Isolated fetal umbilical vein varix and the association with intrauterine fetal death and fetal growth restriction: A systematic review, meta-analysis, and nested retrospective cohort study.

OBJECTIVES: To assess the risk of intrauterine fetal death (IUFD) and fetal growth restriction (FGR) in fetuses with an isolated fetal intra-abdominal umbilical vein varix (i-FIUVV). METHODS: A retrospective cohort study combined with a systematic review and meta-analysis of the literature was performed. In the retrospective cohort study, all singleton fetuses with an i-FIUVV in the fetal medicine units of the Amsterdam UMC (between 2007 and 2023) were analyzed. The primary outcome measures were IUFD and FGR. The sample proportions of IUFD and FGR were depicted as risk percentages. The IUFD proportion was compared to the regional reference population and the FGR proportion was compared to the reported proportions in Europe. The secondary outcome measures were gestational age at diagnosis, initial and maximal FIUVV diameter, fetal monitoring in pregnancy, turbulent flow in the varix, thrombus formation in the varix, induction of labor, gestational age at birth, and birthweight centile. The proportion of fetuses with a birthweight below the 10th centile was compared with that of the regional reference population. The systematic review included all cases from eligible literature published between 2007 and 2023 supplemented by the data of our retrospective cohort study. In the systematic review and meta-analysis, the pooled proportions of IUFD and FGR were assessed in fetuses with i-FIUVV. RESULTS: The retrospective cohort included 43 singletons with an i-FIUVV. The IUFD risk was 0% [Confidence Interval, CI: 0%-8.2%], which did not differ significantly from 0.3% in the reference population, p = 1.0. The risk of FGR was 16.3% [CI: 6.8%-30.7%] in the studied population, which is higher than the reported incidence of FGR in Europe ranging from 5%-10%. The proportion of fetuses with birthweights below the 10th centile was higher in our cohort compared with the reference population (23.3 vs. 9.9%, p < 0.01). The systematic review included 12 articles, three abstracts, and our current cohort. In total, 513 cases with an i-FIUVV were included. The pooled risk was 0.4% [CI: 0.1%-1.7%] for IUFD and 5.2% [CI: 1.1%-21.3%] for FGR. The mean gestational age at birth did not exceed 39 weeks in neither the cohort (38.7 weeks) nor the pooled literature (37.6 weeks). CONCLUSION: An i-FIUVV in singletons is not associated with an increased IUFD risk up to 39 weeks of gestation but is possibly associated with FGR. The incidence of FGR in our cohort was higher than in the pooled literature (16.3% vs. 5%) but FGR definitions in the included studies varied. The proportion of birthweights below the 10th percentile in our cohort was significantly higher than in the reference group. Thus, based on these findings, we suggest conducting sonographic growth assessments while simultaneously assessing the i-FIUVV. No further monitoring and follow-up are indicated up to 39 weeks of gestation. After 39 weeks of gestation, data on fetuses with i-FIUVV and their outcomes are lacking.

The effects of oestrogen on vaginal wound healing: A systematic review and meta-analysis.

AIMS: To determine the effects of oestrogen or oestrogen deprivation on vaginal wound healing. Impaired wound healing following prolapse surgery may increase the risk of recurrent prolapse in the future. Vaginal oestrogen therapy may improve wound healing, hereby possibly improving surgical outcomes. METHODS: A systematic search of OVID MEDLINE, OVID Embase, and Web of Science was conducted up to January 28, 2020. We included original studies comparing wound healing-related outcomes of oestrogen exposed subjects (female animals and women) to hypo-oestrogenic subjects after vaginal surgery. Data on wound healing-related outcome measures were extracted. For each individual comparison, the standardised mean difference (Hedges' g; SMD) and 95% confidence interval (CI) were calculated. RESULTS: Of the 1474 studies reviewed, 14 studies were included for review, and 11 provided data for meta-analysis. Oestrogen improves neovascularisation (SMD: 1.13, 95% CI: 0.67-1.60), microscopic wound closure (SMD: 0.98, 95% CI: 0.66-1.29), collagen synthesis (SMD: 1.08, 95% CI: 0.42-1.74), and tissue strength (SMD: 1.26, 95% CI: 0.53-1.99) in animals. Oestrogen increases granulation (SMD: 1.67, 95% CI: 0.54-2.79) and accelerates macroscopic wound closure (SMD: 1.82, 95% CI: 1.22-2.42) in women and animals. Oestrogen decreases the inflammatory response (SMD: -0.58, 95% CI: -1.14 to -0.02) in women and animals and reduces levels of transforming growth factor (TGF)-ß1 (SMD: -1.68, 95% CI: -2.52 to -0.83) in animals. All results were statistically significant. CONCLUSIONS: Oestrogen therapy has a positive effect on vaginal wound healing. Future studies should determine whether oestrogen therapy has the potential to improve surgical outcomes.

Development of placental abnormalities in location and anatomy.

Low-lying placentas, placenta previa and abnormally invasive placentas are the most frequently occurring placental abnormalities in location and anatomy. These conditions can have serious consequences for mother and fetus mainly due to excessive blood loss before, during or after delivery. The incidence of such abnormalities is increasing, but treatment options and preventive strategies are limited. Therefore, it is crucial to understand the etiology of placental abnormalities in location and anatomy. Placental formation already starts at implantation and therefore disorders during implantation may cause these abnormalities. Understanding of the normal placental structure and development is essential to comprehend the etiology of placental abnormalities in location and anatomy, to diagnose the affected women and to guide future research for treatment and preventive strategies. We reviewed the literature on the structure and development of the normal placenta and the placental development resulting in low-lying placentas, placenta previa and abnormally invasive placentas.

Risk of preterm birth for placenta previa or low-lying placenta and possible preventive interventions: A systematic review and meta-analysis.

Objective: To investigate the risk of preterm birth in women with a placenta previa or a low-lying placenta for different cut-offs of gestational age and to evaluate preventive interventions. Search and methods: MEDLINE, EMBASE, CENTRAL, Web of Science, WHO-ICTRP and clinicaltrials.gov were searched until December 2021. Randomized controlled trials, cohort studies and case-control studies assessing preterm birth in women with placenta previa or low-lying placenta with a placental edge within 2 cm of the internal os in the second or third trimester were eligible for inclusion. Pooled proportions and odds ratios for the risk of preterm birth before 37, 34, 32 and 28 weeks of gestation were calculated. Additionally, the results of the evaluation of preventive interventions for preterm birth in these women are described. Results: In total, 34 studies were included, 24 reporting on preterm birth and 9 on preventive interventions. The pooled proportions were 46% (95% CI [39 - 53%]), 17% (95% CI [11 - 25%]), 10% (95% CI [7 - 13%]) and 2% (95% CI [1 - 3%]), regarding preterm birth <37, <34, <32 and <28 weeks in women with placenta previa. For low-lying placentas the risk of preterm birth was 30% (95% CI [19 - 43%]) and 1% (95% CI [0 - 6%]) before 37 and 34 weeks, respectively. Women with a placenta previa were more likely to have a preterm birth compared to women with a low-lying placenta or women without a placenta previa for all gestational ages. The studies about preventive interventions all showed potential prolongation of pregnancy with the use of intramuscular progesterone, intramuscular progesterone + cerclage or pessary. Conclusions: Both women with a placenta previa and a low-lying placenta have an increased risk of preterm birth. This increased risk is consistent across all severities of preterm birth between 28-37 weeks of gestation. Women with placenta previa have a higher risk of preterm birth than women with a low-lying placenta have. Cervical cerclage, pessary and intramuscular progesterone all might have benefit for both women with placenta previa and low-lying placenta, but data in this population are lacking and inconsistent, so that solid conclusions about their effectiveness cannot be drawn. Systematic review registration: PROSPERO https://www.crd.york.ac.uk/prospero/, identifier CRD42019123675.

Angiogenesis in gynecological cancers and the options for anti-angiogenesis therapy.

Angiogenesis is required in cancer, including gynecological cancers, for the growth of primary tumors and secondary metastases. Development of anti-angiogenesis therapy in gynecological cancers and improvement of its efficacy have been a major focus of fundamental and clinical research. However, survival benefits of current anti-angiogenic agents, such as bevacizumab, in patients with gynecological cancer, are modest. Therefore, a better understanding of angiogenesis and the tumor microenvironment in gynecological cancers is urgently needed to develop more effective anti-angiogenic therapies, either or not in combination with other therapeutic approaches. We describe the molecular aspects of (tumor) blood vessel formation and the tumor microenvironment and provide an extensive clinical overview of current anti-angiogenic therapies for gynecological cancers. We discuss the different phenotypes of angiogenic endothelial cells as potential therapeutic targets, strategies aimed at intervention in their metabolism, and approaches targeting their (inflammatory) tumor microenvironment.

Which second trimester placenta previa remains a placenta previa in the third trimester: A prospective cohort study.

OBJECTIVE: The far majority of women with a placenta previa in the second trimester will no longer have a placenta that overlies the internal os in the third trimester. Women with a placenta previa in the third trimester are at risk for complication such as preterm birth and blood loss. Four counselling purposes we aim to identify which women with a second trimester placenta previa have a low-risk and a high-risk for persistence of the placenta previa. STUDY DESIGN: A prospective cohort study of women with a placenta previa in the second trimester between 2014 and 2019. The odds for having a placenta previa in the third trimester were calculated for different baseline characteristics. Multilevel likelihood ratios for ranges of the placenta overlying the internal os in the second trimester and the corresponding ROC curve were calculated to identify the optimal cut-off values. RESULTS: We included 313 women with a placenta previa in the second trimester. The placenta was more frequently located on the posterior wall (62 %) than on the anterior wall (38 %). At evaluation in the third trimester, 37 women (14 %) still had a placenta previa. Women with a larger distance of the placenta overlying the internal os, women having a previous cesarean delivery and women after a conception with assisted reproductive technique had a significant higher risk of placenta previa persistence (p-values <0.001). Women with a placenta overlying less than 14 mm can be considered as low-risk, indicated by a likelihood ratio of 0. Women with a placenta with more than 55 mm overlap can be considered as high-risk, indicated a the likelihood ratio of ∞. CONCLUSION: The majority of the second trimester placenta previa will no longer overly the internal os in the third trimester. Placenta previa persistence is associated with the distance overlying the internal os, a previous cesarean delivery and assisted reproductive techniques. In the second trimester, women can be identified as low-risk and high-risk for persistence of placenta previa. This can be used for risk stratification, counselling and individualized care for women with a second trimester placenta previa.

Final outcome of a second trimester low-positioned placenta: A systematic review and meta-analysis.

Low-positioned placentas which are located in the lower uterine segment (LUS), either a low-lying placenta or a placenta previa, are associated with increased obstetric risks. However, most second trimester low-positioned placentas resolve during pregnancy and have a higher position in the third trimester, without posing any risks. We performed a systematic review and meta-analysis to evaluate the proportion of second trimester low-positioned placentas that have a position towards the fundus in the third trimester. Our aim was to find a cut-off value that included all women in whom the placenta will remain low in the third trimester, thus who are at increased risk of obstetric complications. Subsequently, we assessed whether an anterior or posterior placental location influenced this proportion. We searched MEDLINE and EMBASE and clinicaltrials.gov up to April 2019 for studies on the sonographic follow-up of second trimester low-positioned placentas, with a distance between the placenta and the internal os of the cervix of 20 mm or less at a gestational age of above 15 week and a follow up after 28 weeks. Studies were scored on methodological quality using the Newcastle-Ottowa Scale (NOS). A meta-analysis was conducted to summarize the proportion of second trimester low-positioned placentas with a position towards the fundus in the third trimester. We calculated the proportion at different cut-off values of the distance from the placental edge to the internal os of the cervix (0 mm, 10 mm and 20 mm). Also, anteriorly and posteriorly located placentas and women with and without a prior cesarean delivery were compared. We included 11 eligible studies which reported on 3586 women with a low-positioned placenta in the second trimester. Proportions of placentas with a position towards the fundus in the third trimester ranged between 0.63 and 1.0. Pooled proportions were 0.90 (95% CI 0.87-0.93) for IOD <10 mm and 0.80 (95% CI 0.74-0.85) for IOD < 0 mm. Due to heterogeneity between studies, the subgroup of <20 mm could not be pooled. Overall, anteriorly located placentas more often had a position towards the fundus in the third trimester, but studies did report conflicting results. Prior cesarean section had no influence except for an IOD of <0 mm, in which women without a prior cesarean delivery more often had a placenta towards the fundus. The majority of second trimester low-positioned placentas will be located towards the fundus at the time of follow-up. However, we could not determine a cut-off value for anterior and posterior placentas that included all women at high risk. The cut-off value, placental side and prior cesarean section should be assessed in a large prospective observational study.

Validation of noninvasive focal depth measurements to determine epithelial thickness of the vaginal wall.

OBJECTIVE: This study investigates whether noninvasive focal depth (FD) measurements correlate with vaginal wall epithelial thickness (ET). If FD accurately reflects ET of the vaginal wall, this would allow noninvasive longitudinal assessment of (newly developed) treatment modalities aiming to increase ET, without the need for invasive biopsies. METHODS: Fourteen women, median age 62 years (inter quartile ranges: 57-65), undergoing vaginal prolapse surgery because of anterior and/or posterior compartment pelvic organ prolapse were included. We used the CytoCam, a handheld video microscope based on incident dark field imaging, and performed FD measurements of the vaginal wall before surgery. Histology was performed on tissue that was removed during the surgical procedure, and ET was measured in stained sections. We compared ET with FD interindividually, and determined the expected linear correlation and agreement between the two measurements. RESULTS: Seventeen ET measurements (mean 125 µm ±â€Š38.7, range 48-181 µm) were compared with 17 FD measurements (mean 128 µm ±â€Š34.3, range 68-182 µm). The lineair correlation between the two measurements was strong (r = 0.902, P < 0.01). Bland-Altman analysis demonstrated a mean difference of 13.5 µm when comparing ET to FD. CONCLUSIONS: The results demonstrate good agreement between ET and FD measurements. We consider the mean difference demonstrated with Bland-Altman analysis acceptable for these measurements. This suggests that FD accurately reflects ET, which further supports the use of FD to measure ET of the vaginal wall. For a complete assessment of the vaginal wall, FD measurements are preferably combined with the assessment of vaginal angioarchitecture.

Longer time interval between semen processing and intrauterine insemination does not affect pregnancy outcome.

OBJECTIVE: To study whether the pregnancy outcome of intrauterine insemination (IUI) is affected by a longer time interval between semen processing and insemination. DESIGN: Retrospective cohort. SETTING: Teaching hospital. PATIENT(S): Couples with subfertility and an indication for IUI over a 10-year period. INTERVENTION (S): Insemination performed the day after but within 24 hours of semen collection and processing (delayed insemination) compared with insemination performed immediately after sperm collection and processing (immediate insemination). MAIN OUTCOME MEASURE(S): Ongoing pregnancy rate, defined as a pregnancy confirmed by ultrasound at 10 to 12 weeks of gestation. RESULT(S): In total, 1,136 cycles were analyzed. In 77 of 547 couples (14%) an ongoing pregnancy occurred after delayed insemination, and in 77 of 589 couples (13%) an ongoing pregnancy occurred after immediate insemination. Both groups had similar baseline characteristics. After adjustment for confounders, there was no difference in the ongoing pregnancy rate between delayed as compared with immediate insemination (odds ratio 0.89; 95% confidence interval, 0.63-1.25). CONCLUSION(S): There is no negative effect on pregnancy rate when IUI of processed sperm is delayed until the next day. This approach allows additional flexibility for couples when the male partner is not available on the day of ovulation, and it allows for a spread of workload in the laboratory.