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The hepatitis C virus, first isolated in 1989, is now prevalent throughout the world, and is estimated to affect approximately three percent of the entire population. The most efficient mode of transmission is through percutaneous exposure to contaminated blood. In a majority of infected patients, chronic hepatitis will ensue, potentially leading to the rare complications of cirrhosis and hepatocellular carcinoma. We aimed to review the natural history of the disease, and discuss screening and preventive strategies as they apply to women.

OBJECTIVE To determine whether fetal erythropoietin (Epo) concentrations are increased in pregnancies extending beyond 41 weeks' gestation and whether this is influenced by the presence of meconium-stained amniotic fluid. METHODS Epo concentrations were measured in 116 fetal umbilical cord blood samples from otherwise uncomplicated pregnancies between 37 to 43 weeks' gestation during the period of October 1996 to October 1997. An enzyme-linked immunosorbent assay kit was used to measure Epo. Maternal demographics and birth outcomes including Apgar score, cord blood pH, and base deficit were obtained. Fetuses born between 41 and 43 weeks' gestation (post-term) were compared with matched controls born between 37 and 40 weeks' gestation (term). In addition, both post-term and term fetuses with meconium-stained amniotic fluid were compared with matched controls without meconium. RESULTS Post-term fetuses without meconium had significantly higher Epo levels compared with term fetuses (mean +/- SEM: 50.6 +/- 6.5 versus 29.5 +/- 3.3 mIU/ml, p = 0.002). When matched for gestational age, fetuses with meconium-stained amniotic fluid had significantly greater Epo concentrations compared with controls without meconium (post-term, 80.7 versus 50.6 mIU/ml; term, 61.4 versus 29.5 mIU/ml; p < 0.05). However, no significant difference in Epo levels was found between post-term fetuses with meconium and term fetuses with meconium (80.7 +/- 15.7 mIU/ml versus 61.4 +/- 12.8 mIU/ml, respectively). Mean cord blood pH and base deficit values for all groups were within normal clinical range. CONCLUSION Cord blood Epo concentrations were significantly increased in pregnancies extending beyond 41 weeks. Irrespective of gestational age, meconium-stained amniotic fluid was associated with a significant rise in Epo. High Epo levels in these pregnancies imply subacute or chronic fetal hypoxia. Close clinical monitoring of post-term fetuses and those with meconium-stained amniotic fluid is warranted.

We tested the effects of the acetylcholinesterase inhibitor eserine (10 mu M), an indicator of the activity of endogenous ACh, on the generation of epileptiform discharges during blockade of inhibitory GABA(A)-mediated potentials by bicuculline (10 mu M), in the CA3 area of hippocampal slices from postnatal days 4-20 (P4-P20) immature and adult rats. Eserine provoked or significantly increased the frequency of spontaneous synchronous epileptiform discharges, in 6/22 (27%) P4-P10 slices, 34/35 P11-P20 slices and 18/18 adult slices, an epileptogenic effect. Ln immature slices, spontaneous discharges showed a stable frequency throughout perfusion with eserine, while in 5/11 adult slices an initial fast frequency was followed by a slower steady-state one. The cholinergic agonist carbachol (CCh, 25 mu M) provoked only transient or no spontaneous synchronous discharges in adult slices (n = 8), thus suggesting that massive activation of cholinergic receptors may lead to suppression of epileptiform activity in adult brain. Stimulus-induced excitatory CA3 responses, were depressed by eserine in approximately half of 20 P4-P10, 45 P11-P20 and 11 adult slices. The depression consisted of a decrease in the amplitude, duration, and number of population spikes of the field potentials by about 30%, a minor neuroprotective effect, which did not change with maturation. The different developmental profiles of the epileptogenic and neuroprotective effects of endogenous ACh suggest that they are mediated by different mechanisms. These experiments demonstrate that, endogenous aCh is sufficient to induce epileptogenesis during a decrease or failure of GABAergic inhibition, in both greater than or equal to P10 immature and in adult hippocampus. We therefore suggest that clinical or behavioral conditions which raise the concentration of endogenous ACh may lower the threshold to seizures. (C) 1999 Elsevier Science B.V. All rights reserved. Brain Res

Objective: This study tested the hypothesis that intra-amniotic iron treatment would enhance fetal red blood cell production after an acute, severe fetal hemorrhage of 40% of estimated blood volume over 2 hours. Study Design: Three groups of late-gestation ovine fetuses were studied for 10 days: (1) control fetuses (n = 8), (2) fetuses hemorrhaged on day 3 (n = 11), and (3) similarly hemorrhaged fetuses supplemented with a single bolus of 60 mg of iron injected intra-amniotically immediately after the hemorrhage (n = 7). Statistical analysis was by 3-factor analysis of variance. Results: At 24 hours after hemorrhage, red blood cell mass increased 5% in the control group and was reduced equally in both hemorrhage groups by 32% below day 3 prehemorrhage values. At 7 days after hemorrhage, red blood cell mass increased 27.8% ± 2.6% (SE) above day 3 baseline values in the control fetuses. In the nonsupplemented hemorrhaged fetuses, red blood cell mass was not different from prehemorrhage values after 7 days (+3.7% ± 4.1%), whereas red blood cell mass increased by 29.9% ± 6.1% above prehemorrhage values in the iron-supplemented hemorrhage group ( P Conclusion: Intra-amniotic iron supplementation resulted in full restoration of red blood cell mass within 7 days after a large loss of blood in fetal sheep, whereas restoration failed without iron supplementation. Intra-amniotic iron treatment may be of therapeutic value in restoring red blood cell mass in human fetuses with certain types of anemia such as that resulting from fetal or fetomaternal hemorrhage. (Am J Obstet Gynecol 1999;180:214-20.)

Objectives The CHIPS Trial (ISRCTN 71416914, http://pre-empt.cfri.ca/CHIPS ) randomized women with non-severe pregnancy hypertension to a diastolic blood pressure (dBP) target of 100 mmHg [‘less tight’ (LT) control] vs. 85 mmHg [‘tight’ (T) control]. LT was associated with no perinatal benefit, but more severe maternal hypertension. Labetalol was the recommended post-randomization antihypertensive. We aimed to: (1) determine whether the difference in outcomes between LT vs. T control depended on antihypertensive used; and (2) compare pregnancy outcomes, taking into account allocated group, between women taking methyldopa and those taking labetalol, the two most commonly used antihypertensives in CHIPS. Methods Logistic regression was used for comparisons outlined in objectives (1) and (2). Both analyses adjusted for the influence of baseline factors, including use of any antihypertensive therapy at randomization. Results Of 987 women in CHIPS, labetalol (but not methyldopa) was taken by 433/837 women on antihypertensive therapy [186 (LT) vs. 247 (T)] and methyldopa (but not labetalol) by 223/837 [98 (LT) vs. 125 (T)]. Following adjustment: (1) ORs for outcomes in LT vs. T control were similar between antihypertensive groups, but (2) methyldopa use was associated with a reduction in some outcomes (Table). Additional sensitivity analyses had a trivial impact on results. Conclusions In this secondary analysis of CHIPS data, outcomes for LT vs. T control were not dependent on use of methyldopa or labetalol. The non-randomized comparisons between methyldopa and labetalol are subject to residual confounding, but there is no evidence that women treated with methyldopa (vs. labetalol) had inferior outcomes. Disclosures L.A. Magee: Research Support Recipient; Commercial Interest: BMGF. P. von Dadelszen: Consultant, Commercial Interest: Alere International. E. Rey: None. S. Ross: None. E. Asztalos: None. K.E. Murphy: None. J. Menzies: None. J. Sanchez: None. J. Singer: None. A. Gafni: None. A. Gruslin: None. M. Helewa: None. E. Hutton: None. S.K. Lee: None. A.G. Logan: None. W. Ganzevoort: None. R. Welch: None. J.G. Thornton: None. J. Moutquin: None.

Erythropoietin is one of the main regulators of haematopoiesis in the human and is being used more and more widely in the treatment of such clinical conditions as anaemia of chronic renal disease which would otherwise require transfusion. Recently, this approach has been extended to pregnant patients and the results have been encouraging. Fetal erythropoietin levels appear to be good indicators of anaemia and hypoxia which, if detected, allow for the identification of compromised fetuses. More data are emerging pointing to erythropoietin's role in fetal central nervous system development and its potential protective role against hypoxia. This carries important implications for the obstetrician/gynaecologist, as erythropoietin is likely to play a major part in the diagnosis and treatment of certain maternal and fetal conditions.

Because maternal antenatal steroid administration has been shown to improve neonatal outcome at gestational age Jess then 34 weeks, many obstetrical practitioners choose to use tocolytic agents in an attempt to delay premature delivery and, thereby, allow enough time for steroid treatment. Unfortunately, tocolytics are not without potentially serious side effects for both mother and fetus. Our objective was to review the complications associated with various tocolytic agents and describe their management.

Our objective was to discuss the role of erythropoietin in fetal erythropoiesis and to review its clinical uses in perinatal medicine. All relevant articles compiled through a MEDLINE search (years 1986-1997) were reviewed. Erythropoietin is essential for fetal erythropoiesis and is produced in response to hypoxia and anemia. Cord blood erythropoietin is purely fetal and reflects tissue oxygenation. It has been found to be increased in many complicated pregnancies with underlying fetal hypoxia. Erythropoietin could be used as a marker of fetal hypoxia because its concentration rises rapidly by increased production in response to hypoxia. Its measurement might enable more accurate timing of hypoxic injury. In addition, erythropoietin levels have been well correlated with perinatal brain damage and may facilitate treatment of high risk neonates. Erythropoietin has also been used successfully in anemia of prematurity, decreasing the transfusion requirement. However, studies are still needed to determine the optimal doses of erythropoietin and iron supplementations required for maximizing the red blood cell response. Erythropoietin has been examined as potential maternal therapy in various disorders during pregnancy. These include end-stage renal disease, severe antepartum iron deficiency anemia, and postpartum anemia. Erythropoietin has been found to be effective and well tolerated in these conditions. An additional promising use lies in the optimization of maternal red blood cell mass to allow autologous blood donation. This may be critical in cases where a large amount of bleeding might be anticipated, as with placenta previa. This would also minimize the donor transfusion-related hazards. Erythropoietin with its wide clinical applications could improve maternal and neonatal outcome.

Alcohol abuse in pregnancy represents a major social, psychological and medical problem with serious consequences for both mother and fetus. Even though its prevalence is noted increasingly in our population, it remains difficult to diagnose, given the patients' barriers and our own. Pregnancy offers a unique opportunity to overcome these barriers. By integrating validated screening questionnaires into routine antenatal care, the obstetrical care provider can identify the abusing patient and immediately initiate referrals and treatment. These patients are at risk for physical and mental abuse as well as depressive illnesses which usually require the expertise of a psychologist or psychiatrist. Their medical complications and their substance use disorders deserve the attention of an addiction specialist. Because of the serious fetal/neonatal effects, perinatologists and neonatologists are needed to assess potential birth defects, including growth restriction, and to provide appropriate care and follow-up after delivery. As alcohol abuse is the leading preventable cause of mental retardation and because maternal and fetal effects are so important, it is essential that obstetrical care providers become familiar with screening techniques and treatment options, and incorporate these into their routine prenatal assessments.

Objective: Our purpose was to determine whether the restoration of fetal red blood cell mass after acute hemorrhage of 40% of the fetal blood volume is related to fetal plasma iron concentration. Study Design: Ten chronically catheterized ovine fetuses were monitored for 10 days beginning at 125 ± 1 (SE) days of gestation. After a 3-day control period 40% of the fetal blood was removed over 2 hours at a rate of approximately 1 ml/min. Fetal plasma iron and erythropoietin concentrations, hematocrit, blood volume, and red blood cell mass were measured daily before and for 7 days after fetal hemorrhage. Statistical analysis was by analysis of variance, correlation, and regression. Results: Although blood volume was restored within 3 days of the hemorrhage (101.0% ± 1.4% of prehemorrhage volume), red blood cell mass was not (81.8% ± 2.8%). Only 6 of 10 fetuses restored their red blood cell mass to prehemorrhage levels by the end of the 7-day posthemorrhage period. On day 10 red blood cell mass correlated positively with prehemorrhage ( r = 0.74, p = 0.015) and posthemorrhage ( r = 0.69, p = 0.045) plasma iron concentration and negatively with posthemorrhage erythropoietin concentration ( r = –0.68, p = 0.047). Conclusion: Fetal plasma iron concentration is an important factor in restoration of fetal red blood cell mass after loss of blood. The negative correlation of erythropoietin concentration with posthemorrhagic red blood cell mass suggests that iron, not erythropoietin, may be the limiting factor in recovery from hemorrhage-induced anemia. Thus iron supplementation of the fetus may be of benefit in the treatment of some types of fetal anemia.

Maternal obesity is associated with an increased risk of a number of pregnancy complications, including fetal demise, which may be linked to impaired placental development as a result of altered trophoblast invasion and vessel remodeling. Therefore, we examined these parameters in pregnant rats fed a control (normal weight) or high fat (HF) diet (obese) at 2 critical times of rat placental development. Early trophoblast invasion was increased by approximately 2-fold in HF-fed dams with a concomitant increase in the expression of matrix metalloproteinase 9 protein, a mediator of tissue remodeling and invasion. Furthermore, we observed significantly higher levels of smooth muscle actin surrounding the placental spiral arteries of HF-fed dams, suggesting impaired spiral artery remodeling. Taken together, the results of this study suggest that altered placental development is an important contributor to the poor pregnancy outcomes and increased fetal demise in our model of lifelong maternal obesity.

Background. Serum lipids including total cholesterol (TC), triglycerides (TG), and low density lipoprotein cholesterol (LDL-C) are increased in pregnancy. Serum proprotein convertase subtilisin kexin 9 (PCSK9) is a significant player in lipoprotein metabolism. Circulating PCSK9 downregulates the LDL receptor on the surface of the liver, inhibiting clearance of LDL-C. Therefore, our study assessed serum PCSK9 concentrations at parturition (Maternal) compared to a nonpregnant (Control) cohort, as well as between mother and newborn (Maternal and Newborn). Methods. Blood was collected from women at parturition and from umbilical cords. Serum lipids and PCSK9 were measured and data were analysed for significance by Mann-Whitney U test at P<0.05 and presented as median levels. Spearman's correlations were made at a 95% confidence interval. Results. Serum PCSK9 was significantly higher in Maternal versus Control cohorts (493.1 versus 289.7 ng/mL; P<0.001, resp.), while the Newborn cohort was significantly lower than Maternal (278.2 versus 493.1 ng/mL; P<0.0001, resp.). PCSK9 was significantly correlated with TC and HDL-C in Maternal and with TC, LDL-C, and HDL-C in Newborn cohorts. Conclusions. Our study provides the first quantitative report on PCSK9 in pregnancy (at parturition) and in umbilical cord blood. Further research will determine how these changes may affect lipoprotein levels during this physiological state.

We evaluated referral patterns for the initial surgery in patients with suspected ovarian cancer and factors associated with that referral. Through a mailed survey we asked gynecologists: (i) to rate the importance of characteristics of the patient, the mass, the surgeon and the hospital on to their decision to operate on or to refer to a gynecologic oncologist a patient with a pelvic mass; (ii) to indicate whether they would operate on or refer five hypothetical patients with masses of increasing complexity; (iii) to estimate on what proportion of patients with suspected ovarian cancer in their practice they currently operate; and (iv) to estimate the residual tumor volume when they perform surgery for ovarian cancer. Gynecologists seeing fewer patients with suspected ovarian cancers, in a teaching vs community hospital, in full-time university vs private practice and working in specific geographical areas, referred more to an oncologist for the primary surgery. Not significant were the gender of the surgeon, number of years in practice and distance to a regional cancer center. A high probability of cancer and characteristics of the surgeon affected referral patterns.

Introduction: congenital intrahepatic portosystemic shunts are abnormal communications between hepatic and portal vessels. We present a case of antenatally diagnosed portohepatic shunt in intrauterine growth restricted (IUGr) fetus with cardiomegaly and transient fetal anemia. case report: A 37-yearold primiparous woman was referred in a late second trimester for fetal growth assessment. Ultrasound revealed IUGr fetus at 9th centile with brain spearing and forward end-diastolic flow in umbilical artery. Middle cerebral artery (McA) peak systolic velocity (PsV) Doppler was high for the gestational age, possibly representing fetal anemia. Fetal liver was enlarged with abnormal circulation consisting of tortuous dilated intrahepatic vessels originating from the umbilical vein and giving off several branches with no clear end point communication sites. Fetal echocardiography showed mild cardiomegaly with hyperdynamic flow state

Maternal floor infarction is a relatively rare condition characterized clinically by severe early onset fetal growth restriction with features of uteroplacental insufficiency. It has a very high recurrence rate and carries a significant risk or fetal demise. Pathological characteristics include massive and diffuse fibrin deposition along the decidua basalis and the perivillous space of the basal plate. We present a case of recurrent maternal floor infarction and propose diagnostic clues as well as potential therapeutic options.

The amniotic membrane (AM) and amniotic fluid (AF) have a long history of use in surgical and prenatal diagnostic applications, respectively. In addition, the discovery of cell populations in AM and AF which are widely accessible, nontumorigenic and capable of differentiating into a variety of cell types has stimulated a flurry of research aimed at characterizing the cells and evaluating their potential utility in regenerative medicine. While a major focus of research has been the use of amniotic membrane and fluid in tissue engineering and cell replacement, AM- and AF-derived cells may also have capabilities in protecting and stimulating the repair of injured tissues via paracrine actions, and acting as vectors for biodelivery of exogenous factors to treat injury and diseases. Much progress has been made since the discovery of AM and AF cells with stem cell characteristics nearly a decade ago, but there remain a number of problematic issues stemming from the inherent heterogeneity of these cells as well as inconsistencies in isolation and culturing methods which must be addressed to advance the field towards the development of cell-based therapies. Here, we provide an overview of the recent progress and future perspectives in the use of AM- and AF-derived cells for therapeutic applications.

Prenatal life is recognised as a critical period where vital physiological processes may be permanently transformed leading to altered susceptibility to disease risk later in life.1 Accordingly, fetal adaptive responses to the maternal milieu, including the in utero effect of a physically active pregnancy, may influence the long-term health and well-being of the developing child. Is there potentially lifelong significance of maternal exercise on fetal health? Although the recent study published in BJSM by Salvesen et al 2 is timely with respect to the fetal response to extreme levels of maternal exertion in competitive Olympic hopefuls, it has limited applicability to the maternal population at large who are mostly inactive.3 The latter may benefit the most from a physically active, healthful pregnancy. In their study examining fetal response and utero-placental blood flow during strenuous treadmill running in the second trimester, Salvesen et al 2 note that fetal HR was within the normal range as long as maternal exertion was below 90% maternal HRmax; an exercise intensity that few women would routinely work at, nor would be encouraged in a typical maternal population. If maternal HR exceeded 90% of maximum value and uterine artery blood flow was simultaneously less than 50% the initial value, fetal bradycardia occurred. However, despite these concerns, following exercise cessation fetal HR reached baseline values, uterine artery flow volume improved to resting values in most women and all birthweights were within the lower normal range for Norwegian children, which is encouraging. Salvasen and …

Fetal growth restriction (FGR) is a leading cause of perinatal mortality and morbidity. Animal studies suggest dysregulation of IGF-binding protein (IGFBP)-4 is significant in the development of FGR, although human data are lacking. We postulated that IGFBP-4 is expressed at the maternal fetal interface and plays a role in regulating IGF bioavailability. Thus, maternal serum levels of IGFBP-4 may be associated with complications of abnormal placental growth and development including FGR.Circulating levels of IGFBP-4 and its protease, pregnancy-associated plasma protein-A (PAPP-A), were examined in healthy pregnancies. Their expression in villi and bed as possible sources of the circulating products were examined by immunohistochemistry. From the large Ottawa and Kingston (OaK) Birth Cohort, a nested case-control study was conducted to examine circulating levels of IGBP-4, PAPP-A, IGF-I, and IGF-II by Western blot in early gestation in 36 women who went on to develop FGR and 36 controls having normal-weight babies.IGFBP-4 was elevated in early pregnancy compared with nonpregnant women and women in later pregnancy, consistent with the presence of abundant extravillous trophoblasts and decidual cells that highly expressed IGFBP-4. High expression of PAPP-A was observed in extravillous trophoblasts and decidual cells in early pregnancy but hardly detectable in the circulation at this time, suggesting maternal circulating PAPP-A originates more likely from syncytiotrophoblasts. Increased IGFBP-4 in the maternal circulation in early pregnancy was associated with the development of FGR [0.48 (0.28-0.74) in control vs. 1.22 (0.66-1.65) in FGR; odds ratio = 22 (95% confidence interval = 2.7-181)]. No difference was observed in circulating PAPP-A, IGF-I and IGF-II in the FGR vs. control group.Our findings support the role of IGFBP-4 in regulating IGF bioavailability and provide new clues for the prevention and treatment of FGR, raising the possibility of clinical use of IGFBP-4 as an early biomarker for this condition.

STUDY QUESTION Does maternal obesity affect insulin-like growth factor (IGF) axis protein expression patterns in maternal and cord blood? SUMMARY ANSWER Maternal obesity attenuates cord blood expression of IGF-binding protein (IGFBP)-4. WHAT IS KNOWN AND WHAT THIS PAPER ADDS The IGF axis plays a critical role in fetal growth and development. Maternal obesity compromises IGF axis protein expression in fetal circulation, which is consistent with the findings of epidemiological studies suggesting that maternal obesity has an independent effect on fetal growth signals during in utero development. STUDY DESIGN This cross-sectional case-control study involved 12 lean [body mass index (BMI) 18.5-24.9 kg/m2] and 12 obese (BMI≥30 kg/m2) women and their neonates at term. At the completion of the study, IGF axis protein expression and hormone concentrations in both maternal and cord blood were examined. PARTICIPANTS AND SETTING We obtained fasting serum samples from cases and controls matched for age, gestation, mode of delivery, parity and glucose tolerance prior to and immediately following elective caesarean section. The corresponding umbilical cord blood was also collected at birth. MAIN RESULTS AND THE ROLE OF CHANCE Between-group comparisons revealed elevated maternal insulin (P=0.03) and leptin (P

The usage of stem cells is a promising strategy for the repair of damaged tissue in the injured brain. Recently, amniotic fluid (AF) cells have received a lot of attention as an alternative source of stem cells for cell-based therapies. However, the success of this approach relies significantly on proper interactions between graft and host tissue. In particular, the reestablishment of functional brain networks requires formation of gap junctions, as a key step to provide sufficient intercellular communication. In this study, we show that AF cells express high levels of CX43 (GJA1) and are able to establish functional gap junctions with cortical cultures. Furthermore, we report an induction of Cx43 expression in astrocytes following injury to the mouse motor cortex and demonstrate for the first time CX43 expression at the interface between implanted AF cells and host brain cells. These findings suggest that CX43-mediated intercellular communication between AF cells and cortical astrocytes may contribute to the reconstruction of damaged tissue by mediating modulatory, homeostatic, and protective factors in the injured brain and hence warrants further investigation. © 2012 Anna Jezierski et al.

Objective To examine the ability of three different proteinuria assessment methods (urinary dipstick, spot urine protein:creatinine ratio [Pr/Cr], and 24-hour urine collection) to predict adverse pregnancy outcomes. Methods We performed a prospective multicentre cohort study, PIERS (Preeclampsia Integrated Estimate of RiSk), in seven academic tertiary maternity centres practising expectant management of preeclampsia remote from term in Canada, New Zealand, and Australia. Eligible women were those admitted with preeclampsia who had at least one antenatal proteinuria assessment by urinary dipstick, spot urine Pr/Cr ratio, and/or 24-hour urine collection. Proteinuria assessment was done either visually at the bedside (by dipstick) or by hospital clinical laboratories for spot urine Pr/Cr and 24-hour urine collection. We calculated receiver operating characteristic area under the curve (95% CI) for each proteinuria method and each of the combined adverse maternal outcomes (within 48 hours) or adverse perinatal outcomes (at any time). Models with AUC ≥ 0.70 were considered of interest. Analyses were run for all women who had each type of proteinuria assessment and for a cohort of women ("ALL measures") who had all three proteinuria assessments. Results More women were proteinuric by urinary dipstick (≥ 2+, 61.4%) than by spot urine Pr/Cr (≥ 30g/mol, 50.4%) or 24-hour urine collection (≥ 0.3g/d, 34.7%). Each proteinuria measure evaluated had some discriminative power, and dipstick proteinuria (categorical) performed as well as other methods. No single method was predictive of adverse perinatal outcome. Conclusion The measured amount of proteinuria should not be used in isolation for decision-making in women with preeclampsia. Dipstick proteinuria performs as well as other methods of assessing proteinuria for prediction of adverse events.

Sildenafil citrate therapy for severe early-onset intrauterine growth restriction. BJOG 2011;118:624-628. Currently, there is no effective therapy for severe early-onset intrauterine growth restriction (IUGR). Sildenafil citrate vasodilates the myometrial arteries isolated from women with IUGR-complicated pregnancies. Women were offered Sildenafil (25 mg three times daily until delivery) if their pregnancy was complicated by early-onset IUGR [abdominal circumference (AC)5th percentile] and either the gestational age was25(+0) weeks or an estimate of the fetal weight was600 g (excluding known fetal anomaly/syndrome and/or planned termination). Sildenafil treatment was associated with increased fetal AC growth [odds ratio, 12.9; 95% confidence interval (CI), 1.3, 126; compared with institutional Sildenafil-naive early-onset IUGR controls]. Randomised controlled trial data are required to determine whether Sildenafil improves perinatal outcomes for early-onset IUGR-complicated pregnancies.

NUMB is a multifunctional protein involved in asymmetric cell differentiation, proliferation and maintenance. Four mammalian NUMB isoforms have been identified, which utilize the phosphotyrosine binding (PTB) domain and the proline rich region (PRR) domain to regulate cell growth and differentiation in the developing nervous system. The observation that a decrease in spongiotrophoblast number and thickness of placentae of null ( Numb −/− ) mouse embryos, which died at E10.5, suggests NUMB may play a role in placental development. In this study, we demonstrated for the first time, that NUMB isoforms 1, 2, 3, and 4 are present in the human placenta and the human extravillous trophoblast (EVT) cell line HTR8/SVneo. We report three novel isoforms, NUMB 7, 8, and 9, identified by cloning of RT-PCR products and sequencing. Corresponding sequences of novel isoforms were submitted to genebank (accession numbers for each new isoform: NUMB 7- EU265736, NUMB 8- EU265737 and NUMB 9-EU265738). Western blot analysis confirmed the presence of all NUMB isofoms in human placental samples in all trimesters and in EVT cells. NUMB immunosignals were extensively localized in human extravillous trophoblasts and decidual cells at the maternal–fetal interface. NUMB 8 appeared to be the predominant isoform in placental villi. Furthermore, cell migration studies revealed NUMB isoform 1 to be involved in EVT cell migration and NUMB isoforms 2 and 4 to induce EVT apoptosis.

Intrauterine growth restriction (IUGR) and preeclampsia (PE) are leading causes of perinatal and maternal morbidity and mortality. Many studies have found association between low levels of insulin-like growth factor binding protein (IGFBP) proteases in the first trimester maternal circulation and the risk of subsequent development of PE and/or IUGR. These results are generally interpreted to reflect decreased production of the proteases by the placenta, leading to reduced proteolysis of IGFBPs and lower free levels of insulin-like growth factor (IGF), resulting in diminished feto-placental development. However, the association between low circulating levels of placental proteins early in pregnancy and the subsequent development of IUGR and/or PE could be due to low exchange in the placenta and not due to reduced production. In contrast, late in pregnancy, the circulating levels of these proteins and their expression in the placenta are often elevated in PE, which may reflect upregulation to compensate for abnormal placental development, that is an adaptive mechanism to increase IGFBP proteolysis, increase local IGF levels and promote feto-placental growth. Further research into the biological mechanisms underlying these associations will aid the identification of high-risk pregnancies and the development of therapeutic targets for diseases for which there are presently no preventative measures.

Recently, human amniotic fluid (AF) cells have attracted a great deal of attention as an alternative cell source for transplantation and tissue engineering. AF contains a variety of cell types derived from fetal tissues, of which a small percentage is believed to represent stem cell sub-population(s). In contrast to human embryonic stem (ES) cells, AF cells are not subject to extensive legal or ethical considerations; nor are they limited by lineage commitment characteristic of adult stem cells. However, to become therapeutically valuable, better protocols for the isolation of AF stem cell sub-populations need to be developed. This study was designed to examine the molecular components involved in self-renewal, neural commitment and differentiation of AF cells obtained at different gestational ages. Our results showed that, although morphologically heterogeneous, AF cells derived from early gestational periods ubiquitously expressed KERATIN 8 (K8), suggesting that the majority of these cells may have an epithelial origin. In addition, AF cells expressed various components of NOTCH signaling (ligands, receptors and target genes), a pathway involved in stem cell maintenance, determination and differentiation. A sub-population of K8 positive cells (

This study presents the results of bypass grafting in 96 patients operated on for triple-vessel coronary artery disease between May 1988 and September 1990. In the first 54 patients a cold crystalloid solution was employed, and in the 42 more recent patients cold blood low-potassium cardioplegia was employed. There were no differences in postoperative cardiac index or left ventricular stroke work index. Yet, in patients with impaired prebypass left ventricular stroke work index, postbypass left ventricular performance correlated negatively with duration of aortic cross-clamping in the cold crystalloid group (r = -0.441, p = 0.045). In contrast, no correlation was found in the cold blood low-potassium group (r = 0.125, p = 0.587). The incidence of myocardial infarction, need for inotropic support, and need for intraaortic balloon counterpulsation were similar among the groups. Release of the myocardial isoenzyme creatine kinase-MB from 12 to 30 hours after operation was significantly less in the low-potassium blood cardioplegia group. The use of low-potassium blood cardioplegia resulted in a marked reduction in the operative administration of fluids (1,527 +/- 87 versus 3,511 +/- 148 mL; p less than 0.001). In conclusion, low-potassium cold blood cardioplegia is a simple and effective method of myocardial protection. The fact that left ventricular stroke work index recovery was not dependent on the duration of aortic occlusion and that release of the MB isoenzyme of creatine kinase was reduced in the low-potassium blood cardioplegia group implies better myocardial protection.

IGF-II plays an important role in physiological and pathological processes involved in growth and metabolism. Despite the fact that "big" IGF-IIs, IGF-II(1–87) and IGF-II(1–104), have been identified in the circulation for decades in addition to "mature" IGF-II, the biological properties of these "big" IGF-IIs and the mechanisms regulating their bioavailability have not been fully elucidated. In this study we demonstrated that IGF - II (1–87), as an abundant "big" IGF-II form, exists at a molar ratio of 0.24 (CI 0.13–0.62) with respect to mature IGF-II in the normal human circulation. Mature and "big" IGF-II can equally form complexes with IGFBP-2 and IGFBP-3 in vitro , resulting in the inhibition of IGF-II's biological function. However, under physiological conditions which entails the presence of both "big" and mature IGF-II, "big" IGF-IIs preferably formed complexes with IGFBP-3 but not IGFBP-2, unlike mature IGF-II which was equally associated with both IGFBP-3 and IGFBP-2. "Big" IGF-II binding to IGFBP-2 was only evident when the "big"/mature IGF-II ratio approached 1 or higher. We concluded that mature IGF-II prevents the formation of "big" IGF-II/IGFBP-2 complex in the circulation of healthy human controls. This finding suggests the presence of previously unknown mechanisms in the regulation of IGF-II bioavailability. Elevation of the ratio of "big" to mature IGF-II in the circulation may result in altered bioavailability of "big" IGF-IIs. This mechanism is relevant in pathological conditions such as Non-Islet Cell Tumor-induced Hypoglycemia (NICTH) and Hepatitis C-associated Osteosclerosis (HCAO), in which "big" IGF-II(1–87) and IGF-II(1–104) are significantly elevated.

OBJECTIVE To review the evidence and provide recommendations on immunization in pregnancy. OUTCOMES Outcomes evaluated include effectiveness of immunization, and risks and benefits for mother and fetus. EVIDENCE The Medline and Cochrane databases were searched for articles published up to June 2007 on the topic of immunization in pregnancy. VALUES The evidence obtained was reviewed and evaluated by the Infectious Diseases Committee of the Society of Obstetricians and Gynaecologists of Canada (SOGC) under the leadership of the principal authors, and recommendations were made according to guidelines developed by the Canadian Task Force on Preventive Health Care. BENEFITS, HARMS, AND COSTS Implementation of the recommendations in this guideline should result in more appropriate immunization of pregnant and breastfeeding women, decreased risk of contraindicated immunization, and better disease prevention.

To review the evidence and provide recommendations on immunization in pregnancy.Outcomes evaluated include effectiveness of immunization, risks and benefits for mother and fetus.The Medline and Cochrane databases were searched for articles published up to June 2008 on the topic of immunization in pregnancy.The evidence obtained was reviewed and evaluated by the Infectious Diseases Committee of the Society of Obstetricians and Gynaecologists of Canada (SOGC) under the leadership of the principal authors, and recommendations were made according to guidelines developed by the Canadian Task Force on Preventive Health Care.Implementation of the recommendations in this guideline should result in more appropriate immunization of pregnant and breastfeeding women, decreased risk of contraindicated immunization, and better disease prevention.The quality of evidence reported in this document has been assessed using the evaluation of evidence criteria in the Report of the Canadian Task Force on Preventive Health Care (Table 1). (1) All women of childbearing age should be evaluated for the possibility of pregnancy before immunization. (III-A). (2) Health care providers should obtain a relevant immunization history from all women accessing prenatal care. (III-A). (3) In general, live and/or live-attenuated virus vaccines should not be administered during pregnancy, as there is a, largely theoretical, risk to the fetus. (II-3B). (4) Women who have inadvertently received immunization with live or live-attenuated vaccines during pregnancy should not be counselled to terminate the pregnancy because of a teratogenic risk. (II-2A). (5) Non-pregnant women immunized with a live or live-attenuated vaccine should be counselled to delay pregnancy for at least four weeks. (III-B). (6) Inactivated viral vaccines, bacterial vaccines, and toxoids can be used safely in pregnancy. (II-1A). (7) Women who are breastfeeding can still be immunized (passive-active immunization, live or killed vaccines). (II-1A) (8) Pregnant women should be offered the influenza vaccine (including H1N1 vaccine, when it is available) when they are pregnant during the influenza season. (II-1A). (9) Pregnant women with suspected or documented H1N1 infection should be treated with oseltamivir (Tamiflu, 75 mg twice daily for 5 days) within 48 hours of onset of symptoms. (III-B).

Objective: This guideline summarizes the quality of the evidence to date and provides a reasonable approach to the diagnosis, evaluation, and treatment of the hypertensive disorders of pregnancy (HDP). Evidence: The literature reviewed included the original HDP guidelines and their reference lists and an update from 1995. Using key words, Medline was searched for literature published between 1995 and 2007. Articles were restricted to those published in French or English. Recommendations were evaluated using the criteria of the Canadian Task Force on Preventive Health Care (Table 1).

To review the evidence and provide recommendations on screening for and management of bacterial vaginosis in pregnancy.The clinical practice options considered in formulating the guideline.Outcomes evaluated include antibiotic treatment efficacy and cure rates, and the influence of the treatment of bacterial vaginosis on the rates of adverse pregnancy outcomes such as preterm labour and delivery and preterm premature rupture of membranes.Medline, EMBASE, CINAHL, and Cochrane databases were searched for articles, published in English before the end of June 2007 on the topic of bacterial vaginosis in pregnancy.The evidence obtained was rated using the criteria developed by the Canadian Task Force on Preventive Health Care.Guideline implementation will assist the practitioner in developing an approach to the diagnosis and treatment of bacterial vaginosis in pregnant women. Patients will benefit from appropriate management of this condition.These guidelines have been prepared by the Infectious Diseases Committee of the SOGC, and approved by the Executive and Council of the SOGC.The Society of Obstetricians and Gynaecologists of Canada.

Objective To review the effects of obesity on reproduction and pregnancy outcome. Methods A search of the literature was performed using key word searching and citation snowballing to identify English language articles published between January 1, 2000, and December 31, 2006, on the subject of obesity and its effects on pregnancy. Once the articles were identified, a thorough review of all results was conducted. Results and conclusions were compiled and summarized. Results Obesity during pregnancy was linked with maternal complications ranging from effects on fertility to effects on delivery and in the postpartum period, as well as many complications affecting the fetus and newborn. The maternal complications associated with obesity included increased risks of infertility, hypertensive disorders, gestational diabetes mellitus, and delivery by Caesarean section. Fetal complications included increased risks of macrosomia, intrauterine fetal death and stillbirth, and admission to the neonatal intensive care unit. Conclusion Obesity causes significant complications for the mother and fetus. Interventions directed towards weight loss and prevention of excessive weight gain must begin in the pre-conception period. Obstetrical care providers must counsel their obese patients regarding the risks and complications conferred by obesity and the importance of weight loss. Maternal and fetal surveillance may need to be heightened during pregnancy; a multidisciplinary approach is useful. Women need to be informed about both maternal and fetal complications and about the measures that are necessary to optimize outcome, but the most important measure is to address the issue of weight prior to pregnancy.

Objective To provide a teratology update for prescription and non-prescription drugs and infections during pregnancy. Options Limited to teratology principles and possible common exposures during pregnancy. Evidence A search of Medline and textbooks was conducted for information published to June 2006 on teratology exposure risks. This document represents an abstraction of the information. Benefits, Harms, and Costs This consensus provides practitioners with a summary of information regarding teratology risks for drug, chemical, and infection exposures during pregnancy.

The process of posttranslational modifications of IGF-II likely has important physiological consequences. In addition to mature IGF-II, glycosylated proIGF-II(156-amino acid peptide) and two glycosylated big IGF-II forms, IGF-II(1-104) and IGF-II(1-87), have been identified in the human circulation. Due to lack of an appropriate methodology, different IGF-II isoforms have not been demonstrated and characterized in the rat circulation, thus preventing a better understanding of the physiological and pathological roles of IGF-II. In the present study, we characterized each IGF-II form and assessed its content in the rat circulation throughout life time by using a highly sensitive Western blot analysis, which is void of the IGF binding protein interference and distinguished all IGF-II forms. For the first time, we demonstrated the presence of IGF-II variants, including proIGF-II, IGF-II(1-87), and mature IGF-II, in the rat circulation during postnatal life, challenging the current impression that IGF-II is absent from sera of adult rats. ProIGF-II is glycosylated and is the predominant form in the rat circulation. Endoproteolytic processing of proIGF-II was clearly activated in fetal, neonatal, and pregnant rats, likely reflecting its involvement in fetal development through the generation of specific forms of IGF-II (e.g. mature IGF-II) that are required for their distinct biological functions. Taken together, our data also suggest that serum IGF-II profiles may reflect underlying physiological conditions.

Objective To determine whether ‘less tight’ (versus ‘tight’) control of nonsevere hypertension results in a difference in diastolic blood pressure (dBP) between groups. Design Randomised controlled trial (ISRCTN#57277508). Setting Seventeen obstetric centres in Canada, Australia, New Zealand, and UK. Population Inclusion: pregnant women, dBP 90–109 mmHg, pre-existing/gestational hypertension; live fetus(es); and 20–33+6 weeks. Exclusion: systolic blood pressure ≥ 170 mmHg and proteinuria, contraindication, or major fetal anomaly. Methods Randomisation to less tight (target dBP, 100 mmHg) or tight (target dBP, 85 mmHg) blood pressure control. Main outcome measures Primary: mean dBP at 28, 32 and 36 weeks. Secondary: clinician compliance and women’s satisfaction. Other: serious perinatal and maternal complications. Results A total of 132 women were randomised to less tight (n= 66; seven had no study visit) or tight control (n= 66; one was lost to follow up; seven had no study visit). Mean dBP was significantly lower with tight control: −3.5 mmHg, 95% credible interval (−6.4, −0.6). Clinician compliance was 79% in both groups. Women were satisfied with their care. With less tight (versus tight) control, the rates of other treatments and outcomes were the following: post-randomisation antenatal antihypertensive medication use: 46 (69.7%) versus 58 (89.2%), severe hypertension: 38 (57.6%) versus 26 (40.0%), proteinuria: 16 (24.2%) versus 20 (30.8%), serious maternal complications: 3 (4.6%) versus 2 (3.1%), preterm birth: 24 (36.4%) versus 26 (40.0%), birthweight: 2675 ± 858 versus 2501 ± 855 g, neonatal intensive care unit (NICU) admission: 15 (22.7%) versus 22 (34.4%), and serious perinatal complications: 9 (13.6%) versus 14 (21.5%). Conclusion The CHIPS pilot trial confirms the feasibility and importance of a large definitive trial to determine the effects of less tight control on serious perinatal and maternal complications.