Gene expression associated with unfavorable vaginal bleeding in women using the etonogestrel subdermal contraceptive implant: a prospective study.

To evaluate gene expression associated with unfavorable vaginal bleeding in users of the Etonogestrel (ENG) contraceptive implant. Prospective study involving 100 women who intended to use the ENG implant. Exclusion criteria included abnormal uterine bleeding, inability to attend a 1-year follow-up, and implant removal for reasons unrelated to vaginal bleeding or loss of follow-up. We obtained endometrial biopsies before implant placement and assessed the expression of 20 selected genes. Users maintained a uterine bleeding diary for 12 months post-implant placement. For statistical analysis, we categorized women into those with or without favorable vaginal bleeding at 3 and 12 months. Women with lower CXCL1 expression had a 6.8-fold increased risk of unfavorable vaginal bleeding at 3 months (OR 6.8, 95% CI 2.21-20.79, p < 0.001), while those with higher BCL6 and BMP6 expression had 6- and 5.1-fold increased risks, respectively. By the 12-month follow-up, women with lower CXCL1 expression had a 5.37-fold increased risk of unfavorable vaginal bleeding (OR 5.37, 95% CI 1.63-17.73, p = 0.006). Women with CXCL1 expression < 0.0675, BCL6 > 0.65, and BMP6 > 3.4 had a higher likelihood of experiencing unfavorable vaginal bleeding at 3 months, and CXCL1 < 0.158 at 12 months. Users of ENG contraceptive implants with elevated BCL6 and BMP6 expression exhibited a higher risk of breakthrough bleeding at the 3-month follow-up. Conversely, reduced CXCL1 expression was associated with an elevated risk of bleeding at both the 3 and 12-month follow-ups.

Gene expression associated with vaginal bleeding in women using the 52-mg levonorgestrel hormonal intrauterine device: A prospective study.

OBJECTIVE: To evaluate gene expression associated with vaginal bleeding in the 52-mg hormonal intrauterine device (IUD) users. MATERIALS AND METHODS: We conducted a prospective study involving 100 women seeking to use the 52-mg hormonal IUD for contraception. We excluded women with a history or current condition of abnormal uterine bleeding and who were unable to attend a 1-year follow up. Women who expelled the device, removed it for reasons unrelated to vaginal bleeding, or were lost to follow up were discontinued. We collected endometrial biopsies immediately before IUD placement and assessed 20 selected genes using reverse transcription quantitative polymerase chain reaction. Users maintained a uterine bleeding diary for 12 months following IUD insertion. For statistical analysis, participants were categorized into groups with or without vaginal bleeding at 3 and 12 months. RESULTS: Women with elevated CXCL9 expression had an 8.15-fold higher likelihood of experiencing vaginal bleeding at 3 months (odds ratio [OR] 8.15, 95% confidence interval [CI] 2.24-29.61, P = 0.001). At 12 months of follow up, women with increased TIMP1 expression had a 2.74-fold higher chance of experiencing vaginal bleeding (OR 2.74, 95% CI 1.08-6.95, P = 0.033). CXCL9 ≥ 1.5 and IL17A ≥ 0.68 were associated with a higher probability of vaginal bleeding at 3 months, while TIMP1 levels ≥0.943 were linked to an increased risk of bleeding at 12 months. CONCLUSION: Users of the 52-mg hormonal IUD with elevated relative CXCL9 expression face an increased risk of vaginal bleeding at 3-month follow up, whereas those with heightened TIMP1 expression are more likely to experience vaginal bleeding at 12 months.

Expression deregulation of matrix metalloproteinases and vasoconstriction related genes in Pakistani females with abnormal uterine bleeding.

BACKGROUND: Abnormal uterine bleeding (AUB) is irregular menstrual bleeding which has great impact on female health and life style. Various genetic factors are involved in etiology and pathology of AUB. Present study was designed to explore the association of PTGFR, MMP9, MMP2, TGFB3 and VEGFB with AUB. METHODS: Blood samples of 212 females with AUB were collected along with age-matched healthy control. Expression variation of targeted genes was evaluated using qPCR. Present study cohort was divided into different groups based on demographic parameters and all targeted genes were correlated with study demographics. RESULTS: Expression of targeted genes was significantly (P < 0.001) downregulated in females with AUB compared to control. Reduced (P < 0.01) expression of targeted genes was observed in all age groups (21-30, 31-40, 41-50 year) of AUB patients compared to respective control. Expression of VEGFB increased (P < 0.05) in AUB females with > 9 days bleeding compared to AUB patient had < 9 days bleeding. AUB women with miscarriage history showed upregulation in MMP2, TGFB3 (P < 0.05), and downregulation in MMP9 and VEGFB (P < 0.05) expression compared to AUB group with no miscarriage history. Expression of MMP2 increased (P < 0.05) in AUB females with > 60 kg body weigh compared to AUB patient with < 60 kg weight. CONCLUSION: Present study open a new window for diagnosis of AUB at early stages and suggested a possible involvement of PTGFR, MMP9, MMP2, TGFB3 and VEGFB as candidate biomarkers in AUB.

Whole-exome sequencing reveals novel variants associated with abnormal uterine bleeding caused by copper intrauterine device.

Aim: This study aimed to explore the genetic risk factors and validate variants of abnormal uterine bleeding after copper intrauterine device insertion. Methods: Whole-exome sequencing was performed and several variants were validated by Sequenom MassARRAY. Results: Eight variants showed potential clinical damage according to American College of Medical Genetics and Genomics criteria. By combined analysis of screening and validation, NFASC RS2802808 C>G p.Ile971Met (Pallele = 0.009 and Pgenotype = 0.027) and PIGR RS2275531 C>T p.Gly365Ser (Pallele = 0.009 and Pgenotype = 0.013) variants were identified as significantly associated with abnormal uterine bleeding with a false discovery rate <0.05. NFASC and PIGR may play a role in abnormal uterine bleeding by regulating coagulation fibrinolysis and endometrial epithelium inflammation functions. Conclusion: These findings provide a genetic basis for clinical individualization and precision of intrauterine device implantation.

Abnormal uterine bleeding (AUB) after Cu intrauterine device (Cu-IUD) insertion is the most common side effect of Cu-IUD use. AUB is a multifactorial process that relates to endometrial-related genetic factors, ovulatory function-related genetic factors, coagulation, the fibrinolytic system, contraction of the uterine arteries and endometritis inflammatory factor. This is the first study to explore the underlying genetic mechanisms of AUB related to the use of Cu-IUDs by whole-exome sequencing in the Chinese Han population. The authors found that variants of NFASC and PIGR genes were significantly associated with AUB in women using Cu-IUDs. NFASC and PIGR may be involved in coagulation fibrinolysis and endometrial epithelium inflammation functions, indicating its potential functions in AUB. This study could provide a genetic basis for studies on the individualization and precision of IUD use in the future.

Obesity and risk of female reproductive conditions: A Mendelian randomisation study.

BACKGROUND: Obesity is observationally associated with altered risk of many female reproductive conditions. These include polycystic ovary syndrome (PCOS), abnormal uterine bleeding, endometriosis, infertility, and pregnancy-related disorders. However, the roles and mechanisms of obesity in the aetiology of reproductive disorders remain unclear. Thus, we aimed to estimate observational and genetically predicted causal associations between obesity, metabolic hormones, and female reproductive disorders. METHODS AND FINDINGS: Logistic regression, generalised additive models, and Mendelian randomisation (MR) (2-sample, non-linear, and multivariable) were applied to obesity and reproductive disease data on up to 257,193 women of European ancestry in UK Biobank and publicly available genome-wide association studies (GWASs). Body mass index (BMI), waist-to-hip ratio (WHR), and WHR adjusted for BMI were observationally (odds ratios [ORs] = 1.02-1.87 per 1-SD increase in obesity trait) and genetically (ORs = 1.06-2.09) associated with uterine fibroids (UF), PCOS, heavy menstrual bleeding (HMB), and pre-eclampsia. Genetically predicted visceral adipose tissue (VAT) mass was associated with the development of HMB (OR [95% CI] per 1-kg increase in predicted VAT mass = 1.32 [1.06-1.64], P = 0.0130), PCOS (OR [95% CI] = 1.15 [1.08-1.23], P = 3.24 × 10-05), and pre-eclampsia (OR [95% CI] = 3.08 [1.98-4.79], P = 6.65 × 10-07). Increased waist circumference posed a higher genetic risk (ORs = 1.16-1.93) for the development of these disorders and UF than did increased hip circumference (ORs = 1.06-1.10). Leptin, fasting insulin, and insulin resistance each mediated between 20% and 50% of the total genetically predicted association of obesity with pre-eclampsia. Reproductive conditions clustered based on shared genetic components of their aetiological relationships with obesity. This study was limited in power by the low prevalence of female reproductive conditions among women in the UK Biobank, with little information on pre-diagnostic anthropometric traits, and by the susceptibility of MR estimates to genetic pleiotropy. CONCLUSIONS: We found that common indices of overall and central obesity were associated with increased risks of reproductive disorders to heterogenous extents in a systematic, large-scale genetics-based analysis of the aetiological relationships between obesity and female reproductive conditions. Our results suggest the utility of exploring the mechanisms mediating the causal associations of overweight and obesity with gynaecological health to identify targets for disease prevention and treatment.

Applicability of ancestral genotyping in pharmacogenomic research with hormonal contraception.

To compare etonogestrel pharmacokinetic and pharmacodynamic outcomes by both self-reported race/ethnicity and genetically determined ancestry among contraceptive implant users. We conducted a secondary analysis of our parent pharmacogenomic study of 350 implant users. We genotyped these reproductive-aged (18-45 years) women for 88 ancestry-informative single nucleotide polymorphisms. We then assigned each participant a proportion value for African (AFR), European (EUR), and Indigenous American (AMR) ancestry based on reference population data. We correlated genetic ancestry with self-reported race/ethnicity and utilized genetic ancestry proportion values as variables for previously performed association analyses with serum etonogestrel concentrations and progestin-related side effects (e.g., bothersome bleeding and subjective weight gain). We successfully estimated genetically determined ancestry for 332 participants. EUR, AFR, and AMR ancestry were each highly correlated with self-reported White/non-Hispanic race (r = 0.64, p = 4.14 × 10-40 ), Black/African American race (r = 0.88, p = 1.36 × 10-107 ), and Hispanic/Latina ethnicity (r = 0.68, p = 4.03 × 10-47 ), respectively. Neither genetically determined ancestry nor self-reported race/ethnicity were significantly associated with serum etonogestrel concentrations. AFR ancestry and self-reported Black race had similar associations with reporting monthly periods (odds ratio [OR] 2.18, p = 0.09 vs. OR 2.22, p = 0.02) and having received treatment for bothersome bleeding (OR 5.19, p = 0.005 vs. OR 4.73, p = 2.0 × 10-4 ). In multivariable logistic regression for subjective weight gain, AMR ancestry dropped out of the model in preference for self-reported Hispanic/Latina ethnicity. We found no new associations between genetically determined ancestry and contraceptive implant pharmacodynamics/pharmacokinetics. Self-reported race/ethnicity were strong surrogates for genetically determined ancestry among this population of contraceptive implant users. Our data suggest that self-reported race/ethnicity, capturing societal and cultural aspects, remain important to the investigation of progestin-related side effects.

Association between habitual coffee consumption and multiple disease outcomes: A Mendelian randomisation phenome-wide association study in the UK Biobank.

BACKGROUND: Coffee is the most commonly consumed beverage in the world after water, however the debate as to whether coffee consumption is beneficial or detrimental to health continues. Current evidence of the link between coffee and health outcomes is predominately observational, thus subject to methodological issues such a confounding and reverse causation. METHODS: This Mendelian randomisation phenome-wide association study (MR-PheWAS) used information from up to 333,214 participants of White-British ancestry in the UK Biobank to examine the causal association between genetically instrumented habitual coffee consumption and the full range of disease outcomes. We constructed a genetic risk score for habitual coffee consumption and screened for associations with disease outcomes across 1117 case-control series. All signals under false discovery rate controlled threshold (5.8 × 10-4) were followed by Mendelian randomisation (MR) analyses, with replication in independent data sources where possible. RESULTS: The initial phenome-wide association analysis identified signals for 13 outcomes representing five distinct diseases. The strongest signal was seen for gout (P = 2.3 × 10-12), but there was notable pleiotropy (Pdistortion <0.001) and MR analyses did not support an association with habitual coffee consumption (inverse variance weighted MR OR 0.41, 95% CI 0.08 to 2.25, P = 0.31). Support for a possible causal relationship between habitual coffee consumption was only obtained for four distinct disease outcomes, including an increased odds of osteoarthrosis (OR 1.23, 95% CI 1.11 to 1.35), other arthropathies (OR 1.22, 95% CI 1.12 to 1.33) and overweight (OR 1.28, 95% CI 1.05 to 1.56), and a lower odds of postmenopausal bleeding (OR 0.72, 95% CI 0.63 to 0.82). Evidence for an association between habitual coffee consumption and these four diseases was also supported by phenotypic associations with self-reported coffee consumption. CONCLUSIONS: This large-scale MR-PheWAS provided little evidence for notable harm or benefit with respect to higher habitual coffee consumption. The only evidence for harm was seen with respect to osteoarthrosis, other arthropathies and obesity.

Bleeding during pregnancy is associated with familial preterm birth.

PURPOSE: the purpose of this study is to identify risk factors for familial, likely genetically-determined, preterm birth. MATERIALS AND METHODS: We performed a case-control study, enrolling 211 patients (103 cases and 108 controls). Cases delivered between 20 and 35 weeks gestation, with a prior preterm birth or first-degree relative born prematurely. Controls delivered between 37-42 weeks. Groups were compared using a comprehensive questionnaire validated by medical record. Multivariate logistic regression assessed risk factor associations. RESULTS: Of cases, 30% reported bleeding during pregnancy compared with 5% of controls, adjusted odds ratio (adjOR) 9.0, 95%CI 3.31-24.47. Of cases that delivered at 20-28 weeks, 44.8% reported bleeding during pregnancy compared with 24.6% at 29-35 weeks, p = .04. Other associations were prior first-trimester miscarriage adjOR 2.55 (CI 1.21-5.35) or second-trimester miscarriage, adjOR 6.3 (CI 1.76-22.56). CONCLUSIONS: Bleeding during pregnancy and prior miscarriage were significantly associated with familial preterm birth. The magnitude of effect for bleeding in pregnancy was higher with earlier preterm births. These associations warrant further investigation.

Factor X heterozygous mutation in a patient with potential risk of bleeding: A case report.

RATIONALE: Factor X (FX) deficiency is a rare autosomal recessive bleeding disorder. The majority of patients carry a missense mutation in F10, and patients with bleeding disorders are either homozygous or compound heterozygous for F10. Nonsense mutations are exceptionally rare, and a heterozygous nonsense mutation is not considered to cause bleeding disorders. PATIENT CONCERNS: A 35-year-old Japanese female with an incidental hemorrhage after gynecologic polypectomy was referred to our hospital. DIAGNOSES: Following differential diagnostic workup, including cross-mixing test, congenital FX deficiency was strongly suspected. INTERVENTION: Coagulation tests and mutation analyses were conducted for the patient and her parents. OUTCOMES: Mutation analysis revealed that she carried a heterozygous nonsense mutation in F10. Pedigree analysis revealed that the mutation was inherited from her mother although there was no familial history of bleeding or hemostatic disturbance. LESSONS: Hemostatic disturbance may occur even in a patient with heterozygous F10. Because heterozygous nonsense mutation in F10 is expected to be hidden in an apparently healthy population, as observed in our patient, unexpected hemostatic disturbance may occur, particularly during the use of direct oral anticoagulant (DOAC)-targeting factor Xa for thrombotic diseases. FX activity should be evaluated before prescribing DOACs to patients.

Expression of matrix metalloproteinase enzymes in endometrium of women with abnormal uterine bleeding.

OBJECTIVES: Abnormal uterine bleeding (AUB) is caused by derangement of physiological processes of tissue growth, shedding and regeneration. It is known that interplay between metalloproteinases (MMP's) and tissue inhibitors of metalloproteinases (TIMP's) may play a crucial role in its occurrence. AIM: To define if expression of proMMP-2, MMP-2 and TIMP-1 in endometrium of women with AUB is dependent on steroid sex hormone concentration and histopathological picture. MATERIALS AND METHODS: Endometrial scraps were taken from 21 women with AUB and 19 controls. Samples were evaluated in light microscopy by a certified pathologist. Activity of proMMP-2 and MMP-2 proteins levels were evaluated by gelatin zymography and TIMP-1 by reversed zymography. The results has been correlated with serum estradiol and progesterone concentrations in linear regression model. RESULTS: Expression: of proMMP-2 in endometrium of women with AUB is correlated with estradiol concentration and inversely correlated with progesterone levels. It was significantly higher in women with dysfunctional endometrium (p<0.001). Expression of MMP-2 was highest in women with endometrial polyps and longer bleeding (p<0.01), while expression of TIMP-1 was independent from hormone concentration. CONCLUSION: Lack of correlation between proMMP-2 and MMP-2 levels suggest different pathway of their activation in AUB. ProMMP-2 is up regulated by estradiol and down regulated by progesterone while MMP-2 levels increase with the length of bleeding.

The molecular and genetic aspects of adolescent girls anomalous uterine bleeding: the role of endothelial dysfunction syndrome.

The objective of the study is to assess NOS3 and ESR1 gene polymorphism in adolescent girls born with low birth weight (LBW) and suffered by anomalous uterine bleeding (AUB). A total 95 adolescent girls were studied including 32 born with LBW and AUB; 36 girls with normal birth weight and AUB; and 27 healthy girls. Single allele gene polymorphism NOS3 786T > C, 894G > T, ESR1 351A > G and 397T > C was studied. The existence of polymorphous allele С gene NOS3 786Т > С (for homozygote OR = 2.03; 95% CI: 1.12-3.68; p = 0.04; for heterozygote OR = 1.68; 95% CI: 1.09-2.60; p = 0.046) and genotype Pvull-CC ESR1 (OR = 4.58; 95% CI: 0.97-21.68; p = 0.04) was detected in LBW girls with AUB. It was suggested that intrauterine programming of endothelial dysfunction syndrome could play a significant role in the development of AUB in adolescent girls born with LBW.

E-Cadherin, CD44v6, and Insulin-Like Growth Factor-II mRNA-Binding Protein 3 Expressions in Different Stages of Hydatidiform Moles.

E-cadherin, CD44v6, and IMP3 expression in partial, complete, and invasive hydatidiform moles (HMs) was evaluated. High E-cadherin expression with low CD44v6 expression was observed in partial, complete, and invasive HMs, as well as in normal placental tissues; and there was no significant difference in E-cadherin and CD44v6 expression among the four groups. However, IMP3 expression was gradually decreased in the order of normal placental tissues, partial HMs, complete HMs, and invasive HMs; wherein, invasive HMs had the lowest level. Low IMP3 expression may serve as a prognostic biomarker for HMs, and IMP3 may play a certain role in HMs progression.

Progestins Upregulate FKBP51 Expression in Human Endometrial Stromal Cells to Induce Functional Progesterone and Glucocorticoid Withdrawal: Implications for Contraceptive- Associated Abnormal Uterine Bleeding.

Use of long-acting progestin only contraceptives (LAPCs) offers a discrete and highly effective family planning method. Abnormal uterine bleeding (AUB) is the major side effect of, and cause for, discontinuation of LAPCs. The endometria of LAPC-treated women display abnormally enlarged, fragile blood vessels, decreased endometrial blood flow and oxidative stress. To understanding to mechanisms underlying AUB, we propose to identify LAPC-modulated unique gene cluster(s) in human endometrial stromal cells (HESCs). Protein and RNA isolated from cultured HESCs treated 7 days with estradiol (E2) or E2+ medroxyprogesterone acetate (MPA) or E2+ etonogestrel (ETO) or E2+ progesterone (P4) were analyzed by quantitative Real-time (q)-PCR and immunoblotting. HSCORES were determined for immunostained-paired endometria of pre-and 3 months post-Depot MPA (DMPA) treated women and ovariectomized guinea pigs (GPs) treated with placebo or E2 or MPA or E2+MPA for 21 days. In HESCs, whole genome analysis identified a 67 gene group regulated by all three progestins, whereas a 235 gene group was regulated by E2+ETO and E2+MPA, but not E2+P4. Ingenuity pathway analysis identified glucocorticoid receptor (GR) activation as one of upstream regulators of the 235 MPA and ETO-specific genes. Among these, microarray results demonstrated significant enhancement of FKBP51, a repressor of PR/GR transcriptional activity, by both MPA and ETO. q-PCR and immunoblot analysis confirmed the microarray results. In endometria of post-DMPA versus pre-DMPA administered women, FKBP51 expression was significantly increased in endometrial stromal and glandular cells. In GPs, E2+MPA or MPA significantly increased FKBP51 immunoreactivity in endometrial stromal and glandular cells versus placebo- and E2-administered groups. MPA or ETO administration activates GR signaling and increases endometrial FKBP51 expression, which could be one of the mechanisms causing AUB by inhibiting PR and GR-mediated transcription. The resultant PR and/or GR-mediated functional withdrawal may contribute to associated endometrial inflammation, aberrant angiogenesis, and bleeding.

Carcinoma de trompa de Falopio: revisión de casos en el Hospital General Universitario de Albacete / Primary fallopian tube carcinoma. Review of cases. Hospital General Albacete

Introducción: El carcinoma de trompa de Falopio primario (CTFP) constituye la neoplasia maligna menos frecuente del aparato genital femenino. Su incidencia es mayor entre la cuarta y la sexta década de la vida. Debido a su baja prevalencia y a su sintomatología inespecífica, el diagnóstico de esta enfermedad raramente se realiza antes de la cirugía. Objetivo: El principal objetivo de esta revisión ha sido conocer la forma de presentación y evolución del CTFP. Para ello se han analizado los casos de CTFP ocurridos en el Hospital General Universitario de Albacete desde el año 2000. Material y métodos: Hemos realizado un estudio descriptivo retrospectivo que incluye una serie de 5 casos de CTFP tratados en nuestro centro. Resultados: La edad media de las pacientes en el momento del diagnóstico es de 55 años. El síntoma más frecuente ha sido la hemorragia genital. En una de las pacientes, a pesar de que el diagnóstico de CTFP se realiza de manera post-operatoria, se sospechó un CTFP con las pruebas diagnósticas previas a la cirugía. El examen histopatológico reveló 3 casos de adenocarcinomas de tipo seroso y 2 de tipo endometrioide. La citología de líquido peritoneal fue positiva en el 80% de los casos. En cuanto al estadio clínico, 2 pacientes se encontraban en estadio I, 2 en estadio II y sólo un caso en estadio III. El seguimiento medio de estas pacientes ha sido de 31 meses, produciéndose recidiva en 3 de los 5 casos, a nivel local, dentro del primer año tras el diagnóstico. Conclusiones: ElCTFP, aunque es una entidad rara, no podemos olvidarlo ante una paciente con hidromenorrea, dolor abdominal, masa anexial y alteraciones citológicas cervicovaginales y/o endometriales (AU)

Introduction: Primary fallopian tube carcinoma (PFTC) is the rarest of all gynecologic cancers. It frequently occurs between fourth and sixth decade of life. Because of its low prevalence and its unspecific symptoms, PFTC is rarely diagnosed before surgery. Objetive: The main objective of this study is to analyze the patients who were diagnosed of PFTC in the General Hospital of Albacete between 2000 and 2009. Material and methods: We present a retrospective descriptive study involving 5 patients with PFTC treated in our hospital. Results: The average age of the patients at the moment of diagnosis is 55 years. The most frequent symptom has been the vaginal bleeding. In one of the patients, although the diagnosis of PFTC was done postoperative, we suspected PFTC with the preoperative study. Histopathological examination revealed 3 cases of serous adenocarcinoma and 2 cases of endometroid adenocarcinoma. Peritoneal cytology was positive in 80% of the cases. As far as the surgical staging is concerned, 2 patients were diagnosed in stage I, 2 patients in stage II and only one patient in stage III. The average follow has been 31 months, appearing recurrence in 3 of the 5 cases during the first year, as a local recurrence. Conclusion: Although PFTC is a very rare malignancy, it should be suspected in a patient with vaginal bleeding, abdominal pain, adnexal mass and abnormalities of cervical or endometrial cytologies (AU)

Early vaginal bleeding has no impact on markers used in first trimester aneuploidy screening.

OBJECTIVE: To assess the impact of early vaginal bleeding on the levels of markers used in first trimester screening for aneuploidy. METHODS: A retrospective analysis was carried out on the free beta human chorionic gonadotrophin (beta-hCG) and pregnancy associated plasma protein-A (PAPP-A) levels and nuchal translucency thickness in 49 653 women with a normal singleton fetus who had first trimester combined screening for Down Syndrome in three centres. Median MoMs and the distribution of log MoMs of the two markers were compared in two groups-7470 women who self-reported vaginal bleeding and 42 183 women who reported no vaginal bleeding at any stage prior to the screening test. RESULTS: The overall median MoM free beta-hCG and that in the bleeding and non-bleeding group were 0.9854, 1.0012 and 0.9832, and for PAPP-A were 1.0407, 1.0413 and 1.037. There was no significant difference between the bleeding and non-bleeding group by median test (p = 0.080) or by t-test comparing log MoMs (p = 0.1305) for free beta-hCG and for PAPP-A with median test (p = 0.5071) or by t-test comparing log MoMs (p = 0.1740). For delta nuchal translucency (NT) there was also no significant difference between the bleeding and non-bleeding group (p = 0.055). CONCLUSION: Vaginal bleeding has little or no impact on first trimester marker levels and no correction is necessary.

Regulation of human endometrial function: mechanisms relevant to uterine bleeding.

This review focuses on the complex events that occur in the endometrium after progesterone is withdrawn (or blocked) and menstrual bleeding ensues. A detailed understanding of these local mechanisms will enhance our knowledge of disturbed endometrial/uterine function--including problems with excessively heavy menstrual bleeding, endometriosis and breakthrough bleeding with progestin only contraception. The development of novel strategies to manage these clinically significant problems depends on such new understanding as does the development of new contraceptives which avoid the endometrial side effect of breakthrough bleeding.

[Management of patients with Type 2B von Willebrand's disease during delivery and puerperium]. / Sub- und postpartales Management von Patientinnen mit von-Willebrand-Jürgens-Syndrom Typ 2B.

Von Willebrand's disease (VWD) is the most common congenital haemorrhagic diathesis inherited as an autosomal dominant trait, with a prevalence estimated to be 1 - 2 %. In subtype 2B an abnormally structured von-Willebrand factor (VWF) leads to an increased binding of VWF molecules to normal platelets, which regularly results in thrombocytopenia in pregnancy. Only few systematic observations in patients with type 2B VWD in the perinatal period have been reported in the literature. Six spontaneous deliveries in two sisters with type 2B VWD are reported. The first patient did not show any bleeding complications in five vaginal deliveries without any factor replacement therapy. The second patient showed a massive haemorrhage on the third postpartum day after administration of factor VIII-VWF concentrate replacement therapy (Haemate(R) HS), only on the day of delivery. No neonatal complications were reported. The clinical management of pregnancy, delivery and puerperium in patients with type 2B VWD requires close collaboration of experienced obstetricians, haematologists, anaesthesiologists and paediatricians. During labour and delivery, but especially in puerperium, there is a significantly increased risk for haemorrhage. Vaginal delivery is generally safe, but the incidence of postpartum haemorrhage is 30 %. These bleedings may be extremely severe. The danger of postpartum bleeding complications cannot be predicted with certainty, neither by past history of bleeding episodes or haematological laboratory tests of VWF activity levels. Hence, in all patients factor VIII-VWF concentrate replacement therapy should be initiated already in the first stage of labour. Post partum replacement therapy along with effective uterotonic therapy should be continued at least for seven days. With this treatment bleeding problems may be largely prevented. The decision to perform epidural block in labour and delivery must be assessed depending on individual risk factors.

Tissue factor is required for uterine hemostasis and maintenance of the placental labyrinth during gestation.

We employed a novel mouse line that expresses low levels of human tissue factor (TF) in the absence of murine TF to analyze the role of TF in gestation. Low-TF female mice had a 14-18% incidence of fatal postpartum uterine hemorrhage, suggesting that TF plays an important role in uterine hemostasis. Low-TF female mice mated with low-TF male mice had a 42% incidence of fatal midgestational hemorrhage (n = 41), whereas no fatal midgestational hemorrhages were observed in low-TF female mice mated with wild-type male mice (n = 43). Placentas of low-TF embryos from both low-TF and normal (+/-) TF females were abnormal and contained numerous maternal blood pools in the labyrinth. Placentas of TF null embryos surviving beyond embryonic day 10.5 exhibited similar defects. The mouse maternal-embryonic placental barrier consists of four cellular layers (layers I, II, and III and endothelial cells), where layer I lines the maternal lacunae. Comparison of TF-deficient placentas with control placentas by immunohistochemical and ultrastructural analyses revealed thinning of layer I and a reduction in the number of cellular contacts of layer I trophoblasts spanning the maternal blood space between adjacent trabeculae. These structural changes in low-TF and TF null placentas result in enlarged maternal lacunae, as determined by morphometric analysis, and placental hemorrhage, which leads to midgestational death of low-TF female mice. This study demonstrated that TF is required for uterine hemostasis and revealed an unexpected role of TF in the maintenance of the placental labyrinth.

[Pre- and postpartum hemostasis in type II Willebrand-Jürgens syndrome]. / Prä- und postpartale Hämostase beim von Willebrand-Jürgens-Syndrom Typ II.

In a female patient with a von Willebrand's disease type II (ristocetin cofactor less than 20%) shortly before and after birth of a son the factor VIII-related antigen and the ristocetin cofactor showed considerable increases, which some weeks later again decreased to the original values. Despite additional thrombocytopenia only on the 4th day post partum an easily controllable uterine haemorrhage was to be established. The risk of haemorrhage in von Willebrand's disease during pregnancy, birth and puerperium seems to be insignificant; nevertheless on the basis of the heterogeneity of this disease a peripartal coagulation-analytic control is regarded necessary.

First-trimester vaginal bleeding and the loss of chromosomally normal and abnormal conceptions.

The frequency of first-trimester vaginal bleeding among 670 women with chromosomally normal fetal losses and 219 women with chromosomally abnormal losses was compared with that among 3089 women delivered at term. Vaginal bleeding early in gestation was predictive of pregnancy outcome in that moderate or heavy bleeding was associated with a fourfold risk of the loss of either chromosomally normal or abnormal conceptions. Spotting or slight bleeding was associated with a 2.7-fold risk of the loss of a chromosomally normal conception but was not associated with the loss of chromosomally abnormal conceptions when all abnormalities were categorized together.