A core outcome set for trials in miscarriage management and prevention: An international consensus development study.

OBJECTIVE: To develop core outcome sets (COS) for miscarriage management and prevention. DESIGN: Modified Delphi survey combined with a consensus development meeting. SETTING: International. POPULATION: Stakeholder groups included healthcare providers, international experts, researchers, charities and couples with lived experience of miscarriage from 15 countries: 129 stakeholders for miscarriage management and 437 for miscarriage prevention. METHODS: Modified Delphi method and modified nominal group technique. RESULTS: The final COS for miscarriage management comprises six outcomes: efficacy of treatment, heavy vaginal bleeding, pelvic infection, maternal death, treatment or procedure-related complications, and patient satisfaction. The final COS for miscarriage prevention comprises 12 outcomes: pregnancy loss <24 weeks' gestation, live birth, gestation at birth, pre-term birth, congenital abnormalities, fetal growth restriction, maternal (antenatal) complications, compliance with intervention, patient satisfaction, maternal hospitalisation, neonatal or infant hospitalisation, and neonatal or infant death. Other outcomes identified as important were mental health-related outcomes, future fertility and health economic outcomes. CONCLUSIONS: This study has developed two core outcome sets, through robust methodology, that should be implemented across future randomised trials and systematic reviews in miscarriage management and prevention. This work will help to standardise outcome selection, collection and reporting, and improve the quality and safety of future studies in miscarriage.

Experiences and well-being of healthcare professionals working in the field of ultrasound in obstetrics and gynaecology as the SARS-CoV-2 pandemic were evolving: a cross-sectional survey study.

OBJECTIVE: Assess experience of healthcare professionals (HCPs) working with ultrasound in obstetrics and gynaecology during the evolving SARS-CoV-2 pandemic, given the new and unprecedented challenges involving viral exposure, personal protective equipment (PPE) and well-being. DESIGN: Prospective cross-sectional survey study. SETTING: Online international survey. Single-best, open box and Hospital Anxiety and Depression Scale (HADS) questions. PARTICIPANTS: The survey was sent to 35 509 HCPs in 124 countries and was open from 7 to 21 May 2020. 2237/3237 (69.1%) HCPs from 115 countries who consented to participate completed the survey. 1058 (47.3%) completed the HADS. PRIMARY OUTCOME MEASURES: Overall prevalence of SARS-CoV-2, depression and anxiety among HCPs in relation to country and PPE availability. ANALYSES: Univariate analyses were used to investigate associations without generating erroneous causal conclusions. RESULTS: Confirmed/suspected SARS-CoV-2 prevalence was 13.0%. PPE provision concerns were raised by 74.1% of participants; highest among trainees/resident physicians (83.9%) and among HCPs in Spain (89.7%). Most participants worked in self-perceived high-risk areas with SARS-CoV-2 (67.5%-87.0%), with proportionately more trainees interacting with suspected/confirmed infected patients (57.1% vs 24.2%-40.6%) and sonographers seeing more patients who did not wear a mask (33.3% vs 13.9%-7.9%). The most frequent PPE combination used was gloves and a surgical mask (22.3%). UK and US respondents reported spending less time self-isolating (8.8 days) and lower satisfaction with their national pandemic response (37.0%-43.0%). 19.8% and 8.8% of respondents met the criteria for moderate to severe anxiety and depression, respectively. CONCLUSIONS: Reported prevalence of SARS-CoV-2 in HCPs is consistent with literature findings. Most respondents used gloves and a surgical mask, with a greater SARS-CoV-2 prevalence compared with those using 'full' PPE. HCPs with the least agency (trainees and sonographers) were not only more likely to see high-risk patients but also less likely to be protected. A fifth of respondents reported moderate to severe anxiety.

Defining safe criteria to diagnose miscarriage: prospective observational multicentre study.

OBJECTIVES: To validate recent guidance changes by establishing the performance of cut-off values for embryo crown-rump length and mean gestational sac diameter to diagnose miscarriage with high levels of certainty. Secondary aims were to examine the influence of gestational age on interpretation of mean gestational sac diameter and crown-rump length values, determine the optimal intervals between scans and findings on repeat scans that definitively diagnose pregnancy failure.) DESIGN: Prospective multicentre observational trial. SETTING: Seven hospital based early pregnancy assessment units in the United Kingdom. PARTICIPANTS: 2845 women with intrauterine pregnancies of unknown viability included if transvaginal ultrasonography showed an intrauterine pregnancy of uncertain viability. In three hospitals this was initially defined as an empty gestational sac <20 mm mean diameter with or without a visible yolk sac but no embryo, or an embryo with crown-rump length <6 mm with no heartbeat. Following amended guidance in December 2011 this definition changed to a gestational sac size <25 mm or embryo crown-rump length <7 mm. At one unit the definition was extended throughout to include a mean gestational sac diameter <30 mm or embryo crown-rump length <8 mm. MAIN OUTCOME MEASURES: Mean gestational sac diameter, crown-rump length, and presence or absence of embryo heart activity at initial and repeat transvaginal ultrasonography around 7-14 days later. The final outcome was pregnancy viability at 11-14 weeks' gestation. RESULTS: The following indicated a miscarriage at initial scan: mean gestational sac diameter ≥ 25 mm with an empty sac (364/364 specificity: 100%, 95% confidence interval 99.0% to 100%), embryo with crown-rump length ≥ 7 mm without visible embryo heart activity (110/110 specificity: 100%, 96.7% to 100%), mean gestational sac diameter ≥ 18 mm for gestational sacs without an embryo presenting after 70 days' gestation (907/907 specificity: 100%, 99.6% to 100%), embryo with crown-rump length ≥ 3 mm without visible heart activity presenting after 70 days' gestation (87/87 specificity: 100%, 95.8% to 100%). The following were indicative of miscarriage at a repeat scan: initial scan and repeat scan after seven days or more showing an embryo without visible heart activity (103/103 specificity: 100%, 96.5% to 100%), pregnancies without an embryo and mean gestational sac diameter <12 mm where the mean diameter has not doubled after 14 days or more (478/478 specificity: 100%, 99.2% to 100%), pregnancies without an embryo and mean gestational sac diameter ≥ 12 mm showing no embryo heartbeat after seven days or more (150/150 specificity: 100%, 97.6% to 100%). CONCLUSIONS: Recently changed cut-off values of gestational sac and embryo size defining miscarriage are appropriate and not too conservative but do not take into account gestational age. Guidance on timing between scans and expected findings on repeat scans are still too liberal. Protocols for miscarriage diagnosis should be reviewed to account for this evidence to avoid misdiagnosis and the risk of terminating viable pregnancies.

Evaluation of ovarian function in 35-40-year-old women with polycystic ovary syndrome.

OBJECTIVE: To assess gonadotrophin secretion, ovarian steroid production and ovarian reserve in PCOS women during the onset of reproductive decline, in order to characterize their ovarian function at this age. STUDY DESIGN: Forty PCOS patients and 35 healthy women (35-40 years of age) were included. Clinical history, anthropometry, transvaginal ultrasound and a leuprolide acetate test (10 µg/kg s.c.) were performed. Gonadotrophins, steroid hormones, SHBG, inhibin B and AMH were determined. RESULTS: Basal and peak LH levels were similar in both groups. Basal and peak FSH levels were significantly higher in the control group. Androgens, peak oestradiol, ovarian volume, antral follicle count and AMH levels were significantly higher in PCOS patients. CONCLUSION: These observations suggest that during late reproductive age, gonadotrophin secretion in women with PCOS is clearly different from that observed in control women and may also differ from that of younger PCOS patients. New features like normal LH and lower FSH levels associated with a higher ovarian reserve may give a different reproductive profile to these women.

A multicenter prospective external validation of the diagnostic performance of IOTA simple descriptors and rules to characterize ovarian masses.

OBJECTIVES: To evaluate the diagnostic performance of the IOTA (International Ovarian Tumor Analysis group) (clinically oriented three-step strategy for preoperative characterization of ovarian masses when ultrasonography is performed by examiners with different background training and experience. METHODS: A 27-month prospective multicenter cross-sectional study was performed. 36 level II ultrasound examiners contributed in three UK hospitals. Transvaginal ultrasonography was performed using a standardized approach. Step one uses simple descriptors (SD), step two ultrasound simple rules (SR) and step three subjective assessment of ultrasound images (SA) by examiners. The final outcome was findings at surgery and the histological diagnosis of surgically removed masses. RESULTS: 1165 women with adnexal masses underwent transvaginal ultrasonography, 301 had surgery. Prevalence of malignancy was 31% (n=92). SD were able to classify 46% of the masses into benign or malignant (step one), with a sensitivity of 93% and specificity of 97%. Applying SD followed by SR to residual unclassified masses by SD enabled 89% of all masses (n=268) to be classified with a sensitivity 95% of and specificity of 95%. SA was then used to evaluate the rest of the masses. Compared to the risk of malignancy index (RMI), the sensitivity and specificity for the three-step (SD+SR+SA) strategy were 93% (95% CI: 86-97%) and 92% (95% CI: 87-95%) vs. 72% (95% CI: 62-80%) and 95% (95% CI: 91-97%) for RMI, respectively. CONCLUSION: The IOTA three-step strategy shows good test performance on external validation in the hands of ultrasonography examiners with different background training and experience. This performance is considerably better than the RMI.

Síndrome de ovario poliquístico y embarazo / Polycystic ovary syndrome and pregnancy

Background: Polycystic ovary syndrome (PCOS) is a common endocrine metabolic dysfunction closely associated with insulin resistance and obesity, which predisposes to pregnancy complications and prenatal programming of the offspring. The aim of this review is to report our experience in PCOS patients who became pregnant and were followed during the whole pregnancy. Firstly, we analyzed the effect of pregnancy on PCOS pathophysiology and secondly the role of PCOS in pregnancy outcomes. Regarding the firstpoint, during normal pregnancy a progressive insulin resistance, serum lipid changes and an increase in androgen levels is observed, which is exacerbated in the PCOS condition. This adverse intrauterine environment could have a prenatal programming effect with detrimental consequences for female or male fetuses. Regarding the second point, PCOS is associated with an increased risk for maternal complications such as gestational diabetes (GDM) and pregnancy-induced hypertension. Moreover, these adverse pregnancy outcomes are more frequently associated with an increase in low birth weight and high birth weight newborns. According to our clinical experience, PCOS patients who became pregnant and were not treated with metformin during the whole pregnancy, showed a higher prevalence of gestational diabetes and SGA newborns, which was improved with metformin treatment. In summary, pregnancy may constitute a period in which an abnormal condition is established or aggravated in the fetus of a PCOS mother. Moreover, PCOS enhanced adverse obstetric and neonatal outcomes.

Relationship between anti-Müllerian hormone (AMH) and insulin levels during different tanner stages in daughters of women with polycystic ovary syndrome.

CONTEXT: We have previously described increased serum levels of anti-Müllerian hormone (AMH) and stimulated insulin in daughters of women with polycystic ovary syndrome (PCOS), suggesting that these girls may have an altered ovarian follicular development which may be modulated by insulin. However, the specific relationship between serum AMH and insulin levels during each Tanner stage of puberty in this cohort has not been established. OBJECTIVE: The aim of our study was to establish the relationship between AMH and poststimulated insulin serum concentrations during each stage of puberty in daughters of women with PCOS (PCOSd), compared to daughters of control women (Cd). DESIGN: We studied 135 PCOSd and 93 Cd classified according to their Tanner stage. Gonadotrophins, sex steroids, sex hormone-binding globulin (SHBG), and AMH were determined in a fasting sample. Ovarian volume was measured by pelvic ultrasound. In addition, in both groups we performed an oral glucose tolerance test with measurements of glucose and insulin. RESULTS: Anti-Müllerian hormone levels were significantly higher in PCOSd compared to Cd at all Tanner stages. Daughters of women with PCOS having AMH concentrations greater than 2 standard deviation (SD) above the mean AMH value for the Cd group showed decreased serum follicle-stimulating hormone (FSH) concentrations and increased stimulated levels of insulin during Tanner stages I, II, and III. CONCLUSIONS: Anti-Müllerian hormone levels are increased in PCOSd during all stages of puberty. We suggest that those PCOSd with the highest AMH levels probably represent a group of girls with more severe ovarian dysfunction and metabolic derangements.

[Polycystic ovary syndrome and pregnancy]. / Síndrome de ovario poliquístico y embarazo.

Polycystic ovary syndrome (PCOS) is a common endocrine metabolic dysfunction closely associated with insulin resistance and obesity, which predisposes to pregnancy complications and prenatal programming of the offspring. The aim of this review is to report our experience in PCOS patients who became pregnant and were followed during the whole pregnancy. Firstly, we analyzed the effect of pregnancy on PCOS pathophysiology and secondly the role of PCOS in pregnancy outcomes. Regarding the firstpoint, during normal pregnancy a progressive insulin resistance, serum lipid changes and an increase in androgen levels is observed, which is exacerbated in the PCOS condition. This adverse intrauterine environment could have a prenatal programming effect with detrimental consequences for female or male fetuses. Regarding the second point, PCOS is associated with an increased risk for maternal complications such as gestational diabetes (GDM) and pregnancy-induced hypertension. Moreover, these adverse pregnancy outcomes are more frequently associated with an increase in low birth weight and high birth weight newborns. According to our clinical experience, PCOS patients who became pregnant and were not treated with metformin during the whole pregnancy, showed a higher prevalence of gestational diabetes and SGA newborns, which was improved with metformin treatment. In summary, pregnancy may constitute a period in which an abnormal condition is established or aggravated in the fetus of a PCOS mother. Moreover, PCOS enhanced adverse obstetric and neonatal outcomes.

Improvement of hyperandrogenism and hyperinsulinemia during pregnancy in women with polycystic ovary syndrome: possible effect in the ovarian follicular mass of their daughters.

OBJECTIVE: To evaluate the ovarian function during early infancy in daughters of women with polycystic ovary syndrome (PCOS) treated with metformin throughout pregnancy (PCOSd+M), as a means to reduce androgen and insulin levels, compared with daughters of nontreated PCOS women (PCOSd-M) and daughters of women who belong to a healthy comparison group (HCd). DESIGN: Descriptive and analytic study. SETTING: Unit of endocrinology and reproductive medicine. PATIENT(S): Fifteen PCOSd+M, 23 PCOSd-M, and 35 HCd were studied at 2-3 months of age. INTERVENTION(S): A GnRH analogue test was performed with determinations of gonadotropins, sex steroids, SHBG, and anti-Müllerian hormone (AMH). MAIN OUTCOME MEASURE(S): Differences in AMH levels between PCOSd+M, PCOSd-M and HCd. RESULT(S): AMH and peak E(2) concentrations were significantly higher in PCOSd-M compared with HCd, whereas PCOSd+M exhibited AMH concentrations and peak E(2) levels similar to those observed in HCd. CONCLUSION(S): The improvement of the altered endocrine-metabolic environment of PCOS mothers reduces AMH levels in their daughters, which might reflect a decrease in their follicular mass.

Metabolic and reproductive features before and during puberty in daughters of women with polycystic ovary syndrome.

CONTEXT: A significant proportion of the first-degree female relatives of women with polycystic ovary syndrome (PCOS) may be at risk for developing PCOS. However, it is not known at which stage of pubertal development the hormonal and metabolic abnormalities ensue in PCOS. OBJECTIVE: The aim of the study was to assess the reproductive and metabolic profiles of daughters of women with PCOS (PCOSd) during the peripubertal period, a stage during which the gonadal axis is activated and PCOS may become clinically manifest. DESIGN: Ninety-nine PCOSd [30 prepubertal and 69 pubertal (Tanner II-V)] and 84 daughters of control women (Cd) (20 prepubertal and 64 pubertal) were studied. An oral glucose tolerance test, a GnRH agonist test (leuprolide acetate, 10 microg/kg sc), and a transabdominal ultrasound were performed. Gonadotropins, sex steroids, SHBG, glucose, insulin, and lipids were determined. RESULTS: Both groups had similar chronological ages and body mass index sd scores according to Tanner stage distribution. Ovarian volume and 2-h insulin were significantly higher in PCOSd compared to Cd at all Tanner stages. In Tanner stages IV and V, basal testosterone and poststimulated LH, testosterone, and 17-hydroxyprogesterone concentrations were significantly higher in PCOSd compared to Cd. CONCLUSIONS: Hyperinsulinemia and an increased ovarian volume are present in PCOSd before the onset of puberty and persist during pubertal development. The biochemical abnormalities of PCOS appear during late puberty. Considering the early onset and the nature of the alterations, PCOSd constitute a high-risk group for metabolic and reproductive derangements.

Muerte fetal: experiencia de 10 años en el Hospital Clínico de la Universidad de Chile / Fetal demise: a 10-year experience in Hospital Clínico of the University of Chile

Objetivo: Conocer la tasa de mortalidad fetal intermedia (TMFI) y tardía (TMFT) en la población gestante atendida en un período de 10 años en el Hospital Clínico de la Universidad de Chile. Material y métodos: Estudio descriptivo donde se analizaron los datos de la muertes fetales ocurridas a partir de las 22 semanas o 500 g de peso entre 1994 y 2004. Resultados: La TMFI fue de 1,43/1000 nacidos vivos (NV) y la TMFT fue de 4,28/1000 NV. Las principales etiologías asociadas según su prevalencia fueron: enfermedad materna, patología de anexos ovulares, malformaciones congénitas e hipoxia (el 39, el 36, el 19 y el 10%, respectivamente). Conclusión: La TMFT en este estudio es similar a la nacional (4,3/1000 NV

Objetive: To know Fetal Mortality Rate during ten years in the Hospital Clínico Universidad de Chile. Material and methods: Intermedial and Late Fetal Mortality Rate (IFMR­LFMR) for Hospital Clínico Universidad de Chile for the period between 1994 to 2004 were analyzed. The information was obtained from clinical date. Results: IFMR: 1,43/1000, LFMR 4,28/1000. Causes of intrauterine fetal death were: maternal diseases (39%), placental and funicular accident (36%), structural abnormality (19%) and hypoxia (10%). Conclusion: LFMR in this study is the same that the Chilean reality (4,3/1000) (AU)

Evaluación de un programa de intervención tendiente a disminuir el número de cesáreas / Assessment of an intervention program that tends to decrease number of cesareans

Introducción. En Chile se estimó una tasa de cesáreas del 40%, valor que supera lo recomendado por la organización Mundial de la Salud (OMS) (< 15%). Existen estrategias empleadas por organizaciones de salud para reducir el número de cesáreas potencialmente evitables, utilizando la auditoría médica. El objetivo del estudio fue comparar los efectos de un sistema de auditoría iniciado en 2003 sobre las tasas de cesáreas entre 1997-2002 y 2003-2005. Material y método. El análisis de auditoría se realizó utilizando la propuesta de Robson et al, asignando de forma prospectiva pacientes a una de las categorías por ellos mencionada, mediante una base de datos en File Maker 5.0 entre 2003-2005. Se comparó estos resultados con el período 1997-2002, utilizando la prueba de Chi cuadrado, considerando significativo un valor de p< 0,05. Resultados. En el grupo global de pacientes y en nulíparas no hubo diferencias estadísticamente significativas. Hubo un incremento significativo del número de cesáreas en multíparas (38,1% a 42,4%, p < 0,007), destacando un aumento en embarazo único, de término, con feto en cefálica (33,6% frente a 38,6%, p < 0,002) y en aquellas con cicatriz de cesárea previa (70,1% frente a 81,2%, p < 0,01). Destaca la reducción significativa de cesáreas en embarazo de pretérmino (56,9% a 41,3%, p < 0,000). Conclusiones. Se produjo un aumento de cesáreas en multíparas probablemente por mayor número de pacientes con cicatriz de cesárea previa y no cumplimiento del sistema de auditoría. Es importante poner en práctica el ciclo de auditoría médica para intentar prevenir que nacimientos no complicados se conviertan en complicados, aumentando así el índice de cesárea en casos "evitables"

Introduction. In Chile, the estimated cesarean section rate is 40%, much more than that recommended by the WHO (< 15%). The medical audit cycle is one of the strategies performed to reduce cesarean section rates. The objective of this study was to compare the effect of the introduction of medical audit cycle between two periods: 1997-2002 and 2003-2005. Study design. The audit analysis was conducted using the Robson et al. model, prospectively assigning patients to one of the categories mentioned by him by a data base in the File Maker 5.0 between 2003-2005. These results were compared with the 1997-2002 period, using the Chi square test (p < 0.05). Results. In the group of all women and nulliparous, there was no significant difference between the two periods. A significant increase in the cesarean rate was observed in multiparous women (38.1%-42.4%, p < 0.007) and the group of women primarily responsible for this were those with scarred uterus (70.1-81.2%, p < 0.01) and singleton, cephalic, term pregnancy (33.6%-38.6%, p < 0.002). On the contrary, we evidenced a reduction in the cesarean rate in the group singleton, cephalic preterm pregnancy (56.9%-41.3%, p < 0.000). Conclusion. The cesarean section rate in multiparous increased probably because of a greater number of women with scarred uterus and the non-fulfillment of the medical audit cycle. It is important to maintain an effective audit cycle to prevent increase in avoidable cesarean sections

[X-linked hyper-IGM syndrome associated to sclerosing cholangitis and gallbladder neoplasm: clinical case]. / Síndrome de hiper-IgM asociado a colangitis esclerosante y neoplasia vesicular: caso clínico.

We report a 11 years old male diagnosed as a X-linked hyper-IgM syndrome that presented with recurrent infections and sclerosing cholangitis and later developed a gallbladder cancer. Immunological evaluation showed decreased levels of serum IgG and IgA with elevated levels of IgM. Study of CD40 ligand expression on mitogen activated peripheral blood mononuclear cells revealed total absence of this marker on T lymphocytes. Molecular analysis detected, in the patient and his mother, a nonsense mutation in exon 1 of the transmembrane segment of the CD40 ligand. He also presented elevation of alkaline phosphatases and mild elevation of liver enzymes. Liver biopsy demonstrated the presence of idiopathic sclerosing cholangitis. The patient was started on monthly IVIG therapy at 400 mg/kg, as well as ursodeoxycholic acid and vitamin E, with normalization of his IgG and IgM levels a decrease in the incidence of infections and normalization of liver function. Three years after diagnosis, we detected the presence of polyps inside the gallbladder that were reported at biopsy as adenocarcinoma. He underwent hepatic bisegmentectomy (VI B-V) and local lymphadenectomy.

Mecanismos de acción de anticonceptivos orales: ¿cumplen los ACO de bajas dosis con el objetivo de inhibir la ovulación? / Mechanisms of action of oral contraceptives: they fulfill the ACO of low doses with the objective to inhibit the ovulation?

La inhibición de la ovulación es el principal mecanismo o efecto buscado en los casos de utilización terapéutica o contraceptiva de los anticonceptivos orales (ACO). Los mecanismos de acción secundarios postfertilización tienen reparos éticos para aquellas pacientes que consideran la concepción como el comienzo del desarrollo de la persona humana. Quisimos saber en qué medida se inhibe la ovulación mediante la administración de ACO de bajas dosis, como primera aproximación al problema ético planteado por los efectos postfertilización y para analizar la eficacia terapéutica de los anticonceptivos orales. Se revisa la literatura entre los años 1985 y 2001 y se seleccionan 3 trabajos comparables entre si de los cuales se desprenden los resultados. En un período de seguimiento de 3 meses, las mujeres que ingieren en forma adecuada ACO monofásicos combinados de bajas dosis que contienen 20 µg de etinilestradiol, presentan ovulación demostrada hormonal y ecográficamente en 2.35 por ciento a 8.3 por ciento de las mujeres. Existe una tendencia al aumento de la actividad ovárica y de los diámetros foliculares a medida que transcurre el tiempo de observación. Si el objetivo terapéutico es la anovulación, estas cifras permiten considerar los ACO como terapias adecuadas. Frente a la utilización individual de los ACO en contracepción, las cifras expuestas permitirán abordar en qué medida actúan los mecanismos secundarios y así considerar parámetros más objetivos en el análisis de los aspectos éticos a evaluar por el médico y la paciente