Safety of non-steroidal anti-inflammatory drugs in postpartum period in women with hypertensive disorders of pregnancy: systematic review and meta-analysis.

OBJECTIVE: To assess the effect of non-steroidal anti-inflammatory drugs (NSAIDs) on blood pressure when administered for postpartum analgesia in women with hypertensive disorders of pregnancy. METHODS: MEDLINE, Scopus, CENTRAL, Clinicaltrials.gov and Google Scholar databases were searched systematically from inception to 5 December 2019 for studies evaluating the safety of postpartum NSAIDs in women with any gestational hypertensive disorder. Randomized controlled trials (RCTs) and cohort studies were eligible for inclusion. Case-control studies, case series and case reports were excluded. The primary outcomes of interest were the incidence of severe hypertension and systolic, diastolic and mean arterial blood pressure. Pooled estimates were obtained by fitting a random-effects statistical model. The quality of evidence was assessed according to Grading of Recommendations, Assessment, Development and Evaluations (GRADE) guidelines. RESULTS: Ten studies were included, comprising five RCTs and five retrospective cohort studies and involving a total of 1647 women. All studies were evaluated qualitatively and eight of them were included in the quantitative meta-analysis. Administration of NSAIDs was not associated with a significantly higher risk of severe postpartum hypertension (odds ratio, 1.52 (95% CI, 0.77-3.01)). Similarly, no significant differences were found in postpartum systolic blood pressure (mean difference (MD), -3.03 mmHg (95% CI, -6.21 to 0.15 mmHg)) and mean arterial pressure (MD, -0.38 mmHg (95% CI, -1.88 to 1.11 mmHg)) between women who received NSAIDs and those who did not, whereas postpartum diastolic blood pressure was marginally lower in women treated with NSAIDs (MD, -2.28 mmHg (95% CI, -4.44 to -0.13 mmHg)). The same effects were observed when studies with a large sample size, RCTs, women with severe pre-eclampsia and studies using ibuprofen as the study drug and acetaminophen as the control treatment were examined separately. The credibility of evidence was judged to be very low according to GRADE, owing to concerns about study limitations, inconsistency and imprecision. CONCLUSIONS: This meta-analysis suggests that postpartum administration of NSAIDs is not associated with elevated blood pressure in women with hypertensive disorders of pregnancy. However, the existing evidence is of very low quality, thus future large-scale RCTs are warranted to verify the safety of postpartum NSAIDs in this population. Copyright © 2020 ISUOG. Published by John Wiley & Sons Ltd.

Agenesis of ductus venosus in sequential first and second trimester screening.

OBJECTIVE: The goal of this study is to evaluate the potential of first trimester (FT) screening in the diagnosis of agenesis of the ductus venosus (ADV) and to study its prevalence in a low-risk population, the associated conditions, and pregnancy outcome. METHOD: Prospective, sequential screening study at two tertiary units with morpho-functional evaluation of the ductus venosus during the first and second trimester screening. We quantified the FT detection rate, prevalence, and associated conditions: umbilical shunting type, concomitant anomalies, and outcome. RESULTS: In 6114 consecutive pregnancies, we identified 11 cases of ADV. Ten (91%) were identified during the FT examination. The prevalence was 1 in 556, similar for both centers (1/478 vs. 1/691). Major structural defects and fetal effusions were detected in 8 (73%). twenty two percent had a major chromosomal abnormality. In 3 cases, the anomaly was isolated and had normal outcome, independent of liver by-pass, caliber of the shunt, and NT thickness. CONCLUSIONS: Agenesis of the ductus venosus can be detected during FT. The early detection of ADV is important given its high association with major abnormalities.

Improved detection rate of structural abnormalities in the first trimester using an extended examination protocol.

OBJECTIVE: To assess the potential of first-trimester sonography in the detection of fetal abnormalities using an extended protocol that is achievable with reasonable resources of time, personnel and ultrasound equipment. METHODS: This was a prospective two-center 2-year study of 5472 consecutive unselected pregnant women examined at 12 to 13 + 6 gestational weeks. Women were examined using an extended morphogenetic ultrasound protocol that, in addition to the basic evaluation, involved a color Doppler cardiac sweep and identification of early contingent markers for major abnormalities. RESULTS: The prevalence of lethal and severe malformations was 1.39%. The first-trimester scan identified 40.6% of the cases detected overall and 76.3% of major structural defects. The first-trimester detection rate (DR) for major congenital heart disease (either isolated or associated with extracardiac abnormalities) was 90% and that for major central nervous system anomalies was 69.5%. In fetuses with increased nuchal translucency (NT), the first-trimester DR for major anomalies was 96%, and in fetuses with normal NT it was 66.7%. Most (67.1%) cases with major abnormalities presented with normal NT. CONCLUSIONS: A detailed first-trimester anomaly scan using an extended protocol is an efficient screening method to detect major fetal structural abnormalities in low-risk pregnancies. It is feasible at 12 to 13 + 6 weeks with ultrasound equipment and personnel already used for routine first-trimester screening. Rate of detection of severe malformations is greater in early- than in mid-pregnancy and on postnatal evaluation. Early heart investigation could be improved by an extended protocol involving use of color Doppler.

Maternal age as a predictive factor of pre-term birth. An epidemiological study from 1999 to 2008 in Greece.

The aim of the study was to estimate the risk of pre-term birth in women giving birth in Greece in different age groups. Data about women giving birth in Greece were retrieved from the Hellenic Vital Statistics covering the years from 1999 to 2008. Relative risk using χ(2) contingency tables was estimated among maternal age groups formed. These groups included mothers < 15 years of age, 15-19, 20-34 (used as a control group) and women > 34 (35-39, 40-44, 45-49 and ≥ 50) years of age. Relative risk of each age group was compared with mothers 20-34 years of age. A total of 1,069,413 valid births were included in the study and 72,156 of them were pre-term (6.75% of total count). Results exhibit a 'U'-shaped distribution of risk. Higher risk of pre-term birth is noted in the groups of < 15 years (Pearson χ(2) = 14.964, p < 0.001, risk = 1.569, CI = 1.249-1.970) and above 34 years of age (Pearson χ(2) = 2991.26, p < 0.001, risk = 1.572, CI = 1.546-1.597). For older women, a steep rise in the relative risk for pre-term birth was noted beyond the 40-44 years of age group. Finally, of interest is the fact that 'late' pre-terms (34-36 gestational weeks) account for most of the pre-term birth in mothers beyond 34 years of age.

VEGF directly suppresses activation of T cells from ascites secondary to ovarian cancer via VEGF receptor type 2.

BACKGROUND: Vascular endothelial growth factor action in tumour angiogenesis is well characterised; nevertheless, it functions as a key element in the promotion of the immune system's evasion by tumours. We sought to investigate the possible direct effect of VEGF on T-cell activation and through which type of VEGF receptor it exerts this effect on cells isolated from ovarian cancer patients' ascites. METHODS: T cells isolated from the ascites of ovarian cancer patients were cultured with anti-CD3 and IL-2, with or without VEGF for 14 days and the number of viable T cells was counted. Cytotoxic activity of cultured T cells and expression of VEGF receptor-2 (VEGFR-2), was assayed. RESULTS: The addition of VEGF in cultures significantly reduced the number and proliferation rate of T cells in a dose-dependent manner and CD3(+) T cells expressed VEGFR-2 on their surface upon activation. Experiments with specific anti-VEGFR-2 antibodies revealed that the direct suppressive effect of VEGF on T-cell proliferation is mediated by VEGFR-2. We also showed that VEGF significantly reduced the cytotoxic activity of T cells. CONCLUSION: Our study showed that ascites-derived T cells secrete VEGF and express VEGFR-2 upon activation. Vascular endothelial growth factor directly suppresses T-cell activation via VEGFR-2.

Fetal MRI: is it really helpful?

OBJECTIVE: The aim of this study is to emphasize on the diagnostic effectiveness of fetal MRI that led to increased utilization in fetal medicine as well as its value in prognosis and decision making in the modern obstetric practice. METHODS: One hundred five (n = 105) pregnant women were referred for a fetal MRI examination after a high detailed ultrasound examination revealed a fetal abnormality. Fetal MRI was performed using 1, 5 Tesla units, with T1, T2-weighted and diffusion-weighted images. The findings were analyzed in comparison to the previous ultrasound findings, according to the fetal organ affected and the value of the MRI for therapeutic decision making was addressed. A statistical analysis was performed. RESULTS: The fetal MRI provides a more accurate diagnosis compared to ultrasound examination, and when the ultrasound detects fetal anomalies, the MRI can efficiently either confirm or reject the finding, proving its high value for prenatal diagnosis and perinatal and management. The sensitivity, specificity and positive predictive value of fetal MRI as a screening tool approaches 100%. CONCLUSIONS: Despite the fact that ultrasound is the method of choice for fetal screening, MRI can add up significantly to the diagnosis and management of congenital abnormalities and the indications for MRI continue to increase as new sequences and shorter acquisition times evolve.

Safety of hormone replacement therapy in gynaecological cancer survivors.

Therapy for endometrial, ovarian and cervical cancer in young women can cause sudden onset of intense menopausal symptoms, such as hot flushes, emotional disorders and sexual dysfunction. In order to overcome these unpleasant and sometimes severe symptoms, hormone replacement therapy (HRT) has proven to be very effective. However, its safety remains controversial. We reviewed English literature and examined whether administration of HRT in this specific population is related with more recurrences and worse prognosis. Current scientific data, comprising mainly retrospective studies, suggest that recurrence rates and survival are comparable between HRT users and non-users. However, large randomised trials are missing and definitive conclusions cannot be drawn. Gynaecological cancer survivors using HRT, although they seem to have little if any risk for recurrence, should be correctly informed about the lack of strong evidence.

PRKAR1A gene analysis and protein kinase A activity in endometrial tumors.

PRKAR1A codes for the type 1a regulatory subunit (RIα) of the cAMP-dependent protein kinase A (PKA), an enzyme with an important role in cell cycle regulation and proliferation. PKA dysregulation has been found in various tumors, and PRKAR1A-inactivating mutations have been reported in mostly endocrine neoplasias. In this study, we investigated PKA activity and the PRKAR1A gene in normal and tumor endometrium. Specimens were collected from 31 patients with endometrial cancer. We used as controls 41 samples of endometrium that were collected from surrounding normal tissues or from women undergoing gynecological operations for other reasons. In all samples, we sequenced the PRKAR1A-coding sequence and studied PKA subunit expression; we also determined PKA activity and cAMP binding. PRKAR1A mutations were not found. However, PKA regulatory subunit protein levels, both RIα and those of regulatory subunit type 2b (RIIß), were lower in tumor samples; cAMP binding was also lower in tumors compared with normal endometrium (P<0.01). Free PKA activity was higher in tumor samples compared with that of control tissue (P<0.01). There are significant PKA enzymatic abnormalities in tumors of the endometrium compared with surrounding normal tissue; as these were not due to PRKAR1A mutations, other mechanisms affecting PKA function ought to be explored.

Three-dimensional power Doppler ultrasound for the study of cervical cancer and precancerous lesions.

OBJECTIVE: To evaluate the blood flow characteristics of the cervix in normal women and in women with cervical precancerous lesions or cervical cancer. METHODS: We studied 165 women with three-dimensional power Doppler ultrasound (3D-PDU), of whom 71 had cervical cancer, 61 had precancerous lesions and 33 were healthy controls. The cervix was manually traced in the stored volumes using 15° rotation steps and the following 3D-PDU indices were calculated: vascularization index (VI), flow index (FI) and vascularization flow index (VFI). These indices were compared among the study groups and were also correlated with features of the precancerous lesions group and cancer group. RESULTS: The three indices were all statistically significantly higher in the cervical cancer group and precancerous lesions group than in controls (P < 0.001). In addition, significantly higher values of all indices were found in the cervical cancer group than in the precancerous lesions group (P < 0.001). Further analysis according to patient characteristics in the cancer group showed that VI, FI and VFI were not significantly different in relation to grade, histology, presence of positive lymph nodes or lymphovascular space involvement (P > 0.05). However, VI was significantly higher in patients with Stages IIIB-IV cancer than in patients with less advanced disease (P = 0.045). In the cervical cancer group there was a significant positive correlation between 3D-PDU indices and cervical volume. CONCLUSION: 3D-PDU assessment of the cervix reveals significant differences in all indices studied between women with cervical precancerous lesions or cancer and healthy women. In women with cervical cancer, an advanced stage is associated with higher VI, but 3D-PDU indices are not related to other pathological characteristics.

Regeneration of uterine cervix at 6 months after large loop excision of the transformation zone for cervical intraepithelial neoplasia.

OBJECTIVE: To sonographically investigate cervical regeneration 6 months after large loop excision of the transformation zone (LLETZ) conisation for cervical intraepithelial neoplasia (CIN) pathology. DESIGN: Prospective observational study. SETTING: University Hospital setting. POPULATION: Women having LLETZ conisation for intraepithelial lesions in response to abnormal Papanicolaou smears or colposcopic findings. METHODS: Cervical dimensions were estimated before conisation and at 6 months with three-dimensional sonography and use of vocal™ software. Cone depth was measured using a ruler before fixation, and cone volume was measured using a volumetric tube and the fluid displacement technique. Cervical regeneration was sonographically estimated. MAIN OUTCOME MEASURES: Correlation of cervical volume regeneration with percentage of initial cervical volume excised and remaining cervical tissue immediately after conisation. RESULTS: A cohort of 112 women were initially recruited over a 2-year period and 73 women presented for ultrasound follow up at 6 months. Multivariate linear regression analysis showed that for women matched for age and initial cervical volume, if cervical volume excised was increased by 1% then regeneration of tissue deficit at the cervical crater was reduced by 1.37%. There also seemed to be a cutoff point suggesting that when >14% of initial cervical volume was excised, the tissue deficit at the cervical crater at 6 months was restored by <75% and there was >25% of remaining tissue deficit. CONCLUSIONS: Cervical regeneration at 6 months after excision is dependent on the percentage of initial cervical volume excised and on the remaining cervical tissue immediately after conisation. The greater the cone and the less cervical tissue remaining, the less the degree of cervical regeneration achieved.

Exercise and sedentary habits among adolescents with PCOS.

STUDY OBJECTIVE: The purpose of this study was the recording of physical activity and sedentary habits of adolescents with polycystic ovarian syndrome (PCOS). METHODS: We performed a structured interview to assess the level of physical activity and sedentary habits of girls with PCOS. We used a group of healthy adolescents as controls. All girls had their age, height, weight, hip and waist circumference measured and their BMI calculated. RESULTS: 81 girls (35 with PCOS and 46 controls) participated in the study. Girls with PCOS engaged in physical activities less than controls. Even when they did, the frequency and intensity of exercise was less. Also, girls with PCOS were less likely to be aware of the positive effects of exercise on their health. Girls in both groups were sedentary in excess of the 4 hours per day limit, which has been linked with obesity. CONCLUSION: Healthy teenagers were involved in a sporting activity more often and more frequently than the PCOS group. Athletic and sedentary habits of adolescents with PCOS may interact with other factors leading to obesity.

KISS1/KISS1R expression in eutopic and ectopic endometrium of women suffering from endometriosis.

BACKGROUND: The KISS1/KISS1R system has been implicated in the physiology of reproduction and many studies have documented the stimulatory effect of kisspeptin on Gonadotropin-releasing Hormone (GnRH) and gonadotropin secretion. In addition, the KISS1/KISS1R system has been implicated in several pathophysiological processes, including cancer. MATERIALS AND METHODS: We examined the pattern of KISS1 and KISS1R expression in eutopic and ectopic endometrium tissues which were obtained from 24 women suffering from endometriosis and 16 control women who underwent laparoscopic excision for other benign gynecological diseases. RESULTS: Significant KISS1R expression was detected in 10 out of the 24 samples of eutopic endometrial biopsies of women suffering from endometriosis, while their matched biopsies of ectopic endometrial lesions did not reveal any KISS1R expression. KISS1R expression was not detected in the endometrial biopsies of control women. In addition, KISS1 expression was not detected in practically any the endometrial tissues of either control women or women with endometriosis. CONCLUSION: The expression of KISS1R in 10/24 samples of human endometrial biopsies of women suffering from endometriosis and the loss of its expression in the samples of matched ectopic endometrial tissues, suggests that the KISS1/KISS1R system may play a role in the pathophysiology of endometriosis only for a particular group of patients. Since KISS1 is not expressed by the endometrium and endometriotic tissue, it is conceivable that the activation of KISS1R in this particular group is mediated by KISS1 expression by non-endometrial tissues (endocrine action).

ESR1, ESR2 and FSH receptor gene polymorphisms in combination: a useful genetic tool for the prediction of poor responders.

PURPOSE: Previous studies in humans concluded that a multigenic model including specific FSHR, ESR1 and ESR2 genotype patterns may partially explain the poor response to FSH. The aim of our study is to analyse three different loci -polymorphisms in ESR1 Pvu II, ESR2 Rsa I and Ser680Asn FSH receptor gene- in a Greek population and their involvement in stimulation outcome and pregnancy rates. METHODS: Each locus was studied alone, and in combination with the others. We performed both restriction fragment length polymorphism analysis and real-time polymerase chain reaction. A total of 109 normally ovulating female patients underwent IVF or ICSI. RESULTS: Studying each locus alone, no significant results were drawn for ESR1 and ESR2 genes. Concerning the FSHR polymorphism, the women carrying the AA variant presented higher total amount of gonadotrophins used (P=0,048) and tended to have higher number of stimulation days (P=0,057). Considering the ESR1 and FSHR gene polymorphisms in combination, the TC/SA combination presents the highest number of pregnancies in poor responders group (3/4 pregnancies carried this genotype), in good responders group (4/12 pregnancies carried this genotype) and in the total population (10/26 pregnancies carried this genotype). Except the CC/AA combination, all other genotype combinations presented incidence of pregnancy, with TC/SA having the highest incidence. The CC/AA genotype presents the worst profile of ovulation induction, confirming a poor responder profile: the total amount of gonadotrophins used was highest in CC/AA group (P < 0,05). The peak E2, the number of follicles and of retrieved oocytes and the pregnancy rate were significantly lower (P < 0,05). This genotype combination seems to be over-presented in the poor responders group in a statistically significant way (P=0,038). Women with CC/AA combination have 1,5-2,4 times more risk to be poor responders in comparison with women that do not carry that combination. CONCLUSION: This study supports the hypothesis that a multigenic model, including the well studied ESR1 and FSHR genes is involved in the controlled ovarian stimulation outcome indicating that the CC/AA genotype presents the worst ovulation induction profile, while the TC/SA genotype presents the higher number of pregnancies in our population.

Prognostic evaluation of tumour type and other histopathological characteristics in advanced epithelial ovarian cancer, treated with surgery and paclitaxel/carboplatin chemotherapy: cell type is the most useful prognostic factor.

AIM: Ovarian carcinomas have been classified into types I and II according to the hypothesised mode of carcinogenesis and molecular characteristics. The prognostic significance of this classification has not been studied. PATIENTS AND METHODS: Five hundred and sixty-eight patients with histologically confirmed, ovarian, fallopian tube or peritoneal carcinomas, international federation of gynecology and obstetrics (FIGO) stages IIC-IV, treated with paclitaxel/platinum following cytoreductive surgery, were included in this analysis. Type I included low-grade serous, mucinous, endometrioid and clear-cell and type II high-grade serous, unspecified adenocarcinomas and undifferentiated carcinomas. RESULTS: Median overall survival (OS) was 49 months for type I versus 45 for type II (p=0.576). In contrast to type II, there was considerable prognostic heterogeneity among the subtypes included in type I. Cox regression analysis showed that cell-type classification: low-grade serous, mucinous, endometrioid, clear-cell, type II (high-grade serous, unspecified adenocarcinomas, undifferentiated carcinoma) was an independent predictor of survival (respective median OS 121 versus 15 versus 64 versus 29 versus 45 months, p=0.003). On the contrary, histopathological subtype or tumour type (I versus II) did not offer additional prognostic information. CONCLUSION: The proposed model of ovarian tumourigenesis does not reflect tumour behaviour in advanced disease. Tumour-cell type is the most relevant histopathological prognostic factor in advanced ovarian cancer treated with platinum/paclitaxel.

Neuroimaging parameters in early open spina bifida detection. Further benefit in first trimester screening?

OBJECTIVE: Morphological investigation of the central nervous system (CNS) in fetuses with positive markers for open spina bifida (OSB) detection, visualized by ultrasound during the first trimester of pregnancy. MATERIALS AND METHODS: Data from fetuses that underwent routine first trimester ultrasound scan in our center during September 2007-March 2011 and presented abnormal aspects of the fourth ventricle, also referred as intracranial translucency (IT), provided the morphological support to evaluate CNS features. A neuro-histological study of posterior cerebral fossa illustrated anatomical features of the structures involved in the sonographic first trimester detection of neural tube defects. RESULTS: Abnormal IT aspects were found in OSB cases examined in the first trimester, but also in other severe cerebral abnormalities. Brain stem antero-posterior diameter (BS) and brain stem to occipital bone (BSOB) ratio may be more specific for OSB detection. Correlations between histological aspects of posterior brain fossa and ultrasound standard assessment have been made; highlighting the anatomical features involved by the new techniques developed for OSB early detection. CONCLUSIONS: Preliminary results show that modern sonographic protocols are capable to detect abnormalities in the morphometry of the posterior brain. First trimester fourth ventricle abnormalities should be followed by careful CNS evaluation because are likely to appear in OSB affected fetuses, but also in other CNS severe anomalies; in such cases, normal BS and BSOB ratio may serve as indirect argument for spine integrity, if specificity is confirmed in large series of fetuses.

Causes of infertility in men with Down syndrome.

Men with Down syndrome are considered as infertile although the causes of infertility are not known in detail yet. Although this constitutes a general rule there are three confirmed cases of parenting by fathers with Down syndrome. Many investigators have addressed the causes of infertility and their studies indicate that the causes may be hormonal deficits, morphological alterations of the gonads, abnormal spermatogenesis, psychological and social factors related to the mental retardation. It is obvious that the extra chromosome 21 has a detrimental direct and indirect effect on the reproductive capacity of the affected male patient. But the definite cause of the insufficient and inadequate spermatogenesis remains to be discovered.

Prognostic factors for early-stage epithelial ovarian cancer, treated with adjuvant carboplatin/paclitaxel chemotherapy: a single institution experience.

OBJECTIVE: Early-stage epithelial ovarian cancer represents a prognostically heterogenous group. We studied prognostic factors in patients treated with adjuvant paclitaxel/carboplatin chemotherapy. METHODS: Data was extracted from 147 patients with FIGO stage IA/IB, grade 2/3 or stage IC/IIA (any grade) who underwent primary surgery followed by paclitaxel/carboplatin chemotherapy. RESULTS: Median follow-up was 88 months. Ten-year relapse-free (RFS) and disease-specific survival (DSS) were: 81% (95% confidence interval [CI]: 73-89) and 81% (95% CI: 73-89). On multivariate analysis, non serous histology was associated with reduced risk for RFS (0.294, 95% CI: 0.112-0.577, p=0.001) and DSS (0.194, 95% CI: 0.075-0.504, p=0.001), while high-risk category (stage IC/IIA and grade 2/3) with increased risk for RFS (3.989, 95% CI: 1.189-13.389, p=0.009) and DSS (3.989, 95% CI: 1.064-16.386, p=0.038). The combination of histology and grade identified 3 groups with distinctly different 10-year RFS and DSS rates (p<0.001): grade 1 (100% and 100%), non-serous grade 2/3 (83% and 86%) and serous grade 2/3 (60% and 60%). CONCLUSIONS: Serous histology is an adverse prognostic factor in early-stage ovarian cancer treated with adjuvant paclitaxel/carboplatin. Risk stratification according to histology and grade is a useful discriminator of prognosis and can be used in the design of future studies.