Role of gestational age at time of placental laser surgery in outcomes of twin-to-twin transfusion syndrome.

OBJECTIVE: There are conflicting data on whether fetoscopic laser photocoagulation of placental anastomoses (FLP) for treating twin-to-twin transfusion syndrome (TTTS) is associated with lower rates of overall survival. The objective of this study is to characterize survival and other associated morbidity after FLP across gestational ages of FLP. METHODS: This is a secondary analysis of prospectively collected data on patients with monochorionic-diamniotic twins that had FLP for TTTS at two centers between 2011 and 2022. Patients were divided into gestational age epochs for FLP before 18 wks, 18 0/7 - 19 6/7 wks, 20 0/7 - 21 6/7 wks, 22 0/7 - 23 6/7 wks, 24 0/7 - 25 6/7 wks and after 26 wks. Demographic characteristics, sonographic characteristics of TTTS and operative characteristics were compared across the gestational age epochs. Outcomes including overall survival, preterm delivery, preterm prelabor rupture of membranes (PPROM), intrauterine fetal demise (IUFD) and neonatal demise (NND) were also compared across gestational age epochs. Multivariate analysis was performed by fitting logistic regression models for these outcomes. Kaplan-Mejer curves were constructed to compare the interval from PPROM to delivery for each gestational age epoch. RESULTS: There were 768 patients that met inclusion criteria. The dual survival rate was 61.3% for FLP performed prior to 18 weeks compared to 78.0% - 86.7% across later gestational age epochs. This appears to be related to increased rates of donor IUFD following FLP performed before, versus after 18 weeks (28.0% vs. 9.3% - 14.1%). Rates of recipient IUFD/NND and donor NND were similar regardless of gestational age of FLP. Rates of PPROM were higher for earlier FLP, ranging from 45.6% for FLP before 18 weeks to 11.9% for FLP at 24 - 26 weeks gestational age. However, the gestational age of delivery was similar across gestational age epochs with a median of 31.7 weeks. In multivariate analysis, donor loss was independently associated with FLP before 18 weeks after adjusting for selective fetal growth restriction, Quintero stage and other covariates. PPROM and PTD were also associated with FLP before 18 weeks after adjusting for cervical length, placental location, trocar size, laser energy and amnioinfusion. CONCLUSION: FLP performed at earlier gestational ages is associated with lower overall survival, which is driven by higher risk of donor IUFD, as opposed to differences in PPROM or PTD. Counseling regarding survival should account for gestational age of presentation. This article is protected by copyright. All rights reserved.

Interventions to prevent preterm delivery in women with short cervix before fetoscopic laser surgery for twin-twin transfusion syndrome.

OBJECTIVE: Preoperative short cervical length (CL) remains a major risk factor for preterm birth after laser surgery for twin-twin transfusion syndrome (TTTS), but the optimal intervention to prolong pregnancy remains elusive. The objective of this study was to compare secondary methods for the prevention of preterm birth in twin pregnancies with TTTS undergoing fetoscopic laser photocoagulation (FLP), in the setting of a short cervix at the time of FLP, in five North American Fetal Treatment Network (NAFTNet) centers. METHODS: This was a secondary analysis of data collected prospectively at five NAFTNet centers, conducted from January 2013 to March 2020. Inclusion criteria were a monochorionic diamniotic twin pregnancy complicated by TTTS, undergoing FLP, with preoperative CL < 30 mm. Management options for a short cervix included expectant management, vaginal progesterone, pessary (Arabin, incontinence or Bioteque cup), cervical cerclage or a combination of two or more treatments. Patients were not included if the intervention was initiated solely on the basis of having a twin gestation rather than at the diagnosis of a short cervix. Demographics, ultrasound characteristics, operative data and outcomes were compared. The primary outcome was FLP-to-delivery interval. Propensity-score matching was performed, with each treatment group matched (1:1) to the expectant-management group for CL, in order to estimate the effect of each treatment on the FLP-to-delivery interval. RESULTS: A total of 255 women with a twin pregnancy complicated by TTTS and a short cervix undergoing FLP were included in the study. Of these, 151 (59%) were managed expectantly, 32 (13%) had vaginal progesterone only, 21 (8%) had pessary only, 21 (8%) had cervical cerclage only and 30 (12%) had a combination of treatments. A greater proportion of patients in the combined-treatment group had had a prior preterm birth compared with those in the expectant-management group (33% vs 9%; P = 0.01). Mean preoperative CL was shorter in the pessary, cervical-cerclage and combined-treatment groups (14-16 mm) than in the expectant-management and vaginal-progesterone groups (22 mm for both) (P < 0.001). There was no significant difference in FLP-to-delivery interval between the groups, nor in gestational age at delivery or the rate of live birth or neonatal survival. Vaginal progesterone was associated with a decrease in the risk of delivery before 28 weeks' gestation compared with cervical cerclage and combined treatment (P = 0.03). Using propensity-score matching for CL, cervical cerclage was associated with a reduction in FLP-to-delivery interval of 13 days, as compared with expectant management. CONCLUSIONS: A large proportion of pregnancies with TTTS and a short maternal cervix undergoing FLP were managed expectantly for a short cervix, establishing a high (62%) risk of delivery before 32 weeks in this condition. No treatment that significantly improved outcome was identified; however, there were significant differences in potential confounders and there were also likely to be unmeasured confounders. Cervical cerclage should not be offered as a secondary prevention for preterm birth in twin pregnancies with TTTS and a short cervix undergoing FLP. A large randomized controlled trial is urgently needed to determine the effects of treatments for the prevention of preterm birth in these pregnancies. © 2021 International Society of Ultrasound in Obstetrics and Gynecology.

Preterm prelabor rupture of membranes after fetoscopic laser surgery for twin-twin transfusion syndrome.

OBJECTIVE: To assess the incidence, clinical course, risk factors and outcomes of preterm prelabor rupture of membranes (PPROM) after fetoscopic laser surgery (FLS) for twin-twin transfusion syndrome (TTTS). METHODS: This was a prospective observational cohort study of 154 consecutive cases of TTTS. PPROM was defined as rupture of membranes before 34 weeks' gestation. Procedure-to-PPROM and PPROM-to-delivery intervals were determined. Relevant preoperative and intraoperative variables were analyzed by univariate and multivariate logistic regression to determine their impact on PPROM after FLS. RESULTS: The incidence of PPROM was 39% (n = 60), occurring at a mean gestational age of 27.2 ± 4.6 weeks. Median procedure-to-PPROM interval was 46 (range, 1-105; interquartile range (IQR), 13-66) days and median PPROM-to-delivery interval was 1 (range, 0-93; IQR, 0-13) day. Mean gestational age at delivery in cases with PPROM was 29.0 ± 4.5 weeks compared with 32.6 ± 3.9 weeks in cases without PPROM (P < 0.0001). Insertion of a collagen plug was the only significant factor found on both univariate and multivariate analysis to be associated with an increased rate of PPROM (odds ratio, 3.1 (95% CI, 1.2-8.0); P = 0.006). There was no statistically significant difference in fetal (P = 0.07) or neonatal (P = 0.08) survival between those with and those without PPROM. CONCLUSIONS: PPROM after FLS increases prematurity by 3.6 weeks. The latency period after PPROM was 2 weeks; 50% of patients delivered within 24 h. No variable thought to be associated with PPROM after FLS was found to be significantly associated with this complication. Other etiologies and mechanisms for PPROM after FLS should be explored. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd.

Preterm delivery after fetoscopic laser surgery for twin-twin transfusion syndrome: etiology and risk factors.

OBJECTIVE: Preterm delivery after fetoscopic laser surgery (FLS) for twin-twin transfusion syndrome (TTTS) is a major complication. The causative factors leading to preterm delivery continue to be elusive and a better understanding of the risk factors could reduce complications. The objective of this study was to determine the etiology of preterm delivery after FLS for TTTS and its associated risk factors. METHODS: This was a secondary analysis of a prospective study of 203 patients with TTTS who underwent FLS at a single center between September 2011 and December 2014. Preoperative, operative, postoperative, delivery and neonatal data were reviewed. Preterm delivery was categorized according to etiology into three groups: spontaneous (SPT), indicated (IND) and elective (ELC). Comparisons between groups were performed by ANOVA. Kaplan-Meier survival analysis was performed to compare the procedure-to-delivery interval between groups. To identify risk factors for preterm delivery, logistic regression, with calculation of relative risks (RR), was performed, with P < 0.05 considered statistically significant. RESULTS: Mean gestational age at time of FLS was 20.6 ± 2.4 weeks and mean gestational age at delivery was 30.9 ± 4.7 weeks. Iatrogenic preterm prelabor rupture of membranes (iPPROM) occurred in 39% of cases. SPT preterm delivery occurred in 97 (48%) patients, IND preterm delivery in 65 (32%) and ELC preterm delivery in 41 (20%). In the IND group, 30 (46%) patients delivered for fetal indications, 31 (48%) for maternal indications and four (6%) for combined fetal and maternal indications. The overall chorioamnionitis rate was 6.4%; of these, nine (9%) were in the SPT group and four (6%) were in the IND group, with no case occurring in the ELC group. There was a significant difference in procedure-to-delivery interval between groups (P < 0.0001). Using variables from the ELC group as a baseline, significant risk factors for SPT preterm delivery were iPPROM (RR, 16.2 (95% CI, 4.5-57.7)), preoperative cervical length (RR, 0.96 (95% CI, 0.92-0.998)) and number of anastomoses (RR, 1.14 (95% CI, 1.02-1.27)). Significant risk factors for IND preterm delivery were iPPROM (RR, 9.6 (95% CI, 2.6-35.0)) and number of ablated anastomoses (RR, 1.13 (95% CI, 1.02-1.30)). CONCLUSION: iPPROM and an increased number of ablated placental anastomoses were associated independently with SPT and IND preterm deliveries. A shorter preoperative cervical length was associated with SPT preterm delivery. Strategies to prevent iPPROM and for management of cervical length shortening are needed urgently in these pregnancies. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd.

Does anemia-polycythemia complicating twin-twin transfusion syndrome affect outcome after fetoscopic laser surgery?

OBJECTIVE: Twin anemia-polycythemia sequence (TAPS) can occur as a unique disease or as a complication of twin-twin transfusion syndrome (TTTS). Middle cerebral artery (MCA) Doppler studies are not currently part of the routine evaluation of monochorionic twins since they are not used in the Quintero staging system. As such, the true incidence of TAPS is unknown. We aimed to compare the characteristics and outcomes of twin pregnancies with TTTS complicated by spontaneous anemia-polycythemia vs those with TTTS alone. METHODS: This was a secondary analysis of data collected prospectively from a cohort of 156 consecutive patients undergoing fetoscopic laser surgery for TTTS, between October 2011 and August 2014. TAPS was defined as discordance in the preoperative MCA peak systolic velocity (PSV), with one twin fetus having MCA-PSV ≤ 1.0 multiples of the median (MoM) and the other having MCA-PSV ≥ 1.5 MoM. Maternal demographics as well as preoperative, operative and postoperative variables were analyzed. RESULTS: Included in the final analysis were 133 patients with complete records: 11 cases with TTTS with anemia-polycythemia and 122 cases with TTTS alone. There was no difference in maternal body mass index, gestational age (GA) at procedure, rate of preterm prelabor rupture of membranes or GA at delivery between the two groups. Patients with TTTS and anemia-polycythemia were more likely to be older (P = 0.03) and parous (P = 0.04) and had a significantly lower number of placental anastomoses (P = 0.01). The dual live-birth rate was similar for both groups (P = 0.76). CONCLUSION: Cases of TTTS with anemia-polycythemia were more likely to be found in parous and older women and were characterized by fewer vascular anastomoses. TTTS with anemia-polycythemia was not associated with worse perinatal outcome after laser therapy. Copyright © 2015 ISUOG. Published by John Wiley & Sons Ltd.

Cervical length in prediction of preterm birth after laser surgery for twin-twin transfusion syndrome.

OBJECTIVES: To determine the risk factors for spontaneous preterm delivery (PTD) or preterm prelabor rupture of membranes (PPROM) at < 34 weeks' gestation after fetoscopic laser surgery for twin-twin transfusion syndrome and to identify the optimal threshold for preoperative cervical length (CL) that indicates a high risk for spontaneous PTD. METHODS: This was a secondary analysis of data prospectively collected from 449 patients at three fetal centers. CL measurements were obtained by preoperative transvaginal ultrasound, at a gestational age of 16-26 weeks. The risk factors associated with spontaneous PTD before 34 weeks' gestation were determined using multivariable logistic regression analysis. We excluded patients with dual fetal demise and those with maternal or fetal indications for delivery without PPROM (n = 63). The optimal threshold for cervical length to predict spontaneous PTD before 34 weeks was determined using a receiver-operating characteristics (ROC) curve and Youden index. Additionally, the CL threshold for spontaneous PTD at 2-week intervals between 24 and 34 weeks was determined. RESULTS: Spontaneous PTD before 34 weeks occurred in 206 (53.4%) of the included patients. Only the preoperative CL was significantly associated with spontaneous PTD. The preoperative CL was normally distributed with a mean of 37.6 ± 10.3 mm (range, 5-66 mm). Maternal age and parity were positively associated, and gestational age at procedure and anterior placenta were negatively associated, with CL on multivariable linear regression analysis. The area under the ROC curve for predicting spontaneous PTD with CL measurements was 0.61 (P = 0.02) and the optimal threshold was 28 mm with a Youden index of 0.19 (sensitivity and specificity of 92% and 27%, respectively). A CL measurement of < 28 mm increased the risk of spontaneous PTD for all gestational age thresholds. CONCLUSIONS: Spontaneous PTD at < 34 weeks' gestation is associated with a preoperative CL of < 28 mm. Preventive strategies should focus on this high-risk group.

Reduction in the severity of early onset severe preeclampsia during gestation may be associated with changes in endothelial cell activation: A pathological case report.

Early severe preeclampsia with changes consistent with the Hemolysis elevated liver enzymes low platelet count (HELLP) variant and severe fetal growth restriction rarely resolves prior to delivery. Established clinical disease is preceded by endothelial dysfunction and inflammation. Endothelial activation is reported in vitro to be raised in the presence of necrotic trophoblastic debris which is deported into the maternal circulation in preeclampsia. We report on an early severe preeclamptic patient admitted at 24 weeks gestation. Maternal serum was taken at day 2, 16, 30 of admission and 45 days postpartum. 20% maternal serum or trophoblastic debris from first trimester placental explants that had been cultured with 10% maternal serum was exposed to endothelial cells. Endothelial cell activation was quantified by the cell surface ICAM-1 expression and U937 monocyte adhesion assay. The clinical condition of this patient improved including the blood pressure, liver function, and platelet count by the 3rd day after antihypertensive treatment and remained normal until delivery at 37 weeks. ICAM-1 expression and U937 moncyte adhesion assay of endothelial cells was significantly increased following exposure of the endothelial cells to the maternal serum or trophoblastic debris from placentae treated with maternal serum drawn on day 2. However, ICAM-1 expression and the monocyte adhesion assay were significantly reduced following exposure of endothelial cells to maternal serum or trophoblastic debris from placenta treated with maternal serum drawn on day 16 or 30. Our data suggest unknown factor(s) in the maternal serum triggered endothelial cell activation when the clinical symptoms were present. The improvement in the clinical condition occurred along with the changes in endothelial cell activation.

Trophoblast debris extruded from preeclamptic placentae activates endothelial cells: a mechanism by which the placenta communicates with the maternal endothelium.

INTRODUCTION: Preeclampsia is characterized by maternal endothelial dysfunction. While the mechanisms leading to preeclampsia are unclear, a factor(s) from the placenta is responsible for triggering the disease. One placental factor implicated in triggering preeclampsia is trophoblast debris which may transmit pathogenic signals from the placenta to endothelial cells. In this study, we investigated whether trophoblast debris from preeclamptic placentae triggered endothelial cell activation. METHODS: Trophoblast debris from preeclamptic or normotensive placentae, or trophoblast debris from normal placental explants that had been cultured with preeclamptic (n = 14) or normotensive sera (n = 14) was exposed to endothelial cells. Activation of the endothelial cells was quantified by cell surface ICAM-1 and U937 adhesion to endothelial cells. The levels of IL-1ß, pro-caspase-1 and active caspase-1 in the trophoblast debris were measured. RESULTS: Compared to controls, the levels of ICAM-1 and U937 adhesion to endothelial cells were significantly increased following exposure of the endothelial cells to trophoblast debris from preeclamptic placentae or placentae treated with preeclamptic sera. The levels IL-1ß, pro-caspase-1 and active caspase-1 were significantly increased in both trophoblast debris from preeclamptic placentae and placentae treated with preeclamptic sera. DISCUSSION: These results provide the first direct evidence that trophoblast debris produced from preeclamptic placentae or placentae treated with preeclamptic sera can activate the endothelium. CONCLUSIONS: Trophoblast debris from preeclamptic but not normotensive placentae can induce endothelial cell activation. This may be one mechanism by which the preeclamptic placenta communicates with the maternal endothelium to induce activation of the endothelium.

Pre-treatment with calcium prevents endothelial cell activation induced by multiple activators, necrotic trophoblastic debris or IL-6 or preeclamptic sera: possible relevance to the pathogenesis of preeclampsia.

INTRODUCTION: A hallmark of preeclampsia is endothelial cell dysfunction/activation in response to "toxins" from the placenta. Necrotic trophoblastic debris (NTD) is one possible placental toxin and others include inflammatory cytokines. Calcium supplementation appears to protect "at-risk" women from developing preeclampsia by an unknown mechanism. In this study we investigate whether the addition of high levels of calcium to endothelial cells prior to their exposure to the preeclampsia-associated activators could reduce the endothelial cell activation. METHODS: NTD was harvested from 1st trimester placental explants. Endothelial cells were treated with varied concentrations of calcium prior to exposure to NTD, IL-6 or preeclamptic sera or low levels of calcium. Activation was monitored by quantifying endothelial cell-surface ICAM-1 by ELISA or U937 adhesion to endothelial cells. The activity of endothelial cell nitric oxide synthetase was blocked with L-NAME. RESULTS: Pre-treatment with increasing concentrations of calcium inhibited the activation of endothelial cells in response to NTD or IL-6 or preeclamptic sera. Inhibiting nitric oxide synthetase, using L-NAME, reduced the ability of high calcium levels to protect endothelial cell activation. Pre-treatment with calcium did not prevent endothelial cell activation induced by the reduction of the levels of calcium but additional calcium treatment did prevent endothelial cell activation induced by low calcium. CONCLUSION: Our results demonstrate calcium supplementation may prevent the activation of the endothelium in response to activators. These results may partially explain the benefits of calcium supplementation in the reduction of risk for developing preeclampsia and provide in vitro mechanistic support for the use of calcium supplementation in at-risk women.

PP168. The role of calcium supplementation in prevention endothelial cell activation, and possible relevance to preeclampsia.

INTRODUCTION: Preeclampsia remains a leading causing of maternal and perinatal mortality and morbidity. Preeclampsia is currently thought to be primarily a disease of endothelial activation and inflammation. OBJECTIVES: The deportation of trophoblast debris form the placenta was first linked to the pathogenesis of preeclampsia over a hundred years ago and it is hypothesised that deportation of necrotic trophoblast debris may contribute to maternal endothelial cell activation in preeclampsia. We have previously shown that treating placental explants with IL-6 results in shedding of more necrotic trophoblast debris from placental explants and that this debris when phagocytosed by endothelial cells results in activation of the endothelial cells. Although delivery remains the only definitive cure for preeclampsia a number of studies suggest that calcium supplementation may reduce the risk of developing preeclampsia by up to 50% but the protective mechanism of calcium supplementation is unclear. The aim of this work was to determine whether calcium supplementation affects either the production of necrotic trophoblast debris from the placenta or influences endothelial cell activation. METHODS: First trimester placental explants were cultured with IL-6 in the presence or absence of increasing concentrations of calcium (CaCl2) for 24h. Trophoblastic debris was collected from the explants and then exposed to monolayers of endothelial cell for 24h and endothelial cell activation measured by ICAM-1 ELISA. In other experiments, endothelial cells were treated with IL-6 or necrotic trophoblastic debris in the presence of increasing concentrations of CaCl2, ranging from 230µg/mL to 700µg/mL, for 24h. In some experiments, ebdothelial cells were treated with low concentration of CaCl2, ranging from 0µg/mL to 230µg/mL for 24h. Endothelial cell activation was measured by quantifying cell-surface ICAM-1 levels by ELISA. CONCLUSION: Our results demonstrate that calcium levels are important to endothelial cell activation and supplemental calcium may reverse the activation of the endothelium induced by proinflammatory mediators while having no effect on the production of trophoblast debris. These results may in part help to explain the benefits of calcium supplementation in the reduction of risk for developing preeclampsia.