Uterine rupture during pregnancy: The URIDA (uterine rupture international data acquisition) study.

OBJECTIVE: To describe the characteristics and peripartum outcomes of patients diagnosed with uterine rupture (UR) by an observational cohort retrospective study on 270 patients. METHODS: Demographic information, surgical history, symptoms, and postoperative outcome of women and neonates after UR were collected in a large database. The statistical analysis searched for correlation between UR, previous uterine interventions, fibroids, and the successive perinatal outcomes in women with previous UR. RESULTS: Uterine rupture was significantly associated with previous uterine surgery, occurring, on average, at 36 weeks of pregnancy in women also without previous uterine surgery. UR did not rise exponentially with an increasing number of uterine operations. Fibroids were related to UR. The earliest UR occurred at 159 days after hysteroscopic myomectomy, followed by laparoscopic myomectomy (251 days) and laparotomic myomectomy (253 days). Fertility preservation was feasible in several women. Gestational age and birth weight seemed not to be affected in the subsequent pregnancy. CONCLUSION: Data analysis showed that previous laparoscopic and abdominal myomectomies were associated with UR in pregnancy, and hysteroscopic myomectomy was associated at earlier gestational ages. UR did not increase exponentially with an increasing number of previous scars. UR should not be considered a contraindication to future pregnancies.

Laparoscopic Intracapsular Myomectomy in Women 40 Years Old and Over with Symptomatic Uterine Fibroids. A Pilot Study.

Authors evaluated the impact of laparoscopic intracapsular myomectomy (LIM) in women 40 years of age and over with desire of future fertility compared with medical management of symptomatic fibroids, by a prospective cohort study in University affiliated Hospitals. This study includes a cohort of women 40 years of age and older with symptomatic intramural fibroids with desire of future fertility. Women with symptomatic fibroid uterus were offered to undergo LIM or medical management. They were encouraged to attempt conception either spontaneously or by assisted reproductive technology (ART) according to their individual preference. All women were followed for 2 years. Fibroid characteristics, pre- and post-surgical variables, including surgical complications, days of hospitalization, pregnancy rate, and obstetrical outcomes were collected. A total of 100 patient were included in the analysis. Fifty patients were assigned to the LIM group and 50 to the medical treatment group (MT). Groups were similar regarding age (43.5 ± 2.4 and 43.5 ± 2.4, p = 0.99), body mass index (23.8 ± 3.1 and 24.2 ± 3.1, p = 0.54), parity (0.46 ± 0.09 and 0.58 ± 0.09, p = 0.37), fibroid number (1.38 ± 0.6 and 1.46 ± 0.6, p = 0.53), and fibroid size (5.92 ± 1.62 cm vs. 5.94 ± 1.49 cm, p = 0.949). Of the patients who underwent LIM, 62% conceived within the study period compared with 56% in the control group ( p = 0.54). Pregnancy was achieved by ART in 44% of the patients of the LIM group and 30% in control group. There was no significant difference in pregnancy rates among the two groups regarding spontaneous pregnancy rate ( p = 0.332), nor in pregnancies obtained by ART with own eggs ( p = 0.146) and oocyte or embryo donation ( p = 0.821). The take home baby rate was 65% (20/31) in the LIM group and 61% (17/28) in the control group ( p = 0.7851). Both groups had similar rate of miscarriage ( p = 0.748). Patients 40 years old and over with symptomatic fibroid uterus who undergo LIM have similar subsequent fertility and obstetrical outcomes than women treated with medical management. LIM has no detrimental impact on future fertility in women 40 years old and over.

Pathways Involved in Premature Ovarian Failure: A Systematic Review of Experimental Studies.

Premature ovarian failure (POF), which may be undetectable for a long time, is associated with impaired fertility. The mechanisms involved in the pathogenesis of POF as well as the concomitant treatments are still unclear. Although many data exist, mainly produced by the study of transgenic animals under various experimental conditions, they remain fragmented. A systematic review of the pathways involved in premature ovarian failure was conducted. Data extraction was performed from experimental studies until 2019. The molecular processes and their correlation with the follicular developmental stage have been described. Furthermore, the effects in other cells, such as oocytes, granulosa and theca cells have been reported. An overall estimation was conducted.

Adrenergic and Cholinergic Uterine Innervation and the Impact on Reproduction in Aged Women.

In recent years, the development of Assisted Reproductive Technique, the egg and embryo donation changed substantially the role of the uterus in recent years. It provided a higher chance for a pregnancy even in women over 45 years or post-menopause. In fact, the number of aged patients and in peri/post-menopause in pregnancy is nowadays increasing, but it increases obstetrical and neonatal related problems. The human uterus is richly innervated and modified especially during pregnancy and labor, and it is endowed with different sensory, parasympathetic, sympathetic and peptidergic neurofibers. They are differently distributed in uterine fundus, body and cervix, and they are mainly observed in the stroma and around arterial vessel walls in the myometrial and endometrial layers. Many neurotransmitters playing important roles in reproductive physiology are released after stimulation by adrenergic or cholinergic nerve fibers (the so called sympathetic/parasympathetic co-transmission). Immunohistochemical study demonstrated the localization and quantitative distribution of neurofibers in the fundus, the body and cervix of young women of childbearing age. Adrenergic and cholinergic effects of the autonomous nervous system are the most implicated in the uterine functionality. In such aged women, the Adrenergic and AChE neurofibers distribution in the fundus, body and cervix is progressively reduced by increasing age. Adrenergic and AChE neurotransmitters were closely associated with the uterine arteries and myometrial smooth muscles, and they reduced markedly by ageing. The Adrenergic and AChE neurofibers decreasing has a dramatical and negative impact on uterine physiology, as the reduction of pregnancy chance and uterine growth, and the increase of abortion risk and prematurity.

The Biological Impact of Ulipristal Acetate on Cellular Networks Regulating Uterine Leiomyoma Growth.

Uterine Fibroids (UFs), or leiomyomas, represent the most frequent pelvic tumor in reproductive-aged women. Although of benign origin, UFs decrease fertility and cause significant reproductive dysfunctions. Compared to normal myometrium, UFs are characterized by a clinical and molecular heterogeneity as demonstrated by the presence of multiple genetic alterations and altered signaling pathways. Recently, selective progesteronereceptor modulators (SPRM), as ulipristal acetate (UPA), have demonstrated their clinical benefits by reducing tumor growth and extracellular matrix deposition. For these reasons, UPA is used in the clinical practice as an intermittent treatment for women symptomatic for UFs or, sometimes, before a myomectomy. However, drug effects on signaling pathways frequently upregulated in UFs remain largely unknown. In fact, the mechanisms of action of the UPA on UFs and on the surrounding areas are not yet understood. To learn more about UPA molecular mechanisms, UF samples were treated ex vivo with UPA and profiled for drug effects on selected markers. During this preliminary ex vivo UPA administration, significant changes were observed in the expression levels of proteins related to cell cycle regulation, cytoskeleton remodeling, and drug resistance. The UPA administration reduced cofilin, Erk and Src phosphorylation, p27 and ezrin protein levels, but not Akt phosphorylation and cyclin D1 and ß-catenin levels. This preliminary ex vivo biological analysis provided new insights into the mechanism of action of UPA in the treatment of UFs, which could better explain the biological functioning of the drug on UFs.

Laparoscopic cholecystectomy versus transvaginal natural orifice transluminal endoscopic surgery cholecystectomy: results of a prospective comparative single-center study.

BACKGROUND AND AIMS: Laparoscopic cholecystectomy (LC) in female individuals has been challenged recently by transvaginal natural orifice transluminal endoscopic surgery cholecystectomy (TVC). TVC has not been widely accepted as a standard procedure, even though it is reported to be a safe and painless alternative to LC. This prospective comparative study aims to not only prove equality of TVC and LC but to underline the advantages of TVC over LC with regard to postoperative pain. METHODS: This study presents an analysis of a single-center and single-surgeon study with 226 unselected consecutive cholecystectomies performed as either TVC or LC. RESULTS: A total of 226 female patients underwent surgery with either LC (136 cases) or TVC (90 cases). There were no postoperative adverse events. Twenty-two patients (24.2%) in the TVC group indicated 0 (no pain) on a visual analog scale postoperatively, whereas only 5 patients (3.7%) did so in the LC group (P = < .0001). Overall consumption of non-steroidal anti-inflammatory drugs was significantly less (P < .0001; t test) in the TVC group (mean, 1.2 ± 0.11 g) compared with the LC group (mean, 2.1 ± 0.1 g). Twenty-three patients (25.5%) in the TVC group needed no postoperative analgesics at all. CONCLUSIONS: TVC is a safe and painless procedure for patients with symptomatic cholelithiasis who are from various ethnic and cultural origins. This benefit, along with an equal safety profile compared with LC, should pave the way for wider application of TVC in women.

Everolimus, an mTOR pathway inhibitor, is highly successful on ovarian hyperstimulation syndrome by reducing ovarian weight and progesterone levels: a preclinical experimental randomized controlled study.

The usefulness of various pathways inhibitors, Everolimus, an inhibitor of mammalian target of rapamycin (mTOR), Infliximab, a monoclonal antibody which blocks the tumor necrosis factor-a (TNF-a), Erlotinib, a tyrosine protein kinase inhibitor of the epidermal growth factor receptor (EGFR), Metformin, an activator of AMP-activated protein kinase enzyme (AMPK) and vascular permeability reducers were explored in an ovarian hyperstimulation syndrome (OHSS) rat model. Sixty-three female Wistar rats were randomly divided in seven groups. The control group received saline, while the OHSS group received recombinant -- follicle-stimulating hormone (rec-FSH) for four consecutive days. The other five groups received rec-FSH for 4 d and Everolimus daily, Infliximab once, Erlotinib daily, Metformin daily and Vitamin C daily, respectively. All groups received human chorionic gonadotropin (hCG) at the fifth day. The efficacy of Everolimus administration for various intervals was also explored. Significantly reduced ovarian weight was observed in the Everolimus group (rec-FSH + hCG + mTOR inhibitor) compared to the OHSS group (p < 0.001). The Everolimus group also showed the lowest progesterone (PRG) concentration (p = 0.007). The Erlotinib group (rec-FSH + hCG + EGFR inhibitor) presented with the lowest graafian follicle number, while the Everolimus group was characterized by the lowest corpus luteum number. The vascular permeability and the estradiol levels did not differ between groups. Finally, the Everolimus intra-comparison showed no difference in all measured outcomes. Studying the different pathways linked to vascular endothelial growth factor (VEGF) pathway, we conclude that targeting mTOR pathways is beneficial for reducing ovarian weight and PRG levels in an OHSS animal model.

Surgical trauma and CO2-insufflation impact on adhesion formation in parietal and visceral peritoneal lesions.

CO2-insufflation and electrocoagulation were advanced as causative factors of postsurgical adhesions. We assumed that severe tissue reaction due to electrocoagulation might obscure CO2-insufflation impact on adhesion formation. Therefore, the purpose of this study was to evaluate the effects and interactions of surgical trauma and CO2-insufflation on adhesion formation. Prospective-randomized study with 60 rats, equally divided into 3 groups. In the control group, the sidewall adhesion model was induced by monopolar coagulation of the uterine horn and ipsilateral parietal peritoneum and by mechanical damaging - in the opposite side through open laparoscopy without CO2-insufflation. In two other groups, CO2 was insufflated for 60 min at 15 cm of water, either before or after the sidewall model-induction. Parameters of sidewall and lesion site adhesions of parietal peritoneum and uterine horns were evaluated by scoring system and analyzed by two-way ANOVA with Bonferroni posttests, one-way ANOVA Student-Newman-Keuls multiple comparisons test, as well as by two-tailed unpaired Mann-Whitney test. Monopolar coagulation significantly increased peritoneal lesion site adhesion scores, as compared with the scores for mechanical damaging (p=0.0001). Visceral peritoneal lesion sites were more predisposed to adhesion formation than parietal peritoneal lesion sites (p=0.0009), whereas CO2 did not affect parameters of either sidewall or peritoneal lesion site adhesions, regardless of the insufflation mode (p>0.05). The data suggest that both surgical trauma and peritoneal lesion sites had a substantial impact on adhesion formation, whereas CO2 did not interfere with adhesion parameters irrespective of its insufflation mode. These findings may improve our insights into adhesion formation pathophysiology and open new perspectives in developing future adhesion prevention strategies.

Aromatase (CYP19) gene variants influence ovarian response to standard gonadotrophin stimulation.

PURPOSE: The association of cytochrome P450 aromatase gene CYP19(TTTA) ( n ) polymorphism with ovarian response to FSH stimulation was explored. METHODS: Three hundred women undergoing medically assisted reproduction and 300 women with at least one spontaneous pregnancy participated in the study. CYP19(TTTA) ( n ) polymorphism was genotyped, while serum hormones were determined. During oocyte retrieval, the follicular size, the follicle and oocyte numbers were recorded. RESULTS: Six CYP19(TTTA) ( n ) alleles with 7 to 12 repeats were revealed. Women homozygous for long CYP19(TTTA) ( n ) alleles presented with lower serum FSH levels at the third day of the menstrual cycle (p < 0.001) and higher large follicle numbers (p < 0.01), compared to women homozygous for short CYP19(TTTA) ( n ) alleles. The CYP19(TTTA) ( 7 ) allele was associated with higher serum FSH levels (p < 0.003), with lower total follicle (p < 0.02) and large follicle numbers (p < 0.03), while CYP19(TTTA) ( 7 ) allele-carriers presented more frequently with small follicles than CYP19(TTTA) ( 7 ) allele-non carriers (p < 0.01). CONCLUSIONS: CYP19 genetic variants were associated with ovarian reserve and response to standard gonadotrophin stimulation of women undergoing in vitro fertilization.

Severe inflammatory reaction induced by peritoneal trauma is the key driving mechanism of postoperative adhesion formation.

BACKGROUND: Many factors have been put forward as a driving mechanism of surgery-triggered adhesion formation (AF). In this study, we underline the key role of specific surgical trauma related with open surgery (OS) and laparoscopic (LS) conditions in postoperative AF and we aimed to study peritoneal tissue inflammatory reaction (TIR), remodelling specific complications of open surgery (OS) versus LS and subsequently evaluating AF induced by these conditions. METHODS: A prospective randomized study was done in 80 anaesthetised female Wistar rats divided equally into 2 groups. Specific traumatic OS conditions were induced by midline incision line (MIL) extension and tissue drying and specific LS conditions were remodelled by intraperitoneal CO2 insufflation at the 10 cm of water. TIR was evaluated at the 24th, 72nd, 120th and 168th hour by scoring scale. Statistical analysis was performed by the non-parametric t test and two-way ANOVA using Bonferroni post-tests. RESULTS: More pronounced residual TIR was registered after OS than after LS. There were no significant TIR interactions though highly significant differences were observed between the OS and LS groups (p < 0.0001) with regard to surgical and time factors. The TIR change differences between the OS and LS groups were pronounced with postoperative time p < 0.05 at the 24th and 72nd; p < 0.01--120th and p < 0.001--168th hrs. Adhesion free wounds were observed in 20.0 and 31.0% of cases after creation of OS and LS conditions respectively; with no significant differences between these values (p > 0.05). However larger adhesion size (41.67 ± 33.63) was observed after OS in comparison with LS (20.31 ± 16.38). The upper-lower 95% confidential limits ranged from 60.29 to 23.04 and from 29.04 to 11.59 respectively after OS and LS groups with significant differences (p = 0.03). Analogous changes were observed in adhesion severity values. Subsequently, severe TIR parameters were followed by larger sizes of severe postoperative adhesions in the OS group than those observed in the LS group. CONCLUSIONS: MIL extension and tissue drying seem to be the key factors in the pathogenesis of adhesion formation, triggering severe inflammatory reactions of the peritoneal tissue surrounding the MIL resulting in local and systemic consequences. CO2 insufflation however, led to moderate inflammation and less adhesion formation.

Effects and clinical significance of GnRH antagonist administration for IUI timing in FSH superovulated cycles: a meta-analysis.

OBJECTIVES: To compare the administration of GnRH antagonist in gonadotropin intrauterine insemination (IUI) cycles with cycles where no intervention took place. DESIGN: Meta-analysis of published prospective randomized trials. PATIENTS(S): Five hundred twenty-one patients who were administered a GnRH antagonist and 548 conservatively treated patients who served as control subjects were included in the meta-analysis. STUDY SELECTION: Prospective trials were retrieved from Medline and Cochrane Library (last update October 2006). Random effect analysis was used in this meta-analysis. Two independent reviewers performed data extraction. MAIN OUTCOME MEASURE(S): Clinical pregnancy rates. RESULT(S): Six comparisons were retrieved including 1,069 patients. Higher pregnancy rates were found in the randomized controlled trials (odds ratio [OR] 1.56, 95% confidence interval [CI] 1.05-2.33) when a GnRH antagonist was added to a gonadotropin superovulated IUI protocol. Early published studies with smaller sample sizes showed stronger associations (OR 2.31, 95% CI 1.15-4.63) than later studies (OR 1.32, 95% CI 0.79-2.23). CONCLUSION(S): From the randomized controlled trials of this meta-analysis, it is clear that allowing for follicle growth and avoiding premature LH rise, increased pregnancy rates are observed with GnRH antagonist administration. A parallel trend for multiple pregnancy rates in the GnRH antagonist group was observed, although this did not reach statistical significance. The flexible regimen was widely used. This meta-analysis of early data might enhance further research in this direction.

Human chorionic gonadotropin administration vs. luteinizing monitoring for intrauterine insemination timing, after administration of clomiphene citrate: a meta-analysis.

OBJECTIVE: To systematically compare hCG administration as a method for intrauterine insemination (IUI) timing with conservative urinary LH surge detection in infertility treatment. DESIGN: Meta-analysis of prospective and retrospective trials. SETTING: Tertiary fertility and IVF center. PATIENT(S): One thousand four hundred sixty-one patients who received hCG after a clomiphene citrate regimen, compared with 1,162 patients who had an LH surge detection for IUI timing. INTERVENTION(S): Both MEDLINE and Cochrane Collaboration were searched. References of retrieved articles were included in the search. The meta-analysis included all controlled trials examining the effectiveness of hCG administration before IUI on clinical-pregnancy rates in comparison with LH detection. Two independent reviewers performed data extraction. MAIN OUTCOME MEASURE(S): Pregnancy rates. RESULT(S): Seven studies with 2,623 patients were included in the meta-analysis (1,461 patients received hCG, and 1,162 had LH surge detection). When all studies were combined, patients who received hCG before IUI demonstrated lower clinical-pregnancy rates than did women who had IUI after spontaneous ovulation (odds ratio, 0.74; 95% confidence interval, 0.57-0.961). In subgroup analysis of studies that considered ovulatory dysfunction to be the infertility reason, the results favored women who received hCG. In contrast, across studies that reported male factor as the infertility reason, as well as across studies including women with unexplained infertility, results appeared to favor the LH surge detection approach. However, none of those subgroup analyses reached statistical significance. CONCLUSION(S): Available data do not demonstrate a consistent, clinically important benefit of hCG-induced ovulation compared with spontaneous ovulation for IUI timing.

Association of estradiol levels on the day of hCG administration and pregnancy achievement in IVF: a systematic review.

BACKGROUND: Evaluation of the association between estradiol (E2) levels on the day of hCG administration and pregnancy achievement in IVF has so far yielded conflicting results. The purpose of the present study was to systematically review the above association in cycles down-regulated with GnRH analogues. METHODS: Literature search was performed using Medline, Embase (1978-2004) and the Cochrane Library. Additionally, references of retrieved articles were hand-searched. Only full articles published in peer-reviewed medical journals were considered for analysis. RESULTS: All the eligible studies (n=9) involved the use of GnRH agonists and were retrospective. Two studies (including 191 patients) suggested that the higher the E2 levels on the day of hCG administration, the higher the probability of pregnancy. However, five studies (including 1875 patients), did not support an association between E2 levels on the day of hCG administration and pregnancy rates. Moreover, two of the studies including (1286 patients) suggested that high E2 levels on the day of hCG administration are associated with a decreased probability of pregnancy. If we consider only studies in which criteria used for administering hCG include follicular development but not E2 levels (including 2687 patients), there is no study suggesting a positive association between E2 levels on the day of hCG administration and pregnancy achievement. CONCLUSIONS: Currently there is no high-quality evidence to support or deny the value of E2 determination on the day of hCG administration for pregnancy achievement in IVF cycles, where pituitary down-regulation is performed with GnRH agonists. Existing retrospective studies suggest that there is no positive association. However, in order to arrive at recommendations for clinical practice, there is a need to perform well-designed prospective studies in both agonist and antagonist cycles.

Association of C677T polymorphism in the methylenetetrahydrofolate reductase gene with hypertension in pregnancy and pre-eclampsia: a meta-analysis.

OBJECTIVE: To evaluate whether the C677T polymorphism of the methylenetetrahydofolate reductase (MTHFR) gene is consistently associated with hypertension in pregnancy. DESIGN: Meta-analysis of studies comparing women with and without hypertension in pregnancy for the C677T MTHFR polymorphism. METHODS: Studies were identified with MEDLINE and EMBASE searches complemented with perusal of bibliographies of retrieved articles and communication with investigators. Between-study heterogeneity was estimated and data were combined with random effects models. Sensitivity analyses examined the effect of population and disease characteristics. Bias diagnostics evaluated the evolution of the postulated genetic effect over time and the potential for publication bias. RESULTS: Across 23 comparisons (3169 hypertensive women, 3044 controls), having the T allele (TT or CT) increased the odds of hypertensive disease of pregnancy by 1.21-fold (95% confidence interval, 1.01-1.44), but there was large between-study heterogeneity (P = 0.003). The results were similar and heterogeneity persisted when sensitivity analyses were limited to studies of Caucasian populations, or those of patients with significant proteinuria. While patients with diastolic hypertension > or = 110 mmHg showed an odds ratio of 1.41 (95% confidence interval, 1.03-1.73), no association was seen in patients with less severe diastolic hypertension (odds ratio, 1.00; 95% confidence interval, 0.61-1.65). Early published studies tended to show stronger associations than the subsequent studies. CONCLUSIONS: While bias cannot be excluded, the meta-analysis suggests that the T allele may increase the risk of severe diastolic hypertension during pregnancy.

Association of Leiden mutation in factor V gene with hypertension in pregnancy and pre-eclampsia: a meta-analysis.

OBJECTIVE: To evaluate whether the V Leiden mutation is consistently associated with hypertension in pregnancy across populations of pregnant women. DESIGN: Meta-analysis of studies comparing women with and without hypertension in pregnancy for the V Leiden mutation. METHODS: Studies were identified with MEDLINE and EMBASE searches complemented with perusal of bibliographies of retrieved articles and communication with investigators. Data were evaluated with random effects models and between-study heterogeneity was estimated. Sensitivity analyses examined the effect of population and study characteristics. Bias diagnostics evaluated the evolution of the postulated effect over time and the potential for publication bias. RESULTS Across 19 studies (2742 hypertensive women, 2403 controls), V Leiden mutation increased the odds of hypertensive disease of pregnancy by 2.25-fold [95% confidence interval (CI), 1.50-3.38], but there was large between-study heterogeneity (P = 0.002). The results were similar and heterogeneity persisted when sensitivity analyses were limited to studies with Caucasians, proteinuria, diastolic hypertension threshold > 110 mmHg, specified selection of cases, and matching. While studies published up to 2000 showed an odds ratio of 3.16 (95% CI, 2.04-4.92), no association was seen in studies published in 2001-2002 (odds ratio 0.97; 95% CI, 0.61-1.54). There was also evidence of potential publication bias: the five largest studies showed no association (odds ratio 1.21; 95% CI, 0.84-1.74). CONCLUSIONS: Although modest effects of V Leiden mutation on the risk of hypertension in pregnancy cannot be excluded, the association observed in early and small studies may be typical of bias, in particular time-lag bias and publication bias.