National and International Comparisons of Gynecological Research in Germany Based on a Bibliometric Analysis of Publications.

Background: Recent years have seen a considerable shift from male doctors to female doctors in the field of gynecology. Female doctors are traditionally more involved with planning and maintaining their family. For gynecology, this could be associated with a risk that research activities will decrease, particularly if results are published in scientific journals. Methods: In view of this shift, a comparative observational study was carried for 2022 in which 1306 publications were matched to 1786 female and male doctors reported on the websites of the 44 locations of university gynecology departments in Germany. In addition, the volume of publications issued between 2014 and 2022 was compared for Germany, France, the United Kingdom, and the United States. In Germany, the volume of publications in Gynecology was additionally compared with the publication outputs of the specialties Urology and Trauma Surgery. Results: Since 2014, the increase in the numbers of publications in the field of Gynecology in Germany was lower (225%) than that of the countries with which it was compared (238%/252%/260% for F/UK/USA). When Gynecology was compared with other medical specialties in Germany, the number of publications in Urology were found to have increased at a lower rate (196%) while the number of publications in the field of Trauma Surgery increased by more (286%) than that of Gynecology. At the start of 2023, the percentage of women who were working as doctors at the lowest hierarchical level (junior doctor) was 81%. The publication output per capita of female doctors working at lower levels in the medical hierarchy, i.e., working as junior doctors and senior physicians, was between 40% and 80% lower than that of male doctors working at the same level. However, female directors published as much as male directors did. In the lower hierarchy levels, men were up to 14% more likely to be without an academic title. Predictors for more extensive publication activities by young female and male doctors include the extent and quality of publications by doctors in senior positions, the presence of a comprehensive cancer center or an institute for human genetics at the location where the young doctors were working, and joint publications with foreign authors. Conclusion: For the German Society of Gynecology and Obstetrics, the results suggest a number of approaches to promote young researchers. The support provided to young female doctors is especially important as this should help to retain them as junior researchers over the long term.

The psychological burden of COVID-19 on the desire for parenthood in minoritized sexual identities: a study on depressive symptoms and family planning in Germany.

BACKGROUND: The COVID-19 pandemic continues to spread across the globe and is associated with significant clinical and humanitarian burden. The desire for parenthood has been described to be positively correlated with psychological well-being: An unfulfilled wish for parenthood is associated with impaired mental health, and the wish for parenthood is a predictor for the development of depressive symptoms. While higher rates of anxiety and depression have been reported in individuals with minoritized sexual identities (compared to heterosexual individuals) during the COVID-19 pandemic, the specific impact of the pandemic and its social restriction measures on this population is poorly understood. METHODS: From April to July 2020, we conducted an anonymous cross-sectional survey online among N = 2463 adults living in Germany. We screened for depressive symptoms (Patient Health Questionnaire-4; PHQ-4) and assessed individuals' desire for parenthood during the pandemic, and motives for or against the desire for parenthood (Leipzig questionnaire on motives for having a child, Version 20; LKM-20), with the aim of identifying differences between individuals with minoritized sexual identities and heterosexual individuals. RESULTS: Compared to heterosexual individuals (n = 1304), individuals with minoritized sexual identities (n = 831) indicated higher levels of depressive symptoms. In our study sample the majority of all participants (81.9%) reported no change in the desire for parenthood since the COVID-19 pandemic. CONCLUSION: The findings underline the unmet need for social, psychological and medical support in regard to family-planning and the desire for parenthood during a pandemic. Furthermore, future research should explore COVID-19-related psychological consequences on individuals' desire for parenthood and building a family.

Reduced Steroid Synthesis in the Follicular Fluid of MTHFR 677TT Mutation Carriers: Effects of Increased Folic Acid Administration.

Objective To compare steroid profiles in the follicular fluid (FF) from women homozygous for the methylenetetrahydrofolate reductase (MTHFR) 677C>T mutation and wildtype controls and to correlate it with the folic acid administration scheme applied at the time of oocyte retrieval. Design Retrospective single center study. Subjects and Methods Infertile patients treated by using assisted reproductive techniques were genotyped routinely for the MTHFR 677C>T mutation. In 2006 they had received folic acid supplementation doses of 400 µg daily per os. This group was designated Group-400 (n = 10). From 2008 onwards, all of our infertility patients received a daily dose of 800 µg folic acid per os. Women from this group were designated Group-800 (n = 28). FF were collected and a panel of steroid hormones (estradiol, estrone, estriol, cortisol, progesterone, 17-OH progesterone, testosterone, androstenedione, aldosterone, DHEA, and DHEA-S) was measured by isotope dilution liquid chromatography-tandem mass spectrometry employing atmospheric pressure photo ionization (APPI). Results In Group-400, the FF hormone profile confirmed a significant reduction of estradiol in homozygous 677TT carriers (0.52 ± 0.08-fold, exact p = 0.032) and for the first time also revealed significantly reduced estriol concentrations in these individuals (0.54 ± 0.05-fold, p = 0.016), as compared to wildtype controls. In Group-800, no significant differences were found for concentrations of any of the steroid hormones between homozygous 677TT carriers and wildtype controls. Conclusions The current findings support and extend previous reports on reduced concentrations of specific steroid hormones in follicular fluids of homozygous MTHFR 677C>T mutation carriers. The restoration of the FF hormone profile by elevated-dose folic acid supplementation might impact performing ART in infertile women with the MTHFR 677TT-genotype. Further adequately powered studies are necessary to verify our finding and to demonstrate the clinical effect of enhanced folic supplementation on ovarian function.

The Impact of the COVID-19 Pandemic on Sexual Health in Cis Women Living in Germany.

BACKGROUND: Preliminary research shows a substantial impact of the COVID-19 pandemic on women's sexual health, whereby empirical work on sexual well-being of minoritized sexual identities is still rare. AIM: The objective of this study was to explore sexual health in heterosexual, lesbian and bisexual cis women during the first wave of COVID-19 pandemic in Germany. METHODS: An anonymous nationwide online survey was conducted among cis women during the first nationwide lockdown in Germany from April 20th to July 20th, 2020. The questionnaire was distributed via e-mail, online chats and social-media platforms. OUTCOMES: Demographic variables and self-report measures from the Sexual Behavior Questionnaire (SBQ-G) "before the pandemic" and "since the pandemic" were collected. RESULTS: A total of 1,368 cis women participants were included: heterosexual women (n = 844), lesbian women (n = 293), bisexual women (n = 231). Results indicate overall decrease in frequency of sexual contacts and masturbation during the COVID-19 pandemic. Regarding differences before and during the pandemic lesbian women showed significant changes in sexual arousal whereas heterosexual women showed significant changes in all dimensions except capability to enjoy sexual intercourse. The data of bisexual women showed significant changes in almost all dimensions except for frequency of sexual intercourse and sexual arousal. Results of the multiple regression analysis revealed that being younger than 36 years-old, and being in a relationship as well as being heterosexual (compared with being lesbian) is positively associated with general satisfaction with sexual life during the pandemic. CLINICAL IMPLICATIONS: The findings suggest that during a pandemic sexual and mental health care for (cis) women should be provided and address the specific needs of sexual minority groups. STRENGTHS & LIMITATIONS: This is the first study to describe sexual behavior in heterosexual, lesbian and bisexual women during the COVID-19 pandemic in Germany. Limitations, however, include the fact that the data described were obtained at only one time point so there is a possibility of recall bias, and that the results cannot be generalized because of the underrepresentation of women over age 46. CONCLUSION: This study examined the impact of the COVID-19 pandemic and resulting social constraints on the sexual health of particular groups of lesbian and bisexual women, which may improve preparedness for future public health and policy crises. Batz F, Lermer E, Hatzler L, et al. The Impact of the COVID-19 Pandemic on Sexual Health in Cis Women Living in Germany. J Sex Med 2022;19:907-922.

Seasonal dynamic of cholecalciferol (D3) and anti-Muellerian hormone (AMH) with impact on ovarian response and IVF/ICSI.

OBJECTIVE: Recent studies revealed intriguing associations between cholecalciferol (D3) and reproductive functions. Seasonal changes of D3 concentrations are well known; however, they are not always considered in the context of reproductive functions. In this study, we analyzed D3 serum concentration in IVF/ICSI patients with respect to seasonal 3-month quartiles and anti-Muellerian hormone (AMH) referring to the impact on Assisted Reproductive Technologies (ART) outcome. MATERIALS AND RESEARCH METHODS: We studied 469 female patients, presenting between 2012 and 2018 for ART treatment in our fertility center. D3 as well as the AMH serum concentrations were measured at the beginning of the follicle stimulation (days 3-5 of menstrual cycles). Results were evaluated with respect to seasonal quartiles and outcome of the ART cycles. RESULTS: D3 concentrations showed significant fluctuations within annual quartiles with a pronounced peak in August-October and a minimum in February-April (26.0 vs. 20.5 mg/dl; p < 0.0001). Similar seasonal dynamics were found for AMH (2.98 vs. 1.78 ng/ml; p = 0.010) and these were associated with significantly shorter stimulation periods during August-October (11.29 vs. 12.12 days; p = 0.042), higher number of fertilized oocytes between August and October (6.23 vs. 4.97; p = 0.05) along with a trend towards higher numbers of cumulus-oocyte complexes. However, no such differences were found for the numbers of MII oocytes or pregnancy rates. CONCLUSION: Our data indicate seasonal 3-month quartile variations of AMH concentrations and characteristics of ART, such as days of ovarian stimulation and number of fertilized oocytes. Highest AMH concentrations were found between August and October and this quartile was associated with highest D3 concentrations.

Effects of intralipid infusions on anti-trophoblast antibody (ATAb)-activities in patients with recurrent pregnancy loss: An observational report.

PROBLEM: Some studies suggest intravenous intralipid infusions (IVIL) to be effective in the treatment of immune-mediated pregnancy failure. To this date it remains to be established, how IVIL might protect pregnancy and therefore a specific subgroup of RPL patients that might benefit from IVIL has not been defined. Anti-trophoblast antibodies (ATAb) have been associated with RPL and appear to mediate immune pathology. We have shown, that ATAb in vitro decrease HCG- and progesterone production pointing to a mechanism how ATAb interfere with normal pregnancies. We have measured ATAb-activities in patients undergoing off label IVIL-treatment. METHOD OF STUDY: Ten RPL-patients with positive ATAb, determined by using the choriocarcinoma cellline JEG-3 and flow cytometry as described before, and otherwise unexplained RPL, received off-label IVIL during pregnancy. Two ATAb-positive RPL patients preferred expectant management. In addition, ATAb-activity was studied in pregnancies of two healthy ATAb-negative volunteers without miscarriages. RESULTS: In RPL patients receiving IVIL, relative ATAb-activity decreased from an average of 56.8±17.0% to 20.8±11.0% (P < .001). The two RPL-patients without IVIL, aborted at 6+3gw and 7+4gw and embryonic genetic testing revealed euploid karyotypes. During pregnancies of the two healthy ATAb-negative individuals, ATAb-activities remained negative (16±9.8%) without significant changes (P = .22). Nine of the 10 pregnancies receiving IVIL proceeded uneventful with healthy newborns ≥37gw. One patient receiving IVIL aborted at 7+6gw and embryonic genetic-testing revealed a trisomy 16. No specific side effects concerning IVIL were noted. CONCLUSIONS: Intralipid preparations during pregnancies of ATAb-positive RPL-patients significantly reduce ATAb-activities and this may indicate a therapeutic mechanism of IVIL.

Well-being during COVID-19 pandemic: A comparison of individuals with minoritized sexual and gender identities and cis-heterosexual individuals.

BACKGROUND: Preliminary empirical data indicates a substantial impact of the COVID-19 pandemic on well-being and mental health. Individuals with minoritized sexual and gender identities are at a higher risk of experiencing such negative changes in their well-being. The objective of this study was to compare levels of well-being among cis-heterosexual individuals and individuals with minoritized sexual and gender identities during the COVID-19 pandemic. METHODS: Using data obtained in a cross-sectional online survey between April 20 to July 20, 2020 (N = 2332), we compared levels of well-being (WHO-5) across subgroups (cis-individuals with minoritized sexual identities, individuals with minoritized gender identities and cis-heterosexual individuals) applying univariate (two-sample t-test) and multivariate analysis (multivariate linear regression). RESULTS: Results indicate overall lower levels of well-being as well as lower levels of well-being in minoritized sexual or gender identities compared to cis-heterosexual individuals. Further, multivariate analyses revealed that living in urban communities as well as being in a relationship were positively associated with higher levels of well-being. Furthermore, a moderation analysis showed that being in a relationship reduces the difference between groups in terms of well-being. CONCLUSION: Access to mental healthcare for individuals with minoritized sexual and gender identities as well as access to gender-affirming resources should be strengthened during COVID-19 pandemic. Healthcare services with low barriers of access such as telehealth and online peer support groups should be made available, especially for vulnerable groups.

Oropharyngeal HPV Detection Techniques in HPV-associated Head and Neck Cancer Patients.

BACKGROUND/AIM: The incidence of human papilloma virus (HPV)-related head and neck squamous cell carcinoma (HNSCC) has been increasing in the last decades. Analysis of oral brushing or rinsing samples for screening or stratification could potentially improve screening and prevention. PATIENTS AND METHODS: Oral brushes and mouthwashes were taken from 20 patients with HPV-associated HNSCC before definite therapy. HPV genotyping was performed for the detection of 14 high-risk HPV subtypes and correlated to DNA isolated from tumor tissue. RESULTS: Ten of 20 patients were tested HPV positive by using either method. There was a significant correlation between macroscopic visibility of tumor and positive HPV detection (p<0.001) and HPV detection and tumor size (p<0.001). HPV was detected in all macroscopically visible tumors. Half of the HPV cases who had macroscopically invisible tumors were missed by both methods. CONCLUSION: Both techniques are limited in the detection of macroscopically non-visible and small tumors. Therefore, the application of these techniques for screening or diagnosis of HNSCC is not recommended.

Anti α-enolase antibody is a novel autoimmune biomarker for unexplained recurrent miscarriages.

BACKGROUND: We recently demonstrated the increased abundance of anti-trophoblast antibodies (ATAB) in sera of patients with unexplained recurrent miscarriages (uRM). Further, the ATAB-positive sera bound to JEG-3 human choriocarcinoma cells in vitro, resulting in decreased productions of ß-human chorionic gonadotropin (ß-hCG) and progesterone in these cells. However, the specific antigenic epitopes of ATAB have remained unknown. Therefore, it was the aim of this study to determine specific targets of ATAB in uRM patients. METHODS: Potential targets of ATAB were analyzed by 2-dimensional difference gel electrophoresis (2D-DIGE) and mass spectrometry, and thereby identifying α-Enolase (ENO1). ATAB targeting of ENO1 was further confirmed in a competitive binding assay. Levels of anti-ENO1 antibodies as well as ß-hCG and progesterone were quantified with enzyme-linked immunosorbent assay (ELISA). Additionally, expression of ENO1 was analyzed in first trimester placentas by immunohistochemistry and immunofluorescence analysis. FINDINGS: We here identified ENO1 as a prominent target of ATAB. Serum levels of anti-ENO1 antibodies were increased in ATAB-positive compared to ATAB-negative patients. Further, increased expression of ENO1 and its co-expression with ß-arrestin was found in the extra villous trophoblasts of uRM patients in first trimester placentas. In vitro, anti-ENO1 antibodies decreased the secretion of ß-hCG and progesterone in JEG-3 and primary human villous trophoblast cells. INTERPRETATION: Serum anti-ENO1 antibodies might be an autoimmune biomarker for uRM. Targeting the formation of anti-ENO1 antibodies or inhibition of ENO1 expression could potentially represent therapeutic strategies for these patients. FUND: All authors declare no conflict of interest. Yao Ye was supported by the China Scholarship Council. Hellen Ishikawa-Ankerhold and Christian Schulz were supported by the SFB914, projects Z01 and A10. None of the rest authors has any conflict of interest to declare.

Correlation of Vitamin D3 (Calcitriol) Serum Concentrations with Vitamin B12 and Folic Acid in Women Undergoing in vitro Fertilisation/Intracytoplasmatic Sperm Injection.

BACKGROUND: The important role of vitamin D3 in human health is well recognized. In this study, we measured serum concentrations of vitamin D3, vitamin B12 and B9 (folic acid) in 410 women undergoing in vitro fertilisation (IVF)/intracytoplasmatic sperm injection (ICSI) with dedicated focus on 3-month changes in consideration of patients' BMI. METHODS: Patients were of European origin and did not take any supplementation of D3. In preparing for pregnancy, patients took ≥4 weeks 400 µg folic acid combined with 9 µg vitamin B12 and 150 µg iodide as recommended. RESULTS: We found a significant 3-month quartile change of D3 serum concentrations (p < 0.0001) with maximum levels in autumn and lowest in spring. D3 correlated significantly with B12 (p = 0.035, ρ = 0.102) and folic acid (p < 0.0001, ρ = 0.191). BMIs however showed a negative correlation with B12 (p = 0.031, ρ = -0.105) and folic acid (p = 0.012, ρ = -0.125). CONCLUSIONS: Our results suggest a model in which the sun exposure during summer months enables storage of D3 followed by a slow release as a major factor to maintain D3 levels throughout the year. Finally, our data indicate that B12 and folic acid uptake might be influenced by vitamin D receptor and D3, where D3 and the BMI appear to have an indirect relationship - via B12 and folic acid.

Assessment of M2/ANXA5 haplotype as a risk factor in couples with placenta-mediated pregnancy complications.

PURPOSE: The aim of this study was to confirm the associated M2/ANXA5 carrier risk in women with placenta-mediated pregnancy complications (PMPC) and to test their male partners for such association. Further analysis evaluated the influence of maternal vs. paternal M2 alleles on miscarriage. METHODS: Two hundred eighty-eight couples with preeclampsia (PE), intrauterine growth restriction (IUGR), or premature birth (PB) were recruited (n = 96 of each phenotype). The prevalence of the M2 haplotype was compared to two control cohorts. They included a group of women with a history of normal pregnancy without gestational pathology (Munich controls, n = 94) and a random population sample (PopGen controls, n = 533). RESULTS: Significant association of M2 haplotype and pregnancy complications was confirmed for women and for couples, where prevalence was elevated from 15.4 to 23.8% (p < 0.001). Post hoc analyses demonstrated an association for IUGR and PB individually. A strong link between previous miscarriages and M2 carrier status was identified which may explain the predisposition to placental pregnancy complication. M2/ANXA5 appears to be a risk factor for adverse pregnancy outcomes related, but not limited to miscarriages, with similar prevalence in women and their male partners. CONCLUSION: These findings support the proposed physiological function of ANXA5 as an embryonic anticoagulant that appears deficient in contiguous specter of thrombophilia-related pregnancy complications culminating more frequently in miscarriage in a maternal M2 carrier background.

The CYCLOCALYX study: Ovulatory cycle affects circulating compartments of the endothelial glycocalyx in blood.

PROBLEM: The endothelial glycocalyx (EGX) plays an important role in vascular integrity. Recently, increased levels of EGX components were detected in the circulating blood of healthy pregnant women and were related to the increased tendency to edema formation during gestation. However, the EGX has not yet been systematically studied in non-pregnant women during ovulatory cycles. METHOD OF STUDY: Serum levels of EGX components syndecan-1, heparan sulfate, and hyaluronan in healthy women (n = 16) at 3 phases of the ovulatory cycle (early follicular phase, at ovulation, and mid-luteal phase) were compared with a control group of healthy men (n = 10). Using immunofluorescence microscopy in cultured human umbilical vein endothelial cells, the effects of progesterone and estrogen on the EGX were measured. RESULTS: Syndecan-1 increased from 11.1 ± 2.4 ng/mL at ovulation to 12.6 ± 2.3 ng/mL in mid-luteal phase (P = .031) and of heparan sulfate from 663 ± 35 ng/mL to 782 ± 55 ng/mL (P = .011). In contrast to estrogen, there was a detrimental effect of progesterone on the EGX in HUVECs. CONCLUSION: The relationship between the natural menstrual cycle and the EGX as an indicator of vascular permeability may provide a new explanation for premenstrual edema in healthy women. This may be an attendant phenomenon of a regular physiological process, the hormonal downregulation of the vascular barrier during pregnancy.

Unexplained recurrent miscarriages are associated with an aberrant sperm protamine mRNA content.

STUDY QUESTION: Are unexplained recurrent miscarriages associated with abnormal protamine-1 and protamine-2 mRNA levels in spermatozoa? SUMMARY ANSWER: Both protamine-1 and protamine-2 mRNA levels as well as the protamine-1 to protamine-2 mRNA ratio in spermatozoa from men whose female partners experienced two or more consecutive miscarriages were significantly different compared to those from both healthy control men and subfertile couples undergoing IVF/ICSI. WHAT IS KNOWN ALREADY: Aberrant sperm protamine ratios are known to be associated with male-factor infertility. Data from this study suggest that the protamine mRNA ratio may additionally affect early embryo development. STUDY DESIGN, SIZE, DURATION: The study population was recruited from men whose female partners presented with two or more consecutive unexplained miscarriages in a consultation for recurrent pregnancy loss between 2014 and 2016. At the research laboratory of the Urological Clinic of the University Giessen, spermatozoa from cases and controls were subjected to reverse transcription quantitative PCR (RTqPCR) using specific primer pairs for protamine-1 and protamine-2. PARTICIPANTS/MATERIALS, SETTING, METHODS: Protamine-1 and protamine-2 mRNA levels were analysed in semen samples from 25 men whose female partners experienced at least two consecutive idiopathic miscarriages before the 20th week of gestation. The couples were recruited during consultation at the Fertility Center of the LMU Munich, Germany, and at the Clinical Division of Gynecologic Endocrinology and Reproductive Medicine of the Medical University of Vienna, Austria. Results were compared with those from 32 healthy donors (WHO, 2010) recruited at the Department of Urology, Pediatric Urology and Andrology, Giessen, Germany, and 107 men whose partners participated in an IVF/ICSI program at the Fertility Center of the LMU Munich, Germany. MAIN RESULTS AND THE ROLE OF CHANCE: Protamine-1 and protamine-2 mRNA levels as well as the protamine mRNA ratio and all routine semen parameters revealed significant differences between recurrent miscarriage couples and healthy volunteers (P < 0.01). When comparing recurrent miscarriage couples with couples undergoing IVF/ICSI, Ct-values of protamine-1 and protamine-2 mRNAs were significantly higher and the protamine mRNA ratio was significantly lower in RM couples (P < 0.01). When comparing protamine mRNA levels and the protamine mRNA ratio with routine semen parameters, a significant negative correlation was evident between progressive motility and the protamine-2 mRNA level (P = 0.015), as well as between non-progressive motility and the protamine mRNA ratio (P = 0.023). LIMITATIONS REASONS FOR CAUTION: Although our data demonstrate significant abnormalities in RM, larger sample sizes will be needed to confirm our results. Larger sample sizes should also balance the fact that we had to focus mainly on median protamine mRNA levels. Finally, men in the healthy control group were younger in age than those in the case group, which might have introduced some bias, at least concerning the classic semen parameters. Moreover, only protamine mRNA instead of protein levels could be measured. WIDER IMPLICATIONS OF THE FINDINGS: Although the exact mechanism remains to be elucidated, our data suggest that protamine mRNA levels in spermatozoa are not only important for successful fertilization, but also for proper development of the early embryo. STUDY FUNDING/COMPETING INTEREST(S): Grant from the University Clinic Giessen and Marburg (UKGM 29/2015GI). There are no competing interests. TRIAL REGISTRATION NUMBER: N/A.

Role of Plasminogen Activator Inhibitor Type 1 in Pathologies of Female Reproductive Diseases.

Normal pregnancy is a state of hypercoagulability with diminishing fibrinolytic activity, which is mainly caused by an increase of plasminogen activator inhibitor type 1 (PAI-1). PAI-1 is the main inhibitor of plasminogen activators, including tissue-type plasminogen activator (tPA) and urokinase-type plasminogen activator (uPA). In human placentas, PAI-1 is expressed in extravillous interstitial trophoblasts and vascular trophoblasts. During implantation and placentation, PAI-1 is responsible for inhibiting extra cellular matrix (ECM) degradation, thereby causing an inhibition of trophoblasts invasion. In the present study, we have reviewed the literature of various reproductive diseases where PAI-1 plays a role. PAI-1 levels are increased in patients with recurrent pregnancy losses (RPL), preeclampsia, intrauterine growth restriction (IUGR), gestational diabetes mellitus (GDM) in the previous pregnancy, endometriosis and polycystic ovary syndrome (PCOS). In general, an increased expression of PAI-1 in the blood is associated with an increased risk for infertility and a worse pregnancy outcome. GDM and PCOS are related to the genetic role of the 4G/5G polymorphism of PAI-1. This review provides an overview of the current knowledge of the role of PAI-1 in reproductive diseases. PAI-1 represents a promising monitoring biomarker for reproductive diseases and may be a treatment target in the near future.

Short interval between two Pap smears: effect on the result of the second smear? A prospective randomized trial.

PURPOSE: A repeat Pap smear is sometimes necessary after a short time interval or even immediately, when patients seek for a second opinion or due to study participation. Only limited information is available on the possible impact of a short interval between two Pap smears. Most institutions therefore practice a minimum time span of 6-8 weeks before obtaining a second smear since a short interval is commonly believed to be associated with an increase of false negative results in the second smear. METHODS: Two consecutive Pap smears were obtained from 81 women. 41 smears were processed using the conventional technique, whereas liquid-based cytology was used in the remaining 40 women. Smears were independently evaluated by four different cytopathologists. We analyzed the effect of time interval, both processing techniques and inter-observer variance in cytological evaluation. RESULTS: While the result of the second smear shows a tendency towards a more benign outcome (odds ratio (OR) 1.436, 95% CI 0.972-2.121), this difference was not statistically significant (p = 0.07). No significant differences were observed between conservative and liquid-based cytology (OR 1.554, 95% CI 0.659-3.667, p = 0.31). There was considerable inter-observer variability, and the observer was a strong predictor of the cytological result (OR 0.632-5.083, 95% CI 0.355-8.975, p < 0.01). CONCLUSIONS: We document a tendency towards a more benign outcome without statistical significance in the second smear. Inter-observer variability of different cytopathologists is high and should be kept in mind when evaluating cytology results.

Lessons From the EThIGII Trial: Proper Putative Benefit Assessment of Low-Molecular-Weight Heparin Treatment in M2/ANXA5 Haplotype Carriers.

This study presents sample size considerations derived from the Efficacy of Thromboprophylaxis as an Intervention during Gravidity (EThIGII) trial (ClinicalTrials.gov: NCT00400387) to address the question of low-molecular-weight heparin (LMWH) treatment in women with recurrent pregnancy loss (RPL) depending on the M2/ANXA5 haplotype. To evaluate the possible influence of such treatment on miscarriage rates of trial participants, a post hoc analysis of ANXA5 promoter genotypes in the light of M2/ANXA5 (RPRGL3) distribution was performed using logistic models. DNA for genotyping was available from 129 LMWH and 95 control patients, 44 (19.6%) of whom were M2/ANXA5 carriers. Miscarriages occurred in 1 (4.0%) of 25 M2/ANXA5 carriers from the LMWH group compared to 4 (21.1%) of 19 in the control group, resulting in an odds ratio (95% confidence interval) for miscarriage of 0.16 (0.016-1.5) for women treated with LMWH. In noncarriers, miscarriage rates were 6 (5.8%) of 104 versus 7 (9.2%) of 76 for the LMWH and the control groups, respectively, corresponding to an odds ratio for miscarriage of 0.60 (0.19-1.9). The apparent beneficial effects of miscarriage rate reduction in M2/ANXA5 carriers with RPL concur with biological considerations about improvement in reduced ANXA5 function through LMWH treatment in an adequate murine model. The data obtained were instrumental to design proper assessment of the existence and magnitude of this effect.

Ascending Aortic Disease is Associated with Earlier Menopause and Shorter Reproductive Life Span.

OBJECTIVES: The incidence of cardiovascular morbidity and mortality in premenopausal women is comparatively low, but increases sharply after menopause. The principal aim of this study was to determine whether women with ascending aortic disease (AAD) have a different reproductive history from that of an age-matched control group. METHODS: In this retrospective study, women who had undergone ascending aortic aneurysm (AscAA) repair between 2000 and 2010 were asked to complete a questionnaire concerning risk factors and reproductive history. Data from 142 women with AAD were evaluated, and a subgroup (n = 64) with AscAA ≥5 cm was analyzed and compared to an age-matched random control group without known aortic diseases. RESULTS: Almost all women were menopausal at the time of the questionnaire (98.4% vs. 90.6%, AscAA ≥5 cm subcohort vs. control, p = 0.12) and all subjects presented with a comparable age of menarche (13.7 ± 2.6 years vs. 14.2 ± 1.8 years, AscAA ≥5 cm subcohort vs. control, log-rank 0.04, p = 0.84). However, mean menopausal age was significantly lower in the case subcohort than in controls (48.1 ± 4.8 years vs. 50.6 ± 5.8 years, AscAA ≥5 cm subcohort vs. control, log-rank 8.35, p = 0.004), and reproductive life span was correspondingly shorter (34.2 ± 5.2 years vs. 36.2 ± 5.7 years, p = 0.04). Furthermore, hypertension was more prevalent in women with AscAA ≥5 cm compared to controls (89.1% vs. 61.9%, AscAA ≥5 cm subcohort vs. control, p < 0.001). CONCLUSION: Women who experience menopause at an earlier age than the regional mean could profit from screening for cardiovascular disease in general and particularly for AAD. Screening would enable early aneurysm detection and could, therefore, reduce morbidity and mortality.