Targeting neonatal Fc receptor: potential clinical applications in pregnancy.

The neonatal Fc receptor (FcRn) plays an important role in the transfer of the immunoglobulin G isotype (IgG) from the mother to the fetus. FcRn expressed on endothelial cells also binds to IgG and albumin, regulating the circulating half-lives of these proteins. Alloimmune and autoimmune IgG antibodies have been implicated in various perinatal immune-mediated diseases. FcRn-mediated placental transfer of pathogenic antibodies can result in cell and tissue injury in the fetus and neonate, with devastating outcomes. Thus, blockade of FcRn may be an effective treatment strategy in managing these conditions and could additionally reduce the concentration of pathogenic antibodies in the maternal circulation by preventing IgG recycling. In this review, we discuss the biology of FcRn, the rationale and considerations for development of FcRn-blocking agents, and their potential clinical applications in various perinatal immune-mediated diseases. © 2022 International Society of Ultrasound in Obstetrics and Gynecology.

Primary vs patch-based skin closure for in-utero spina bifida repair.

OBJECTIVE: During in-utero spina bifida (SB) repair, closure of large defects is often challenging, requiring tissue graft for watertight skin closure. No prior studies have compared primary skin closure vs patch-based repair. Our objective was to compare neonatal and 1-year outcomes associated with these two types of skin closure for in-utero SB repair. METHODS: This was a prospective cohort study of 102 patients undergoing open prenatal SB repair from September 2011 to August 2021 at a single institution. All patients met the inclusion criteria of the Management of Myelomeningocele Study (MOMS), and the surgical procedure for in-utero SB repair was similar to that described in the MOMS trial. During the surgery, if primary skin approximation was not feasible due to the large size of the defect, the decision was at the discretion of the pediatric neurosurgeon to utilize a patch for closure. Neonatal outcomes at birth and 1-year outcomes were compared between the primary skin and patch-based closure groups. RESULTS: Of 102 patients included in the study, 70 (68.6%) underwent primary skin closure and 32 (31.4%) patch-based closure. The patch type included acellular bovine skin matrix (Durepair®; n = 31) and human acellular dermal matrix (Alloderm®; n = 1). Fetuses with myeloschisis were more likely to require patch-based repair than those with myelomeningocele. The median time of fetal repair was 4 min longer for patch-based compared with primary skin closure (37 vs 33 min; P = 0.001). Following patch-based repair, neonates had a longer length of stay in the neonatal intensive care unit (NICU) by 24 days (adjusted risk ratio, 2.40 (95% CI, 1.41-4.29)) compared to those that underwent primary skin closure. There was no difference between the two groups in the other neonatal outcomes, including the need for ventriculoperitoneal shunt placement and cerebrospinal fluid leakage. Outcome at 1 year of age was available for 90 infants. Need for wound revision within their first year after birth was more common in infants who underwent patch-based vs those with primary skin closure (19.4% vs 5.1%; P = 0.05). There was no difference between the two groups in other 1-year outcomes, including the need for ventriculoperitoneal shunt placement by 1 year of age and surgery for tethered cord. CONCLUSIONS: Patch-based closure during SB repair is often needed in fetuses with myeloschisis and is associated with prolonged fetal surgery time, long NICU stay and need for wound revision within the first year after birth. Further studies are required to identify optimal patches for SB repair or alternative methods to improve outcome. © 2022 International Society of Ultrasound in Obstetrics and Gynecology.

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.

Anti-Vel alloimmunization and severe hemolytic disease of the fetus and newborn.

Only rare cases of anti-Vel-associated mild-to-moderate hemolytic disease of the fetus and newborn have been previously reported. No case of fetal anemia requiring prenatal therapy has been noted to date. We report such a case recently encountered at our Fetal Center. Strategies are discussed for managing pregnancy complicated with alloimmunization to an antibody to a high-prevalence antigen, including sources of red blood cells for intrauterine transfusions.Only rare cases of anti-Vel­associated mild-to-moderate hemolytic disease of the fetus and newborn have been previously reported. No case of fetal anemia requiring prenatal therapy has been noted to date. We report such a case recently encountered at our Fetal Center. Strategies are discussed for managing pregnancy complicated with alloimmunization to an antibody to a high-prevalence antigen, including sources of red blood cells for intrauterine transfusions.

Cardiac pathophysiology in twin-twin transfusion syndrome: new insights into its evolution.

OBJECTIVES: In twin-twin transfusion syndrome (TTTS), unbalanced transfer of vasoactive mediators and fluid from the donor to the recipient cotwin alters their cardiovascular function. The aims of this study were to describe the impact of TTTS on fetal cardiac function in a large cohort of monochorionic-diamniotic (MCDA) pregnancies, and determine the early hemodynamic response to selective fetoscopic laser photocoagulation (SFLP). METHODS: Echocardiography was performed in 145 MCDA pregnancies, including 26 uncomplicated MCDA, 61 TTTS Stages I+II and 58 TTTS Stages III+IV pregnancies, prior to SFLP for TTTS. Echocardiographic data after SFLP were available in a subset of 41/119 (34%) TTTS cases at a mean of 1.7 ± 1.9 days. Mitral (MAPSE) and tricuspid (TAPSE) annular systolic excursion, myocardial performance index (MPI), tissue Doppler velocities (E', A', S') and filling pressures (E/E') were measured and transformed into Z-scores. Ventricular pressure was estimated from peak atrioventricular regurgitation velocity. RESULTS: Left ventricular hemodynamics of the recipient twin were affected in early TTTS. In all stages of TTTS, left MPI and E/E' of the recipient twin were elevated in comparison to those of the donor (all P < 0.05), with reduced recipient left S' in TTTS Stages III+IV (P < 0.001). Ventricular pressure was elevated for gestational age (median, 42 mmHg (range, 20-65 mmHg)) in 11 of 14 recipients in which this parameter was measured. Between-group difference in right ventricular E/E' was significant only in TTTS Stages III+IV recipients compared with TTTS Stages I+II (P = 0.007) and uncomplicated MCDA (P = 0.041). Recipient left and right MPI decreased while S', MAPSE and TAPSE increased after SFLP; in donors, left E/E' and cardiac output increased. CONCLUSIONS: Cardiac function of the recipient twin in TTTS is abnormal, even in the early stages of the disease. Left ventricular filling pressures are elevated and systolic function is decreased before abnormalities in the right heart become apparent. SFLP produces rapid hemodynamic improvement. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.

Impact of cannula size on recurrent twin-twin transfusion syndrome and twin anemia-polycythemia sequence after fetoscopic laser surgery.

OBJECTIVE: The optimal outcome after fetoscopic laser surgery (FLS) for twin-twin transfusion syndrome (TTTS) depends on the successful ablation of all placental anastomoses. The objective of this study was to determine the incidence of and risk factors for recurrent TTTS (rTTTS) or twin anemia-polycythemia sequence (TAPS) after FLS, focusing on the impact of cannula diameter. METHODS: This was a secondary analysis of data collected prospectively at two centers from 666 consecutive patients undergoing FLS for TTTS. The main outcomes were rTTTS and TAPS following FLS. Variables assessed included gestational age at intervention, stage of disease, recipient maximum vertical pocket, anterior placenta, number of anastomoses ablated, cannula diameter/operative scopes and use of the Solomon technique. Cannula diameter and corresponding scopes used were as follows: 8 Fr and 1.3 mm/0°; 9 Fr and 2.7 mm/0°; 10 Fr and 3 mm/0°; or 12 Fr and 3.3-3.7 mm/30-70°. Cannula diameter was used as a surrogate for scopes during analysis. Multivariate logistic regression analysis was performed to identify risk factors associated with rTTTS or TAPS after FLS; 'center' was considered an independent variable to account for variations in practice. In a nested cohort of pregnancies in which both fetuses survived, placental dye injection was performed in 315 placentae. Multivariate logistic regression analysis was performed to evaluate variables associated with the presence of residual anastomoses. RESULTS: rTTTS or TAPS occurred in 61 (9%) cases following FLS (rTTTS in eight (1%) and TAPS in 53 (8%)). Factors associated significantly with the risk of rTTTS/TAPS on multivariate analysis were cannula diameter (when an 8-Fr, 9-Fr, 10-Fr or 12-Fr cannula was used, there was rTTTS/TAPS in 24%, 13%, 2% or 0.8% of cases, respectively (P < 0.001)) and use of the Solomon technique (rTTTS/TAPS occurred in 4.2% of those in which it was used vs 18.1% in those in which it was not (P < 0.001)). Only use of the Solomon technique was associated significantly with no residual anastomoses found after delivery. CONCLUSIONS: Following FLS for TTTS, a lower incidence of rTTTS/TAPS was seen when the Solomon technique was used, as well as when a 10-Fr or 12-Fr cannula was used. A lower complication rate may be due to the use of a scope with better optics during placental mapping. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.

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

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

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

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

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

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

Aortic distensibility as a surrogate for intertwin pulse pressure differences in monochorionic pregnancies with and without twin-twin transfusion syndrome.

OBJECTIVES: Twin-twin transfusion syndrome (TTTS) complicates 10-15% of monochorionic diamniotic (MCDA) twin pregnancies. The donor response to hypovolemia allows the transfer of vasoactive mediators to the recipient, causing increased recipient afterload and hypertension. Our objective was to apply a novel speckle-tracking technique to measure the aortic fractional area change (AFAC) during the cardiac cycle in MCDA twins with and without TTTS, and identify intertwin differences in AFAC and parameters of cardiac function. METHODS: High-frame rate four-chamber views of the fetal heart, including the mid-thoracic aorta, were collected prospectively in MCDA twin pairs referred to our center between June 2014 and April 2015. Using speckle-tracking software, the endovascular border of the aorta was traced manually during systole, with guidance on cardiac cycle timing by anatomical M-mode. AFAC, defined as the difference between maximum and minimum area divided by minimum area, expressed as a percentage, was calculated offline and averaged over three cardiac cycles. Tissue Doppler and displacement were used to measure long-axis cardiac function. Intra- and interclass correlation coefficients were used to test observer variability. RESULTS: Fifty-one MCDA twin pregnancies were included, comprising uncomplicated MCDA (n = 14), TTTS Stages 1/2 (n = 21) and TTTS Stages 3/4 (n = 16). Median gestational age was 20.4 (range, 16.2-27.5) weeks. Mean ± SD heart rate was 142.6 ± 7.2 bpm with no significant intertwin pair differences. AFAC was significantly higher in recipients than in donors of TTTS pairs (Stages 1/2: 72.3 ± 29.9% vs 43.7 ± 19.3%, P < 0.001; Stages 3/4: 75.2 ± 29.2% vs 42.5 ± 18.4%, P = 0.002), consistent with higher recipient pulse pressure. No intertwin differences in AFAC were seen in uncomplicated MCDA pairs. Inter- and intraclass correlation coefficients for AFAC were 0.894 and 0.888. AFAC correlated significantly with combined cardiac output (r = 0.252, P = 0.011) and left and right E/E' ratio (left: r = 0.302, P = 0.004; right: r = 0.247, P = 0.030). CONCLUSION: AFAC is a quantifiable and reproducible method to assess aortic distensibility and is a promising tool to monitor the response to prelaser therapeutic interventions in pregnancies with TTTS. Copyright © 2015 ISUOG. Published by John Wiley & Sons Ltd.

Changes in ductus venosus flow profile in twin-twin transfusion syndrome: role in risk stratification.

OBJECTIVES: To evaluate changes in ductus venosus (DV) waveforms and the timing of these changes in twin-twin transfusion syndrome (TTTS), to relate these to disease severity and to assess the clinical applicability of the suggested measurements in the prediction of TTTS. METHODS: DV time intervals and velocity-time integrals (VTI) normalized to cardiac cycle and total VTI, respectively, as well as velocity ratios were analyzed in 149 monochorionic diamniotic (MCDA) twin pairs. Pregnancies were assigned to the following groups: uncomplicated MCDA (n = 29); TTTS Stages I+II (n = 50); TTTS Stages III+IV (n = 49); and pre-TTTS (n = 21), of which 14 remained stable and seven progressed to TTTS. Intertwin differences were calculated as larger/recipient minus smaller/donor and related to disease severity. Receiver-operating characteristics curve analysis was used to distinguish TTTS vs uncomplicated MCDA and pre-TTTS progressing to TTTS vs non-progressing pre-TTTS. Intra- and interobserver reliability of measurement of DV parameters were evaluated using intraclass correlation coefficients (ICCs). RESULTS: No intertwin differences in DV parameters were found in uncomplicated MCDA pregnancies. Diastolic VTIs and filling times were significantly shorter in recipient twins in TTTS cases and in larger pre-TTTS twins in comparison with their cotwins. Time intervals, VTIs and velocity ratios correlated significantly with Quintero stages. An intertwin difference in early filling time (eT) normalized to cardiac cycle, eT (%) ≤ -3.6%, could differentiate TTTS from uncomplicated MCDA pregnancies (82.8% sensitivity; 79.8% specificity) and eT (%) ≤ -2.8% predicted progression to TTTS (73.1% sensitivity; 67.4% specificity). CONCLUSIONS: DV flow profiles and timing of waveform events are already altered in pre-TTTS and early-stage disease, reflecting abnormal ventricular filling and circulatory imbalance. Intertwin comparison of filling times and VTI may allow prediction of evolving TTTS in MCDA pregnancies. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd.

Cryopreserved human umbilical cord patch for in-utero spina bifida repair.

OBJECTIVE: To identify a patch system to repair surgically created spina bifida in a sheep model for its efficacy in healing the skin defect, protecting the underlying spinal cord and reducing the Chiari II malformation. METHODS: Spina bifida was created surgically in 16 fetuses from eight timed-pregnant sheep at gestational age of 75 days. Two fetuses did not survive the procedure. Repeat hysterotomy was performed at 95 days' gestation to cover the defect with either biocellulose film with underwater adhesive (BCF-adhesive) (n = 7) or human umbilical cord with suture (HUC-suture) (n = 7). Three fetuses without formation of the defect served as reference controls. The skin healing was examined by direct visualization after a planned Cesarean section at term, followed by histological analysis using hematoxylin and eosin and Masson's trichrome stains. Mid-sagittal sections of the fetal cranium and upper cervical spine were analyzed by a pediatric neuroradiologist who was blinded to the type of patch received. RESULTS: Three fetuses that received the BCF-adhesive and six fetuses that received the HUC-suture survived to term for final analysis. As a result of dislodgment of the BCF-adhesive, all spina bifida defects repaired using BCF-adhesive were not healed and showed exposed spinal cord with leakage of cerebrospinal fluid. In contrast, all spinal defects repaired by HUC-suture were healed with complete regrowth of epidermal, dermal and subdermal tissue components, with no exposed spinal cord. The maximal skin wound width was 21 ± 3.6 mm in the BCF-adhesive group but 3 ± 0.8 mm in the HUC-suture group (P < 0.001). The spinal cord area (P = 0.001) and the number of anterior horn cells (P = 0.03) was preserved to a greater degree in the HUC-suture group than in the BCF-adhesive group, whilst psammoma bodies, signifying neuronal degeneration, were only observed in the BCF-adhesive group. Anatomic changes, indicative of Chiari II malformation, were seen in all three fetuses of the BCF-adhesive group but in none of the HUC-suture group (P < 0.01). CONCLUSION: Cryopreserved umbilical cord graft is a promising regenerative patch for intrauterine repair of spina bifida.

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

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

Outcome of fetoscopic laser ablation for twin-to-twin transfusion syndrome in dichorionic-triamniotic triplets compared with monochorionic-diamniotic twins.

OBJECTIVE: To compare outcome of dichorionic-triamniotic (DCTA) triplet gestations with that of a paired cohort of monochorionic-diamniotic (MCDA) twin gestations undergoing laser therapy for treatment of twin-to-twin transfusion syndrome (TTTS). METHODS: All DCTA triplets treated at four referral centers between specified dates were included. A matched cohort group of MCDA twin gestations affected by TTTS was used for comparison. RESULTS: Sixteen sets of DCTA triplets treated with laser photocoagulation of placental anastomoses were compared with 32 matched sets of MCDA twins. All of the 'singleton' fetuses in the triplet gestations survived to birth and to the end of the neonatal period. There were no differences in single or double survival or the rate of non-survivors to birth and at age 28 days. A mean 3-week difference was found in the procedure-to-delivery interval in DCTA triplets vs MCDA twins (60 ± 35.8 days vs 83.6 ± 33.2 days; P = 0.029). A mean difference of 3 weeks was also found in the gestational age at delivery in DCTA triplets vs MCDA twins (28.5 ± 3.5 weeks vs 31.9 ± 5 weeks; P = 0.024). A similar post-laser fetal growth pattern in donors and recipients of both groups was noted. CONCLUSIONS: DCTA triplet gestations with TTTS have a similar rate of post-laser survival but deliver earlier than can be expected for twins treated with laser. These findings have potential implications for the risk of prematurity and long-term outcomes.

Risk factors associated with preterm delivery after fetoscopic laser ablation for twin-twin transfusion syndrome.

OBJECTIVE: Despite improved perinatal survival following fetoscopic laser ablation (FLA) for twin-twin transfusion syndrome (TTTS), prematurity remains an important contributor to perinatal mortality and morbidity. The objective of the study was to identify risk factors for complicated preterm delivery after FLA. METHODS: Retrospective cohort study of prospectively collected data on maternal/fetal demographics and pre-operative, operative and postoperative variables of 459 patients treated with FLA in three USA fetal centers. Multivariate linear regression was performed to identify significant risk factors associated with preterm delivery, which were cross-validated using the k-fold method. Multivariate logistic regression was performed to identify risk factors for early compared with late preterm delivery based on median gestational age at delivery of 32 weeks. RESULTS: There were significant differences in case selection and outcomes between the centers. After controlling for the center of surgery, multivariate analysis indicated that a lower maternal age at procedure, a history of previous prematurity, shortened cervical length, use of amnioinfusion, a cannula diameter of 12 French (Fr), lack of a collagen plug placement and iatrogenic preterm premature rupture of membranes (iPPROM) were significantly associated with a lower gestational age at delivery. CONCLUSIONS: Specific fetal/maternal and operative variables are associated with preterm delivery after FLA for the treatment of TTTS. Further studies to modify some of these variables may decrease the perinatal morbidity after laser therapy.

Indirect pump: unique presentation of a monochorionic-triamniotic triplet gestation complicated by TRAP sequence and successfully managed with radiofrequency ablation of the acardiac fetus.

Twin reversed arterial perfusion (TRAP) sequence is a rare complication of multiple gestations. Only a few cases of TRAP sequence in monochorionic triplets have been reported. Here we report a case of TRAP sequence in a monochorionic-triamniotic triplet gestation treated with radiofrequency ablation of the acardiac fetus. The response to the radiofrequency ablation procedure and subsequent examination of the placenta support the hypothesis of an 'indirect' pump triplet.

Absorbable gelatin plug does not prevent iatrogenic preterm premature rupture of membranes after fetoscopic laser surgery for twin-twin transfusion syndrome.

OBJECTIVE: Despite fetoscopic laser ablation (FLA) having emerged as an effective treatment for twin-twin transfusion syndrome (TTTS), major postintervention challenges, such as iatrogenic preterm premature rupture of membranes (iPPROM), remain. A chorioamniotic plug (CAP) made of absorbable gelatin sponge has been used to seal the trocar entry site in the chorioamniotic layers to promote healing and prevent iPPROM, yet the results have been equivocal. Our objective was to test the hypothesis that, following FLA for TTTS, iPPROM may be prevented by placement of an absorbable gelatin CAP. METHODS: A retrospective cohort study was performed on prospectively collected data from 134 consecutive patients who underwent FLA for TTTS. The decision for CAP placement was at the discretion of the physician. Preoperative, operative and postoperative variables were collected and analyzed. The primary outcome was the incidence of iPPROM, and the secondary outcomes were procedure-to-delivery interval and gestational age at delivery. Comparative statistical analysis was performed as appropriate. RESULTS: A CAP was placed in 72 (54%) of 134 patients. Factors significantly associated with CAP placement were higher gravidity (P = 0.03), anterior placentation (P = 0.04), general endotracheal intubation (P = 0.02) and a cannula diameter of 12-Fr (P = 0.003). There were no differences between CAP and no-CAP groups in the rate of iPPROM (39% vs 34%, respectively; P = 0.42) or in the procedure-to-delivery interval (65.3 ± 34.7 days vs 58.2 ± 30.8 days, respectively; P = 0.21). The gestational age at delivery was later in the CAP group compared with the no-CAP group (30.7 ± 4.5 weeks vs 28.9 ± 3.9 weeks, respectively; P = 0.02). CONCLUSIONS: CAP did not reduce the overall risk for iPPROM and did not increase the procedure-to-delivery interval. Further research is needed to identify other methods to prevent iPPROM and prolong pregnancy after laser therapy.