Pain scores after open fetal spina bifida repair and caesarean section - a longitudinal cohort study.

INTRODUCTION: In fetal surgery, successful pain management is crucial for postoperative mobilization, prophylaxis of contractions, and fast recovery. This study analyzed patient's pain experience after open fetal spina bifida (fSB) repair in comparison to pain scores after the subsequent Caesarean section (C-section). MATERIALS AND METHODS: Data was collected with a questionnaire given to 91 women, who had fSB repair and then C-section at our center between 2019 and 2022. It comprised 12 questions covering different aspects of pain experience and satisfaction with pain therapy and was answered by 67 women after fSB repair and 53 after C-section. Postoperative pain was rated on a Likert scale from 0 (slight/rarely) to 100 (strongest/always). Outcomes after fSB repair were compared to those after C-section. Additionally, subgroup analysis compared outcomes of women with different pain levels (group 1-5) after fSB repair. RESULTS: Compared to women after C-section women after fSB repair reported significantly higher maximum pain scores (MPS) (p = 0.03), higher sleep disturbance due to pain (p = 0.03), and sedation rates (p = 0.001) as side effect from pain therapy. No differences were found regarding feelings of insecurity (p = 0.20) or helplessness (p = 0.40), as well as involvement in (p = 0.3) and satisfaction with pain therapy (p = 0.5). Subgroup analysis revealed that women with higher MPS after fSB repair were significantly more often non-Caucasians (p = 0.003) and more often affected by pain while lying in bed (p = 0.007) and during mobilization (p = 0.005). Additionally they reported higher rates of dizziness (p = 0.02) and lower satisfaction rates with pain therapy (p = 0.03). Postoperative complication rate did not differ among groups. CONCLUSION: Although women after fSB repair reported higher MPS compared to after C-section, the current pain management was generally perceived as satisfactory.

Enhanced Recovery after Surgery (ERAS) in open fetal spina bifida repair.

INTRODUCTION: For open fetal spina bifida (fSB) repair, a maternal laparotomy is required. Hence, enhanced maternal recovery after surgery (ERAS) is paramount. A revision of our ERAS protocol was made, including changes in operative techniques and postoperative pain management. This study investigates eventual benefits. METHODS: Our study included 111 women with open fSB repair at our center. The old protocol group (group 1) either received a transverse incision of the fascia with transection of the rectus abdominis muscle (RAM) or a longitudinal incision of the fascia without RAM transection, depending on placental location. The new protocol required longitudinal incisions in all patients (group 2). Postoperative pain management was changed from tramadol to oxycodone/naloxone. Outcomes of the two different protocol groups were analyzed and compared regarding the primary endpoint, the length of hospital stay after fetal surgery (LOS), as well as regarding the following secondary endpoints: postoperative pain scores, day of first mobilization, removal of urinary catheter, bowel movement, and the occurrence of maternal and fetal complications. RESULTS: Out of 111 women, 82 (73.9%) were in group 1 and 29 (26.1%) were in group 2. Women in group 2 showed a significantly shorter LOS (18 [14-23] days vs. 27 [18-39] days, p = 0.002), duration until mobilization (3 [2-3] days vs. 3 [3-4] days, p = 0.03), and removal of urinary catheter (day 3 [3-3] vs. day 4 [3-4], p = 0.004). Group 2 less often received morphine subcutaneously (0% vs. 35.4%, p < 0.001) or intravenously (0% vs. 17.1%, p = 0.02), but more often oxycodone (69.0% vs. 18.3%, p < 0.001). No significant differences were seen regarding pain scores, bowel movement, and maternal and/or fetal complications. CONCLUSION: The new ERAS protocol that combined changes in surgical technique and pain medication led to better outcomes while reducing LOS. Continuous revisions of current ERAS protocols are essential to improve patient care continuously.

Fetal Spina Bifida Repair in Obese Mothers: Is Maternal and Fetal Safety Compromised?

INTRODUCTION: The Management of Myelomeningocele Study (MOMS) eligibility criteria preclude in utero surgery for fetal spina bifida (fSB) when the maternal body mass index (BMI) is ≥35 kg/m2. Some centers still respect this criterion, while others, like ours, do not. This study aimed to assess whether maternal and fetal safety is compromised with higher maternal BMIs. METHODS: Data of 192 patients with open fSB repair at our center were retrospectively analyzed. According to their BMI, patients were divided into three groups: group 1 (BMI <30 kg/m2), group 2 (BMI 30-35 kg/m2), and group 3 (BMI >35 kg/m2). Subgroup analysis was performed to assess differences in maternal and fetal outcomes. Additionally, complications were divided into grades 1 to 5 according to their severity and outcome consequences and compared among groups. RESULTS: Out of 192 patients, 146 (76.0%) had a BMI <30 kg/m2, 28 (14.6%) had a BMI 30-35 kg/m2, and 18 (9.4%) had a BMI >35 kg/m2. Significant differences occurring more often in either group 2 or 3 compared to group 1 were maternal wound seroma (50% or 56% vs. 32%, p = 0.04), amniotic fluid leakage (14% or 6% vs. 2%, p = 0.01) as well as vaginal bleeding (11% or 35% vs. 9%, p = 0.01). On the contrary, duration of tocolysis with atosiban was shorter in patients with BMI >30 kg/m2 (4 or 5 vs. 6 days, p = 0.01). When comparing severity of maternal or fetal complications, grade 1 intervention-related complications occurred significantly more often in group 3 compared to group 1 or 2 (78% vs. 45% or 57%, p = 0.02). Gestational age at delivery was around 36 weeks in all groups without significant differences. CONCLUSION: This investigation did not identify clinically relevant maternal and/or fetal outcome problems related to BMIs >35 kg/m2. Additional studies are however needed to confirm our results.

The expression pattern of cytokeratin 6a in epithelial cells of different origin in dermo-epidermal skin substitutes in vivo.

Keratinocytes are the predominant cell type of skin epidermis. Through the programmed process of differentiation, they form a cornified envelope that provides a physical protective barrier against harmful external environment. Keratins are major structural proteins of keratinocytes that together with actin filaments and microtubules form the cytoskeleton of these cells. In this study, we examined the expression pattern and distribution of cytokeratin 6a (CK6a) in healthy human skin samples of different body locations, in fetal and scar skin samples, as well as in dermo-epidermal skin substitutes (DESSs). We observed that CK6a expression is significantly upregulated in fetal skin and scar tissue as well as in skin grafts after short-term transplantation. Importantly, the abundance of CK6a corresponds directly to the expression pattern of wound healing marker CK16. We postulate that CK6a is a useful marker to accurately evaluate the homeostatic state of DESSs.

Thalamic connectivity topography in newborns with spina bifida: association with neurological functional level but not developmental outcome at 2 years.

Spina bifida affects spinal cord and cerebral development, leading to motor and cognitive delay. We investigated whether there are associations between thalamocortical connectivity topography, neurological function, and developmental outcomes in open spina bifida. Diffusion tensor MRI was used to assess thalamocortical connectivity in 44 newborns with open spina bifida who underwent prenatal surgical repair. We quantified the volume of clusters formed based on the strongest probabilistic connectivity to the frontal, parietal, and temporal cortex. Developmental outcomes were assessed using the Bayley III Scales, while the functional level of the lesion was assessed by neurological examination at 2 years of age. Higher functional level was associated with smaller thalamo-parietal, while lower functional level was associated with smaller thalamo-temporal connectivity clusters (Bonferroni-corrected P < 0.05). Lower functional levels were associated with weaker thalamic temporal connectivity, particularly in the ventrolateral and ventral anterior nuclei. No associations were found between thalamocortical connectivity and developmental outcomes. Our findings suggest that altered thalamocortical circuitry development in open spina bifida may contribute to impaired lower extremity function, impacting motor function and independent ambulation. We hypothesize that the neurologic function might not merely be caused by the spinal cord lesion, but further impacted by the disruption of cerebral neuronal circuitry.

Prenatal Spina Bifida Repair: Defendable Trespassing of MOMS Criteria Results in Commendable Personalized Medicine.

INTRODUCTION: We hypothesize that after publication of the quintessence of the MOMS trial, eligibility criteria for prenatal spina bifida (SB) repair may be modified if a tenable argumentation underlies this decision. METHODS: Our first 154 fetal surgery patients were analyzed with particular focus on how many, which, and why the original eligibility criteria, set forth by the MOMS Trial Protocol, were disobeyed, and what the eventually detectable, negative and positive impacts of these deviations on outcomes were. RESULTS: A total of 152 patients (2 missing consent) were included (100%). In 69 patients (45.4%), a total of 89 eligibility criteria were disobeyed. In 54 (35.6%) cases, the following maternal criteria were concerned: gestational age at operation of >25+6 weeks in 17 (11.2%), uterine pathologies in 13 (8.6%) women, preoperative BMI ≥35 kg/m2 in 12 (7.9%), previous hysterotomy in 7 (4.6%), previous prematurity in 3 (2%), HIV/hepatitis B in 2 (1.3%), psychosocial issues in 2 (1.3%), and placenta praevia in 1 (0.7%). In 32 (21.1%) cases, fetal criteria were disobeyed 34 times: Fetal anomaly unrelated to SB in 19 (12.5%), no/minimal evidence of hindbrain herniation in 13 (8.6%), and severe kyphosis in 2 (1.3%). We could not identify cases where non-observation of criteria led to clear-cut maternal and/or fetal disadvantages. CONCLUSION: This study shows that MOMS trial eligibility criteria for prenatal SB repair should be modified or even abandoned with adequate medical and ethical argumentation, and with written parental informed consent after non-directive, full disclosure counseling. This clear-cut change of paradigm is a necessity as it leads toward personalized medicine, allowing more fetuses to benefit from fetal surgery than would have benefitted with the former, published, MOMS criteria in place.

M-Sign in Middle Cerebral Artery Doppler Waveforms: A Sign of Fetal Vasoconstriction Before and After Open Fetal Spina Bifida Repair.

BACKGROUND: Increased pulse wave reflection in the fetal arterial system, illustrated by a second systolic peak (M-sign) in middle cerebral artery (MCA) Doppler waveforms, allows interpretation of fetal systemic vasoconstriction. Little is known about fetal vascular regulation during fetal spina bifida (fSB) repair. Therefore, the aim of this study was to analyze MCA-Doppler waveform changes before, during, and after fSB repair. PATIENTS AND METHODS: 31 pregnant women who underwent fSB repair were included. Fetal MCA-Doppler waveforms were prospectively analyzed before, during and after fSB repair, and categorized as follows: normal systolic downslope, systolic shoulder, second systolic peak (M-sign), and concave systolic downslope. These MCA waveforms were related to maternal and fetal characteristics, to anesthetic medication, and to umbilical artery (UA) waveforms. RESULTS: Before fSB repair, all fetuses repeatedly presented M-signs. After initiation of desflurane for general anesthesia, systolic shoulder and the M-sign vanished in 24/31 (78%) fetuses and 19/31 (61%) showed transient UA ARED flow. A significant association between these two Doppler findings was found (p=0.007). After fSB repair, signs of increased pulse wave reflection reappeared but resolved over time (23 days ± 20, SD) in all fetuses. CONCLUSION: Both fSB and intrauterine repair influence fetal vascular regulation. This phenomenon can be illustrated by MCA-Doppler waveforms. While anesthetic agents transiently eliminated M-signs and often provoked a UA ARED flow, fSB repair finally led to normalization of MCA-Doppler waveforms indicating return to normal fetal vascular regulation.

Subsequent Pregnancy Outcomes after Open in utero Spina Bifida Repair.

INTRODUCTION: Fetal spina bifida (SB) repair is a distinct therapeutic option in selected cases. Since this procedure may not only be associated with short-term obstetrical complications, the aim of this study was to assess the outcomes of subsequent pregnancies after open fetal SB repair. METHODS: 138 patients having had open fetal SB repair at our center received a questionnaire regarding the occurrence, course, and outcome of subsequent pregnancies. Additionally, medical records were reviewed. All subsequent pregnancies with complete outcome data that progressed beyond 20 gestational weeks (GW) were included for further analysis. RESULTS: 70% of all women answered the questionnaire. Out of this cohort, 35 subsequent pregnancies were reported in 29% of women. The rate of early pregnancy loss including elective terminations was 14%. All 29 pregnancies processing >20 GW ended in live births without preterm births <34th GW. Mean gestational age at delivery was 37.3 ± 1.4 GW. Uterine rupture occurred in two cases (7%) and uterine thinning/dehiscence was present in six cases (21%). No maternal transfusions were required. CONCLUSION: When counseling women undergoing open fetal SB repair, one should consider possible risks for subsequent pregnancies, especially the one of uterine dehiscence and rupture that is similar compared to numbers reported after classical cesarean deliveries.

Stage 2: The Vaginal Flora in Women Undergoing Fetal Spina Bifida Repair and Its Potential Association with Preterm Rupture of Membranes and Preterm Birth.

INTRODUCTION: Vaginal dysbiosis affects pregnancy outcomes, however, the relevance of abnormal findings on pre/post-surgical vaginal culture in women undergoing fetal spina bifida (fSB) repair is unknown. OBJECTIVES: To describe the incidence of normal and abnormal pre- and post-surgical vaginal microorganisms in fSB patients and to investigate potential associations between the type of vaginal flora and the occurrence of preterm prelabour rupture of membranes (PPROM) and preterm birth (PTB). METHODS: 99 women undergoing fSB repair were eligible (2010-2019). Pre-surgical vaginal culture was routinely taken before surgery. Post-surgical cultures were taken on indication. Vaginal flora was categorized into four categories: healthy vaginal flora (HVF), bacterial vaginosis (BV), desquamative inflammatory vaginitis (DIV), and yeast infection. RESULTS: The incidence of HVF, BV, DIV, or yeast infections was not statistically different between the pre- and postoperative patients. Furthermore, an abnormal pre/post-surgical vaginal flora was not associated with PPROM (OR 1.57 (0.74-3.32), p = 0.213)/OR 1.26 (0.62-2.55), p = 0.515), or with PTB (OR 1.19 (0.82-1.73), p = 0.315)/(OR 0.86 (0.60-1.24), p = 0.425). CONCLUSIONS: Abnormal vaginal microbiome was not associated with PPROM and PTB when appropriate treatment was performed.

Human fetal skin derived merkel cells display distinctive characteristics in vitro and in bio-engineered skin substitutes in vivo.

Human skin contains specialized neuroendocrine Merkel cells responsible for fine touch sensation. In the present study, we performed in-depth analysis of Merkel cells in human fetal back skin. We revealed that these Merkel cells expressed cytokeratin 20 (CK20), were positive for the neuroendocrine markers synaptophysin and chromogranin A, and the mechanosensitive ion channel Piezo2. Further, we demonstrated that Merkel cells were present in freshly isolated human fetal epidermal cells in vitro, and in tissue-engineered human dermo-epidermal skin substitutes 4 weeks after transplantation on immune-compromised rats. Merkel cells retained the expression of CK20, synaptophysin, chromogranin A, and Piezo2 after isolation and in culture, and in the skin substitutes after transplantation. Interestingly, we observed that in fetal skin and in skin substitutes, only Merkel cells were positive for CK8, while in culture, also non-Merkel cells showed positivity for CK8. In summary, human fetal Merkel cells showed phenotypical features confirming their cell identity. This findings are of pivotal importance for the future application of fetal tissue-engineered skin in clinics.

Fetal-Maternal Surgery for Spina Bifida in a HIV-Infected Mother.

INTRODUCTION: In select cases, in utero surgery for myelomeningocele (MMC) leads to better outcomes than postnatal repair. However, maternal HIV infection constitutes a formal exclusion criterion due to the potential of vertical HIV transmission. Encouraged by a previous case of a successful fetal spina bifida repair in a Hepatitis Bs antigen-positive woman, a plan was devised allowing for fetal surgery. CASE REPORT: In utero MMC repair was performed although the mother was HIV-infected. To minimize the risk of in utero HIV transmission, the mother was treated by highly active antiretroviral therapy throughout gestation as well as intravenous zi-dovudine administration during maternal-fetal surgery. The mother tolerated all procedures very well without any sequelae. The currently 20 month-old toddler is HIV negative and has significantly benefitted from fetal surgery. DISCUSSION/CONCLUSION: This case shows that maternal HIV is not a priori a diagnosis that excludes fetal surgery. Rather, it might be a surrogate for moving towards personalized medicine and away from applying too rigorous exclusion criteria in the selection of candidates for maternal-fetal surgery.

Determination of Anatomical Levels in Spina Bifida Fetuses with Ultrasound and MRI.

PURPOSE: The goal of this study was to assess the accuracy of prenatal anatomical level determination by ultrasound (US) and magnetic resonance imaging (MRI) by analyzing the congruence with the "true" anatomical level identified by postnatal MRI. PATIENTS AND METHODS: The first 60 patients undergoing fetal myelomeningocele surgery at The Zurich Center for Fetal Diangosis and Therapy were included in this study. Anatomical levels (i. e., first dysraphic vertebra) determined by prenatal US and MRI were compared to postnatal MRI. The level of agreement between the imaging modalities was evaluated with a Cohen's kappa test. Results > 0.6 were interpreted as good agreement, > 0.8 as excellent. RESULTS: The exact congruence between prenatal US and MRI compared to postnatal MRI was 33 % and 48 %, respectively, for an accuracy within one level difference of 80 % and 90 %, and within two levels difference of 95 % and 98 %, respectively. The level of agreement of prenatal US and MRI compared to postnatal MRI was 0.62 and 0.79, respectively. Most of the prenatally incorrectly assigned levels were assigned too high (worse) than the "true" level (US 88 % vs. MRI 65 %). CONCLUSION: Reliable exact prenatal level determination by US and MRI is not possible. However, the prenatal determination of the anatomical level of the lesion is good within one level margin of error. Prenatal US as well as MRI demonstrate a systematic error towards higher levels. The above considerations must be integrated into prenatal counselling.

Emerging magnetic resonance imaging techniques in open spina bifida in utero.

Magnetic resonance imaging (MRI) has become an essential diagnostic modality for congenital disorders of the central nervous system. Recent advancements have transformed foetal MRI into a clinically feasible tool, and in an effort to find predictors of clinical outcomes in spinal dysraphism, foetal MRI began to unveil its potential. The purpose of our review is to introduce MRI techniques to experts with diverse backgrounds, who are involved in the management of spina bifida. We introduce advanced foetal MRI postprocessing potentially improving the diagnostic work-up. Importantly, we discuss how postprocessing can lead to a more efficient utilisation of foetal or neonatal MRI data to depict relevant anatomical characteristics. We provide a critical perspective on how structural, diffusion and metabolic MRI are utilised in an endeavour to shed light on the correlates of impaired development. We found that the literature is consistent about the value of MRI in providing morphological cues about hydrocephalus development, hindbrain herniation or outcomes related to shunting and motor functioning. MRI techniques, such as foetal diffusion MRI or diffusion tractography, are still far from clinical use; however, postnatal studies using these methods revealed findings that may reflect early neural correlates of upstream neuronal damage in spinal dysraphism.

Laparoscopic Ureteroureterostomy vs. Common Sheath Ureteral Reimplantation in Children With Duplex Kidney Anomalies.

Purpose: Laparoscopic ureteroureterostomy (LUU) has been proposed as an alternative to common sheath ureteral reimplantation (CSUR) in children with symptomatic duplex kidneys. However, data is limited for LUU in the pediatric population. The aim of this study was to analyze our experience with LUU and to compare the results with those after CSUR to assess whether a less invasive surgical approach could be a valid alternative. Patients and methods: The data of all children with duplex kidneys who underwent either LUU or CSUR at our center from 2006 to 2018 were reviewed retrospectively. After parental counseling, the option of LUU was provided as an alternative to CSUR for unilateral procedures and in the absence of vesicoureteral reflux to the receiving ureter. Baseline characteristics, indication for surgery, hospitalization and operative times, and intraoperative, post-operative, and late complications were analyzed. Preoperative and 1-year post-operative sonographies were reviewed by a pediatric radiologist. Increasing renal pelvic diameter (Δ >5 mm) was regarded as a sign of ureteral obstruction. Results: Forty children were included in this study, with 16 children receiving LUU and 24 children receiving CSUR. The children had a mean age of 2.7 years (7 months-9.8 years) and were followed up in our outpatient clinic for an average of 3.9 years (3 months-10.6 years) after surgery. The median hospital stay was 2 days shorter after LUU. Initially, a considerably longer time was needed for LUU, but after more experience was gained, similar operative times were observed for both procedures. Complications were encountered in both groups. After LUU, two patients developed anastomotic leakage: one was managed conservatively, and one required temporary nephrostomy. In the CSUR group, one patient developed vesicoureteral obstruction during follow-up and required reoperation with LUU. The occurrence of post-operative urinary tract infections was similar in both groups. No complications related to the ureteral stump after LUU arose. Conclusion: LUU is a safe and efficacious treatment option for children with duplex kidney anomalies and can be used as an alternative to CSUR. All children receiving LUU showed a non-obstructive, patent anastomosis and no signs for stenotic compromise of the receiving ureter.

Fetal surgery for spina bifida in Zurich: results from 150 cases.

PURPOSE: Over the past 10 years, over 150 fetal spina bifida surgeries were performed at the Zurich Center for Fetal Diagnosis and Therapy. This study looks at surrogates for success and failure of this approach. METHODS: We focused on key outcome parameters including hydrocephalus shunt rate at one year, bladder control at 4, independent ambulation at 3 years, and maternal, fetal, and neonatal complications. RESULTS: From the first 150 patients undergoing fetal surgery for spina bifida, 148 (98.7%) were included in the study. Maternal-fetal surgery was uneventful in 143/148 (97%) cases. Intraoperative problems included resuscitation in 4/148 fetuses (2.7%). 1/148 fetuses (0.7%) died on postoperative day 4. Maternal complications included chorioamniotic membrane separation in 22/148 (15%), lung embolism in 3/148 (2.1%), chorioamnionitis in 2/148 (1.4%), AV-block III and uterine rupture in 1/148 each (0.7%). 1/148 (0.7%) newborn death was recorded. Hindbrain herniation was identified preoperatively in 132/148 (90%) fetuses and resolved completely in 119/132 (90%). At one year, 39/106 (37%) children had required a CSF diversion. At 4 years, 4/34 patients (12%) had normal bladder control. At 3 years, 48/57 (84%) walked independently. CONCLUSION: A majority of patients benefitted from prenatal intervention, in that the shunt rate was lower and the rates of continent and walking patients were higher than reported with postnatal care.

Hindbrain Herniation and Banana and Lemon Sign After Open Fetal Myelomeningocele Repair - When Do These Signs Disappear and is Shunting Predictable?

PURPOSE: The aim was to describe the sonographic follow-up of hindbrain herniation (HH), the banana and lemon sign after fetal myelomeningocele (fMMC) repair, and the time of disappearance of these signs after the intervention, and to investigate any predictive value for the necessity of shunting during the infant's first year of life. Additionally, the sonographic evolution of the transcerebellar diameter (TCD) before and after fetal intervention was assessed. PATIENTS AND METHODS: The first 50 patients that underwent fMMC repair at Zurich Center for Fetal Diagnosis and Therapy (www.swissfetus.ch) were included in this study. Sonographic scans performed weekly after fMMC repair focusing on HH and banana and lemon signs were analyzed and compared between the shunted and the non-shunted group. ROC curves were generated for the time intervals of resolution of the signs in order to show their predictive accuracy for the need for shunting until 1 year of age. RESULTS: HH resolved in 48 fetuses (96 %) before delivery. The sonographic disappearance of HH within the first two weeks after fMMC repair was associated with a significantly lower incidence of shunt placement (OR 0.19; 95 % CI 0.4-0.9) during the first year of life (p = 0.03). All fetuses with persistent HH before delivery received a shunt. TCD growth was observed in all fetuses. CONCLUSION: The reversibility of HH within two weeks after fMMC repair is associated with an 80 % lower incidence of shunt placement during the infant's first year of life. Moreover, it allows the cerebellum to grow and to normalize its configuration.

Urological Outcome after Fetal Spina Bifida Repair: Data from the Zurich Cohort.

INTRODUCTION: Neurogenic lower urinary tract dysfunction (NLUTD) represents a severe burden for patients with open spina bifida (OSB). The effect of fetal OSB repair on the urological outcome remains unclear, as controversial data exist. The aim of this study was to further increment existing outcome data and to demonstrate that our earlier published positive preliminary results are not erratic. METHODS: Data from standardized urological follow-up appointments of patients with fetal OSB repair operated at our center were analyzed. Data were obtained from urodynamic studies (UDSs) and radiologic exams performed in the newborn (gestational age 37-39 weeks), at ages of 6, 12, 18, and 24 months, and then at yearly intervals. RESULTS: Of 82 patients (mean age 2.6 years, range 6 months to 7 years), 26 (32%) had a normal bladder function as demonstrated by UDSs. Of the 56 (68%) patients with NLUTD, 29 (51%) patients showed initially a normal UDS, but developed NLUTD in the follow-up, 19 (66%) of them spontaneously and another 10 (34%) in association with growth and development, or surgery of inclusion cysts. Radiologic abnormalities (upper tract dilatation and vesico-uretero-renal reflux) were seen in 15%, mainly patients with NLUTD. CONCLUSION: Our results add an important set of information to the existing body of evidence. The data reconfirm our earlier published favorable preliminary results and support other studies that show a possible benefit of prenatal OSB repair on the urological outcome, but they also demonstrate that the positive effect remains limited.

Prenatal Sonographic Head Circumference and Cerebral Ventricle Width Measurements Before and After Open Fetal Myelomeningocele Repair - Prediction of Shunting During the First Year of Life.

PURPOSE: The aim of this study was to describe the sonographic evolution of fetal head circumference (HC) and width of the posterior horn of the lateral ventricle (Vp) after open fetal myelomeningocele (fMMC) repair and to assess whether pre- or postoperative measurements are helpful to predict the need for shunting during the first year of life. PATIENTS & METHODS: All 30 children older than one year by January 2017 who previously had fMMC repair at the Zurich Center for Fetal Diagnosis and Therapy were included. Sonographic evolution of fetal HC and Vp before and after fMMC repair was assessed and compared between the non-shunted (N = 16) and the shunted group (N = 14). ROC curves were generated for the fetal HC Z-score and Vp in order to show their predictive accuracy for the need for shunting until 1 year of age. RESULTS: HC was not an independent factor for predicting shunting. However, the need for shunting was directly dependent on the preoperative Vp as well as the Vp before delivery. A Vp > 10 mm at evaluation for fMMC repair or > 15 mm before delivery identifies 100 % of the infants needing shunt placement at a false-positive rate of 44 % and 25 %, respectively. All fetuses with a Vp > 15 mm at first evaluation received a shunt. CONCLUSION: Fetuses demonstrating a Vp of > 15 mm before in utero MMC repair are extremely likely to develop hydrocephalus requiring a shunt during the first year of life. This compelling piece of evidence must be appropriately integrated into prenatal counseling.

Bioengineering and in utero transplantation of fetal skin in the sheep model: A crucial step towards clinical application in human fetal spina bifida repair.

An intricate problem during open human fetal surgery for spina bifida regards back skin closure, particularly in those cases where the skin defect is much too large for primary closure. We hypothesize that tissue engineering of fetal skin might provide an adequate autologous skin substitute for in utero application in such situations. Eight sheep fetuses of four time-mated ewes underwent fetoscopic skin biopsy at 65 days of gestation. Fibroblasts and keratinocytes isolated from the biopsy were used to create fetal dermo-epidermal skin substitutes. These were transplanted on the fetuses by open fetal surgery at 90 days of gestation on skin defects (excisional wounds) created during the same procedure. Pregnancy was allowed to continue until euthanasia at 120 days of gestation. The graft area was analyzed macroscopically and microscopically. The transplanted fetal dermo-epidermal skin substitutes was well discernable in situ in three of the four fetuses available for analysis. Histology confirmed healed grafts with a close to natural histological skin architecture four weeks after in utero transplantation. This experimental study generates evidence that laboratory grown autologous fetal skin analogues can successfully be transplanted in utero. These results have clinical implications as an analogous procedure might be applied in human fetuses undergoing prenatal repair to facilitate primary skin closure. Finally, this study may also fertilize the field of fetal tissue engineering in general, particularly when more interventional, minimally invasive, and open fetal surgical procedures become available.

Bioengineering of Fetal Skin: Differentiation of Amniotic Fluid Stem Cells into Keratinocytes.

PURPOSE: Open fetal spina bifida repair has become a novel clinical standard of care. In very large spina bifida lesions, the skin defect cannot be covered primarily, asking for alternative solutions. We hypothesize that amniotic fluid stem cells (AFSC) could be differentiated into keratinocytes that could then be used to bioengineer autologous skin usable for in utero back coverage. METHODS: To obtain human AFSC, amniotic fluid samples obtained from fetal surgeries were subjected to immunoselection for c-kit. C-kit-positive samples and controls were cultured with the additives morphogenetic protein 4 and vitamin C to induce differentiation towards keratinocytes. This process was monitored by measuring the expression of K8 and K14 via immunohistochemical staining, flow cytometry, and polymerase chain reaction. RESULTS: After immunoselection and expansion, most cells were positive for K8, but none for K14. After completion of the differentiation protocol, cell colonies with keratinocyte-like appearance could be observed, but cells remained positive for K8 and negative for K14, indicating failed differentiation into keratinocytes. CONCLUSIONS: Culturing of keratinocyte-like cells from AFSC, harvested intraoperatively, was not feasible in this setting. The reasons for failure must be investigated and eliminated, as bioengineering of fetal skin for clinical use during fetal surgery for spina bifida remains an attractive goal.