Prenatal Diagnosis of Fetal Aqueductal Stenosis: A Multicenter Prospective Observational Study through the North American Fetal Therapy Network (NAFTNet).

INTRODUCTION: A critical component of an evidence-based reassessment of in-utero intervention for fetal aqueductal stenosis (fetal AS) is determining if the prenatal diagnosis can be accurately made at a gestational age amenable to in-utero intervention. METHODS: A multicenter, prospective, observational study was conducted through the North American Fetal Therapy Network (NAFTNet). Pregnancies complicated by severe CNS ventriculomegaly (lateral ventricle diameter >15 mm) not secondary to a primary diagnosis (myelomeningocele, encephalocele, etc.) were recruited at diagnosis. Imaging and laboratory findings were recorded in an online REDCap database. After evaluation, investigators were asked to render their degree of confidence in the diagnosis of fetal AS. The prenatal diagnosis was compared to the postnatal diagnosis obtained through neonatal neuroimaging. Performance characteristics of ultrasound and MRI were calculated, as was the mean gestational age at diagnosis. RESULTS: Between April 2015 and October 2022, eleven NAFTNet centers contributed 64 subjects with severe fetal CNS ventriculomegaly. Of these, 56 had both prenatal and postnatal diagnoses recorded. Ultrasound revealed 32 fetal AS true positives, 4 false positives, 7 false negatives, and 13 true negatives rendering a sensitivity of 0.82, a specificity of 0.76, a positive predictive value of 0.89, and a negative predictive value of 0.65. The mean gestational age at diagnosis by ultrasound was 25.5 weeks (std +/- 4.7w). The proportion of agreement (true positive + true negative/n) was highest at 24 weeks gestation. For fetal MRI (n=35), the sensitivity for fetal AS was 0.95, specificity was 0.69, positive predictive value was 0.84, and negative predictive value was 0.90. MRI was performed at 25 weeks on average. CONCLUSION: The prenatal diagnosis of fetal aqueductal stenosis can be made with accuracy at a gestational age potentially amenable to in-utero intervention. Only 7% of subjects were incorrectly diagnosed prenatally with fetal AS by ultrasound and 11% by MRI. Diagnostic accuracy of fetal AS will likely improve with increased experience.

Abnormal Shape and Size of the Cardiac Ventricles Are Associated with a Higher Risk of Neonatal Death in Fetuses with Isolated Left Congenital Diaphragmatic Hernia.

INTRODUCTION: The objective of this study was to evaluate the association between fetal cardiac deformation analysis (CDA) and cardiac function with severe adverse perinatal outcomes in fetuses with isolated left congenital diaphragmatic hernia (CDH). METHODS: CDA in each ventricle (contractility, size, and shape), evaluated by speckle tracking and novel FetalHQ software, and markers of cardiac function (E/A ratios, pulmonary and aortic peak systolic velocities, and sigmoid annular valve diameters), were evaluated in fetuses with isolated left CDH. Two evaluations were performed: at referral (CDA and function) and within 3 weeks of delivery (CDA). Severe adverse neonatal outcomes were considered neonatal death (ND) or survival with CDH-associated pulmonary hypertension (CDH-PH). Differences and associations between CDA, cardiac function, and severe adverse outcomes were estimated. RESULTS: Fifty fetuses were included, and seventeen (34%) had severe adverse neonatal outcomes (11 ND and 6 survivors with CDH-PH). At first evaluation, the prevalence of a small left ventricle was 34% (17/50) with a higher prevalence among neonates presenting severe adverse outcomes (58.8 [10/17] vs. 21.2% [7/33]; p = 0.01; OR, 5.03 [1.4-19.1; p = 0.01]) and among those presenting with neonatal mortality (8/11 [72.7] vs. 9/39 [23.0%]; p = 0.03; OR, 8.9 [1.9-40.7; p = 0.005]). No differences in cardiac function or strain were noted between fetuses with or without severe adverse outcomes. Within 3 weeks of delivery, the prevalence of small left ventricle was higher (19/34; 55.8%) with a more globular shape (reduced transverse/longitudinal ratio). A globular right ventricle was significantly associated with ND or survival with CDH-PH (OR, 14.2 [1.5-138.3]; p = 0.02). CONCLUSION: Fetuses with isolated CDH at risk of perinatal death or survival with CDH-PH had a higher prevalence of a small left ventricle and abnormal shape of the right ventricle.

Fetoscopic Endoluminal Tracheal Occlusion for Severe, Left-Sided Congenital Diaphragmatic Hernia: The North American Fetal Therapy Network Fetoscopic Endoluminal Tracheal Occlusion Consortium Experience.

OBJECTIVE: To report the outcomes of fetoscopic endoluminal tracheal occlusion in a multicenter North American cohort of patients with isolated, left-sided congenital diaphragmatic hernia (CDH) and to compare neonatal mortality and morbidity in patients with severe left-sided congenital diaphragmatic hernia who underwent fetoscopic endoluminal tracheal occlusion with those expectantly managed. METHODS: We analyzed data from 10 centers in the NAFTNet (North American Fetal Therapy Network) FETO (Fetoscopic Endoluminal Tracheal Occlusion) Consortium registry, collected between November 1, 2008, and December 31, 2020. In addition to reporting procedure-related surgical outcomes of fetoscopic endoluminal tracheal occlusion, we performed a comparative analysis of fetoscopic endoluminal tracheal occlusion compared with contemporaneous expectantly managed patients. RESULTS: Fetoscopic endoluminal tracheal occlusion was successfully performed in 87 of 89 patients (97.8%). Six-month survival in patients with severe left-sided congenital diaphragmatic hernia did not differ significantly between patients who underwent fetoscopic endoluminal tracheal occlusion and those managed expectantly (69.8% vs 58.1%, P =.30). Patients who underwent fetoscopic endoluminal tracheal occlusion had higher rates of preterm prelabor rupture of membranes (54.0% vs 14.3%, P <.001), earlier gestational age at delivery (median 35.0 weeks vs 38.3 weeks, P <.001), and lower birth weights (mean 2,487 g vs 2,857 g, P =.001). On subanalysis, in patients for whom all recorded observed-to-expected lung/head ratio measurements were below 25%, patients with fetoscopic endoluminal tracheal occlusion required fewer days of extracorporeal membrane oxygenation (ECMO) (median 9.0 days vs 17.0 days, P =.014). CONCLUSION: In this cohort, fetoscopic endoluminal tracheal occlusion was successfully implemented across several North American fetal therapy centers. Although survival was similar among patients undergoing fetoscopic endoluminal tracheal occlusion and those expectantly managed, fetoscopic endoluminal tracheal occlusion in North American centers may reduce morbidity, as suggested by fewer days of ECMO in those patients with persistently reduced lung volumes (observed-to-expected lung/head ratio below 25%).

Does Prediction of Neonatal Mortality by the Observed/Expected Lung-To-Head Ratio Change during Pregnancy in Fetuses with Left Congenital Diaphragmatic Hernia?

INTRODUCTION: The aim of this study was to evaluate prediction of neonatal mortality in fetuses with isolated left congenital diaphragmatic hernia (CDH) when the observed/expected lung-to-head ratio (O/E LHR) was estimated at two different gestational time points during pregnancy. METHODS: Forty-four (44) fetuses with isolated left CDH were included. O/E LHR was estimated at the time of referral (first scan) and before delivery (last scan). The main outcome was neonatal death due to respiratory complications. RESULTS: There were 10/44 (22.7%) perinatal deaths. The areas under (AU) the ROC curves were: first scan, 0.76, best O/E LHR cut-off 35.5% with 76% sensitivity and 70% specificity; last scan, AU-ROC 0.79, best O/E LHR cut-off 35.2%, with 79.0% sensitivity and 80% specificity. Considering an O/E LHR cut-off ≤35% to define high-risk fetuses at any examination, prediction for perinatal mortality showed: 80% sensitivity, 73.5% specificity, 47.1% positive and 92.6% negative predictive values, and 3.02 (95% CI 1.59-5.73) positive and 0.27 (95% CI 0.08-0.96) negative likelihood ratios. Prediction was similar in the two evaluations as 16/21 (76.2%) of fetuses considered at risk had an O/E LHR ≤35% in the two examinations; in the remaining 5 cases, two were identified only in the first and three only in the last scan. CONCLUSION: The O/E LHR is a good predictor of perinatal death in fetuses with left isolated CDH. Approximately 80% of fetuses at risk of perinatal death can be identified with an O/E LHR ≤35%, and 90% of them will have similar O/E LHR values at the first and at the last ultrasound examinations prior to delivery. In general, 88.6% of all CDH fetuses have a similar severity classification based on the O/E LHR at the first diagnostic ultrasound or at the ultrasound examination prior to delivery.

Quincke versus Diamond-Tip Needles for Entry in Placental Laser Surgery for Twin-to-Twin Transfusion Syndrome.

INTRODUCTION: Chorioamniotic membrane separation (CAS), preterm prelabor rupture of membranes (PPROM), and preterm delivery (PTD) remain as major complications of fetoscopic laser photocoagulation (FLP) for twin-to-twin transfusion syndrome (TTTS). We sought to examine whether use of Quincke-tip needles for initial entry during FLP reduces the risk of these complications. METHODS: This is a secondary analysis of prospectively collected data from patients that had FLP for TTTS at a single tertiary care center (2011-2021). We excluded patients for whom direct trocar entry was used. Patients for whom a Quincke-tip needle was used were compared to those for whom a diamond-tip needle was used during Seldinger entry. Demographics, ultrasound findings and operative characteristics were compared between groups. Postoperative outcomes and complications (including CAS, PPROM, and PTD) were also compared. Multivariate logistic regression models were fit to assess independent risk factors for complications. RESULTS: 386 patients met inclusion criteria; Quincke-tip needles were used in 81 (21.0%) cases, while diamond-tip needles were used in 305 (79.0%). Rates of CAS (11.1 vs. 9.5%, p = 0.67) and PPROM (44.4 vs. 41.0%, p = 0.57) were similar between groups. Patients in the Quincke-tip group delivered 1.5 weeks earlier than those in the diamond-tip group (30.5 vs. 32.0 weeks, p = 0.01). However, these patients were more likely to be delivered for maternal (35.9 vs. 19.0%) and fetal (23.1 vs. 15.3%) indications (p < 0.01). In multivariate analysis, needle type was not identified as an independent risk factor for PPROM. However, Quincke-tip needle use was associated with PTD less than 32 weeks (aOR 1.74, 95% CI: 1.02-2.97, p = 0.043). CONCLUSION: Membrane complications following FLP were not associated with the needle type used for entry. Earlier delivery in the Quincke-tip group was likely attributable to higher rates of delivery for maternal and fetal indications, and not membrane complications. The needle chosen for entry is likely best determined by operator preference.

The significance of hindbrain herniation reversal following prenatal repair of neural tube defects.

OBJECTIVE: The aim of this study was to determine whether reversal of hindbrain herniation (HBH) on MRI following prenatal repair of neural tube defects (NTDs) is associated with reduced rates of ventriculoperitoneal (VP) shunt placement or endoscopic third ventriculostomy (ETV) within the 1st year of life. METHODS: This is a secondary analysis of prospectively collected data from all patients who had prenatal open repair of a fetal NTD at a single tertiary care center between 2012 and 2020. Patients were offered surgery according to inclusion criteria from the Management of Myelomeningocele Study (MOMS). Patients were excluded if they were lost to follow-up, did not undergo postnatal MRI, or underwent postnatal MRI without a report assessing hindbrain status. Patients with HBH reversal were compared with those without HBH reversal. The primary outcome assessed was surgical CSF diversion (i.e., VP shunt or ETV) within the first 12 months of life. Secondary outcomes included CSF leakage, repair dehiscence, CSF diversion prior to discharge from the neonatal intensive care unit (NICU), and composite neonatal morbidity. Demographic, prenatal sonographic, and operative characteristics as well as outcomes were assessed using standard univariate statistical methods. Multivariate logistic regression models were fit to assess for independent contributions to the primary and secondary outcomes. RESULTS: Following exclusions, 78 patients were available for analysis. Of these patients, 38 (48.7%) had HBH reversal and 40 (51.3%) had persistent HBH on postnatal MRI. Baseline demographic and preoperative ultrasound characteristics were similar between groups. The primary outcome of CSF diversion within the 1st year of life was similar between the two groups (42.1% vs 57.5%, p = 0.17). All secondary outcomes were also similar between groups. Patients who had occurrence of the primary outcome had greater presurgical lateral ventricle width than those who did not (16.1 vs 12.1 mm, p = 0.02) when HBH was reversed, but not when HBH was persistent (12.5 vs 10.7 mm, p = 0.49). In multivariate analysis, presurgical lateral ventricle width was associated with increased rates of CSF diversion before 12 months of life (adjusted OR 1.18, 95% CI 1.03-1.35) and CSF diversion prior to NICU discharge (adjusted OR 1.18, 95% CI 1.02-1.37). CONCLUSIONS: HBH reversal was not associated with decreased rates of CSF diversion in this cohort. Predictive accuracy of the anticipated benefits of prenatal NTD repair may not be augmented by the observation of HBH reversal on MRI.

The Delphi definition for selective fetal growth restriction may not improve detection of pathologic growth discordance in monochorionic twins.

BACKGROUND: A consensus definition of selective fetal growth restriction in monochorionic diamniotic twins was recently proposed following a Delphi procedure involving an international panel of experts. The new definition augments the traditional definition with additional sonographic criteria. OBJECTIVE: We sought to determine whether the augmentations of the "Delphi definition" identified additional morbidity and mortality compared with a traditional definition. Furthermore, we sought to determine the benefit of each definition in identifying pathologic growth restriction relative to uncomplicated monochorionic diamniotic twins. STUDY DESIGN: This was a retrospective analysis of unselected monochorionic diamniotic twins that underwent fortnightly ultrasound surveillance at a single center between 2011 and 2020. Patients with concomitant twin-to-twin transfusion syndrome, twin anemia polycythemia sequence, or twin reversed arterial perfusion sequence at the time of diagnosis of selective fetal growth restriction were excluded. The diagnosis of selective fetal growth restriction using the Delphi definition required either an estimated fetal weight of <3rd percentile or presence of 2 of 4 observations in the smaller twin: (1) estimated fetal weight of <10th percentile, (2) estimated fetal weight discordance of >25% compared with the larger twin, (3) abdominal circumference of <10th percentile, (4) umbilical artery pulsatility index of >95th percentile. Diagnosis using the traditional definition required an estimated fetal weight of <10th percentile and an estimated fetal weight discordance of >25%. To determine the efficacy of the augmentations in the Delphi definition, 3 groups were compared: group I, uncomplicated monochorionic diamniotic twins; group II, twins with selective fetal growth restriction using the traditional definition (and therefore the Delphi definition); and group III, twins with selective fetal growth restriction solely using the Delphi definition. Demographic characteristics, subsequent development of twin-to-twin transfusion syndrome or twin anemia polycythemia sequence, pregnancy outcomes, and neonatal outcomes were compared. RESULTS: There were 325 patients with monochorionic diamniotic twins that met inclusion criteria. Of these, 213 (66%; group I) were uncomplicated, 37 (11%; group II) met the traditional definition for selective fetal growth restriction, and 112 (35%) met the Delphi definition for selective fetal growth restriction with 75 (67%) meeting solely the Delphi definition (group III). Demographic characteristics were similar between groups. Patients in group II delivered earlier than uncomplicated twins (32.1 vs 35.7 weeks of gestation; P<.01) and patients in group III (32.1 vs 35.6 weeks of gestation; P<.01). Furthermore, they were more likely to have critical umbilical artery Doppler abnormalities (38% vs 4%; P<.01) and be delivered for deteriorating fetal status (30% vs 5%; P<.01) than those in group III. Overall, survival was lower in group II than groups I and III (89% vs 96% and 100%, respectively; P=.04). Moreover, composite neonatal morbidity and mortality were greater in group II (30%) than either group I (6%; P<.01) or group III (9%; P<.01). The rates of composite neonatal morbidity and mortality were similar between groups I and III (P=.28). CONCLUSION: The addition of abdominal circumference and umbilical artery pulsatility index thresholds and isolated estimated fetal weight of <3%, as proposed by the Delphi definition, increased the diagnosis of selective fetal growth restriction; however, there was no added benefit in the identification of growth discordant pregnancies at risk of adverse outcomes. Prospective analysis of monochorionic diamniotic twins is required to contextualize these findings.

The Future of Fetal Surgery.

The field of fetal medicine has evolved significantly over the past several decades. Our ability to identify and treat the unborn patient has been shaped by advancements in imaging technology, genetic diagnosis, an improved understanding of fetal physiology, and the development and optimization of in utero surgical techniques. The future of the field will be shaped by medical innovators pushing for the continued refinement of minimally invasive surgical technique, the application of pioneering technologies such as robotic surgery and in utero stem cell and gene therapies, and the development of innovative ex utero fetal support systems.

Allografts for Skin Closure during In Utero Spina Bifida Repair in a Sheep Model.

OBJECTIVES: Use of off-label tissue graft materials, such as acellular dermal matrix (ADM), for in utero repair of severe spina bifida (SB), where primary skin layer closure is not possible, is associated with poor neurological outcomes. The cryopreserved human umbilical cord (HUC) patch has regenerative, anti-inflammatory, and anti-scarring properties, and provides watertight SB repair. We tested the hypothesis that the HUC is a superior skin patch to ADM for reducing inflammation at the repair site and preserving spinal cord function. METHODS: In timed-pregnant ewes with twins, on gestational day (GD) 75, spina bifida was created without a myelotomy (functional model). On GD 95, repair was performed using HUC vs. ADM patches (randomly assigned) by suturing them to the skin edges. Additionally, full thickness skin closure as a primary skin closure (PSC) served as a positive control. Delivery was performed on GD 140, followed by blinded to treatment neurological assessments of the lambs using the Texas Spinal Cord Injury Scale (TSCIS) for gait, proprioception, and nociception. Lambs without spina bifida were used as controls (CTL). Ex vivo magnetic resonance imaging of spines at the repair site were performed, followed by quantitative pathological assessments. Histological assessments (blinded) included Masson's trichrome, and immunofluorescence for myeloperoxidase (MPO; neutrophils) and for reactive astrocytes (inflammation) by co-staining vimentin and GFAP. RESULTS: The combined hind limbs' TSCIS was significantly higher in the HUC group than in ADM and PSC groups, p = 0.007. Both ADM and PSC groups exhibited loss of proprioception and mild to moderate ataxia compared to controls. MRI showed increased pathological findings in the PSC group when compared to the HUC group, p = 0.045. Histologically, the meningeal layer was thickened (inflammation) by 2-3 fold in ADM and PSC groups when compared to HUC and CTL groups, p = 0.01. There was lower MPO positive cells in the HUC group than in the ADM group, p = 0.018. Posterior column astrocyte activation was increased in ADM and PSC lambs compared to HUC lambs, p = 0.03. CONCLUSION: The HUC as a skin patch for in utero spina bifida repair preserves spinal cord function by reducing underlying inflammation when compared to ADM.

Risk Factors and Outcomes Following Septostomy during Fetoscopic Surgery for Twin-to-Twin Transfusion Syndrome.

Fetoscopic laser photocoagulation (FLP) of placental anastomoses is the preferred treatment for twin-to-twin transfusion syndrome (TTTS). Iatrogenic septostomy (IOS) during FLP is associated with increased risk of neonatal morbidity and mortality. We sought to identify risk factors for IOS and quantify the resultant outcomes. This is a secondary analysis of prospectively collected cases of TTTS in monochorionic diamniotic twins following FLP at a single center. Pre-operative ultrasound characteristics and operative technique (i.e., cannula size, total energy used) were compared between cases with vs. without IOS. Pregnancy and neonatal outcomes were also compared. Of 475 patients that had FLP, 33 (7%) were complicated by IOS. There was no association between operative technique and IOS. IOS was more common with later diagnosis, but less likely when selective fetal growth restriction (sFGR) was present. Survival was similar between groups (76% vs. 76% dual survivors, p = 0.95); however, IOS was associated with earlier delivery (29.7 vs. 32.0 wks, p < 0.01) and greater composite neonatal morbidity (25% vs. 8% in both twins, p = 0.02). Risks of IOS at greater gestational ages without sFGR may be related to a larger collapsed intervening membrane area and the resulting increased risk of puncture on entry.

Predicting fetal and neonatal demise after fetoscopy for twin-twin transfusion syndrome using recursive partitioning.

OBJECTIVE: Donor demise after laser surgery for twin-twin transfusion syndrome (TTTS) is well-characterized, but recipient demise is not, nor is neonatal death. This study aims to characterize factors associated with recipient death, donor death, and dual twin death after laser, both before and after birth. METHODS: This is a prospective cohort study of monochorionic twin pairs who underwent laser ablation for TTTS. Risk factors for fetal and neonatal death of both twins were identified using univariable analysis and recursive partitioning, a novel statistical method to quantify contributions of each factor to outcomes. RESULTS: In 413 twin pairs, death of both twins occurred in 9.2% (38/413), donor death in 12.1% (50/413), and recipient death in 2.4% (10/413). Recursive partitioning showed that gestational age at delivery predicts dual twin death (below 23.7 weeks, likely [p < 0.001], above 28.3 weeks, unlikely [p = 0.004]). Abnormal umbilical artery Doppler and weight discordance predict donor demise (p < 0.001 and p = 0.033, respectively). Cervical length under 16 mm predicts neonatal death of both twins (p < 0.001). CONCLUSIONS: Parents can gain individualized information about the survival of each fetus based on variables available from preoperative and delivery variables. Short cervix and premature delivery cause significant mortality in TTTS.

Low Transverse versus Midline Abdominal Skin Incisions for in utero Spina Bifida Repair.

OBJECTIVE: The 2 types of maternal skin incisions for in utero spina bifida repair are low transverse (LT) incision perceived to be cosmetic benefit and midline longitudinal (ML) incision, typically associated with a reduction in surgical time and lower blood loss. Our objective was to compare short- and long-term outcomes associated with these 2 types of skin incisions following in utero spina bifida repair. METHODS: Prospective observational cohort of 72 patients undergoing fetal spina bifida repair at a single institution between September 2011 and August 2018. The decision for the type of incision was at the discretion of the surgeons. The primary outcome was total operative time. Secondary outcomes included an analog scale of wound pain score on postoperative day 3, duration of postoperative stay, and postoperative wound complications within the first 4 weeks. The Patient Scar Assessment Questionnaire, a validated questionnaire, was obtained for all patients (≥6 months from delivery) using 4 categories (appearance, consciousness, satisfaction with appearance and with symptoms), with higher scores reflecting a poorer perception of the scar. RESULTS: There were 43 women (59.7%) in the LT group and 29 (40.3%) in the ML group. In all patients, the same incision was used during cesarean delivery. The total operative time was higher in the LT group by 33 min (p < 0.001), primarily due to abdominal wall incision time (open and closure). No significant differences were found between the groups in pain score, length of postoperative stay, or the rate of wound complications. Fifty-three patients (73.6%) responded to the questionnaire, 36/43 from the LT group and 17/29 from the ML group. There was no difference in the scores of appearance, consciousness, and satisfaction with appearance and symptoms between the groups. CONCLUSION: ML incisions shorten operative times without altering long-term incision-related satisfaction when compared to LT incisions.

The effect of microbiome exposure at birth on pediatric outcomes using a twin cohort discordant for microbiome exposure at birth.

OBJECTIVE: Microbiome exposure at birth has been associated with long-term pediatric outcomes. However, it is difficult to determine if differences in outcomes are truly due to microbiome exposure at birth or other exposures after birth and in early infancy. Using a twin cohort, we sought to determine the association between length of exposure to the maternal vaginal-fecal microbiome and long-term pediatric health outcomes by comparing outcomes between presenting and nonpresenting twins born to women who labored. METHODS: We performed a mail-based survey study of women in a single maternal-fetal medicine practice who delivered twin pregnancies ≥24 weeks. The survey study was sent to women when twins were between 2 and 10 years old to assess the long-term health outcomes, including any medical diagnoses or problems with grown and development. For this study, we included all women who labored, and we compared health outcomes for the presenting versus nonpresenting twin with the primary outcome being the development of asthma/reactive airway disease and allergies. The length of exposure to the maternal vaginal-fecal microbiome was measured using the time from rupture of membranes (ROM) to delivery of each twin. Chi-square and Student's t-test were used. RESULTS: Two hundred fifty-seven sets of twins were eligible for analyses. The presenting twin had a longer time of ROM than the nonpresenting twin (617 ± 2408 min versus 2 ± 5 minutes, p < .001). There were no significant differences between health outcomes for the presenting versus nonpresenting twin in the overall cohort, including the development of asthma/reactive airway disease (9.3 versus 10.1%, p = .77) or allergies (12.5 versus 7.8%, p = .08). There were no differences in any outcomes when comparing the presenting versus nonpresenting twin for those twins delivered vaginally or by cesarean delivery. CONCLUSION: In twins born to women who labored and either delivered vaginally or via cesarean section, delivery order was not associated with any significant increase in defined adverse pediatric outcomes, including the development of asthma or allergies. Using twins as a model for microbiome exposure may help to elucidate the role of the maternal vaginal-fecal microbiome on long-term pediatric health outcomes.

Outcomes after In Utero Myelomeningocele Repair Based on Delivery Location.

Maternal and pediatric delivery outcomes may vary in patients who underwent open fetal myelomeningocele repair and elected to deliver at the fetal center where their fetal intervention was performed versus at the referring physician's hospital. A prospective cohort study of 88 patients were evaluated following in utero open fetal myelomeningocele repair at a single fetal center between the years 2011-2019. Exclusion criteria included patients that delivered within two weeks of the procedure (n = 6), or if a patient was lost to follow-up (n = 1). Of 82 patients meeting inclusion criteria, 36 (44%) patients were delivered at the fetal center that performed fetal intervention, and 46 (56%) were delivered locally. Comparative statistics found that with the exception of parity, baseline characteristics and pre-operative variables did not differ between the groups. No differences in oligohydramnios incidence, preterm rupture of membranes, gestational age at delivery or delivery indications were found. Patients who delivered with a referring physician were more likely to be multiparous (p = 0.015). With the exception of a longer neonatal intensive care unit (NICU) stay in the fetal center group (median 30.0 vs. 11.0 days, p = 0.004), there were no differences in neonatal outcomes, including wound dehiscence, cerebrospinal fluid leakage, patch management, ventricular diversion, or prematurity complications. Therefore, we conclude that it is safe to allow patients to travel home for obstetric and neonatal management after open fetal myelomeningocele repair.

Middle Cerebral Artery Doppler Velocimetry for the Diagnosis of Twin Anemia Polycythemia Sequence: A Systematic Review.

Twin anemia polycythemia sequence (TAPS) is a rare complication of monochorionic diamniotic (MCDA) twins. Middle cerebral artery peak systolic velocity (MCA-PSV) measurements are used to screen for TAPS while fetal or neonatal hemoglobin levels are required for definitive diagnosis. We sought to perform a systematic review of the efficacy of MCA-PSV in diagnosing TAPS. Search criteria were developed using relevant terms to query the Pubmed, Embase, and SCOPUS electronic databases. Publications reporting diagnostic characteristics of MCA-PSV measurements (i.e., sensitivity, specificity or receiver operator curves) were included. Each article was assessed for bias using the Quality Assessment of Diagnostic Accuracy Studies II (QUADAS II) tool. Results were assessed for uniformity to determine whether meta-analysis was feasible. Data were presented in tabular form. Among publications, five met the inclusion criteria. QUADAS II analysis revealed that four of the publications were highly likely to have bias in multiple areas. Meta-analysis was precluded by non-uniformity between definitions of TAPS by MCA-PSV and neonatal or fetal hemoglobin levels. High-quality prospective studies with consistent definitions and ultrasound surveillance protocols are still required to determine the efficacy of MCA-PSV in diagnosing TAPS. Other ultrasound findings (e.g., placenta echogenicity discordance) may augment Doppler studies.

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

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

Pregnancy outcomes associated with chorioamnion membrane separation severity following fetoscopic laser surgery for twin-twin transfusion syndrome.

OBJECTIVE: We tested the hypothesis that increasing severity of chorioamnion membrane separation (CAS) after fetoscopic laser surgery (FLS) for twin-twin transfusion syndrome (TTTS) is associated with worse pregnancy outcomes. METHODS: Prospective cohort of patients undergoing FLS for TTTS between 2011 and 2018. CAS was defined as separation of fetal membranes from the uterine wall on post-operative ultrasound. Patient groups were defined: Group 1: No CAS; Group 2: CAS lower than 50th centile; Group 3: CAS upper than 50th centile or complete CAS. Comparative analysis was performed. RESULTS: Of 387 patients meeting inclusion criteria, 29 (7.5%) had CAS (median 9.8 mm [4.9-30.8 mm]). Group 1 patients were more likely to undergo FLS at later gestational age, had increased recipient maximum vertical pocket, and higher amnioreduction volume than Group 3. Group 3 had higher rates of preterm premature rupture of membrane, delivered earlier and were more likely to terminate than Group 1. Group 2 had fewer neonatal survivors than Group 1. Survival analysis for gestational age at delivery and Cox proportional hazards model indicated increased risk for early delivery in Groups 2 and 3 compared with Group 1. CONCLUSIONS: Patients with CAS ≥9.8 mm or complete CAS after FLS for TTTS had worse obstetric and neonatal outcomes.

Steroid Hormone Levels in Recipient Amniotic Fluid in Twin-Twin Transfusion Syndrome and Their Association with Preterm Delivery.

OBJECTIVE: Preterm delivery following fetoscopic laser surgery (FLS) of twin-twin transfusion syndrome (TTTS) is associated with severe perinatal morbidity and mortality. The role of steroid hormones in amniotic fluid (AF) after FLS remains unknown. STUDY DESIGN: A prospective cohort study of consecutive case series of FLS for TTTS was performed from April 2012 to February 2017. Cases were divided into early (≤27 weeks) spontaneous preterm delivery (ED) and late delivery (LD; ≥34 weeks) following FLS and compared. AF supernatants were assessed for protein, estradiol, progesterone and cortisol levels (using the ELISA kit), and normalized to total protein levels to adjust for dilution. RESULTS: A total of 294 consecutive cases of FLS for TTTS in monochorionic-diamniotic twins were performed during the study period. AF was available in 44 ED patients and 50 LD patients. On logistic regression, ED was associated with higher normalized progesterone levels (odds ratio [OR]: 1.25; 95% confidence interval [CI]: 1.12-1.41), lower normalized cortisol (OR: 0.78; 95% CI: 0.64-0.96), and higher estradiol levels (OR: 1.3; 95% CI: 1.03-1.63). CONCLUSION: Elevated AF normalized progesterone and estradiol, and lower normalized cortisol levels were associated with ED. This novel finding requires further exploration to establish the molecular mechanism operational in pregnancies complicated by TTTS to potentially prevent early preterm birth after fetal surgery.

Distance Traveled to a Fetal Center and Pregnancy Outcomes in Twin-Twin Transfusion Syndrome.

BACKGROUND: Fetoscopic laser photocoagulation (FLP) is the definitive treatment for twin-twin transfusion syndrome (TTTS). Due to variability in geographic proximity to high-volume fetal centers, many patients travel great distances to receive experienced care. We sought to determine whether distance traveled (DT) is associated with gestational age (GA) at delivery and neonatal survival. METHODS: A prospective cohort study of patients within the continental United States referred to our center between September 23, 2011 and July 25, 2018 undergoing planned FLP for TTTS (n = 393; GA 20.6 ± 2.5 weeks; stage I: n = 50; stage II: n = 118; stage III: n = 208; stage IV: n = 17) was performed. The great-circle distance to our center was calculated using patients' home zip codes. DT was stratified into groups containing equal patient numbers and pregnancy outcomes assessed. RESULTS: A total of 393 patients met the inclusion criteria. The threshold distance from our center was <250 miles (n = 181), 250-499 miles (n= 119), and ≥500 miles (n = 93). There was no significant difference between any of the preoperative variables among the three groups, with the exception of race and rural status. Furthermore, there was no significant association between DT and GA at delivery (p = 0.34), time interval from procedure to delivery (p = 0.37), and the number of neonatal survivors (p= 0.21). Preterm premature rupture of membranes (PPROM) at <34 weeks was highest (47.9%, p = 0.04) in the group traveling 250-499 miles. CONCLUSION: To our knowledge, this is the largest study to show that in TTTS, DT is not associated with GA at delivery, time interval from procedure to delivery, or neonatal survival. Although PPROM at <34 weeks was higher in the group traveling 250-499 miles, there was no significant difference in GA at delivery. While patients with advanced disease may choose to seek treatment based on proximity, traveling long distances does not adversely affect pregnancy outcomes.

Accuracy of sonographic estimated fetal weight in suspected macrosomia: the likelihood of overestimating and underestimating the true birthweight.

Objective: Macrosomia has increased risk of serious adverse outcomes for both infants and their mothers. As such, many providers recommend induction of labor or cesarean delivery (CD) based on sonographic estimated fetal weight (sonoEFW) cutoffs. It is known that sonoEFW is a poor predictor of birthweight (BW), especially at the extremes of weight. It is not clear, however, whether sonoEFWs tend to underestimate or overestimate the true BW among fetuses with suspected macrosomia. The objective of this study was to compare rates of overestimation of BW among women with suspected macrosomia by sonoEFW.Methods: This was a retrospective cohort study of women who presented to a single maternal-fetal medicine ultrasound unit within 2 weeks prior to delivery from January 2011 to November 2017. We identified women who received a sonoEFW ≥4000 g. The study sample was divided into four sonoEFW categories: 4000-4249, 4250-4499, 4500-4749, and ≥4750 g. Accuracy of sonoEFW was compared across groups, with the primary outcome being overestimation of BW.Results: A total of 502 patients were included, of whom 301 (60.1%) had a sonoEFW 4000-4249 g, 135 (26.9%) had a sonoEFW 4250-4499 g, 45 (9.0%) had a sonoEFW 4500-4749 g, and 21 (4.2%) had a sonoEFW ≥4750 g. In each sonoEFW group, the risk of overestimating BW was greater than 50%, and the likelihood of overestimation of BW increased significantly across sonoEFW groups (69.4, 76.3, 80.0, 95.2%, p < .001). This held true after adjusting for differences in baseline characteristics, including diabetes and amniotic fluid index. BW ≥4500 g was not accurately predicted. Among women with sonoEFW 4500-4749 g, only 28.9% delivered a neonate with a BW >4500 g; for women with a sonoEFW ≥4750 g, only 47.6% had a BW >4500 g. One hundred sixty-one (32.1%) women underwent CD for suspected macrosomia. Of these CDs, 48 (29.8%) of neonates had a BW <4000 g and 134 (83.2%) had a BW <4500 g.Conclusion: In patients undergoing sonoEFW within 2 weeks of delivery, sonoEFWs ≥4000 g are significantly more likely to overestimate than underestimate the true BW. Obstetricians should be cautious about intervening based on sonoEFW alone, given the high risk that this value is an overestimation of the true weight.