Role of recombinant factor VIIa in the clinical management of severe postpartum hemorrhage: consensus among European experts.

OBJECTIVES: There have been significant advances in the medical management of severe postpartum hemorrhage (sPPH) over recent decades, which is reflected in numerous published guidelines. To date, many of the currently available national and international guidelines recommend recombinant factor VIIa (rFVIIa) to be used only at a very late stage in the course of sPPH, as a "last resort", before or after hysterectomy. Based on new safety data, rFVIIa has recently been approved by the European Medicines Agency (EMA) and Swissmedic for use in sPPH, if uterotonics are insufficient to achieve hemostasis, which in fact is significantly earlier in the course of postpartum hemorrhage (PPH). We therefore aimed to develop expert consensus guidance as a step toward standardizing care with the use of rFVIIa for clinicians managing women experiencing life-threatening sPPH. METHODS: The consensus process consisted of one face-to-face meeting with a group of nine experts, including eight obstetrician-gynecologists and a hematologist highly experienced in sPPH care in tertiary care perinatal centers. The panel was representative of multidisciplinary expertise in the European obstetrics community and provided consensus opinion in answer to pre-defined questions around clinical practice with rFVIIa in the management of sPPH. Recommendations have been based on current national and international guidelines, extensive clinical experience, and consensus opinion, as well as the availability of efficacy and new safety data. RESULTS: The expert panel developed 17 consensus statements in response to the 13 pre-defined questions on the use of rFVIIa in the management of sPPH including: available efficacy and safety data and the need for interdisciplinary expertise between obstetricians, anesthesiologists, and hematologists in the management of sPPH. Based on novel data, the experts recommend: (1) earlier administration of rFVIIa in patients with sPPH who do not respond to uterotonic administration to optimize the efficacy of rFVIIa; (2) the importance of hematological parameter prerequisites prior to the administration of rFVIIa to maximize efficacy; and (3) continued evaluation or initiation of further invasive procedures according to standard practice. Furthermore, recommendations on the timing of rFVIIa treatment within the sPPH management algorithm are outlined in a range of specified clinical scenarios and settings, including vaginal delivery, cesarean section, and smaller birthing units before transfer to a tertiary care center. The panel agreed that according to available, and new data, as well as real-world experience, there is no evidence that the use of rFVIIa in patients with sPPH increases the risk of thromboembolism. The authors acknowledge that there is still limited clinical effectiveness data, as well as pharmacoeconomic data, on the use of rFVIIa in sPPH, and recommend further clinical trials and efficacy investigation. CONCLUSIONS: This expert panel provides consensus guidance based on recently available data, clinical experience, and expert opinion, augmented by the recent approval of rFVIIa for use in sPPH by the EMA. These consensus statements are intended to support clinical care for sPPH and may help to provide the impetus and a starting point for updates to existing clinical practice guidelines.

Retraction Note: Randomized, double blind placebo-controlled trial: effects of Myo-inositol on ovarian function and metabolic factors in women with PCOS.

The article "Randomized, double blind placebo-controlled trial: effects of Myo-inositol on ovarian function and metabolic factors in women with PCOS", by S. Gerli, E. Papaleo, A. Ferrari, G.C. Di Renzo, published in 2007; 11 (5): 347-354-PMID: 18074942 has been retracted by the Editor in Chief for the following reasons. The paper has been recently issued on PubPeer as multiple textual overlaps have been detected between this article and a previous article published by the same group of authors in 2003 (S. Gerli, M. Mignosa, G.C. Di Renzo. Effects of inositol on ovarian function and metabolic factors in women with PCOS: a randomized double blind placebo-controlled trial. Eur Rev Med Pharmacol Sci 2003; 7 (6): 151-159. PMID-15206484). After having informed the Editor in Chief of a possible duplicate publication, the corresponding author was contacted to clarify this issue according to the policies of the journal. The corresponding author admitted that the 2007 paper had been written by an uncredited student, who adapted the 2003 paper and submitted it as novel work without the consent of the authors. Therefore, given the evidence, the Editor in Chief decided to withdraw the manuscript. The Publisher apologizes for any inconvenience this may cause. https://www.europeanreview.org/article/458.

Detoxification treatment in Gynecology using a modified molded sorbent.

Postpartum endometritis is a common complication of cesarean section, the progression of which often leads to the loss of the uterus and the patient's fertility. We evaluated a detoxification therapy for treating patients with postpartum endometritis using an intrauterine application of a modified molded sorbent containing polyvinylpyrrolidone. A retrospective, controlled study included 124 patients with postpartum endometritis. The study group, n = 63, was composed of puerperae with postpartum endometritis after cesarean section, receiving antibacterial therapy in combination with the intrauterine application of a molded modified sorbent containing polyvinylpyrrolidone (FSMP) for 24 h daily for 5 days. The control group, n = 61, was composed of puerperae with postpartum endometritis after cesarean section, receiving antibacterial treatment only. The uterine cavity was infected by coccal flora (Enterococcus faecalis (26.6%), Staphylococcus spp. (21.3%), E. faecium (14.3%), and Gram-negative Escherichia coli (9.6%). A combination of these microorganisms was present in 40.5% of crops. Antibiotic resistance was detected in 53.6%-68.3% of the cases. In the study group, we observed: a faster and higher decrease in neutrophils (p < 0.05); a lower uterine concentration of pro-inflammatory cytokines: interleukin-1 beta (IL-1ß) and tumor necrosis factor α (TNFα) - 4.0 and 3.2 times, respectively, compared with the control group (p < 0.05); and a significant decrease in the uterus volume and cavity (M-echo). Using a newly modified sorbent associated with antibiotic treatment in patients with postpartum endometritis, compared with antibiotics alone, we showed a sharp reduction of inflammatory parameters, residual microorganism growth, and faster uterine volume involution. Moreover, the frequency of hysterectomy decreased by 14.4 times.

Maternal insulin-like growth factors and insulin-like growth factor-binding proteins for macrosomia prediction in diabetic and nondiabetic pregnancy: A prospective study.

OBJECTIVE: Attributable to the insulin-like growth factor (IGF) axis involvement in fetal growth regulation, possible contribution of the maternal IGF axis to antenatal fetal macrosomia diagnosis is a subject of particular interest in diabetic pregnancy. METHODS: A total of 130 women were prospectively enrolled in a longitudinal single-center cohort study. The four study groups were: type 1 diabetes (n = 40), type 2 diabetes (n = 35), gestational diabetes (n = 40), and control (n = 15). IGF-1 and IGF-2 and insulin-like growth factor-binding protein (IGFBP) 1, 3, 6, and 7 serum levels were analyzed in 11- to 14-week and 30- to 34-week samples with a specific immunoassay. RESULTS: In mothers of large-for-gestational-age neonates (90th percentile), higher (median test) first-trimester IGF-1 (P = 0.007) and lower IGFBP-1 (P = 0.035) were observed. The IGF-1/IGFBP-1 ratio was positively associated with neonatal weight (r = 0.434, P < 0.001). Receiver operating characteristic analysis revealed an association between large for gestational age and the first-trimester IGF-1 (area under the curve [AUC] = 0.747, P < 0.001), IGFBP-1 (AUC = 0.334, P = 0.011), and IGF-1/IGFBP-1 ratio (AUC = 0.750, P < 0.001). IGF-1/IGFBP-1 ratio had better performance for prediction of birth weight over 4000 g (AUC = 0.822, P < 0.001). CONCLUSION: The authors detected different first-trimester IGF-1 and IGF-1/IGFBP-1 thresholds applicable for either supposition or rejection of macrosomia diagnosis. Further investigation is needed to determine how the maternal IGF axis can contribute to fetal macrosomia prediction.

From Myo-inositol to D-chiro-inositol molecular pathways.

OBJECTIVE: Inositol is a carbocyclic sugar polyalcohol. By epimerization of its hydroxyl groups, nine possible stereoisomers can be generated, two of major physiological and clinical relevance: myo-inositol and D-chiro-inositol. Myo-inositol and D-chiro-inositol are normally stored in kidney, brain and liver and are necessary for functions, such as signal transduction, metabolic flux, insulin signaling, regulation of ion-channel permeability, stress response and embryo development. In this narrative review, we summarize the mechanisms by which myo-inositol and D-chiro-inositol can be synthesized and absorbed and their possible role in the etiopathogenesis of neural tube defects. MATERIALS AND METHODS: We performed an online search in the PubMed database using the following keywords: "inositol", "D-chiro-inositol", "myo-inositol", "neural tube defects and inositol". RESULTS: Inositol requirements are partly met by dietary intake, while the rest is synthesized endogenously. Inositol deficiency may be involved in the pathogenesis of diseases, such as metabolic syndrome, spina bifida (a neural tube defect), polycystic ovary syndrome and diabetes. Supplementation of the two inositol stereoisomers, D-chiro-inositol and myo-inositol is important to prevent these conditions. CONCLUSIONS: Inositol is fundamental for signal transduction in the brain, kidneys, reproductive organs and other tissues in response to neurotransmitters, hormones and growth factors. Various genes are involved in inositol metabolism and associated pathways. Altered inositol concentrations are observed in several diseases. Analysis of the genes involved in inositol metabolism may provide important information for the clinical management of these conditions.

Analysis of risk factors and predictors of pregnancy loss and strategies for the management of cervical insufficiency in pregnant women at a high risk of preterm birth.

AIM: To identify risk factors and predictors of pregnancy loss and to compare the efficacy of Arabin's pessary with cervical cerclage in women at a high risk of pregnancy loss. MATERIALS AND METHODS: This was a two-center retrospective case-control study that included 240 women at a high risk of preterm delivery. Group I (n = 161) included women who underwent insertion of the Arabin's pessary between 14 and 24 weeks of pregnancy. Group II (n = 79) included women who had undergone circular cervical cerclage during the current pregnancy. All women included in the study received micronized vaginal progesterone at the dose of 200 mg/day until and including 34 weeks of gestation. RESULTS: Threatened pregnancy loss defined as spotting or vaginal bleeding in the first trimester was diagnosed in 29.8% (48/161) of patients in Group I versus 37.9% in Group II (p = .448). Postpartum bleeding occurred in 8.1% (13/161) in women in Group I versus 22.8% in Group II (χ2 = 6.500; p = .011). Our study showed that cervical cerclage was most suitable for patients with history of obstetric complications, cervical length <15 mm, and large isthmic uterine fibroids. The use of the Arabin's pessary reduced the rate of preterm births by 1.7-fold. A cluster analysis demonstrated that predictors of preterm birth in women with a high risk of pregnancy loss included: threatened pregnancy loss associated with chorionic/placental abruption, cervical incompetence, uterine fibroid growth to a large size, history of multiple spontaneous pregnancy losses, cervical tears during past labor, and gestational diabetes diagnosed for the first time during the current pregnancy. CONCLUSIONS: Women with a high risk of pregnancy loss treated with Arabin's pessary or cerclage plus vaginal progesterone had a term delivery rate of 70.4% (169/240). The combined strategy of pregnancy management allowed to markedly reduce the number of preterm births.

The role of operative vaginal birth in the 21st century and a way forward.

Effective devices and effective, validated training can improve operative vaginal birth outcomes for women and their babies. TWEETABLE ABSTRACT: Effective devices and effective, validated training can improve operative vaginal birth outcomes for women and their babies.

Intrapartum GBS screening and antibiotic prophylaxis: a European consensus conference.

Group B streptococcus (GBS) remains worldwide a leading cause of severe neonatal disease. Since the end of the 1990s, various strategies for prevention of the early onset neonatal disease have been implemented and have evolved. When a universal antenatal GBS screening-based strategy is used to identify women who are given an intrapartum antimicrobial prophylaxis, a substantial reduction of incidence up to 80% has been reported in the USA as in other countries including European countries. However recommendations are still a matter of debate due to challenges and controversies on how best to identify candidates for prophylaxis and to drawbacks of intrapartum administration of antibiotics. In Europe, some countries recommend either antenatal GBS screening or risk-based strategies, or any combination, and others do not have national or any other kind of guidelines for prevention of GBS perinatal disease. Furthermore, accurate population-based data of incidence of GBS neonatal disease are not available in some countries and hamper good effectiveness evaluation of prevention strategies. To facilitate a consensus towards European guidelines for the management of pregnant women in labor and during pregnancy for the prevention of GBS perinatal disease, a conference was organized in 2013 with a group of experts in neonatology, gynecology-obstetrics and clinical microbiology coming from European representative countries. The group reviewed available data, identified areas where results were suboptimal, where revised procedures and new technologies could improve current practices for prevention of perinatal GBS disease. The key decision issued after the conference is to recommend intrapartum antimicrobial prophylaxis based on a universal intrapartum GBS screening strategy using a rapid real time testing.

Morbidity and chronic pain following different techniques of caesarean section: A comparative study.

Research examining long-term outcomes after childbirth performed with different techniques of caesarean section have been limited and do not provide information on morbidity and neuropathic pain. The study compares two groups of patients submitted to the 'Traditional' method using Pfannenstiel incision and patients submitted to the 'Misgav Ladach' method ≥ 5 years after the operation. We find better long-term postoperative results in the patients that were treated with the Misgav Ladach method compared with the Traditional method. The results were statistically better regarding the intensity of pain, presence of neuropathic and chronic pain and the level of satisfaction about cosmetic appearance of the scar.

Maternal smoking does not affect the amount of cell-free fetal DNA in maternal plasma during the 1st trimester of pregnancy.

CffDNA, from 344 non-smoking, 38 smoking and 33 ex-smoking pregnant women at 11 (+0)-13 (+6) gestational weeks, was extracted and quantified by the multicopy DYS14, as the fetal DNA marker and using the quantitative real-time PCR 7300 detection system. The smoking habit was based on maternal self-report, confirmed by cotinine levels and male fetuses were verified by phenotype at birth. The genders of newborns were compared with DYS14-cffDNA analysis, achieving a 100% diagnostic accuracy of the test. A total of 177 non-smokers, 18 smokers and 22 ex-smoker pregnancies with male fetuses were identified by the cffDNA concentration. Results showed that smoking status was not associated with different amounts of DYS14-cffDNA (p = 0.159), suggesting the possibility of offering cffDNA testing to all pregnant women, even if they are active smokers or ex-smokers, and the test can be unadjusted for smoking status.

Early ultrasonographic diagnosis of placental mesenchymal dysplasia.

Placental mesenchymal dysplasia (PMD) is a rare pathology characterized by vascular anomalies, placentomegaly and grapelike vesicles resembling partial molar pregnancy. PMD is often associated with fetal growth restriction or intrauterine fetal demise. We report a case of an early diagnosis of PMD at 10 weeks' gestation, with a regular intrauterine growth and a fetal demise occurring at 31 week's gestation. The placenta showed aneurysmally dilated and tortuous vessels with luminal thrombosis. Even in presence of a regular fetal growth, a fetal demise may always occur, suggesting the option of an early heparin administration to reduce the risk of thrombosis of chorionic vessels.

Endometrial carcinoma in women 40 year old or younger: a case report and literature review.

Endometrial cancer is the most frequent gynecologic cancer. Although it mainly occurs in menopausal women, it can hit younger patients as well. Only few cases of affected women under the age of 30 are reported. A case of a 23-year-old patient with endometrioid carcinoma grade II-III is presented. Hysterectomy is considered the standard treatment and it could represent a problem for those young women who desire to preserve fertility. A conservative management can be offered to these patients when the tumor is well differentiated and advanced stage is excluded. Several studies are available in literature about fertility sparing approach. Progestin treatment, combined or not with hysteroscopic ablation seem to be the most validated conservative management. Anyhow this treatment is not free risk, because it is not always effective and disease progression during or after treatment is possible. Then a strict evaluation and selection of patients before starting treatment is mandatory.

Myo-inositol, D-chiro-inositol, folic acid and manganese in second trimester of pregnancy: a preliminary investigation.

DESIGN AND PURPOSE: The supplemental administration of myo-inositol, D-chiro-inositol, folic acid and manganese (MDFM) was tested in a prospective, randomized, double-blind, placebo controlled clinical trial, pilot study, to test the hypothesis that its supplemental administration in the second trimester of pregnancy would improve glucose and glycemic parameters and blood pressure. SUBJECTS AND METHODS: Non-obese uniparous healthy pregnant women between 13th and 24th week of pregnancy were divided into two groups: group I, control group with placebo, and the group II, women in treatment with myo-inositol, D-chiro-inositol, folic acid and manganese. The main outcome measures were the comparative analysis of the parameters analyzed at time 0, after 30 days and 60 days; secondary outcome measure was the overall analysis of investigated parameters. RESULTS: 24 women were allocated to receive MDFM and 24 the placebo. The two groups did not significantly differ for demographic, lipidic and glycemic parameter and blood pressure. After 30 days, significantly lower cholesterol (p = 0.0001), significantly lower LDL (p = 0.0013), lower TG (p < 0.0001) and lower glycemia (p = 0.0021) were observed all favoring group II. No significant difference was observed for HDL, diastolic and systolic blood pressure. After 60 days, significant difference was observed for cholesterol (p = 0.0001), LDL (p = 0.0001), HDL (p = 0.0001), TG (p = 0.0001), glycemia (p = 0.0064), all favoring the group treated with MDFM. No significant differences were observed for systolic (p = 0.12) and diastolic blood pressure (p = 0.42). When examining for overall differences between the two groups, a significant difference was observed for examined parameters at time 0 and at time 60; cholesterol (p = 0.0001), LDL (p = 0.0001), HDL (p = 0.047), TG (p = 0.0001) and glycemia (p = 0.019) were reduced in the MDFM group. A significant reduction was also observed in group II for systolic blood pressure after 60 days of intervention (p = 0.0092), but not for diastolic blood pressure (p = 0.29). CONCLUSIONS: MDFM administration after 30 days in pregnancy improved glycemic and lipidic parameters, with significant gain after 60 days, without affecting diastolic blood pressure levels.

Caspase 3 activation and PARP cleavage in lymphocytes from newborn babies of diabetic mothers with unbalanced glycaemic control.

Several epidemiological studies showed that gestational diabetes mellitus is the most frequent metabolic disorder of pregnancy, the pathogenesis of which has yet to be completely clarified. The aim of this study was to investigate the presence and processing of caspase 3 (Casp3) and poly(ADP-ribose) polymerase 1 (PARP1) in cord blood lymphocytes as markers of apoptosis in relation to glycaemic control during intrauterine life. Our results showed a specific positive correlation between the levels of active Casp3 (17-19 kDa) and the inactive form of PARP1 (89 kDa) in lymphocytes isolated from newborn babies of diabetic women with unbalanced glycaemic control, with a direct correlation between the activation of casp3 and the inactivation of PARP1, that makes lymphocytes unresponsive towards lipopolysaccharide stimulation, highlighting an altered functional response. Besides more studies are required to fully correlate the activation of the apoptotic process during the intrauterine life with the foetal health later in life, our study indicates that a cord blood lymphocyte, an easily accessible source, is informative about the activation of apoptotic stimuli in circulating cells of newborn babies in relation to the glycaemic control reached by the mother during pregnancy.