Prediction of complications in early-onset pre-eclampsia (PREP): development and external multinational validation of prognostic models.

BACKGROUND: Unexpected clinical deterioration before 34 weeks gestation is an undesired course in early-onset pre-eclampsia. To safely prolong preterm gestation, accurate and timely prediction of complications is required. METHOD: Women with confirmed early onset pre-eclampsia were recruited from 53 maternity units in the UK to a large prospective cohort study (PREP-946) for development of prognostic models for the overall risk of experiencing a complication using logistic regression (PREP-L), and for predicting the time to adverse maternal outcome using a survival model (PREP-S). External validation of the models were carried out in a multinational cohort (PIERS-634) and another cohort from the Netherlands (PETRA-216). Main outcome measures were C-statistics to summarise discrimination of the models and calibration plots and calibration slopes. RESULTS: A total of 169 mothers (18%) in the PREP dataset had adverse outcomes by 48 hours, and 633 (67%) by discharge. The C-statistics of the models for predicting complications by 48 hours and by discharge were 0.84 (95% CI, 0.81-0.87; PREP-S) and 0.82 (0.80-0.84; PREP-L), respectively. The PREP-S model included maternal age, gestation, medical history, systolic blood pressure, deep tendon reflexes, urine protein creatinine ratio, platelets, serum alanine amino transaminase, urea, creatinine, oxygen saturation and treatment with antihypertensives or magnesium sulfate. The PREP-L model included the above except deep tendon reflexes, serum alanine amino transaminase and creatinine. On validation in the external PIERS dataset, the reduced PREP-S model showed reasonable calibration (slope 0.80) and discrimination (C-statistic 0.75) for predicting adverse outcome by 48 hours. Reduced PREP-L model showed excellent calibration (slope: 0.93 PIERS, 0.90 PETRA) and discrimination (0.81 PIERS, 0.75 PETRA) for predicting risk by discharge in the two external datasets. CONCLUSIONS: PREP models can be used to obtain predictions of adverse maternal outcome risk, including early preterm delivery, by 48 hours (PREP-S) and by discharge (PREP-L), in women with early onset pre-eclampsia in the context of current care. They have a potential role in triaging high-risk mothers who may need transfer to tertiary units for intensive maternal and neonatal care. TRIAL REGISTRATION: ISRCTN40384046 , retrospectively registered.

Impact of Laser Power and Firing Angle on Coagulation Efficiency in Laser Treatment for Twin-Twin Transfusion Syndrome: An ex vivo Placenta Study.

OBJECTIVE: To assess the impact of laser power and firing angle on coagulation efficiency for closing placental anastomoses in the treatment of twin-twin transfusion syndrome. METHODS: We used an ex vivo blood-perfused human placenta model to compare time to complete coagulation using 30 vs. 50 W of neodymium-doped yttrium aluminum garnet laser power and using a firing angle of 90° vs. 45°. Placentas were perfused with pig blood at 5 mL/min. Differences were analyzed using independent-samples t test, Mann-Whitney U test, or χ2 test as appropriate. RESULTS: Coagulation took less time and energy using 50 W (n = 53) compared to 30 W (n = 52), 11 vs. 22 s (p < 0.001), and 557 vs. 659 J (p = 0.007). Perpendicular coagulation (n = 53) took less time and energy compared to a 45° angle (n = 21), 11 vs. 17 s (p = 0.004), and 557 vs. 871 J (p = 0.004). Bleeding complicated 2 (3%) measurements in the 50-W group, 5 (10%) in the 30-W group, and 3 (14%) in the 45° group. DISCUSSION: In a highly controlled model, a 50-W laser power setting was more energy efficient than 30 W in coagulating a placental vein. A more perpendicular laser firing angle resulted in more efficient coagulation. Furthermore, bleeding due to vessel wall disruption occurred more often with lower power and a more tangential approach.

Is the Sequential Laser Technique for Twin-to-Twin Transfusion Syndrome Truly Superior to the Standard Selective Technique? A Meta-Analysis.

BACKGROUND AND OBJECTIVE: To investigate the efficacy of sequential laser coagulation in the treatment of twin-to-twin transfusion syndrome (TTTS). DATA SOURCES: MEDLINE, EMBASE and the Cochrane Library were systematically searched for comparative studies on the efficacy of sequential versus standard selective laser coagulation for TTTS. The primary outcome measure in these studies was survival of at least one twin, both twins and fetal demise. RESULTS: Three cohort studies comparing the selective laser treatment technique (n = 120) versus the sequential technique (n = 224) in 344 monochorionic twin pregnancies were included. Mean survival of at least one twin was 88% in the selective group versus 92% (p = 0.22) in the sequential group. Mean survival of both twins was lower in the selective group (52%) than in the sequential group (75%) (p = 0.002). Donor fetal demise decreased from 34% in the selective to 10% in the sequential group (p < 0.01), and recipient fetal demise decreased from 16 to 7% (p = 0.02). CONCLUSION: Limited evidence suggests improved double neonatal survival as well as decreased donor and recipient fetal demise with the use of the sequential technique. However, these results are based on small non-randomized studies with evident forms of bias and methodological limitations. A randomized controlled trial to assess the efficacy of sequential laser technique is therefore required.

Twenty-Five Years of Fetoscopic Laser Coagulation in Twin-Twin Transfusion Syndrome: A Systematic Review.

OBJECTIVE: The aim of this study was to assess the perinatal outcome of pregnancies with twin-twin transfusion syndrome (TTTS) treated with laser therapy over the past 25 years, and in relation to different techniques used in this time period. METHODS: A systematic review of studies reporting on perinatal outcome according to the Meta-Analysis of Observational Studies in Epidemiology (MOOSE) guidelines was conducted. The MEDLINE, Embase and Cochrane Library databases were systematically searched. Comparisons were made in respect to time period and laser technique and Quintero stages. RESULTS: In total, 34 studies reporting on 3,868 monochorionic twin pregnancies were included. The mean survival of both twins increased from 35 to 65% (p = 0.012) and for at least one twin from 70 to 88% (p = 0.009) over the past 25 years. Mean gestational age at birth remained stable over the years at 32 weeks gestation. Also, we showed a significantly improved perinatal survival with the evolution of the laser technique from non-selective to selective, selective sequential and the Solomon technique (p = 0.010). DISCUSSION: Since the introduction of laser therapy for TTTS more than two decades ago, perinatal survival improved significantly. Improved outcome is probably associated with several factors, including evolution of the laser technique, learning curve effect, better referral and improved early neonatal care.

Post-Laser Twin Anemia Polycythemia Sequence: Diagnosis, Management, and Outcome in an International Cohort of 164 Cases.

The aim of this study was to investigate the management and outcome in the post-laser twin anemia polycythemia sequence (TAPS). Data of the international TAPS Registry, collected between 2014 and 2019, were used for this study. The primary outcomes were perinatal mortality and severe neonatal morbidity. Secondary outcomes included a risk factor analysis for perinatal mortality and severe neonatal morbidity. A total of 164 post-laser TAPS pregnancies were included, of which 92% (151/164) were diagnosed antenatally and 8% (13/164) postnatally. The median number of days between laser for TTTS and detection of TAPS was 14 (IQR: 7-28, range: 1-119). Antenatal management included expectant management in 43% (62/151), intrauterine transfusion with or without partial exchange transfusion in 29% (44/151), repeated laser surgery in 15% (24/151), selective feticide in 7% (11/151), delivery in 6% (9/151), and termination of pregnancy in 1% (1/151). The median gestational age (GA) at birth was 31.7 weeks (IQR: 28.6-33.7; range: 19.0-41.3). The perinatal mortality rate was 25% (83/327) for the total group, 37% (61/164) for donors, and 14% (22/163) for recipients (p < 0.001). Severe neonatal morbidity was detected in 40% (105/263) of the cohort and was similar for donors (43%; 51/118) and recipients (37%; 54/145), p = 0.568. Independent risk factors for spontaneous perinatal mortality were antenatal TAPS Stage 4 (OR = 3.4, 95%CI 1.4-26.0, p = 0.015), TAPS donor status (OR = 4.2, 95%CI 2.1-8.3, p < 0.001), and GA at birth (OR = 0.8, 95%CI 0.7-0.9, p = 0.001). Severe neonatal morbidity was significantly associated with GA at birth (OR = 1.5, 95%CI 1.3-1.7, p < 0.001). In conclusion, post-laser TAPS most often occurs within one month after laser for TTTS, but may develop up to 17 weeks after initial surgery. Management is mostly expectant, but varies greatly, highlighting the lack of consensus on the optimal treatment and heterogeneity of the condition. Perinatal outcome is poor, particularly due to the high rate of perinatal mortality in donor twins.

What is the impact of placental tissue damage after laser surgery for twin-twin transfusion syndrome? A secondary analysis of the Solomon trial.

BACKGROUND: The introduction of the Solomon technique for the treatment of twin-twin transfusion syndrome (TTTS) increased placental exposure to laser energy. This study aims to identify the impact of power and energy used in laser treatment on placental tissue and pregnancy outcome. METHODS: Pictures of all dye-injected placentas since the start of the Solomon trial were analyzed. Placental damage was scored using a grading system including visual scar depth and affected proportion of the vascular equator. Parameters analyzed included laser power and total energy, gestational age (GA) at laser, GA at birth, laser-to-delivery interval and preterm prelabor rupture of membranes (PPROM). RESULTS: We included 122 cases in the analysis. More placental damage occurred more often in the Solomon group (42%) compared to the selective group (15%) (p < 0.001). In multivariate analysis, more placental damage was associated with higher laser energy (regression coefficient B 0.002) but not with higher power setting (regression coefficient B -0.442). More damage was associated with earlier GA at birth (regression coefficient B -0.167), higher incidence of PPROM <32 weeks (regression coefficient B 0.003) and a shorter laser-to-delivery interval (regression coefficient B -0.168). CONCLUSIONS: Placental damage is positively associated with more laser energy but negatively associated with higher power setting. More placental damage was associated with a lower GA at birth, shorter laser-to-delivery interval and higher PPROM rate. Whether these results should lead to a change in surgical technique requires more research, both further ex-vivo experiments on human placentas and clinical studies.

Development and validation of prediction models for risk of adverse outcomes in women with early-onset pre-eclampsia: protocol of the prospective cohort PREP study.

BACKGROUND: Early-onset pre-eclampsia with raised blood pressure and protein in the urine before 34 weeks' gestation is one of the leading causes of maternal deaths in the UK. The benefits to the child from prolonging the pregnancy need to be balanced against the risk of maternal deterioration. Accurate prediction models of risks are needed to plan management. METHODS: We aim to undertake a multicentre prospective cohort study (Prediction of Risks in Early onset Pre-eclampsia (PREP)) to develop clinical prediction models in women with early-onset pre-eclampsia, for risk of adverse maternal outcomes by 48 h and by discharge. We will externally validate the models in two independent cohorts with 634 and 216 women. In the secondary analyses, we will assess risk of adverse fetal and neonatal outcomes at birth and by discharge. DISCUSSION: The PREP study will quantify the risk of maternal complications at various time points and provide individualised estimates of overall risk in women with early-onset pre-eclampsia to plan the management. TRIAL REGISTRATION: ISRCTN registry, ISRCTN40384046.

Development and validation of Prediction models for Risks of complications in Early-onset Pre-eclampsia (PREP): a prospective cohort study.

BACKGROUND: The prognosis of early-onset pre-eclampsia (before 34 weeks' gestation) is variable. Accurate prediction of complications is required to plan appropriate management in high-risk women. OBJECTIVE: To develop and validate prediction models for outcomes in early-onset pre-eclampsia. DESIGN: Prospective cohort for model development, with validation in two external data sets. SETTING: Model development: 53 obstetric units in the UK. Model transportability: PIERS (Pre-eclampsia Integrated Estimate of RiSk for mothers) and PETRA (Pre-Eclampsia TRial Amsterdam) studies. PARTICIPANTS: Pregnant women with early-onset pre-eclampsia. SAMPLE SIZE: Nine hundred and forty-six women in the model development data set and 850 women (634 in PIERS, 216 in PETRA) in the transportability (external validation) data sets. PREDICTORS: The predictors were identified from systematic reviews of tests to predict complications in pre-eclampsia and were prioritised by Delphi survey. MAIN OUTCOME MEASURES: The primary outcome was the composite of adverse maternal outcomes established using Delphi surveys. The secondary outcome was the composite of fetal and neonatal complications. ANALYSIS: We developed two prediction models: a logistic regression model (PREP-L) to assess the overall risk of any maternal outcome until postnatal discharge and a survival analysis model (PREP-S) to obtain individual risk estimates at daily intervals from diagnosis until 34 weeks. Shrinkage was used to adjust for overoptimism of predictor effects. For internal validation (of the full models in the development data) and external validation (of the reduced models in the transportability data), we computed the ability of the models to discriminate between those with and without poor outcomes (c-statistic), and the agreement between predicted and observed risk (calibration slope). RESULTS: The PREP-L model included maternal age, gestational age at diagnosis, medical history, systolic blood pressure, urine protein-to-creatinine ratio, platelet count, serum urea concentration, oxygen saturation, baseline treatment with antihypertensive drugs and administration of magnesium sulphate. The PREP-S model additionally included exaggerated tendon reflexes and serum alanine aminotransaminase and creatinine concentration. Both models showed good discrimination for maternal complications, with anoptimism-adjusted c-statistic of 0.82 [95% confidence interval (CI) 0.80 to 0.84] for PREP-L and 0.75 (95% CI 0.73 to 0.78) for the PREP-S model in the internal validation. External validation of the reduced PREP-L model showed good performance with a c-statistic of 0.81 (95% CI 0.77 to 0.85) in PIERS and 0.75 (95% CI 0.64 to 0.86) in PETRA cohorts for maternal complications, and calibrated well with slopes of 0.93 (95% CI 0.72 to 1.10) and 0.90 (95% CI 0.48 to 1.32), respectively. In the PIERS data set, the reduced PREP-S model had a c-statistic of 0.71 (95% CI 0.67 to 0.75) and a calibration slope of 0.67 (95% CI 0.56 to 0.79). Low gestational age at diagnosis, high urine protein-to-creatinine ratio, increased serum urea concentration, treatment with antihypertensive drugs, magnesium sulphate, abnormal uterine artery Doppler scan findings and estimated fetal weight below the 10th centile were associated with fetal complications. CONCLUSIONS: The PREP-L model provided individualised risk estimates in early-onset pre-eclampsia to plan management of high- or low-risk individuals. The PREP-S model has the potential to be used as a triage tool for risk assessment. The impacts of the model use on outcomes need further evaluation. TRIAL REGISTRATION: Current Controlled Trials ISRCTN40384046. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

Predicting complications in pre-eclampsia: external validation of the fullPIERS model using the PETRA trial dataset.

OBJECTIVE: The internally validated fullPIERS model predicts adverse maternal outcomes in women with pre-eclampsia within 48h after eligibility. Our objective was to assess generalizability of this prediction model. STUDY DESIGN: External validation study using prospectively collected data from two tertiary care obstetric centers. METHODS: The existing PETRA dataset, a cohort of women (n=216) with severe early-onset pre-eclampsia, eclampsia, HELLP syndrome or hypertension-associated fetal growth restriction was used. The fullPIERS model equation was applied to all women in the dataset using values collected within 48h after inclusion. The performance (ROC area and R-squared) of the model, risk stratification and calibration were assessed from 48h up to a week after inclusion. RESULTS: Of 216 women in the PETRA trial, 73 (34%) experienced an adverse maternal outcome(s) at any time after inclusion. Adverse maternal outcome was observed in 32 (15%) cases within 48h and 62 (29%) within 7 days after inclusion. The fullPIERS model predicted adverse maternal outcomes within 48h (AUC ROC 0.97, 95% CI: 0.87-0.99) and up to 7 days after inclusion (AUC ROC 0.80, 95% CI: 0.70-0.87). CONCLUSIONS: The fullPIERS model performed well when applied to the PETRA dataset. These results confirm the usability of the fullPIERS prediction model as a 'rule-in' test for women admitted with severe pre-eclampsia, eclampsia, HELLP syndrome or hypertension-associated fetal growth restriction. Future research should focus on intervention studies that assess the clinical impact of strategies using the fullPIERS model.