of pregnancy. Whole-body insulin resistance, measured by decreased glucose infusion rate during hyperinsulinemia, was milder in offspring of semistarved rats (O-SR) than in offspring of diabetic rats (O-DR). The basal GMI did not differ among the three groups in any tissue except tibialis anterior; during hyperinsulinemia, GMI was significantly greater in the insulin-sensitive tissues of all three groups. GMI of skeletal muscles and adipose tissue during hyperinsulinemia did not differ between control rats and O-SR; in contrast, the GMI was 25-50% lower in skeletal muscles of O-DR during hyperinsulinemia than in those of control rats or O-SR. Thus, maternal semistarvation and diabetes have dissimilar effects on peripheral insulin sensitivity of the adult female offspring. Because both conditions are associated with perinatal growth retardation and fetal hypoinsulinemia, other mechanisms must be identified to explain impaired glucose uptake by skeletal muscles in the offspring of diabetic rats.

Objective: To prove the presence of interleukin-11 (IL-11) in the follicular fluid (FF), to determine its source and the correlation between IL-11 and fertilization outcome, follicular size, number of follicles per patient, steroids, and insulin-like growth factor-1 (IGF-I) levels., Design: Interleukin-11 levels were measured in FFs, aspirated during oocyte pickup for IVF., Setting: Academic hospital and research environment., Patient(s): Follicular fluid and serum were obtained with informed consent from 44 patients undergoing IVF-ET. Granulosa cells were isolated from 17 patients., Main Outcome Measure(s): We hypothesized that IL-11 might play a role in follicular development, as do other related cytokines present in FF. Interleukin-11 was measured with ELISA., Result(s): Interleukin-11 was absent in the serum but present in FF and in conditioned medium from granulosa cells. Atretic follicles had higher concentrations of IL-11. No correlation was found between IL-11 and fertilization outcome, follicular size, steroid, IGF-I, and total protein concentrations., Conclusion(s): We conclude that IL-11 is present in FF. The role of IL-11 in follicular development should be the object of further investigations.

Objective: Trophoblast from preeclamptic patients shows impairment of various functions, including restricted invasive behavior of extravillous trophoblast. In this light the effect of different matrix components on attachment and differentiation of primary trophoblast cultures derived from normal and preeclamptic pregnancies was investigated., Study Design: Trophoblast was isolated from placentas of normotensive (n = 5) and preeclamptic patients (n = 5) and cultured up to 7 days on LabTek slides precoated with fibronectin, laminin, or vitronectin. Attachment was evaluated 24 hours after plating, the degree of syncytialization was evaluated, and slides were immunocytochemically stained for cytokeratin, vimentin, human chorionic gonadotropin, and human placental lactogen., Results: Trophoblast from placentas of preeclamptic patients showed a significantly lower attachment on fibronectin and vitronectin compared with controls. Diminished multinuclear cell formation was found on uncoated and laminin-coated slides in preeclamptic cases. No difference was found in the percentage of human chorionic gonadotropin- and human placental lactogen-positive cells between groups., Conclusions: Lower trophoblast attachment on fibronectin and vitronectin was observed in preeclamptic pregnancies, which may reflect differences in expression of matrix receptors. Lower syncytialization of trophoblast in this group indicates an intrinsic defect in differentiation, but otherwise no differences were found in differentiation between normotensive and preeclamptic patients.

Objective: The purpose of the present study was to investigate insulin sensitivity in adult rats after perinatal malnutrition., Methods: Wistar rats were food-restricted (about 50% of normal food intake) during pregnancy (group A) or during pregnancy and lactation (group B) and compared with rats fed ad libitum during pregnancy and lactation (group C). The insulin sensitivity in the adult female offspring was assessed with the hyperinsulinemic euglycemic clamp technique in combination with isotopic measurement of glucose turnover. Hepatic and peripheral insulin sensitivities were determined in the basal state and after 3, 10, or 50 mU/kg/minute insulin., Results: Group A and group B rats had lower non-fasting plasma insulin levels (0.15 +/- 0.07 and 0.15 +/- 0.01 nmol/L, respectively) than group C rats (0.26 +/- 0.03 nmol/L) (P < .001). During hyperinsulinemia, the steady-state glucose infusion rate was lower in groups A and B, with 10 and 50 mU/kg/minute insulin, indicating insulin resistance. Hepatic glucose production in the basal state was normal, but its suppression by 10 and 50 mU/kg/minute insulin was dampened in group A and B rats, indicating decreased insulin responsiveness of the liver. Peripheral glucose utilization, however, in the basal state and during hyperinsulinemia remained normal in groups A and B., Conclusion: After perinatal malnutrition, adult rats have decreased plasma insulin concentrations and exhibit insulin resistance, with decreased insulin responsiveness of the liver.

Cotinine levels in blood and cervical fluid of smokers and non-smokers were analysed using capillary-column gas chromatography. These levels were not related to numerical cell densities of intraepithelial S100-protein- and LN2-positive Langerhans cells or to MAC-387-positive macrophages in the stroma of the transformation zone of normal uterine cervices. A decrease in the number of Langerhans cells was noted in smokers, especially in those using oral contraceptives (OCs). Macrophages were more numerous in the endocervical stroma of smokers, suggesting a local response to smoke constituents. These findings may indicate a synergistic suppression of local cervical immunity by smoking and OCs.

This study evaluates the presence of Langerhans' cells and expression of L1 antigen in squamous epithelium of the normal and dysplastic transformation zone of the cervix uteri and determines the influence of tobacco smoking and pregnancy. Women who smoked and pregnant women showed a decrease of Langerhans' cell counts in normal epithelium. In cervical intraepithelial neoplasia (CIN) 1 lesions, decreased Langerhans' cell counts were noted. L1 antigen expression was significantly less in CIN of all grades. Normal squamous epithelium of smokers showed weaker staining for L1 antigen but total staining scores were not significantly different. These data suggest a decrease in epithelial cell-mediated immune response in smokers, pregnant women and in low-grade CIN. Dysplastic squamous cells probably have intracellular regulatory problems independent of other immune cells.

Diabetes and pregnancy are associated with an increased incidence of preeclampsia. The pathogenesis is not exactly known. However endothelial factors and more special the prostacyclin-thromboxane system may be involved. Perinatal morbidity and mortality is increased in a diabetic pregnancy implicated with preeclampsia. Prevention and a curative approach is necessary.

Five antibodies that stained renin in the kidney were used to investigate the presence of renin in human placenta and fetal membranes. Despite a large number of experimental approaches to enhance penetration of the immunoglobulins, only two of them showed immunostaining in placenta and fetal membranes. Staining was found in placental syncytiotrophoblast, the amnionic epithelium overlying the placenta, and in glandular epithelial cells present in the decidua adhering to the fetal membranes. It was most consistent, however, in a small infiltrating cell type dispersed through the fetoplacental layers. The two antibodies that revealed immunostaining in all preparations showed high affinity cross-reactivity with cathepsin D. Among other, less plausible, explanations, this raises the possibility that the bulk of 'renin' found in placenta and fetal membranes is not identical to renal renin, but may be cathepsin D or a substance related to both cathepsin D and renin.

Chorionic trophoblast, decidual cells, and macrophages have all been named as the site of renin in the placental membranes. To establish more clearly the nature of the renin-containing cells in the placental membranes, double immunostaining techniques were used to stain renin and specific cell markers in the same tissue sections. Cytokeratin was selected as an ectodermal cell marker and CD68 as a cytoplasmic macrophage marker. Cross-binding between antibodies was prevented by blocking species-related binding sites between the first and second sequence of the double-immunostaining procedures and by using highly selective immunostaining techniques in the second sequence. The results clearly show renin immunostaining in CD68-positive macrophages and not in cytokeratin-positive trophoblast. The anti-renal renin monoclonal antibody showed high affinity cross-reactivity with cathepsin D, another aspartic proteinase that can release angiotensin I from angiotensinogen. This should be seen in the context of earlier findings that only two of four anti-renal renin monoclonal antibodies showed staining in uterine and placental tissues and both cross-reacted with cathepsin D. The results indicate that differentiation between renin and cathepsin D and, possibly, other substances with shared properties and epitope homology deserves more attention than it has received thus far.

Psychometric tests (State-Trait Anxiety Index and Utrechtse Coping Lijst) were administered to 23 primigravidae hospitalized for preterm labor and to 22 controls in order to investigate whether women with and without preterm labor present a different coping style or (in) effectiveness of this coping and whether the coping style predicts duration of hospitalization and gestational age at delivery. No significant differences in trait anxiety nor in coping style were found between women with and women without preterm labor. However, within the group of women with preterm labor, coping mechanisms are important predictors of course and outcome of the preterm contractions. Palliative coping and social support seeking are protective mechanisms while active coping has an adverse effect upon outcome: an older gestational age at the moment of delivery is for 44% predicted by a higher social support seeking and a lower active coping.