Consensus protocol for management of early and late twin-twin transfusion syndrome: Delphi study.

OBJECTIVE: Fetoscopic laser photocoagulation (FLP) is a well-established treatment for twin-twin transfusion syndrome (TTTS) between 16 and 26 weeks' gestation. High-quality evidence and guidelines regarding the optimal clinical management of very early (prior to 16 weeks), early (between 16 and 18 weeks) and late (after 26 weeks) TTTS are lacking. The aim of this study was to construct a structured expert-based clinical consensus for the management of early and late TTTS. METHODS: A Delphi procedure was conducted among an international panel of experts. Participants were chosen based on their clinical expertise, affiliation and relevant publications. A four-round Delphi survey was conducted using an online platform and responses were collected anonymously. In the first round, a core group of experts was asked to answer open-ended questions regarding the indications, timing and modes of treatment for early and late TTTS. In the second and third rounds, participants were asked to grade each statement on a Likert scale (1, completely disagree; 5, completely agree) and to add any suggestions or modifications. At the end of each round, the median score for each statement was calculated. Statements with a median grade of 5 without suggestions for change were accepted as the consensus. Statements with a median grade of 3 or less were excluded from the Delphi process. Statements with a median grade of 4 were modified according to suggestions and reconsidered in the next round. In the last round, participants were asked to agree or disagree with the statements, and those with more than 70% agreement without suggestions for change were considered the consensus. RESULTS: A total of 122 experts met the inclusion criteria and were invited to participate, of whom 53 (43.4%) agreed to take part in the study. Of those, 75.5% completed all four rounds. A consensus on the optimal management of early and late TTTS was obtained. FLP can be offered as early as 15 weeks' gestation for selected cases, and can be considered up to 28 weeks. Between 16 and 18 weeks, management should be tailored according to Doppler findings. CONCLUSIONS: A consensus-based treatment protocol for early and late TTTS was agreed upon by a panel of experts. This protocol should be modified at the discretion of the operator, according to their experience and the specific demands of each case. This should advance the quality of future studies, guide clinical practice and improve patient care. © 2023 International Society of Ultrasound in Obstetrics and Gynecology.

Patient empowerment improves follow-up data collection after fetal surgery for spina bifida: institutional audit.

OBJECTIVES: To define and grade fetal and maternal adverse events following fetal surgery for spina bifida and to report on the impact of engaging patients in collecting follow-up data. METHODS: This prospective single-center audit included 100 consecutive patients undergoing fetal surgery for spina bifida between January 2012 and December 2021. In our setting, patients return to their referring unit for further pregnancy care and delivery. On discharge, referring hospitals were requested to return outcome data. For this audit, we prompted patients and referring hospitals to provide data in cases of missing outcomes. Outcomes were categorized as missing, returned spontaneously or returned following additional request, by the patient and/or referring center. Postoperative maternal and fetal complications until delivery were defined and graded according to Maternal and Fetal Adverse Event Terminology (MFAET) and the Clavien-Dindo classification. RESULTS: There were no maternal deaths, but severe maternal complications occurred in seven women (anemia in pregnancy, postpartum hemorrhage, pulmonary edema, lung atelectasis, urinary tract obstruction and placental abruption). No cases of uterine rupture were reported. Perinatal death occurred in 3% of fetuses and other severe fetal complications in 15% (perioperative fetal bradycardia/cardiac dysfunction, fistula-related oligohydramnios, chorioamnionitis and preterm prelabor rupture of membranes (PPROM) before 32 weeks). PPROM occurred in 42% of patients and, overall, delivery took place at a median gestational age of 35.3 weeks (interquartile range, 34.0-36.6 weeks). Information provided following additional request, from both centers and patients but mainly from the latter, reduced missing data by 21% for gestational age at delivery, 56% for uterine-scar status at birth and 67% for shunt insertion at 12 months. Compared with the generic Clavien-Dindo classification, the MFAET system ranked complications in a more clinically relevant way. CONCLUSIONS: The nature and rate of severe complications following fetal surgery for spina bifida were similar to those reported in other large series. Spontaneous return of outcome data by referring centers was low, yet patient empowerment improved data collection. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Early imaging predictors of fetal cerebral ischemic injury in monochorionic twin pregnancy complicated by spontaneous single intrauterine death.

OBJECTIVE: Monochorionic twin pregnancies are at increased risk of single intrauterine death (sIUD) and subsequent brain injury in the surviving twin owing to shared placentation. We assessed the association between middle cerebral artery peak systolic velocity (MCA-PSV) and cerebral injury on magnetic resonance imaging (MRI) and examined the association between cerebral findings on diffusion-weighted imaging (DWI) and those on T2-weighted imaging following spontaneous sIUD. METHODS: This was a retrospective cohort study of monochorionic pregnancies complicated by spontaneous sIUD followed at a tertiary center between January 2008 and January 2020. Pregnancies with sIUD following laser treatment, those with selective feticide, double IUD occurring on the same day or sIUD before 14 weeks' gestation were excluded, as were cases in which MCA-PSV was not measured or DWI-MRI was not performed. The ability of MCA-PSV Doppler to predict subsequent cerebral injury on MRI was assessed, and DWI findings were analyzed and compared with those on susceptibility-weighted imaging (SWI) and T2-weighted MRI to determine its diagnostic accuracy. RESULTS: We assessed 64 monochorionic pregnancies complicated by spontaneous sIUD. Of these, 47 (73.4%) pregnancies underwent fetal brain MRI and met the inclusion criteria. Sixteen (34.0%) of these fetuses demonstrated cerebral injury on MRI. The median interval between the diagnosis of sIUD and MRI examination was 5 days. Fetuses with increased MCA-PSV > 1.5 multiples of the median (MoM) following sIUD were significantly more likely to demonstrate cerebral injury on MRI than were those with normal MCA-PSV (68.8% vs 38.7%; P = 0.05). The sensitivity and specificity of MCA-PSV > 1.5 MoM for predicting cerebral injury on MRI were 68.8% (95% CI, 41.3-88.9%) and 61.3% (95% CI, 42.2-78.2%), respectively. Patterns of early cerebral injury on T2-weighted and SWI-MRI included acute or subacute tissue swelling (n = 6), parenchymal atrophy (n = 7), loss of cortical ribbon (n = 1) and hemorrhage (n = 8). Early MRI within approximately 2 weeks after the diagnosis of sIUD demonstrated abnormal DWI along with coexisting SWI and T2-weighted sequelae in 56.3% (9/16) of cases. When DWI was normal and a second MRI examination was performed later (n = 7), there were no ischemic changes evident on T2-weighted imaging. CONCLUSIONS: Increased MCA-PSV is associated with, but predicts poorly, cerebral injury after sIUD. Early MRI with DWI within approximately 2 weeks after the diagnosis of sIUD is valuable in identifying any cerebral injury. © 2021 International Society of Ultrasound in Obstetrics and Gynecology.

Umbilical venous diameter and flow in monochorionic diamniotic twin pregnancy: association with placental sharing and fetal demise.

OBJECTIVE: To examine the association of umbilical venous diameter and flow in monochorionic diamniotic twin pregnancy with placental sharing and fetal demise. METHODS: This was a prospective longitudinal cohort study of a consecutive series of monochorionic diamniotic twin pregnancies that underwent ultrasound assessments at 12, 16, 20 and 28 weeks' gestation. Fetal biometry (crown-rump length at 12 weeks or estimated fetal weight (EFW) thereafter) and cord insertion sites were recorded at each visit, as well as the diameter of the umbilical vein (UV) in both the intra-abdominal part and a free loop of the umbilical cord. Time-averaged maximum velocity in the intra-abdominal part of the UV was measured to calculate UV-flow. Univariate and multivariate linear regression analyses were performed to assess the relationship between intertwin ratios of these variables and placental sharing at 12, 16, 20 and 28 weeks' gestation. Placental sharing was calculated by dividing the larger by the smaller placental share, as measured on placental injection studies after birth. Additionally, the Mann-Whitney U-test and receiver-operating-characteristics-curve analysis were used to explore the relationship between the occurrence of fetal demise and intertwin differences in fetal biometry, cord insertion sites, UV diameters and flow at 12, 16, 20 and 28 weeks. RESULTS: Of 200 consecutive monochorionic twin pregnancies enrolled, injection studies were performed in 165 (82.5%) placentas. On univariate analysis, intertwin differences in fetal biometry, cord insertions and UV variables were associated significantly with placental sharing at 12, 16, 20 and 28 weeks' gestation. On multivariate analysis, intertwin differences in fetal biometry, cord insertions and all three UV variables remained associated significantly with placental sharing at 12 and 16 weeks. However, at 20 and 28 weeks, only the intertwin EFW ratio was associated consistently with placental sharing. Fetal demise of one or both twins complicated 26 (13.0%) pregnancies. Differences in EFW and cord insertion sites were not associated significantly with fetal demise, while at 16 weeks, differences in intra-abdominal UV diameter and flow were associated with an increased risk of subsequent fetal demise. CONCLUSIONS: At 12 and 16 weeks' gestation, intertwin differences in UV diameter and flow reflect placental sharing more accurately than do differences in fetal growth and cord insertion sites. At 16 weeks, discordance in intra-abdominal UV diameter and flow is also associated with an increased risk of fetal demise. © 2022 International Society of Ultrasound in Obstetrics and Gynecology.

Growth patterns of monochorionic twin pregnancy complicated by Type-III selective fetal growth restriction.

OBJECTIVES: Little is known regarding fetal growth patterns in monochorionic twin pregnancy complicated by Type-III selective fetal growth restriction (sFGR). We aimed to assess fetal growth and umbilical artery Doppler pattern in Type-III sFGR across gestation and evaluate the effect of changing Doppler flow pattern on growth and intertwin growth discordance. METHODS: This was a retrospective cohort study of all Type-III sFGR pregnancies managed at nine fetal centers over a 12-year time period. Higher-order multiple pregnancy and cases with major fetal anomaly or other monochorionicity-related complications at presentation were excluded. Estimated fetal weight (EFW) was assessed on ultrasound for each twin pair at five timepoints (16-20, 21-24, 25-28, 29-32 and > 32 weeks' gestation) and compared with singleton and uncomplicated monochorionic twin EFW. EFW and intertwin EFW discordance were compared between pregnancies with normalization of umbilical artery Doppler of the smaller twin later in pregnancy and those with persistently abnormal Doppler. RESULTS: Overall, 328 pregnancies (656 fetuses) met the study criteria. In Type-III sFGR, the smaller twin had a lower EFW than an average singleton fetus (EFW Z-score ranging from -1.52 at 16 weeks to -2.69 at 36 weeks) and an average monochorionic twin in uncomplicated pregnancy (Z-score ranging from -1.73 at 16 weeks to -1.49 at 36 weeks) throughout the entire gestation, while the larger twin had a higher EFW than an average singleton fetus until 22 weeks' gestation and was similar in EFW to an average uncomplicated monochorionic twin throughout gestation. As pregnancy advanced, growth velocity of both twins decreased, with the larger twin remaining appropriately grown and the smaller twin becoming more growth restricted. Intertwin EFW discordance remained stable throughout gestation. On multivariable longitudinal modeling, normalization of fetal umbilical artery Doppler was associated with better growth of the smaller twin (P = 0.002) but not the larger twin (P = 0.1), without affecting the intertwin growth discordance (P = 0.09). CONCLUSIONS: Abnormal fetal growth of the smaller twin in Type-III sFGR was evident early in pregnancy, while EFW of the larger twin remained normal throughout gestation. Normalization of umbilical artery Doppler was associated with improved fetal growth of the smaller twin. © 2021 International Society of Ultrasound in Obstetrics and Gynecology.

Prediction of fetal death in monochorionic twin pregnancies complicated by Type-III selective fetal growth restriction.

OBJECTIVE: Monochorionic diamniotic twin pregnancies complicated by Type-III selective fetal growth restriction (sFGR) are at high risk of fetal death. The aim of this study was to identify predictors of fetal death in these pregnancies. METHODS: This was an international multicenter retrospective cohort study. Type-III sFGR was defined as fetal estimated fetal weight (EFW) of one twin below the 10th percentile and intertwin EFW discordance of ≥ 25% in combination with intermittent absent or reversed end-diastolic flow in the umbilical artery of the smaller fetus. Predictors of fetal death were recorded longitudinally throughout gestation and assessed in univariable and multivariable logistic regression models. The classification and regression trees (CART) method was used to construct a prediction model of fetal death using significant predictors derived from the univariable analysis. RESULTS: A total of 308 twin pregnancies (616 fetuses) were included in the analysis. In 273 (88.6%) pregnancies, both twins were liveborn, whereas 35 pregnancies had single (n = 19 (6.2%)) or double (n = 16 (5.2%)) fetal death. On univariable analysis, earlier gestational age at diagnosis of Type-III sFGR, oligohydramnios in the smaller twin and deterioration in umbilical artery Doppler flow were associated with an increased risk of fetal death, as was larger fetal EFW discordance, particularly between 24 and 32 weeks' gestation. None of the parameters identified on univariable analysis maintained statistical significance on multivariable analysis. The CART model allowed us to identify three risk groups: a low-risk group (6.8% risk of fetal death), in which umbilical artery Doppler did not deteriorate; an intermediate-risk group (16.3% risk of fetal death), in which umbilical artery Doppler deteriorated but the diagnosis of sFGR was made at or after 16 + 5 weeks' gestation; and a high-risk group (58.3% risk of fetal death), in which umbilical artery Doppler deteriorated and gestational age at diagnosis was < 16 + 5 weeks' gestation. CONCLUSIONS: Type-III sFGR is associated with a high risk of fetal death. A prediction algorithm can help to identify the highest-risk group, which is characterized by Doppler deterioration and early referral. Further studies should investigate the potential benefit of fetal surveillance and intervention in this cohort. © 2022 International Society of Ultrasound in Obstetrics and Gynecology.

Outcome of monochorionic twin pregnancy complicated by Type-III selective intrauterine growth restriction.

OBJECTIVE: Type-III selective intrauterine growth restriction (sIUGR) is associated with a high and unpredictable risk of fetal death and fetal brain injury. The objective of this study was to describe the prospective risk of fetal death and the risk of adverse neonatal outcome in a cohort of twin pregnancies complicated by Type-III sIUGR and treated according to up-to-date guidelines. METHODS: We reviewed retrospectively all monochorionic diamniotic twin pregnancies complicated by Type-III sIUGR managed at nine fetal centers over a 12-year period. Higher-order multiple gestations and pregnancies with major fetal anomalies or other monochorionicity-related complications at initial presentation were excluded. Data on fetal and neonatal outcomes were collected and management strategies reviewed. Composite adverse neonatal outcome was defined as neonatal death, invasive ventilation beyond the resuscitation period, culture-proven sepsis, necrotizing enterocolitis requiring treatment, intraventricular hemorrhage Grade > I, retinopathy of prematurity Stage > II or cystic periventricular leukomalacia. The prospective risk of intrauterine death (IUD) and the risk of neonatal complications according to gestational age were evaluated. RESULTS: We collected data on 328 pregnancies (656 fetuses). After exclusion of pregnancies that underwent selective reduction (n = 18 (5.5%)), there were 51/620 (8.2%) non-iatrogenic IUDs in 35/310 (11.3%) pregnancies. Single IUD occurred in 19/328 (5.8%) pregnancies and double IUD in 16/328 (4.9%). The prospective risk of non-iatrogenic IUD per fetus declined from 8.1% (95% CI, 5.95-10.26%) at 16 weeks, to less than 2% (95% CI, 0.59-2.79%) after 28.4 weeks and to less than 1% (95% CI, -0.30 to 1.89%) beyond 32.6 weeks. In otherwise uncomplicated pregnancies with Type-III sIUGR, delivery was generally planned at 32 weeks, at which time the risk of composite adverse neonatal outcome was 29.0% (31/107 neonates). In twin pregnancies that continued to 34 weeks, there was a very low risk of IUD (0.7%) and a low risk of composite adverse neonatal outcome (11%). CONCLUSIONS: In this cohort of twin pregnancies complicated by Type-III sIUGR and treated at several tertiary fetal centers, the risk of fetal death was lower than that reported previously. Further efforts should be directed at identifying predictors of fetal death and optimal antenatal surveillance strategies to select a cohort of pregnancies that can continue safely beyond 33 weeks' gestation. © 2020 International Society of Ultrasound in Obstetrics and Gynecology.

Fetal endoscopic tracheal occlusion reverses the natural history of right-sided congenital diaphragmatic hernia: European multicenter experience.

OBJECTIVE: To evaluate the neonatal outcome of fetuses with isolated right-sided congenital diaphragmatic hernia (iRCDH) based on prenatal severity indicators and antenatal management. METHODS: This was a retrospective review of prospectively collected data on consecutive cases diagnosed with iRCDH before 30 weeks' gestation in four fetal therapy centers, between January 2008 and December 2018. Data on prenatal severity assessment, antenatal management and perinatal outcome were retrieved. Univariate and multivariate logistic regression analysis were used to identify predictors of survival at discharge and early neonatal morbidity. RESULTS: Of 265 patients assessed during the study period, we excluded 40 (15%) who underwent termination of pregnancy, two cases of unexplained fetal death, two that were lost to follow-up, one for which antenatal assessment of lung hypoplasia was not available and six cases which were found to have major associated anomalies or syndromes after birth. Of the 214 fetuses with iRCDH included in the neonatal outcome analysis, 86 were managed expectantly during pregnancy and 128 underwent fetal endoscopic tracheal occlusion (FETO) with a balloon. In the expectant-management group, lung size measured by ultrasound or by magnetic resonance imaging was the only independent predictor of survival (observed-to-expected lung-to-head ratio (o/e-LHR) odds ratio (OR), 1.06 (95% CI, 1.02-1.11); P = 0.003). Until now, stratification for severe lung hypoplasia has been based on an o/e-LHR cut-off of 45%. In cases managed expectantly, the survival rate was 15% (4/27) in those with o/e-LHR ≤ 45% and 61% (36/59) for o/e-LHR > 45% (P = 0.001). However, the best o/e-LHR cut-off for the prediction of survival at discharge was 50%, with a sensitivity of 78% and specificity of 72%. In the expectantly managed group, survivors with severe pulmonary hypoplasia stayed longer in the neonatal intensive care unit than did those with mildly hypoplastic lungs. In fetuses with an o/e-LHR ≤ 45% treated with FETO, survival rate was higher than in those with similar lung size managed expectantly (49/120 (41%) vs 4/27 (15%); P = 0.014), despite higher prematurity rates (gestational age at birth: 34.4 ± 2.7 weeks vs 36.8 ± 3.0 weeks; P < 0.0001). In fetuses treated with FETO, gestational age at birth was the only predictor of survival (OR, 1.25 (95% CI, 1.04-1.50); P = 0.02). CONCLUSIONS: Antenatal measurement of lung size can predict survival in iRCDH. In fetuses with severe lung hypoplasia, FETO was associated with a significant increase in survival without an associated increase in neonatal morbidity. © 2020 International Society of Ultrasound in Obstetrics and Gynecology.

Monochorionic twins after in-vitro fertilization: do they have poorer outcomes?

OBJECTIVE: To compare the outcome of monochorionic diamniotic (MCDA) twin pregnancies conceived by in-vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) with that of spontaneously conceived MCDA twins. METHODS: This was a retrospective cohort study of MCDA twin pregnancies conceived after IVF/ICSI or spontaneously, followed from the first trimester onwards at a single center between January 2002 and September 2018. The primary outcome was survival per fetus from the first trimester until 28 days after birth. Secondary outcome measures were number of survivors, miscarriage, termination of pregnancy, intrauterine and neonatal death, major congenital anomalies, twin-twin transfusion syndrome, selective fetal growth restriction, gestational age at birth, delivery before 32 weeks' gestation, mode of delivery, admission to the neonatal intensive care unit, birth weight and birth-weight discordance. RESULTS: Of the 654 MCDA pregnancies included in the analysis, 80 were conceived by IVF/ICSI and 574 spontaneously. Overall fetal and neonatal survival was significantly lower in the IVF/ICSI group than in the spontaneous-conception group (79% vs 90%; P = 0.001). In the IVF/ICSI group, compared with the spontaneous-conception group, loss of one or both twins occurred twice as often (29% vs 14%; P = 0.001) and there was a higher risk of second-trimester miscarriage (8% vs 1%; P = 0.002). CONCLUSIONS: MCDA twins conceived after IVF/ICSI have lower overall survival rates and higher rates of second-trimester miscarriage than do spontaneously conceived MCDA twins. Copyright © 2020 ISUOG. Published by John Wiley & Sons Ltd.

Outcome of monochorionic twin pregnancy with selective fetal growth restriction at 16, 20 or 30 weeks according to new Delphi consensus definition.

OBJECTIVES: To report the outcome of selective fetal growth restriction (sFGR) diagnosed according to the new Delphi consensus definition, and determine potential predictors of survival, in a cohort of unselected monochorionic diamniotic twin pregnancies. METHODS: This was a retrospective study of monochorionic diamniotic twin pregnancies followed from the first trimester onward, which were diagnosed with sFGR at 16, 20 or 30 weeks' gestation. sFGR was defined according to the new Delphi consensus criteria as presence of either an estimated fetal weight (EFW) < 3rd centile in one twin or at least two of the following: EFW of one twin < 10th centile, abdominal circumference of one twin < 10th centile, EFW discordance ≥ 25% or umbilical artery pulsatility index of the smaller twin > 95th centile. The primary outcomes were the overall survival rate (up to day 28 after birth) and risk of loss of one or both twins. We further determined possible predictors of survival using uni- and multivariate generalized estimated equation modeling. RESULTS: We analyzed 675 pregnancies, of which 177 (26%) were diagnosed with sFGR at 16, 20 or 30 weeks. The overall survival rate was 313/354 (88%) with 146/177 (82%) pregnancies resulting in survival of both twins, 21/177 (12%) in survival of one twin and 10/177 (6%) in loss of both twins. Subsequent twin anemia-polycythemia sequence (TAPS) developed in 6/177 (3%) and twin-twin transfusion syndrome (TTTS) in 17/177 (10%) pregnancies. All TAPS fetuses survived. The survival rate in sFGR pregnancies that subsequently developed TTTS was 65% (22/34), compared with 91% (279/308) in those with isolated sFGR (no subsequent TAPS or TTTS) (P < 0.001). The majority of sFGR cases were Type I (110/177 (62%)) and had a survival rate of 96% (212/220), as compared with a survival of 55% (12/22) in those with Type-II (P < 0.001) and 83% (55/66) in those with Type-III (P = 0.006) sFGR. The majority of sFGR pregnancies (130/177 (73%)) were first diagnosed at 16 or 20 weeks (early onset), with a survival rate of 85% (221/260), as compared with a survival of 98% (92/94) in sFGR first diagnosed at 30 weeks (late onset) (P = 0.04). A major anomaly in at least one twin was present in 28/177 (16%) sFGR cases. In these pregnancies, survival was 39/56 (70%), compared with 274/298 (92%) in those without an anomaly (P < 0.001). Subsequent development of TTTS (odds ratio (OR), 0.18 (95% CI, 0.06-0.52)), Type-II sFGR (OR, 0.06 (95% CI, 0.02-0.24)) and Type-III sFGR (OR, 0.21 (95% CI, 0.07-0.60)) and presence of a major anomaly in at least one twin (OR, 0.12 (95% CI, 0.04-0.34)), but not gestational age at first diagnosis, were independently associated with decreased survival. CONCLUSIONS: Isolated sFGR is associated with a 90% survival rate in monochorionic diamniotic twin pregnancies. The subsequent development of TTTS, absent or reversed end-diastolic flow in the umbilical artery of the smaller twin and the presence of a major anomaly adversely affect survival in sFGR. Copyright © 2020 ISUOG. Published by John Wiley & Sons Ltd.

Consensus diagnostic criteria and monitoring of twin anemia-polycythemia sequence: Delphi procedure.

OBJECTIVES: Twin anemia-polycythemia sequence (TAPS) is associated with increased perinatal morbidity and mortality. Inconsistencies in the diagnostic criteria for TAPS exist, which hinder the ability to establish robust evidence-based management or monitoring protocols. The main aim of this study was to determine, by expert consensus using a Delphi procedure, the key diagnostic features and optimal monitoring approach for TAPS. METHODS: A Delphi process was conducted among an international panel of experts on TAPS. Panel members were provided with a list of literature-based parameters for diagnosing and monitoring TAPS. They were asked to rate the importance of the parameters on a five-point Likert scale. Consensus was sought to determine the cut-off values for accepted parameters, as well as parameters used in the monitoring of and assessment of outcome in twin pregnancy complicated by TAPS. RESULTS: A total of 132 experts were approached. Fifty experts joined the first round, of whom 33 (66%) completed all three rounds. There was agreement that the monitoring interval for the development of TAPS should be every 2 weeks and that the severity should be assessed antenatally using a classification system based on middle cerebral artery (MCA) peak systolic velocity (PSV), but there was no agreement on the gestational age at which to start monitoring. Once the diagnosis of TAPS is made, monitoring should be scheduled weekly. For the antenatal diagnosis of TAPS, the combination of MCA-PSV ≥ 1.5 MoM in the anemic twin and ≤ 0.8 MoM in the polycythemic twin was agreed. Alternatively, MCA-PSV discordance ≥ 1 MoM can be used to diagnose TAPS. Postnatally, hemoglobin difference ≥ 8 g/dL and intertwin reticulocyte ratio ≥ 1.7 were agreed criteria for diagnosis of TAPS. There was no agreement on the cut-off of MCA-PSV or its discordance for prenatal intervention. The panel agreed on prioritizing perinatal and long-term survival outcomes in follow-up studies. CONCLUSIONS: Consensus-based diagnostic features of TAPS, as well as cut-off values for the parameters involved, were agreed upon by a panel of experts. Future studies are needed to validate these diagnostic features before they can be used in clinical trials of interventions. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.

Core outcome set for studies investigating management of selective fetal growth restriction in twins.

OBJECTIVE: Selective fetal growth restriction (sFGR) occurs in monochorionic twin pregnancies when unequal placental sharing leads to restriction in the growth of just one twin. Management options include laser separation of the fetal circulations, selective reduction or expectant management, but what constitutes the best treatment is not yet known. New trials in this area are urgently needed but, in this rare and complex group, maximizing the relevance and utility of clinical research design and outputs is paramount. A core outcome set ensures standardized outcome collection and reporting in future research. The objective of this study was to develop a core outcome set for studies evaluating treatments for sFGR in monochorionic twins. METHODS: An international steering group of clinicians, researchers and patients with experience of sFGR was established to oversee the process of development of a core outcome set for studies investigating the management of sFGR. Outcomes reported in the literature were identified through a systematic review and informed the design of a three-round Delphi survey. Clinicians, researchers, and patients and family representatives participated in the survey. Outcomes were scored on a Likert scale from 1 (limited importance for making a decision) to 9 (critical for making a decision). Consensus was defined a priori as a Likert score of ≥ 8 in the third round of the Delphi survey. Participants were then invited to take part in an international meeting of stakeholders in which the modified nominal group technique was used to consider the consensus outcomes and agree on a final core outcome set. RESULTS: Ninety-six outcomes were identified from 39 studies in the systematic review. One hundred and three participants from 23 countries completed the first round of the Delphi survey, of whom 88 completed all three rounds. Twenty-nine outcomes met the a priori criteria for consensus and, along with six additional outcomes, were prioritized in a consensus development meeting, using the modified nominal group technique. Twenty-five stakeholders participated in this meeting, including researchers (n = 3), fetal medicine specialists (n = 3), obstetricians (n = 2), neonatologists (n = 3), midwives (n = 4), parents and family members (n = 6), patient group representatives (n = 3), and a sonographer. Eleven core outcomes were agreed upon. These were live birth, gestational age at birth, birth weight, intertwin birth-weight discordance, death of surviving twin after death of cotwin, loss during pregnancy or before final hospital discharge, parental stress, procedure-related adverse maternal outcome, length of neonatal stay in hospital, neurological abnormality on postnatal imaging and childhood disability. CONCLUSIONS: This core outcome set for studies investigating the management of sFGR represents the consensus of a large and diverse group of international collaborators. Use of these outcomes in future trials should help to increase the clinical relevance of research on this condition. Consensus agreement on core outcome definitions and measures is now required. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.

Outcome of twin-to-twin transfusion syndrome in monochorionic monoamniotic twin pregnancy: systematic review and meta-analysis.

OBJECTIVES: To explore the outcome of monochorionic monoamniotic (MCMA) twin pregnancies affected by twin-to-twin transfusion syndrome (TTTS). METHODS: MEDLINE and EMBASE databases were searched for studies reporting the outcome of MCMA twin pregnancies complicated by TTTS. The primary outcome was intrauterine death (IUD); secondary outcomes were miscarriage, single IUD, double IUD, neonatal death (NND), perinatal death (PND), survival of at least one twin, survival of both twins and preterm birth (PTB) before 32 weeks' gestation. Outcomes were assessed in MCMA twins affected by TTTS not undergoing intervention and in those treated with amniodrainage, laser therapy or cord occlusion. Subgroup analysis was performed including cases diagnosed before 24 weeks. Random-effects meta-analysis of proportions was used to analyze the data. RESULTS: Fifteen cohort studies, including 888 MCMA twin pregnancies, of which 44 were affected by TTTS, were included in the review. There was no randomized trial comparing the different management options in MCMA twin pregnancies complicated by TTTS. In cases not undergoing intervention, miscarriage occurred in 11.0% of fetuses, while the incidence of IUD, NND and PND was 25.2%, 12.2% and 31.2%, respectively. PTB complicated 50.5% of these pregnancies. In cases treated by laser surgery, the incidence of miscarriage, IUD, NND and PND was 19.6%, 27.4%, 7.4% and 35.9%, respectively, and the incidence of PTB before 32 weeks' gestation was 64.9%. In cases treated with amniodrainage, the incidence of IUD, NND and PND was 31.3%, 13.5% and 45.7% respectively, and PTB complicated 76.2% of these pregnancies. Analysis of cases undergoing cord occlusion was affected by the very small number of included cases. Miscarriage occurred in 19.2%, while there was no case of IUD or NND of the surviving twin. PTB before 32 weeks occurred in 50.0% of these cases. CONCLUSIONS: MCMA twin pregnancies complicated by TTTS are at high risk of perinatal mortality and PTB. Further studies are needed in order to elucidate the optimal type of prenatal treatment in these pregnancies. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.

Treatment and outcome of 370 cases with spontaneous or post-laser twin anemia-polycythemia sequence managed in 17 fetal therapy centers.

OBJECTIVE: To investigate the antenatal management and outcome in a large international cohort of monochorionic twin pregnancies with spontaneous or post-laser twin anemia-polycythemia sequence (TAPS). METHODS: This study analyzed data of monochorionic twin pregnancies diagnosed antenatally with spontaneous or post-laser TAPS in 17 fetal therapy centers, recorded in the TAPS Registry between 2014 and 2019. Antenatal diagnosis of TAPS was based on fetal middle cerebral artery peak systolic velocity > 1.5 multiples of the median (MoM) in the TAPS donor and < 1.0 MoM in the TAPS recipient. The following antenatal management groups were defined: expectant management, delivery within 7 days after diagnosis, intrauterine transfusion (IUT) (with or without partial exchange transfusion (PET)), laser surgery and selective feticide. Cases were assigned to the management groups based on the first treatment that was received after diagnosis of TAPS. The primary outcomes were perinatal mortality and severe neonatal morbidity. The secondary outcome was diagnosis-to-birth interval. RESULTS: In total, 370 monochorionic twin pregnancies were diagnosed antenatally with TAPS during the study period and included in the study. Of these, 31% (n = 113) were managed expectantly, 30% (n = 110) with laser surgery, 19% (n = 70) with IUT (± PET), 12% (n = 43) with delivery, 8% (n = 30) with selective feticide and 1% (n = 4) underwent termination of pregnancy. Perinatal mortality occurred in 17% (39/225) of pregnancies in the expectant-management group, 18% (38/215) in the laser group, 18% (25/140) in the IUT (± PET) group, 10% (9/86) in the delivery group and in 7% (2/30) of the cotwins in the selective-feticide group. The incidence of severe neonatal morbidity was 49% (41/84) in the delivery group, 46% (56/122) in the IUT (± PET) group, 31% (60/193) in the expectant-management group, 31% (57/182) in the laser-surgery group and 25% (7/28) in the selective-feticide group. Median diagnosis-to-birth interval was longest after selective feticide (10.5 (interquartile range (IQR), 4.2-14.9) weeks), followed by laser surgery (9.7 (IQR, 6.6-12.7) weeks), expectant management (7.8 (IQR, 3.8-14.4) weeks), IUT (± PET) (4.0 (IQR, 2.0-6.9) weeks) and delivery (0.3 (IQR, 0.0-0.5) weeks). Treatment choice for TAPS varied greatly within and between the 17 fetal therapy centers. CONCLUSIONS: Antenatal treatment for TAPS differs considerably amongst fetal therapy centers. Perinatal mortality and morbidity were high in all management groups. Prolongation of pregnancy was best achieved by expectant management, treatment by laser surgery or selective feticide. © 2020 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of the International Society of Ultrasound in Obstetrics and Gynecology.

Core outcome set for research studies evaluating treatments for twin-twin transfusion syndrome.

OBJECTIVE: To develop, using a Delphi procedure and a nominal group technique, a core outcome set (COS) for studies evaluating treatments for twin-twin transfusion syndrome (TTTS), which should assist in standardizing outcome selection, collection and reporting in future research studies. METHODS: An international steering group comprising healthcare professionals, researchers and patients with experience of TTTS guided the development of this COS. Potential core outcomes, identified through a comprehensive literature review and supplemented by outcomes suggested by the steering group, were entered into a three-round Delphi survey. Healthcare professionals, researchers, and patients or relatives of patients who had experienced TTTS were invited to participate. Consensus was defined a priori using the 15%/70% definition of the Core Outcome Measures in Effectiveness Trials (COMET) initiative. The modified nominal group technique was used to evaluate the consensus outcomes in a face-to-face consultation meeting and identify the final COS. RESULTS: One hundred and three participants, from 29 countries, participated in the three-round Delphi survey. Of those, 88 completed all three rounds. Twenty-two consensus outcomes were identified through the Delphi procedure and entered into the modified nominal group technique. The consensus meeting was attended by 11 healthcare professionals, two researchers and three patients; 12 core outcomes were prioritized for inclusion in the COS. Fetal core outcomes included live birth, pregnancy loss (including miscarriage, stillbirth, termination of pregnancy and neonatal mortality), subsequent death of a cotwin following single-twin demise at the time of treatment, recurrence of TTTS, twin anemia-polycythemia sequence and amniotic band syndrome. Neonatal core outcomes included gestational age at delivery, birth weight, brain injury syndromes and ischemic limb injury. Maternal core outcomes included maternal mortality and admission to Level-2 or -3 care setting. One aspirational outcome, neurodevelopment at 18-24 months of age, was also prioritized. CONCLUSIONS: Implementing the COS for TTTS within future research studies could make a substantial contribution to advancing the usefulness of research in TTTS. Standardized definitions and measurement instruments are now required for individual core outcomes. Copyright © 2018 ISUOG. Published by John Wiley & Sons Ltd.

Consensus definition and essential reporting parameters of selective fetal growth restriction in twin pregnancy: a Delphi procedure.

OBJECTIVES: Twin pregnancy complicated by selective fetal growth restriction (sFGR) is associated with increased perinatal mortality and morbidity. Inconsistencies in the diagnostic criteria for sFGR employed in existing studies hinder the ability to compare or combine their findings. It is therefore challenging to establish robust evidence-based management or monitoring pathways for these pregnancies. The main aim of this study was to determine, by expert consensus using a Delphi procedure, the key diagnostic features of and the essential reporting parameters in sFGR. METHODS: A Delphi process was conducted among an international panel of experts in sFGR in twin pregnancy. Panel members were provided with a list of literature-based parameters for diagnosing sFGR and were asked to rate their importance on a five-point Likert scale. Parameters were described as solitary (sufficient to diagnose sFGR, even if all other parameters are normal) or contributory (those that require other abnormal parameter(s) to be present for the diagnosis of sFGR). Consensus was sought to determine the cut-off values for accepted parameters, as well as parameters used in the monitoring, management and assessment of outcome of twin pregnancy complicated by sFGR. The questions were presented in two separate categories according to chorionicity. RESULTS: A total of 72 experts were approached, of whom 60 agreed to participate and entered the first round; 48 (80%) completed all four rounds. For the definition of sFGR irrespective of chorionicity, one solitary parameter (estimated fetal weight (EFW) of one twin < 3rd centile) was agreed. For monochorionic twin pregnancy, at least two out of four contributory parameters (EFW of one twin < 10th centile, abdominal circumference of one twin < 10th centile, EFW discordance of ≥ 25%, and umbilical artery pulsatility index of the smaller twin > 95th centile) were agreed. For sFGR in dichorionic twin pregnancy, at least two out of three contributory parameters (EFW of one twin < 10th centile, EFW discordance of ≥ 25%, and umbilical artery pulsatility index of the smaller twin > 95th centile) were agreed. CONCLUSIONS: Consensus-based diagnostic features of sFGR in both monochorionic and dichorionic twin pregnancies, as well as cut-off values for the parameters involved, were agreed upon by a panel of experts. Future studies are needed to validate these diagnostic features before they can be used in clinical trials of interventions. Copyright © 2018 ISUOG. Published by John Wiley & Sons Ltd.

Does site of cord insertion increase risk of adverse outcome, twin-to-twin transfusion syndrome and discordant growth in monochorionic twin pregnancy?

OBJECTIVES: It is not currently well known to what extent the sites of cord insertion influence the risk of complicated outcome in monochorionic twin pregnancy. The objectives of this study were to examine whether the sites of cord insertion, as determined on prenatal ultrasound examination, affect the risks of adverse outcome, twin-to-twin transfusion syndrome (TTTS) and discordant growth, and whether discordance in insertion sites or velamentous insertion in one or both twins best predicts risk. METHODS: This was a retrospective cohort study of monochorionic diamniotic twin pregnancies followed from the first trimester. The cohort was divided into three groups of increasing discordance in cord insertion sites: concordant (normal-normal; marginal-marginal; velamentous-velamentous), intermediate (normal-marginal; marginal-velamentous) and discordant (normal-velamentous). Adverse outcome was defined as fetal or neonatal loss or birth prior to 32 weeks. The associations of adverse outcome, TTTS and discordant growth were assessed using logistic regression analysis with the following predictors: the three groups of insertion sites and velamentous insertion in one or both twins. RESULTS: Included in the analysis were 518 pregnancies. On univariate analysis, both discordant and velamentous insertions in one twin increased the risk of adverse outcome, TTTS and discordant growth. Intermediate insertion only increased the risk of discordant growth. Velamentous insertion in both twins increased the risk of adverse outcome and TTTS, but not of discordant growth. Multivariate logistic regression analysis showed velamentous insertion in one or both twins to independently predict adverse outcome and TTTS. For discordant growth, both intermediate/discordant and velamentous cord insertion in one twin were independent predictors. CONCLUSIONS: Velamentous cord insertion in one or both twins increases the risk of adverse outcome and TTTS, irrespective of discordance in the insertion sites, whereas the risk of discordant growth is determined by both discordance in insertion sites and velamentous cord insertion in one twin. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.

Fertility, pregnancy and gynecological outcomes after fetoscopic surgery for congenital diaphragmatic hernia.

STUDY QUESTION: What is the impact of fetoscopic surgery for isolated Congenital Diaphragmatic Hernia (CDH) on future reproductive and gynecological outcomes? SUMMARY ANSWER: We did not observe an increase of obstetric or gynecological problems after fetoscopic surgery nor was there an increased risk for subsequent infertility. WHAT IS KNOWN ALREADY: The reproductive and gynecological outcomes of patients undergoing open maternal-fetal surgery are known. The most relevant counseling items are the elevated risk for uterine dehiscence and rupture (up to 14%). STUDY DESIGN, SIZE, DURATION: Bi-centric study over a 10-year period including 371 women carrying a fetus with isolated CDH either managed expectantly (n = 167) or operated in utero (n = 204). PARTICIPANTS/MATERIALS, SETTING, METHODS: Consenting patients filled out a survey with 23 questions (2 open and 21 multiple choice). Questionnaires were custom designed to obtain information on subsequent reproductive or gynecological problems as well as psychological impact. MAIN RESULTS AND THE ROLE OF CHANCE: The response rate was 40% (147/371). More women in the FETO group attempted a subsequent pregnancy: 70% (62/89) when compared with 47% (27/58) in controls (P = 0.009). This coincided with a longer follow-up in the FETO group (76 versus 59 months; P < 0.001) and a lower survival rate in the index pregnancy (53 versus 72%; P = 0.028). There was no difference in the number of nulliparous or parous women, neither in the conception rate. In total, there were 129 subsequent pregnancies. Nobody reported secondary fertility problems. Four women in the FETO group and one in the control reported a congenital anomaly in a subsequent pregnancy. Twenty-one pregnancies were reported with at least one complication (FETO: 23% (14/60), controls 27% (7/26)). During delivery or in the post-partum period 11 patients reported at least 1 complication (FETO 17% (10/59), controls 4% (1/24)). New onset gynecological problems occurred in 14 participants (10%). None of these events were more likely in one or the other group. Psychological and emotional impacts were frequent in both the FETO (41%) and the control groups (46%) (P = 0.691). LIMITATIONS, REASONS FOR CAUTION: The response rate was 40% (147/371), less than desired. The use of unvalidated self-reported outcomes may skew exact determination of the nature and severity of medical complications. The number of observations for uncommon events was low. The mean follow-up period to detect gynecological complications may be too short. WIDER IMPLICATIONS OF THE FINDINGS: This is the first evidence that fetoscopic surgery for CDH does not compromise future reproductive potential or obstetrical outcome when compared with expectant management. A pregnancy complicated by a serious congenital birth defect, such as CDH, frequently has a measurable psychological impact. STUDY FUNDING/COMPETING INTEREST: The authors have no conflicts to declare. J.D. receives a fundamental clinical research grant of the Fonds Wetenschappelijk Onderzoek - Vlaanderen (FWO; 18.01207). A.C.E. is supported by the Erasmus+Program of the European Union (Framework agreement number 2013-0040; contract 1011990). This was presented at the 61st meeting of the Society of Gynaecologic Investigation, in Florence, March 2014 (F-111).

Operator competence in fetoscopic laser surgery for twin-twin transfusion syndrome: validation of a procedure-specific evaluation tool.

OBJECTIVES: Fetoscopic laser surgery for twin-twin transfusion syndrome is a procedure for which no objective tools exist to assess technical skills. To ensure that future fetal surgeons reach competence prior to performing the procedure unsupervised, we developed a performance assessment tool. The aim of this study was to validate this assessment tool for reliability and construct validity. METHODS: We made use of a procedure-specific evaluation instrument containing all essential steps of the fetoscopic laser procedure, which was previously created using Delphi methodology. Eleven experts and 13 novices from three fetal medicine centers performed the procedure on the same simulator. Two independent observers assessed each surgery using the instrument (maximum score: 52). Interobserver reliability was assessed using Spearman correlation. We compared the performance of novices and experts to assess construct validity. RESULTS: The interobserver reliability was high (Rs = 0.974, P < 0.001). Checklist scores for experts and novices were significantly different; the median score for novices was 28/52 (54%), whereas that for experts was 47.5/52 (91%) (P < 0.001). The procedure time and fetoscopy time were significantly shorter (P < 0.001) for experts. Residual anastomoses were found in 1/11 (9%) procedures performed by experts and in 9/13 (69%) procedures performed by novices (P = 0.005). Multivariable analysis showed that the checklist score, independent of age and gender, predicted competence. CONCLUSIONS: The procedure-specific assessment tool for fetoscopic laser surgery shows good interobserver reliability and discriminates experts from novices. This instrument may therefore be a useful tool in the training curriculum for fetal surgeons. Further intervention studies with reassessment before and after training may increase the construct validity of the tool. Copyright © 2015 ISUOG. Published by John Wiley & Sons Ltd.