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  1. Home
  2. Books
  3. Fetal Therapy
  • Edited by Mark D. Kilby, Department of Fetal Medicine, University of Birmingham, Anthony Johnson, Baylor College of Medicine, Texas, Dick Oepkes, Department of Obstetrics, Leiden University Medical Center
Publisher:
Cambridge University Press
Online publication date:
February 2013
Print publication year:
2012
Online ISBN:
9780511997778
DOI:
https://doi.org/10.1017/CBO9780511997778
Subjects:
Obstetrics and Gynecology, Reproductive Medicine, Medicine
Information

Book description

Fetal treatment, particularly complex fetal therapy, is an emergent and expanding field. This comprehensive text focuses on areas of fetal disease and pathophysiology that can be treated in utero and the benefits and problems with such therapy. Both medical (non-invasive) and surgical procedures are discussed, drawing on the expertise of an internationally renowned author team. Each chapter includes a comprehensive overview of the basic science underlying fetal pathology, as well as discussing the highest level of technical performance of fetal interventions. Contributions from fetal therapy 'centers-of-excellence' around the world collectively emphasize the need for an evidence-based approach to the field. This volume is useful both as a quick reference guide to the latest fetal therapy options and as an in-depth study book for maternal-fetal medicine and neonatology specialists at any stage of their career who are seeking to acquire essential background knowledge. Indispensable on any bookshelf in fetal medicine units.

Reviews

'It is both scientific and pragmatic and should satisfy a variety of curiosities in this fascinating field of therapeutic medicine. As such, it is a "must have" for fetal medicine specialists and trainees, but also medical libraries.'

Source: The Obstetrician and Gynaecologist

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Contents

Page 2 of 2

Contents
  • Chapter 14.1 - Fetal urinary tract obstruction
    pp 238-245
  • Pathophysiology
  • View abstract

    Summary

    Fetal urinary tract obstruction accounts for the largest identifiable cause of kidney failure in infants and children. The site of obstruction along the urinary tract varies from the ureteropelvic junction (UPJ), to the ureterovesical junction and urethra. Congenital obstructive lesions may be associated with abnormal renal development, resulting in renal agenesis, hypoplasia. The effects of urinary tract obstruction to impair nephrogenesis and to injure already-formed nephrons clearly compound perinatal risk factors as well as those accumulating throughout life. The role of angiotensin II in normal kidney development is well established, and numerous cases of renal maldevelopment and injury are reported in fetuses born to mothers exposed to angiotensin II inhibitors. The functional response of the fetal kidney to urinary tract obstruction depends on the location and timing of the obstruction. Numerous factors combine to determine the immediate and long-term impact of fetal urinary tract obstruction in affected infants.
  • Chapter 14.2 - Fetal urinary tract obstruction
    pp 246-252
  • Prenatal assessment and prognosis
  • View abstract

    Summary

    The natural history of congenital lower urinary tract obstruction (LUTO) is highly variable and dependent on the gender, severity, duration, and age of onset of the obstruction. Outcome is measured in terms of postnatal survival and is dependent on two factors: pulmonary development and renal function. Complete urethral obstruction or significant restriction of urethral flow results in accumulation of urine within the fetal bladder, leading to marked distention. Prolonged obstruction results in smooth muscle hypertrophy and hyperplasia within the bladder wall, and eventual impairment of contractile capacity as well as compliance and elasticity. Histological studies indicate a progressive dilatation of the distal to proximal renal tubules associated with development of peritubular and interstitial fibrosis. Component of the prenatal evaluation is the serial analysis of fetal urine, obtained by vesicocentesis. More recent studies were designed to focus on the long-term outcomes of children with specific documented urethral obstructions.
  • Chapter 14.3 - Fetal urinary tract obstruction
    pp 253-260
  • Fetal cystoscopy
  • View abstract

    Summary

    The natural history of lower urinary tract obstruction (LUTO) is dependent on the degree of bladder outflow obstruction (complete or partial) and gestational age at presentation. These two factors may be inter-related since complete bladder obstruction is associated with earlier manifestations of the obstructive uropathy. Prenatal ultrasonography is a fundamental method to assess other associated anomalies as well as to evaluate the renal characteristics which are important prognostic factors. MRI may provide more detailed analysis of the urethral obstruction, although it has not been demonstrated to date that this method can determine the underlying etiology of the LUTO. The advantages of fetal cystoscopy may be to permit a more physiological drainage of the obstructed bladder and an endoscopic examination of the dilated posterior urethra allowing the diagnosis of the cause of the obstructive uropathy (posterior urethral valves (PUV) or urethral atresia (UA)).
  • Chapter 14.4 - Fetal urinary tract obstruction
    pp 261-270
  • In-Utero Intervention
  • View abstract

    Summary

    Lower urinary tract obstruction (LUTO) is rare and is associated with significant congenital bladder neck obstruction, but also associated with high perinatal mortality and morbidity that tracks into child- and adulthood. The poor clinical outcomes associated with this disease have led to considerable research, both using animal models and clinically, to further elucidate the underlying pathogenesis of the condition and to evaluate methods of clinical diagnosis, investigation, and triage. Antenatal ultrasound diagnosis occurs prospectively in two-thirds of LUTO cases; however, other studies have shown that the timing of ultrasound is important, with <50% being detected at the routine mid-trimester scan increasing to 80% with ultrasound after 28 weeks of gestation. The basis for intervention is the theoretical belief that relief of the urinary tract obstruction will subsequently lead to a sustained improvement in fetal renal function and liquor volume.
  • 15.1 - Fetal lung growth, development, and lung fluid
    pp 271-281
  • Physiology and pathophysiology
  • View abstract

    Summary

    This chapter focuses on how normal lung development is regulated before birth, and how it is affected by the intrauterine environment. Lung development is completed during early postnatal life; therefore, after infancy there is limited scope for repairing abnormal lung development. At least four or five distinct stages of lung development are recognized, based on microscopic appearance: these are the embryonic, pseudoglandular, canalicular, and saccular-alveolar stages. A final stage of microvascular maturation can also be recognized. For the lung to develop normally it must be able to expand to a higher degree than is seen after birth; this requires adequate intrathoracic space, fetal breathing movements (FBM), and the ongoing production of lung liquid across the airway epithelium. Changes in the environment of the developing lung that chronically affect the degree of lung expansion will result in either lung hypoplasia or hyperplasia.
  • Chapter 15.2 - Fetal lung growth, development, and lung fluid
    pp 282-300
  • Clinical management of pleural effusion and pulmonary pathology
  • View abstract

    Summary

    This chapter discusses the most common pulmonary pathologies, including fetal pleural effusions (FPE), pulmonary adenomatoid malformations, and congenital high airway obstruction sequence (CHAOS). It reviews the evidence-based methods of fetal therapy, and available data on fetal and neonatal outcome following antenatal intervention. The appearance of lung septations or solid components suggests an alternate diagnosis, such as congenital pulmonary airway malformation (CPAM) or congenital diaphragmatic hernia (CDH). The most commonly identified prenatal anomalies are congenital cystic adenomatoid malformations (CCAM) and bronchopulmonary sequestration (BPS). CCAM lesions were originally classified based on postnatal histological features: type I macrocystic, type II mixed macrocystic and microcystic, and type III microcystic. CHAOS presents as a syndrome of predicted ultrasound findings, resulting from the various causes of laryngeal or tracheal obstruction in the fetus. The chapter describes three fetal intervention cases with an antenatal diagnosis of CHAOS.
  • Chapter 16.1 - Neural tube defects
    pp 301-310
  • Pathophysiology and prevention
  • View abstract

    Summary

    Open neural tube defects (NTDs) result from failure of the embryonic process of neural tube closure. This chapter discusses pathophysiology and preventative strategies within each of these recognized subgroups: folate, chromosomal, single gene defects, genetic syndromes, diabetes and obesity, medications and smoking, hyperthermia, amniotic bands, twinning, genes and environment. The greatest success story in NTD prevention is folate supplementation. Through individual supplementation and population-based strategies such as food fortification there has been between a 20% and 70% reduction in NTDs reported across all countries actively supplementing. Diabetes and obesity are potentially modifiable risk factors for NTDs; however, despite general health campaigns regarding the health risks of obesity it remains an ever increasing problem amongst reproductive aged women. Medication and smoking exposures are amenable to prevention with health education advice and further research into safer medication use in pregnancy.
  • Chapter 16.2 - Neural tube defects
    pp 311-319
  • Clinical management
  • View abstract

    Summary

    The increasing use of screening ultrasonography and amniocentesis has resulted in early detection of neural tube defects (NTDs), and the use of fetal MRI has improved accuracy of the diagnosis. Spina bifida is considered a potential candidate for in-utero treatment, since the condition is routinely detected before 20 weeks of gestation. Technical difficulties associated with the small size of the fetus and fragility of the tissues generally preclude surgery before 18 weeks' gestation, and after 27 weeks there appears to be no benefit of fetal surgery. Initial screening is carried out with review of data already obtained locally by the treating obstetrician, supplemented by high-resolution ultrasound and MRI performed by the fetal team. The mortality rate for fetal surgery for spina bifida was 6% at Children's Hospital of Philadelphia (CHOP) prior to the trial, but in the Management of Myelomeningocele (MOMS) trial, the mortality was only 3%.
  • Chapter 17.1 - Fetal tumors
    pp 320-328
  • Pathophysiology
  • View abstract

    Summary

    Many of the tumors that are regarded as malignant in older children may behave in a more benign fashion in the fetus and neonate, including neuroblastoma, congenital myeloproliferative disorder in Trisomy 21, congenital fibrosarcoma, and hereditary retinoblastoma. A number of genetic, chromosomal, and syndromic associations are reported for fetal and neonatal tumors. Germ cell tumors comprise both benign and malignant tumors and can arise in both gonadal and extragonadal locations; the latter are usually found in the midline, including the sacrococcygeal area, mediastinum, and neck. Teratomas contain tissues derived from all three embryonic layers (viz. ectoderm, mesoderm, and endoderm) with a wide range of histological patterns. Neuroblastoma represents a classical embryonal tumor of neuronal lineage that may occur in the adrenal medulla and any other sites of sympathetic ganglia, from the neck to the presacral region.
  • Chapter 17.2 - Fetal tumors
    pp 329-340
  • Clinical management
  • View abstract

    Summary

    This chapter outlines the prenatal imaging and clinical diagnoses of neonatal and pediatric tumors. It discusses the antenatal natural history, and reviews available treatment options during the pre- and postnatal period for fetuses with prenatally diagnosed tumors. The differential diagnosis of a prenatally diagnosed intracranial tumor includes teratoma, which make up the majority of lesions, hemangioma and papilloma. Prenatal ultrasonography and fetal MRI are useful in evaluating and determining the etiology of the intracranial tumor. The surgical approach to bronchopulmonary sequestrations (BPS) is straightforward, with a muscle sparing thoracotomy or thoracoscopic approach for chest lesions and laparotomy or laparoscopy for subdiaphragmatic BPS, with particular attention to first controlling the anomalous blood supply in all cases. The most common primary hepatic tumor is hemangioma, followed by mesenchymal hamartoma, and hepatoblastoma. The differential diagnosis of mesoblastic nephroma includes hydronephrosis and multicystic dysplastic kidney, focal renal dysplasia, and diffuse nephroblastomatosis and nephroblastoma.
  • Chapter 18.1 - Intrauterine growth restriction
    pp 341-354
  • placental basis and implications for clinical practice
  • View abstract

    Summary

    Advances in obstetrical ultrasound, combined with ancillary magnetic resonance imaging and rapid molecular testing of amniotic fluid, have greatly improved the diagnostic capabilities when assessing the fetus with suspected intrauterine growth restriction (IUGR). Placental villi are covered by the fetally derived epithelial layer termed villous trophoblast; this is a distinct lineage under separate transcriptional control from the extravillous trophoblast (EVT) in mammalian placentae. The maternal-fetal interface, or decidua, is rich in cell lineages of the maternal immune system, in particular large granular lymphocytes and uterine natural killer (NK) cells. The net effect of abnormal maternal perfusion of the placental villi is one or more of the following: spiral artery thrombosis and unstable perfusion. The developmentally abnormal placenta, characterized by decidual bed pathology, structurally abnormal villi with defective or damaged areas of syncytiotrophoblast is prone to thrombosis.
  • Chapter 18.2 - Intrauterine growth restriction
    pp 355-369
  • differential diagnosis and management
  • View abstract

    Summary

    The accurate diagnosis of intrauterine growth restriction (IUGR) is achieved using a combination of clinical examination, relevant laboratory tests, and a variety of ultrasound techniques, including detailed anatomical scanning, placental evaluation, and Doppler assessment of placental and fetal vessels. The risk factors for IUGR are increasing over time and these include increased maternal age, coexistent medical problems, and assisted reproductive technology. Fetal causes of IUGR may be classified according to genetic diseases, congenital malformations, infections, and multiple gestation. Once a diagnosis has been established, consideration of the need for further investigations, consultation, or advice from a regional perinatal center and ongoing maternal-fetal surveillance should be instituted. Management will be directed according to the presence or absence of uteroplacental vascular insufficiency. The optimal timing of delivery is currently the source of much controversy, due to the many relevant clinical and ultrasound factors that clinicians must consider, in addition to patient preferences.
  • Chapter 19.1 - Congenital diaphragmatic hernia
    pp 370-375
  • Pathophysiology
  • View abstract

    Summary

    In congenital diaphragmatic hernia (CDH) pulmonary hypoplasia is variable depending on the size of the diaphragmatic defect and the amount and timing of visceral herniation. In CDH pulmonary hypoplasia may arise from loss of lung fluid, decreased fetal breathing secondary to diaphragmatic dysfunction, and decreased intrathoracic volume. The lungs in CDH appear to be arrested in the saccular phase of development with poorly developed airspaces and thickened interalveolar septums. Pulmonary hypoplasia and decreased lung compliance contribute to the increased susceptibility to ventilation-induced lung injury seen in CDH. Persistent pulmonary hypertension of the newborn is the failure of the normal circulatory transition after birth. Four major components of surfactant proteins have been identified: surfactant protein A and D are hydrophilic and protein B and C are hydrophobic. A surfactant deficiency is clearly seen in the experimental lamb model of CDH.
  • Chapter 20.1 - Fetal stem cell transplantation
    pp 389-396
  • stem cell biology basics
  • View abstract

    Summary

    This chapter summarizes some basic features of stem cells, including their defining properties, the range of different stem cell types, and the ways in which they can be identified and characterized. It considers the therapeutic application of stem cells. Stem cells with only a limited period of activity underlie the formation of the embryo from a single fertilized cell through to the fully formed fetus. The precise way in which a transplantation assay of stem cells is performed depends on the type of cell being characterized and whether it is a same species assay or a xenograft. The assay of hematopoietic stem cells (HSCs) involves irradiation of the host mouse to completely ablate its resident bone marrow stem cells and hematopoietic system. Cellular therapy that can be performed in the fetus is also a special case because of the status of the immune system.
  • Chapter 20.2 - Fetal stem cell transplantation
    pp 397-406
  • Clinical potential
  • View abstract

    Summary

    Transplantation of stem cells into the preimmune fetal environment to treat congenital disorders or to achieve donor-specific tolerance is a very potent treatment strategy. The fetal lamb model is the animal model that has given most experimental support for fetal stem cell transplantation to date. Potential beneficial effect of in-utero transplantations (IUT) are proven in several animal models. Transplanting human fetal mesenchymal stem cells (MSCs) in utero to mice suffering from osteogenesis imperfecta shows great effect with reduction of fractures and increased bone strength, thickness, and length, and also improvements in multiscale tissue properties. Human MSCs can be isolated from fetal tissues such as the first and second trimester blood, liver, bone marrow, and lung. The discovery of human stem cells has laid the foundation for a rapid development regarding clinical stem cell transplantations. The most successful group of patients transplanted in utero is the group of fetuses with immunodeficiencies.
  • Chapter 20.3 - Fetal stem cell transplantation
    pp 407-416
  • fetal tissue engineering
  • View abstract

    Summary

    This chapter summarizes the fetal stem cell transplantation and reviews the current status of fetal tissue engineering, along with other relevant information. Tissue engineering is almost universally hampered by certain predictable complications, namely vascularization and growth limitations, differentiation and function restraints, etc. A variety of sites, in addition to the fetus itself, can be sources of fetal cells in procurable amounts compatible with tissue engineering processing. At this time, proven viable sources have included the amniotic fluid, placenta, Wharton's jelly, and umbilical cord blood. Treatment of many congenital anomalies is hindered by the scarce availability of normal tissues or organs especially at birth. The ever present severe donor shortage that hampers practically all forms of transplantation is even more pronounced during the neonatal period. Fetal tissue engineering has emerged as a viable option to overcome these obstacles, posing a new alternative for the treatment of these anomalies.
  • Chapter 21 - Gene therapy
    pp 417-432
  • physiological principles and clinical potential
  • View abstract

    Summary

    Proof-of-principle prenatal gene therapy studies have shown long-term expression of proteins at therapeutic levels and induction of immune tolerance in both small and large animals and cured congenital disease in some animal models. This chapter describes current progress with fetal gene therapy and discusses how this therapy may be eventually translated into the clinic. The genodermatoses may be good candidates for prenatal gene therapy, where gene transfer to the skin via the amniotic fluid may provide an obvious advantage to cumbersome postnatal therapy. Most of this work is performed in animals, mostly in mice that can provide transgenic models of human disease necessary to demonstrate proof-of-principle. The most commonly tested vectors in prenatal gene therapy pre-clinical studies have been adenovirus and adeno-associated virus, lentivirus and retrovirus vectors. Targeting of vectors to organs or specific tissues is the ultimate goal, and will most likely require the use of several combined approaches.
  • Chapter 22 - The future
    pp 433-439
  • Fetal therapy and translational studies: global alignment, coordination, and collaboration in perinatal research: The Global Obstetrics Network (GONet) initiative
  • View abstract

    Summary

    This chapter talks about the Global Obstetrics Network (GONet) mission, its collaborators, structure and function, and plans for the future. The GONet mission will provide insight and camaraderie, cooperate on data elements to allow future collaborations, and identify and highlight the pressing issues in maternal-fetal medicine. The collaborative networks initiated in the USA, the UK and Canada inspired clinicians and researchers in other countries to start similar initiatives. The groups collaborating in GONet include: Maternal-Fetal Medicine Units Network (NICHD), Maternal-fetal medicine research, the NIHR Comprehensive Local Research Network, Dutch Obstetric Research Consortium and Hong Kong Maternal-Fetal Medicine Network. The collaboration will also facilitate new forms of meta-analysis, such as prospective meta-analysis and individual patient data meta-analysis. The board also includes a representative from PREBIC, the international consortium to prevent preterm birth, as well as liaisons with the World Health Organization (WHO) and the Cochrane collaboration.

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