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Objective This study evaluates whether clinical phenotypes of small for gestational (SGA) fetuses can be identified and used for adverse perinatal outcome risk stratification to facilitate decision-making. Methods This multicentre observational cohort study was conducted in two tertiary care university hospitals. It included 17,631 consecutive singleton pregnancies, among which 1274 (7.2%) were defined as SGA at birth according to INTERGROWTH-21st standards. The main outcome was the development of clinical clusters of SGA phenotypes. Results Nine SGA clinical phenotypes were identified using a predefined conceptual framework. Every delivery and perinatal outcome analysed showed statistically significant differences between phenotypes. The total SGA cohort had a 3 times increased risk of perinatal mortality than non-SGA fetuses (1.4% vs 0.4%; pConclusions We identified nine SGA clinical phenotypes associated with different patterns of risk for adverse perinatal outcomes. Our results suggest that adding clinical characteristics to ultrasound results would improve risk stratification and decision-making for SGA fetuses. Future clinical trials on the control of fetuses with SGA should take into account, in addition to Doppler and estimated fetal weight, this clinical information.

Pregnancy planning in women with highly active multiple sclerosis (HAMS) who need a high-efficacy disease-modifying therapy (heDMT) currently requires a careful risk-benefit evaluation. This includes minimizing fetal drug toxicity and preventing MS reactivation. We describe our experience with natalizumab in women with HAMS and unplanned pregnancy by implementing a clinical practice protocol (NAP-30) designed to maintain the effectiveness of natalizumab during pregnancy, reduce fetal exposure and prevent complications.This was an observational retrospective study including women with HAMS on active treatment with natalizumab who became unexpectedly pregnant in the period 2018-2021 and continued this treatment during pregnancy according to the NAP-30 protocol. MS clinical and radiological variables were analyzed before and during pregnancy and in the postpartum period, along with maternal and fetal toxicity during pregnancy and safety findings in newborns. We also describe the NAP-30 protocol, which includes the use of a bridging dose to adjust and maintain natalizumab infusions every 6 weeks during pregnancy up to week 30 and scheduled delivery at week 40.Six women (one in her first gestation) with a median age of 31.5 years at the onset of pregnancy (min-max: 24-37 years) were included. All were negative for anti-John Cunningham virus (JCV) antibodies and were on treatment with intravenous natalizumab 300 mg every 4 weeks. At the time of conception, three patients had received 12, 17 and 53 infusions of natalizumab, respectively, while for the remaining three patients natalizumab was their first DMT (two patients had received 6 infusions and one patient had received 3 infusions of natalizumab). All six patients received 6 doses of natalizumab during pregnancy according to the NAP-30 protocol. After delivery, all six patients restarted natalizumab every 4 weeks (median: 3 days; range: 2-4 days). No patients had relapses during pregnancy or at 6 months postpartum, nor did they develop any general health or laboratory abnormalities. The MRI scan performed at 4-6 months postpartum showed no new T2 lesions or gadolinium-enhancing lesions. No miscarriages or threatened miscarriages were reported. One of the patients underwent elective preterm delivery at week 35 after mild-to-moderate anemia was detected by fetal Doppler scan. The newborn had low birth weight (2080 g) and mild anemia, which resolved within two months with oral iron supplementation. The other infants were born with normal birth weight and showed no blood count abnormalities. After a median follow-up of 10 months, all six babies showed normal development with no complications detected.Based on our experience, the implementation of the NAP-30 protocol in women with HAMS and unplanned pregnancy undergoing treatment with natalizumab allows the continuation of natalizumab during pregnancy, with a very favorable clinical and radiological effectiveness and maternal-fetal safety profile during pregnancy and postpartum. Both in pregnancy with HAMS and in general, and particularly for successful implementation of the NAP-30 protocol, obstetric support and monitoring is essential for adequate pregnancy management.

Objective: To determine the contribution of short femur diaphysis length (FDL) at 19–22 weeks of gestation in the prediction of adverse pregnancy outcomes. Methods: The study included singleton pregnant women who underwent a routine anomaly scan at 19–22 weeks of gestation at the Virgen de la Arrixaca University Clinical Hospital (Murcia, Spain) between August 2011 and August 2012. Fetal biometry and Doppler ultrasound of uterine arteries were assessed as part of the anomaly scan, and the mean pulsatility index of both uterine arteries was recorded. Maternal obstetric characteristics, such as ethnicity, age, weight, parity, cigarette smoking, and medical history including hypertension and diabetes mellitus were collected from our database system. Results: A total of 6,366 women were included in the study after excluding cases with abnormal karyotype, major fetal abnormalities, or termination of pregnancy. There were 88 cases of preeclampsia (PE) (1.4%). Logistic regression was performed including maternal and fetal characteristics. Short FDL at 19–22 weeks was significantly associated with subsequent development of PE (OR = 0.89, 95% CI: 0.80–0.99, p = 0.025). The best model to predict PE from our sample included gestational age at scan, parity, maternal weight, chronic hypertension, mean pulsatility index in the uterine arteries, and FDL (AUC = 0.78, 95% CI: 0.71–0.84). Regarding small for gestational age (SGA) neonates, there were also significant differences in FDL and FDL Discussion: Our results suggest that FDL at 19–22 weeks of gestation is an independent predictor of PE and SGA newborns.

Objective To evaluate the acceptability, tolerability, and effects on vulvovaginitis symptoms and signs of a non-soap, herbal-based intimate solution (Zelesse®). Methods We conducted a prospective, observational, multicenter study including adult women with symptoms and signs of vulvovaginitis with various etiologies, including candidiasis, trichomoniasis, bacterial vaginosis, and atrophic and irritative vaginitis. The presence and intensity of signs (edema, erythema, vaginal discharge) and symptoms (pruritus) of vulvovaginitis were evaluated before and after 5–15 days of daily use of Zelesse® alone or as a coadjuvant in antimicrobial therapy. Variables following a normal distribution and categorical variables were analyzed using the Student t-test and chi-square or Fisher’s exact test, respectively. Results A total 137 women were enrolled in the study; 87 (63.5%) women received concomitant antimicrobials and 50 (36.5%) used Zelesse® only. Global symptom scores and frequency of patients with vulvovaginitis signs and symptoms, and their mean intensity, decreased after treatment in both patient groups. Vaginal pH and (in the Zelesse®-only group) vaginal flora remained unaltered. The product was safe, well tolerated, and highly accepted by patients. Conclusions Zelesse®, the non-soap herbal-based solution in this study, may represent a safe and effective option for symptomatic relief of vulvovaginitis.

Objective: To examine the potential value of fetal ultrasound and maternal characteristics in the prediction of antepartum stillbirth after 32 weeks’ gestation. Methods: This was a retrospective multicenter study in Spain. In 29 pregnancies, umbilical artery pulsatility index (UA PI), middle cerebral artery pulsatility index (MCA PI), cerebroplacental ratio (CPR), estimated fetal weight (EFW), and maternal characteristics were recorded within 15 days prior to a stillbirth. The values of UA PI, MCA PI, and CPR were converted into multiples of the normal median (MoM) for gestational age and the EFW was expressed as percentile according to a Spanish reference range for gestational age. Data from the 29 pregnancies with stillbirths and 2298 control pregnancies resulting in livebirths were compared and multivariate logistic regression analysis was used to determine significant predictors of stillbirth. Results: The only significant predictor of stillbirth was CPR (OR ¼ 0.161, 95% confidence interval [CI] 0.035, 0.654; p¼.014); the area under the receiver operating characteristics curve was 0.663 (95% CI 0.545, 0.782) and the detection rate (DR) was 32.14% at a 10% false-positive rate (FPR). In addition, when we included MCA and UA PI MoM instead of CPR, only MCA PI MoM was significant (OR¼0.104, 95% confidence interval [CI] 0.013, 0.735; p¼.029), with similar prediction abilities (area under the curve (AUC) 0.645, DR 28.6%, FPR 10%). Conclusions: The CPR and MCA PI are predictors of late stillbirth but the performance of prediction is poor. pre-print 401 KB

Objective This study aimed to evaluate the evidence of mother-to-child transmission of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Methods This is a descriptive, multicenter, observational study in nine tertiary care hospitals throughout Spain. The study population was women with COVID-19 during pregnancy. Mother-to-child transmission was defined as positive real-time reverse-transcriptase-polymerase-chain-reaction (RT-PCR) of SARS-CoV-2 in amniotic fluid, cord blood, placenta or neonatal nasopharyngeal swabs taken immediately after birth. Results We included 43 singleton pregnant women and one twin pregnancy, thus we obtained 45 samples of placenta, amniotic fluid and umbilical cord blood. The median gestational age at diagnosis was 34.7 weeks (range 14 to 41.3). The median interval between positive RT-PCR and delivery was 21.5 days (range 0 to 141 days). Fourteen women (31.8%, 95%CI 18.6-47.6%) were positive at the time of delivery. There was one singleton pregnancy with SARS-CoV-2 RT-PCR positive in the placenta, amniotic fluid and umbilical cord blood (2.2%, 95%CI 0.1-11.8%). Nasopharyngeal aspiration was performed on 38 neonates at birth, all of which were negative (0%, 95%CI 0-9.3%). In 11 neonates the nasopharyngeal aspiration was repeated at 24-48 hours, and one returned positive (9.1%, 95%CI 0.2-41.3%). Conclusions The presence of the SARS-CoV-2 in placenta, amniotic fluid and cord blood shows that mother-to-child transmission is possible but uncommon.

Objectives A high ratio of soluble fms-like tyrosine kinase-1 (sFlt-1) to placental growth factor (PlGF) has been linked with pre-eclampsia (PE). We evaluated the sFlt-1/PlGF ratio as a predictive marker for early-onset PE in women at risk of PE. Methods This prospective, Spanish, multicenter study included pregnant women with PE risk factors (including: history of intrauterine growth restriction; PE; eclampsia; hemolysis, elevated liver enzymes and low platelet count syndrome; pre-gestational diabetes; and abnormal uterine artery Doppler ultrasound). The primary objective was to show that the sFlt-1/PlGF ratio at 20, 24, and 28 weeks’ gestation was predictive of early-onset PE (

Objective: Establish reference ranges for the Elecsys® soluble fms-like tyrosine kinase-1 (sFlt-1)/placental growth factor (PlGF) immunoassay ratio in twin pregnancies. Methods: Data analyzed were from 3 prospective studies: Prediction of Short-Term Outcome in Pregnant Women with Suspected Preeclampsia (PE) (PROGNOSIS), Study of Early-onset PE in Spain (STEPS), and a multicenter case-control study. Median, 5th, and 95th percentiles for sFlt-1, PlGF, and the sFlt-1/PlGF ratios were determined for normal twin pregnancies for 7 gestational windows and compared with the previous data for singleton pregnancies. Results: The reference range analysis included 269 women with normal twin pregnancies. Before 29 weeks’ gestation, median, 5th, and 95th percentiles for sFlt-1/PlGF ratios did not differ between twin and singleton pregnancies. From 29 weeks’ gestation to delivery, median, 5th, and 95th percentiles for sFlt-1/PlGF ratios were substantially higher in twin versus singleton pregnancies. sFlt-1 values were higher in women with twin pregnancies across all gestational windows. PlGF values were similar or higher in twin versus singleton pregnancies; PlGF concentrations increased from 10 weeks + 0 days to 28 weeks + 6 days’ gestation. Conclusions: Reference ranges for the sFlt-1/PlGF ratio are similar in women with twin and singleton pregnancies until 29 weeks’ gestation but appear higher in twin pregnancies thereafter.

Neonatal platelets are hypo-reactive to the tyrosine kinase-linked receptor agonist collagen. Here, we have investigated whether the hypo-responsiveness is related to altered levels of glycoprotein VI (GPVI) and integrin α2β1, or to defects in downstream signalling events by comparison to platelet activation by C-type lectin-like receptor 2 (CLEC-2). GPVI and CLEC-2 activate a Src- and Syk-dependent signalling pathway upstream of phospholipase C (PLC) γ2. Phosphorylation of a conserved YxxL sequence known as a (hemi) immunotyrosine-based-activation-motif (ITAM) in both receptors is critical for Syk activation. Platelets from human pre-term and full-term neonates display mildly reduced expression of GPVI and CLEC-2, as well as integrin αIIbβ3, accounted for at the transcriptional level. They are also hypo-responsive to the two ITAM receptors, as shown by measurement of integrin αIIbβ3 activation, P-selectin expression and Syk and PLCγ2 phosphorylation. Mouse platelets are also hypo-responsive to GPVI and CLEC-2 from late gestation to 2 weeks of age, as determined by measurement of integrin αIIbβ3 activation. In contrast, the response to G protein-coupled receptor agonists was only mildly reduced and in some cases not altered in neonatal platelets of both species. A reduction in response to GPVI and CLEC-2, but not protease-activated receptor 4 (PAR-4) peptide, was also observed in adult mouse platelets following immune thrombocytopenia, whereas receptor expression was not impaired. Our results demonstrate developmental differences in platelet responsiveness to GPVI and CLEC-2, and also following immune platelet depletion leading to reduced Syk activation. The rapid generation of platelets during development or following platelet depletion is achieved at the expense of signalling by ITAM-coupled receptors.

To determine the prevalence of genitourinary syndrome of menopause (GSM) and urogynecological conditions associated with menopause, and to evaluate the impact of GSM on quality of life in a cohort of Spanish postmenopausal women.Multicenter, cross-sectional, and observational study involving 430 women.The prevalence of GSM was 70%. GSM was diagnosed in 60.2% of women with no known diagnosis of vulvovaginal atrophy or GSM. Most prevalent symptoms were vaginal dryness (93.3%) and reduced lubrication with sexual activity (90.0%). Most prevalent signs were decreased moisture (93.7%) and loss of vaginal rugae (78.4%). GSM was significantly associated with stress or mixed urinary incontinence, overactive bladder, and vaginal prolapse. Symptoms showed a low-moderate impact on quality of life, mainly in sexual functioning and self-concept and body image.The GSM is very prevalent in Spanish postmenopausal women, affecting up to 70% of those consulting the gynecologist. Despite the high prevalence of symptoms and signs and its impact on the women's well-being, GSM remains underdiagnosed and undertreated. Given its relationship with urogynecological conditions, it seems necessary to provide an adequate evaluation of postmenopausal women for identifying potential co-morbidities and providing most adequate treatments. An adequate management of GSM will contribute to an improvement in the quality of life of these women.

Objective The objective of this study was to determine the contribution of uterine (UtA) and umbilical arteries (UA) Doppler examination at 28 weeks to predict adverse pregnancy outcomes in women who had increased resistance in UtA in the early second trimester. Methods Women with UtA mean pulsatility index (PI) above the 95th centile at 19–22 weeks of gestation were offered a growth scan including Doppler examination of UtA and UA at 28 weeks. Adverse pregnancy outcomes included small for gestational age (SGA), defined as birth weight below the tenth centile, preeclampsia (PE) and early-onset PE (PE before 34 weeks). Results We studied 266 pregnant women with elevated PI in the UtAs in the second trimester and ultrasound reassessment at 28 weeks. UtA PI >95th centile at 28 weeks was associated with subsequent PE [odds ratio (OR): 10.0, 95% CI: 2.3–43.5], early-onset PE (OR: 57.7, 95% CI: 3.8–87.6) and SGA less than the tenth centile (OR: 5.5, 2.2–13.9). UA PI >95th centile at 28 weeks was not significantly associated with any adverse outcome. Conclusions In women with abnormal UtA Doppler in the early second trimester scan, persistence of elevated UtA PI, but not abnormal UA PI, is associated with adverse pregnancy outcomes including PE, early-onset PE and SGA. © 2014 John Wiley & Sons, Ltd.

Neonatal platelets are hyporeactive and show impaired agonist-induced secretion despite no obvious abnormalities in their granules. Here, we examined, for the first time, the ultrastructure of neonatal and adult platelets following agonist activation. Under resting conditions, neonatal and adult platelets appeared ultrastructurally identical. Following agonist stimulation, however, noticeable degranulation occurred in adult platelets, while granules in neonatal platelets remained clearly visible and apparently unable to centralize or fuse. To investigate the underlying mechanisms, we first examined the expression levels of the main SNARE proteins, which mediate the membrane fusion events required for exocytosis. Neonatal platelets showed significantly reduced levels of syntaxin-11 and its regulator, Munc18b. Since granule centralization depends on contraction of the microtubule ring, we also examined the expression of its main component, β1-tubulin. Noteworthy, we found decreased TUBB1 mRNA and protein levels in neonatal platelets, while TUBB2A and TUBB isoforms were overexpressed, partially compensating for that deficiency. Finally, supporting the functional consequences of defective exocytosis, adhesion kinetic assays, performed in plasma-free medium, demonstrated delayed adhesion and spreading of neonatal platelets. This is the first report showing marked reductions of syntaxin-11–Munc18b complex and β1-tubulin in neonatal platelets, indicating that these proteins, required for platelet degranulation, are developmentally regulated.

The purpose of this study is to investigate the potential role of the mean external iliac artery pulsatility index (EIA-PI) as a predictor of adverse obstetric outcomes such as preeclampsia, gestational hypertension and small for gestational age (SGA).In women attending for first trimester screening at 11 + 0-13 + 6 weeks of gestation, we recorded maternal characteristics and measured EIA mean PI and uterine artery mean PI. We compared EIA mean PI in those that developed preeclampsia (n = 84), gestational hypertension (n = 50) or small for gestational age (n = 444) with those unaffected (n = 3736). Regression analysis was used to first determine which of the factors among the maternal variables were significant predictors of EIA mean PI in the unaffected group and, second, to predict adverse pregnancy outcomes.In the unaffected group, EIA mean PI increased with maternal age and decreased with mean blood pressure. Additionally, EIA mean PI was lower in cigarette smokers. Compared with the unaffected group, EIA mean PI was significantly lower in women who develop gestational hypertension or SGA below third centile.EIA mean PI in the first trimester is decreased in women who develop gestational hypertension and in those complicated by SGA below third centile. More studies are needed to confirm these findings.

Objective The aim of this study was to determine the clinical utility of Doppler assessment of the umbilical artery in the second trimester scan for predicting adverse pregnancy outcomes. Methods Singleton pregnancies that had undergone routine anomaly scan at 19 to 22 weeks of gestation with umbilical and uterine artery Doppler measurements. Receiver operating characteristic curves were constructed to evaluate the ability of umbilical artery pulsatility index (PI) to predict small for gestational age and preeclampsia. Results The final study population comprised 4565 singleton pregnancies. Multiple regression analysis showed significant independent contribution of umbilical artery PI in predicting SGA 90th centile, the likelihood ratio of SGA

Introduction The soluble fms-like tyrosine kinase 1 (sFlt-1)/placental growth factor (PlGF) ratio is CE-mark approved for short-term prediction of preeclampsia in women with clinical suspicion of the syndrome (gestational age 24weeks+0d–36weeks+6d). Objectives We evaluated sFlt-1/PlGF as a predictive marker for early-onset preeclampsia in women at high risk of preeclampsia. Methods STEPS (prospective/multicenter) included pregnant women with preeclampsia risk factors (including history of IUGR/preeclampsia/eclampsia/HELLP syndrome, pre-gestational diabetes, antiphospholipid antibodies, and abnormal uterine artery Doppler). Primary objective: to show that sFlt-1/PlGF was predictive of early-onset preeclampsia ( ® sFlt-1 and PlGF assays, cobas electrochemiluminescence platform, Roche Diagnostics, Germany); bilateral uterine artery Doppler; blood pressure/proteinuria/preeclampsia status assessment. Results were compared by ANOVA/Dunnet and Wilcoxon signed-rank test. For prediction of early-onset preeclampsia, the area under the curve (AUC) of receiver operating characteristic curves (ROC) was calculated. Singleton pregnancies are reported. Results 819 subjects were enrolled. Of 442 women with singleton pregnancies 42 (9.5%) developed preeclampsia (14 early-onset/28 late-onset). The mean (SD) sFlt-1/PlGF ratio at 20, 24, and 28 weeks was: 7.86 (8.61), 5.9 (12.38) and 4.59 (5.65) for subjects who did not develop preeclampsia (control); 53.15 (61.79), 69.25 (105.53) and 180.37 (241.83) for early-onset preeclampsia; and 7.81 (4.45), 5.09 (3.34) and 13.39 (34.52) for late-onset preeclampsia. Compared with early-onset preeclampsia the sFlt-1/PlGF ratio was significantly lower for control, chronic hypertension, transient hypertension, and late-onset preeclampsia (Figure). Prediction of early-onset preeclampsia (ROC AUC [95% CI]) was best for sFlt-1/PlGF plus clinical data (0.94 [0.90–0.98], 0.94 [0.89–1.0], 0.94 [0.86–1.0], at 20, 24 and 28 weeks) vs sFlt-1/PlGF alone (0.78 [0.62–0.95], 0.82 [0.65–0.98], 0.86 [0.72–1.0]) or Doppler alone (0.71 [0.56–0.86], 0.73 [0.54–0.91], 0.87 [0.74–1.0]). Conclusion The sFlt-1/PlGF ratio can improve prediction of early-onset preeclampsia for women at high risk of preeclampsia.

To compare the time in the third stage of labour, differences in maternal hematologic parameters 48h after birth and acid-base status in the umbilical cord between the early cord clamping (ECC) and delayed cord clamping (DCC).97 healthy pregnancies at term and a spontaneous vertex delivery at Clinic University Hospital "Virgen de la Arrixaca" (Murcia, Spain), were randomized to ECC group (10s post-delivery) or to DCC group (2min post-delivery). Duration of the third stage of labour was measured. Samples for acid-base status were taken both from the umbilical artery and vein. Blood samples were taken from the mothers 48h after birth.No statistical differences were found in the time of the third stage of labour (p=0.35). No statiscally significant differences were found between the number of red cells (p=0.25), hemoglobin (p=0.08) or hematocrit (p=0.15) in mothers. Umbilical acid-base status or gas analysis did not show any differences between the two groups CONCLUSIONS: Delayed cord clamping does not affect significantly the time of the third stage of labour. It does not show either any effect on the hematological parameters in the mother 48h after birth.

Objective To explore the reliability of examining the external iliac artery (EIA) at 11+0 to 13+6 weeks of gestation with Doppler ultrasound and its relationship with maternal characteristics and uterine artery blood flow. Study design Cross-sectional study of 451 pregnant women undergoing an ultrasound scan in the first trimester. Mean pulsatility index (PI) of both EIAs was correlated to maternal characteristics (maternal age, parity, body mass index and mean arterial blood pressure (MAP)) and ultrasound parameters (crown-rump length (CRL) and mean uterine artery PI). Mean EIA-PI was logarithmically transformed to perform multiple linear regression analysis. The intra- and inter-observer reproducibilities of EIA-PI were examined. Results Satisfactory flow velocity waveforms were obtained from both EIA in all patients. There is a significant negative correlation between mean EIA pulsatility index and maternal blood pressure. Multiple linear regression analysis showed an independent contribution of MAP to log EIA-PI (mean) (standardized regression coefficient = −0.20, 95% CI: −0.005 to −0.002). The intra-class correlation coefficients (ICCs) for intraobserver and interobserver reproducibility were 0.94 (95% CI, 0.88–0.97) and 0.87 (0.76–0.94) respectively. Conclusions Examining blood flow in the external iliac artery using Doppler ultrasound in the first trimester is feasible and reproducible. There is a negative correlation between mean EIA-PI and maternal blood pressure.

Objectives To investigate the pharmacokinetics, safety and preliminary effectiveness of ultra-low-dose estriol vaginal gel formulations (20 μg/g (T1) and 50 μg/g (T2)) compared to Ovestinon® (estriol 500 μg/0.5 g (R)) and placebo in postmenopausal women. Methods Forty-three volunteers were randomly assigned to received T1, T2, R or placebo once daily for 21 days. Absorption of estriol after single and multiple administration was analyzed. Cytological changes in the vagina, tolerability and safety were also investigated. Results Thirty-six women were included in the pharmacokinetic analysis. Systemic absorption was lower with test formulations (AUC0-t: 171.65 ± 80.18 (T1) and 406.75 ± 199.53 (T2) pg/ml × h) than with Ovestinon® (1221.97 ± 549.06 pg/ml × h). Estriol exposure of the test formulations after multiple administration (AUCss: 36.33 ± 30.52 (T1) and 73.71 ± 46.86 (T2) pg/ml × h) was significantly lower than after single-dose administration and not significantly different between them. In contrast, the exposure after repeated administration of Ovestinon® was considerable and not statistically different from levels after single administration. All estriol formulations produced similar improvement in the vaginal maturation value, while placebo showed a small and not significant change. Overall safety and acceptability were good. Conclusions Estriol 20 and 50 μg/g formulations, while showing a comparable capacity for reversing vaginal atrophy, present a highly favorable safety profile, producing a very low systemic absorption of estriol and significantly lower than that of Ovestinon®.

Introduction The Elecsys® immunoassay soluble fms-like tyrosine kinase (sFlt-1)/placental growth factor (PlGF) ratio is a CE-IVD-approved diagnostic and predictive aid for preeclampsia. Reference ranges for Elecsys® sFlt-1, PlGF and the sFlt-1/PlGF ratio were generated for normal singleton pregnancies [1,2]. Ranges in normal multiple pregnancies may be different [3,4]. Objectives To establish reference ranges for the Elecsys® immunoassay sFlt-1/PlGF ratio in normal multiple pregnancies. Methods We analyzed sFlt-1/PlGF ratio, sFlt-1 and PlGF data from three studies in women with normal multiple pregnancies (without preeclampsia/eclampsia/HELLP syndrome/IUGR). The Prediction of Short-Term Outcome in Pregnant Women with Suspected Preeclampsia Study (PROGNOSIS) derived and validated an sFlt-1/PlGF ratio cut-off of 38 to rule out preeclampsia within 1 week in women with suspicion of preeclampsia (24 w + 0 d–36 w + 6 d; 25 normal multiple pregnancies) [5]. The Study of Early Preeclampsia in Spain (STEPS) evaluated the sFlt-1/PlGF ratio as a predictive marker for early-onset preeclampsia (11/20/24/28 w gestation; 729 women [188 normal multiple pregnancies] at risk of the syndrome) [6]. A multicenter case-control study (10 w + 0 d–delivery; 234 women with preeclampsia/915 normal pregnancies including 30 multiple pregnancies) examined the sFlt-1/PlGF ratio as a preeclampsia diagnostic aid [1]. Results Median sFlt-1/PlGF ratio, sFlt-1 and PlGF values in normal multiple pregnancies were generated (6 gestational age windows). Median sFlt-1/PlGF ratios were: 30.6 (10 w + 0 d–14 w+ 6d); 6.39 (15 w + 0 d–19 w + 6 d); 3.84 (20 w + 0d–23 w + 6 d); 3.81 (24 w + 0 d–28 w + 6 d); 22.2 (29 w + 0 d–33 w + 6 d); 47.1 (34 w + 0 d–36 w + 6 d). These values were not different to the median sFlt-1/PlGF ratios in singleton pregnancies up to gestational age 28 w + 6 d; from 29 w + 0 d–36 w + 6 d, the median sFlt-1/PlGF ratios were higher for multiple pregnancies (although the sample size was small here). Compared with singleton pregnancies, median sFlt-1 values were higher for multiple pregnancies, and median PlGF values were higher in multiple pregnancies until 28 w + 6 d, and then lower. Conclusion Reference ranges for the sFlt-1/PlGF ratio, sFlt-1 and PlGF in multiple pregnancies were different to singleton pregnancies; from 29 w + 0 d, the median sFlt-1/PlGF ratio was higher in multiple pregnancies. The Elecsys® immunoassay sFlt-1/PlGF ratio, sFlt-1 and PlGF reference ranges (median [5th–95th percentile]) in normal multiple pregnancies, compared with singleton pregnancies. Download : Download high-res image (671KB) Download : Download full-size image

We investigated whether clinical severity indices and biomarkers for preeclampsia (PE) are associated with low plasmatic 2-methoxyestradiol (2ME) in the third trimester of gestation. Blood was collected from 53 women with PE and 73 control pregnant women before parturition. The concentration of 2ME was significantly higher in controls than in patients with PE (2906.43 ± 200.69 pg/mL vs 1818.41 ± 189.25 pg/mL). The risk of PE decreased as 2ME levels increased. The 2ME values were negatively correlated with systolic peak arterial pressure and proteinuria in PE. Additionally, those women with PE with lower 2ME had a more serious clinical situation and needed a more aggressive therapy. Finally, 2ME levels (in patients with PE and total population) were significantly correlated with concentrations of soluble fms-like tyrosine kinase 1 and placental growth factor . Summarizing, patients with PE had lower 2ME levels that were correlated with different clinical indices and biomarkers of severity, indicating that 2ME could be taken into account for the clinical management of this syndrome.

The objective of this study was to determine the contribution of uterine (UtA) and umbilical arteries (UA) Doppler examination at 28 weeks to predict adverse pregnancy outcomes in women who had increased resistance in UtA in the early second trimester.Women with UtA mean pulsatility index (PI) above the 95th centile at 19-22 weeks of gestation were offered a growth scan including Doppler examination of UtA and UA at 28 weeks. Adverse pregnancy outcomes included small for gestational age (SGA), defined as birth weight below the tenth centile, preeclampsia (PE) and early-onset PE (PE before 34 weeks).We studied 266 pregnant women with elevated PI in the UtAs in the second trimester and ultrasound reassessment at 28 weeks. UtA PI95th centile at 28 weeks was associated with subsequent PE [odds ratio (OR): 10.0, 95% CI: 2.3-43.5], early-onset PE (OR: 57.7, 95% CI: 3.8-87.6) and SGA less than the tenth centile (OR: 5.5, 2.2-13.9). UA PI95th centile at 28 weeks was not significantly associated with any adverse outcome.In women with abnormal UtA Doppler in the early second trimester scan, persistence of elevated UtA PI, but not abnormal UA PI, is associated with adverse pregnancy outcomes including PE, early-onset PE and SGA. © 2014 John WileySons, Ltd.

In this study, we tested whether estrogen deficiency is associated with oxidative stress and decreased nitric oxide (NO) production, which could be responsible for an increased blood pressure in ovariectomized rats. Hemodynamic studies were performed on conscious, chronically instrumented rats. Chronic estrogen replacement on ovariectomized rats lowered blood pressure ∼13 mmHg, from 119 ± 3 mmHg in ovariectomized rats to 106 ± 3 mmHg in ovariectomized-treated rats; it was also accompanied by an increase in cardiac index and vascular conductance, achieving hemodynamic values similar to those shown by sham-operated rats. N G-nitro-l-arginine methyl ester administration lowered significantly less the vascular conductance (0.14 ± 0.01 vs. 0.22 ± 0.03 and 0.26 ± 0.01 ml · min−1 · mmHg−1/100 g; P < 0.05) in ovariectomized rats than in the sham-operated and estrogen-treated ovariectomized rats, respectively. Estrogen replacement prevented the lower plasma levels of nitrites/nitrates observed in ovariectomized rats. The lower plasma total antioxidant status and reduced thiol groups and the increase in plasma lipoperoxides presented in ovariectomized animals were reestablished with the estrogen treatment. These results show that estrogen administration decreases blood pressure and increases vascular conductance in ovariectomized rats. This effect may be related to an increase in NO synthesis and/or preventing oxidative stress, then improving endothelial function.

Buckyballs represent a new and fascinating molecular allotropic form of carbon that has received a lot of attention by the chemical community during the last two decades. The unabating interest on this singular family of highly strained carbon spheres has allowed the establishing of the fundamental chemical reactivity of these carbon cages and, therefore, a huge variety of fullerene derivatives involving [60] and [70]fullerenes, higher fullerenes, and endohedral fullerenes have been prepared. Much less is known, however, of the chemistry of the uncommon non-IPR fullerenes which currently represent a scientific curiosity and which could pave the way to a range of new fullerenes. In this review on buckyballs we have mainly focused on the most recent and novel covalent chemistry of fullerenes involving metal catalysis and asymmetric synthesis, as well as on some of the most significant advances in supramolecular chemistry, namely H-bonded fullerene assemblies and the search for efficient concave receptors for the convex surface of fullerenes. Furthermore, we have also described the recent advances in the macromolecular chemistry of fullerenes, that is, those polymer molecules endowed with fullerenes which have been classified according to their chemical structures. This review is completed with the study of endohedral fullerenes, a new family of fullerenes in which the carbon cage of the fullerene contains a metal, molecule, or metal complex in the inner cavity. The presence of these species affords new fullerenes with completely different properties and chemical reactivity, thus opening a new avenue in which a more precise control of the photophysical and redox properties of fullerenes is possible. The use of fullerenes for organic electronics, namely in photovoltaic applications and molecular wires, complements the study and highlights the interest in these carbon allotropes for realistic practical applications. We have pointed out the so-called non-IPR fullerenes – those that do not follow the isolated pentagon rule – as the most intriguing class of fullerenes which, up to now, have only shown the tip of the huge iceberg behind the examples reported in the literature. The number of possible non-IPR carbon cages is almost infinite and the near future will show us whether they will become a reality.

The aim of this study was to determine the clinical utility of Doppler assessment of the umbilical artery in the second trimester scan for predicting adverse pregnancy outcomes.Singleton pregnancies that had undergone routine anomaly scan at 19 to 22 weeks of gestation with umbilical and uterine artery Doppler measurements. Receiver operating characteristic curves were constructed to evaluate the ability of umbilical artery pulsatility index (PI) to predict small for gestational age and preeclampsia.The final study population comprised 4565 singleton pregnancies. Multiple regression analysis showed significant independent contribution of umbilical artery PI in predicting SGA10th and SGA5th centiles (adjusted odds ratios of 2.51 and 3.51, respectively). By using a cutoff of umbilical artery PI90th centile, the likelihood ratio of SGA5th centile is 2.3 (95% CI: 1.7-3.0).Umbilical artery PI at 19 to 22 weeks of gestation is significantly associated with SGA below the tenth and fifth centiles. A multivariate model combining umbilical and uterine artery Doppler measurements with additional maternal and sonographic characteristics may help predict small for gestational age, particularly those below the fifth centile.

Buckyballs represent a new and fascinating molecular allotropic form of carbon that has received a lot of attention by the chemical community during the last two decades. The unabating interest on this singular family of highly strained carbon spheres has allowed the establishing of the fundamental chemical reactivity of these carbon cages and, therefore, a huge variety of fullerene derivatives involving [60] and [70]fullerenes, higher fullerenes, and endohedral fullerenes have been prepared. Much less is known, however, of the chemistry of the uncommon non-IPR fullerenes which currently represent a scientific curiosity and which could pave the way to a range of new fullerenes. In this review on buckyballs we have mainly focused on the most recent and novel covalent chemistry of fullerenes involving metal catalysis and asymmetric synthesis, as well as on some of the most significant advances in supramolecular chemistry, namely H-bonded fullerene assemblies and the search for efficient concave receptors for the convex surface of fullerenes. Furthermore, we have also described the recent advances in the macromolecular chemistry of fullerenes, that is, those polymer molecules endowed with fullerenes which have been classified according to their chemical structures. This review is completed with the study of endohedral fullerenes, a new family of fullerenes in which the carbon cage of the fullerene contains a metal, molecule, or metal complex in the inner cavity. The presence of these species affords new fullerenes with completely different properties and chemical reactivity, thus opening a new avenue in which a more precise control of the photophysical and redox properties of fullerenes is possible. The use of fullerenes for organic electronics, namely in photovoltaic applications and molecular wires, complements the study and highlights the interest in these carbon allotropes for realistic practical applications. We have pointed out the so-called non-IPR fullerenes - those that do not follow the isolated pentagon rule - as the most intriguing class of fullerenes which, up to now, have only shown the tip of the huge iceberg behind the examples reported in the literature. The number of possible non-IPR carbon cages is almost infinite and the near future will show us whether they will become a reality.

Objective: The aim of this study was to evaluate the efficacy and safety of a new low-concentration estriol formulation (0.005% estriol vaginal gel), providing an ultra low dose of estriol per application (50 mu g), for the local treatment of postmenopausal vaginal atrophy. Methods: Postmenopausal women with symptoms and signs of vaginal atrophy were enrolled in a prospective, double-blind, placebo-controlled study. Women received either 1 g of vaginal gel containing 50 mu g of estriol or placebo gel, daily for 3 weeks and then twice weekly up to 12 weeks. A cytological vaginal study, evaluation of vaginal pH, and assessment of symptoms and signs of vaginal atrophy were performed, and changes between baseline and weeks 3 and 12 were assessed. Adverse events were recorded. Results: A total of 167 women were included (114 received estriol and 53 received placebo). After 12 weeks of therapy, a superiority of estriol compared with placebo gel was shown in the change in maturation value and vaginal pH (P < 0.001 and P < 0.001, respectively). The superiority of estriol was well demonstrated in improvement of vaginal dryness (P = 0.001) and the Global Symptom Score (P = 0.018). Estriol gel proved also superior in the improvement of several of the most outstanding vaginal signs of vaginal atrophy evaluated. After 3 weeks, estriol gel also showed a superiority over the placebo gel in most symptoms and signs evaluated. Treatment-related adverse events were similar among groups. Conclusions: 0.005% Estriol vaginal gel, a new formulation providing an ultra low dose of estriol per application, was shown to be safe and effective in the treatment of postmenopausal vaginal atrophy.

Objective To evaluate the association between fetal and maternal catechol- O -methyltransferase (COMT) Val158Met and methyl tetrahydrofolate reductase (MTHFR) C677T functional polymorphisms and preeclampsia, examining its influence on placental COMT and in maternal 2-methoxyestradiol (2-ME) plasma levels. Design Prospective case-control study. Setting University hospital. Patient(s) A total of 53 preeclamptic and 72 normal pregnant women. Intervention(s) Maternal and cord blood samples and placental tissue samples were obtained. Main Outcome Measure(s) Maternal and fetal COMT and MTHFR polymorphisms were genotyped. Maternal plasma 2-ME and homocysteine levels, and expression and activity of placental COMT were measured. Result(s) The odds ratio for the risk of preeclampsia for fetal COMT Met/Met was 3.22, and it increased to 8.65 when associated with fetal MTHFR TT. Placental COMT activity and expression were influenced by genotype, but COMT activity in preeclamptic placentas did not differ from control pregnancies. There was no association between any genotypes and maternal 2-ME. Homocysteine levels were higher in women with preeclampsia than in normal pregnancies, and were inversely correlated with 2-ME plasma levels, indicating that its altered metabolism may lower COMT activity in vivo. Conclusion(s) Fetal Met-Met COMT genotype reduces COMT placental expression and activity in vitro and increases preeclampsia, risk but it does not explain the difference in maternal 2-ME levels between preeclamptic and normal pregnancies. However, the preeclamptic patients had elevated homocysteine levels that correlated inversely with 2-ME, indicating that an altered methionine-homocysteine metabolism may contribute to reduce COMT activity in vivo and explain the decreased levels of 2-ME in preeclamptic women.

Vaginal moisturizers are used for symptomatic relief of vulvovaginal atrophy (VVA) caused by estrogen deficiency. The quality of life of postmenopausal women can be negatively affected with these symptoms and it should not be underestimated. Current Guidelines advice on the regular use of long acting non-hormonal moisturizers as first-line therapies to alleviate symptoms, being dryness and dyspareunia the most frequent and bothersome. The efficacy of a polycarbophilic vaginal moisturizing gel (Ainara®) for relieving severe symptoms of VVA was evaluated in 32 postmenopausal women suffering from severe vaginal dryness or severe dyspareunia. Allwomen received 1g of the gel daily during 3 weeks and twiceweekly up to 12weeks. Symptomswere evaluated with a validated numeric scale (0 = absent, 1 =mild, 2 =moderate and 3= severe) at baseline and at after 3 and 12weeks of treatment. Significant change in the intensity of the symptoms was evaluated using Wilcoxon tests. The percentage of women that improved the symptoms was also calculated. After 3 weeks, 78% women improved vaginal dryness and 65% improved dyspareunia. After 12 weeks, 78% women improved vaginal dryness and 69% improved dyspareunia. The intensity of the vaginal dryness decreased from 2.8 to 1.6 (p

Methods: The CNF investigation was performed by histochemical cholinesterase (CE) detection with alternative method by Crevier and Belanger in modification of Savay and Csillik. Results: On early terms of disease the CNF are presented by nerve bundleswith dense network of fine terminal fibrils ending on myocytes. Several CNF have different CE activity and look like dotted line. At the same time the lowCNF density area are observed. As the termof thedisease growth theCNFdensity decreases. Thefibers become thinner and truncated with deformations, fragmentations and decreasing of their color intensity. The nerve bundles take less space and become lighter, indicating the CE activity decreasing. However, in some areas the increased CNF density are observed that can be considered as a compensatory mechanisms signs. Conclusions: The analysis of the bladder cholinergic activity in perimenopausal women with OAB has showed the progressive parasympathetic denervation with a direct correlation with the term of disease.

Previous reports correlate plasma levels of estrogen with increased nitric oxide (NO) production. To investigate whether the hemodynamic effects of estrogens are mediated by NO, we compared the hemodynamic changes induced by 17β-estradiol (100 μg/kg) in the absence and presence of the NO synthesis inhibitor N ω-nitro-l-arginine methyl ester (l-NAME). All protocols were performed in ovariectomized, conscious rats. Estradiol alone resulted in no significant changes in cardiac index (CI) or mean arterial pressure (MAP). However, in the presence ofl-NAME, estradiol induced a significant increase in total peripheral resistance (TPR) of 37.3 ± 11.7% and a decrease in CI of 27 ± 4.9%, without changes in MAP. Previous blockade of angiotensin II AT1 receptors with losartan prevented any change in CI and TPR induced by 17β-estradiol in the presence of l-NAME. These observations suggest that NO is necessary to offset a vasoconstrictor action of angiotensin II, which is stimulated by estradiol administration.

Farma-Cros Iberica, S.L., C/Castilla-La Mancha 7, Pol. Ind. Camporrosso, 02520 Chinchilla de Montearagon, Albacete, Spain Medical Department, Italfarmaco S.A., San Rafael 3, 28108 Alcobendas, Madrid, Spain Hospital Universitario Marques de Valdecilla, Avenida Herrera Oria, s/n, 39011 Santander, Spain Hospital Universitario “Virgen de la Arrixaca”, Carretera Madrid-Cartagena, s/n, 30120. El Palmar, Murcia, Spain R&D Department, Italfarmaco S.A., San Rafael 3, 28108 Alcobendas, Madrid, Spain

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ResumenLa experiencia realizada en las aulas de Educacion Especial en la ciudad de Jaen pone de relieve los problemas educativos que plantean las mismas. Presentamos un tratamiento rehabilitador aplicado a un grupo de ninos de educacion especial y se contrastan los resultados con otros dos grupos que no reciben directamente el programa. Los resultados obtenidos revelan la efectividad del tratamiento y la inadecuacion del actual sistema de aulas de Educacion Especial en el contexto escolar. Se discuten y analizan los factores implicados y se ofrece evidencia experimental de los mismos. A partir de los resultados se extrae una serie de consecuencias de interes, sobre todo de cara a la aplicacion educativa.