The effect of prolapse surgery on voiding function.

INTRODUCTION AND HYPOTHESIS: Of women with symptomatic prolapse, 13-39% experience voiding dysfunction (VD). The aim of our observational cohort study was to determine the effect of prolapse surgery on voiding function. METHODS: Retrospective analysis of 392 women who underwent surgery between May 2005 and August 2020. All had a standardized interview, POP-Q, uroflowmetry and 3D/4D transperineal ultrasound (TPUS) pre-and postoperatively. Primary outcome was change in VD symptoms. Secondary outcomes were changes in maximum urinary flow rate (MFR) centile and post-void residual urine (PVR). Explanatory measures were change in pelvic organ descent as seen on POP-Q and TPUS. RESULTS: Of 392 women, 81 were excluded due to missing data, leaving 311. Mean age and BMI were 58 years and 30 kg/m2, respectively. Procedures performed included anterior repair (n = 187, 60.1%), posterior repair (n = 245, 78.8%), vaginal hysterectomy (n = 85, 27.3%), sacrospinous colpopexy (n = 170, 54.7%) and mid-urethral sling (MUS) (n = 192, 61.7%). Mean follow-up was 7 (1-61) months. Pre-operatively, 135 (43.3%) women reported symptoms of VD. Postoperatively, this decreased to 69 (22.2%) (p < 0.001), and of those, 32 (10.3%) reported de novo VD. The difference remained significant after excluding concomitant MUS surgery (n = 119, p < 0.001). Postoperatively, there was a significant decrease in mean PVR (n = 311, p < 0.001). After excluding concomitant MUS surgery, there was a significant increase in mean MFR centile (p = 0.046). CONCLUSIONS: Prolapse repair significantly reduces symptoms of VD and improves PVR and flowmetry.

Does Cystocele Type Vary Between Vaginally Parous and Nulliparous Women?

OBJECTIVES: To evaluate whether cystocele type varies with vaginal parity. METHODS: Retrospective analysis of 464 vaginally nulliparous women seen at 2 urogynecology units between November 2006 and November 2019. A control group consisted of 871 vaginally parous women seen between July 2017 and November 2019. Patients underwent a standardized interview, POPQ, urodynamic testing, and translabial ultrasound. On imaging, significant cystocele was defined as bladder descent to ≥10 mm below symphysis pubis. Volume datasets were analyzed offline and blinded against clinical data. RESULTS: Of 5266 women seen during the inclusion period, 464 were vaginally nulliparous. Three were excluded due to missing data, leaving 461. A control group of 871 parous women was generated from patients seen during the last 2.5 years of the inclusion period. Vaginally nulliparous women were presented at a younger age compared to vaginally parous women (P < .001). Symptoms of prolapse were reported in 104 (22%) nulliparae and 489 (56%) parous women (P < .0001). Vaginally parous women demonstrated more bladder descent (P < .0001) and more cystocele (418/871 versus 43/461, P < .0001), with a higher proportion of type III cystocele (cystocele with intact retrovesical angle) (20/43 versus 273/ 418, P < .0001). Cystourethrocele (Green type II) was more common in nulliparae and cystocele type III in parous women (P = .015). On multivariate analysis, these differences in proportions remained significant (P = .049). CONCLUSIONS: Nulliparity was associated with a higher proportion of Green type II cystoceles. Green type III cystocele was more common in vaginally parous women, suggesting that the latter may be more likely to be due to childbirth-related pelvic floor trauma.

Higher Thyroid fT3-to-fT4 Ratio Is Associated with Gestational Diabetes Mellitus and Adverse Pregnancy Outcomes.

Aim: To determine the association between thyroid function and the risk of developing gestational diabetes mellitus (GDM) and adverse pregnancy outcomes. Methods: This case−control study was a sub-analysis of the BEDIP-N study, in which 199 GDM women were matched for age and body mass index with 398 controls. Thyroid-stimulating hormone (TSH), free thyroxine (fT4), free triiodothyronine (fT3), and thyroid peroxidase (TPO) antibodies were measured at 6−14 weeks and 26−28 weeks during pregnancy. TSH and fT4 were also measured in early postpartum in GDM women. Results: The fT3-to-fT4 ratio at 26−28 weeks was positively associated with GDM risk with an adjusted odds ratio (aOR for smoking, education, parity, ethnicity, gestational weight gain, and (family) history of diabetes or GDM) of 2.12 (95% CI 1.07; 4.23), comparing the highest with the lowest tertile. Higher fT3 levels and a higher fT3-to-fT4 ratio were associated with a less favorable metabolic profile with higher BMI and more insulin resistance during pregnancy and postpartum. Women in the upper fT3 tertile and the upper fT3-to-fT4 ratio had a higher rate of preeclampsia [4.6% (10) vs. 1.0% (2), p = 0.040, and 4.4% (9) vs. 0.5% (1), p = 0.020], gestational hypertension [8.3% (18) vs. 3.1% (6), p = 0.034 and 8.9% (18) vs. 2.0% (4), p = 0.003], and caesarean sections [29.4% (63) vs. 16.1% (31), p = 0.002 and 32.2% (65) vs. 12.7% (25), p < 0.001]. Conclusion: A higher fT3-to-fT4 ratio late into pregnancy was associated with GDM, adverse pregnancy outcomes, and an adverse metabolic profile in early postpartum.

Rectocele: victim of availability bias? Results of a Belgian survey of colorectal and gynecological surgeons.

INTRODUCTION AND HYPOTHESIS: Women with a symptomatic rectocele may undergo different trajectories depending on the specialty consulted. This survey aims to evaluate potential differences between colorectal surgeons and gynecologists concerning the management of a rectocele. METHODS: A web-based survey was sent to abdominal surgeons (CS group) and gynecologists (G group) asking about their perceived definition, diagnostic workup, multidisciplinary discussion (MDT) and surgical treatment of rectoceles. The answers of both groups were analyzed with the chi-square test or Fisher's exact test at p < 0.050. RESULTS: A rectocele was defined as a prolapse of the posterior vaginal wall by 78% of the G and 41% of the CS group. All gynecologists and 49% of the CS group evaluated a rectocele clinically in dorsal decubitus, with 91% of gynecologists using a speculum and 65% using the Pelvic Organ Prolapse-Quantification (POP-Q) scoring system, compared to < 1/3 of colorectal surgeons. A digital rectal examination was performed by 90% of the CS group and 57% of the G group. A transvaginal ultrasound was only used by the G group, while anal manometry was opted for by the CS group (65%) and minimally by the G group (14%). In the G group, a posterior repair was the preferred surgical technique (78%), whereas 63% of the CS group preferred a rectopexy. Multidisciplinary discussions (MDT) were mostly organized ad hoc. CONCLUSIONS: An availability bias is seen in different aspects of rectocele evaluation and treatment. Colorectal surgeons and gynecologists are acting based on their training and experience. Motivation for pelvic floor MDT starts with creating awareness of the availability bias.

Preference of Women for Gestational Diabetes Screening Method According to Tolerance of Tests and Population Characteristics.

Aims: To determine the preferred method of screening for gestational diabetes mellitus (GDM). Methods: 1804 women from a prospective study (NCT02036619) received a glucose challenge test (GCT) and 75g oral glucose tolerance test (OGTT) between 24-28 weeks. Tolerance of screening tests and preference for screening strategy (two-step screening strategy with GCT compared to one-step screening strategy with OGTT) were evaluated by a self-designed questionnaire at the time of the GCT and OGTT. Results: Compared to women who preferred one-step screening [26.2% (472)], women who preferred two-step screening [46.3% (834)] were less often from a minor ethnic background [6.0% (50) vs. 10.7% (50), p=0.003], had less often a previous history of GDM [7.3% (29) vs. 13.8% (32), p=0.008], were less often overweight or obese [respectively 23.1% (50) vs. 24.8% (116), p<0.001 and 7.9% (66) vs. 18.2% (85), p<0.001], were less insulin resistant in early pregnancy (HOMA-IR 8.9 (6.4-12.3) vs. 9.9 (7.2-14.2), p<0.001], and pregnancy outcomes were similar except for fewer labor inductions and emergency cesarean sections [respectively 26.6% (198) vs. 32.5% (137), p=0.031 and 8.2% (68) vs. 13.0% (61), p=0.005]. Women who preferred two-step screening had more often complaints of the OGTT compared to women who preferred one-step screening [50.4% (420) vs. 40.3% (190), p<0.001]. Conclusions: A two-step GDM screening involving a GCT and subsequent OGTT is the preferred GDM screening strategy. Women with a more adverse metabolic profile preferred one-step screening with OGTT while women preferring two-step screening had a better metabolic profile and more discomfort of the OGTT. The preference for the GDM screening method is in line with the recommended Flemish modified two-step screening method, in which women at higher risk for GDM are recommended a one-step screening strategy with an OGTT, while women without these risk factors, are offered a two-step screening strategy with GCT. Clinical Trial Registration: NCT02036619 https://clinicaltrials.gov/ct2/show/NCT02036619.

MicroRNAs targeting VEGF are related to vascular dysfunction in preeclampsia.

In preeclampsia (PE), pre-existent maternal endothelial dysfunction leads to impaired placentation and vascular maladaptation. The vascular endothelial growth factor (VEGF) pathway is essential in the placentation process and VEGF expression is regulated through post-transcriptional modification by microRNAs (miRNAs). We investigated the expression of VEGF-related circulating miR-16, miR-29b, miR-126, miR-155 and miR-200c in PE vs healthy pregnancies (HPs), and their relation with vascular function, oxidative stress (OS) and systemic inflammation. In this case-control study, 24 women with early PE (<34 weeks) were compared with 30 women with HP. Circulating microRNA levels (RT-qPCR), OS and systemic inflammation were assessed in plasma samples (PE 29.5 vs HP 25.8 weeks) and related to extensive in vivo vascular function (flow-mediated dilatation (FMD), modified FMD (mFMD), carotid-femoral pulse wave velocity (CF-PWV), heart rate corrected augmentation index (AIx75) and reactive hyperemia index (RHI)). FMD, CF-PWV, AIx75 and RHI were all significantly impaired in PE (P<0.05). PE patients had reduced levels of miR-16 (5.53 ± 0.36 vs 5.84 ± 0.61) and increased levels of miR-200c (1.34 ± 0.57 vs 0.97 ± 0.68) (P<0.05). Independent of age and parity, miR-16 was related to impaired FMD (ß 2.771, 95% C.I.: 0.023-5.519, P=0.048) and mFMD (ß 3.401, 95% C.I.: 0.201-6.602, P=0.038). Likewise, miR-200c was independently associated with CF-PWV (ß 0.513, 95% C.I.: 0.034-0.992, P=0.036). In conclusion, circulating levels of miR-16 were lower in PE, which correlated with impaired endothelial function. Circulating miR-200c was increased in PE and correlated with higher arterial stiffness. These findings suggest a post-transcriptional dysregulation of the VEGF pathway in PE and identify miR-16 and miR-200c as possible diagnostic biomarkers for PE.

Association between maternal cervicovaginal swab positivity for Ureaplasma spp. or other microorganisms and neonatal respiratory outcome and mortality.

OBJECTIVE: We investigated the association between maternal cervicovaginal cultures, its antibiotic treatment, and neonatal outcome. STUDY DESIGN: This retrospective cohort study enrolled 480 neonates born prior to 32 weeks' gestation. They were divided into groups according to maternal cervicovaginal culture results. Multivariate logistic regression analysis was used to predict neonatal outcome based on maternal culture results, adjusted for perinatal risk factors and neonatal morbidities. RESULT: Maternal cervicovaginal Ureaplasma colonization was independently associated with bronchopulmonary dysplasia at 36 weeks (BPD) (OR 8.34; 95% CI 1.21-57.45). In neonates with and without maternal cervicovaginal Ureaplasma colonization BPD occurred in 12.3% and 3.8%, respectively. Maternal colonization with other microorganisms was associated with a higher neonatal mortality (p = 0.002), lower gestational age (p = 0.026), and birth weight (p = 0.036). CONCLUSIONS: This study underscores the role of the maternal cervicovaginal microbiome as a predictor of neonatal outcome. Cervicovaginal Ureaplasma colonization seems not to be an innocent bystander in the multifactorial etiology of BPD.

Cervicovaginal cellular angiofibroma.

Cellular angiofibroma is a rare type of benign mesenchymal tumour that arises mostly in middle-aged women. It needs to be distinguished from other neoplasms and has a predilection for the vulvovaginal region. To our knowledge, this is the first case of a cervical cellular angiofibroma. A 34-year-old nulligravid woman was referred with a large mass bulging in the fornix posterior. Ultrasound scanning and MRI showed a large solid mass projecting in the pouch of Douglas. Laparoscopic surgical excision was performed. Histopathological examination showed a well-demarcated, unencapsulated tumour, consisting of short fascicles of spindle cells in-between thick-walled medium-sized vessels. On immunohistochemistry, there was strong reactivity with antibodies against CD34 and oestrogen receptor. Angiofibromas are benign mesenchymal tumours mostly occurring in middle-aged women. They can cause abnormal swelling and uterine bleeding and need to be distinguished from other (malignant) neoplasms.

Estimating the risk of gestational diabetes mellitus based on the 2013 WHO criteria: a prediction model based on clinical and biochemical variables in early pregnancy.

AIMS: We aimed to develop a prediction model based on clinical and biochemical variables for gestational diabetes mellitus (GDM) based on the 2013 World Health Organization (WHO) criteria. METHODS: A total of 1843 women from a Belgian multi-centric prospective cohort study underwent universal screening for GDM. Using multivariable logistic regression analysis, a model to predict GDM was developed based on variables from early pregnancy. The performance of the model was assessed by receiver-operating characteristic (AUC) analysis. To account for over-optimism, an eightfold cross-validation was performed. The accuracy was compared with two validated models (van Leeuwen and Teede). RESULTS: A history with a first degree relative with diabetes, a history of smoking before pregnancy, a history of GDM, Asian origin, age, height and BMI were independent predictors for GDM with an AUC of 0.72 [95% confidence interval (CI) 0.69-0.76)]; after cross-validation, the AUC was 0.68 (95% CI 0.64-0.72). Adding biochemical variables, a history of a first degree relative with diabetes, a history of GDM, non-Caucasian origin, age, height, weight, fasting plasma glucose, triglycerides and HbA1c were independent predictors for GDM, with an AUC of the model of 0.76 (95% CI 0.72-0.79); after cross-validation, the AUC was 0.72 (95% CI 0.66-0.78), compared to an AUC of 0.67 (95% CI 0.63-0.71) using the van Leeuwen model and an AUC of 0.66 (95% CI 0.62-0.70) using the Teede model. CONCLUSIONS: A model based on easy to use variables in early pregnancy has a moderate accuracy to predict GDM based on the 2013 WHO criteria.

Chromosomal microarray analysis in prenatal diagnosis: ethical considerations of the Belgian approach.

Detection of genetic aberrations in prenatal samples, obtained through amniocentesis or chorion villus biopsy, is increasingly performed using chromosomal microarray (CMA), a technique that can uncover both aneuploidies and copy number variants throughout the genome. Despite the obvious benefits of CMA, the decision on implementing the technology is complicated by ethical issues concerning variant interpretation and reporting. In Belgium, uniform guidelines were composed and a shared database for prenatal CMA findings was established. This Belgian approach sparks discussion: it is evidence-based, prevents inconsistencies and avoids parental anxiety, but can be considered paternalistic. Here, we reflect on the cultural and moral bases of the Belgian reporting system of prenatally detected variants.

Prevalence and Distribution of Human Papillomavirus Genotypes Among Women in Kinshasa, The Democratic Republic of the Congo.

PURPOSE: Cervical cancer is the leading cause of mortality by cancer in sub-Saharan Africa. The human papillomavirus (HPV) infection is recognized as a necessary and sufficient cause for cervical cancer. Population-specific estimates of HPV prevalence in the Democratic Republic of the Congo (DRC) are unknown. This study aims to estimate the prevalence of HPV and identify predominant genotypes circulating in Kinshasa, DRC. METHODS: Between July 2015 and July 2017, women were invited to attend a screening program at Mont-Amba Health Centre in Kinshasa. Cervical specimens were collected using the Preservcyt medium. HPV DNA testing was performed for all specimens using real-time polymerase chain reaction. RESULTS: During the 2-year period, a total of 1,870 women age 25 to 82 years were screened. The mean age was 46 years (± 11.4 years). The overall HPV prevalence was 28.2% (95% CI, 26.1% to 30.3%). High-risk HPV prevalence was 24.8% (95% CI, 22.8% to 26.8%). Women younger than 30 years had the highest overall HPV prevalence (42.2%; 95% CI, 34.7% to 49.9%). A second peak of prevalence was observed in women age 60 years and older. HPV68 (5.5%; 95% CI, 4.5% to 6.6%) was the most prevalent HPV type. CONCLUSION: The distribution of HPV genotypes among women in our population was different compared with other world regions. A key finding was that HPV68 was the most prevalent high-risk HPV genotype. These findings highlight the need for the determination in our population of the etiologic fraction of different HPV types in invasive cervical cancers.

Impact of antiviral AV2 in the topical treatment of HPV-associated lesions of the cervix: Results of a phase III randomized placebo-controlled trial.

BACKGROUND: Non-surgical topical therapies have been assessed in the treatment of precancerous lesions of the cervix. Their use can offer logistical and feasibility advantages in low-resource settings. Antiviral AV2® is a mixture of natural essential oils (eugenol, carvone, nerolidol, geraniol) in olive oil, and has a broad spectrum anti-viral activity. In a phase II randomized controlled trial (RCT), AV2® proved effective in reducing the size of cervical lesions associated with human papillomavirus (HPV). The purpose of the present study was to further evaluate the efficacy of AV2 over placebo in the topical treatment of HPV-associated cervical lesions. METHODS: Women aged 25 years and older were included in this phase 3 RCT. Cytology screening, HPV testing and visual inspection of the cervix with 5% acetic acid (VIA) were performed on all participants. VIA-positive women were randomized to one of two groups to receive treatment by either AV2® or placebo. The treatment consisted of 2 puffs of spray of the investigational drug directed to the cervix. Participants were subjected to repeat examinations two months and six months later for assessment of outcomes. The primary outcome was the change of lesions on VIA at 2 months after application of the investigational drug. Secondary outcomes were: HPV clearance and cytologic regression at 2 months and 6 months, and number of participants with AEs. RESULTS: A total 327 VIA positive women were randomized in two groups (168 in AV2 group and 159 in placebo group). Women in the 2 groups were similar with respect to baseline demographics and clinical characteristics. At 2 months, regression of lesions on VIA was observed in 127 (89.4%) out of 142 women in AV2 group compared to 120 (91.6%) out of 131 women in placebo group (P = 0.7). On cytology, regression of lesions occurred in 14 (56%) out of 25 women in the AV2 arm and in 13 (48.1) out of 27 women in the placebo arm (p = 0.7), and HPV clearance rates were 34.1% and 35% in AV2 group and placebo group respectively (p = 0.8). At 6 months cytologic regression was observed in 64.7% of women in AV2 group and 45.8% in placebo group (p = 0.2), while HPV clearance occurred in 11 (51.9%) out of 17 women in AV2 arm versus 11 (34.4%) in placebo arm (p = 0.3).Some local side effects (burning, itching, irritation) were similarly noted in the 2 groups (p-values = 0.169, 0.623 and 0.172 respectively) but they were mild and transitory. CONCLUSION: A topical application of AV2 onto the cervix can induce the regression of cervical precancerous lesions, but its efficacy does not significantly differ with that of placebo. The discrepancy between the expected and the recorded sample size as well as the huge number of lost to follow-up probably impeded the power of analyses, which could be one of the reasons for the lack of difference seen between AV2 and placebo. Further evaluation of the effects of AV2 with different diagnostic methods and treatment regimen and arms is warranted. CLINICAL TRIAL REGISTRATION: NCT02346227 registered on November 8, 2014.

Efficacy of commercially available biological agents for the topical treatment of cervical intraepithelial neoplasia: a systematic review.

BACKGROUND: Cervical cancer is a major public health issue in the world, especially in developing countries. It can be prevented through vaccination against HPV (primary prevention) and through screening and treatment of cervical intraepithelial neoplasia (CIN) (secondary prevention). Surgical methods for treatment of CIN are linked to complications such as bleeding and adverse pregnancy outcomes. Furthermore, these methods are not generally available in resource-poor settings. Therefore, topical agents for local application on the cervix have been used since decades to overpass complications and limitations of the surgical methods. AIMS: Review of the literature on the efficacy of commercially available biological agents used for topical treatment of cervical intraepithelial neoplasia (CIN). METHODS: A systematic search through PubMed and the Cochrane database was performed up to December 2017, using the medical subheadings (MesH) for topical agent, treatment, and cervical intraepithelial neoplasia. Appropriate inclusion/exclusion criteria have been used for the selection of eligible clinical studies. Clinical studies containing a minimum of 20 women, aged 18-50 with a diagnosis of CIN 1-3, and at least a 4 weeks follow-up after the end of the topical treatment were included. RESULTS: The initial electronic database search resulted in a total of 849 articles. After screening titles and abstracts, 62 articles were selected as potential studies. Of these, six articles were included in the review after reading the full text: two were on 5-FluoroUracil, two on trans retinoic acid, one on Imiquimod, and one on Cidofovir. The reported regression/remission rates for CIN differed among studies. In CIN2 patients, the overall remission rate ranged between 43 and 93% for the active agents. CONCLUSION: Among the topical agents studied, 5-FluoroUracil showed good remission rates above 80%. Varying results seen in this review is due to the differences in quality of the design between studies. Large-scale and less biaised studies are needed to elucidate the true efficacy and safety of topical agents in the treatment of CIN.

Oxidative stress in healthy pregnancy and preeclampsia is linked to chronic inflammation, iron status and vascular function.

BACKGROUND: During normal pregnancy, placental oxidative stress (OS) is present during all three trimesters and is necessary to obtain normal cell function. However, if OS reaches a certain level, pregnancy complications might arise. In preeclampsia (PE), a dangerous pregnancy specific hypertensive disorder, OS induced in the ischemic placenta causes a systemic inflammatory response and activates maternal endothelial cells. In this study, we aimed to quantify superoxide concentrations (as a measure of systemic OS) using electron paramagnetic resonance (EPR) and correlate them to markers of systemic inflammation, iron status and vascular function. METHODS: Fifty-nine women with a healthy pregnancy (HP), 10 non-pregnant controls (NP) and 28 PE patients (32±3.3weeks) were included. During HP, blood samples for superoxide, neutrophil to lymphocyte ratio (NLR), mean platelet volume (MPV) and iron status were taken at 10, 25 and 39 weeks. Vascular measurements for arterial stiffness (carotid-femoral pulse wave velocity (CF-PWV), augmentation index (AIx), augmentation Pressure (AP)) and microvascular endothelial function (reactive hyperemia index (RHI)) were performed at 35 weeks. In PE, all measurements were performed at diagnosis. CMH (1-hydroxy-3-methoxycarbonyl-2,2,5,5-tetramethylpyrrolidine) was used as spin probe for EPR, since the formed CM radical corresponds to the amount of superoxide. RESULTS: Superoxide concentration remains stable during pregnancy (p = 0.92), but is significantly higher compared to the NP controls (p<0.0001). At 25 weeks, there is a significant positive correlation between superoxide and ferritin concentration. (p = 0.04) In PE, superoxide, systemic inflammation and iron status are much higher compared to HP (all p<0.001). During HP, superoxide concentrations correlate significantly with arterial stiffness (all p<0.04), while in PE superoxide is significantly correlated to microvascular endothelial function (p = 0.03). CONCLUSIONS: During HP there is an increased but stable oxidative environment, which is correlated to ferritin concentration. If superoxide levels increase, there is an augmentation in arterial stiffness. In PE pregnancies, systemic inflammation and superoxide concentrations are higher and result in a deterioration of endothelial function. Together, these findings support the hypothesis that vascular function is directly linked to the amount of OS and that measurement of OS in combination with vascular function tests might be used in the prediction of PE.

Mal de Debarquement Syndrome: A Retrospective Online Questionnaire on the Influences of Gonadal Hormones in Relation to Onset and Symptom Fluctuation.

INTRODUCTION: Mal de Debarquement Syndrome (MdDS) is a condition characterized by a persistent perception of self-motion, in most cases triggered from exposure to passive motion (e.g., boat travel, a car ride, flights). Patients whose onset was triggered in this way are categorized as Motion-Triggered (MT) subtype or onset group. However, the same syndrome can occur spontaneously or after non-motion events, such as childbirth, high stress, surgery, etc. Patients who were triggered in this way are categorized as being of the Spontaneous/Other (SO) subtype or onset group. The underlying pathophysiology of MdDS is unknown and there has been some speculation that the two onset groups are separate entities. However, despite the differences in onset between the subtypes, symptoms are parallel and a significant female predominance has been shown. To date, the role of gonadal hormones in MdDS pathophysiology has not been investigated. This study aimed to evaluate the hormonal profile of MdDS patients, the presence of hormonal conditions, the influence of hormones on symptomatology and to assess possible hormonal differences between onset groups. In addition, the prevalence of migraine and motion sickness and their relation to MdDS were assessed. METHOD: Retrospective online surveys were performed in 370 MdDS patients from both onset groups. Data were analyzed using Fisher's exact test or Fisher-Freeman-Hanlon exact test. When possible, data were compared with normative statistical data from the wider literature. RESULTS: From the data collected, it was evident that naturally cycling female respondents from the MT group were significantly more likely to report an aggravation of MdDS symptoms during menses and mid-cycle (p < 0.001). A few preliminary differences between the onset groups were highlighted such as in regular menstrual cycling (p = 0.028), reporting menses during onset (p < 0.016), and migraine susceptibility after onset (p = 0.044). CONCLUSION: These results demonstrate a potential relation between hormone fluctuations and symptom aggravation in the MT group. This study is an important first step to suggest a hormonal involvement in the pathophysiology of MdDS and provides a base for further hormonal investigation. Future prospective studies should expand upon these results and explore the implications for treatment.

Prenatal homozygosity mapping detects a novel mutation in CHST3 in a fetus with skeletal dysplasia and joint dislocations.

In selected cases, homozygosity mapping followed by direct sequencing of one or a few carefully selected candidate genes in a prenatal setting can be beneficial to obtain diagnosis in consanguineous families.

Rationale and design of ASTEROID 2, a randomized, placebo- and active comparator-controlled study to assess the efficacy and safety of vilaprisan in patients with uterine fibroids.

BACKGROUND: Uterine fibroids (UFs) may be treated with progesterone receptor modulators (PRMs), which have been shown to reduce heavy menstrual bleeding and the size of UFs. To date, one PRM (ulipristal acetate) has received regulatory approval for the treatment of UFs; therapy comprises intermittent treatment courses of up to 3months each, followed by a break to allow two menstruations to occur. We report the design of ASTEROID (Assess Safety and efficacy of vilaprisan in patients with uTERine fibrOIDs) 2, a phase 2 study examining the efficacy and safety of a novel PRM, vilaprisan, in women with UFs. METHODS/DESIGN: In this randomized multi-arm study, vilaprisan (2mg daily) will be administered in different regimens: continuous treatment for 12 or 24weeks, or two 12-week treatment periods separated by a break to allow one menstruation to occur. Efficacy and safety will be compared with that of ulipristal acetate (5mg daily) and placebo. Patients randomized to receive placebo for 12weeks will also be given active treatment for 12weeks. The primary measure of efficacy will be amenorrhoea rate; secondary measures include time to normalized menstrual bleeding and percentage change in UF volume. Endometrial changes will be monitored throughout the study. DISCUSSION: The placebo- and active comparator-controlled trial ASTEROID 2 is the first study to evaluate systematically the efficacy and safety of different treatment regimens of PRMs in women with UFs. The findings of this study will direct the planning of future clinical trials of vilaprisan.

Efficacy of antiviral drug AV2 in the treatment of human papillomavirus-associated precancerous lesions of the uterine cervix: A randomized placebo-controlled clinical trial in Kinshasa, DR Congo. (KINVAV study).

BACKGROUND: Cervical Cancer (CC) is a major public health problem in DR Congo; the high incidence of CC is due to the inexistence of effective screening programs based on cytology and/or HPV detection followed by appropriate treatments. This situation highlights the need to implement efficacious and inexpensive treatment methods. This study aims at evaluating the efficacy of a topical antiviral drug named AV2® as a treatment for HPV-associated lesions of the cervix. METHODS: Women will undergo cytology sampling, HPV testing and Visual inspection of the cervix after application of 5% acetic acid (VIA). VIA-positive women will be randomized to one of two groups to receive treatment by either AV2®or placebo. They will undergo control examinations after two months and after six months. In case of persistent lesions on VIA, treatment by cryotherapy will be done. The primary outcomes will be the change of lesions, the clearance of HPV DNA, and the correlation of the two 2 months after treatment with AV2®. CONCLUSION: This study is the first large-scale study in Africa to evaluate systematically the efficacy and safety of a topical antiviral drug for the treatment of HPV- associated lesions of the cervix. Its findings will direct the planning of suitable algorithms for CC screening and treatment. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov - Unique identifier: NCT02346227, registered on November 8, 2014.

Nifedipine versus atosiban for threatened preterm birth (APOSTEL III): a multicentre, randomised controlled trial.

BACKGROUND: In women with threatened preterm birth, delay of delivery by 48 h allows antenatal corticosteroids to improve neonatal outcomes. For this reason, tocolytics are often administered for 48 h; however, there is no consensus about which drug results in the best maternal and neonatal outcomes. In the APOSTEL III trial we aimed to compare the effectiveness and safety of the calcium-channel blocker nifedipine and the oxytocin inhibitor atosiban in women with threatened preterm birth. METHODS: We did this multicentre, randomised controlled trial in ten tertiary and nine teaching hospitals in the Netherlands and Belgium. Women with threatened preterm birth (gestational age 25-34 weeks) were randomly assigned (1:1) to either oral nifedipine or intravenous atosiban for 48 h. An independent data manager used a web-based computerised programme to randomly assign women in permuted block sizes of four, with groups stratified by centre. Clinicians, outcome assessors, and women were not masked to treatment group. The primary outcome was a composite of adverse perinatal outcomes, which included perinatal mortality, bronchopulmonary dysplasia, sepsis, intraventricular haemorrhage, periventricular leukomalacia, and necrotising enterocolitis. Analysis was done in all women and babies with follow-up data. The study is registered at the Dutch Clinical Trial Registry, number NTR2947. FINDINGS: Between July 6, 2011, and July 7, 2014, we randomly assigned 254 women to nifedipine and 256 to atosiban. Primary outcome data were available for 248 women and 297 babies in the nifedipine group and 255 women and 294 babies in the atosiban group. The primary outcome occurred in 42 babies (14%) in the nifedipine group and in 45 (15%) in the atosiban group (relative risk [RR] 0·91, 95% CI 0·61-1·37). 16 (5%) babies died in the nifedipine group and seven (2%) died in the atosiban group (RR 2·20, 95% CI 0·91-5·33); all deaths were deemed unlikely to be related to the study drug. Maternal adverse events did not differ between groups. INTERPRETATION: In women with threatened preterm birth, 48 h of tocolysis with nifedipine or atosiban results in similar perinatal outcomes. Future clinical research should focus on large placebo-controlled trials, powered for perinatal outcomes. FUNDING: ZonMw (the Netherlands Organisation for Health Research and Development).

Reproducibility of hormone-driven regional grey matter volume changes in women using SPM8 and SPM12.

Aim of this work was to evaluate the reproducibility of hormone driven regional grey matter volume differences in women, and their correlations with premenstrual symptoms, as determined by voxel-based morphometry (VBM). After data quality control, a total of 138 T1-weighted MR images were included in this longitudinal study, and were analyzed as three different subgroups. Women with a natural menstrual cycle were scanned at three time-points: follicular, ovulatory and luteal phase. Two groups of women, using androgenic and anti-androgenic hormonal contraceptives, respectively, were scanned twice: during the pill-free week and during pill intake. Additionally, subjects were asked to complete a "daily rating of severity of problems" questionnaire, to quantify premenstrual symptoms. All data were analyzed using SPM8 and SPM12 with identical parameter settings. In the natural menstrual cycle group, the regional grey matter volume of the insula is larger at ovulation, as compared to the luteal phase. Premenstrual symptoms correlate differently with regional grey matter volumes between women with a natural cycle and hormonal contraceptive users. Changes in hormonal environment can to various extents affect VBM findings in women. We suggest that researchers take these confounding factors into account while applying this technique, to avoid heterogeneity in data acquisition and to safeguard the sensitivity of findings. Additionally, we suggest validating the consistency of results using more than one software package.