Fetal surgery for open neural tube defect with severe ventriculomegaly.

OBJECTIVE: Prenatal open neural tube defect (ONTD) repair is performed to decrease the risk of needing treatment for hydrocephalus after birth and to preserve motor function. Some centers may not consider patients to be candidates for surgery if severe ventriculomegaly is present and there is no expected benefit in risk for hydrocephalus treatment. This study sought to compare the postnatal outcome of fetuses with ONTD and severe ventriculomegaly (ventricular width ≥ 15 mm) that underwent prenatal repair with the outcome of fetuses with severe ventriculomegaly that underwent postnatal repair and fetuses without severe ventriculomegaly (< 15 mm) that underwent prenatal repair. METHODS: This was a retrospective study of fetuses with ONTD that underwent prenatal or postnatal repair between 2012 and 2021 at a single institution. The cohort was divided into two groups based on preoperative fetal ventricular size: those with severe ventriculomegaly (ventricular width ≥ 15 mm) and those without severe ventriculomegaly (< 15 mm). Fetal ventricular size was measured by magnetic resonance imaging before surgery using the standardized approach and the mean size of the left and right ventricles was used for analysis. Motor function of the lower extremities was assessed at the time of referral by ultrasound and if flexion-extension movements of the ankle were seen it was considered as preserved S1 motor function. Postnatal outcomes, including motor function of the lower extremities at birth and the need for a diversion procedure for hydrocephalus treatment during the first year after birth, were collected and compared between groups. Multivariate regression analysis was used to adjust for potential confounders. RESULTS: In this study, 154 patients were included: 145 underwent fetal surgery (101 fetoscopic and 44 open hysterotomy) and nine with severe ventriculomegaly underwent postnatal repair. Among the 145 patients who underwent fetal surgery, 22 presented with severe ventriculomegaly. Fetuses with severe ventriculomegaly at referral that underwent prenatal repair were significantly more likely to need hydrocephalus treatment by 12 months after birth than those without severe ventriculomegaly (61.9% vs 28.9%, P < 0.01). However, motor function assessment at birth was similar between both prenatal repair groups (odds ratio, 0.92 (95% CI, 0.33-2.59), P = 0.88), adjusted for the anatomical level of the lesion. The prenatal repair group with severe ventriculomegaly had better preserved motor function at birth compared to the postnatal repair group with severe ventriculomegaly (median level, S1 vs L3, P < 0.01; proportion with S1 motor function, 68.2% vs 11.1%, P < 0.01). Fetuses with severe ventriculomegaly that underwent prenatal repair had an 18.9 (95% CI, 1.2-290.1)-times higher chance of having intact motor function at birth, adjusted for ethnicity, presence of club foot at referral and gestational age at delivery, compared with the postnatal repair group. There was no significant difference in the need for hydrocephalus treatment in the first year after birth between prenatal and postnatal repair groups with severe ventriculomegaly (61.9% vs 87.5%, P = 0.18). CONCLUSIONS: Although fetuses with ONTD and severe ventriculomegaly do not seem to benefit from fetal surgery in terms of postnatal hydrocephalus treatment, there is an increased chance of preserved motor function at birth. Results from this study highlight the benefit of prenatal ONTD repair for cases with severe ventriculomegaly at referral to preserve motor function. © 2024 International Society of Ultrasound in Obstetrics and Gynecology.

Perforation of cavum septi pellucidi in open spina bifida and need for hydrocephalus treatment by 1 year of age.

OBJECTIVE: In-utero repair of an open neural tube defect (ONTD) reduces the risk of developing severe hydrocephalus postnatally. Perforation of the cavum septi pellucidi (CSP) may reflect increased intraventricular pressure in the fetal brain. We sought to evaluate the association of perforated CSP visualized on fetal imaging before and/or after in-utero ONTD repair with the eventual need for hydrocephalus treatment by 1 year of age. METHODS: This was a retrospective cohort study of consecutive patients who underwent laparotomy-assisted fetoscopic ONTD repair between 2014 and 2021 at a single center. Eligibility criteria for surgery were based on those of the Management of Myelomeningocele Study (MOMS), although a maternal prepregnancy body mass index of up to 40 kg/m2 was allowed. Fetal brain imaging was performed with ultrasound and magnetic resonance imaging (MRI) at referral and 6 weeks postoperatively. Stored ultrasound and MRI scans were reviewed retrospectively to assess CSP integrity. Medical records were reviewed to determine whether hydrocephalus treatment was needed within 1 year of age. Parametric and non-parametric tests were used as appropriate to compare outcomes between cases with perforated CSP and those with intact CSP as determined on ultrasound at referral. Logistic regression analysis was performed to assess the predictive performance of various imaging markers for the need for hydrocephalus treatment. RESULTS: A total of 110 patients were included. Perforated CSP was identified in 20.6% and 22.6% of cases on preoperative ultrasound and MRI, respectively, and in 26.6% and 24.2% on postoperative ultrasound and MRI, respectively. Ventricular size increased between referral and after surgery (median, 11.00 (range, 5.89-21.45) mm vs 16.00 (range, 7.00-43.5) mm; P < 0.01), as did the proportion of cases with severe ventriculomegaly (ventricular width ≥ 15 mm) (12.7% vs 57.8%; P < 0.01). Complete CSP evaluation was achieved on preoperative ultrasound in 107 cases, of which 22 had a perforated CSP and 85 had an intact CSP. The perforated-CSP group presented with larger ventricles (mean, 14.32 ± 3.45 mm vs 10.37 ± 2.37 mm; P < 0.01) and a higher rate of severe ventriculomegaly (40.9% vs 5.9%; P < 0.01) compared to those with an intact CSP. The same trends were observed at 6 weeks postoperatively for mean ventricular size (median, 21.0 (range, 13.0-43.5) mm vs 14.3 (range, 7.0-29.0) mm; P < 0.01) and severe ventriculomegaly (95.0% vs 46.8%; P < 0.01). Cases with a perforated CSP at referral had a lower rate of hindbrain herniation (HBH) reversal postoperatively (65.0% vs 88.6%; P = 0.01) and were more likely to require treatment for hydrocephalus (89.5% vs 22.7%; P < 0.01). The strongest predictor of the need for hydrocephalus treatment within 1 year of age was lack of HBH reversal on MRI (odds ratio (OR), 36.20 (95% CI, 5.96-219.12); P < 0.01) followed by perforated CSP on ultrasound at referral (OR, 23.40 (95% CI, 5.42-100.98); P < 0.01) and by perforated CSP at 6-week postoperative ultrasound (OR, 19.48 (95% CI, 5.68-66.68); P < 0.01). CONCLUSIONS: The detection of a perforated CSP in fetuses with ONTD can reliably identify those cases at highest risk for needing hydrocephalus treatment by 1 year of age. Evaluation of this brain structure can improve counseling of families considering fetal surgery for ONTD, in order to set appropriate expectations about postnatal outcome. © 2023 International Society of Ultrasound in Obstetrics and Gynecology.

Ambulation after in-utero fetoscopic or open neural tube defect repair: predictors for ambulation at 30 months.

OBJECTIVES: To compare the ambulatory status of a cohort of children who had undergone prenatal repair of an open neural tube defect (ONTD) using one of two different methods (fetoscopic or open hysterotomy) with that of a cohort who had undergone postnatal repair, and to identify the best predictors of ambulation at 30 months of age. METHODS: This was a retrospective review of a cohort of children who underwent ONTD repair either prenatally (n = 110), by fetoscopic surgery (n = 73) or open hysterotomy surgery (n = 37), or postnatally (n = 51), in a single tertiary hospital between November 2011 and May 2023. The cohort comprised a consecutive sample of cases who had undergone ONTD repair in-utero following Management of Myelomeningocele Study (MOMS) trial criteria and cases who had undergone postnatal repair, meeting the same criteria, which were also followed up after birth at the same institution. Motor function assessment by ultrasound was recorded at referral, 6 weeks after prenatal repair, or after referral in postnatally repaired cases, and at the last ultrasound scan before delivery. Clinical examinations to assess motor function at birth and at 12 months were retrieved from records. Intact motor function was defined as first sacral myotome (S1) motor function. Ambulatory status data at each follow-up visit were collected. The proportion of children who were able to walk independently after 30 months of age was compared between those who had undergone fetoscopic vs open prenatal surgery and between prenatal (by either fetoscopic or open surgery) and postnatal ONTD repair. Logistic regression analyses were performed to identify predictors for independent ambulation. RESULTS: After 30 months, the proportion of infants who were able to walk independently was higher in prenatally vs postnatally repaired cases (51.8% vs 15.7%, P < 0.01), and there was no difference between those with fetoscopic (52.1%) vs open (51.4%) prenatal repair (P = 0.66). In the prenatally repaired group, having intact motor function at 12 months (adjusted odds ratio (aOR), 9.14 (95% CI, 2.64-31.63), P < 0.01) and at birth (aOR, 4.50 (95% CI, 1.21-16.80), P = 0.02) were significant predictors of independent walking at 30 months; an anatomical level of lesion below L2 at referral (aOR, 1.83 (95% CI, 1.30-2.58), P = 0.01) and female gender (aOR, 3.51 (95% CI, 1.43-8.61), P < 0.01) were also predictive for this outcome. CONCLUSIONS: Prenatally repaired cases of ONTD have a better chance of being able to walk independently at 30 months than do those who undergo postnatal repair. In patients with prenatally repaired ONTD, ambulatory status at 30 months can be predicted by observing a low lesion level at referral (below L2) and intact motor function postnatally. These results have implications for parental counseling and planning for supportive therapy in pregnancies affected by ONTD. © 2024 International Society of Ultrasound in Obstetrics and Gynecology.

Outcome of laser photocoagulation in monochorionic diamniotic twin pregnancy complicated by Type-II selective fetal growth restriction.

OBJECTIVES: To evaluate the outcome of monochorionic diamniotic (MCDA) twins complicated by Type-II selective fetal growth restriction (sFGR) who underwent fetoscopic laser photocoagulation and to validate a previously proposed subclassification system for Type-II sFGR in a large multicenter cohort. METHODS: This retrospective multicenter cohort study included all MCDA twins complicated by Type-II sFGR who underwent laser photocoagulation of placental anastomoses at four large tertiary fetal-care centers between 2006 and 2020. Cases were subclassified according to a recently proposed system based on Doppler evaluation of the ductus venosus (DV) and middle cerebral artery (MCA) into Type-IIA (normal DV flow and MCA peak systolic velocity (PSV) of the growth-restricted fetus) or Type-IIB (absent or reversed flow in the DV during atrial contraction and/or MCA-PSV ≥ 1.5 multiples of the median of the growth-restricted fetus). Demographic characteristics and pregnancy outcomes were compared between the groups. Data are presented as mean ± SD or n (%) as appropriate. P-values < 0.05 were considered statistically significant. RESULTS: A total of 98 patients with MCDA twins met our inclusion criteria, with 56 subclassified as Type IIA and 42 as Type IIB. Demographic characteristics were similar between the groups; however, Type-IIB cases had a significantly earlier gestational age at diagnosis and at laser surgery, as well as larger intertwin estimated fetal weight discordance, which may be a reflection of disease severity. Postnatal survival of the growth-restricted fetus to 30 days of age was significantly lower in Type-IIB compared to Type-IIA cases (23.8% vs 46.4%; P = 0.034). CONCLUSIONS: In MCDA twins complicated by Type-II sFGR and treated with laser photocoagulation of placental anastomoses, preoperative Doppler assessment of the DV and MCA helped identify a subset of patients at increased risk of demise of the growth-restricted fetus following intervention. This study provides valuable information for guiding surgical management and patient counseling. © 2023 International Society of Ultrasound in Obstetrics and Gynecology.

Effect of preoperative low-normal cervical length on perinatal outcome after laparotomy-assisted fetoscopic spina bifida repair.

OBJECTIVE: To determine if preoperative cervical length in the low-normal range increases the risk of adverse perinatal outcome in patients undergoing fetoscopic spina bifida repair. METHODS: This was a retrospective cohort study of patients who underwent fetal spina bifida repair between September 2014 and May 2022 at a single center. Cervical length was measured on transvaginal ultrasound during the week before surgery. Eligibility for laparotomy-assisted fetoscopic spina bifida repair was as per the criteria of the Management of Myelomeningocele Study, although maternal body mass index (BMI) up to 40 kg/m2 was allowed. Laparotomy-assisted fetoscopic spina bifida repair was performed, with carbon dioxide insufflation via two 12-French ports in the exteriorized uterus. All patients received the same peri- and postoperative tocolysis regimen, including magnesium sulfate, nifedipine and indomethacin. Postoperative follow-up ultrasound scans were performed either weekly (< 32 weeks' gestation) or twice a week (≥ 32 weeks). Perinatal outcome was compared between patients with a preoperative cervical length of 25-30 mm vs those with a cervical length > 30 mm. Logistic regression analyses and generalized linear mixed regression analyses were used to predict delivery at less than 30, 34 and 37 weeks' gestation. RESULTS: The study included 99 patients with a preoperative cervical length > 30 mm and 12 patients with a cervix 25-30 mm in length. One further case which underwent spina bifida repair was excluded because cervical length was measured > 1 week before surgery. No differences in maternal demographics, gestational age (GA) at surgery, duration of surgery or duration of carbon dioxide uterine insufflation were observed between groups. Cases with low-normal cervical length had an earlier GA at delivery (median (range), 35.2 (25.1-39.7) weeks vs 38.2 (26.0-40.9) weeks; P = 0.01), higher rates of delivery at < 34 weeks (41.7% vs 10.2%; P = 0.01) and < 30 weeks (25.0% vs 1.0%; P < 0.01) and a higher rate of preterm prelabor rupture of membranes (PPROM) (58.3% vs 26.3%; P = 0.04) at an earlier GA (mean ± SD, 29.3 ± 4.0 weeks vs 33.0 ± 2.4 weeks; P = 0.05) compared to those with a normal cervical length. Neonates of cases with low-normal cervical length had a longer stay in the neonatal intensive care unit (20 (7-162) days vs 9 (3-253) days; P = 0.02) and higher rates of respiratory distress syndrome (50.0% vs 14.4%; P < 0.01), sepsis (16.7% vs 1.0%; P = 0.03), necrotizing enterocolitis (16.7% vs 0%; P = 0.01) and retinopathy (33.3% vs 1.0%; P < 0.01). There was an association between preoperative cervical length and risk of delivery at < 30 weeks which was significant only for patients with a maternal BMI < 25 kg/m2 (odds ratio, 0.37 (95% CI, 0.07-0.81); P = 0.02). CONCLUSIONS: Low-normal cervical length (25-30 mm) as measured before in-utero laparotomy-assisted fetoscopic spina bifida repair may increase the risk of adverse perinatal outcomes, including PPROM and preterm birth, leading to higher rates of neonatal complications. These data warrant further research and are of critical relevance for clinical teams considering the eligibility of patients for in-utero spina bifida repair. Based on this evidence, patients with a low-normal cervical length should be aware of their increased risk for adverse perinatal outcome. © 2022 International Society of Ultrasound in Obstetrics and Gynecology.

Prediction of dual survival following fetoscopic laser photocoagulation for twin-twin transfusion syndrome.

OBJECTIVE: To develop a model based on factors available at the time of diagnosis of twin-twin transfusion syndrome (TTTS) for predicting the probability of dual twin survival following fetoscopic laser photocoagulation (FLP) using a machine-learning algorithm. METHODS: This was a retrospective study of data collected at two university-affiliated tertiary fetal centers between 2012 and 2021. The cohort included monochorionic diamniotic twin pregnancies complicated by TTTS that underwent FLP. Data were stratified based on survival 30 days after delivery, and cases with dual survival were compared to those without dual survival. A random forest machine-learning algorithm was used to construct a prediction model, and the relative importance value was calculated for each parameter that presented a statistically significant difference between the two study groups and was included in the model. The holdout method was applied to check overfitting of the random forest algorithm. A prediction model for dual twin survival 30 days after delivery was presented based on the test set. RESULTS: The study included 537 women with monochorionic diamniotic twin pregnancy, of whom 346 (64.4%) had dual twin survival at 30 days after delivery and were compared with 191 (35.6%) cases that had one or no survivors. Univariate analysis demonstrated no differences in demographic parameters between the groups. At the time of diagnosis, the dual-survival group had lower rates of estimated fetal weight (EFW) < 10th centile for gestational age in the donor twin (56.4% vs 69.4%; P = 0.004), intertwin EFW discordance > 25% (40.8% vs 56.5%; P = 0.001) and anterior placenta (40.5% vs 50.0%; P = 0.034). Comparison of Doppler findings between the two groups demonstrated significant differences in the donor twin, with a lower rate of pulsatility index (PI) > 95th centile in the umbilical artery and ductus venosus and a lower rate of PI < 5th centile in the fetal middle cerebral artery in the dual-survival group. Relative importance values for each of these six parameters were calculated, allowing the construction of a prediction model with an area under the receiver-operating-characteristics curve of 0.916 (95% CI, 0.887-0.946). CONCLUSIONS: We developed a predictive model for dual survival in monochorionic twin pregnancies following FLP for TTTS, which incorporates six variables obtained at the time of diagnosis of TTTS, including donor EFW < 10th centile, intertwin EFW discordance > 25%, anterior placenta and abnormal PI in the umbilical artery, ductus venosus and middle cerebral artery of the donor twin. This clinically applicable tool may improve treatment planning and patient counseling. © 2022 International Society of Ultrasound in Obstetrics and Gynecology.

Implication of chromosomal microarray analysis prior to in-utero repair of fetal open neural tube defect.

OBJECTIVE: In-utero repair of open neural tube defects (ONTD) is an accepted treatment option with demonstrated superior outcome for eligible patients. While current guidelines recommend genetic testing by chromosomal microarray analysis (CMA) when a major congenital anomaly is detected prenatally, the requirement for an in-utero repair, based on the Management of Myelomeningocele Study (MOMS) criteria, is a normal karyotype. In this study, we aimed to evaluate if CMA should be recommended as a prerequisite for in-utero ONTD repair. METHODS: This was a retrospective cohort study of pregnancies complicated by ONTD that underwent laparotomy-assisted fetoscopic repair or open-hysterotomy fetal surgery at a single tertiary center between September 2011 and July 2021. All patients met the MOMS eligibility criteria and had a normal karyotype. In a subset of the pregnancies (n = 77), CMA testing was also conducted. We reviewed the CMA results and divided the cohort into two groups according to whether clinically reportable copy-number variants (CNV) were detected (reportable-CNV group) or not (normal-CMA group). Surgical characteristics, complications, and maternal and early neonatal outcomes were compared between the two groups. The primary outcomes were fetal or neonatal death, hydrocephalus, motor function at 12 months of age and walking status at 30 months of age. Standard parametric and non-parametric statistical tests were employed as appropriate. RESULTS: During the study period, 146 fetuses with ONTD were eligible for and underwent in-utero repair. CMA results were available for 77 (52.7%) patients. Of those, 65 (84%) had a normal CMA and 12 (16%) had a reportable CNV, two of which were classified as pathogenic. The first case with a pathogenic CNV was diagnosed with a 749-kb central 22q11.21 deletion spanning low-copy-repeat regions B-D of chromosome 22; the second case was diagnosed with a 1.3-Mb interstitial deletion at 1q21.1q21.2. Maternal demographics, clinical characteristics, operative data and postoperative complications were similar between those with normal CMA results and those with reportable CNVs. There were no significant differences in gestational age at delivery or any obstetric and early neonatal outcome between the study groups. Motor function at birth and at 12 months of age, and walking status at 30 months of age, were similar between the two groups. CONCLUSIONS: Standard diagnostic testing with CMA should be offered when an ONTD is detected prenatally, as this approach has implications for counseling regarding prognosis and recurrence risk. Our results indicate that the presence of a clinically reportable CNV should not a priori affect eligibility for in-utero repair, as overall pregnancy outcome is similar in these cases to that of cases with normal CMA. Nevertheless, significant CMA results will require a case-by-case multidisciplinary discussion to evaluate eligibility. To generalize the conclusion of this single-center series, a larger, multicenter long-term study should be considered. © 2023 International Society of Ultrasound in Obstetrics and Gynecology.

Efficacy of long-term indomethacin therapy in prolonging pregnancy after fetoscopic laser surgery for twin-to-twin transfusion syndrome: a collaborative cohort study.

OBJECTIVE: To evaluate the efficacy of long-term indomethacin therapy (LIT) in prolonging pregnancy and reducing spontaneous preterm birth (PTB) in patients undergoing fetoscopic laser surgery (FLS) for the management of twin-to-twin transfusion syndrome (TTTS). DESIGN: Retrospective cohort study of prospectively collected data. SETTING: Collaborative multicentre study. POPULATION: Five hundred and fifty-seven consecutive TTTS cases that underwent FLS. METHODS: Long-term indomethacin therapy was defined as indomethacin use for at least 48 hours. Log-binomial regression was used to estimate the relative risk of PTB in the LIT group compared with a non-LIT group. Cox regression was used to evaluate the association between LIT use and FLS-to-delivery survival. MAIN OUTCOME MEASURES: Gestational age (GA) at delivery. RESULTS: Among the 411 pregnancies included, a total of 180 patients (43.8%) received LIT after FLS and 231 patients (56.2%) did not. Median GA at fetal intervention did not differ between groups (20.4 weeks). Median GA at delivery was significantly higher in the LIT group (33.6 weeks) compared with the non-LIT group (31.1 weeks; P < 0.001). FLS-to-delivery interval was significantly longer in the LIT group (P < 0.001). The risks of PTB before 34, 32, 28 and 26 weeks of gestation were all significantly lower in the LIT group compared with the non-LIT group (relative risks 0.69, 0.51, 0.37 and 0.18, respectively). The number needed to treat with LIT to prevent one PTB before 32 weeks of gestation was four, and to prevent one PTB before 34 weeks was five. CONCLUSION: Long-term indomethacin after FLS for TTTS was found to be associated with prolongation of pregnancy and reduced risk for PTB. TWEETABLE ABSTRACT: Long-term indomethacin used after fetoscopic laser surgery for twin-to-twin transfusion syndrome is effective in prolonging pregnancy and reducing the risk for preterm birth; especially extreme preterm birth.

Perinatal outcomes of fetoscopic laser surgery for twin-twin transfusion syndrome in triplet pregnancy: cohort study, systematic review and meta-analysis.

OBJECTIVES: The aims of this study were to investigate the perinatal outcome of dichorionic triamniotic (DCTA) and monochorionic triamniotic (MCTA) triplet pregnancies complicated by twin-twin transfusion syndrome (TTTS) treated with fetoscopic laser photocoagulation (FLP) in two academic fetal centers, and to conduct a systematic review of previously published data to investigate perinatal survival in this targeted population. METHODS: The first part of the study was a retrospective cohort study of prospectively collected data of consecutive triplet pregnancies with TTTS that underwent FLP at two fetal treatment centers between 2012 and 2020. Demographic, preoperative and operative variables and postoperative outcome were collected. Perinatal outcomes were investigated. The second part of the study was a systematic review and meta-analysis of studies evaluating the outcome of DCTA and/or MCTA triplet pregnancies, including our cohort study. PubMed, Web of Science and Scopus were searched from inception to September 2020. Primary outcomes were fetal survival (survival to birth), neonatal survival (survival to 28 days of age) and gestational age (GA) at birth. RESULTS: A total of 31 sets of triplets with TTTS managed with FLP were included in the cohort study. Of these, 24 were DCTA and seven were MCTA. There were no significant differences in preoperative and operative variables between the two groups. There were also no significant differences between groups in GA at delivery or perinatal survival rate, including fetal and neonatal survival of at least one triplet, at least two triplets and all three triplets. Nine studies, including our cohort study, were included in the systematic review (156 DCTA and 37 MCTA triplet pregnancies treated with FLP). The overall fetal and neonatal survival was 79% (95% CI, 75-83%) and 75% (95% CI, 71-79%), respectively, in DCTA cases and 74% (95% CI, 52-92%) and 71% (95% CI, 49-89%), respectively, in MCTA cases. The rate of preterm birth before 28 weeks and before 32 weeks' gestation was 14% (95% CI, 4-29%) and 61% (95% CI, 50-72%), respectively, in DCTA triplets and 21% (95% CI, 3-45%) and 82% (95% CI, 62-96%), respectively, in MCTA triplets. CONCLUSIONS: Triplet pregnancies with TTTS are at high risk of adverse perinatal outcome and preterm birth, regardless of chorionicity. The rate of survival after FLP in MCTA triplets was higher in our study than that reported in previous studies and is currently comparable with survival in DCTA triplets, which could be due to improved surgical skills. © 2022 International Society of Ultrasound in Obstetrics and Gynecology.

Iatrogenic chorioamniotic separation and septostomy following fetoscopic laser photocoagulation for twin-twin transfusion syndrome.

OBJECTIVE: To compare the perinatal outcomes of pregnancies complicated by chorioamniotic separation (CAS) vs septostomy following fetoscopic laser photocoagulation (FLP) for twin-twin transfusion syndrome (TTTS). METHODS: This was a retrospective cohort analysis of monochorionic diamniotic twin pregnancies with TTTS that underwent FLP at one of two university-affiliated tertiary medical centers between January 2012 and December 2020. CAS and septostomy were diagnosed either during the procedure or by ultrasonography within 24-48 h after FLP. Data on procedure and postprocedure parameters, pregnancy outcomes and survival were collected from the patients' electronic medical records. Pregnancies were stratified according to the presence of CAS, septostomy or neither. Patients diagnosed with both CAS and septostomy were analyzed separately. RESULTS: Of the 522 women included in the cohort, 38 (7.3%) were diagnosed with CAS, 68 (13.0%) with septostomy and 23 (4.4%) with both CAS and septostomy. The remaining 393 (75.3%) women comprised the control group. Groups did not differ in demographic characteristics. The septostomy group had a lower rate of selective fetal growth restriction than did the CAS and control groups (24.2% vs 36.8% vs 42.7%, respectively; P = 0.017). Moreover, intertwin size discordance was lower in the septostomy group (15.1% vs 23.4% in the CAS group and 25.5% in the control group; P = 0.001). Median gestational age at FLP was significantly lower in the CAS group (19.3 weeks vs 20.4 weeks in controls and 20.9 weeks in the septostomy group; P = 0.049). The rate of delivery prior to 34 weeks was significantly higher in the CAS group (89.2%), followed by the septostomy group (80.9%), compared with the control group (69.0%) (P = 0.006). A secondary analysis demonstrated that patients with both CAS and septostomy presented the highest rates of delivery prior to 34 weeks (100%) and 32 weeks (68.2%). CONCLUSIONS: CAS and septostomy following laser surgery for TTTS are independently associated with higher rates of preterm delivery. The presence of these two findings in the same patient enhances the risk of prematurity. © 2021 International Society of Ultrasound in Obstetrics and Gynecology.

Prediction of post-laser fetal death in selective growth restriction complicating twin-twin transfusion syndrome using standardized definitions.

OBJECTIVE: Selective fetal growth restriction (sFGR) complicating twin-twin transfusion syndrome (TTTS) is associated with a 3-6-fold increased risk of fetal demise after fetoscopic laser surgery (FLS). Identifying these patients is challenging due to varying definitions of sFGR used in the literature. The objective of this study was to determine the association of three currently used definitions for sFGR with demise of the smaller twin, typically the donor, following FLS for TTTS. METHODS: This was a retrospective cohort study of monochorionic diamniotic twin pregnancies undergoing FLS for TTTS between January 2015 and December 2018. Classification of the cohort as sFGR or non-sFGR was performed using three different definitions: (1) estimated fetal weight (EFW) of one twin < 10th centile and intertwin EFW discordance > 25%, according to the International Society of Ultrasound in Obstetrics and Gynecology (ISUOG) (Definition A); (2) EFW of one twin < 3rd centile, according to the solitary criterion for sFGR reported in a Delphi consensus (Definition B); and (3) presence of at least two of four of the following criteria: EFW of one twin < 10th centile, abdominal circumference of one twin < 10th centile, intertwin EFW discordance of ≥ 25% and umbilical artery pulsatility index of the smaller twin > 95th centile, according to the contributory criteria for sFGR in monochorionic diamniotic twin pregnancies reported in the Delphi consensus (Definition C). Pearson's χ2 and univariate and multivariate logistic regression analyses were performed to assess the association of classification as sFGR according to the different definitions with fetal demise within 48 h after FLS. RESULTS: A total of 124 pregnancies underwent FLS for TTTS during the study period. Of these, 46/124 (37.1%) were identified as having sFGR according to the ISUOG criteria (Definition A), 57/124 (46.0%) based on EFW < 3rd centile (Definition B) and 70/124 (56.5%) according to the Delphi contributory criteria (Definition C). There were no differences in maternal body mass index, recipient twin amniotic fluid volume, gestational age (GA) at intervention or GA at delivery between sFGR and non-sFGR cases for any of the three definitions. There were also no differences in the rates of postprocedure recipient demise or Doppler abnormalities in the recipient. Regardless of the definition used, sFGR cases showed a significantly higher rate of postprocedure donor twin demise compared with that in non-sFGR cases (Definition A: 28.3% vs 3.8%, P < 0.01; Definition B: 22.8% vs 4.5%, P = 0.02; Definition C: 22.9% vs 0%, P < 0.01). For all of the sFGR definitions, the rate of Stage-III TTTS was increased in sFGR compared to non-sFGR cases (Definition A: 65.2% vs 35.9%, P ≤ 0.01; Definition B: 59.6% vs 35.8%, P = 0.04; Definition C: 62.9% vs 25.9%, P < 0.01). All cases of donor demise met the criteria for sFGR according to Definition C. Classification as sFGR according to Definition C was associated with a significantly higher rate of post-FLS donor demise compared to Definitions A and B (χ2 , 15.32; P < 0.01). Logistic regression analysis demonstrated that sFGR cases had an increased risk of donor demise (Definition A: odds ratio (OR), 4.97 (95% CI, 1.77-13.94), P < 0.01; Definition B: OR, 4.39 (95% CI, 1.36-14.15), P = 0.01) and that staging of TTTS was also predictive of demise (OR, 2.26 (95% CI, 1.14-4.47), P = 0.02). After adjusting for GA at intervention and stage of TTTS, the results were similar (Definition A: OR, 6.48 (95% CI, 2.11-24.56), P = 0.002; Definition B: OR, 4.16 (95% CI, 1.35-15.74), P = 0.02). CONCLUSIONS: The rate of fetal demise following FLS for TTTS is increased in the presence of sFGR. Improving diagnosis of sFGR should improve counseling and may affect management. The Delphi method of defining sFGR based on the presence of at least two of four contributory criteria had the highest predictive value for donor demise following FLS for TTTS. © 2020 International Society of Ultrasound in Obstetrics and Gynecology.

Perinatal outcomes of iatrogenic chorioamniotic separation following fetoscopic surgery: systematic review and meta-analysis.

OBJECTIVE: To compare the perinatal outcomes between pregnancies with and those without iatrogenic chorioamniotic separation (iCAS) following fetoscopic intervention. METHODS: We performed a search in PubMed, EMBASE, Scopus, Web of Science and Google Scholar from inception up to December 2020 for studies comparing perinatal outcomes between pregnancies that developed and those that did not develop iCAS after fetoscopic intervention for twin-to-twin transfusion syndrome (TTTS), open neural tube defect (ONTD) or congenital diaphragmatic hernia. A random-effects model was used to pool the mean differences (MD) or odds ratios (OR) and the corresponding 95% CI. The primary outcome was neonatal survival. Secondary outcomes included gestational age (GA) at intervention and at delivery, interval from intervention to delivery and incidence of preterm prelabor rupture of membranes (PPROM) and preterm delivery. The methodological quality of the included studies was evaluated using the Newcastle-Ottawa scale. RESULTS: The search identified 348 records, of which seven studies (six on fetoscopic laser photocoagulation (FLP) for TTTS and one on fetoscopic repair for ONTD) assessed the perinatal outcomes of pregnancies that developed iCAS after fetoscopic intervention. Given that only one study reported on fetoscopic ONTD repair, the meta-analysis was limited to TTTS pregnancies and included six studies (total of 1881 pregnancies). Pregnancies that developed iCAS after FLP for TTTS, compared with those that did not, had significantly lower GA at the time of intervention (weeks) (MD, -1.07 (95% CI, -1.89 to -0.24); P = 0.01) and at delivery (weeks) (MD, -1.74 (95% CI, -3.13 to -0.34); P = 0.01) and significantly lower neonatal survival (OR, 0.41 (95% CI, 0.24-0.70); P = 0.001). In addition, development of iCAS after FLP for TTTS increased significantly the risk for PPROM < 34 weeks' gestation (OR, 3.98 (95% CI, 1.76-9.03); P < 0.001) and preterm delivery < 32 weeks (OR, 1.80 (95% CI, 1.16-2.80); P = 0.008). CONCLUSIONS: iCAS is a common complication after FLP for TTTS. In patients undergoing FLP for TTTS, iCAS develops more often with earlier GA at intervention and is associated with earlier GA at delivery, higher risk of PPROM < 34 weeks' gestation and preterm delivery < 32 weeks and lower neonatal survival. Given the limitations of this meta-analysis and lack of literature reporting on other types of fetoscopic intervention, the presented findings should be interpreted with caution and should not be generalized to fetoscopic procedures used to treat other fetal conditions. © 2021 International Society of Ultrasound in Obstetrics and Gynecology.

Perinatal risk factors of neurodevelopmental impairment after fetoscopic laser photocoagulation for twin-twin transfusion syndrome: systematic review and meta-analysis.

OBJECTIVE: Monochorionic twins with twin-twin transfusion syndrome (TTTS) treated with fetoscopic laser photocoagulation (FLP) are at increased risk of neurodevelopmental impairment (NDI). This meta-analysis aimed to identify the prevalence of and perinatal risk factors for NDI in TTTS survivors treated with FLP. METHODS: We performed a search in PubMed, EMBASE, Scopus and Web of Science, from inception to 13 February 2021, for studies evaluating perinatal risk factors for NDI in children diagnosed prenatally with TTTS managed by FLP. Data on severity of TTTS at the time of diagnosis, defined according to the Quintero staging system, FLP-related complications and perinatal outcomes were compared between children with a history of TTTS treated with FLP with and those without NDI, which was defined as performance on a cognitive or developmental assessment tool ≥ 2 SD below the mean or a defined motor or sensory disability. A random-effects model was used to pool the mean differences or odds ratios (OR) with the corresponding 95% CIs. Heterogeneity was assessed using the I2 statistic. RESULTS: Nine studies with a total of 1499 TTTS survivors were included. The overall incidence of NDI was 14.0% (95% CI, 9.0-18.0%). The occurrence of NDI in TTTS survivors was associated with later gestational age (GA) at FLP (mean difference, 0.94 weeks (95% CI, 0.50-1.38 weeks); P < 0.0001, I2 = 0%), earlier GA at delivery (mean difference, -1.44 weeks (95% CI, -2.28 to -0.61 weeks); P = 0.0007, I2 = 49%) and lower birth weight (mean difference, -343.26 g (95% CI, -470.59 to -215.92 g); P < 0.00001, I2 = 27%). Evaluation of different GA cut-offs showed that preterm birth before 32 weeks was associated with higher risk for NDI later in childhood (OR, 2.25 (95% CI, 1.02-4.94); P = 0.04, I2 = 35%). No statistically significant difference was found between cases with and those without NDI with respect to Quintero stage of TTTS, recipient or donor status, development of postlaser twin anemia-polycythemia sequence, recurrence of TTTS and incidence of small- for-gestational age or cotwin fetal demise. CONCLUSIONS: TTTS survivors with later GA at the time of FLP, earlier GA at delivery and lower birth weight are at higher risk of developing NDI. No significant association was found between Quintero stage of TTTS and risk of NDI. Our findings may be helpful for parental counseling and highlight the need for future studies to understand better the risk factors for NDI in TTTS survivors. © 2021 International Society of Ultrasound in Obstetrics and Gynecology.

Early laser surgery is not associated with very preterm delivery or reduced neonatal survival in TTTS.

OBJECTIVE: To evaluate the association of laser photocoagulation of placental anastomoses (LPA) prior to 18 weeks' gestation (early LPA) with very preterm delivery and neonatal survival in pregnancies with twin-twin transfusion syndrome (TTTS). METHODS: This was a retrospective cohort study of monochorionic diamniotic twin pregnancies with TTTS undergoing LPA between 2002 and 2018 at two institutions. The rates of delivery < 28, < 30 and < 32 weeks' gestation, preterm prelabor rupture of membranes (PPROM) and 30-day survival of one or both infants were compared between pregnancies undergoing early LPA and those undergoing LPA ≥ 18 weeks' gestation. Regression analysis was performed to determine the association of early LPA with very preterm delivery and 30-day survival, adjusted for Quintero stage, study phase, selective fetal growth restriction, gestational age at delivery, maternal age ≥ 35 years, body mass index > 35 kg/m2 , placental location, use of Seldinger method to place the operative trocar, size of the trocar, participating center, use of Solomon technique, cerclage and PPROM. Survival analysis using the Cox proportional hazard model was applied to examine the LPA-to-delivery interval according to the timing of surgery, adjusted for confounding variables. RESULTS: A total of 414 TTTS pregnancies were included in the study, of which 68 (16.4%) underwent early LPA. In the total cohort, the incidence of delivery at < 28, < 30 and < 32 weeks' gestation was 22.7%, 39.6% and 53.4%, respectively. Survival of both twins and survival of at least one twin at 30 days were 67.5% and 90.8%, respectively. No significant difference was noted between pregnancies that underwent early LPA and those that had LPA ≥ 18 weeks in the rate of delivery < 28 weeks (19.1% vs 23.4%; P = 0.4), < 30 weeks (38.2% vs 39.9%; P = 0.8) and < 32 weeks (44.1% vs 55.2%; P = 0.1) and PPROM (29.0% vs 24.1%; P = 0.4), or in the incidence of double-twin survival (63.9% vs 68.1%; P = 0.5) and survival of at least one infant (91.8% vs 90.6%; P = 0.7) at 30 days. Early LPA was not associated with very preterm delivery or neonatal survival in the regression analyses. Early LPA was associated with a longer LPA-to-delivery interval compared with LPA performed ≥ 18 weeks (median, 106.9 days (range, 2-164 days) vs median, 69.3 days (range, 0-146 days); P < 0.001) when adjusted for confounding variables (hazard ratio, 2.56 (95% CI, 1.76-3.73); P < 0.001). CONCLUSION: Laser surgery before 18 weeks is not associated with an increased rate of very preterm delivery and PPROM or with reduced neonatal survival when compared with LPA after 18 weeks. © 2020 International Society of Ultrasound in Obstetrics and Gynecology.

Trend in ventricle size during pregnancy and its use for prediction of ventriculoperitoneal shunt in fetal open neural tube defect.

OBJECTIVES: Fetal surgery for repair of open neural tube defect (ONTD) typically results in decreased need for a ventriculoperitoneal shunt (VPS). Our objectives were to determine the trend in ventricle size (VS) during pregnancy and whether VS and change in VS, as assessed by ultrasound, were predictive of the need for VPS in pregnancy with ONTD. METHODS: This was a retrospective analysis of prospectively collected data of consecutive pregnancies with ONTD, evaluated in a single center from January 2012 to May 2018. Two groups were identified: the first consisted of pregnancies that underwent in-utero repair (IUR) and the second those that had postnatal repair (PNR). Penalized B splines were used to determine the trend in VS, across 2-week gestational-age (GA) epochs, between 24 and 36 weeks of gestation. VS at each GA epoch and the change in VS between each GA epoch were compared between the IUR and PNR groups. To determine whether VS at any GA was predictive of VPS, receiver-operating-characteristics (ROC) curves were used and the optimal cut-off at each GA epoch was identified. Univariate analysis and multiple logistic regression were used for further analysis. RESULTS: ONTD was diagnosed in 110 fetuses, of whom 69 underwent IUR and 41 had PNR. Fetuses in the IUR group were more likely to have Chiari II malformation (100.0% vs 82.9%; P < 0.01), lower GA at delivery (34.9 ± 3.2 vs 37.1 ± 2.1 weeks; P < 0.01) and lower rates of VPS within the first year postpartum (36.2% vs 61.0%; P = 0.02) compared with the PNR group. In both groups, VS increased steadily with GA from the initial evaluation to delivery. In the IUR group, there was a significant change in VS between the 24 + 0 to 25 + 6-week and the 26 + 0 to 27 + 6-week epochs (2.3 (95% CI, 0.4-4.1) mm; P = 0.02). There was a positive trend in the change in VS at later GAs, but this was not significant. Although there was no significant change in VS in the PNR group before 30 weeks, there was a positive trend after that time. On multivariate analysis, each week of advancing GA was associated with a mean increase of 0.74 mm in VS (P < 0.0001) in both groups. VS was not associated with the level or type of lesion, but presence of Chiari II malformation was associated with a mean increase of 5.88 mm (P < 0.0001) in VS in both the IUR and PNR groups. VS was modestly predictive of need for VPS in both groups, with area under ROC curves between 0.68 and 0.76 at the different GA epochs. Change in VS between the first and last measurements was also modestly predictive of the need for VPS, with better performance in the PNR group. CONCLUSIONS: VS increased with advancing GA in all fetuses with ONTD, although in the IUR group this increase occurred immediately after fetal surgery and in the PNR group it occurred after 30 weeks of gestation. In-utero surgery was associated with a decreased rate of VPS and was more predictive of need for VPS than was VS. Postnatal factors resulting in increased need for VPS in the PNR group need to be assessed further. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.

Fetal ventricular strain in uncomplicated and selective growth-restricted monochorionic diamniotic twin pregnancies and cardiovascular response in pre-twin-twin transfusion syndrome.

OBJECTIVES: Our primary aim was to confirm whether intertwin discordance in ventricular strain and ductus venosus (DV) time intervals predicts twin-twin transfusion syndrome (TTTS). Secondary aims were to create gestational-age ranges for ventricular strain in uncomplicated monochorionic diamniotic (MCDA) twin pregnancies without selective intrauterine growth restriction (sIUGR) and to characterize the relationship of ventricular strain with gestational age in MCDA twin pregnancies with sIUGR that did not develop TTTS. METHODS: In the period 2015-2018, we enrolled 150 MCDA twin pregnancies consecutively into this prospective, blinded study of global longitudinal left and right ventricular strain. With the observer blinded to twin pairing and pregnancy outcome, videoclips of the four-chamber view, which had been recorded during ultrasound surveillance in the usual window for development of TTTS (16-26 completed gestational weeks), underwent offline measurement of strain. Uncomplicated MCDA twin pregnancies, without sIUGR, were used to test the association between strain, gestational age and estimated fetal weight using mixed-effects multilevel regression. Inter-rater reliability was tested in 208 strain measurements in 31 fetuses from pregnancies which did not develop TTTS and within-fetus variation was assessed in 16 such fetuses, in which multiple four-chamber views were taken on the same day. The effect of sIUGR on strain in otherwise uncomplicated MCDA twin pregnancy was analyzed. MCDA twin pregnancies were defined as 'pre-TTTS' when, having been referred for TTTS evaluation, they did not satisfy Quintero staging criteria, but subsequently developed TTTS requiring laser treatment. MCDA pregnancies which did not develop TTTS comprised the 'non-TTTS' group. Cardiovascular parameters measured in these cases included tissue Doppler parameters and DV early filling time as a percentage of the cardiac cycle (DVeT%). Intertwin strain and DVeT% discordance was compared between non-TTTS and pre-TTTS cases, matched for gestational age. RESULTS: Paired strain data were available for intertwin comparison in 127/150 MCDA twin pregnancies, comprising 14 pre-TTTS and 113 non-TTTS pregnancies, after exclusions. Scans were collected at a median frame rate of 97 (range, 28-220) Hz. Laser therapy was performed at a median gestational age of 20.6 (range, 17.2-26.6) weeks. There were no group differences in right (RV) or left (LV) ventricular strain discordance between 68/113 non-TTTS and 13/14 pre-TTTS MCDA twin pregnancies < 20 completed gestational weeks (RV, P = 0.338; LV, P = 0.932). DVeT% discordance > 3.6% was found in eight of 13 pre-TTTS pregnancies. In non-TTTS pregnancies, the estimated variability in ventricular strain within each twin during the day was high (RV, 19.7; LV, 12.9). However, within each pair (intertwin variation), variability was low (RV, 5.5; LV, 2.9). Interclass correlation reflecting the proportion of total variability represented by the variability between twin pairs was low (RV, 0.22; LV, 0.18). Both RV (P < 0.001) and LV (P = 0.025) strain showed a negative association with gestational age. Among non-TTTS MCDA twin pregnancies, LV strain was, on average, higher by 1.83 in sIUGR compared with normally grown fetuses (P = 0.023), with no statistically significant difference in RV strain (P = 0.271). CONCLUSIONS: Although ventricular strain has been reported previously as a possible predictor of developing TTTS, in this blinded, prospective study, we found no significant intergroup differences in ventricular strain in pre-TTTS compared with age-matched non-TTTS MCDA twin pregnancies. We recommend using DVeT% discordance as a more practical screening tool in MCDA twin pregnancies. This study also provides new information on the changes with gestational age, and the biological and technical variation, of global longitudinal ventricular strain in uncomplicated MCDA twin pregnancies and those with isolated sIUGR. © 2019 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Effect of intra-amniotic fluid pressure from polyhydramnios on cervical length in patients with twin-twin transfusion syndrome undergoing fetoscopic laser surgery.

OBJECTIVES: To determine the relationship between intra-amniotic pressure and cervical length (CL) in patients with twin-twin transfusion syndrome (TTTS) undergoing fetoscopic laser photocoagulation (FLP), and to identify pre- or intraoperative factors associated with increased intra-amniotic pressure in this population. METHODS: This was a prospective cohort study of patients undergoing FLP for TTTS. Exclusion criteria were triplet or higher-order gestation and prior cervical cerclage, amnioreduction or FLP procedure. CL was assessed using preprocedure transvaginal ultrasound. Intra-amniotic pressure measurements were obtained on initial placement of the trocar into the amniotic cavity, using a direct hydrostatic pressure gauge. The relationship between intra-amniotic pressure and CL was assessed using multivariate linear regression analysis, including relevant preoperative and intraoperative variables. RESULTS: In total, 283 pregnancies met the inclusion criteria. Quintero stage of TTTS was I in 33 pregnancies, II in 88, III in 150 and IV in 12. Mean gestational age (GA) at FLP was 20.7 ± 3 weeks. Mean intra-amniotic pressure was 23.1 ± 9 mmHg. On unadjusted linear regression analysis, there was no significant association between intra-amniotic pressure and preoperative CL (P = 0.24) or GA at delivery (P = 0.22). On multivariate analysis, the factors associated significantly with intra-amniotic pressure were: number of prior term deliveries (P = 0.03), recipient maximum vertical pocket (P < 0.0001), Quintero stage IV (P = 0.01) and type of anesthesia (sedation vs general anesthesia; P = 0.01). CONCLUSION: In pregnancies with TTTS, intra-amniotic pressure is not associated with CL or GA at delivery. This novel finding suggests that cervical shortening in this population is not mechanically driven. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.