Beyond defence: Immune architects of ovarian health and disease.

Throughout the individual's reproductive period of life the ovary undergoes continues changes, including cyclic processes of cell death, tissue regeneration, proliferation, and vascularization. Tissue-resident leucocytes particularly macrophages, play a crucial role in shaping ovarian function and maintaining homeostasis. Macrophages crucially promote angiogenesis in the follicles and corpora lutea, thereby supporting steroidogenesis. Recent research on macrophage origins and early tissue seeding has unveiled significant insights into their role in early organogenesis, e.g. in the testis. Here, we review evidence about the prenatal ovarian seeding of leucocytes, primarily macrophages with angiogenic profiles, and its connection to gametogenesis. In the prenatal ovary, germ cells proliferate, form cysts, and undergo changes that, following waves of apoptosis, give rice to the oocytes contained in primordial follicles. These follicles constitute the ovarian reserve that lasts throughout the female's reproductive life. Simultaneously, yolk-sac-derived primitive macrophages colonizing the early ovary are gradually replaced or outnumbered by monocyte-derived fetal macrophages. However, the cues indicating how macrophage colonization and follicle assembly are related are elusive. Macrophages may contribute to organogenesis by promoting early vasculogenesis. Whether macrophages contribute to ovarian lymphangiogenesis or innervation is still unknown. Ovarian organogenesis and gametogenesis are vulnerable to prenatal insults, potentially programming dysfunction in later life, as observed in polycystic ovary syndrome. Experimental and, more sparsely, epidemiological evidence suggest that adverse stimuli during pregnancy can program defective folliculogenesis or a diminished follicle reserve in the offspring. While the ovary is highly sensitive to inflammation, the involvement of local immune responses in programming ovarian health and disease remains to be thoroughly investigated.

National and International Comparisons of Gynecological Research in Germany Based on a Bibliometric Analysis of Publications.

Background: Recent years have seen a considerable shift from male doctors to female doctors in the field of gynecology. Female doctors are traditionally more involved with planning and maintaining their family. For gynecology, this could be associated with a risk that research activities will decrease, particularly if results are published in scientific journals. Methods: In view of this shift, a comparative observational study was carried for 2022 in which 1306 publications were matched to 1786 female and male doctors reported on the websites of the 44 locations of university gynecology departments in Germany. In addition, the volume of publications issued between 2014 and 2022 was compared for Germany, France, the United Kingdom, and the United States. In Germany, the volume of publications in Gynecology was additionally compared with the publication outputs of the specialties Urology and Trauma Surgery. Results: Since 2014, the increase in the numbers of publications in the field of Gynecology in Germany was lower (225%) than that of the countries with which it was compared (238%/252%/260% for F/UK/USA). When Gynecology was compared with other medical specialties in Germany, the number of publications in Urology were found to have increased at a lower rate (196%) while the number of publications in the field of Trauma Surgery increased by more (286%) than that of Gynecology. At the start of 2023, the percentage of women who were working as doctors at the lowest hierarchical level (junior doctor) was 81%. The publication output per capita of female doctors working at lower levels in the medical hierarchy, i.e., working as junior doctors and senior physicians, was between 40% and 80% lower than that of male doctors working at the same level. However, female directors published as much as male directors did. In the lower hierarchy levels, men were up to 14% more likely to be without an academic title. Predictors for more extensive publication activities by young female and male doctors include the extent and quality of publications by doctors in senior positions, the presence of a comprehensive cancer center or an institute for human genetics at the location where the young doctors were working, and joint publications with foreign authors. Conclusion: For the German Society of Gynecology and Obstetrics, the results suggest a number of approaches to promote young researchers. The support provided to young female doctors is especially important as this should help to retain them as junior researchers over the long term.

Fetoscopic laser coagulation for twin-to-twin transfusion syndrome: a comparison of flexible 1.0/1.2 mm fetoscopes with curved sheaths of 2.7/3.3 mm2 vs. 2 mm fetoscopic lens technique with sheaths of 6.6/11.3 mm2.

OBJECTIVES: Fetoscopic laser coagulation of placental anastomoses is usually performed for a treatment of twin-to-twin transfusion syndrome (TTTS). A common complication of fetoscopic laser coagulation for TTTS is preterm preliminary rupture of fetal membranes (PPROM) aggravating the neonatal outcome significantly. However, use of an flexible 1 mm fetoscope with an curved sheath could reduce iatrogenic damage of the amniotic membrane and improve neonatal outcomes after laser treatment. The aim of this study was to compare neonatal outcomes using this flexible fetoscope with curved sheath vs. use of a standard lens technique. METHODS: Outcomes were retrospective analyzed after use of a standard lens fetoscope of 2 mm (sheath 6.63 mm2 or 11.27 mm2 for anterior placenta) and a flexible fetoscope of 1 mm or 1.2 mm (sheath 2.65 mm2 or 3.34 mm2) in two German centers of fetal surgery, performed during 2006-2019. RESULTS: Neonatal outcome of 247 TTTS patients were analyzed including the rates of double and single fetal survival. The survival of at least one fetus was 97.2 % in the group with the ultrathin technique (n=154) compared to 88.3 % (n=93) in the group with the standard lens fetoscope (p=0.008). Survival of both fetuses was not different between groups (81.0 vs. 75.3 %). The procedure to delivery interval was significantly increased using the ultrathin fetoscope (89.1±35.0 d vs. 71.4±35.4 d, p=0.001) resulting in an increased gestational age at delivery by 11 days on average (231.9±28.1 d vs. 221.1±32.7 d, p=0.012). CONCLUSIONS: Fetal survival can be significantly increased following TTTS using flexible fetoscope of 1 mm or 1.2 mm (sheath 2.65 mm2 or 3.34 mm2).

The Impact of Increased Maternal sFlt-1/PlGF Ratio on Motor Outcome of Preterm Infants.

Background: The sFlt-1 (soluble fms-like tyrosine kinase-1)/PlGF (placental growth factor) ratio serves as a clinical biomarker to predict the hypertensive, placenta-derived pregnancy disorder pre-eclampsia which is often associated with placental dysfunction and fetal growth restriction. Additionally elevated levels also indicate an increased risk for prematurity. However, its predictive value for subsequent neonatal neurological outcome has not been studied. Objective: This study aimed to evaluate the correlation of maternal sFlt-1/PlGF ratio with early motor outcome of preterm infants. Design/Methods: 88 preterm infants (gestational age ≤ 34 + 0) born between February 2017 and August 2020 at the Department of Obstetrics and Gynecology, University Hospital Essen in Germany, were included, when the following variables were available: maternal sFlt-1/PlGF levels at parturition and general movement assessment of the infant at the corrected age of 3 to 5 months. The infants were stratified into high and low ratio groups according to maternal sFlt-1/PlGF cut-off values of 85. To investigate the early motor repertoire and quality of spontaneous movements of the infant, the Motor Optimality Score (MOS-R) based on antigravity movements and posture patterns, was applied. In the given age, special attention was paid to the presence of fidgety movements. Linear regressions were run to test differences in infants motor repertoire according to the maternal sFlt-1/PIGF ratio. Results: Linear regression analysis showed that the sFlt-1/PlGF ratio does not predict the MOS-R score (ß=≤0.001; p=0.282). However, children with birth weight below the 10th percentile scored significantly lower (mean 20.7 vs 22.7; p=0.035). These children were 91% in the group with an increased ratio, which in turn is a known predictor of low birth weight (ß= -0.315; p <0.001). In the group with a high sFlt-1/PLGF ratio above 85 the mothers of female infants had a lower average sFlt-1/PlGF ratio compared to a male infant (median: 438 in female vs. 603 in male infant, p=0.145). Conclusions: In our cohort, especially low birth weight, which correlated with an elevated sFlt-1/PlGF ratio, had a negative effect on the outcome in the MOS-R. A direct correlation between an increased ratio and a worse motor outcome was not demonstrated.

Latency duration of preterm premature rupture of membranes and neonatal outcome: a retrospective single-center experience.

In preterm premature rupture of membranes (PPROM), a decision between early delivery with prematurity complications and pregnancy prolongation bearing the risk of chorioamnionitis has to be made. To define disadvantages of delayed prolongation, latency duration of PPROM in expectantly managed pregnancies was investigated. We included those PPROMs > 48 h leading to preterm birth prior 37 weeks' gestation and retrospectively analyzed 84 preterm infants fulfilling these criteria. The association between latency duration/appearance of PPROM and respiratory outcome (primary outcomes) and neurological outcome (secondary outcomes) was investigated. The study showed that latency duration of PPROM is not associated with clinical or histological chorioamnionitis (p = 0.275; p = 0.332). As the numerous clinical parameters show multicollinearity between each other, we performed a multiple regression analysis to consider this fact. Respiratory distress syndrome is significantly associated with gestational age at PPROM (p < 0.001), and surfactant application is significantly associated with PPROM duration (p = 0.014). The other respiratory parameters including steroids and diuretics therapy, bronchopulmonary dysplasia, and the neurological parameters (intraventricular hemorrhage, Bayley II testing at a corrected age of 24 months) were not significantly associated with PPROM duration or gestational age at PPROM diagnosis.Conclusion: Latency duration of PPROM was not associated with adverse neonatal outcome in expectantly and carefully managed pregnancies, but respiratory distress syndrome was pronounced. The observed effect of pronounced respiratory distress syndrome can be treated with surfactant preparations and was not followed by increased rate of bronchopulmonary dysplasia. What is Known: • In case of preterm premature rupture of membranes, a decision between pregnancy prolongation with the risk of chorioamnionitis and early delivery with prematurity complications has to be made. • Chorioamnionitis is a dangerous situation for the pregnant woman and the fetus. • Impaired neurodevelopmental outcome is strongly correlated with pronounced prematurity due to the increased rate of serious complications. What is New: • Respiratory distress syndrome is significantly associated with gestational age at PPROM, and surfactant application is significantly associated with PPROM duration. • Latency duration of PPROM is not associated with adverse respiratory neonatal outcome (therapy with continuous positive airway pressure, therapy with diuretics and/or steroids, bronchopulmonary dysplasia) in expectantly and carefully managed pregnancies. • Intraventricular hemorrhage and Bayley II testing at a corrected age of 24 months are not associated with latency duration of PPROM when pregnancies are carefully observed.

Circulating Maternal sFLT1 (Soluble fms-Like Tyrosine Kinase-1) Is Sufficient to Impair Spiral Arterial Remodeling in a Preeclampsia Mouse Model.

[Figure: see text].

Human Cord Blood B Cells Differ from the Adult Counterpart by Conserved Ig Repertoires and Accelerated Response Dynamics.

Neonatal and infant immune responses are characterized by a limited capability to generate protective Ab titers and memory B cells as seen in adults. Multiple studies support an immature or even impaired character of umbilical cord blood (UCB) B cells themselves. In this study, we provide a comprehensive molecular and functional comparison of B cell subsets from UCB and adult peripheral blood. Most UCB B cells have a mature, naive B cell phenotype as seen in adults. The UCB Ig repertoire is highly variable but interindividually conserved, as BCR clonotypes are frequently shared between neonates. Furthermore, UCB B cells show a distinct transcriptional program that confers accelerated responsiveness to stimulation and facilitated IgA class switching. Stimulation drives extensive differentiation into Ab-secreting cells, presumably limiting memory B cell formation. Humanized mice suggest that the distinctness of UCB versus adult B cells is already reflected by the developmental program of hematopoietic precursors, arguing for a layered B-1/B-2 lineage system as in mice, albeit our findings suggest only partial comparability to murine B-1 cells. Our study shows that UCB B cells are not immature or impaired but differ from their adult mature counterpart in a conserved BCR repertoire, efficient IgA class switching, and accelerated, likely transient response dynamics.

Abnormal expression of the costimulatory molecule B7-H4 in placental chorionic villous and decidual basalis tissues of patients with preeclampsia and HELLP syndrome.

BACKGROUND: B7-H4, a checkpoint molecule of the B7 family, regulates a broad spectrum such as T-cell activation, cytokine secretion, tumour progression, and invasion capacities. Our previous data revealed that soluble B7-H4 (sB7-H4) blood serum levels are elevated in women at high risk for the hypertensive pregnancy disorder preeclampsia (PE) in the first trimester, as well as in patients with confirmed early/late-onset PE. AIM: We here aim to investigate the expression pattern of B7-H4 in placental tissues of PE and HELLP Syndrome versus control group. METHODS: B7-H4 protein expression and localization were investigated by immunoblotting and co-immunohistochemistry in placental chorionic villous and decidual basalis tissues. RESULTS: B7-H4 protein was prominently expressed at the cell membrane, in the cytoplasm of the syncytiotrophoblast (STB) and interstitial extravillous trophoblast (EVT). B7-H4 protein levels in placental chorionic villous tissue were significantly higher in women with early-onset/late-onset PE and HELLP, while it was decreased in decidual basalis tissues of early-onset PE and HELLP compared with controls. CONCLUSION: B7-H4 was inversely expressed in placental chorionic villous and decidual basalis tissues of PE and HELLP patients. The increase in B7-H4 in the STB in PE and HELLP may lead to excessive apical expression and release of soluble B7-H4 in the maternal circulation. In contrast, the decrease in B7-H4 in decidual basalis tissues could be related to the decrease in invasion ability of the EVT in PE. Thus, the current results strongly suggest that B7-H4 is involved in the pathogenesis of PE and HELLP.

Evaluation of carcinoembryonic antigen-related cell adhesion molecule 1 blood serum levels in women at high risk for preeclampsia.

PROBLEM: The aim of this study was to evaluate the sCEACAM1 concentrations in serum from patients in the first trimester who have a high risk for developing PE during pregnancy. METHOD OF THE STUDY: Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) levels were determined with ELISA. The patients (n = 109) were divided into two groups: patients who have a high risk of developing PE early-onset and a control group. Patients who have a high risk of developing PE were then divided into two subgroups depending on PE development in third trimester of pregnancy: PE in third trimester versus no PE in third trimester. RESULTS: sCEACAM1 concentrations in patients who were screened as having a high risk for developing PE were significantly higher than in healthy pregnant women in the first trimester (p = .03). The highest sCEACAM1 concentration was found in the high-risk group with PE development compared to the control group (p = .004). CONCLUSION: Elevated sCEACAM1 blood serum levels in women with PE suggest that there is immune dysregulation in early pregnancy, which may be helpful in PE prediction and therapy.

CCN3 Signaling Is Differently Regulated in Placental Diseases Preeclampsia and Abnormally Invasive Placenta.

Objectives: An adequate development of the placenta includes trophoblast differentiation with the processes of trophoblast migration, invasion, cellular senescence and apoptosis which are all crucial to establishing a successful pregnancy. Altered placental development and function lead to placental diseases such as preeclampsia (PE) which is mainly characterized by insufficient trophoblast invasion and abnormally invasive placenta (AIP) disorders (Placenta accreta, increta, or percreta) which are characterized by excessive trophoblast invasion. Both of them will cause maternal and fetal morbidity/mortality. However, the etiology of these diseases is still unclear. Our previous study has shown that the matricellular protein nephroblastoma overexpressed (NOV, CCN3) induces G0/G1 cell cycle arrest, drives trophoblast cells into senescence and activates FAK and Akt kinases resulting in reduced cell proliferation and enhanced migration capability of the human trophoblast cell line SGHPL-5. The present study focuses on whether CCN3 can alter cell cycle-regulated pathways associated with trophoblast senescence and invasion activity in pathological versus gestational age-matched control placentas. Methods: Cell cycle regulator proteins were investigated by immunoblotting and qPCR. For localization of CCN3, p16, p21, and Cyclin D1 proteins, co-immunohistochemistry was performed. Results: In early-onset PE placentas, CCN3 was expressed at a significantly lower level compared to gestational age-matched controls. The decrease of CCN3 level is associated with an increase in p53, Cyclin E1 and pRb protein expression, whereas the level of cleaved Notch-1, p21, Cyclin D1, pFAK, pAKT, and pmTOR protein decreased. In term AIP placentas, the expression of CCN3 was significantly increased compared to matched term controls. This increase was correlated to an increase in p53, p16, p21, Cyclin D1, cleaved Notch-1, pFAK, pAkt, and pmTOR whereas pRb was significantly decreased. However, in late PE and early AIP placentas, no significant differences in CCN3, p16, p21, Cyclin D1, p53, and cleaved Notch-1 expression were found when matched to appropriate controls. Conclusions: CCN3 expression levels are correlated to markers of cell cycle arrest oppositely in PE and AIP by activating the FAK/AKT pathway in AIP or down-regulating in PE. This may be one mechanism to explain the different pathological features of placental diseases, PE and AIP.

Further evidence for POMK as candidate gene for WWS with meningoencephalocele.

BACKGROUND: Walker-Warburg syndrome (WWS) is a rare form of alpha-dystroglycanopathy characterized by muscular dystrophy and severe malformations of the CNS and eyes. Bi-allelic pathogenic variants in POMK are the cause of a broad spectrum of alpha-dystroglycanopathies. POMK encodes protein-O-mannose kinase, which is required for proper glycosylation and function of the dystroglycan complex and is crucial for extracellular matrix composition. RESULTS: Here, we report on male monozygotic twins with severe CNS malformations (hydrocephalus, cortical malformation, hypoplastic cerebellum, and most prominently occipital meningocele), eye malformations and highly elevated creatine kinase, indicating the clinical diagnosis of a congenital muscular dystrophy (alpha-dystroglycanopathy). Both twins were found to harbor a homozygous nonsense mutation c.640C>T, p.214* in POMK, confirming the clinical diagnosis and supporting the concept that POMK mutations can be causative of WWS. CONCLUSION: Our combined data suggest a more important role for POMK in the pathogenesis of meningoencephalocele. Only eight different pathogenic POMK variants have been published so far, detected in eight families; only five showed the severe WWS phenotype, suggesting that POMK-associated WWS is an extremely rare disease. We expand the phenotypic and mutational spectrum of POMK-associated WWS and provide evidence of the broad phenotypic variability of POMK-associated disease.

Fetal subdural hematoma, sickle cell disease and storage pool disease: A case report.

A fetal subdural hematoma (SDH) was diagnosed in a patient with sickle cell disease (SCD) during a routine ultrasound exam in the 30th week of pregnancy. A scan performed a few days earlier had revealed no abnormalities. After interdisciplinary consultation with neurosurgeons and neonatologists, a cesarean section was performed since acute subdural bleeding was hypothesized and the mother's condition was critical. After surgery, the diagnostic procedures revealed that the child and the mother had also suffered from thrombocytopathy, which probably jointly contributed to causing the bleeding; in general, anemia and hypoxia may also play an important role. The newborn had a good neurological outcome. Ultrasound features do not reflect the underlying cause and therefore predicting the prognosis is challenging. In most cases, prenatal counseling is difficult because of the unknown underlying cause and because there are no ultrasound or magnetic resonance imaging criteria to define which cases can benefit from delivery or expectant management. Where there is acute bleeding, the child could benefit from delivery and surgical evacuation of the hematoma. Further investigation to identify the cause of the bleeding can improve management and prognosis.

Human multipotent hematopoietic progenitor cell expansion is neither supported in endothelial and endothelial/mesenchymal co-cultures nor in NSG mice.

Endothelial and mesenchymal stromal cells (ECs/MSCs) are crucial components of hematopoietic bone marrow stem cell niches. Both cell types appear to be required to support the maintenance and expansion of multipotent hematopoietic cells, i.e. hematopoietic stem cells (HSCs) and multipotent progenitors (MPPs). With the aim to exploit niche cell properties for experimental and potential clinical applications, we analyzed the potential of primary ECs alone and in combination with MSCs to support the ex vivo expansion/maintenance of human hematopoietic stem and progenitor cells (HSPCs). Even though a massive expansion of total CD34+ HSPCs was observed, none of the tested culture conditions supported the expansion or maintenance of multipotent HSPCs. Instead, mainly lympho-myeloid primed progenitors (LMPPs) were expanded. Similarly, following transplantation into immunocompromised mice the percentage of multipotent HSPCs within the engrafted HSPC population was significantly decreased compared to the original graft. Consistent with the in vitro findings, a bias towards lympho-myeloid lineage potentials was observed. In our conditions, neither classical co-cultures of HSPCs with primary ECs or MSCs, even in combination, nor the xenograft environment in immunocompromised mice efficiently support the expansion of multipotent HSPCs. Instead, enhanced expansion and a consistent bias towards lympho-myeloid committed LMPPs were observed.

Reliability of prenatal detection of X-linked hypohidrotic ectodermal dysplasia by tooth germ sonography.

OBJECTIVE: In X-linked hypohidrotic ectodermal dysplasia (XLHED), dysfunction of ectodysplasin A1 (EDA1) due to EDA mutations results in malformation of hair, teeth, and sweat glands. Hypohidrosis, which can cause life-threatening hyperthermia, is amenable to intrauterine therapy with recombinant EDA1. This study aimed at evaluating tooth germ sonography as a noninvasive means to identify affected fetuses in pregnant carrier women. METHODS: Sonography, performed at 10 study sites between gestational weeks 18 and 28, led to the diagnosis of XLHED if fewer than six tooth germs were detected in mandible or maxilla. The assessment was verified postnatally by EDA sequencing and/or clinical findings. Estimated fetal weights and postnatal weight gain of boys with XLHED were assessed using appropriate growth charts. RESULTS: In 19 of 38 sonographic examinations (23 male and 13 female fetuses), XLHED was detected prenatally. The prenatal diagnosis proved to be correct in 37 cases; one affected male fetus was missed. Specificity and positive predictive value were both 100%. Tooth counts obtained by clinical examination corresponded well with findings on panoramic radiographs. We observed no weight deficits of subjects with XLHED in utero but occasionally during infancy. CONCLUSION: Tooth germ sonography is highly specific and reliable in detecting XLHED prenatally.

Trends in anti-Müllerian hormone concentrations across different stages of pregnancy in women with polycystic ovary syndrome.

RESEARCH QUESTION: What are the trends in anti-Müllerian hormone (AMH) concentrations from pre-conception to the third trimester of pregnancy in women with polycystic ovary syndrome (PCOS)? DESIGN: Observational study including cross-sectional and longitudinal data analysis. The Beckman Coulter AMH Gen II Assay was used to determine AMH levels longitudinally before pregnancy from 52 women with PCOS and 51 controls during all trimesters. Differences in AMH levels across successive stages of pregnancy were examined with the Wilcoxon signed-rank test for paired values. Linear regression models, adjusted for body-mass index (BMI), gestational and maternal age were used to compare AMH levels of PCOS and controls. RESULTS: AMH levels decreased significantly (all P < 0.05) from pre-pregnancy level throughout each trimester in women with PCOS and healthy controls. After adjusting for maternal age, gestational age and maternal BMI, AMH levels before pregnancy were 1.89 (95% CI 1.46 to 2.44; P < 0.0001) times higher among women with PCOS compared with controls (median 7.66 versus 2.67 ng/ml). During the first trimester, AMH levels were 1.61 (95% CI 1.22 to 2.13; P = 0.001) times higher among women with PCOS compared with controls (median 5.33 versus 2.48 ng/ml). Differences in AMH levels between women with PCOS and controls in the second trimester (1.68 times higher; 95% CI 0.94 to 3.01; median: 5.50 versus 2.20 ng/ml) and the third trimester (1.45 times higher; 95% CI 1.01 to 2.07; median: 1.36 versus 1.06 ng/ml) were not statistically significant. CONCLUSION: These findings indicate a pregnancy-associated AMH-decline independent of pre-pregnancy elevated AMH levels.

Tight interplay in early pregnancy between follistatin and anti-mullerian hormone in women with polycystic ovarian syndrome (PCOS).

PURPOSE: Follistatin levels increase during the course of pregnancy and may play a role in ovarian arrest, reflected by the simultaneous decrease of anti-mullerian-hormone (AMH) levels. The aim of the study was to investigate AMH and follistatin levels during the hormonal window at the beginning of pregnancy. Since both parameters are described as deregulated in polycystic ovarian syndrome (PCOS), subgroup analysis of PCOS patients may additionally elucidate their interplay and effects on ovarian activity. METHODS: Serum samples were retrospectively analyzed using the AMH Gen II ELISA and the Human Follistatin Quantikine ELISA Kit. Samples were collected longitudinally from 57 patients (32 with PCOS and 25 controls) before conception and during the first trimester. In 18 patients, measurements from the early and the late first trimester were available. Potential associations of AMH and follistatin levels with PCOS-related parameters were compared between the subgroups as well as longitudinally before and in the first trimester of pregnancy. For statistical analysis, the Spearman's correlation, Wilcoxon test, t test, Friedman test and multiple linear regression analysis was performed. RESULTS: In contrast to AMH, follistatin levels differed not between controls and PCOS patients before and in pregnancy. In both subgroups, AMH levels significantly decreased and follistatin levels significantly increased in longitudinally performed measurements before conceiving and in the first trimester of pregnancy. CONCLUSION: Follistatin levels are not suited as a biomarker for PCOS, but could be involved in suppressing ovarian activity, as reflected by AMH levels at the beginning of pregnancy.

Soluble CEACAM1 and CEACAM6 are differently expressed in blood serum of pregnant women during normal pregnancy.

PROBLEM: CEACAM1 and CEACAM6 belong to the carcinoembryonic antigen (CEA) family and may play an immune-modulatory role during pregnancy. The aim of the study was to determine the blood serum levels of soluble CEACAM1 and CEACAM6 over the course of pregnancy and postpartum. METHOD OF STUDY: CEACAM1 and CEACAM6 levels were determined with customized in-house Sandwich-enzyme-linked immunosorbent assay (ELISA) systems. The study population (n=125) was divided into four groups according to the pregnancy trimester and postpartum. Additionally, samples of non-pregnant women (n=14) were analyzed. RESULTS: Serum levels of CEACAM1 in healthy pregnant women were much lower than in non-pregnant women, a difference not seen for CEACAM6. Comparison between the trimesters and postpartum revealed a significant difference in CEACAM1 serum levels. The highest CEACAM1 levels were detected in third trimester. These levels were statistically significantly different from the CEACAM1 levels in first trimester and second trimester. The lowest levels were observed in the second trimester. Postpartum CEACAM1 serum concentrations were slightly lower than in the third trimester, but higher than in the first trimester and significantly higher compared to levels in the second trimester. CONCLUSION: Decreased concentration of CEACAM1 during the pregnancy suggests its regulatory role in the immune tolerance during the course of pregnancy.

Impact of maternal serum levels of Visfatin, AFP, PAPP-A, sFlt-1 and PlGF at 11-13 weeks gestation on small for gestational age births.

OBJECTIVE: Investigating potential value of maternal serum Visfatin, sFlt-1, PlGF, AFP, PAPP-A levels at first trimester for prediction of small for gestational age (SGA) at birth. METHODS: Measurements were performed in 20 SGA and 65 control cases. Logistic regression analysis adjusted for age and weeks of pregnancy at data collection was performed to estimate odds ratios (OR), 95% confidence intervals (95% CI) and p values separately for each potential predictor. A multiple regression model was used to assess the impact of all the promising predictors adjusted for each other. Receiver operating characteristic (ROC) analysis was used to indicate the ability to discriminate between SGA cases and controls. RESULTS: There was an association of serum PlGF levels (OR 0.53 per interquartile range [IQR] increase in PlGF; 95% CI 0.24-1.16), sFlt-1/PlGF ratio (OR 1.42 per IQR increase in sFlt-1/PlGF; 95% CI 1.03-1.96), serum Visfatin levels (OR 0.31 per IQR increase in Visfatin; 95% CI 0.10-0.95) and smoking (OR 4.24; 95% CI 1.10-16.37) with SGA at birth. CONCLUSIONS: Associations between SGA and lower PlGF, Visfatin levels as well as increased sFlt-1/PlGF ratio and smoking status were detected which may contribute to predict SGA.

CD133 allows elaborated discrimination and quantification of haematopoietic progenitor subsets in human haematopoietic stem cell transplants.

The success of haematopoietic stem cell (HSC) transplantation largely depends on numbers of transplanted HSCs, which reside in the CD34(+) populations of bone marrow (BM), peripheral blood stem cells (PBSC) and umbilical cord blood (UCB). More specifically HSCs reside in the CD38(low/-) subpopulation, which cannot be objectively discriminated from mature CD34(+)  CD38(+) progenitors. Thus, better marker combinations for the quantification of more primitive haematopoietic stem and progenitor cells in transplants are required. Recently, by combining CD34 and CD133 we could clearly distinguish CD133(+)  CD34(+) multipotent and lympho-myeloid from CD133(low)  CD34(+) erythro-myeloid progenitors in UCB samples. To qualify the assessment of CD133 for routine quality control of adult HSC sources, we analysed the developmental potentials of CD133(+) and CD133(low) subpopulations in BM and PBSC. Similar to UCB, CD133 expression objectively discriminated functionally distinct subpopulations in adult HSC sources. By implementing anti-CD45RA staining, which separates multipotent (CD133(+)  CD34(+)  CD45RA(-) ) from lympho-myeloid (CD133(+)  CD34(+)  CD45RA(+) ) progenitor fractions, UCB was found to contain 2-3 times higher multipotent progenitor frequencies than BM and PBSC. To test for the consistency of CD133 expression, we compared CD133(+)  CD34(+) contents of 128 UCB samples with maternal and obstetrical factors and obtained similar correlations to related studies focusing on CD34(+) cell contents. In conclusion, implementation of anti-CD133 staining into existing routine panels will improve the quality control analyses for HSC transplants.

Intraindividual right-left comparison of sonographic features in polycystic ovary syndrome (PCOS) diagnosis.

OBJECTIVE: Sonographic features of polycystic ovaries consist of elevated antral follicle count or ovarian volume of at least one ovary. The aim of this prospective cross-sectional study was to estimate intraindividual differences in sonographic measurements between the both ovaries of PCOS patients and controls and clinical consequences. STUDY DESIGN: Both ovaries of 85 PCOS patients and 48 controls were scanned transvaginally and agreement of sonographic measurements was analyzed using the Bland-Altman method. Concordance correlation coefficients (CCC) were computed. RESULTS: Mean differences between right and left ovaries were 0.24 (95% confidence interval [95% CI]: -0.32-0.80) follicles for AFC and 1.14 (95% CI: 0.34-1.92)ml for OV in the whole study population, 0.14 (95% CI: -0.68-0.96) follicles for AFC and 1.48 (95% CI: 0.39-2.58)ml for OV in PCOS patients, 0.42 (95% CI: -0.19-1.02) follicles for AFC and 0.53 (95% CI: -0.50-1.56)ml for OV in controls. Rather wide limits of agreement and low CCCs (<0.7 for all estimates) indicated poor agreement between the ovaries for both sonographic measurements. Width between lower and upper limits of agreement was higher for PCOS patients than for controls. 23.5% of the PCOS patients showed polycystic ovarian morphology (PCOM) only in one ovary, resulting in 9.4% potentially missed PCOS diagnosis according to the Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group. CONCLUSION: Substantial differences in antral follicle count and ovarian volume between the right and left ovary were observed. In approximately 10% of the PCOS patients in our study only the examination of both ovaries has led to a reliable diagnosis of PCOS. In clinical practice it is recommended to scan both ovaries for a reliable diagnosis of abnormal sonographic findings in PCOM and PCOS diagnosis.