Search

Abstract Background Congenital diaphragmatic hernia (CDH) is a rare disease that affects the development of the diaphragm, leading to abnormal lung development. Unfortunately, there is no established therapy for CDH. Retinoic acid pathways are implicated in the ethology of CDH and macrophages are known to play a role in repairing organ damage. Methods We have analyzed the effect of several Toll like receptor (TLR) ligands in the nitrofen-induced CDH model in pregnant rats widely used to study this disease and in the G2-GATA4Cre;Wt1fl/fl CDH genetic mice model. Morphometric and histological studies were carried out. Immune cell infiltration was assayed by immunochemistry and immunofluorescence and retinoic pathway gene expression analyzed in vivo and in vitro in macrophages. Results We found that administering a single dose of atypical TLR2/4 ligands (CS1 or CS2), 3 days after nitrofen, cured diaphragmatic hernia in 73% of the fetuses and repaired the lesion with complete diaphragm closure being on the other hand nontoxic for the mothers or pups. Moreover, these immunomodulators also improved pulmonary hypoplasia and alveolar maturation and vessel hypertrophy, enhancing pulmonary maturity of fetuses. We also found that CS1 treatment rescued the CDH phenotype in the G2-GATA4Cre;Wt1fl/fl CDH genetic mice model. Only 1 out of 11 mutant embryos showed CDH after CS1 administration, whereas CDH prevalence was 70% in untreated mutant embryos. Mechanistically, CS1 stimulated the infiltration of repairing M2 macrophages (CD206+ and Arg1+) into the damaged diaphragm and reduced T cell infiltration. Additionally, those TLR ligands induced retinol pathway genes, including RBP1, RALDH2, RARα, and RARβ, in the affected lungs and the diaphragm and in macrophages in vitro. Conclusions Our research has shown that TLR ligand immunomodulators that influence anti-inflammatory macrophage activation can be effective in treating CDH, being nontoxic for the mothers or pups suggesting that those TLR ligands are a promising solution for CDH leading to orphan drug designation for CS1. The immune system of the fetus would be responsible for repairing the damage and closure of the hernia in the diaphragm and enhanced proper lung development after CS1 treatment.

Abstract Objectives We aimed to investigate prenatal predictors for ambulation without assistance in children following prenatal repair of open spina bifida (OSB). Methods A systematic search was conducted in three databases until June 2022. We included articles reporting on prenatal repair of open spina bifida (OSB) and ambulation outcomes. The random‐effect model was used. Effect sizes are presented as odds ratio (OR), using the Mantel–Haenszel test, with 95% confidence interval (CI). Results Five studies encompassing 460 pregnancies that underwent prenatal repair of OSB of which a total of 234 had data on ambulation and were included. The follow‐up age for all included studies was 30 months. Two studies were open repairs, two were fetoscopic repairs, and one included both open and fetoscopic repairs. Of the 234 included population, ambulation without assistance occurred in 159/234, 68% (95% CI 58, 76), and ambulation with assistance occurred in 75/234, 32% (95% CI 23.6, 41.6). Significant prenatal preoperative predictors that are negatively associated with ambulation without assistance were lateral ventricle (LV) width ≥15 mm (OR: 0.29; 95% CI 0.12, 0.69, I2 = 0.0%; p

Timely identification of fetal conditions enables comprehensive evaluation, counseling, postnatal planning, and prenatal treatments. This study assessed the existing evidence on how social determinants of health (SDOH) influence diagnosis timing of fetal conditions appropriate for care in fetal care centers (FCCs). Eligible studies were conducted in the U.S. and published in English after 1999. We employed the Healthy People 2020 SDOH framework to categorize and analyze data from 16 studies, where 86% focused solely on congenital heart disease (CHD). Studies primarily focused on individual-level SDOH, with only 36% addressing structural-level factors. A total of 31 distinct indicators of SDOH were identified, with 68% being unique to individual studies. Indicators often varied in definition and specificity. Three studies covered all five SDOH categories in the Healthy People 2020 Framework. Studies revealed varying and often conflicting associations with SDOH indicators, with race and ethnicity being the most explored (100%), followed by socioeconomic status (69%), maternal age (57%), residence (43%), and structural factors (29%). Our findings highlight the need for more comprehensive research, including conditions beyond CHD, and the establishment of consensus on indicators of SDOH. Such efforts are necessary to gain a deeper understanding of the underlying factors driving disparities in fetal diagnosis and treatment.

Abstract Background Thrombosis of one of the umbilical arteries is a rare complication of pregnancy and is associated with adverse pregnancy outcomes, including stillbirth and intrauterine growth restriction. Although extremely rare, umbilical artery thrombosis (UAT) in monochorionic diamniotic twins is difficult to diagnose prenatally and manage. UAT has a poor prognosis and is associated with an increased perinatal mortality rate. In most previous cases, emergency cesarean section was performed or intrauterine fetal death occurred at the time of UAT diagnosis. Case presentation: Herein, we report an extremely rare case of sequential UAT in monochorionic diamniotic twins diagnosed via ultrasound at 29+ 5 weeks of gestation in a 34-year-old woman. Following expectant management with intensive monitoring for 16 days, two healthy infants were delivered through an emergency cesarean section. UAT in both fetuses was confirmed by pathological examination. The mother and twins described in this case underwent long-term follow-up and are currently in good health without any complications. Conclusions Based on our experience, we suggest that expectant management should be undertaken as long as the mother and infants are stable on ultrasonographic scans and are closely monitored. When UAT is suspected, we believe that the best delivery time should be determined by considering complaints of unusual fetal movements, non-stress test evidence, gestational age, amniotic fluid volume, and blood flow in the umbilical artery, middle cerebral artery, and ductus venosus. Obstetricians should ensure that the patients and their families are clearly informed about all potential risks of expectant management for UAT.

BackgroundThe development of prenatal diagnosis technology allows prompt detection of severe fetal diseases. To address adverse factors that threaten fetal survival, fetal therapy came into existence, which aims to preserve the function after birth to a higher degree and improve the quality of life.ObjectiveTo conduct a comprehensive bibliometric analysis of studies on fetal therapy in the past decade and explore the research trends and hotspots in this field.MethodsWe conducted a systematic search on the Web of Science Core Collection to retrieve studies related to fetal therapy published from 2012 to 2022. VOSviewer and CiteSpace were used to analyze the key features of studies, including annual output, countries/regions, institutions, authors, references, research hotspots, and frontiers.ResultsA total of 9,715 articles were included after eliminating duplicates. The annual distribution of the number of articles showed that the number of articles published in fetal therapy had increased in the past decade. Countries and institutions showed that fetal therapy is more mature in the United States. Author analysis showed the core investigators in the field. Keyword analysis showed the clustering and emergence frequency, which helped summarize the research results and frontier hotspots in this field. The cocited references were sorted out to determine the literature with a high ranking of fetal therapy in recent years, and the research trend in recent years was analyzed.ConclusionsThis study reveals that countries, institutions, and researchers should promote wider cooperation and establish multicenter research cooperation in fetal therapy research. Moreover, fetal therapy has been gradually explored from traditional surgical treatment to gene therapy and stem cell therapy. In recent years, fetoscopic laser surgery, guideline, and magnetic resonance imaging have become the research hotspots in the field.

Background: This study aimed to analyze prenatally diagnosed fetal cardiac anomaly cases in a tertiary center with respect to the incidence, type of anomalies, and rate of correct diagnosis based on postnatal diagnosis (by comparing pre- versus post-natal diagnosis). Methods: In this retrospective study, the data of 250 patients diagnosed with fetal cardiac abnormalities who were evaluated in a perinatology department between January 2021 and May 2023 were analyzed. Results: A total of 250 cases were in our study with a mean maternal age of 27.6 ± 5.1 years and a median gestational week of first assessment at our center of 27 weeks (14–39 weeks). Ventricular septal defect (37 cases, 14.8%) was the most common fetal cardiac anomaly detected prenatally in this study while corrected transposition of the great arteries (L-TGA), left ventricle hypoplasia, coarctation of aorta (CoA) and situs inversus were the least common. Termination of pregnancy was performed in 21 cases (3.1%) and 3 fetuses died antenattally during pregnancy follow-up. While genetic testing was performed in 49 cases (19.6%), chromosomal abnormalities were found in 15 cases (6%). Postnatally, a detailed follow-up was available for 141 cases (56%) and prenatal diagnosis was confirmed in 101 cases. The accuracy rate for prenatal and postnatal diagnoses was 71.63%. Conclusions: Detailed ultrasound examination of the fetal heart identifies more than 2/3 of fetuses complicated with major cardiac pathology. In addition, a systematic approach to these abnormalities aids in identifying the accurate diagnosis of isolated cardiac defects, connected with other systems or a part of a syndrome. A comprehensive examination of anatomical scans might play a crucial role in enhancing diagnostic accuracy.

Iatrogenic preterm premature rupture of fetal membranes (iPPROM) after fetal surgery remains a strong trigger for premature birth. As fetal membrane defects do not heal spontaneously and amniotic fluid leakage and chorioamniotic membrane separation may occur, we developed a biocompatible, fetoscopically-applicable collagen plug with shape memory to prevent leakage. This plug expands directly upon employment and seals fetal membranes, hence preventing amniotic fluid leakage and potentially iPPROM.Lyophilized type I collagen plugs were given shape memory and crimped to fit through a fetoscopic cannula (Ø 3 mm). Expansion of the plug was examined in phosphate buffered saline (PBS). Its sealing capacity was studied ex vivo using human fetal membranes, and in situ in a porcine bladder model.The crimped plug with shape memory expanded and tripled in diameter within 1 min when placed into PBS, whereas a crimped plug without shape memory did not. In both human fetal membranes and porcine bladder, the plug expanded in the defect, secured itself and sealed the defect without membrane rupture.In conclusion, collagen plugs with shape memory are promising as medical device for rapid sealing of fetoscopic defects in fetal membranes at the endoscopic entry point.

Abstract Background Twin anemia polycythemia sequence is a rare complication in monochorionic twin pregnancy. Case presentation We describe a case of dichorionic twin pregnancy presenting with suspected twin anemia polycythemia sequence. A 31-year-old White female, on her third pregnancy, had a routine ultrasound scan at 12 weeks gestation, which demonstrated a dichorionic twin pregnancy with one placenta located in the anterior wall and the other in the posterior wall of the uterus. At 21 weeks, a scan demonstrated a 24% growth discordance between the two fetuses with normal Doppler studies and amniotic fluid. At 27 weeks, one twin showed signs of anemia and the other polycythemia; the fetal middle cerebral artery peak systolic velocity was high in the anemic fetus and low in the polycythemic twin (1.8 and 0.5 multiples of the median). An intrauterine blood transfusion was carried out and this increased the fetal hemoglobin concentration in the anemic twin from 3.5 to 12.5 g/dL. At 29 weeks, delivery by cesarean section was carried out because of evidence from middle cerebral artery peak systolic velocity of recurrence of anemia in one twin and worsening polycythemia in the co-twin; at birth the hemoglobin concentrations were 5.6 and 24.9 g/dL, respectively. Histopathological examination confirmed dichorionicity with no communicating vessels between the two placentas. Conclusions This is the first case of twin anemia polycythemia sequence in a dichorionic, diamniotic twin pregnancy where intrauterine blood transfusion was used to prolong the pregnancy by almost 2 weeks in a “twin anemia polycythemia sequence-like” setting.

Abstract Background Prevention of pregnancy-related alloimmunization and the management of hemolytic disease of the fetus and newborn (HDFN) has significantly improved over the past decades. Considering improvements in HDFN care, the objectives of this systematic literature review were to assess the prenatal treatment landscape and outcomes of Rh(D)- and K-mediated HDFN in mothers and fetuses, to identify the burden of disease, to identify evidence gaps in the literature, and to provide recommendations for future research. Methods We performed a systematic search on MEDLINE, EMBASE and clinicaltrials.gov. Observational studies, trials, modelling studies, systematic reviews of cohort studies, and case reports and series of women and/or their fetus with HDFN caused by Rhesus (Rh)D or Kell alloimmunization. Extracted data included prevalence; treatment patterns; clinical outcomes; treatment efficacy; and mortality. Results We identified 2,541 articles. After excluding 2,482 articles and adding 1 article from screening systematic reviews, 60 articles were selected. Most abstracted data were from case reports and case series. Prevalence was 0.047% and 0.006% for Rh(D)- and K-mediated HDFN, respectively. Most commonly reported antenatal treatment was intrauterine transfusion (IUT; median frequency [interquartile range]: 13.0% [7.2–66.0]). Average gestational age at first IUT ranged between 25 and 27 weeks. weeks. This timing is early and carries risks, which were observed in outcomes associated with IUTs. The rate of hydrops fetalis among pregnancies with Rh(D)-mediated HDFN treated with IUT was 14.8% (range, 0–50%) and 39.2% in K-mediated HDFN. Overall mean ± SD fetal mortality rate that was found to be 19.8%±29.4% across 19 studies. Mean gestational age at birth ranged between 34 and 36 weeks. Conclusion These findings corroborate the rareness of HDFN and frequently needed intrauterine transfusion with inherent risks, and most births occur at a late preterm gestational age. We identified several evidence gaps providing opportunities for future studies.

Introduction: Duchenne muscular dystrophy (DMD) is a progressive disease that leads to damage of muscle and myocardium due to genetic abnormalities in the dystrophin gene. In utero cell transplantation that might facilitate allogenic transplantation is worth considering to treat this disease. Methods: We performed allogeneic in utero transplantation of GFP-positive myoblasts and adipose-derived mesenchymal stem cells into murine DMD model animals. The transplantation route in this study was fetal intraperitoneal transplantation and transplacental transplantation. Transplanted animals were examined at 4-weeks old by immunofluorescence staining and RT-qPCR. Results: No GFP-positive cells were found by immunofluorescence staining of skeletal muscle and no GFP mRNA was detected by RT-qPCR in any animal, transplantation method and cell type. Compared with previous reports, myoblast transplantation exhibited an equivalent mortality rate, but adipose-derived stem cell (ASC) transplantation produced a higher mortality rate. Conclusions: In utero transplantation of myoblasts or ASCs to murine models of DMD does not lead to engraftment and, in ASC transplantation primarily, frequently results in fetal death.

Abstract Background Lysosomal storage diseases (LSDs) are inherited metabolic disorders that may lead to severe multi-organ disease. Current ERTs are limited by anti-drug antibodies, the blood–brain barrier, and early disease onset and progression before ERT is started. We have opened a phase I clinical trial of enzyme replacement therapy (ERT) for fetuses with LSDs (NCT04532047). We evaluated the attitudes of parents and patients with LSDs towards fetal clinical trials and therapies. Methods A multidisciplinary team designed a survey which was distributed by five international patient advocacy groups. We collected patients’ demographic, diagnostic, and treatment information. Associations between respondent characteristics and attitudes towards fetal therapies/trials were analyzed using multivariate ordinal logistic regression. Results The survey was completed by 181 adults from 19 countries. The majority of respondents were mothers from the United States. The most common diseases were MPS1 (26%), MPS3 (19%), and infantile-onset Pompe (14%). Most patients (88%) were diagnosed after birth, at a median of 21 months. Altogether, 65% of participating patients and children of participants had received ERT, 27% a stem cell transplant, and 4% gene therapy. We found that half (49%) of respondents were unlikely to terminate a future affected pregnancy, 55% would enroll in a phase I clinical trial for fetal ERT, and 46% would enroll in a fetal gene therapy trial. Respondents who received postnatal ERT were significantly more likely enroll in a trial for fetal ERT or gene therapy (ERT OR 4.48, 95% CI 2.13–9.44, p

Hypophosphatasia (HPP) is a congenital skeletal disease. Impairment of bone mineralization and seizures are due to a deficiency of tissue-nonspecific alkaline phosphatase (TNAP). Enzyme replacement therapy (ERT) is available as a highly successful treatment for pediatric-onset HPP. However, the potential for prenatal ERT has not been fully investigated to date. In this study, we assessed outcomes and maternal safety using a combinational approach with prenatal and postnatal administration of recombinant TNAP in Akp2−/− mice as a model of infantile HPP. For the prenatal ERT, we administered subcutaneous injections of recombinant TNAP to pregnant mice from embryonic day 11.5–14.5 until delivery, and then sequentially to Akp2−/− pups from birth to day 18. For the postnatal ERT, we injected Akp2−/− pups from birth until day 18. Prenatal ERT did not cause any ectopic mineralization in heterozygous maternal mice. Both prenatal and postnatal ERT preserved growth, survival rate and improved bone calcification in Akp2−/− mice. However, the effects of additional prenatal treatment to newborn mice appeared to be minimal, and the difference between prenatal and postnatal ERT was subtle. Further improvement of the prenatal ERT schedule and long-term observation will be required. The present paper sets a standard for such future studies.

Resumen: El ex-utero intrapartum treatment (EXIT) es una estrategia de parto que permite brindar soporte cardiopulmonar al feto con el objetivo de realizar una intervención vital durante la transición a la vida extrauterina. El EXIT proporciona tiempo para el abordaje de una variedad de malformaciones potencialmente mortales en un ambiente de máximo control fisiológico.Según la finalidad de tratamiento, se han descrito distintos tipos de EXIT, incluyendo EXIT-to-airway (para el control de la vía aérea fetal), EXIT-to-ECMO (para la colocación de cánulas de oxigenación por membrana extracorpórea), EXIT-to-resection (para la resección de masas que impiden la ventilación o el retorno venoso) y EXIT-to-separation (para el abordaje de siameses). El objetivo general de un EXIT es mejorar la seguridad de procedimientos que resultan críticos para la supervivencia del recién nacido.La relajación uterina máxima y controlada para maximizar la perfusión placentaria y fetal, manteniendo el bienestar fetal y materno, son los paradigmas de cualquier tipo de EXIT. El aspecto más importante de una intervención en soporte placentario es consolidar un equipo multidisciplinario altamente capacitado, bien coordinado y preparado para cualquier contingencia. Una evaluación prenatal completa, incluyendo ultrasonido, ecocardiografía fetal, resonancia magnética y pruebas genéticas, es imprescindible para la selección de pacientes. La planificación preoperatoria exhaustiva, las reuniones de equipo ad-hoc y las simulaciones quirúrgicas para casos desafiantes son estrategias críticas para lograr los mejores resultados clínicos.El presente artículo describe el algoritmo de estudio prenatal, la planificación preoperatoria, los aspectos técnicos, los principios básicos y los fundamentos del procedimiento EXIT. Summary: Ex-utero intrapartum treatment (EXIT) is a delivery strategy that allows for providing fetal cardiopulmonary support while performing a vital intervention during the transition to newborn life. EXIT provides time to address a variety of life-threatening congenital malformations in an environment of maximum physiological control.Depending on the treatment purpose, different types of EXIT have been described; including EXIT-to-airway (to establish a fetal airway), EXIT-to-ECMO (for extracorporeal membrane oxygenation circuit cannulation), EXIT -to-resection (for the resection of masses that impair ventilation or venous return), and EXIT-to-separation (for the approach of conjoined twins). The overall goal of an EXIT is to improve the safety of procedures that are critical to the survival of the newborn.Maximal but controlled uterine relaxation to ensure placental perfusion and thus fetal oxygenation, while maintaining fetal and maternal well-being, are the paradigms of any type of EXIT. The most important aspect of any intervention on placental support is to consolidate a highly trained, well-coordinated, multidisciplinary team that is prepared for every contingency. A comprehensive prenatal assessment, including ultrasound, fetal echocardiogram, MRI, and genetic testing, is imperative for the selection of patients. Extensive preoperative planning, ad-hoc team meetings, and surgical simulations for challenging cases are critical strategies to achieve the best clinical outcomes.This article outlines the prenatal work-up, preoperative planning, technical aspects, basic principles, and fundamentals for a successful EXIT procedure.

“Fetus as patient” indicates fundamental concept of fetal therapy. With advance in maternal serum analysis and fetal imaging, prenatal screening has become standard of care. Accurate diagnosis in early gestation allows intervention to reverse pathophysiology and delay progression immediately. Non-invasive, minimally invasive and invasive therapies demonstrate their therapeutic potential in certain diseases. Recently, stem cell and gene therapies have been developed to avoid irreversible impairment. To elevate efficacy of treatment modality, extensive studies should be conducted according to regulatory authority. Striking a balance between scientific and ethical integrity is essential, so long-term follow up should be arranged for protecting mother and fetus.

Postnatal penile length is a reliable, standardized, and widely used marker for the diagnosis of genitourinary pathology, as well as genetic and hormonal disorders. In contrast, prenatal diagnosis has not been developed equally and there is a lack of relevant literature. Our objective is to review the studies on fetal penile length, and apply findings to clinical practice. Although the most used technique is the outer penile length, there is no consensus regarding the appropriate technique for prenatal measurement. Several reports have provided reference data with high correlation. However, important issues like poor correlation with post-natal measures or presence of confounding variables are still present. Diagnosis of both a micropenis and macropenis can indicate related pathologies, and this information may benefit parental counseling and facilitate fetal management. Therefore, it is necessary to carry out prospective studies that provide reliable normative data.

Annachiara Vitucci, Anna Fichera, Nicola Fratelli, Enrico Sartori, Federico Prefumo Division of Obstetrics and Gynecology, ASST Spedali Civili, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, ItalyCorrespondence: Federico PrefumoDivision of Obstetrics and Gynecology, ASST Spedali Civili, Department of Clinical and Experimental Sciences, University of Brescia, Piazzale Spedali Civili 1, Brescia 25123, ItalyTel +39 030 3995340Fax +39 030 3995034Email federico.prefumo@unibs.itAbstract: Twin reversed arterial perfusion (TRAP) sequence is a specific and severe complication of monochorionic multiple pregnancy, characterized by vascular anastomosis and partial or complete lack of cardiac development in one twin. Despite its rarity, interest in the international literature is rising, and we aimed to review its pathogenesis, prenatal diagnostic features and treatment options. Due to the parasitic hemodynamic dependence of the acardiac twin on the pump twin, the management of these pregnancies aims to maximize the pump twin’s chances of survival. If treatment is needed, the best timing of intervention is still debated, although the latest studies encourage intervention in the first trimester of pregnancy. As for the technique of choice to interrupt the vascular supply to the acardiac twin, ultrasound-guided laser coagulation and radiofrequency ablation of the intrafetal vessels are usually the preferred approaches.Keywords: TRAP sequence, acardiac twin, pump twin, clinical management, fetal therapy

With recent advances in fetal medicine, various attempts have been made to save fetuses facing perinatal death or devastating consequences despite optimal management after birth. The concept of the fetus as a patient has been established through the application of in utero treatments. This paper reviews fetal therapies in order to highlight the role of perinatal medicine as standard prenatal care. Fetal therapies consist of medical therapy, percutaneous ultrasound-guided surgery, fetoscopic surgery, and open fetal surgery. In the 1980s, with advances in ultrasound imaging, percutaneous ultrasound-guided surgeries such as vesicoamniotic shunting for lower urinary tract obstruction and thoracoamniotic shunting (TAS) for fetal hydrothorax (FHT) were started. In the 1990s, fetoscopic laser surgery (FLS) for twin-twin transfusion syndrome (TTTS) was introduced, and later, a fetoscopic approach for congenital diaphragmatic hernia was also established. The revival of open fetal surgery, introduced in the 1980s by pediatric surgeons, began in the 2010s after a successful clinical study for myelomeningocele. Although many fetal therapies are still considered experimental, some have proven effective, such as FLS for TTTS, TAS for primary FHT, and radiofrequency ablation (RFA) for twin reversed arterial perfusion (TRAP) sequence. These three fetal therapies have been approved for coverage by Japan National Health Insurance as a result of clinical studies performed in Japan. FLS for TTTS, TAS for primary FHT, and RFA for TRAP sequence have become standard prenatal care approaches in Japan. These three minimally invasive fetal therapies will help improve the perinatal outcomes of fetuses with these disorders.

X-linked hypohidrotic ectodermal dysplasia with the cardinal symptoms hypodontia, hypotrichosis and hypohidrosis is caused by a genetic deficiency of ectodysplasin A1 (EDA1). Prenatal EDA1 replacement can rescue the development of skin appendages and teeth. Tabby mice, a natural animal model of EDA1 deficiency, additionally feature a striking kink of the tail, the cause of which has remained unclear. We studied the origin of this phenomenon and its response to prenatal therapy. Alterations in the distal spine could be noticed soon after birth, and kinks were present in all Tabby mice by the age of 4 months. Although their vertebral bones frequently had a disorganized epiphyseal zone possibly predisposing to fractures, cortical bone density was only reduced in vertebrae of older Tabby mice and even increased in their tibiae. Different availability of osteoclasts in the spine, which may affect bone density, was ruled out by osteoclast staining. The absence of hair follicles, a well-known niche of epidermal stem cells, and much lower bromodeoxyuridine uptake in the tail skin of 9-day-old Tabby mice rather suggest the kink being due to a skin proliferation defect that prevents the skin from growing as fast as the skeleton, so that caudal vertebrae may be squeezed and bent by a lack of skin. Early postnatal treatment with EDA1 leading to delayed hair follicle formation attenuated the kink, but did not prevent it. Tabby mice born after prenatal administration of EDA1, however, showed normal tail skin proliferation, no signs of kinking and, interestingly, a normalized vertebral bone density. Thus, our data prove the causal relationship between EDA1 deficiency and kinky tails and indicate that hair follicles are required for murine tail skin to grow fast enough. Disturbed bone development appears to be partially pre-determined in utero and can be counteracted by timely EDA1 replacement, pointing to a role of EDA1 also in osteogenesis.

Rhabdomyoma is the most common fetal cardiac tumor, and its development is related to tuberous sclerosis. Fetal cardiac rhabdomyomas often spontaneously regress in utero or after birth, but large tumors can cause hemodynamic obstruction. Sirolimus, a mammalian target of rapamycin (mTOR) inhibitor, has been used as an immunosuppressant after organ transplantation. The mTOR inhibitors are well-known to have anti-tumor activity, and they have been used for the treatment of patients with tuberous sclerosis. In the current case, fetal cardiac rhabdomyoma was completely resolved in utero during oral sirolimus treatment in the mother with tuberous sclerosis. This case shows that oral sirolimus therapy in pregnancy may be a treatment for multiple or large fetal cardiac rhabdomyomas.

Purpose: Congenital lower urinary tract obstruction (cLUTO) includes a heterogeneous group of conditions caused by a functional or mechanical outlet obstruction. Early vesicoamniotic shunting (VAS) possibly reduces the burden of renal impairment. Postpartum, pediatric urologists are confronted with neonates who have a shunt in place and a potentially impassable urethra with a narrow caliber. Early management of these patients can be challenging. Here, we would like to share the approach we have developed over time.Materials and Methods: We conducted a single-center retrospective analysis from 2016 to 2020 and included all patients diagnosed with cLUTO. Data focusing on time point and type of intervention was collected. Furthermore, patients with temporary diversion via a percutaneous VAS were selected for a more detailed review.Results: In total, 71 cases of cLUTO were identified during the study period. Within this group, 31 neonates received postnatal management and surgical intervention in our center. VAS was performed in 55% of these cases (N = 17). The postnatal treatment varied between transurethral or suprapubic catheterization and early Blocksom vesicostomy. In five infants with VAS, the urinary drainage was secured through the existing VAS by inserting a gastric tube (N = 1) or a 4.8 Fr JJ-stent (N = 4). To our knowledge, this is the first report of a stent-in-stent scheme, which can remain indwelling until the definite treatment.Conclusion: Having a secure urine drainage through a VAS allows the often premature infant to grow until definite surgery can be performed. This avoids placing a vesicostomy, which requires anesthesia.

Introduction: Various anatomical defects predispose patients with congenital diaphragmatic hernia (CDH) to develop gastroesophageal reflux disease (GERD). The fetal endoscopic tracheal occlusion (FETO) has increased the survival of patients with severe CDHs. The aim of this study was to study GERD in patients who underwent FETO.Materials and Methods: We included patients with CDH treated with or without FETO (“FETO” and “no-FETO” group, respectively) from 2013 to 2016. Data on gestational age (GA), birth weight (BW), initial observed/expected lung to head ratio (O/E LHR), final O/E LHR, duration of ventilation and hospitalization, maximal tracheal diameter, and pulmonary volume were collected. All patients underwent pH-metry after 1 year of life, and the results were compared between groups and correlated to risk factors.Results: Thirty-two patients were included in the study: 10 FETO and 22 no-FETO. No significant differences were observed in the pH-metric results of the two groups. No correlation was found between GA, BW, initial O/E LHR, maximal tracheal diameter, pulmonary volume, and pH-metric results. pH-metric results were correlated with the total duration of ventilation (R = 0.5, p = 0.003) and of hospitalization (R = 0.54, p = 0.001). Gastric herniation is associated with the worse pH-metric result.Conclusions: The FETO procedure does not seem to represent an independent risk factor for GERD. However, patients with the most severe CDH have the worst GERD.

Pulmonary sequestration (PS) is mostly asymptomatic but there is a proportion of fetuses that develop hydrops, leading to fetal or neonatal death. Fetal treatments are available, but postnatal management of the residual lesions is not uniformly defined. We present two cases of combined pre- and postnatal minimally invasive approach to complicated extra-lobar PS. Patient 1 presented with complicated PS at 31 weeks of gestation. Ultrasound-guided laser coagulation of the anomalous artery was successful. The patient was born asymptomatic at 38 weeks. Neonatal magnetic resonance imaging (MRI) showed a residual mass, confirmed by computed tomography (CT) at 6 months. No systemic artery was described, but perfusion was present. We decided for thoracoscopic resection. A residual artery was identified and sealed. Patient 2 presented with complicated PS at 25 weeks of gestation, underwent laser coagulation of the anomalous artery and was born asymptomatic at 38 weeks. Neonatal MRI showed persistence of the lesion, confirmed by CT scan at 4 months. We proceeded with thoracoscopic resection. A residual vessel was ligated. The patients 1 and 2 are now 24 and 21 months old, respectively, and healthy. Prenatal treatment of complicated PS is a life-saving procedure. Postnatal thoracoscopic resection of the residual lesion is feasible and safe; we believe it is the best course of treatment to grant the complete excision of the malformation.

The ex utero intrapartum treatment (EXIT) procedure was introduced to reduce fetal hypoxic damage while establishing an airway in fetuses with upper and lower airway obstruction. Delivery of the fetal head and shoulders while maintaining the uteroplacental circulation offers time to secure the fetal airway. Here, we report two cases of EXIT procedure for fetal airway obstruction, which were successfully managed with extensive preoperative planning by a professional multidisciplinary team.

Abstract Background Mirror syndrome (MS) is a rare obstetric condition usually defined as the development of maternal edema in association with fetal hydrops. The pathogenesis of MS remains unclear and may be misdiagnosed as pre-eclampsia. Case presentation We report a case series of MS in which fetal therapy (intrauterine blood transfusion and pleuroamniotic shunt) resulted in fetal as well as maternal favourable course with complete resolution of the condition in both mother and fetus. Conclusions Our case series add new evidence to support that early diagnosis of MS followed by fetal therapy and clinical maternal support are critical for a good outcome.

Background: Fetal ovarian cysts are the most frequently diagnosed intra-abdominal cysts; however, the evidence for perinatal management remains controversial. Methods: We retrospectively reviewed cases of fetal ovarian cysts diagnosed by prenatal ultrasonography at our institution between January 2010 and January 2020. The following were investigated: gestational age at diagnosis, cyst size, appearance, prenatal ultrasound findings, and postnatal outcomes. Prior to 2018, expectant management was applied in all cases; after 2018, in utero aspiration (IUA) of simple cysts ≥40 mm was performed. Results: We diagnosed 29 and seven simple and complex cysts, respectively. Fourteen patients had simple cysts with a maximum diameter

Despite benefits of prenatal in utero repair of myelomeningocele, a severe type of spina bifida aperta, many of these patients will still suffer mild to severe impairment. One potential source of stem cells for new regenerative medicine-based therapeutic approaches for spinal cord injury repair is neural progenitor cells (NPCs) in cerebrospinal fluid (CSF). To this aim, we extracted CSF from the cyst surrounding the exposed neural placode during the surgical repair of myelomeningocele in 6 fetuses (20 to 26 weeks of gestation). In primary cultured CSF-derived cells, neurogenic properties were confirmed by in vitro differentiation into various neural lineage cell types, and NPC markers expression (TBR2, CD15, SOX2) were detected by immunofluorescence and RT-PCR analysis. Differentiation into three neural lineages was corroborated by arbitrary differentiation (depletion of growths factors) or explicit differentiation as neuronal, astrocyte, or oligodendrocyte cell types using specific induction mediums. Differentiated cells showed the specific expression of neural differentiation markers (βIII-tubulin, GFAP, CNPase, oligo-O1). In myelomeningocele patients, CSF-derived cells could become a potential source of NPCs with neurogenic capacity. Our findings support the development of innovative stem-cell-based therapeutics by autologous transplantation of CSF-derived NPCs in damaged spinal cords, such as myelomeningocele, thus promoting neural tissue regeneration in fetuses.

Myelomeningocele (MMC) is a congenital disease without genetic abnormalities. Neurological symptoms are irreversibly impaired after birth, and no effective treatment has been reported to date. Only surgical repairs have been reported so far. In this study, we performed antenatal treatment of MMC with an artificial skin using induced pluripotent stem cells (iPSCs) generated from a patient with Down syndrome (AF-T21-iPSCs) and twin-twin transfusion syndrome (AF-TTTS-iPSCs) to a rat model. We manufactured three-dimensional skin with epidermis generated from keratinocytes derived from AF-T21-iPSCs and AF-TTTS-iPSCs and dermis of human fibroblasts and collagen type I. For generation of epidermis, we developed a protocol using Y-27632 and epidermal growth factor. The artificial skin was successfully covered over MMC defect sites during pregnancy, implying a possible antenatal surgical treatment with iPSC technology.

We reviewed the literature addressing outcomes of fetal intervention of conditions that require post-natal urological management including lower urinary tract obstruction, hydrometrocolpos, congenital adrenal hyperplasia, and myelomeningocele. Despite several decades of fetal intervention for these conditions, benefits remain elusive in part because of the enormous difficulty of conducting prospective randomized studies. In this review, we reached the following conclusions: Prenatal intervention in lower urinary tract obstruction (LUTO) improves survival in the worst cases by improving pulmonary function and it may be advantageous for renal function, particularly in patients with adverse urine parameters.Prenatal treatment of female fetuses at risk of having congenital adrenal hyperplasia (CAH) reduces virilization. Non-invasive fetal DNA analysis allows earlier diagnosis, reducing the risk of treating with dexamethasone males and non-affected fetuses.Fetal treatment of myelomeningocele (MMC) is gaining momentum. Prospective studies including standardized urologic evaluation will determine if the encouraging results reported by some hold on the long term follow-up.

Optimal prenatal management of giant placental chorangioma (also known as chorioangioma, angiomyxoma, fibroangiomyxoma, or fibroma) has yet to be determined. Interventions intended to devascularize the tumor such as interstitial laser, bipolar coagulation, fetoscopic laser photocoagulation, and chemical embolization have met mixed results. We report a minimally invasive, extra-amniotic approach, technically similar to cordocentesis, of microcoil embolization of the feeding vessel. These percutaneously placed microcoils initiate clot formation at the site of insertion and are unable to migrate through the tumor, thereby minimizing fetal harm by downstream embolic phenomena. Intervention at 26 and 22 weeks resulted in intraoperative fetal loss in the former and vaginal delivery at term of a healthy neonate in the latter. Preoperative, intraoperative, and placental findings are highlighted. The ease and safety of this procedure may alter the risk–benefit equation toward earlier intervention with potentially better clinical outcomes.

Objective: The aim of this study is to clarify the feasibility and efficacy of fetoscopic laser photocoagulation of placental vascular communicating vessels (FLP) on twin–twin transfusion syndrome (TTTS) after 26 weeks of gestation. Materials and Methods: This is a prospective pilot study investigating all cases of TTTS between 26 weeks and 27 weeks during 2012 and 2013 in Japan. The primary endpoints in this study were the feasibility of FLP and rate of harmful complications for the mother's health. Also, perinatal prognosis was investigated. Results: Six cases were enrolled and underwent FLP. Two of the six cases were classified preoperatively as Quintero Stage II and four cases were Stage III. FLP was completely achieved in all six cases. No severe maternal complications were noted during and immediately after the surgery. All but one case continued the pregnancies > 14 days after FLP. The median gestational age at delivery was 33.4 weeks (28.0–36.6 weeks). All 12 fetuses survived at the 28th day in the neonatal period. No case was diagnosed with cerebral lesion at the neonatal period. Conclusion: This prospective pilot study shows that FLP could be a therapeutic option for TTTS between 26 weeks and 27 weeks of gestation.

We report two cases of pulmonary hypoplasia due to fetal ascites in symptomatic congenital cytomegalovirus (CMV) infections despite fetal therapy. The patients died soon after birth. The pathogenesis of pulmonary hypoplasia in our cases might be thoracic compression due to massive fetal ascites as a result of liver insufficiency. Despite aggressive fetal treatment, including multiple immunoglobulin administration, which was supposed to diminish the pathogenic effects of CMV either by neutralization or immunomodulatory effects, the fetal ascites was uncontrollable. To prevent development of pulmonary hypoplasia in symptomatic congenital CMV infections, further fetal intervention to reduce ascites should be considered.

Objectives: The objective of our study is to retrospectively analyze a single-centre series of antenatally detected pulmonary malformations (PM) and to evaluate their postnatal outcome. Materials and Methods: We retrospectively reviewed all prenatally diagnosed PM patients referred to our Centre in the period between January 1999 and December 2014. All cases were diagnosed by one of our Maternal-Fetal Specialists by US examination. Congenital pulmonary airway malformation (CPAM) volume ratio (CVR), development of fetal complications, need for fetal therapy, need for neonatal resuscitation and timing of surgery were analyzed. Results: A total of 70 fetuses were diagnosed with a PM in the period of study. An initial CVR higher than 1.6 was found in 16/70 patients (22.8%); 14/16 developed fetal complications (pConclusion: CVR > 1.6 and the presence of fetal complications can be considered as predictors of respiratory distress at birth and of the need for early surgery. Nevertheless, the vast majority of PM are asymptomatic at birth and only a small group of fetuses require prenatal and postnatal treatment and support.

OBJECTIVE: To report our initial institutional experience with fetoscopic laser photocoagulation of placental anastomoses in severe twin-twin transfusion syndrome using a 1.0 mm endoscope. METHODS: Between July 2006 and June 2008, 19 monochorionic diamniotic twin pregnancies complicated by severe TTTS (Quintero stages III and IV) underwent fetoscopic laser therapy. Perinatal data were prospectively collected and compared according to the Quintero stages. RESULTS: Nine patients were classified as stage III and ten as stage IV. The Mean gestational ages at diagnosis and procedure were 20 (range: 17-25) and 22.0 (range: 19.0-26.0) weeks, respectively, with no statistical difference between the two groups. Preterm premature rupture of the membranes occurred in two cases (10.5%), and spontaneous preterm delivery in eight (42.1%). Overall mean gestational age at delivery was 32.1 (range: 26.0-38.0) weeks. Prematurity was more severe in stage IV patients (p

In utero hematopoietic cell transplantation (IUHCTx) is a promising strategy to circumvent the challenges of postnatal hematopoietic stem cell (HSC) transplantation. The goal of IUHCTx is to introduce donor cells into a naïve host prior to immune maturation, thereby inducing donor–specific tolerance. Thus, this technique has the potential of avoiding host myeloablative conditioning with cytotoxic agents. Over the past two decades, several attempts at IUHCTx have been made to cure numerous underlying congenital anomalies with limited success. In this review, we will briefly review the history of IUHCTx and give a perspective on alpha thalassemia major, one target disease for its clinical application.

Acardiac twinning, or the twin reversed arterial perfusion (TRAP) sequence, occurs in 1% of monozygotic twins, or 1 in 35,000 births. It is caused by the development of arterioarterial vascular anastomoses between the umbilical arteries of monozygotic twins early in embryogenesis. The pump twin may be associated with congenital anomalies and chromosomal abnormalities. Therefore, it is recommended that prenatal genetic testing be offered whenever pregnancy is complicated by acardiac twinning. The treatment options for acardiac twinning include observation, medical management, amniodrainage, and invasive treatment such as hysterotomy with selective delivery of the acardiac twin, intrafetal ablation of the acardiac twin by alcohol, laser, thermocoagulation or radiofrequency, fetoscope-guided funicular occlusion by ligation, laser or thermocoagulation, and ultrasound-guided funicular occlusion by ligation, cord compression, thermocoagulation or intrafunicular embolization with foreign bodies. If invasive treatment is indicated, the simplicity, safety, and efficacy of the chosen technique should be considered. An intrafetal approach has been shown to be superior to a funicular occlusion approach. Ultrasound-guided intrafetal laser ablation or radiofrequency ablation is believed to be the treatment of choice based on currently available data. This review emphasizes the necessity to carefully search for any possible associated anomaly in the pump twin by both genetic testing and sonographic examination, and to prudently consider invasive treatment only in pregnancies which would potentially benefit from the prenatal intervention.

A abordagem das uropatias diagnosticadas no período pré-natal é controversa, principalmente, porque o prognóstico desses fetos é variável. Contudo, trabalhos pioneiros têm demonstrado que a drenagem pré-natal do trato urinário obstruído pode melhorar o resultado em fetos selecionados. O objetivo deste trabalho é relatar a experiência do Serviço no tratamento das lesões obstrutivas do trato urinário, utilizando o cateter desenvolvido no Centro de Medicina Fetal do Hospital das Clínicas da UFMG. No total, 25/25 fetos com uropatia obstrutiva receberam o cateter. Três fetos necessitaram de mais de uma inserção; 10 dos 25 fetos que receberam o cateter (40%) sobreviveram com boa função renal e pulmonar pós-natal. Ocorreram complicações em 12/25 casos (48%) incluindo 6 com drenagem inadequada ou migração do cateter (24%); 1/25 (4%) ascite urinária; 1/25 (4%) descolamento prematuro de placenta; 1/25 (4%) rutura prematura de membrana; 2/25 (08%) trabalho de parto prematuro; 01/25 (04%) fibrose ou cicatrização do parênquima renal. Três dos 25 fetos (12%) morreram intra-útero e 12 (48%) fetos morreram no período neonatal. Concluindo, a drenagem do trato urinário com esse cateter provou ser tecnicamente possível e segura para mãe e feto, com uma taxa de sobrevida de 40%.Management of prenatally diagnosed uropathies is controversial, mainly because the prognosis for these fetuses is quite different. However pioneering studies have shown that prenatal drainage of obstructed urinary tract can improve the outcome of selected fetuses. The aim of this study is to describe the experience of the Service with the treatment of fetal obstrutive uropathy with the catheter developed by the Centro de Medicina Fetal do Hospital das Clínicas da UFMG. A total of 25 fetuses with obstructive uropathy received the catheter. Three fetuses required more than one insertion. Ten of 25 (40%) shunted fetuses survived with good postnatal renal and pulmonary function. Complications occurred in 12/25 (48%) cases including: 06/25 (24%) inadequate shunt drainage or migration; 01/25 (04%) urinary ascitis; 01/25 (04%) DPP, 01/25 (04%) premature rupture of membranes, 02/25 (08%) premature labor, 01/25 (04%) scarring and fibrosis of the renal parenchyma. Three of 25 (12%) fetuses died intra-utero and 12 (48%) died during the neonatal period. In conclusion, the drainage of the obstructed urinary tract with this catheter proved to be technically feasible and safe for both mother and fetus, with a survival rate of 40%.

Abstract Background Giant placental chorioangiomas have been associated with a number of severe fetal complications and high perinatal mortality. Case presentation We report a case of giant chorioangioma with fetal hydrops, additionally complicated by severe anemia, mild cardiomegaly with hyperdinamic heart circulation and maternal mirror syndrome. Intrauterine blood transfusion and amniodrainage was performed at 29 weeks. Worsening of the fetal and maternal condition prompted us to proceed with delivery at 29 + 5 weeks. The newborn died 3 hours later due to pulmonary hypoplasia and hemodynamic failure. Maternal course was favourable, mirror syndrome resolved in the second day and the patient was discharged four days following delivery. Conclusions In the case described here, fetal condition got worse despite of the anemia correction and amniodrainage. Our outcome raises the issue whether additional intrauterine clinical intervention, as intersticial laser, should have been performed to stop further deterioration of the fetal condition when progressive severe hydrops develops.

CONTEXT: Macrocystic adenomatoid malformation of the lung can cause severe mediastinal shift, hydrops and polyhydramnios, thereby increasing the risk of perinatal deaths. After 33 weeks of gestation, repeated puncturing of the cyst is recommended. We present a case in which a cyst-amniotic shunt was placed instead of performing this procedure. CASE REPORT: A cyst-amniotic shunt was placed at 33 weeks of gestation because of a large macrocystic adenomatoid malformation of the lung associated with severe mediastinal shift and polyhydramnios. Although it was confirmed that the catheter was in the correct place, the cyst increased in size again two weeks later, associated with repetition of polyhydramnios. It was postulated that the catheter was blocked, and we chose to place another catheter instead of performing repeated punctures. The cystic volume, polyhydramnios and mediastinal shift regressed progressively. At 38.5 weeks, a 3,310/g male infant was delivered without presenting any respiratory distress. The infant underwent thoracotomy on the 15th day of life. Thus, in the present study, we discuss the possibility of placing a cyst-amniotic shunt instead of performing repeated cystic punctures, even at a gestational age close to full term.