Risk of thrombosis and bleeding in gynecologic noncancer surgery: systematic review and meta-analysis.

OBJECTIVE: This study aimed to provide procedure-specific estimates of the risk for symptomatic venous thromboembolism and major bleeding in noncancer gynecologic surgeries. DATA SOURCES: We conducted comprehensive searches on Embase, MEDLINE, Web of Science, and Google Scholar. Furthermore, we performed separate searches for randomized trials that addressed the effects of thromboprophylaxis. STUDY ELIGIBILITY CRITERIA: Eligible studies were observational studies that enrolled ≥50 adult patients who underwent noncancer gynecologic surgery procedures and that reported the absolute incidence of at least 1 of the following: symptomatic pulmonary embolism, symptomatic deep vein thrombosis, symptomatic venous thromboembolism, bleeding that required reintervention (including re-exploration and angioembolization), bleeding that led to transfusion, or postoperative hemoglobin level <70 g/L. METHODS: A teams of 2 reviewers independently assessed eligibility, performed data extraction, and evaluated the risk of bias of the eligible articles. We adjusted the reported estimates for thromboprophylaxis and length of follow-up and used the median value from studies to determine the cumulative incidence at 4 weeks postsurgery stratified by patient venous thromboembolism risk factors and used the Grading of Recommendations Assessment, Development and Evaluation approach to rate the evidence certainty. RESULTS: We included 131 studies (1,741,519 patients) that reported venous thromboembolism risk estimates for 50 gynecologic noncancer procedures and bleeding requiring reintervention estimates for 35 procedures. The evidence certainty was generally moderate or low for venous thromboembolism and low or very low for bleeding requiring reintervention. The risk for symptomatic venous thromboembolism varied from a median of <0.1% for several procedures (eg, transvaginal oocyte retrieval) to 1.5% for others (eg, minimally invasive sacrocolpopexy with hysterectomy, 1.2%-4.6% across patient venous thromboembolism risk groups). Venous thromboembolism risk was <0.5% for 30 (60%) of the procedures; 0.5% to 1.0% for 10 (20%) procedures; and >1.0% for 10 (20%) procedures. The risk for bleeding the require reintervention varied from <0.1% (transvaginal oocyte retrieval) to 4.0% (open myomectomy). The bleeding requiring reintervention risk was <0.5% in 17 (49%) procedures, 0.5% to 1.0% for 12 (34%) procedures, and >1.0% in 6 (17%) procedures. CONCLUSION: The risk for venous thromboembolism in gynecologic noncancer surgery varied between procedures and patients. Venous thromboembolism risks exceeded the bleeding risks only among selected patients and procedures. Although most of the evidence is of low certainty, the results nevertheless provide a compelling rationale for restricting pharmacologic thromboprophylaxis to a minority of patients who undergo gynecologic noncancer procedures.

Risk of thrombosis and bleeding in gynecologic cancer surgery: systematic review and meta-analysis.

OBJECTIVE: This study aimed to provide procedure-specific estimates of the risk of symptomatic venous thromboembolism and major bleeding in the absence of thromboprophylaxis, following gynecologic cancer surgery. DATA SOURCES: We conducted comprehensive searches on Embase, MEDLINE, Web of Science, and Google Scholar for observational studies. We also reviewed reference lists of eligible studies and review articles. We performed separate searches for randomized trials addressing effects of thromboprophylaxis and conducted a web-based survey on thromboprophylaxis practice. STUDY ELIGIBILITY CRITERIA: Observational studies enrolling ≥50 adult patients undergoing gynecologic cancer surgery procedures reporting absolute incidence for at least 1 of the following were included: symptomatic pulmonary embolism, symptomatic deep vein thrombosis, symptomatic venous thromboembolism, bleeding requiring reintervention (including reexploration and angioembolization), bleeding leading to transfusion, or postoperative hemoglobin <70 g/L. METHODS: Two reviewers independently assessed eligibility, performed data extraction, and evaluated risk of bias of eligible articles. We adjusted the reported estimates for thromboprophylaxis and length of follow-up and used the median value from studies to determine cumulative incidence at 4 weeks postsurgery stratified by patient venous thromboembolism risk factors. The GRADE approach was applied to rate evidence certainty. RESULTS: We included 188 studies (398,167 patients) reporting on 37 gynecologic cancer surgery procedures. The evidence certainty was generally low to very low. Median symptomatic venous thromboembolism risk (in the absence of prophylaxis) was <1% in 13 of 37 (35%) procedures, 1% to 2% in 11 of 37 (30%), and >2.0% in 13 of 37 (35%). The risks of venous thromboembolism varied from 0.1% in low venous thromboembolism risk patients undergoing cervical conization to 33.5% in high venous thromboembolism risk patients undergoing pelvic exenteration. Estimates of bleeding requiring reintervention varied from <0.1% to 1.3%. Median risks of bleeding requiring reintervention were <1% in 22 of 29 (76%) and 1% to 2% in 7 of 29 (24%) procedures. CONCLUSION: Venous thromboembolism reduction with thromboprophylaxis likely outweighs the increase in bleeding requiring reintervention in many gynecologic cancer procedures (eg, open surgery for ovarian cancer and pelvic exenteration). In some procedures (eg, laparoscopic total hysterectomy without lymphadenectomy), thromboembolism and bleeding risks are similar, and decisions depend on individual risk prediction and values and preferences regarding venous thromboembolism and bleeding.

Systematic reviews of observational studies of Risk of Thrombosis and Bleeding in General and Gynecologic Surgery (ROTBIGGS): introduction and methodology.

BACKGROUND: Venous thromboembolism (VTE) and bleeding are serious and potentially fatal complications of surgical procedures. Pharmacological thromboprophylaxis decreases the risk of VTE but increases the risk of major post-operative bleeding. The decision to use pharmacologic prophylaxis therefore represents a trade-off that critically depends on the incidence of VTE and bleeding in the absence of prophylaxis. These baseline risks vary widely between procedures, but their magnitude is uncertain. Systematic reviews addressing baseline risks are scarce, needed, and require innovations in methodology. Indeed, systematic summaries of these baseline risk estimates exist neither in general nor gynecologic surgery. We will fill this knowledge gap by performing a series of systematic reviews and meta-analyses of the procedure-specific and patient risk factor stratified risk estimates in general and gynecologic surgeries. METHODS: We will perform comprehensive literature searches for observational studies in general and gynecologic surgery reporting symptomatic VTE or bleeding estimates. Pairs of methodologically trained reviewers will independently assess the studies for eligibility, evaluate the risk of bias by using an instrument developed for this review, and extract data. We will perform meta-analyses and modeling studies to adjust the reported risk estimates for the use of thromboprophylaxis and length of follow up. We will derive the estimates of risk from the median estimates of studies rated at the lowest risk of bias. The primary outcomes are the risk estimates of symptomatic VTE and major bleeding at 4 weeks post-operatively for each procedure stratified by patient risk factors. We will apply the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach to rate evidence certainty. DISCUSSION: This series of systematic reviews, modeling studies, and meta-analyses will inform clinicians and patients regarding the trade-off between VTE prevention and bleeding in general and gynecologic surgeries. Our work advances the standards in systematic reviews of surgical complications, including assessment of risk of bias, criteria for arriving at the best estimates of risk (including modeling of the timing of events and dealing with suboptimal data reporting), dealing with subgroups at higher and lower risk of bias, and use of the GRADE approach. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42021234119.

Pregnancy and perinatal outcomes after transfer of binucleated or multinucleated frozen-thawed embryos: a case-control study.

Blastomere multinucleation in human embryos is a common phenomenon, but data on its effect on pregnancy outcome and the health of newborns are scarce. In this case-control study, we assessed pregnancy and perinatal outcomes from 136 binucleated and multinucleated frozen-thawed embryo transfer cycles against a control group of 136 non-binucleated and multinucleated frozen embryo transfer cycles. Clinical pregnancy and live birth rates were lower among the case group (29.4% versus 44.1%, P = 0.012; 22.1% versus 36.0%, P = 0.011, respectively), but perinatal outcomes (gestational week at delivery, birth weight, placental weight and occurrence of congenital anomalies) were similar. Live birth rates among patients receiving embryos with multinucleation compared with binucleation was not significantly different (24.7% versus 13.2%). Consequently, frozen-thawed cleavage-stage embryos with bi- or multinucleation have lower than normal but still acceptable implantation potential and ability to produce healthy pregnancies and newborns. The study is limited by its retrospective nature. Time-lapse monitoring would be a more sensitive method of detecting multinucleation. Controls and cases were matched only by age at the time of oocyte retrieval, and other characteristics were only interpreted statistically. Although larger than previously reported, the number of cases is limited.

Clinical course of untreated cervical intraepithelial neoplasia grade 2 under active surveillance: systematic review and meta-analysis.

OBJECTIVE: To estimate the regression, persistence, and progression of untreated cervical intraepithelial neoplasia grade 2 (CIN2) lesions managed conservatively as well as compliance with follow-up protocols. DESIGN: Systematic review and meta-analysis. DATA SOURCES: Medline, Embase, and the Cumulative Index to Nursing and Allied Health Literature (CINAHL) from 1 January 1973 to 20 August 2016. ELIGIBILITY CRITERIA: Studies reporting on outcomes of histologically confirmed CIN2 in non-pregnant women, managed conservatively for three or more months. DATA SYNTHESIS: Two reviewers extracted data and assessed risk of bias. Random effects model was used to calculate pooled proportions for each outcome, and heterogeneity was assessed using I2 statistics. MAIN OUTCOME MEASURES: Rates of regression, persistence, or progression of CIN2 and default rates at different follow-up time points (3, 6, 12, 24, 36, and 60 months). RESULTS: 36 studies that included 3160 women were identified (seven randomised trials, 16 prospective cohorts, and 13 retrospective cohorts; 50% of the studies were at low risk of bias). At 24 months, the pooled rates were 50% (11 studies, 819/1470 women, 95% confidence interval 43% to 57%; I2=77%) for regression, 32% (eight studies, 334/1257 women, 23% to 42%; I2=82%) for persistence, and 18% (nine studies, 282/1445 women, 11% to 27%; I2=90%) for progression. In a subgroup analysis including 1069 women aged less than 30 years, the rates were 60% (four studies, 638/1069 women, 57% to 63%; I2=0%), 23% (two studies, 226/938 women, 20% to 26%; I2=97%), and 11% (three studies, 163/1033 women, 5% to 19%; I2=67%), respectively. The rate of non-compliance (at six to 24 months of follow-up) in prospective studies was around 10%. CONCLUSIONS: Most CIN2 lesions, particularly in young women (<30 years), regress spontaneously. Active surveillance, rather than immediate intervention, is therefore justified, especially among young women who are likely to adhere to monitoring. SYSTEMATIC REVIEW REGISTRATION: PROSPERO 2014: CRD42014014406.

Long-term Impact of Mode of Delivery on Stress Urinary Incontinence and Urgency Urinary Incontinence: A Systematic Review and Meta-analysis.

CONTEXT: Stress urinary incontinence (SUI) and urgency urinary incontinence (UUI) are associated with physical and psychological morbidity, and large societal costs. The long-term effects of delivery modes on each kind of incontinence remain uncertain. OBJECTIVE: To investigate the long-term impact of delivery mode on SUI and UUI. EVIDENCE ACQUISITION: We searched Medline, Scopus, CINAHL, and relevant major conference abstracts up to October 31, 2014, including any observational study with adjusted analyses or any randomized trial addressing the association between delivery mode and SUI or UUI ≥1 yr after delivery. Two reviewers extracted data, including incidence/prevalence of SUI and UUI by delivery modes, and assessed risk of bias. EVIDENCE SYNTHESIS: Pooled estimates from 15 eligible studies demonstrated an increased risk of SUI after vaginal delivery versus cesarean section (adjusted odds ratio [aOR]: 1.85; 95% confidence interval [CI], 1.56-2.19; I(2)=57%; risk difference: 8.2%). Metaregression demonstrated a larger effect of vaginal delivery among younger women (p=0.005). Four studies suggested no difference in the risk of SUI between spontaneous vaginal and instrumental delivery (aOR: 1.11; 95% CI, 0.84-1.45; I(2)=50%). Eight studies suggested an elevated risk of UUI after vaginal delivery versus cesarean section (aOR: 1.30; 95% CI, 1.02-1.65; I(2)=37%; risk difference: 2.6%). CONCLUSIONS: Compared with cesarean section, vaginal delivery is associated with an almost twofold increase in the risk of long-term SUI, with an absolute increase of 8%, and an effect that is largest in younger women. There is also an increased risk of UUI, with an absolute increase of approximately 3%. PATIENT SUMMARY: In this systematic review we looked for the long-term effects of childbirth on urinary leakage. We found that vaginal delivery is associated with an almost twofold increase in the risk of developing leakage with exertion, compared with cesarean section, with a smaller effect on leakage in association with urgency.

[Premature ovarian insufficiency--a threat to a woman's health?]. / Munasarjojen toiminnan ennenaikainen hiipuminen--uhka naisen terveydelle?

Premature ovarian insufficiency (POI) is characterized by cessation of menstruation and elevated follicle stimulating hormone levels before the age of 40. Patients may have hypoestrogenic symptoms such as hot flushes. Most cases are idiopathic but the underlying mechanisms can be genetic, autoimmune-based or iatrogenic. Long-term deprivation of estrogen has serious implications for cardiovascular health and bone density. Early impaired fertility and infertility may be the main concerns for the patients. Hormone replacement therapy until the normal age of menopause is recommended, even though the scientific evidence is inadequate. The only proven method of achieving pregnancy in these patients is by ovum donation.

Molecular profiling of polycystic ovaries for markers of cell invasion and matrix turnover.

OBJECTIVE: To study gene expression profiles of connective tissue components in polycystic ovaries using complementary deoxyribonucleic acid (cDNA) array technology. DESIGN: Descriptive study of normal and polycystic human ovarian biopsy samples analyzed by cDNA array hybridizations. SETTING: Experimental laboratory research. PATIENT(S): Eight women with polycystic ovary syndrome (PCOS) and two normally cycling women treated with electrocauterization and hysterectomy, respectively. INTERVENTIONS: Ovarian biopsy samples. MAIN OUTCOME MEASURE(S): Expression levels of 588 genes involved in cellular invasion, extracellular matrix (ECM) turnover, and cell-ECM interactions in polycystic ovaries. RESULT(S): A majority of the 30 genes down-regulated in PCOS ovaries represented those related to cell adhesion and motility, as well as angiogenesis, followed by regulators of cell cycle and growth. The 14 up-regulated genes represented those regulating cell fate and development, growth factors, cytokines, chemokines, and cell-cell interactions. Of the 44 transcripts exhibiting marked changes in the cDNA array analysis, only one - proliferating cell nuclear antigen messenger ribonucleic acid (PCNA mRNA) - was systematically down-regulated; 2 transcripts, for CDC27HS protein and CD9 antigen, were down-regulated in 7 out of 8 PCOS samples. CONCLUSION(S): The present data suggest that gene expression profiling may become a useful tool to classify PCOS patients into subgroups with different etiologies. Genome-wide expression profiling using microarrays should be performed to better understand the metabolic derangement(s) in PCOS.

Altered expression of genes involved in the production and degradation of endometrial extracellular matrix in patients with unexplained infertility and recurrent miscarriages.

During the secretory phase of the menstrual cycle, the composition of extracellular matrix (ECM) in endometrium changes to favour implantation. In the present study, we have analysed whether some cases of unexplained infertility and recurrent abortions could be explained by abnormal production or turnover of endometrial ECM. Comparison of mRNA levels of a panel of collagens, matrix metalloproteinases (MMP), tissue inhibitors of metalloproteinases (TIMP) and cathepsins in the samples revealed higher levels of type I collagen, MMP-2 and cathepsin H and decreased levels of TIMP-3 mRNA in mid-secretory endometrium of patients with unexplained infertility and/or recurrent miscarriages when compared with normal mid-secretory endometrium. Furthermore, changes were also seen in the levels of type I collagen and TIMP-3 mRNA between the proliferative and mid-secretory phases of normal endometrium. The results suggest an altered ECM turnover in the endometrium of patients with fertility disorders prior to implantation.

Characterization of the murine Timp4 gene, localization within intron 5 of the synapsin 2 gene and tissue distribution of the mRNA.

Tissue inhibitor of matrix metalloproteinases type 4 (TIMP-4), the newest member in the mammalian TIMP family of inhibitors of matrix metalloproteinases (MMPs), differs from the other three TIMPs by its restricted expression pattern. This suggests that TIMP-4 could play a role in tissue-specific regulation of extracellular matrix (ECM) turnover. To define this role, modulation of TIMP-4 production by overexpression, aberrant expression and inactivation of the Timp4 gene in transgenic mice should be performed. In preparation for such experiments we have cloned and characterized the murine Timp4 gene and determined the tissue distribution of its mRNA in mice. The gene spans 7.1 kb, consists of five exons and shares considerable homology with the other Timp genes. The gene is located on mouse chromosome 6 in an antisense orientation between exons 5 and 6 of the mouse synapsin 2 (Syn2) gene. A similar organization is common to all four human/mouse TIMP and SYN genes and to the single synapsin/Timp locus in Drosophila. The highest levels of TIMP-4 mRNA were seen in postnatal mouse heart, ovary and brain. Determination of the spatial expression pattern of TIMP-4 mRNA by in situ hybridization in the heart revealed a diffuse distribution in cardiac muscle cells. In the ovary, cyclic variation was observed in TIMP-4 mRNA levels. In situ hybridization demonstrated the strongest expression of TIMP-4 mRNA in the corpus luteum. The data suggest that TIMP-4 plays a role in the normal physiology of the heart and the ovary, most likely related to maintenance of the delicate balance between MMPs and TIMPs.