Prenatal surgery in fetal myelomeningocele with severe ventriculomegaly.

OBJECTIVES: Prenatal myelomeningocele (MMC) repair is performed to decrease risk for treatment of hydrocephalus after birth and to preserve motor function. Some centers may not consider patients candidates for surgery if severe ventriculomegaly is present and there is no expected benefit in decreased risk for hydrocephalus treatment. This study sought to compare postnatal outcomes of fetuses with MMC and severe ventriculomegaly (>15mm) who underwent prenatal repair, with fetuses with severe ventriculomegaly who underwent postnatal repair and fetuses with ventriculomegaly (<15mm) who underwent prenatal repair. METHODS: This was a retrospective study of fetuses with MMC that underwent prenatal or postnatal repair between 2012 and 2021 at a single institution. The cohort was divided based on preoperative fetal ventricular size into two groups, those with severe ventriculomegaly (≥15 mm) and those without severe ventriculomegaly (<15 mm). Fetal ventricular size was measured by MRI prior to surgery using the standardized approach and the mean of the left and right ventricle was used for analysis. Motor function of 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 lower extremities assessed at birth and need for diversion procedure for hydrocephalus treatment during the first year of life were collected and compared between groups. Data was presented as median and range or number and percentages as appropriate. P value >0.05 was considered statistically significant. Multivariate regression analysis was used to adjust for potential confounders. RESULTS: 154 patients were included in this study: 145 patients underwent fetal surgery (101 fetoscopic and 44 open hysterotomy) and 9 patients with severe ventriculomegaly underwent postnatal repair. Among the 145 patients who underwent fetal surgery, 22 presented with severe ventriculomegaly. Prenatally repaired fetuses with severe ventriculomegaly at referral were at a significantly higher need for hydrocephalus treatment by 12 months than those without severe ventriculomegaly (62% vs. 29%, p<0.01). However, motor function assessment at birth was similar between both prenatally repaired groups (OR=0.92, 95% CI [0.33-2.59], p=0.88) adjusted for the anatomical level of the lesion. The prenatally repaired group with severe ventriculomegaly had better preserved motor function levels at birth compared to the postnatal repair group with severe ventriculomegaly (L3 with 11.1% S1 motor function; p=<0.01 and p=<0.01). Prenatally repaired patients with severe ventriculomegaly had an 18.9 times chance of having an intact motor function at birth [95% CI (1.2 - 290.1)] adjusted for ethnicity, presence of clubfeet at referral, and gestational age at delivery compared to postnatal repair. There was not a significant difference in the need for hydrocephalus treatment in the first year of life between prenatal and postnatal repair of patients with severe ventriculomegaly (61.9% vs 87.5%, p=0.18). CONCLUSIONS: Although fetuses with MMC and severe ventriculomegaly do not seem to benefit from fetal surgery in terms of postnatal hydrocephalus treatment, they benefit from increased chance of preserved motor function at birth. Results from this study highlight the benefits of having prenatal MMC repair for cases with severe ventriculomegaly at referral to preserve motor function. This article is protected by copyright. All rights reserved.

Ambulation after in-utero fetoscopic and open spina bifida repair: predictors for ambulation at 30 months.

OBJECTIVE: Ambulatory outcomes from children who underwent a new minimally invasive fetal spina bifida surgery approach are included in this study for the first time. Identifying cases with better chances of independent ambulation from fetal life can have an important impact on patient counseling. The objectives of this study were: (1) To compare the ambulatory status of a cohort of children who had a prenatal spina bifida repair using two different methods (fetoscopic and open) with a cohort who underwent postnatal repair; and (2) to identify the best predictors for ambulation. METHODS: Retrospective review of a cohort of children who had spina bifida repair from 2011-2023 using prenatal fetoscopic surgery (N=73), prenatal open-hysterotomy surgery (N=37) or postnatal repair (N=51) in a single tertiary hospital. Consecutive sample of cases who underwent a spina bifida repair in utero following MoMs trial criteria and cases who underwent postnatal repair, meeting same criteria, also followed up after birth at the same institution. Motor function (MF) assessment by ultrasound was recorded at initial evaluation (MF1), 6 postoperative weeks or equivalent (MF2) and prior to delivery (MF3). Clinical exams to assess MF at birth and at 12 months were recorded. First sacral myotome (S1) MF was classified as "intact MF". Ambulatory status data at each follow-up visit was collected. The proportion of cases who were able to walk independently were compared between fetoscopic and open prenatal surgeries and between prenatal (by fetoscopic or open surgery) and postnatal spina bifida repair. Logistic regression analyses were performed to identify predictors for independent ambulation. RESULTS: At 30 months, the proportion of independent ambulators was higher in prenatally vs. postnatally repaired cases (51.8% vs.15.7%; p<0.01). No differences in ambulatory outcomes were seen in the comparison between fetoscopic (52%) vs. open (51.3%; p=0.95) prenatal repair. In the prenatal repair group, having an "intact MF" at 12 months [Odds ratio 7.71 (95%CI: 2.77-21.47), p<0.01] and at birth [4.38 (1.53-12.56), p<0.01], predicted significantly being an independent ambulator by 30 months; the anatomical level of lesion below L2 was also predictive for this outcome [3.68(1.33-9.88), p=0.01]. CONCLUSION: Ambulatory status by 30 months can be predicted by observing S1 MF postnatally. Results from this study have implications for parental counseling and planning for supportive therapies. This article is protected by copyright. All rights reserved.

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.

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.

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.

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.

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.

Complex gastroschisis: a new indication for fetal surgery?

Gastroschisis (GS) is a congenital abdominal wall defect, in which the bowel eviscerates from the abdominal cavity. It is a non-lethal isolated anomaly and its pathogenesis is hypothesized to occur as a result of two hits: primary rupture of the 'physiological' umbilical hernia (congenital anomaly) followed by progressive damage of the eviscerated bowel (secondary injury). The second hit is thought to be caused by a combination of mesenteric ischemia from constriction in the abdominal wall defect and prolonged amniotic fluid exposure with resultant inflammatory damage, which eventually leads to bowel dysfunction and complications. GS can be classified as either simple or complex, with the latter being complicated by a combination of intestinal atresia, stenosis, perforation, volvulus and/or necrosis. Complex GS requires multiple neonatal surgeries and is associated with significantly greater postnatal morbidity and mortality than is simple GS. The intrauterine reduction of the eviscerated bowel before irreversible damage occurs and subsequent defect closure may diminish or potentially prevent the bowel damage and other fetal and neonatal complications associated with this condition. Serial prenatal amnioexchange has been studied in cases with GS as a potential intervention but never adopted because of its unproven benefit in terms of survival and bowel and lung function. We believe that recent advances in prenatal diagnosis and fetoscopic surgery justify reconsideration of the antenatal management of complex GS under the rubric of the criteria for fetal surgery established by the International Fetal Medicine and Surgery Society (IFMSS). Herein, we discuss how conditions for fetoscopic repair of complex GS might be favorable according to the IFMSS criteria, including an established natural history, an accurate prenatal diagnosis, absence of fully effective perinatal treatment due to prolonged need for neonatal intensive care, experimental evidence for fetoscopic repair and maternal and fetal safety of fetoscopy in expert fetal centers. Finally, we propose a research agenda that will help overcome barriers to progress and provide a pathway toward clinical implementation. © 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.

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.

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.

Prenatal predictors of motor function in children with open spina bifida: a retrospective cohort study.

OBJECTIVE: To identify predictors for intact motor function (MF) at birth and at 12 months of life in babies with prenatally versus postnatally repaired open spina bifida (OSB). DESIGN: Retrospective cohort study. SETTING: Texas Children's Hospital, 2011-2018. POPULATION: Patients who underwent either prenatal or postnatal OSB repair. METHODS: Prenatal MF of the lower extremities was evaluated by ultrasound following a metameric distribution at the time of diagnosis (US1), 6 weeks postoperatively (or 6 weeks after initial evaluation in postnatally repaired cases) (US2) and at the last ultrasound before delivery (US3). At birth and at 12 months, MF was assessed clinically. Intact MF (S1) was defined as the observation of plantar flexion of the ankle. Results from logistic regression analysis are expressed as odds ratios (95% confidence intervals, P values). RESULTS: A total of 127 patients were included: 93 with prenatal repair (51 fetoscopic; 42 open hysterotomy repair) and 34 with postnatal repair. In the prenatal repair group, predictors for intact MF at birth and at 12 months included: absence of clubfeet (OR 11.3, 95% CI 3.2-39.1, P < 0.01; OR 10.8 95% CI 2.4-47.6, P < 0.01); intact MF at US1 (OR 19.7, 95% CI 5.0-76.9, P < 0.01; OR 8.7, 95% CI 2.0-38.7, P < 0.01); intact MF at US2 (OR 22, 95% CI 6.5-74.2, P < 0.01; OR 13.5, 95% 3.0-61.4, P < 0.01); intact MF at US3 (OR 13.7, 95% CI 3.4-55.9, P < 0.01; OR 12.6, 95% CI 2.5-64.3, P < 0.01); and having a flat lesion (OR 11.2, 95% CI 2.4-51.1, P < 0.01; OR 4.1, 95% CI 1.1-16.5, P = 0.04). In the postnatal repair group, the only predictor of intact MF at 12 months was having intact MF at birth (OR 15.2, 95% CI 2.0-113.3, P = 0.03). CONCLUSIONS: The detection of intact MF in utero from mid-gestation to delivery predicts intact MF at birth and at 12 months in babies who undergo prenatal OSB repair. TWEETABLE ABSTRACT: Detection of intact motor function in utero predicts intact motor function at birth and at 1 year in fetuses who undergo prenatal OSB repair.

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.

Economic analysis of prenatal fetoscopic vs open-hysterotomy repair of open neural tube defect.

OBJECTIVE: Fetal repair of an open neural tube defect (ONTD) by open hysterotomy has been shown to reduce the need for ventriculoperitoneal shunting and improve motor outcomes for infants, but increases the risk of Cesarean section and prematurity. Fetoscopic repair is an alternative approach that may confer similar neurological benefits but allows for vaginal delivery and reduces the incidence of hysterotomy-related complications. We sought to compare the costs of care from fetal surgery until neonatal discharge, as well as the clinical outcomes, associated with each surgical approach. METHODS: This was a retrospective cohort study of patients who underwent prenatal ONTD repair, using either the open-hysterotomy or the fetoscopic approach, at a single institution between 2012 and 2018. Clinical outcomes were collected by chart review. A cost-consequence analysis was conducted from the hospital perspective, and included all inpatient and ambulatory hospital and physician costs incurred for the care of mothers and their infants, from the time of maternal admission for fetal ONTD repair up to postnatal maternal and infant discharge. Costs were estimated using cost-to-charge ratios for hospital billing and the Medicare physician fee schedule for physician billing. RESULTS: Seventy-eight patients were included in the analysis, of whom 47 underwent fetoscopic repair and 31 underwent open-hysterotomy repair. In the fetoscopic-repair group, compared with the open-repair group, fewer women underwent Cesarean section (53% vs 100%; P < 0.001) and the median gestational age at birth was significantly higher (38.1 weeks (interquartile range (IQR), 35.2-39.1 weeks) vs 35.7 weeks (IQR, 33.9-37.0 weeks); P < 0.001). No case of uterine dehiscence was observed in the fetoscopic-repair group, compared with an incidence of 16% in the open-repair group. After adjusting for baseline characteristics, there was no significant difference in the total cost of care between the fetoscopic-repair and the open-repair groups (median, $76 978 (IQR, $60 312-$115 386) vs $65 103 (IQR, $57 758-$108 103); P = 0.458). CONCLUSIONS: Fetoscopic repair of ONTD, when compared with the open-hysterotomy approach, reduces the incidence of Cesarean section and preterm delivery with no significant difference in total costs of care from surgery to infant discharge. This novel approach may represent a cost-effective alternative to improve maternal and neonatal outcomes for this high-risk population. © 2021 International Society of Ultrasound in Obstetrics and Gynecology.

Impact of the size of the lesion in prenatal neural tube defect repair on imaging, neurosurgical and motor outcomes: a retrospective cohort study.

OBJECTIVES: (1) To compare brain findings between large and non-large neural tube defect (NTD); (2) to evaluate the impact of large lesion on the surgical parameters; (3) to study any associations between the size of the lesions and brain findings 6 weeks postoperatively and neurological short-term outcomes. DESIGN: Retrospective cohort study. SETTING: Texas Children's Hospital, between 2011 and 2018. POPULATION: Patients who underwent prenatal NTD repair. METHODS: Large lesion was defined when the lesion's surface was >75th centile of our cohorts' lesions. MAIN OUTCOME MEASURES: Time of referral: ventriculomegaly and anatomical level of the lesion; surgery: duration and need for relaxing incisions. 6 weeks postoperative: hindbrain herniation (HBH) and ventriculomegaly. After delivery: dehiscence, need for hydrocephalus treatment and motor function. RESULTS: A total of 99 patients were included, 25 of whom presented with large lesions. Type of lesion and ventriculomegaly were comparable between individuals with large and non-large lesions. Individuals with large lesions were associated with increased need for relaxing incisions by 5.4 times (95% CI 1.3-23.2, P = 0.02). Six weeks postoperatively, having a large lesion decreased by ten times the likelihood of having a postoperative reversal of HBH (odds ratio = 0.1, 95% CI 0.1-0.4, P < 0.01). At birth, larger lesions increased the risk for repair dehiscence by 6.1 times (95% CI 1.6-22.5, P < 0.01) and the risk of dehiscence or leakage of cerebrospinal fluid at birth by 5.5 times (95% CI 1.6-18.9, P < 0.01). CONCLUSION: Prenatal repair of patients with large NTD presents a lower proportion of HBH reversal 6 weeks after the surgery, a higher risk of dehiscence and a higher need for postnatal repair. TWEETABLE ABSTRACT: Evaluation of the size of fetal NTD can predict adverse neurological outcomes after prenatal NTD repair.

Longitudinal evaluation of motor function in patients who underwent prenatal or postnatal neural tube defect repair.

OBJECTIVE: To compare the evolution of motor function from mid-gestation to 12 months of age between prenatally and postnatally repaired cases of open neural tube defect (ONTD). METHODS: This was a retrospective cohort study of all fetuses that underwent prenatal (fetoscopic or open hysterotomy) or postnatal ONTD repair at a single institution between November 2011 and December 2018. The anatomical level of the lesion was defined as the upper bony spinal defect at initial magnetic resonance imaging assessment. Prenatal motor function of the lower extremities was evaluated by ultrasound according to the metameric level of the neurological lesion, based on the methodology of Carreras et al. Fetal motor function was assessed at referral, at 6 weeks after surgery in prenatally repaired cases or 6 weeks after referral in postnatally repaired cases (6-week follow-up) and at the last scan before delivery. In addition, motor function was assessed by a detailed neurological examination at birth and 12 months of age. First sacral (S1) neurological level of the lesion was considered as intact motor function. For statistical comparisons, we attributed numerical scores to each neurological level and motor function was expressed as median (range) neurological level. Motor function (as numerical score) and the proportion of cases with intact motor function and with motor function two or more levels better than expected based on the anatomical level of the lesion were compared between the prenatal- and postnatal-repair groups. Fetal motor function was compared to the anatomical level of the lesion at referral and a better motor function was defined when it was two or more levels better than the anatomical level of the lesion. To assess the evolution of motor function, we compared motor function at referral with that at each follow-up assessment using paired t-tests. RESULTS: We included 127 patients with ONTD, of whom 93 underwent prenatal (51 fetoscopic and 42 open hysterotomy) and 34 postnatal repair. At the time of referral, cases in the prenatal- and postnatal-repair groups presented with a similar anatomical level of lesion (L3 (T9-S1) vs L3 (T7-S1); P = 0.52), similar motor function (S1 (L1-S1) vs S1 (L1-S1); P = 0.52) and a similar proportion of cases with intact motor function (81% vs 79%; P = 0.88) and with motor function two or more levels better than expected based on the anatomical level of the lesion (62% vs 74%; P = 0.24). When compared with prenatally repaired cases, postnatally repaired cases showed worse motor function at birth (S1 (L1-S1) vs L4 (L1-S1); P < 0.01) and at 12 months of age (S1 (L1-S1) vs L4 (L1-S1); P < 0.01). In the prenatal-repair group, motor function remained stable from the time of referral to 12 months of age (P = 0.26). Furthermore, the proportion of patients with intact motor function at referral (81% (75/93)) was similar to that at the 6-week follow-up (74% (64/87)), at the last scan before birth (74% (42/57)), at birth (68% (63/93)) and at 12 months of age (67% (39/58)) in the prenatal-repair group. In the postnatal-repair group, worse motor function, starting from the third trimester to 12 months of age, was observed. The proportion of patients with intact motor function at referral (79% (27/34)) was similar to that at 6-week follow-up (80% (12/15); P = 0.92), but was lower at the last assessment before birth (25% (2/8); P < 0.01), at birth (24% (8/34); P < 0.01) and at 12 months of age (28% (7/25); P < 0.01). Similar findings were noted when assessing the evolution of the proportion of cases with motor function two or more levels better than expected based on the anatomical level of the lesion in each group. CONCLUSIONS: Infants with ONTD that underwent postnatal repair had worse motor function at birth and at 12 months of age than at mid-gestation and when compared with infants that underwent prenatal ONTD repair. Prenatal motor function assessment by ultrasound is an adequate tool to identify those infants who should have a good clinical motor function after delivery. Information obtained by fetal motor function assessment can have an important role for patient counseling and case selection for surgery. © 2020 International Society of Ultrasound in Obstetrics and Gynecology.

Association between impedance to blood flow in umbilical arteries and infant survival in twin-to-twin transfusion syndrome.

OBJECTIVE: To evaluate infant survival according to the Doppler pattern of impedance to blood flow in the umbilical arteries (UAs) prior to laser surgery, in pregnancies with twin-to-twin transfusion syndrome (TTTS). METHODS: This was a retrospective study of women with a monochorionic diamniotic twin pregnancy who underwent laser surgery for TTTS between January 2012 and May 2018 at a single institution. Absolute intertwin difference in UA pulsatility index (DUAPI) was measured within 48 h prior to laser surgery. Twins with intermittent or persistent absent/reversed end-diastolic flow (EDF) in the UA (UA-EDF) were analyzed separately. Survival of both or at least one infant at birth and at 30 days postpartum was compared between pregnancies with an intertwin DUAPI of ≥ 0.4 and those with an intertwin DUAPI of < 0.4, as well as between fetuses with intermittent and those with persistent absent/reversed UA-EDF. Parametric and non-parametric tests were used for analysis. Regression analysis was performed to determine if intertwin DUAPI and intermittent or persistent absent/reversed UA-EDF were associated independently with infant survival, while controlling for gestational age at delivery, Quintero stage and other important confounding variables. RESULTS: Of 231 TTTS pregnancies that underwent laser surgery during the study period, UA Doppler information could be retrieved for 206 and delivery information was available for 184, which comprised the study population. Rates of double-twin survival at birth were significantly higher in pregnancies with an intertwin DUAPI of < 0.4 than in those with an intertwin DUAPI of ≥ 0.4 (83.9% (78/93) vs 50.0% (12/24); P < 0.001). Double-infant survival at birth was higher in pregnancies with intermittent compared to those with persistent absent/reversed UA-EDF (73.0% (27/37) vs 36.7% (11/30); P = 0.003). Regression analysis demonstrated that an intertwin DUAPI of < 0.4 was associated with increased survival of both twins at delivery (P < 0.001) and at 30 days postpartum (P = 0.002), as well as increased survival of at least one twin at delivery (P = 0.009). Similarly, intermittent absent/reversed UA-EDF was associated with increased survival of both twins at delivery (P = 0.007) and at 30 days after birth (P = 0.015). CONCLUSIONS: Evaluation of intertwin differences in UA impedance to blood flow as well as identification of intermittent or persistent absent or reversed UA-EDF prior to laser surgery could help in the prediction of double-infant survival at birth and to 30 days in twin pregnancies with TTTS. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.