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Worldwide, post-partum haemorrhage (PHH) remains one of the leading causes for maternal mortality. The German Society of Gynaecology and Obstetrics, the German Midwifes' Society, the German Society of Thrombosis and Haemostasis and the German Society of Anaesthesiology and Intensive Care updated the former guideline. The resulting recommendations are the results of a structured literature search and a formal consensus process and contain all aspects of PPH including diagnosis, causes, risk factors and therapy. Key aspect of the anaesthesiological and haemostatic therapies is the development of an interdisciplinary standard operating procedure containing medical options related to the bleeding's cause and severity as well as the surgical option. For suspected PPH, this guideline emphasizes clinical and laboratory-based diagnostics, as only those will enable an early identification of the bleeding's causes and the resulting causative therapy. Recommendations cover evidence-based application of uterotonics for atony as well as tranexamic acid, calcium, factor concentrates and blood products. Additionally, recommendations are given on the topics of cell salvage, controlled hypotension and restrictive transfusion triggers., (© Georg Thieme Verlag Stuttgart · New York.)

Question: Detection and treatment of infections during pregnancy are important for both maternal and child health. The objective of this study was to describe testing practices and adherence to current national guidelines in Switzerland., Methods: We invited all registered practicing obstetricians and gynaecologists in Switzerland to complete an anonymous web-based questionnaire about strategies for testing for 14 infections during pregnancy. We conducted a descriptive analysis according to demographic characteristics., Results: Of 1138 invited clinicians, 537 (47.2%) responded and 520 (45.6%) were eligible as they are currently caring for pregnant women. Nearly all eligible respondents tested all pregnant women for group B streptococcus (98.0%), hepatitis B virus (HBV) (96.5%) and human immunodeficiency virus (HIV) (94.7%), in accordance with national guidelines. Although testing for toxoplasmosis is not recommended, 24.1% of respondents tested all women and 32.9% tested at the request of the patient. Hospital doctors were more likely not to test for toxoplasmosis than doctors working in private practice (odds ratio [OR] 2.52, 95% confidence interval [CI] 1.04-6.13, p = 0.04). Only 80.4% of respondents tested all women for syphilis. There were regional differences in testing for some infections. The proportion of clinicians testing all women for HIV, HBV and syphilis was lower in Eastern Switzerland and the Zurich region (69.4% and 61.2%, respectively) than in other regions (range 77.1-88.1%, p <0.001). Most respondents (74.5%) said they would appreciate national guidelines about testing for infections during pregnancy., Conclusions: Testing practices for infections in pregnant women vary widely in Switzerland. More extensive national guidelines could improve consistency of testing practices.

Aldosterone is an important factor supporting placental growth and fetal development. Recently, expression of placental growth factor (PlGF) has been observed in response to aldosterone exposure in different models of atherosclerosis. Thus, we hypothesized that aldosterone up-regulates growth-adaptive angiogenesis in pregnancy, via increased placental PlGF expression. We followed normotensive pregnant women (n = 24) throughout pregnancy and confirmed these results in a second independent first trimester cohort (n = 36). Urinary tetrahydroaldosterone was measured by gas chromatography-mass spectrometry and corrected for creatinine. Circulating PlGF concentrations were determined by ELISA. Additionally, cultured cell lines, adrenocortical H295R and choriocarcinoma BeWo cells, as well as primary human third trimester trophoblasts were tested in vitro. PlGF serum concentrations positively correlated with urinary tetrahydroaldosterone corrected for creatinine in these two independent cohorts. This observation was not due to PlGF, which did not induce aldosterone production in cultured H295R cells. On the other hand, PlGF expression was specifically enhanced by aldosterone in the presence of forskolin (p < 0.01) in trophoblasts. A pronounced stimulation of PlGF expression was observed with reduced glucose concentrations simulating starvation (p < 0.001). In conclusion, aldosterone stimulates placental PlGF production, enhancing its availability during human pregnancy, a response amplified by reduced glucose supply. Given the crucial role of PlGF in maintaining a healthy pregnancy, these data support a key role of aldosterone for a healthy pregnancy outcome., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Background: During pregnancy, many patients with rheumatoid arthritis (RA) experience disease improvement, whereas patients with ankylosing spondylitis often suffer from persistent active disease. Here we investigated whether pregnancy-related changes in disease activity were associated with changes in the proportion and function of γδT cells., Methods: The study population comprised 55 patients with RA, 31 patients with ankylosing spondylitis, and 35 healthy controls. Among these participants, 28 RA patients, 21 ankylosing spondylitis patients, and 23 healthy controls were investigated once before conception when possible, at each trimester of pregnancy, and at 8 weeks postpartum. Data were compared with age-matched non-pregnant patients to obtain disease-related background. In all subjects, peripheral Vδ1 and Vδ2 T cells were analyzed for cell frequencies, the activation marker CD69, the cytotoxicity markers NKG2D and NKG2A, and the intracellular cytokines tumor necrosis factor (TNF)α, interferon (IFN)γ, interleukin (IL)-17 and IL-10., Results: Pregnant patients showed a decreased Vδ2/Vδ1 ratio in the third trimester, which resulted from a slightly reduced proportion of Vδ2 cells. Changes in RA disease activity during pregnancy and postpartum were not associated with numerical proportions of γδT cells but with changes of the cell activation marker CD69 on Vδ1 and Vδ2 cells. Only RA patients showed reduced proportions of TNFα-positive Vδ1and Vδ2 cells and IFNγ-positive Vδ2 cells at the third trimester of pregnancy, a finding that was not apparent in the entire population of CD3 T cells. The proportions of IL-17-positive γδT cells and IL-10-positive γδT cells did not differ between pregnant and non-pregnant women of the different groups., Conclusions: Changes of disease activity in pregnant RA patients were associated with functional changes in both γδT cell subsets. This reduced pro-inflammatory profile of γδT cells might contribute to the immunomodulation resulting in pregnancy-induced improvement of RA.

Objective: The aim of this study was first to assess whether first-trimester serum concentrations of placental growth factor (PlGF) differ between patients with and without gestational diabetes (GDM) and second to test whether there is a correlation between glycosylated hemoglobin (HbA1c), a factor recently shown to be useful in predicting GDM, and PlGF., Methods: PlGF was measured at 8-14 weeks with the Kryptor Immunoassay Analyzer (Brahms, Berlin, Germany). Absolute values were converted to multiples of the median using the software provided by the Fetal Medicine Foundation London. GDM was diagnosed using internationally accepted criteria. HbA1c levels were quantified using the TOSOH G7 automated hemoglobin analyzer., Results: From January to December 2014, 328 women were included in the study, 51 (15.5%) of whom developed GDM. First-trimester PlGF quantification does not discriminate between women at risk to develop GDM and controls, while HbA1c is able to do so. No correlation was found between PlGF and HbA1c., Conclusion: Our findings do not lend support to the hypothesis that early PlGF values are different in women who later develop GDM., (© 2015 S. Karger AG, Basel.)

Introduction: Our aim was to investigate the prognostic value of first-trimester glycosylated hemoglobin (HbA1c) in pregnant women with risk factors for developing gestational diabetes mellitus (GDM)., Material and Methods: This is an observational retrospective cohort study conducted at the Department of Obstetrics and Gynecology, University Hospital Bern, Switzerland. We included pregnant women at high risk for GDM (n = 208), who had an HbA1c measurement in the first trimester. We compared HbA1c values of women who later developed GDM with those who did not develop GDM. Diagnosis of GDM was made on the basis of a 75-g oral glucose tolerance test performed between 24 and 28 weeks of gestation. We further examined the prevalence of GDM in relation to the first-trimester HbA1c value., Results: The prevalence of GDM in our high-risk group was 14.7%. Women who developed GDM had significantly higher first-trimester HbA1c values [5.43 ± 0.31% (36 ± 3 mmol/mol) vs. 5.23 ± 0.28% (34 ± 3 mmol/mol); p = 0.0026]. Moreover, all pregnant women with HbA1c ≥ 6.0% (42 mmol/mol) developed GDM, whereas those with < 4.5% (26 mmol/mol) did not., Conclusions: Women at risk for GDM have higher first-trimester HbA1c levels and values ≥ 6.0% (42 mmol/mol) are predictive of GDM. This information may be useful for counseling these women and providing appropriate advice on diet and lifestyle modification early in pregnancy., (© 2015 Nordic Federation of Societies of Obstetrics and Gynecology.)

Background: Normal pregnancy depends on pronounced adaptations in steroid hormone concentrations. Although in recent years, the understanding of these hormones in pregnancy has improved, the interpretation is hampered by insufficient reference values. Our aim was to establish gestation-specific reference intervals for spot urinary steroid hormone levels in normal singleton pregnancies and 6 weeks postpartum., Methods: Cross-sectional multicentre observational study. Women recruited between 2008 and 2013 at 3 University Hospitals in Switzerland (Bern), Scotland (Glasgow) and Austria (Graz). Spot urine was collected from healthy women undergoing a normal pregnancy (age, 16-45 years; mean, 31 years) attending routine antenatal clinics at gestation weeks 11, 20, and 28 and approximately 6 weeks postpartum. Urine steroid hormone levels were analysed using gas-chromatography mass spectrometry. Creatinine was also measured by routine analysis and used for normalisation., Results: From the results, a reference interval was calculated for each hormone metabolite at each trimester and 6 weeks postpartum. Changes in these concentrations between trimesters and postpartum were also observed for several steroid hormones and followed changes proposed for index steroid hormones., Conclusions: Normal gestation-specific reference values for spot urinary steroid hormones throughout pregnancy and early postpartum are now available to facilitate clinical management and research approaches to steroid hormone metabolism in pregnancy and the early postpartum period.

Problem: Given the important role of regulatory T cells (Treg) for successful pregnancy, the ability of soluble maternal and fetal pregnancy factors to induce human Treg was investigated., Method of Study: Peripheral blood mononuclear cells (PBMCs) or isolated CD4+CD25‒ cells were cultured in the presence of pooled second or third trimester pregnancy sera, steroid hormones or supernatants from placental explants, and the numbers and function of induced CD4+CD25+FOXP3+ Treg were analysed., Results: Third trimester pregnancy sera and supernatants of early placental explants, but not sex steroid hormones, induced an increase of Tregs from PBMCs. Early placental supernatant containing high levels of tumour necrosis factor-α, interferon-γ, interleukins -1, -6 and -17, soluble human leucocyte antigen-G, and transforming growth factor-β1, increased the proportion of Treg most effectively and was able to induce interleukin-10-secreting-Treg from CD4+CD25‒cells., Conclusions: Compared with circulating maternal factors, placental- and fetal-derived factors appear to exert a more powerful effect on numerical changes of Treg, thereby supporting fetomaternal tolerance during human pregnancy.

Question Under Study: The epidemiology of preeclampsia in Switzerland is known only from a retrospective registry study. This analysis aimed to prospectively determine the incidence of preeclampsia in a cohort of pregnant women in Switzerland., Methods: Pregnant women presenting at gestational week 11-14 at their obstetrician's office were consecutively included and prospectively followed-up until the end of pregnancy. Ultrasound characteristics, blood pressure measurements, body mass index, and personal history were recorded. Duration of pregnancy, occurrence of preeclampsia, birth weight and Apgar scores were recorded as outcomes., Results: There were 1,300 pregnancies with follow-up available for analysis. Median age was 30 years (interquartile range [IQR] 27-33), median body mass index (BMI) 23.3 kg/m² (IQR 21.2-26.1), median systolic blood pressure 117 mm Hg (IQR 109-126) and median diastolic blood pressure 70 mm Hg (IQR 64-77). A total of 30 women developed preeclampsia, corresponding to an incidence of 2.31% (95% confidence interval [CI] 1.62%-3.28%). Of the women with preeclampsia, 6.66% (95% CI 2.04%-21.42%) had early-onset preeclampsia, 13.33% (95% CI 5.45%-29.83%) progressed to eclampsia, whereas 10% (95% CI 3.63%-28.75%) developed HELLP syndrome (haemolysis, elevated liver enzymes, low platelet count). Nulliparity and prior history of preeclampsia were more frequently seen in pregnancies with preeclampsia than in pregnancies without preeclampsia. BMI, as well as systolic and diastolic blood pressure were higher in pregnancies subsequently developing preeclampsia., Conclusion: The incidence of preeclampsia in Switzerland is in line with frequencies observed elsewhere in the world. Extrapolation to a national level indicates that about 1,911 (range 1,340-2,713) preeclampsia cases per year can be expected to occur in Switzerland.

Objectives: To evaluate possible differences in periodontal inflammatory, microbiological and clinical parameters between women with preterm premature rupture of membranes (PPROM) and controls with uncomplicated pregnancies., Materials and Methods: Fifty-six women (32 test (PPROM) and 24 controls (uncomplicated pregnancies)) were examined at three time-points (T1: gestational weeks 20-35, T2: within 48 h after parturition, T3: 4-6 weeks after parturition). The examinations included assessment of the Periodontal Screening Index, collection of gingival crevicular fluid (GCF) and subgingival as well as vaginal bacterial sampling., Results: Periodontal inflammation was found to be higher in the test compared with the control group (p < 0.05) and decreased over time in both groups (p < 0.05). Microbiological outcomes showed no intergroup differences (p > 0.05) in prevalence of bacteria, but a decrease in subgingival periodontopathogens from T1 to T2 in the test group (p < 0.05) was observed. Interleukin (IL)-1β levels in GCF at T2 were not different between groups (p > 0.05). In women with PPROM, GCF levels of IL-8 (p < 0.05) and C-reactive protein (p < 0.05) were lower and IL-10 levels higher (p < 0.05) compared with controls., Conclusions: Periodontal inflammation is elevated during pregnancy and seems to be more pronounced in women with PPROM., Clinical Relevance: The findings of the present study revealed an association between periodontal inflammation and PPROM, thus emphasizing the importance of optimizing self-performed oral hygiene in pregnant women.

Caesarean section is one of the most frequently performed operations in human medicine. It has become a routine procedure with a very low morbidity and mortality. Over the centuries, it has emerged an essential achievement in obstetric medicine. In the presence of cephalo-pelvic-disproportion, cervical dystocia, malpresentation, preterm birth, macrosomia, placental insufficiency, placenta praevia or fetal distress it is crucial to improve the perinatal morbiditiy and mortality of mother and child. The procedure has become much more frequent over the past 20 years for multiple reasons. There is variety in incidence between countries but also regional differences. It's occurrence is being influenced by level of education and socio-economic status of the pregnant woman. In the meantime, also the longterm consequences of cesarean section are well known. The potential hazards for future pregnancies and deliveries are well described. Actual controversy addresses cesarean section on demand without any medical indication, which in fact is only seldom performed in Switzerland. The ethical justification of this procedure needs to be discussed in view of the current tendency towards autonomy and self-determination of the pregnant woman.

Dysfunction and loss of neurons are the major characteristics of CNS disorders that include stroke, multiple sclerosis, and Alzheimer's disease. Activation of the Toll-like receptor 7 by extracellular microRNA let-7, a highly expressed microRNA in the CNS, induces neuronal cell death. Let-7 released from injured neurons and immune cells acts on neighboring cells, exacerbating CNS damage. Here we show that a synthetic peptide analogous to the mammalian PreImplantation factor (PIF) secreted by developing embryos and which is present in the maternal circulation during pregnancy inhibits the biogenesis of let-7 in both neuronal and immune cells of the mouse. The synthetic peptide, sPIF, destabilizes KH-type splicing regulatory protein (KSRP), a key microRNA-processing protein, in a Toll-like receptor 4 (TLR4)-dependent manner, leading to decreased production of let-7. Furthermore, s.c. administration of sPIF into neonatal rats following hypoxic-ischemic brain injury robustly rescued cortical volume and number of neurons and decreased the detrimental glial response, as is consistent with diminished levels of KSRP and let-7 in sPIF-treated brains. Our results reveal a previously unexpected mechanism of action of PIF and underscore the potential clinical utility of sPIF in treating hypoxic-ischemic brain damage. The newly identified PIF/TLR4/KSRP/let-7 regulatory axis also may operate during embryo implantation and development.

Preeclampsia is a human pregnancy-specific disorder characterized by a placental pro-inflammatory response in combination with an imbalance of angiogenic factors and clinical symptoms, including hypertension and proteinuria. Insufficient uteroplacental oxygenation in preeclampsia due to impaired trophoblast invasion during placentation is believed to be responsible for many of the molecular events leading to the clinical manifestations of this disease. We investigated the use of hypoxic treatment of the dual placental perfusion system as a model for preeclampsia. A modified perfusion technique allowed us to achieve a mean soluble oxygen tension within the intervillous space (IVS) of 5-7% for normoxia and <3% for hypoxia (as a model for preeclampsia). We assayed for the levels of different inflammatory cytokines, oxidative stress markers, as well as other factors, such as endothelin (ET)-1 that are known to be implicated as part of the inflammatory response in preeclampsia. Our results show a significant increase under hypoxia in the levels of different inflammatory cytokines, including IL-6 (P=0.002), IL-8 (P<0.0001), TNF-α (P=0.032) and IFN-γ (P=0.009) at 360 min in maternal venous samples (n=6). There was also a significant increase in ET-1 levels under hypoxia both on the maternal side at 30 min (P=0.003) and fetal side at 360 min (P=0.036) (n=6). Other markers of oxidative stress, including malondialdehyde and 8-iso-protaglandin F2α (P=0.009) also show increased levels. Overall, these findings indicate that exposure of ex vivo dually perfused placental tissue to hypoxia provides a useful model for mimicking the inflammatory response characteristic of preeclampsia. This would therefore provide a powerful tool for studying and further delineating the molecular mechanisms involved in the underlying pathophysiology of preeclampsia.

Objective: Group B streptococci (GBS) may lead to early onset neonatal sepsis with severe morbidity and mortality of newborns. Intrapartum detection of GBS is needed. The objective was to compare a PCR-based test performed in the laboratory versus labor ward., Study Design: 300 patients were included prospectively. In phase I, swabs were analyzed by selective culture and rapid PCR in the laboratory. In phase II, swabs were analyzed accordingly, but the PCR test was conducted in labor ward. Test performances were analyzed and compared., Results: In phase I the rapid PCR test had a sensitivity of 85.71% and a specificity of 95.9%. The GBS colonization rate was 18.67%. Overall 8.5% of the PCR results were invalid. In phase II the PCR test showed a sensitivity of 85.71% and a specificity of 95.65%. The GBS colonization rate was 23.3%. Overall 23.5% of swabs tested with PCR were invalid. Initiation of specific, short 2-hour training for operating personnel in the labor ward reduced the invalid test rate to 13.4%., Conclusion: The rapid PCR-based test yields adequate results to identify GBS colonization when performed in labor ward. In order to reduce the number of invalid tests a short training period is needed., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Tocolysis is an important treatment in the improvement of outcome in preterm labor and preterm birth, provided that its use follows clear evidence-based recommendations. In this expert opinion, the most recent evidence about efficacy and side effects of different tocolytics is being reviewed and evidence-based recommendation about diagnosis and treatment of preterm labor is given. Further aspects such as progesterone administration or antibiotic treatment for the prevention of preterm birth are included. Our review demonstrates that an individualized choice of different tocolytics and additional treatments is necessary to improve short- and long-term neonatal outcome in preterm labor and preterm birth.

Objective: To evaluate the rates of penicillin, clindamycin and erythromycin resistance and the serotype distribution among isolates of group B streptococcus (GBS) obtained from pregnant women at the University Hospital of Bern in Switzerland., Methods: We prospectively collected screening samples for GBS colonisation at the University Women's Hospital Bern, Switzerland, between March 2009 and August 2010. We included 364 GBS isolates collected from vaginal, cervical or vaginal-perianal swabs at any gestation time. The minimal inhibitory concentrations for penicillin, clindamycin and erythromycin were established using Etest with 24 hours of incubation, and inducible clindamycin resistance was tested with double disk diffusion tests. Serotyping was done with a rapid latex agglutination test or, if not conclusive, with polymerase chain-reaction (PCR) testing. We looked for significant associations between resistance patterns, age groups, serotype and ethnicity., Results: All isolates were susceptible to penicillin. Resistance rates were 14.5% for erythromycin and 8.2% for clindamycin. Of 364 isolates, 5.8% were susceptible to clindamycin but not to erythromycin, although demonstrating inducible clindamycin resistance. Hence, the final reported clindamycin resistance rate was 14%. Serotype III was the most frequent serotype (29%), followed by V (25%) and Ia (19%). Serotype V was associated with erythromycin resistance (p = 0.0007). In comparison with all other ethnicities, patients from Asia showed a higher proportion of erythromycin and clindamycin resistance (p = 0.018). No significant association between resistance patterns and age groups was found., Conclusion: In pregnant women with GBS colonisation, penicillin is the antibiotic of choice for intrapartum prophylaxis to prevent neonatal early-onset GBS sepsis. In women with penicillin allergy and at high risk for anaphylactic reaction, clindamycin may be an alternative. The resistance rate for clindamycin at our institution was 14%; therefore, susceptibility must be tested before administration.

Postpartum hemorrhage (PPH) is one of the main causes of maternal deaths even in industrialized countries. It represents an emergency situation which necessitates a rapid decision and in particular an exact diagnosis and root cause analysis in order to initiate the correct therapeutic measures in an interdisciplinary cooperation. In addition to established guidelines, the benefits of standardized therapy algorithms have been demonstrated. A therapy algorithm for the obstetric emergency of postpartum hemorrhage in the German language is not yet available. The establishment of an international (Germany, Austria and Switzerland D-A-CH) "treatment algorithm for postpartum hemorrhage" was an interdisciplinary project based on the guidelines of the corresponding specialist societies (anesthesia and intensive care medicine and obstetrics) in the three countries as well as comparable international algorithms for therapy of PPH.The obstetrics and anesthesiology personnel must possess sufficient expertise for emergency situations despite lower case numbers. The rarity of occurrence for individual patients and the life-threatening situation necessitate a structured approach according to predetermined treatment algorithms. This can then be carried out according to the established algorithm. Furthermore, this algorithm presents the opportunity to train for emergency situations in an interdisciplinary team.

Objective: Caesarean section (CS) rates have risen over the past two decades. The aim of this observational study was to identify time-dependent variations in CS and vaginal delivery rates over a period of 11 years., Method: All deliveries (13,701 deliveries during the period 1999-2009) at the University Women's Hospital Bern were analysed using an internationally standardised and approved ten-group classification system. Caesarean sections on maternal request (CSMR) were evaluated separately., Results: We detected an overall CS rate of 36.63% and an increase in the CS rate over time (p <0.001). Low-risk profile groups were the two largest populations and displayed low CS rates, with significantly decreasing relative size over time. The relative size of groups with induced labour increased significantly, but this did not have an impact on the overall CS rate. Pregnancies complicated by breech position, multiple pregnancies and abnormal lies did not have an impact on overall CS rate. The biggest contributor to a high CS rate was preterm delivery and the existence of a uterine scar from a previous CS. CSMR was 1.45% and did not have an impact on the overall CS rate., Conclusion: The observational study identified wide variations in caesarean section and vaginal delivery rates across the groups over time, and a shift towards high-risk populations was noted. The biggest contributors to high CS rates were identified; namely, previous uterine scar and preterm delivery. Interventions aiming to reduce CS rates are planned.

A successful pregnancy requires an accommodating environment. Salt and water availability are critical for plasma volume expansion. Any changes in sodium intake would alter aldosterone, a hormone previously described beneficial in pregnancy. To date, it remains ambiguous whether high aldosterone or high salt intake is preferable. We hypothesized that increased aldosterone is a rescue mechanism and appropriate salt availability is equally effective in maintaining a normotensive blood pressure (BP) phenotype in pregnancy. We compared normotensive pregnant women (n=31) throughout pregnancy with young healthy female individuals (n=31-62) and performed salt sensitivity testing within the first trimester. Suppression of urinary tetrahydro-aldosterone levels by salt intake as measured by gas chromatography-mass spectrometry and urinary sodium excretion corrected for creatinine, respectively, was shifted toward a higher salt intake in pregnancy (P<0.0001). In pregnancy, neither high urinary tetrahydro-aldosterone nor sodium excretion was correlated with higher BP. In contrast, in nonpregnant women, systolic BP rose with aldosterone (P<0.05). Testing the impact of salt on BP, we performed salt sensitivity testing in a final cohort of 19 pregnant and 24 nonpregnant women. On salt loading, 24-hour mean arterial pressure rose by 3.6±1.5 and dropped by -2.8±1.5 mm Hg favoring pregnant women (P<0.01; χ(2)=6.04; P<0.02). Our data suggest first that salt responsiveness of aldosterone is alleviated in conditions of pregnancy without causing aldosterone-induced hypertension. Second, salt seems to aid in BP lowering in pregnancy for reasons incompletely elucidated, yet involving renin suppression and potentially placental sensing mechanisms. Further research should identify susceptible individuals and clarify effector mechanisms.

Background: Fetal weight estimation (FWE) is an important factor for clinical management decisions, especially in imminent preterm birth at the limit of viability between 23(0/7) and 26(0/7) weeks of gestation. It is crucial to detect and eliminate factors that have a negative impact on the accuracy of FWE., Data Sources: In this systematic literature review, we investigated 14 factors that may influence the accuracy of FWE, in particular in preterm neonates born at the limit of viability., Results: We found that gestational age, maternal body mass index, amniotic fluid index and ruptured membranes, presentation of the fetus, location of the placenta and the presence of multiple fetuses do not seem to have an impact on FWE accuracy. The influence of the examiner's grade of experience and that of fetal gender were discussed controversially. Fetal weight, time interval between estimation and delivery and the use of different formulas seem to have an evident effect on FWE accuracy. No results were obtained on the impact of active labor., Discussion: This review reveals that only few studies investigated factors possibly influencing the accuracy of FWE in preterm neonates at the limit of viability. Further research in this specific age group on potential confounding factors is needed.

Introduction: Transplacental feto-maternal lipid exchange through the ATP-binding cassette transporters ABCA1 and ABCG1 is important for normal fetal development. However, only scarce and conflicting data exist on the involvement of these transporters in gestational disease., Methods: Placenta samples (n = 72) derived from common gestational diseases, including pre-eclampsia (PE), HELLP, intrauterine growth restriction (IUGR), intrahepatic cholestasis of pregnancy and gestational diabetes, were assessed for their ABCA1 and ABCG1 expression levels and compared to age-matched control placentas with qRT-PCR and immunohistochemistry. ABCA1 expression was additionally investigated with immunoblot in placental membrane vesicles. Furthermore, placental cholesterol and phospholipid contents were assessed., Results: ABCA1 mRNA levels differed significantly between preterm and term control placentas (p = 0.0013). They were down-regulated in isolated PE and PE with IUGR (p = 0.0006 and p = 0.0012, respectively), but unchanged in isolated IUGR, isolated HELLP and other gestational diseases compared to gestational age-matched controls. Correspondingly, in PE, ABCA1 protein expression was significantly reduced in the apical membrane of the villous syncytiotrophoblast (p = 0.011) and in villous fetal endothelial cells (p = 0.036). Furthermore, in PE there was a significant increase in the placental content of total and individual classes of phospholipids which were partially correlated with diminished ABCA1 expression. Conversely, ABCG1 mRNA and protein levels were stable in the investigated conditions., Conclusions: In gestational disease, there is a specific down-regulation of placental ABCA1 expression at sites of feto-maternal lipid exchange in PE. At a functional level, the increase in placental lipid concentrations provides indirect evidence of an impaired transport capacity of ABCA1 in this disease., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Objectives: The association between periodontal disease and adverse pregnancy outcomes (APO), primarily preterm birth (PTB), is still controversially discussed in the literature. Therefore, the aim of the present systematic review was to analyze the existing literature on the potential association between inflammatory mediators detected in gingival crevicular fluid (GCF) and APO., Materials and Methods: MEDLINE (PubMed) and EMBASE databases were searched for entries up to April 2012 and studies were selected by two independent reviewers., Results: The majority of the eight studies included confirmed a positive association between GCF mediators, such as interleukin-1β, prostaglandin E2, and tumor necrosis factor-alpha, and APO. Due to the heterogeneity and variability of the available studies, no meta-analysis could be performed., Conclusions: A positive association between GCF inflammatory mediator levels and APO/PTB might be present but the results need to be considered with great caution because of the heterogeneity and variability among the studies. Further studies with an adequate number of patients allowing for an appropriate analysis are warranted to definitely confirm this association., Clinical Relevance: The present findings suggest that an association between GCF inflammatory mediator levels and APO might exist.

It has been highlighted that RNA quality and appropriate reference gene selection is crucial for the interpretation of RT-qPCR results in human placental samples. In this context we investigated the effect of RNA degradation on the mRNA abundance of seven frequently used reference genes in 119 human placental samples. Combining RNA integrity measurements, RT-qPCR analysis and mathematical modeling we found major differences regarding the effect of RNA degradation on the measured expression levels between the different reference genes. Furthermore, we demonstrated that a modified RNA extraction method significantly improved RNA quality and consequently increased transcript levels of all reference genes., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Introduction: The appearance of end-diastolic flow velocities (EDF) in the umbilical artery (UA), usually between 10 and 14 weeks of gestation, has been associated with the opening of the spiral arteries and consequently of the intervillous space., Objectives: The aim of our study was to compare first trimester UA pulsatility index (PI) and EDF between women who developed preeclampsia (cases) and controls., Methods: Our database was searched for cases who had UA Doppler between 10-14 weeks. UA PI and EDF were compared between cases and two gestational age (GA) matched controls., Results: 15 cases with severe preeclampsia (PE) were matched to 30 controls. GA with negative EDF was lower than with positive EDF (12.1±0.79 vs. 12.8±0.34; p=0.001). UA PI in cases was higher than in controls, although not significant (cases: 2.18±0.6 vs., Controls: 1.92±0.48; p=0.12). However, comparing groups with negative EDF, the difference became significant (PI cases: 2.45±0.57 vs. PI controls: 1.94±0.56; p=0.038), while no difference was found comparing groups with positive EDF., Conclusion: First trimester UA PI is significantly higher in women which will develop PE than in controls. Interestingly, the timing of screening for PE by UA Doppler seems to play an important issue., (Copyright © 2013. Published by Elsevier B.V.)

Objective: To test a possible neuroprotective activity of 17β-estradiol in the neonatal rat brain exposed to hypoxic-ischemia (controlled hypoxia after unilateral carotid artery ligation)., Methods: Seven-day-old Wistar rats underwent ligation of the left common carotid artery followed by 80 minutes hypoxia in 8% oxygen inducing an ipsilateral brain damage. Seven days later (d14), brains were analyzed quantitatively using a macroscopic and microscopic score for structural damage, hemisphere volumes were calculated, and immunohistochemistry for cleaved-caspase-3 (marker for apoptotic cells) was performed. Animals from the study group (n = 19) received 17β-estradiol (0.05 µg/g body weight intraperitoneally) before (-64, -40, and -16 hours) and after (+3 hours) the hypoxia (hour 0: start of the hypoxia) and the control group (n = 21) received mock treatment., Results: Of the 21 pups, 13 in the NaCl group had macroscopically a severe brain damage and 7 of 19 animals in the study group encountered only discrete to mild lesions. Microscopic brain damage in the study group was significantly lower (score 1.5 ± 0.7 vs 2.8 ± 0.8, P < .05). The determined volumes of the affected hemisphere were significantly lower in the NaCl group than in the treatment group. The numbers of apoptotic cells in both hemispheres was equal in the estradiol group, but in the control group, there were significantly more apoptotic cells in the affected hemisphere (control group: ipsilateral: 1435 ± 653 vs contralateral: 143 ± 57 cells, P < .05)., Discussion: 17β-Estradiol protects newborn rat brains from hypoxic-ischemic injury, in terms of both microscopic cell injury and apoptosis.

Physiological pregnancy is associated with an increase in lipids from the first to the third trimester. This is a highly regulated response to satisfy energy and membrane demands of the developing fetus. Pregnancy disorders, such as pre-eclampsia, are associated with a dysregulation of lipid metabolism manifesting in increased maternal plasma lipid levels. In fetal placental tissue, only scarce information on the lipid profile is available, and data for gestational diseases are lacking. In the present study, we investigated the placental lipid content in control versus pre-eclamptic samples, with the focus on tissue phospholipid levels and composition. We found an increase in total phospholipid content as well as changes in individual phospholipid classes in pre-eclamptic placental tissues compared to controls. These alterations could be a source of placental pathological changes in pre-eclampsia, such as lipid peroxide insult or dysregulation of lipid transport across the syncytiotrophoblast.

Objective: To assess the efficacy of paracetamol (acetaminophen) for neonatal pain relief., Study Design: Randomized, double-blind placebo-controlled trial in 3 Swiss university hospitals. Term and near-term infants (n = 123) delivered by forceps or vacuum were randomized to receive 2 suppositories with paracetamol (60/80/100 mg in infants <3000 g/3000-4000 g/>4000 g birth weight) or placebo at 2 and 8 hours of life. Pain and discomfort during the first 24 hours was assessed by the échelle de douleur et d'inconfort du nouveau né [neonatal pain and discomfort scale] score. The response to the subsequent heel prick for metabolic screening at days 2-3 of life was investigated by the Bernese Pain Scale for Neonates (BPSN)., Results: The échelle de douleur et d'inconfort du nouveau né [neonatal pain and discomfort scale] pain scale ratings after assisted vaginal delivery were low and declined within 4 hours of life (P < .01) irrespective of paracetamol administration. At 2-3 days of life, BPSN scores after heel prick were significantly higher in infants who had received paracetamol, compared with controls, both when BPSN were scored by nurses at the bedside (median [IQR] 4 [2-7] vs 2 [0-5], P = .017) or off-site from videos (4 [2-8] vs 2 [1-7], P = .04). Thirty-five of 62 (57%) infants treated with paracetamol cried after heel prick, compared with 25 of 61 (41%) controls (P = .086)., Conclusions: Infants born by assisted vaginal delivery have low pain scores in the immediate period after birth. Paracetamol given to newborns soon after birth may aggravate a subsequent stress response., (Copyright © 2013 Mosby, Inc. All rights reserved.)

Objective: Acute stress reactions (ASR) and postpartum depressive symptoms (PDS) are frequent after childbirth. The present study addresses the change and overlap of ASR and PDS from the 1- to 3-week postpartum and examines the interplay of caregiver support and subjective birth experience with regard to the development of ASR/PDS within a longitudinal path model., Method: A total of 219 mothers completed questionnaires about caregiver support and subjective birth experience (Salmon's Item List) at 48-6-h postpartum. ASR and PDS were measured for 1- and 3-week postpartum. The Impact of Event Scale (IES) was used to assess ASR, and the Edinburgh Postnatal Depression Scale (EPDS) was used to assess PDS., Results: ASR was frequent 1-week postpartum (44.7%) and declined till week 3 (24.8%, p <.001), while the prevalence of PDS was continuous (14.2% week 1; 12.6% week 3; p = .380). Favorable reports of caregiver support were related to better subjective childbirth experience, which was related to lower ASR and PDS (controlled for age, mode of delivery, parity, EDA and duration of childbirth)., Conclusion: High quality of intrapartum care and positive birth experiences facilitate psychological adjustment in the first 3-week postpartum.

Objective: The objective of the study was to compare the stress response and pain expression of newborns (NBs) in the early postpartum period., Study Design: This was a prospective study with 280 NBs enclosed at 3 Swiss university hospitals. Stress response and pain reaction were analyzed according to the mode of delivery: elective cesarean section (ELCS), spontaneous vaginal delivery, and assisted vaginal delivery by vacuum extraction (VE). Saliva cortisol and clinical pain expression were evaluated after delivery and before and after heel prick for metabolic screening., Results: Significant differences were evident during the first 72 hours postpartum with highest nominations in the VE group. Meconium-stained amniotic fluid was the only intrapartum stress factor with an impact on clinical pain expression., Conclusion: NBs delivered vaginally show a higher incidence of stress response and pain expression than infants of the ELCS group. The long-term impact of these findings remains to be determined., (Copyright © 2012 Mosby, Inc. All rights reserved.)

Introduction: Antenatal maternal administration of corticosteroids has been shown to reduce morbidity and mortality rates in preterm delivery. Threatened spontaneous or medically indicated preterm delivery for maternal or fetal indications between 24 and 34 weeks of gestation with unknown fetal lung maturity status are indications for antenatal corticosteroid administration. Recent studies have challenged current practice of antenatal glucocorticoid use. The goal of this expert letter is to provide recommendations based for the clinical use of antenatal glucocorticoids based on the current evidence from published studies., Methods: The published literature (PubMed search), as well as the recommendations of other national societies, has been searched and taken into consideration for these recommendations., Results/conclusions: The standard regimen of antenatal corticosteroids involves a single course of 2 × 12 mg betamethasone administered intramuscularly within 24 h. The administration of corticosteroids usually is performed between 24 and 34 weeks gestation. However, under particular circumstances it may be beneficial even at 23 weeks and at 35-36 weeks of gestation. The evidence to date is clearly against the routine administration of multiple antenatal steroid courses. In special clinical situations, a second course of betamethasone ("rescue course") may be justifiable. Tocolysis during administration of steroids is not routinely indicated in the absence of contractions, cervical shortening or rupture of membranes.

Objective: To identify candidate genes that are regulated by human pregnancy and have the potential to modulate rheumatoid arthritis (RA) disease activity., Methods: Peripheral blood mononuclear cells (PBMCs) from healthy pregnant volunteers were analyzed using Affymetrix GeneChips at 4 time points (during the first, second, and third trimesters and 6 weeks postpartum). Based on the GeneChip data, target genes were further analyzed via real-time quantitative polymerase chain reaction (qPCR) using PBMCs from healthy controls and RA patients. In order to determine the cellular source of the candidate gene messenger RNA (mRNA), monocytes and lymphocytes from healthy controls and RA patients were positively selected using magnetic beads, and their mRNA was analyzed by qPCR., Results: One-way analysis of variance identified 1,286 mRNAs that were differentially expressed with regard to the 4 time points. The changes became more pronounced as pregnancy progressed, and they were reversed postpartum. A subsequent pathway analysis suggested a regulatory role of pregnancy on the adipocytokine pathway as well as on the peroxisome proliferator-activated receptor (PPAR) signaling pathway. Of 19 preselected candidate genes, AKT3, SOCS3, FADS2, STAT1, and CD36 proved to be differentially regulated by pregnancy. In samples from RA patients, the differences were concordant with those in healthy controls but more pronounced. Both T lymphocytes and monocytes contributed to the regulated expression of these genes., Conclusion: Our findings indicate that normal human pregnancy leads to changes in the expression of several molecular pathways in PBMCs, which are reversed postpartum. Changes in RA patients, although concordant, exceed the levels observed in healthy controls. Genes of the adipocytokine and PPAR signaling pathways qualify as candidates for the modulation of RA disease activity during pregnancy., (Copyright © 2012 by the American College of Rheumatology.)

Introduction: Preeclampsia contributes to an increased perinatal morbidity and mortality of both the mother and the fetus. The exact pathogenesis of PE is unclear; it is generally believed, however, that the placenta plays a pivotal role in this process., Objectives: The aim of this study was to analyse the effect of the placental mass on the severity of PE., Methods: Following PE placentae were analyzed and their weights were compared with those of normal pregnancies [1]. Moderate and severe PE as well as HELLP syndrome were defined according to international guidelines. To compare placental weights obtained at different gestational ages, a ratio between observed (O) and expected (E) weights were calculated. Chi(2)-test and Kruskal-Wallis-test were used for statistical analysis and significance was considered when p<0.05., Results: Two hundred and eight placentae following singleton pregnancies complicated by preeclampsia were enrolled. The mean gestational age at birth was 31.8±3.8 weeks, 130 (62.5%) cases delivered before the 34th week. The group with severe PE delivered earlier than that with moderate PE (mean±SD, 32±3.9 vs. 34±3 weeks; p<0.01). Severe PE was found in 176 (84.6%) cases; 85 of this group were associated with a HELLP-syndrome. Isolated HELLP were found in 4 (1.9%) cases. In 144 (69.2%) cases placental weight was below the 10th percentile. The mean of the weights was higher in the group with moderate PE than in those with severe PE, PE with HELLP and isolated HELLP (410±67g, respectively, 376±79g, 344±86g, 341±88g). When normalized using the O/E-ratio (in order to correct for gestational age) these differences were not significant (moderate PE 0.75±0.24; severe PE 0.74±0.22, PE with HELLP 0.73±0.22; isolated HELLP 0.88±0.05; p=NS)., Conclusion: Our data show that the placental mass is not associated with the severity of PE. We hypothesize that once the pathogenesis of PE is triggered (by placental factors), the severity of the disease is modulated mainly by the maternal response and not by the placental mass., (Copyright © 2012. Published by Elsevier B.V.)

Introduction: Angiogenic signals are a vital signal of placental integrity. Aldosterone has recently been shown to enhance placental growth factor (PlGF) expression in the peripheral vasculature [1] and to promote trophoblast growth [2]. The plgf gene possesses a functional mineralocorticoid receptor responsive element in the promoter region., Objectives: Thus, we hypothesized that aldosterone adapts placental angiogenesis to trophoblast growth by secreting PlGF., Methods: The human choriocarcinoma cell line BeWo and first and third trimester human primary trophoblasts cells were subjected to several syncytialization signals. Upon visual confirmation, the cultured cells were subjected to either control conditions, the known stimulator forskolin, and increasing amounts of aldosterone (10(-9) to 10(-6)M) with and without the competitive aldosterone receptor blocker spironolactone. After 6 and 24h of incubation, RNA and protein were extracted. PlGF transcripts were quantified by Taqman PCR normalized to several housekeeping genes. Protein expression was quantified by ELISA., Results: PlGF mRNA expression increased 3-fold with forskolin in BeWo cells. In this cell line, aldosterone could slightly stimulate PlGF production. In non-syncytialized primary human first trimester trophoblasts, aldosterone did not exert a specific effect. In contrast, the term primary human trophoblasts did respond with a 2.5-fold increase after incubation with aldosterone (10(-7)M) in the presence of forskolin to allow forming a syncytial layer. PlGF protein was already slightly upregulated following 6h of incubation with aldosterone., Conclusion: We concluded that aldosterone does regulate PlGF expression in specified conditions during pregnancy. Inappropriately low aldosterone levels such as in preeclampsia might such not only compromise plasma volume and trophoblast growth but also placental vascularization and systemic PlGF availability. These observations merit further investigation., (Copyright © 2010. Published by Elsevier B.V.)

Objective: Oral iron substitution has shown to be insufficient for treatment of severe iron deficiency anemia in pregnancy. Ferric carboxymaltose is a new intravenous (i.v.) iron formulation promising to be more effective and as safe as iron sucrose. We aimed to assess side effects and tolerance of ferric carboxymaltose compared to i.v. iron sucrose in pregnant women., Methods: We performed a retrospective analysis of 206 pregnant women who were treated either with ferric carboxymaltose or iron sucrose for iron-deficiency anemia with intolerability to oral iron substitution, or insufficient hemoglobin increase after oral iron treatment, or need for rapid hemoglobin reconstitution. Primary endpoint was to evaluate the maternal safety and tolerability. Secondary endpoint was to assess efficacy of the treatment and exclude safety concerns for the fetus., Results: The incidence of drug-related adverse events was low and mostly mild in both groups. Mild adverse events occurred in 7.8% for ferric carboxymaltose and in 10.7% for iron sucrose. The mean rise of hemoglobin value was 15.4 g/L for ferric carboxymaltose and 11.7 g/L for iron sucrose., Conclusion: Ferric carboxymaltose administration in pregnant women is well tolerated and is not associated with any relevant clinical safety concerns. Ferric carboxymaltose has a comparable safety profile to iron sucrose but offers the advantage of a much higher iron dosage at a time reducing the need for repeated applications and increasing patients' comfort. Ferric carboxymaltose is the drug of choice, if i.v. iron treatment becomes necessary in the second or third trimester of pregnancy.

Objective: The purpose of this study is to compare the safety and efficacy of intravenous (IV) high-dose iron carboxymaltose (ICM) with iron sucrose (IS) for the treatment of postpartum anemia., Study Design: We performed a retrospective cohort study with 210 anemic inpatient women in the postpartum period who received IV high-dose ICM (15 mg/kg; maximum, 1000 mg) or IS (2×200 mg), respectively. Safety and tolerability of both groups were compared on the basis of reported systemic and local adverse events. The cohorts were matched for baseline characteristics and their initial hemoglobin (Hb) values. The secondary endpoint included drug efficacy assessment by measurement of Hb level increase up to 8 days after treatment., Results: Rapid administration of high ICM doses was as well tolerated as IS with overall adverse events of 5% (ICM) vs. 6% (IS). The most common complaint was burning and pain at the injection site. ICM was as effective as IS in changing Hb levels from the baseline. There was no difference in the mean daily Hb increase between the groups. Women with severe anemia showed the most effective responsiveness., Conclusions: IV ICM is as safe as IS in the management of postpartum (IDA) iron deficiency anemia despite five times of higher dosage. Both drugs are effective and offer a rapid normalization of Hb after delivery. The single application of ICM shows advantages of lower incidence of side effects at the injection site, a shorter treatment period, and better patient compliance.

Background Aims: Umbilical cord blood (UCB) is a source of hematopoietic stem cells that initially was used exclusively for the hematopoietic reconstitution of pediatric patients. It is now suggested for use for adults as well, a fact that increases the pressure to obtain units with high cellularity. Therefore, the optimization of UCB processing is a priority., Methods: The present study focused on parameters influencing total nucleated cell (TNC), mononucleated cell (MNC) and CD34+ cell (CD34C) recovery after routine volume reduction of 1553 UCB units using hydroxyethyl starch-induced sedimentation with an automated device, under routine laboratory conditions., Results: We show that the unit volume rather than the TNC count significantly affects TNC, MNC and CD34C processing efficiency (PEf), and this in a non-linear fashion: when units were sampled according to the collection volume, including pre-loaded anticoagulant (gross volume), PEf increased up to a unit volume of 110-150 mL and decreased thereafter. Thus units with initial gross volumes < 90 mL and > 170 mL similarly exhibited a poor PEf., Conclusions: These data identify unit gross volume as a major parameter influencing PEf and suggest that fractionation of large units should be contemplated only when the resulting volume of split units is > 90 mL.

Objective: Off-label use of drugs is frequent in obstetrical practice. No data however are available about nation-wide off-label use in obstetrics regarding frequency and patient information. The objective of our study was to assess the clinical practice of off-label use of misoprostol for labor induction., Study Design: We performed a prospective nation-wide survey study by means of a validated questionnaire in three languages in Switzerland. All registered obstetricians/gynaecologists in Switzerland were included. Of 1100 subjects, 725 (66%) answered the questionnaire; 69 subjects were excluded because they were not actively practicing OB/GYN, resulting in a total of 656 questionnaires included in the analysis., Results: A total of 512 out of 656 obstetricians/gynaecologists (78%) use misoprostol for labor induction. The most frequent administration route of misoprostol is intravaginal (86%), in a single dose of 50μg (94%), at a dose interval range from 4 to 6h (85%). Among the users of misoprostol, 314 (61%) answered that they do not inform their patients about the off-label use of the medication. Among the non-users of misoprostol, the main reason for non-use is absent license for obstetric indications (48%) and non-availability (14%). If misoprostol were to be licensed for this indication, and commercially available, 69% of current non-users would use it. Non-users of misoprotol use prostaglandin E2 vaginal gel, ovules or slow-release vaginal insert, and oxytocin for labor induction., Conclusion: Misoprostol is the single most commonly used drug for labor induction in Switzerland, although it is not licensed and although there are effective, licensed alternative drugs available. A minority of practitioners inform the patients about the off-label use., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Purpose: Umbilical vein pulsations (UV-P) are due to various etiologies. The aim of the present study was to investigate the incidence and type of UV-P in monochorionic twins with twin-twin transfusion syndrome (TTTS)., Materials and Methods: TTTS cases diagnosed between 1999 and 2009 were examined retrospectively. The UV flow pattern taken from a free floating loop of the umbilical cord was classified as "non-pulsatile" (NP), "monophasic" (MP) and "complex" (CP). Only Doppler flow analyses prior to intervention were examined., Results: Of 106 cases seen during the study period, 56 cases met the inclusion criteria. Of those, 62.5% were classified as stage III TTTS, and fetoscopic laser therapy was performed in 45 cases. NP flow patterns were more likely found in the donor twin (80.4 vs. 28.6%; p < 0.0001), while the incidence of MP (50 vs. 17.9%; p < 0.0006) and CP flow patterns (21.4 vs. 1.7%; p < 0.01) was higher in the recipient twin. Moreover, the perinatal mortality was highest in cases with CP (CP: 76.9 vs. MP 42.1 vs. NP: 26.2%; p < 0.01) as well as the rate of cases with double death., Conclusion: CP patterns are more frequently found in the recipient twin and are associated with a considerably high mortality rate. Studying the umbilical vein flow pattern in TTTS may provide additional information for counseling and prognosis similar to that obtained by expensive fetal echocardiography., (© Georg Thieme Verlag KG Stuttgart · New York.)

Perinatal care of pregnant women at high risk for preterm delivery and of preterm infants born at the limit of viability (22-26 completed weeks of gestation) requires a multidisciplinary approach by an experienced perinatal team. Limited precision in the determination of both gestational age and foetal weight, as well as biological variability may significantly affect the course of action chosen in individual cases. The decisions that must be taken with the pregnant women and on behalf of the preterm infant in this context are complex and have far-reaching consequences. When counselling pregnant women and their partners, neonatologists and obstetricians should provide them with comprehensive information in a sensitive and supportive way to build a basis of trust. The decisions are developed in a continuing dialogue between all parties involved (physicians, midwives, nursing staff and parents) with the principal aim to find solutions that are in the infant's and pregnant woman's best interest. Knowledge of current gestational age-specific mortality and morbidity rates and how they are modified by prenatally known prognostic factors (estimated foetal weight, sex, exposure or nonexposure to antenatal corticosteroids, single or multiple births) as well as the application of accepted ethical principles form the basis for responsible decision-making. Communication between all parties involved plays a central role. The members of the interdisciplinary working group suggest that the care of preterm infants with a gestational age between 22 0/7 and 23 6/7 weeks should generally be limited to palliative care. Obstetric interventions for foetal indications such as Caesarean section delivery are usually not indicated. In selected cases, for example, after 23 weeks of pregnancy have been completed and several of the above mentioned prenatally known prognostic factors are favourable or well informed parents insist on the initiation of life-sustaining therapies, active obstetric interventions for foetal indications and provisional intensive care of the neonate may be reasonable. In preterm infants with a gestational age between 24 0/7 and 24 6/7 weeks, it can be difficult to determine whether the burden of obstetric interventions and neonatal intensive care is justified given the limited chances of success of such a therapy. In such cases, the individual constellation of prenatally known factors which impact on prognosis can be helpful in the decision making process with the parents. In preterm infants with a gestational age between 25 0/7 and 25 6/7 weeks, foetal surveillance, obstetric interventions for foetal indications and neonatal intensive care measures are generally indicated. However, if several prenatally known prognostic factors are unfavourable and the parents agree, primary non-intervention and neonatal palliative care can be considered. All pregnant women with threatening preterm delivery or premature rupture of membranes at the limit of viability must be transferred to a perinatal centre with a level III neonatal intensive care unit no later than 23 0/7 weeks of gestation, unless emergency delivery is indicated. An experienced neonatology team should be involved in all deliveries that take place after 23 0/7 weeks of gestation to help to decide together with the parents if the initiation of intensive care measures appears to be appropriate or if preference should be given to palliative care (i.e., primary non-intervention). In doubtful situations, it can be reasonable to initiate intensive care and to admit the preterm infant to a neonatal intensive care unit (i.e., provisional intensive care). The infant's clinical evolution and additional discussions with the parents will help to clarify whether the life-sustaining therapies should be continued or withdrawn. Life support is continued as long as there is reasonable hope for survival and the infant's burden of intensive care is acceptable. If, on the other hand, the health care team and the parents have to recognise that in the light of a very poor prognosis the burden of the currently used therapies has become disproportionate, intensive care measures are no longer justified and other aspects of care (e.g., relief of pain and suffering) are the new priorities (i.e., redirection of care). If a decision is made to withhold or withdraw life-sustaining therapies, the health care team should focus on comfort care for the dying infant and support for the parents.

Pentalogy of Cantrell (PC) is a rare congenital syndrome involving the abdominal wall, sternum, diaphragm, pericardium, and heart. The embryonic period in which PC develops coincides with that of umbilical cord (UC) formation. The aim of the following study was to address the question of whether PC is associated with UC pathologies. Four cases, prenatally identified between 2002 and 2008, were enrolled in this study. Umbilical cord pathologies defined as single umbilical artery, short cord, or UC with atypical coiling pattern were retrospectively assessed on stored ultrasound images and from autopsy reports. The literature regarding PC and UC pathologies was reviewed. Three singleton pregnancies and 1 monoamniotic twin pregnancy with twin reversed arterial perfusion sequence were reviewed. All had a normal karyotype. Three showed the classical PC stigmata, with ectopia cordis. One fetus had no ectopia cordis; this case had a normal UC, whereas all others fetuses showed a short UC with atypical coiling pattern. Of 26 publications dealing with PC, the UC was described in only 8 cases, 7 of which were abnormal. There seems to be a strong correlation between the PC and UC abnormalities, in particular in cases with ectopia cordis. We speculate that the insult leading to the classical malformations of PC and UC abnormalities is the same or the sequence of malformations itself may alter the early fetoplacental blood flow and therefore the normal development of the UC angioarchitecture.

The uncommon simultaneous occurrence of an exuberant, angioma-like proliferation of superficial cerebral microvessels along with absence of the kidneys has been proposed to constitute a syndromic complex for which the term "meningocerebral angiodysplasia (or angiomatosis) with renal agenesis" (MCA-RA) is being descriptively used. We observed this constellation in one of a pair of dichorionic male twins following postpartal death in the 38th week of pregnancy. General autopsy revealed rudimentary metanephric anlagen made up of few residual glomeruli, cysts lined by flattened tubular epithelium, and islands of cartilage - corresponding to renal aplastic dysplasia. Largely inconspicuous with respect to its gyral pattern, as well as the configuration of the ventricular system, the brain microscopically showed extensive replacement of the cortex by a lattice of proliferating capillaries with necrosis of the intervening parenchyma. Minute foci of calcified necrosis were scattered in the deep subcortical white matter as well, while the ventricular ependyma and the subventricular germ cell layer remained remarkably intact. The cerebellum and brain stem appeared unaffected as well. Karyotyping of skin fibroblasts indicated a normal chromosome set of 46XY without gross structural anomalies. We interpret these findings as ones apt to being reasonably accommodated within the spectrum of MCA-RA. Although exceedingly rare, accurate identification of individual cases of MCA-RA is relevant both to differential diagnosis from its prognostically different look-alike "proliferative vasculopathy and hydranencephaly-hydrocephaly" (PVHH), and to refine the nosology of unconventional pediatric vascular malformations, for which the rather nonspecific label "angiodysgenetic necrotizing encephalopathy" is still commonly used., (Copyright © 2011 Elsevier GmbH. All rights reserved.)

The ATP-binding cassette transporter A1 (ABCA1) mediates the transport of cholesterol, phospholipids, and other lipophilic molecules across cellular membranes. Recent data provide evidence that ABCA1 plays an important role in placental function but the exact cellular sites of ABCA1 action in the placenta remain controversial. To clarify this issue, we analyzed the cellular and subcellular localization of ABCA1 with immunocytochemistry, immunofluorescence and subsequent confocal or immunofluorescence microscopy in different types of isolated primary placenta cells: cytotrophoblast cells, amnion epithelial cells, villous macrophages (Hofbauer cells), and mesenchymal cells isolated from chorionic membrane and placental villi. After 12 h of cultivation, primary cytotrophoblast cells showed intensive membrane and cytoplasmic staining for ABCA1. After 24 h, with progressive syncytium formation, ABCA1 staining intensity was markedly reduced and ABCA1 was dispersed in the cytoplasm of the forming syncytial layer. In amnion epithelial cells, placental macrophages and mesenchymal cells, ABCA1 was predominantly localized at the cell membrane and cytoplasmic compartments partially corresponding to the endoplasmic reticulum. In these cell types, the ABCA1 staining intensity was not dependent on the cultivation time. In conclusion, ABCA1 shows marked expression levels in diverse placental cell types. The multitopic localization of ABCA1 in diverse human placental cells not all directly involved in materno-fetal exchange suggests that this protein may not only participate in transplacental lipid transport but could have additional regulatory functions., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

During pregnancy, trophoblasts grow to adapt the feto-maternal unit to fetal requirements. Aldosterone and cortisol levels increase, the latter being inactivated by a healthy placenta. By contrast, preeclamptic placental growth is reduced while aldosterone levels are low and placental cortisol tissue levels are high due to improper deactivation. Aldosterone acts as a growth factor in many tissues, whereas cortisol inhibits growth. We hypothesized that in preeclampsia low aldosterone and enhanced cortisol availability might mutually affect placental growth and function. Proliferation of cultured human trophoblasts was time- and dose-dependently increased with aldosterone (P < 0.04 to P < 0.0001) and inhibited by spironolactone and glucocorticoids (P < 0.01). Mineralo- and glucocorticoid receptor expression and activation upon agonist stimulation was verified by visualization of nuclear translocation of the receptors. Functional aldosterone deficiency simulated in pregnant mice by spironolactone treatment (15 μg/g body weight/day) led to a reduced fetal umbilical blood flow (P < 0.05). In rat (P < 0.05; R(2) = 0.2055) and human (X(2) = 3.85; P = 0.0249) pregnancy, placental size was positively related to plasma aldosterone. Autocrine production of these steroid hormones was excluded functionally and via the absence of specific enzymatic transcripts for CYP11B2 and CYP11B1. In conclusion, activation of mineralocorticoid receptors by maternal aldosterone appears to be required for trophoblast growth and a normal feto-placental function. Thus, low aldosterone levels and enhanced cortisol availability may be one explanation for the reduced placental size in preeclampsia and related disorders.

Purpose: To evaluate diffusion-weighted magnetic resonance (MR) imaging of the human placenta in fetuses with and fetuses without intrauterine growth restriction (IUGR) who were suspected of having placental insufficiency., Materials and Methods: The study was approved by the local ethics committee, and written informed consent was obtained. The authors retrospectively evaluated 1.5-T fetal MR images from 102 singleton pregnancies (mean gestation ± standard deviation, 29 weeks ± 5; range, 21-41 weeks). Morphologic and diffusion-weighted MR imaging were performed. A region of interest analysis of the apparent diffusion coefficient (ADC) of the placenta was independently performed by two observers who were blinded to clinical data and outcome. Placental insufficiency was diagnosed if flattening of the growth curve was detected at obstetric ultrasonography (US), if the birth weight was in the 10th percentile or less, or if fetal weight estimated with US was below the 10th percentile. Abnormal findings at Doppler US of the umbilical artery and histopathologic examination of specimens from the placenta were recorded. The ADCs in fetuses with placental insufficiency were compared with those in fetuses of the same gestational age without placental insufficiency and tested for normal distribution. The t tests and Pearson correlation coefficients were used to compare these results at 5% levels of significance., Results: Thirty-three of the 102 pregnancies were ultimately categorized as having an insufficient placenta. MR imaging depicted morphologic changes (eg, infarction or bleeding) in 27 fetuses. Placental dysfunction was suspected in 33 fetuses at diffusion-weighted imaging (mean ADC, 146.4 sec/mm(2) ± 10.63 for fetuses with placental insufficiency vs 177.1 sec/mm(2) ± 18.90 for fetuses without placental insufficiency; P < .01, with one false-positive case). The use of diffusion-weighted imaging in addition to US increased sensitivity for the detection of placental insufficiency from 73% to 100%, increased accuracy from 91% to 99%, and preserved specificity at 99%., Conclusion: Placental dysfunction associated with growth restriction is associated with restricted diffusion and reduced ADC. A decreased ADC used as an early marker of placental damage might be indicative of pregnancy complications such as IUGR., Supplemental Material: http://radiology.rsna.org/lookup/suppl/doi:10.1148/radiol.10092283/-/DC1., (© RSNA, 2010)

Introduction: Iron-deficiency anaemia during pregnancy and postpartum occurs frequently and may lead to severe maternal and foetal complications. New treatment regimens include intravenous iron administration in particular clinical situations. The aim of the study was to determine optimal diagnostic and therapeutic approaches to iron-deficiency anaemia during pregnancy and postpartum., Methods: The evidence from data available from published studies and recommendations regarding diagnosis and treatment were reviewed. As conclusions, recommendations are given by an expert panel., Results: During pregnancy, oral iron therapy is given as first-line treatment. In cases with lack of efficacy, unwarranted side effects or very low haemoglobin values, intravenous iron treatment with iron carboxymaltose is a preferable alternative, although data regarding safety are limited. In the postpartum period, haemoglobin values less than 95 g/L are treated ideally by intravenous carboxymaltose, leading to more rapid haemoglobin recovery., Conclusion: New intravenous iron preparations such as iron carboxymaltose have an excellent efficacy, side effect profile and advantages as compared to oral iron preparations for particular clinical indications.

Normal pregnancy corresponds to a procoagulant state. Acute myocardial infarction during pregnancy is rare, yet considering the low non-pregnant risk score of childbearing women it is still surprisingly frequent. We report a case of postpartum recurrent non-ST elevation myocardial infarction in a 40-year-old caucasian woman with essential thrombocythaemia in the presence of a positive JAK-2 mutation and an elevated anti-cardiolipin IgM antibody titer. In the majority of cases of myocardial infarction in pregnancy or in the peripartal period, atherosclerosis, a thrombus or coronary artery dissection is observed. The combination of essential thrombocythaemia and elevated anti-cardiolipin IgM antibody titer in the presence of several cardiovascular risk factors seems to be causative in our case. In conclusion, with the continuing trend of childbearing at older ages, rare or unlikely conditions leading to severe events such as myocardial infarction must be considered in pregnant women.

Among the many cell types that may prove useful to regenerative medicine, mounting evidence suggests that human term placenta-derived cells will join the list of significant contributors. In making new cell therapy-based strategies a clinical reality, it is fundamental that no a priori claims are made regarding which cell source is preferable for a particular therapeutic application. Rather, ongoing comparisons of the potentiality and characteristics of cells from different sources should be made to promote constant improvement in cell therapies, and such comparisons will likely show that individually tailored cells can address disease-specific clinical needs. The principle underlying such an approach is resistance to the notion that comprehensive characterization of any cell type has been achieved, neither in terms of phenotype nor risks-to-benefits ratio. Tailoring cell therapy approaches to specific conditions also requires an understanding of basic disease mechanisms and close collaboration between translational researchers and clinicians, to identify current needs and shortcomings in existing treatments. To this end, the international workshop entitled "Placenta-derived stem cells for treatment of inflammatory diseases: moving toward clinical application" was held in Brescia, Italy, in March 2009, and aimed to harness an understanding of basic inflammatory mechanisms inherent in human diseases with updated findings regarding biological and therapeutic properties of human placenta-derived cells, with particular emphasis on their potential for treating inflammatory diseases. Finally, steps required to allow their future clinical application according to regulatory aspects including good manufacturing practice (GMP) were also considered. In September 2009, the International Placenta Stem Cell Society (IPLASS) was founded to help strengthen the research network in this field.

Purpose: In this study we examined the arterial-adaptive dilatation and Doppler velocimetry, especially RI values, in normal fetuses with a single umbilical artery (SUA)., Materials and Methods: We studied 195 fetuses from 18 to 39 weeks of gestational age with a prenatally identified SUA retrospectively. They were enrolled in this study if the following information applied: > 18 weeks of gestational age, no structural or chromosomal abnormalities, and histopathological confirmation of SUA. Sonographic examination included evaluation of the umbilical artery resistance and the cross-sectional area of the umbilical cord, and its vessels were measured in all cases. Small for gestational age (SGA) was diagnosed when the birth weight was below the 10th percentile for gestational age. Fetuses with intrauterine growth restriction were defined as those with biometric data below the 5th percentile., Results: There were 119 cases of prenatally identified SUA which met the inclusion criteria. RI values were below the 10th percentile in 33/119 (27.33) and below the 50th percentile in 73/119 (61.33). RI values below the 10th percentile were significantly more likely to be in the normal collective than in the growth restricted collective [31/87 (35.63%) vs. 2/32 (6.25%); p = 0.001]. Even more significant differences became apparent when comparing the RI values below the 50th percentile of both groups. An umbilical artery diameter over the 90th percentile was found in 49 (41.9%) of cases and was significantly more likely to be present in normal growing fetuses than in the growth restricted group., Conclusion: Normal fetuses with SUA are at higher risk to be born as SGA. With our study results we can confirm the hypothesis that Doppler flow measurements and arterial diameter in SUA are different from those found in normal fetal umbilical arteries. RI values over the 50th percentile or a cross-sectional area of the artery below 95th percentile after 26th week of gestation significantly increases the risk of SGA., (Georg Thieme Verlag KG Stuttgart, New York.)