Maternal and perinatal outcomes in twin pregnancies following assisted reproduction: a systematic review and meta-analysis involving 802 462 pregnancies.

BACKGROUND: ART is associated with higher rates of twin pregnancies than singleton pregnancies. Whether twin pregnancies conceived following ART have additional maternal and neonatal complications compared with non-ART twin pregnancies is not known. OBJECTIVE AND RATIONALE: The objective was to quantify the risk of adverse maternal and perinatal outcomes among twin pregnancies conceived following ART compared with non-ART and natural conception. Existing reviews vary in the reported outcomes, with many studies including triplet pregnancies in the study population. Therefore, we aimed to perform an up-to-date review with an in-depth analysis of maternal and perinatal outcomes limited to twin pregnancies. SEARCH METHODS: We searched electronic databases MEDLINE and EMBASE from January 1990 to May 2023 without language restrictions. All cohort studies reporting maternal and perinatal outcomes following ART compared with non-ART twin pregnancies and natural conception were included. Case-control studies, case reports, case series, animal studies, and in vitro studies were excluded. The Newcastle-Ottawa Scale was used to assess the methodological quality of the studies. Using random-effects meta-analysis, the estimates were pooled and the findings were reported as odds ratios (OR) with 95% CI. OUTCOMES: We included 111 studies (802 462 pregnancies). Twin pregnancies conceived following ART were at higher risk of preterm birth at <34 weeks (OR 1.33, 95% CI 1.14-1.56, 29 studies, I2 = 73%), <37 weeks (OR 1.26, 95% CI 1.19-1.33, 70 studies, I2 = 76%), hypertensive disorders in pregnancy (OR 1.29, 95% CI 1.14-1.46, 59 studies, I2 = 87%), gestational diabetes mellitus (OR 1.61, 95% CI 1.48-1.75, 51 studies, I2 = 65%), and caesarean delivery (OR 1.80, 95% CI 1.65-1.97, 70 studies, I2 = 89%) compared with non-ART twins. The risks for the above maternal outcomes were also increased in the ART group compared with natural conception. Of the perinatal outcomes, ART twins were at significantly increased risk of congenital malformations (OR 1.17, 95% CI 1.05-1.30, 39 studies, I2 = 59%), birthweight discordance (>25% (OR 1.31, 95% CI 1.05-1.63, 7 studies, I2 = 0%)), respiratory distress syndrome (OR 1.32, 95% CI 1.09-1.60, 16 studies, I2 = 61%), and neonatal intensive care unit admission (OR 1.24, 95% CI 1.14-1.35, 32 studies, I2 = 87%) compared with non-ART twins. When comparing ART with natural conception, the risk of respiratory distress syndrome, intensive care admissions, and birthweight discordance >25% was higher among the ART group. Perinatal complications, such as stillbirth (OR 0.83, 95% CI 0.70-0.99, 33 studies, I2 = 49%), small for gestational age <10th centile (OR 0.90, 95% CI 0.85-0.95, 26 studies, I2 = 36%), and twin-twin transfusion syndrome (OR 0.45, 95% CI 0.25-0.82, 9 studies, I2 = 25%), were reduced in twin pregnancies conceived with ART versus those without ART. The above perinatal complications were also fewer amongst the ART group than natural conception. WIDER IMPLICATIONS: ART twin pregnancies are associated with higher maternal complications than non-ART pregnancies and natural conception, with varied perinatal outcomes. Women seeking ART should be counselled about the increased risks of ART twin pregnancies and should be closely monitored in pregnancy for complications. We recommend exercising caution when interpreting the study findings owing to the study's limitations.

Sleep improvements following atopic dermatitis management in young children.

OBJECTIVES: The purpose of this pilot study was to assess improvements in associated sleep and caregiver mood following treatment of atopic dermatitis in young children. METHODS: Participants included children (n = 23; Mage = 22.0 months) and their caregivers. Topical management of atopic dermatitis was conducted for 2 weeks, with measures of skin, sleep (child, caregiver), and mood (caregiver) at baseline and day 14. RESULTS: Topical management resulted in significant improvements in child skin, with associated increases in sleep consolidation. There were similar improvements in caregiver nightwakings, with nighttime sleep duration improving by over an hour. Caregivers also reported more energy to engage with their family and feeling better rested. CONCLUSIONS: Overall, topical management significantly improved atopic dermatitis. There were concomitant improvements in sleep outcomes for children and their caregivers, as well as caregiver mood. Daily management of atopic dermatitis may result in improvements in not just skin health but also sleep and family well-being.

Biochemical predictors of preterm birth in twin pregnancies: A systematic review involving 6077 twin pregnancies.

In women with twin pregnancies biomarkers are not used to predict preterm birth in clinical practice. This systematic review assessed the risk of both spontaneous and iatrogenic preterm birth in twin pregnancies based on biochemical predictors. We searched the electronic databases from January 1990 to June 2019 without language restrictions. All studies on twin pregnancies where biochemical predictors and preterm birth were evaluated were included. We reported our findings as odds ratio (OR) with 95 % confidence intervals (CI) and pooled the estimates using random-effects meta-analysis for various predictor thresholds. From 12,623 citations, we included 33 studies involving 6077 pregnancies. The odds of preterm birth <28 weeks (OR 12.06, 95 % CI 4.90-29.70, I2 = 0%), <32 weeks (OR 10.03, 95 % CI 6.11-16.47, I2 = 0%), <34 weeks (OR 6.26, 95 % CI 3.85-10.17, I2 = 30 %), <37 weeks (OR 5.34, 95 % CI 3.68-7.76, I2 = 15 %) and delivery within 14 days of testing (OR 13.95, 95 % CI 4.33-44.98, I2 = 0%) was increased among women with a positive fetal Fibronectin (fFN) test who were either symptomatic or asymptomatic for preterm birth. Similarly, higher odds of preterm birth was also seen among twin pregnancies asymptomatic for preterm birth with a positive fFN test at gestations <32 weeks (OR 10.54, 95 % CI 5.66-19.64, I2 = 19 %), < 34 weeks (OR 8.07, 95 % CI 5.28-12.33, I2 = 0%) and < 37 weeks (OR 6.21, 95 % CI 4.34-8.87, I2 = 0%). As for other biomarkers, a significantly higher odds of preterm birth <37 weeks was seen among women with elevated maternal serum human Chorionic Gonadotrophin (mshCG) (OR 1.51, 95 % CI 1.07-2.13, I2 = 0%), 25 Hydroxy Vitamin D level <75 nmol/l (OR 2.59, 95 % CI 1.35-4.95, I2=NA), positive phosphorylated Insulin-like Growth Factor Binding Protein-1 (phIGFBP-1) (OR 4.23, 95 % CI 1.97-9.09, I2 = 0%) and in those with elevated Interleukin 8 (IL-8) (OR 3.13, 95 % CI 1.18-8.34, I2=NA). A higher odds of preterm birth at <34 weeks gestation was seen among women with maternal serum Alpha fetoprotein (AFP)>3.5 MoM (OR 2.35, 95 % CI 1.12-4.96, I2=NA) while higher odds of preterm birth at <32 weeks was seen among women with 25 Hydroxy Vitamin D level <75 nmol/l (OR 3.01, 95 % CI 1.26-7.19, I2=NA). Delivery within seven days of testing was significantly increased in women with a positive Matrix Metallo Protein-8 (MMP-8) test (OR 10.59, 95 % CI 3.70-30.29, I2=NA). Fetal Fibronectin is strongly associated with predicting preterm birth among women with twin pregnancies who are either asymptomatic or symptomatic for preterm birth as well as in those asymptomatic for preterm birth. Other biomarkers have shown a positive association in the prediction of preterm birth among women with twin pregnancies. Further studies are recommended to evaluate their role.

Maternal clinical predictors of preterm birth in twin pregnancies: A systematic review involving 2,930,958 twin pregnancies.

In twin pregnancies, which are at high risk of preterm birth, it is not known if maternal clinical characteristics pose additional risks. We undertook a systematic review to assess the risk of both spontaneous and iatrogenic early (<34 weeks) or late preterm birth (<37 weeks) in twin pregnancies based on maternal clinical predictors. We searched the electronic databases from January 1990 to November 2017 without language restrictions. We included studies on women with monochorionic or dichorionic twin pregnancies that evaluated clinical predictors and preterm births. We reported our findings as odds ratio (OR) with 95% confidence intervals (CI) and pooled the estimates using random-effects meta-analysis for various predictor thresholds. From 12, 473 citations, we included 59 studies (2,930,958 pregnancies). The risks of early preterm birth in twin pregnancies were significantly increased in women with a previous history of preterm birth (OR 2.67, 95% CI 2.16-3.29, I2 = 0%), teenagers (OR 1.81, 95% CI 1.68-1.95, I2 = 0%), BMI > 35 (OR 1.63, 95% CI 1.30-2.05, I2 = 52%), nulliparous (OR 1.51, 95% CI 1.38-1.65, I2 = 73%), non-white vs. white (OR 1.31, 95% CI 1.20-1.43, I2 = 0%), black vs. non-black (OR 1.38, 95% CI 1.07-1.77, I2 = 98%), diabetes (OR 1.73, 95% CI 1.29-2.33, I2 = 0%) and smokers (OR 1.30, 95% CI 1.23-1.37, I2 = 0%). The odds of late preterm birth were also increased in women with history of preterm birth (OR 3.08, 95% CI 2.10-4.51, I2 = 73%), teenagers (OR 1.36, 95% CI 1.18-1.57, I2 = 57%), BMI > 35 (OR 1.18, 95% CI 1.02-1.35, I2 = 46%), nulliparous (OR 1.41, 95% CI 1.23-1.62, I2 = 68%), diabetes (OR 1.44, 95% CI 1.05-1.98, I2 = 55%) and hypertension (OR 1.49, CI 1.20-1.86, I2 = 52%). The additional risks posed by maternal clinical characteristics for early and late preterm birth should be taken into account while counseling and managing women with twin pregnancies.

Prospective observational study to determine the accuracy of first-trimester serum biomarkers and uterine artery Dopplers in combination with maternal characteristics and arteriography for the prediction of women at risk of preeclampsia and other adverse pregnancy outcomes.

OBJECTIVES: To assess the efficacy of biomarkers, arteriography and uterine artery Dopplers for predicting hypertensive disease of pregnancy, small for gestational age (SGA) and stillbirth. METHODS: This was a prospective first-trimester study. Ultrasound was used to assess uterine artery Doppler. Maternal arteriography was performed and serum was taken for the measurement of placental growth factor (PlGF), alpha-fetoprotein (AFP), pregnancy-associated plasma protein (PAPP-A) and beta-human chorionic gonadotrophin levels. Logistic regression with stepwise selection was performed to determine multivariate models. RESULTS: One thousand and forty-five women were left for analysis after exclusions. Fourteen developed preeclampsia, 23 pregnancy induced hypertension, 64 SGA <5th centile, 118 SGA <10th centile and three stillbirth. Systolic blood pressure (SBP) in the aorta (SBPAO) (p = .002) was significantly associated with preeclampsia. Detection rate (DR) was 72% for a false-positive rate (FPR) of 15%, an area under the curve (AUC) of 0.81, 95% CI 0.69-0.93. MAP and maternal weight (p = .001) were significantly associated with PIH. DR 48%, AUC 0.76, 95% CI 0.65-0.86. Low PAPP-A and PlGF were significantly associated with SGA <10th centile (p = .007 and .004, respectively), DR 30%, AUC 0.608, 95% CI 0.54-0.68. SGA <5th centile was significantly associated with low PlGF (p = <.001), DR 57%, AUC 0.73, 95% CI 0.65-0.80. CONCLUSIONS: No association was found between first-trimester biomarkers and preeclampsia/PIH. There was a significant association between low PlGF and PAPP-A and SGA.

External validation of preexisting first trimester preeclampsia prediction models.

OBJECTIVE: To validate the increasing number of prognostic models being developed for preeclampsia using our own prospective study. STUDY DESIGN: A systematic review of literature that assessed biomarkers, uterine artery Doppler and maternal characteristics in the first trimester for the prediction of preeclampsia was performed and models selected based on predefined criteria. Validation was performed by applying the regression coefficients that were published in the different derivation studies to our cohort. We assessed the models discrimination ability and calibration. RESULTS: Twenty models were identified for validation. The discrimination ability observed in derivation studies (Area Under the Curves) ranged from 0.70 to 0.96 when these models were validated against the validation cohort, these AUC varied importantly, ranging from 0.504 to 0.833. Comparing Area Under the Curves obtained in the derivation study to those in the validation cohort we found statistically significant differences in several studies. CONCLUSION: There currently isn't a definitive prediction model with adequate ability to discriminate for preeclampsia, which performs as well when applied to a different population and can differentiate well between the highest and lowest risk groups within the tested population. The pre-existing large number of models limits the value of further model development and future research should be focussed on further attempts to validate existing models and assessing whether implementation of these improves patient care.

Kisspeptin Is a Novel Regulator of Human Fetal Adrenocortical Development and Function: A Finding With Important Implications for the Human Fetoplacental Unit.

Context: The human fetal adrenal (HFA) is an integral component of the fetoplacental unit and important for the maintenance of pregnancy. Low kisspeptin levels during pregnancy are associated with miscarriage, and kisspeptin and its receptor are expressed in the HFA. However, the role of kisspeptin in fetal adrenal function remains unknown. Objective: To determine the role of kisspeptin in the developing HFA. Design: Experiments using H295R and primary HFA cells as in vitro models of the fetal adrenal. Association of plasma kisspeptin levels with HFA size in a longitudinal clinical study. Setting: Academic research center and tertiary fetal medicine unit. Participants: Thirty-three healthy pregnant women were recruited at their 12-week routine antenatal ultrasound scan. Main Outcome Measures: The spatiotemporal expression of Kiss1R in the HFA. The production of dehydroepiandrosterone sulfate (DHEAS) from HFA cells after kisspeptin treatment, alone or in combination with adrenocorticotropic hormone or corticotropin-releasing hormone. Fetal adrenal volume (FAV) and kisspeptin levels at four antenatal visits (∼20, 28, 34, and 38 weeks' gestation). Results: Expression of Kiss1R was present in the HFA from 8 weeks after conception to term and was shown in the inner fetal zone. Kisspeptin significantly increased DHEAS production in H295R and second-trimester HFA cells. Serial measurements of kisspeptin confirmed a correlation with FAV growth in the second trimester, independent of sex or estimated fetal weight. Conclusions: Kisspeptin plays a key role in the regulation of the HFA and thus the fetoplacental unit, particularly in the second trimester of pregnancy.

Abnormal blood biomarkers in early pregnancy are associated with preeclampsia: a meta-analysis.

OBJECTIVE: Our aim was to evaluate the strength of association between abnormal levels of first trimester maternal blood biomarkers and the risk of preeclampsia. STUDY DESIGN: We searched MEDLINE, EMBASE and Cochrane databases from inception until April 2013. Studies that assessed the association between any abnormal maternal blood biomarker in the first trimester and preeclampsia were included. Two independent reviewers selected studies, extracted data and assessed the quality. Results were summarized as pooled odds ratios with 95% confidence intervals. RESULTS: From 1071 citations, we identified 30 studies (65,538 women) for inclusion. Twenty four studies assessed preeclampsia of any onset, 10 studied early onset preeclampsia and seven evaluated late onset preeclampsia (after 34 weeks of gestation). The biomarkers PAPP-A (OR 2.1, 95% CI 1.6, 2.6), PP13 (OR 4.4, 95% CI 2.9, 6.8), sFlt-1 (OR 1.3, 95% CI 2.9, 6.8), pentraxin (OR 5.3, 95% CI 1.9, 15.0) and inhibin-A (OR 3.6, 95% CI 1.7, 7.6) were significantly associated with any preeclampsia. The odds of early onset preeclampsia were significantly increased when the biomarkers PlGF (OR 3.4, 95% CI 1.6, 7.2), PAPP-A (OR 4.8, 95% CI 2.5, 22.5), PP13 (OR 7.5, 95% CI 2.5, 22.5), soluble endoglin (OR 18.5, 95% CI 8.4, 41.0) and inhibin-A (OR 4.1, 95% CI 1.9, 8.8) were abnormal. Two biomarkers, soluble endoglin (OR 2.1, 95% CI 1.9, 2.4) and inhibin-A (OR 1.9, 95% CI 1.4, 2.8) were significantly associated with late onset preeclampsia. CONCLUSION: Abnormal maternal blood biomarkers in early pregnancy are significantly associated with preeclampsia, particularly early onset disease.

Results from a prospective observational study of men with premature ejaculation treated with dapoxetine or alternative care: the PAUSE study.

BACKGROUND: Dapoxetine hydrochloride is a selective serotonin reuptake inhibitor and the first drug approved for the on-demand treatment of premature ejaculation (PE). Its safety was established in a thorough clinical development program. OBJECTIVE: To characterize the safety profile of dapoxetine in PE treatment and to report the incidence, severity, and type of adverse events. DESIGN, SETTING, AND PARTICIPANTS: We conducted a 12-wk, open-label, observational study with a 4-wk, postobservational contact. A total of 10,028 patients were enrolled, with 6712 patients (67.6%) treated with dapoxetine 30-60 mg (group A) and 3316 (32.4%) treated with alternative care/nondapoxetine (group B). INTERVENTIONS: Treatment with dapoxetine or alternative care/nondapoxetine. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Treatment-emergent adverse events (TEAEs) and concomitant therapy use during the 12-wk observational and the postobservational period were reported. RESULTS AND LIMITATIONS: The mean age for all patients was 40.5 yr. In group A, 93.0% of the patients were initially prescribed dapoxetine 30 mg. Treatment options for group B patients included clomipramine, paroxetine, fluoxetine, sertraline, topical drugs, condoms, and behavioral counseling. Both treatment regimens were well tolerated. TEAEs were reported by 12.0% and 8.9% of group A and group B, respectively, with the highest incidence observed in patients aged >65 yr for group A (21.4%) and 30-39 yr (9.8%) for group B. The most commonly reported TEAEs were nausea, headache, and vertigo, with a higher incidence in group A (3.1%, 2.6%, and 1.0%, respectively) than in group B (oral drugs: 2.3%, 1.3%, and 0.9%, respectively). There were no cases of syncope in group A and one case in group B. A major limitation is that this was a nonrandomized, open-label, short-term study lacking efficacy data. CONCLUSIONS: The results of this postmarketing observational study demonstrated that dapoxetine for treatment of PE has a good safety profile and low prevalence of TEAEs. Syncope and major cardiovascular adverse events were not reported. The high level of adherence by healthcare providers to the contraindications, special warnings, and precautions for dapoxetine minimizes the risk for its use in routine clinical practice. The current risk minimization measures for its identified and potential risks are effective.

Efficacy and safety of dapoxetine in men with premature ejaculation and concomitant erectile dysfunction treated with a phosphodiesterase type 5 inhibitor: randomized, placebo-controlled, phase III study.

INTRODUCTION: Men with comorbid erectile dysfunction (ED) and premature ejaculation (PE) may be concomitantly prescribed a phosphodiesterase type 5 (PDE5) inhibitor and dapoxetine. AIM: Evaluate efficacy and safety of dapoxetine 30 mg and 60 mg on demand (prn) in men with PE and ED who were being treated with PDE5 inhibitors. METHODS: This randomized, double-blind, placebo-controlled, flexible-dose, multicenter study enrolled men ≥18 years who met diagnostic criteria for PE including intravaginal ejaculatory latency time (IELT) of ≤2 minutes in ≥75% of sexual intercourse episodes; were on stable regimen of a PDE5 inhibitor; and had International Index of Erectile Function-erectile function domain score ≥21. Subjects received placebo, dapoxetine 30 mg, or dapoxetine 60 mg prn (1-3 hours before intercourse) for 12 weeks. MAIN OUTCOME MEASURE: Stopwatch-measured average IELT, Clinical Global Impression of Change (CGIC) in PE, Premature Ejaculation Profile (PEP), and treatment-emergent adverse events (TEAEs). RESULTS: Of 495 subjects randomized, 429 completed the study. Arithmetic mean average IELT significantly increased with dapoxetine vs. placebo at end point (5.2 vs. 3.4 minutes) and weeks 4, 8, and 12 (P ≤ 0.002 for all). Men who described their PE at least "better" using the CGIC were significantly greater with dapoxetine vs. placebo at end point (56.5% vs. 35.4%) and weeks 4, 8, and 12 (P ≤ 0.001 for all). Significantly better outcomes were also reported with dapoxetine vs. placebo on PEP measures. Incidence of TEAEs was 20.0% and 29.6% in placebo- and dapoxetine-treated subjects, respectively (P = 0.0135). TEAEs led to discontinuation in 1.6% of subjects in both groups. Most frequent TEAEs were known adverse drug reactions of dapoxetine treatment including nausea (9.2%), headache (4.4%), diarrhea (3.6%), dizziness (2.4%), and dizziness postural (2.4%). CONCLUSIONS: In men with PE and comorbid ED on a stable regimen of PDE5 inhibitor, dapoxetine provided meaningful treatment benefit and was generally well tolerated.

The role of nitrates in the prevention of preeclampsia: an update.

PURPOSE OF REVIEW: Defective nitric oxide synthesis and nitric oxide-mediated vasodilatation is widely documented in the pathophysiology of preeclampsia, a leading cause of maternal and perinatal morbidity and mortality worldwide. Several studies demonstrated the beneficial role of nitric oxide agents, especially glyceryl trinitrate and L-arginine in reducing the blood pressure and improving the uteroplacental blood flow velocities. However, there is insufficient evidence on the efficacy and safety of these agents in the prevention of preeclampsia and its complications, as there are very few randomized controlled trials with small number of women. The aim of this review is to summarize and evaluate the role of nitrates in the prevention of preeclampsia based on the available evidence in the literature till date and suggestions for future research. RECENT FINDINGS: Supplementation with L-arginine and antioxidant vitamins reduced the incidence of preeclampsia in women at high risk of preeclampsia [P < 0.001, absolute risk reduction 0.17 (confidence interval 0.12-0.21)]. SUMMARY: On the basis of the recent evidence, nitric oxide agents may be beneficial in the prevention of preeclampsia. Randomized controlled trials initiated in the first trimester and using long-acting nitrates are needed in high-risk women to validate these findings.

Radiological appearances of gynaecological emergencies.

BACKGROUND: The role of various gynaecological imaging modalities is vital in aiding clinicians to diagnose acute gynaecological disease, and can help to direct medical and surgical treatment where appropriate. It is important to interpret the imaging findings in the context of the clinical signs and patient's pregnancy status. METHODS: Ultrasound and Doppler are readily available in the emergency department, and demonstrate features of haemorrhagic follicular cysts, ovarian cyst rupture, endometriotic cysts and pyosalpinx. Adnexal torsion may also be identified using ultrasound and Doppler, although the diagnosis cannot be safely excluded based on imaging alone. Computed tomography (CT) is not routinely employed in diagnosing acute gynaecological complications. However due to similar symptoms and signs with gastrointestinal and urinary tract pathologies, it is frequently used as the initial imaging modality and recognition of features of gynaecological complications on CT is important. RESULTS: Although MRI is not frequently used in the emergency setting, it is an important modality in characterising features that are unclear on ultrasound and CT. CONCLUSION: MRI is particularly helpful in identifying the site of origin of large pelvic masses, such as haemorrhagic uterine fibroid degeneration and fibroid prolapse or torsion. In this article, we review the imaging appearances of gynaecological emergencies in non-pregnant patients. TEACHING POINTS: • Ultrasonography is easily accessible and can identify life-threatening gynaecological complications. • Tomography scanners and computed radiography are not routinely used but are important to recognise key features. • MRI is used for the characterisation of acute gynaecological complications. • Recognition of the overlap in symptoms between gastrointestinal and gynaecological conditions is essential.

Cardiovascular safety profile of dapoxetine during the premarketing evaluation.

The cardiovascular safety profile of dapoxetine, a novel selective serotonin reuptake inhibitor (SSRI) developed as an on-demand oral treatment for premature ejaculation (PE) in men, is evaluated. The cardiovascular assessment of dapoxetine was conducted throughout all stages of drug development, with findings from preclinical safety pharmacology studies, phase I clinical pharmacology studies investigating the effect of dapoxetine on QT/corrected QT (QTc) intervals in healthy men, and phase III, randomized, placebo-controlled studies evaluating the safety (and efficacy) of the drug. Preclinical safety pharmacology studies did not suggest an adverse electrophysiologic or hemodynamic effect with concentrations of dapoxetine up to 2-fold greater than recommended doses. Phase I clinical pharmacology studies demonstrated that dapoxetine did not prolong the QT/QTc interval and had neither clinically significant electrocardiographic effects nor evidence of delayed repolarization or conduction effects, with dosing up to 4-fold greater than the maximum recommended dosage. Phase III clinical studies of dapoxetine in men with PE indicated that dapoxetine was generally safe and well tolerated with the dosing regimens used (30 mg and 60 mg as required). Events of syncope were reported during the clinical development program, with the majority occurring during study visits (on site) on day 1 following administration of the first dose when various procedures (e.g. orthostatic maneuvers, venipunctures) were performed, suggesting that the procedures contributed to the incidence of syncope. This was consistent with previous reports showing that these and similar factors contribute to or trigger vasovagal syncope. Findings of the dapoxetine development program demonstrate that dapoxetine is associated with vasovagal-mediated (neurocardiogenic) syncope. No other associated significant cardiovascular adverse events were identified.

Efficacy and safety of dapoxetine for the treatment of premature ejaculation: integrated analysis of results from five phase 3 trials.

INTRODUCTION: Dapoxetine has been evaluated for the on-demand treatment of premature ejaculation (PE) in five phase 3 studies in various populations worldwide and has recently been approved in several countries. AIM: To present integrated efficacy and safety data from phase 3 trials of dapoxetine. METHODS: Data were from five randomized, multicenter, double-blind, placebo-controlled studies conducted in over 25 countries. Men (N=6,081)≥18 years who met the Diagnostic and Statistical Manual of Mental Disorders, fourth edition, text revision criteria for PE; four studies required a baseline intravaginal ejaculatory latency time (IELT) of ≤2 minutes. Dapoxetine 30 and 60 mg on demand (prn; 1-3 hours before intercourse) were evaluated for either 12 or 24 weeks in four studies; one study evaluated dapoxetine 60 mg daily (qd; included in safety assessments only) or prn for 9 weeks. MAIN OUTCOME MEASURES: End points included stopwatch-measured IELT, Premature Ejaculation Profile (PEP) items, clinical global impression of change (CGIC) in PE, and adverse events (AEs). RESULTS: Average IELT (mean [standard deviation], geometric mean [standard error]) increased from baseline (across groups, 0.9 [0.49] minutes, 0.8 [1.01] minutes) to a significantly greater extent with dapoxetine 30 (3.1 [3.91] minutes, 2.0 [1.03] minutes) and 60 mg (3.6 [3.85] minutes, 2.3 [1.03] minutes) vs. placebo (1.9 [2.43] minutes, 1.3 [1.02] minutes; P<0.001 for all) at week 12 (geometric mean fold increase, 2.5, 3.0, and 1.6, respectively). All PEP items and CGIC improved significantly with both doses of dapoxetine vs. placebo (P<0.001 for all). The most common AEs included nausea, dizziness, and headache, and evaluation of validated instruments demonstrated no anxiety, akathisia, suicidality, or changes in mood with dapoxetine use and no discontinuation syndrome following abrupt withdrawal. CONCLUSIONS: In this diverse population, dapoxetine significantly improved all aspects of PE and was generally well tolerated.

Baseline characteristics and treatment outcomes for men with acquired or lifelong premature ejaculation with mild or no erectile dysfunction: integrated analyses of two phase 3 dapoxetine trials.

INTRODUCTION: Premature ejaculation (PE) is classified as an acquired or lifelong condition but data on baseline characteristics and response to treatment of men with acquired or lifelong PE and mild erectile dysfunction (ED) or normal erectile function (EF) is limited. AIM: To present integrated analyses of baseline characteristics and treatment outcomes from phase 3 dapoxetine trials in men with acquired or lifelong PE and mild or no ED. METHODS: Data were analyzed from two randomized, double-blind, placebo-controlled, phase 3 clinical trials (International and Asia-Pacific) that evaluated efficacy and safety of dapoxetine (30 mg or 60 mg as needed [PRN]) in patients with PE. Men were ≥18 years, in a stable monogamous relationship for ≥6 months, met DSM-IV-TR criteria for PE for ≥6 months, had an International Index of Erectile Function EF domain score ≥21, and had an intravaginal ejaculatory latency time (IELT) ≤2 minutes in ≥75% of intercourse episodes. MAIN OUTCOME MEASURES: Demographics, sexual history, and PE symptomatology at baseline, and mean IELT and patient-reported outcomes (PROs) at study end (week 12), were analyzed for men with acquired or lifelong PE and mild or no ED (EF score 21-25 vs. ≥26). RESULTS: Baseline characteristics except duration of PE were similar in men with acquired and lifelong PE, with no other differentiating features by ED status. Dapoxetine treatment improved significantly mean IELT (arithmetic and geometric) and PRO responses (perceived control over ejaculation, satisfaction with sexual intercourse, ejaculation-related personal distress, and interpersonal difficulty) for acquired and lifelong subtypes, but presence of mild ED diminished PRO responsiveness in both subtypes, particularly those with lifelong PE. CONCLUSIONS: Baseline characteristics and treatment outcomes were generally similar in men with acquired and lifelong PE. The presence of mild ED appears to be associated with a more modest treatment response, irrespective of lifelong or acquired PE subtype.

Validity of the patient-reported Clinical Global Impression of Change as a measure of treatment response in men with premature ejaculation.

INTRODUCTION: The Clinical Global Impression of Change (CGIC) measures have high utility in clinical practice. However, it is unknown whether the CGIC is valued for assessing premature ejaculation (PE) symptoms and/or the relationship between CGIC and other validated PE patient-reported measures. AIM: The study aims to assess the validity of the patient-reported CGIC measure in men with PE and to examine the relationship between CGIC ratings and assessments of control, satisfaction, personal distress, and interpersonal difficulty. METHODS: Data from a randomized, double-blind, 24-week phase 3 trial in 1,162 men with PE who received dapoxetine (30 mg or 60 mg) or placebo on demand provided the basis for the analysis. Patients were ≥18 years, in a stable monogamous relationship for ≥6 months, met the Diagnostic and Statistical Manual of Mental Disorders-Fourth Edition-Text Revision criteria for PE for ≥6 months, and had an intravaginal ejaculatory latency time (IELT) ≤2 minutes in ≥75% of intercourse episodes. MAIN OUTCOME MEASURES: The CGIC asked patients to rate improvement or worsening of their PE compared with the start of the study using a 7-point response scale; other patient-reported measures were control over ejaculation, satisfaction with sexual intercourse, interpersonal difficulty, and personal distress related to ejaculation. Stopwatch-measured IELT was recorded. Associations between CGIC and change in other measures at study end point were assessed. RESULTS: The magnitude of IELT increased for each category of improvement on the CGIC: 1.63, 4.03, and 7.15 minutes for slightly better, better, and much better, respectively. Higher CGIC ratings were correlated with greater improvement in control (r = 0.73), satisfaction (r = 0.62), greater reduction in distress (r = -0.52), and interpersonal difficulty (r = -0.39). Total variance accounted for was 57.4%: control (48.7%), satisfaction (4.5%), IELT (2.8%), and distress (1.15%). CONCLUSIONS: The analyses support the validity of the CGIC measure in men with PE. The CGIC can provide clinicians in practice with a valid and brief outcome assessment of their patient's condition.

Second trimester maternal serum cystatin C levels in preeclamptic and normotensive pregnancies: A small case-control study.

BACKGROUND/AIMS: Cystatin C (CC) is a marker of glomerular filtration rate (GFR) and is elevated in cases of established preeclampsia (PE). It also has widespread presence in extracellular space and high levels in PE might reflect placental ischemia. The aim of this study was to measure CC levels in the second trimester in women who subsequently develop PE and in those who remained normotensive. METHODS: Maternal serum taken at time of the anomaly scan from 15 women was analysed for CC and creatinine levels. Six women later developed PE and 9 remained normotensive. RESULTS: Cystatin C levels were significantly higher in women who developed preeclampsia (mean value 0.76 vs. 0.53 mg/L, p = 0.008). However, creatinine levels showed no statistical difference (mean value 76.1 vs. 65.5 micromol/L, p = 0.066). The range of CC was 0.41-0.55 mg/L in normotensive pregnancies and 0.50-1.26 mg/L in pregnancies with PE. CONCLUSION: This small observational study showed that serum CC is raised as early as the second trimester in women who subsequently develop PE in third trimester. Larger studies are needed to evaluate the potential role of CC as an early marker for the prediction of PE.

Pharmacokinetics of dapoxetine hydrochloride in healthy Chinese, Japanese, and Caucasian men.

Dapoxetine is a short-acting selective serotonin reuptake inhibitor developed for the on-demand treatment of premature ejaculation and is approved in some European Union countries, as well as Mexico and Korea, for this indication. The pharmacokinetics of dapoxetine 30 mg and 60 mg in healthy Chinese (single dose), Japanese, and Caucasian men (single and multiple dose) were assessed in 2 studies. In the 3 ethnic groups, dapoxetine was rapidly absorbed following oral administration, with peak plasma concentrations evident approximately 1 hour after dosing, independent of dose, dosing frequency (single or multiple dosing), or ethnicity. Dapoxetine was eliminated in a biphasic manner with an apparent mean terminal half-life of 14 to 17 hours. There was a dose-proportional increase in dapoxetine maximum plasma concentration (C(max)) and area under concentration-time curves (AUCs). The single-dose pharmacokinetic parameters of dapoxetine metabolites were also similar for the 3 ethnic groups, as were the pharmacokinetics of dapoxetine and its metabolites following single and multiple dosing in Caucasian and Japanese men. Dapoxetine was well tolerated by all 3 ethnic groups.

Treatment of premature ejaculation in the Asia-Pacific region: results from a phase III double-blind, parallel-group study of dapoxetine.

INTRODUCTION: Dapoxetine is a short-acting selective serotonin reuptake inhibitor that was recently approved for the on-demand treatment of premature ejaculation (PE). AIM: To evaluate the efficacy and safety of dapoxetine 30 mg and 60 mg on demand (prn) in men with PE from the Asia-Pacific region. METHODS: This randomized, double-blind, parallel-group, placebo-controlled trial enrolled men who were 18 years or older; in a monogamous, heterosexual relationship for at least 6 months; met the Diagnostic and Statistical Manual of Mental Disorders, fourth edition, text revision, criteria for PE for at least 6 months; and had an intravaginal ejaculatory latency time (IELT) of 2 minutes or less in at least 75% of sexual intercourse episodes. Subjects received placebo, dapoxetine 30 mg, or dapoxetine 60 mg prn (1-3 hours before intercourse) for 12 weeks. MAIN OUTCOME MEASURES: Stopwatch-measured Average IELT, the Premature Ejaculation Profile (PEP), Clinical Global Impression (CGI) of change in PE, treatment-emergent adverse events (TEAEs). RESULTS: Of the 1,067 subjects randomized, 858 completed the study. Mean Average IELT increased from approximately 1.1 minutes at baseline (across groups) to 2.4, 3.9, and 4.2 minutes with placebo, dapoxetine 30 mg, and dapoxetine 60 mg, respectively, and geometric mean Average IELT increased from approximately 0.9 minutes at baseline (across groups) to 1.8, 2.7, and 3.1 minutes, respectively (fold-increases of 2.0, 2.8, and 3.3, respectively). All PEP measures and the CGI of change were significantly improved with dapoxetine vs. placebo at study endpoint (P < or = 0.005 for all). The most common TEAEs with dapoxetine included nausea, dizziness, somnolence, headache, vomiting, diarrhea, and nasopharyngitis; TEAEs led to discontinuation in 0.3%, 1.7%, and 5.1% of subjects with placebo, dapoxetine 30 mg, and dapoxetine 60 mg, respectively. CONCLUSIONS: Dapoxetine treatment significantly prolonged IELT and improved PEP measures and was generally well tolerated in men with PE in the Asia-Pacific region.