New approaches suggest term and preterm human fetal membranes may have distinct biomechanical properties.

Preterm prelabour rupture of membranes is the leading cause of preterm birth and its associated infant mortality and morbidity. However, its underlying mechanism remains unknown. We utilized two novel biomechanical assessment techniques, ball indentation and Optical Coherence Elastography (OCE), to compare the mechanical properties and behaviours of term (≥ 37 weeks) and preterm (33-36 weeks) human fetal membranes from ruptured and non-ruptured regions. We defined the expression levels of collagen, sulfated glycosaminoglycans (sGAG), matrix metalloproteinase (MMP-9, MMP-13), fibronectin, and interleukin-1ß (IL-1ß) within membranes by biochemical analysis, immunohistochemical staining and Western blotting, both with and without simulated fetal movement forces on membrane rupture with a new loading system. Preterm membranes showed greater heterogeneity in mechanical properties/behaviours between ruptured and non-ruptured regions compared with their term counterparts (displacement rate: 36% vs. 15%; modulus: 125% vs. 34%; thickness: 93% vs. 30%; collagen content: 98% vs. 29%; sGAG: 85% vs 25%). Furthermore, simulated fetal movement forces triggered higher MMP-9, MMP-13 and IL-1ß expression in preterm than term membranes, while nifedipine attenuated the observed increases in expression. In conclusion, the distinct biomechanical profiles of term and preterm membranes and the abnormal biochemical expression and activation by external forces in preterm membranes may provide insights into mechanisms of preterm rupture of membranes.

A randomized, double-blind study on efficacy and safety of sepranolone in premenstrual dysphoric disorder.

Women with premenstrual dysphoric disorder (PMDD) experience mood symptoms related to the increase in progesterone and the neuroactive steroid allopregnanolone. Our hypothesis is that allopregnanolone is the symptom provoking factor. The rationale for the present study was to treat PMDD patients with the GABAA receptor modulating steroid antagonist, sepranolone (isoallopregnanolone). Patients (n = 206) with PMDD from 12 European centers were randomized in a parallel double-blind study and treated with placebo, sepranolone 10 mg and 16 mg. Patients administered sepranolone subcutaneously every 48 h during the 14 premenstrual days of three consecutive menstrual cycles. After obtaining informed consent, the PMDD diagnosis was confirmed according to DSM-5 and verified with two menstrual cycles of daily symptom ratings using the Daily Record of Severity of Problems (DRSP) scale in an eDiary. Inclusion and exclusion criteria stipulated that the women should be essentially healthy, not pregnant, have no ongoing psychiatric disorder or take interfering medications, and have regular menstrual cycles. The study's primary endpoint was the Total symptom score (Sum21, the score for all 21 symptom questions in the DRSP). In the prespecified statistical analysis the average score of the 5 worst premenstrual days in treatment cycles 2 and 3 were subtracted from the corresponding average score in the two diagnostic cycles. The treatment effects were tested using analysis of variance in a hierarchal order starting with the combined active sepranolone treatments vs. placebo. The prespecified analysis of Sum21 showed a large treatment effect of all three treatments but no statistically significant difference to placebo. However, the ratings of distress showed a significant treatment effect of sepranolone compared to placebo (p = 0.037) and the ratings of impairment showed a trend to greater treatment effect of sepranolone compared to placebo. Many women with PMDD had symptoms during a longer period than the late luteal phase. It has previously been shown that 9 premenstrual days may be more representative for comparison of PMDD symptom periods than the 5 worst premenstrual days. A post hoc analysis was undertaken in the per protocol population investigating the treatment effect during 9 premenstrual days in the third treatment cycle. The Sum21 results of this analysis showed that the sepranolone 10 mg was significantly better than placebo (p = 0.008). Similar significant treatment effects were found for the impairment and distress scores. A significantly larger number of individuals experienced no or minimal symptoms (Sum21 <42 points) with the 10 mg sepranolone treatment compared to placebo (p = 0.020). The results indicate that there is an attenuating effect by sepranolone on symptoms, impairment, and distress in women with PMDD especially by the 10 mg dosage. Sepranolone was well tolerated, and no safety concerns were identified.

Pictorial methods to assess heavy menstrual bleeding in research and clinical practice: a systematic literature review.

BACKGROUND: Pictorial blood loss assessment charts (PBACs) represent the most widely used method to assess menstrual blood loss (MBL) in clinical trials. The aims of this review were to: (1) determine the diagnostic accuracy of PBACs that have been validated against the reference alkaline hematin technique; (2) categorize the pitfalls of using obsolete and nonvalidated charts; (3) provide guidelines for development of a new PBAC or use of an existing chart to measure MBL in clinical trials; and (4) consider the feasibility of using pictorial charts in primary care. METHODS: A literature review was conducted using Embase and MEDLINE databases. The review identified reports of women with self-perceived or actual heavy menstrual bleeding (HMB), bleeding disorders, abnormal uterine bleeding, leiomyomata (uterine fibroids) or endometriosis, and women undergoing treatment for HMB, as well as those with normal menstrual periods. Data were reviewed from studies that focused on the development and validation of PBACs and from those that used derivative noncertified charts to assess HMB. RESULTS: Nine studies reported validation of PBAC scoring systems against the alkaline hematin technique. Across these studies, the sensitivity was 58-97%, the specificity was 7.5-95.5%, the positive and negative likelihood ratios were 1.1-13.8 and 0.14-0.56, respectively, and the diagnostic odds ratio was 2.6-52.4. The cut-off score above which the diagnosis of HMB was made ranged from 50 to 185. Several modifications of these PBACs were used in other studies; however, objective confirmation of their validity was not reported. Overall, there was widespread inconsistency of chart design, scoring systems, diagnostic cut-off limits and post-treatment outcome measures. CONCLUSIONS: PBACs are best suited to the controlled and specific environment of clinical studies, where clinical outcome parameters are defined. The current lack of standardization precludes widespread use of the PBAC in primary care. REVIEW REGISTRATION NUMBER: PROSPERO international prospective register of systematic reviews: CRD42016030083.

A systematic review of methods to measure menstrual blood loss.

BACKGROUND: Since the publication over 50 years ago of the alkaline hematin method for quantifying menstrual blood loss (MBL) many new approaches have been developed to assess MBL. The aim of this systematic review is to determine for methods of measuring MBL: ability to distinguish between normal and heavy menstrual bleeding (HMB); practicalities and limitations in the research setting; and suitability for diagnosing HMB in routine clinical practice. METHODS: Embase®™, MEDLINE®, and ClinicalTrials.gov were screened for studies on the development/validation of MBL assessment methods in women with self-perceived HMB, actual HMB or uterine fibroids, or patients undergoing treatment for HMB. Studies using simulated menstrual fluid and those that included women with normal MBL as controls were also eligible for inclusion. Extracted data included study population, results of validation, and advantages/disadvantages of the technique. RESULTS: Seventy-one studies fulfilled the inclusion criteria. The sensitivity and/or specificity of diagnosing HMB were calculated in 16 studies of methods involving self-perception of MBL (11 pictorial), and in one analysis of the menstrual-fluid-loss (MFL) method; in 13 of these studies the comparator was the gold standard alkaline hematin technique. Sensitivity and specificity values by method were, respectively: MFL model, 89, 98%; pictorial blood loss assessment chart (PBAC), 58-99%, 7.5-89%; menstrual pictogram, 82-96%, 88-94%; models/questionnaires, 59-87%, 62-86%, and complaint of HMB, 74, 74%. The power of methods to identify HMB was also assessed using other analyses such as comparison of average measurements: statistical significance was reported for the PBAC, MFL, subjective complaint, and six questionnaires. In addition, PBAC scores, menstrual pictogram volumes, MFL, pad/tampon count, iron loss, and output from three questionnaires correlated significantly with values from a reference method in at least one study. In general, pictorial methods have been more comprehensively validated than questionnaires and models. CONCLUSIONS: Every method to assess MBL has limitations. Pictorial methods strike a good balance between ease of use and validated accuracy of MBL determination, and could complement assessment of HMB using quality of life (QoL) in the clinical and research setting. TRIAL REGISTRATION: PRISMA registration number: CRD42016032956 .

Preterm Delivery and Future Risk of Maternal Cardiovascular Disease: A Systematic Review and Meta-Analysis.

BACKGROUND: Preterm delivery (<37 weeks gestational age) affects 11% of all pregnancies, but data are conflicting whether preterm birth is associated with long-term adverse maternal cardiovascular outcomes. We aimed to systematically evaluate and summarize the evidence on the relationship between preterm birth and future maternal risk of cardiovascular diseases. METHODS AND RESULTS: A systematic search of MEDLINE and EMBASE was performed to identify relevant studies that evaluated the association between preterm birth and future maternal risk of composite cardiovascular disease, coronary heart disease, stroke, and death caused by cardiovascular or coronary heart disease and stroke. We quantified the associations using random effects meta-analysis. Twenty-one studies with over 5.8 million women, including over 338 000 women with previous preterm deliveries, were identified. Meta-analysis of studies that adjusted for potential confounders showed that preterm birth was associated with an increased risk of maternal future cardiovascular disease (risk ratio [RR] 1.43, 95% confidence interval [CI], 1.18, 1.72), cardiovascular disease death (RR 1.78, 95% CI, 1.42, 2.21), coronary heart disease (RR 1.49, 95% CI, 1.38, 1.60), coronary heart disease death (RR 2.10, 95% CI, 1.87, 2.36), and stroke (RR 1.65, 95% CI, 1.51, 1.79). Sensitivity analysis showed that the highest risks occurred when the preterm deliveries occurred before 32 weeks gestation or were medically indicated. CONCLUSIONS: Preterm delivery is associated with an increase in future maternal adverse cardiovascular outcomes, including a 2-fold increase in deaths caused by coronary heart disease. These findings support the assessment of preterm delivery in cardiovascular risk assessment in women.

Early Pregnancy Biomarkers in Pre-Eclampsia: A Systematic Review and Meta-Analysis.

Pre-eclampsia (PE) complicates 2%-8% of all pregnancies and is an important cause of perinatal morbidity and mortality worldwide. In order to reduce these complications and to develop possible treatment modalities, it is important to identify women at risk of developing PE. The use of biomarkers in early pregnancy would allow appropriate stratification into high and low risk pregnancies for the purpose of defining surveillance in pregnancy and to administer interventions. We used formal methods for a systematic review and meta-analyses to assess the accuracy of all biomarkers that have been evaluated so far during the first and early second trimester of pregnancy to predict PE. We found low predictive values using individual biomarkers which included a disintegrin and metalloprotease 12 (ADAM-12), inhibin-A, pregnancy associated plasma protein A (PAPP-A), placental growth factor (PlGF) and placental protein 13 (PP-13). The pooled sensitivity of all single biomarkers was 0.40 (95% CI 0.39-0.41) at a false positive rate of 10%. The area under the Summary of Receiver Operating Characteristics Curve (SROC) was 0.786 (SE 0.02). When a combination model was used, the predictive value improved to an area under the SROC of 0.893 (SE 0.03). In conclusion, although there are multiple potential biomarkers for PE their efficacy has been inconsistent and comparisons are difficult because of heterogeneity between different studies. Therefore, there is an urgent need for high quality, large-scale multicentre research in biomarkers for PE so that the best predictive marker(s) can be identified in order to improve the management of women destined to develop PE.

Validation of a new menstrual pictogram (superabsorbent polymer-c version) for use with ultraslim towels that contain superabsorbent polymers.

OBJECTIVE: To validate the menstrual pictogram (superabsorbent polymer-c version) for Always Ultra-slim feminine towels containing superabsorbent polymers. DESIGN: Prospective, multicenter, evaluator-blinded study. SETTING: Three gynecology research clinics in the United Kingdom. PATIENT(S): Women with self-perceived light, normal, or heavy menstrual periods who had not previously used a graphical method to assess their menstrual loss. INTERVENTION(S): One hundred twenty-two women were asked to complete the menstrual pictogram throughout two menstrual periods and collect their feminine towels for measurements of menstrual blood loss (MBL) by the alkaline hematin method and total menstrual fluid loss (MFL) by fluid weight. MAIN OUTCOME MEASURE(S): Agreement of menstrual pictogram MBL and MFL scores with alkaline hematin and towel weight, respectively. The percentage blood fraction was determined at various volumes of menstrual discharge. RESULT(S): Alkaline hematin and fluid weight were highly correlated (r = .97). However, the percentage blood fraction progressively increased with total MFL and MBL score. After correction for this incremental rise in blood fraction, the menstrual pictogram gave a sensitivity of 82% and a specificity of 92% for a diagnosis of heavy menstrual bleeding. CONCLUSION(S): The menstrual pictogram (superabsorbent polymer-c version) provides a simple means of measuring MBL in the clinical setting.

A new menstrual pictogram for use with feminine products that contain superabsorbent polymers.

OBJECTIVE: To determine whether the menstrual pictogram (the superabsorbent polymer-c or SAP-c version) can reliably estimate blood and total menstrual fluid volumes on prestained Always Ultra slim feminine towels (Proctor & Gamble) that contain superabsorbent polymers. DESIGN: Randomized blinded study using simulated menstrual fluid (SMF: 50% blood, 50% saline mixture). SETTING: Gynecology research clinic. PATIENT(S): 12 premenopausal women with regular menstrual cycles who had not previously used a graphical method to assess menstrual loss. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Assignment of 135 prestained towels containing known volumes of 0.5-25.0 mL of SMF to five pictorial icons of the menstrual pictogram, and correlation of pictogram scores to blood recovered from towels by the alkaline hematin method and total fluid applied to towels by measurement of soiled towel weight. RESULT(S): There was a high level of agreement between individual scores. For 112 (83%) of 135 towels, the participants' readings either completely concurred or differed by only a single icon. There was a statistically significant correlation between the volume of blood applied (SMF/2) and that recovered by alkaline hematin, and volume of fluid applied and soiled towel weight. CONCLUSION(S): The menstrual pictogram (SAP-c version) is a potential diagnostic tool for heavy menstrual bleeding and would be suitable for testing in a clinical trial.

Clinical subtypes of core premenstrual disorders: a Delphi survey.

The purpose of this study was to classify the clinical subtypes of core premenstrual disorders during the International Society for Premenstrual Disorders' second consensus meeting. Multiple iterations were used to achieve consensus between a group of experts; these iterations included a two-generational Delphi technique that was preceded and followed by open group discussions. The first round was to generate a list of all potential clinical subtypes, which were subsequently prioritized using a Delphi methodology and then finalised in a final round of open discussion. On a six-point scale, 4 of the 12 potential clinical subtypes had a mean score of ≥5.0 following the second iteration and only 3 of the 4 still had a mean score of ≥5.0 after the third iteration. The final list consisted of these three subtypes and an additional subtype, which was introduced and agreed upon, in the final iteration. There is consensus amongst experts that core premenstrual disorder is divided into three symptom-based subtypes: predominantly physical, predominantly psychological and mixed. A proportion of psychological and mixed subtypes may meet the DSM-IV diagnostic criteria for premenstrual dysphoric disorder.

Classification of premenstrual disorders as proposed by the International Society for Premenstrual Disorders.

Premenstrual disorders have been recognized as affecting innumerable women for decades but unlike most other medical conditions universally accepted criteria for definition and diagnosis are not established. Although premenstrual syndrome (PMS) occurs throughout reproductive life, there are some women who become particularly troubled. Those approaching the menopause may also have a mixture of PMS and menopause symptoms, not to mention heavy periods. Furthermore, some of the symptoms are similar in nature and so it is a challenge to identify which set of symptoms belongs to which spectrum. This is an area that has not been explored well. Various classifications have been proposed over the last few decades. A further effort towards the classification was made by an international multidisciplinary group of experts established as the International Society for Premenstrual Disorders (ISPMD) in Montreal in September 2008. Their deliberations resulted in a unified diagnosis, classification of premenstrual disorders (PMD) along with their quantification and guidelines on clinical trial design. This classification of PMS is far more comprehensive and inclusive than previous attempts. PMD in the ISPMD Montreal consensus are divided into two categories: Core and Variant PMD. Core PMD are typical, pure or reference disorders associated with spontaneous ovulatory menstrual cycles while Variant PMD exist where more complex features are present. Further, the consensus group considered that PMD may be subdivided into three subgroups predominantly physical, predominantly psychological and mixed. Variant PMD encompass primarily four different types; premenstrual exacerbation, PMD with anovulatory ovarian activity, PMD with absent menstruation and progestogen-induced PMD.

Validation of a rapid alkaline hematin technique to measure menstrual blood loss on feminine towels containing superabsorbent polymers.

OBJECTIVE: To validate the semiautomated alkaline hematin technique for rapid measurement of menstrual blood loss on ultrathin sanitary towels with a superabsorbent polymer component. DESIGN: Laboratory study using simulated menstrual fluid (SMF) and Always Ultra Normal, Long, and Night "with wings" sanitary towels. SETTING: Laboratorium für Klinische Forschung, Germany. PATIENT(S): None. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Linearity and blood recovery over a range of SMF volumes applied to towels, the lower limit of reliable detection, and the effect of storing soiled towels for up to 5 weeks at 20°C and 4°C before analysis, were determined. Recovery from 63 SMF samples comprising between 5% to 100% blood and 0.05-35 mL applied volume was compared with duplicates analyzed at Keele Menstrual Disorders Laboratory (manual reference method). RESULT(S): Linearity was confirmed, and ≥85% recovery was reproducibly achieved at up to 30 mL applied blood at all tested SMF compositions, except at low volume or high dilution equivalent to <4 mL blood. Samples could be stored for 3 weeks at 4°C without loss of recovery. Linear regression analysis showed good agreement with the reference method. CONCLUSION(S): The semiautomated alkaline hematin technique is a reliable method for measuring menstrual blood loss from Always Ultra sanitary towels containing superabsorbent polymers.

Menstrual blood loss measurement: validation of the alkaline hematin technique for feminine hygiene products containing superabsorbent polymers.

OBJECTIVE: To validate the alkaline hematin technique for measurement of menstrual blood loss using ultra-thin sanitary towels that contain superabsorbent polymer granules as the absorptive agent. DESIGN: Laboratory study using simulated menstrual fluid (SMF) and Always Ultra Normal, Long, and Night "with wings" sanitary towels. SETTING: Keele Menstrual Disorders Laboratory. PATIENT(S): None. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Recovery of blood, linearity, and interassay variation over a range of SMF volumes applied to towels. Because of the variable percentage of blood in menstrual fluid, blood recovery was assessed from SMF constituted as 10%, 25%, 50%, and 100% blood. The lower limit of reliable detection and the effect of storing soiled towels for up to 4 weeks at 15°C-20°C, 4°C, and -20°C before analysis were determined. RESULT(S): Ninety percent recovery was reproducibly achieved up to 30 mL applied volume at all tested SMF compositions, except at low volume or high dilution equivalent to <2 mL whole blood. Samples could be stored for 3 weeks at all tested temperatures without loss of recovery. The technique was suitable for processing towels individually or in batches. CONCLUSION(S): The alkaline hematin technique is a suitable and validated method for measuring menstrual blood loss from Always Ultra sanitary towels that contain superabsorbent polymers.

Analysis of the serotonin transporter promoter rs25531 polymorphism in premenstrual dysphoric disorder.

OBJECTIVE: The objective of this study was to investigate whether the functional rs25531 promoter polymorphism in the serotonin transporter gene is associated with premenstrual dysphoric disorder. STUDY DESIGN: The study sample comprised 53 women with clinically diagnosed premenstrual dysphoric disorder (age range, 27-46 years; mean, 37.7 years) and 52 healthy control subjects (age range, 22-48 years; mean, 36.2 years). The rs25531 polymorphism was genotyped in both groups. Because of its close proximity to rs25531, the 5-HTTLPR promoter polymorphism was also genotyped. Genotype and allele frequencies for rs25531 and for the composite 5-HTTLPR/rs25531 marker were analyzed by chi(2) test. RESULTS: There was no significant association between any genotype and clinical category and no significant allele distribution profiles for rs25531 or 5-HTTLPR/rs25531 in either the premenstrual dysphoric disorder or the control groups. CONCLUSION: These findings do not support a major role for rs25531, either in isolation or combined with 5-HTTLPR, in contributing to susceptibility to premenstrual dysphoria.

Update on research and treatment of premenstrual dysphoric disorder.

Many women in their reproductive years experience some mood, behavioral. or physical symptoms in the week prior to menses. Variability exists in the level of symptom burden in that some women experience mild symptoms, whereas a small minority experience severe and debilitating symptoms. For an estimated 5%-8% of premenopausal women, work or social functioning are affected by severe premenstrual syndrome. Many women in this group meet diagnostic criteria for premenstrual dysphoric disorder (PMDD). Among women who suffer from PMDD, mood and behavioral symptoms such as irritability, depressed mood, tension, and labile mood dominate. Somatic complaints, including breast tenderness and bloating, also can prove disruptive to women's overall functioning and quality of life. Recent evidence suggests that individual sensitivity to cyclical variations in levels of gonadal hormones may predispose certain women to experience these mood, behavioral, and somatic symptoms. Treatments include: antidepressants of the serotonin reuptake inhibitor class, taken intermittently or throughout the menstrual cycle; medications that suppress ovarian cyclicity; and newer oral contraceptives with novel progestins.

Tests for predicting complications of pre-eclampsia: a protocol for systematic reviews.

BACKGROUND: Pre-eclampsia is associated with several complications. Early prediction of complications and timely management is needed for clinical care of these patients to avert fetal and maternal mortality and morbidity. There is a need to identify best testing strategies in pre eclampsia to identify the women at increased risk of complications. We aim to determine the accuracy of various tests to predict complications of pre-eclampsia by systematic quantitative reviews. METHOD: We performed extensive search in MEDLINE (1951-2004), EMBASE (1974-2004) and also will also include manual searches of bibliographies of primary and review articles. An initial search has revealed 19500 citations. Two reviewers will independently select studies and extract data on study characteristics, quality and accuracy. Accuracy data will be used to construct 2 x 2 tables. Data synthesis will involve assessment for heterogeneity and appropriately pooling of results to produce summary Receiver Operating Characteristics (ROC) curve and summary likelihood ratios. DISCUSSION: This review will generate predictive information and integrate that with therapeutic effectiveness to determine the absolute benefit and harm of available therapy in reducing complications in women with pre-eclampsia.

Hormonal management of premenstrual syndrome.

Premenstrual syndrome (PMS) is a psychological and somatic disorder of unknown aetiology. The symptoms of PMS regularly occur during the luteal phase of the menstrual cycle and resolve by the end of menstruation. The severe and predominantly psychological form of PMS is called 'premenstrual dysphoric disorder'. PMS results from ovulation and appears to be caused by the progesterone produced following ovulation in women who have enhanced progesterone sensitivity. This enhanced sensitivity may be due to neurotransmitter dysfunction. Treatment is aimed at suppressing ovulation or reducing progesterone sensitivity. This chapter will describe the role of hormones and hormonal treatments in PMS.