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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
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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 1 of 2

Contents
  • Section 1 - General principles
  • View abstract

    Summary

    Initial therapies such as intrauterine transfusion for severe hemolytic disease of the fetus were undertaken based on sound physiological principles and an understanding of the basic pathogenesis but were never subjected to randomized clinical trials. More recent targeted interventions for such conditions as treatment for severe twin-to-twin transfusion syndrome (TTTS), myelomeningocele (MMC) and congenital diaphragm hernia (CDH) have been the subject of well-designed randomized investigations. This chapter elucidates the history and the basis for the treatment of these fetal interventions. Routine induction of labor at a premature gestation was the only therapy that could be offered to attempt to curb the inevitable death due to hemolytic disease of the fetus and newborn (HDFN) that occurred in 30% of cases. The human fetus has indeed become a patient and development of treatments is a work in progress.
  • Chapter 2 - Insights into pathogenesis of adult cardiovascular disease from fetal animal studies
    pp 12-23
  • View abstract

    Summary

    This chapter reviews the current status of research into the notion that the current epidemic of non-communicable disease, particularly adult cardiovascular disease (CVD), originates during early development. It describes the potential of animals as models of human fetal development and presents the evidence from human and animal studies. The fetus offers the potential for detection of an individual's risk of disease even earlier in life, and may provide future early routes for intervention. However, in light of the ethical restrictions on human fetal investigations, suitable animal model alternatives are crucial in advancing this area of research. There is now considerable human and animal evidence to suggest that risk of later CVD is initiated by fetal phenotypic changes in response to a suboptimal intrauterine environment. Such prenatal adaptive responses may start as a response which is made to enhance immediate fetal survival or to optimize phenotype for the predicted later environment.
  • Chapter 3 - Human embryology
    pp 24-38
  • Molecular mechanisms of embryonic disease
  • View abstract

    Summary

    There are five major signaling pathways that control embryogenesis, comprising the Hedgehog, Wnt, TGFβ/Bmp, Notch, and fibroblast growth factor (FGF) signaling families. Together these control cell proliferation, cell survival, changes in cell shape, migration, adhesion, and cell differentiation. Mutation in components of these pathways results in a number of human syndromes. This chapter discusses the five key signaling pathways that control embryonic development. It describes the various roles, mechanisms of action of each pathway and highlights syndromes that are due to mutations in components of these signaling pathways. The chapter explains how mutations in transcription factors, matrix molecules, and epigenetic factors can affect embryonic development. During embryonic development, the vertebrae and axial musculature develop from somites, which are epithelial balls that periodically bud off from the unsegmented paraxial mesoderm. Deregulation of the notch pathway affects somite development by deregulating the clock and preventing the formation of boundaries.
  • Chapter 4 - Ethics of fetal therapy
    pp 39-44
  • View abstract

    Summary

    This chapter provides an ethical framework to guide clinical investigation and the translation of its results into clinical practice. It describes the ethical framework for fetal therapy in clinical research as well as in practice. Medical ethics identifies the ethical obligations of physicians and healthcare organizations to patients as well as the obligations of patients. The ethical concept of the fetus as a patient is based on both the ethical principle of beneficence and the ethical principle of respect for the pregnant woman's autonomy. Innovation in fetal therapy research begins with the design of an intervention and its implementation in animal models, followed by a single case and then case series. Three criteria must be satisfied in order to conduct such preliminary investigations in fetal research in an ethically responsible fashion, by taking into account beneficence-based obligations to the fetal patient and beneficence-based obligations to the pregnant woman.
  • Chapter 5 - Fetal therapy choices
    pp 45-54
  • About risks, emotions, and the doctor’s role in the decision-making process
  • View abstract

    Summary

    This chapter discusses the difficulties and the possibilities for doctors in supporting parents/patients in making difficult decisions using the case of fetal lung anomalies. It also discusses the difficulties in parental understanding of the information given and the way people use information while making a decision. The following aspects are important when delivering information to parents and family: People in general are able to only process a limited amount of information at a single interview; people process information in an intuitive and emotional way; and people, in general, find it difficult to understand risk information. In most clinical cases there is a trade-of between benefits and risks for the choice of different treatment options. The affective impact of the mental images of risks about the outcome of a decision contributes to a binary perception of risks.
  • Section 2 - Fetal disease
  • Pathogenesis and principles
  • View abstract

    Summary

    This chapter discusses the role of fetal therapy for fetal anemia, which has been one of the success stories of fetal medicine. There is a risk of red cell alloimmunization in any pregnancy where the mother is exposed to fetal red cells that possess antigens for which her own red cells are negative. A number of pregnancy-related events are associated with a risk of fetomaternal hemorrhage (FMH). A number of techniques have evolved over time to facilitate assessment of pregnancies at risk of 'hemolytic disease of the fetus and newborn' (HDFN). The aim of assessment is to identify the anemic fetus requiring intrauterine transfusion (IUT) before hydrops fetalis develops. However, monitoring an identified at-risk pregnancy to the point at which hydrops fetalis develops would be considered a management failure. Although less common than RhD disease, profound fetal anemia, hydrops, and intrauterine death can result from Kell alloimmunization.
  • Chapter 7 - Fetal and neonatal alloimmune thrombocytopenia
    pp 67-77
  • View abstract

    Summary

    This chapter focuses on fetal and neonatal alloimmune thrombocytopenia (FNAIT), which is one of the major causes of both severe thrombocytopenia and intracranial hemorrhage (ICH) in fetuses and term neonates. FNAIT is caused by maternal immunization against human platelet antigens (HPAs) on fetal platelets, inherited from the father and different from those present in the mother. The chapter also focuses on the current insights in the etiology, diagnosis, and management of pregnancies at known risk of FNAIT. The diagnosis of FNAIT is unequivocal when paternal incompatibility with corresponding maternal alloantibodies is present. The primary goal of the management of a neonate with FNAIT is to prevent or stop thrombocytopenic bleeding. In suspected cases of FNAIT, babies with severe thrombocytopenia can be transfused with random platelets transfusions, until the diagnosis is established and matched platelets are available.
  • Chapter 8.1 - Fetal dysrhythmias
    pp 78-86
  • The effects of antiarrhythmic therapy on the immature heart
  • View abstract

    Summary

    Antiarrhythmic agents affect the generation and/or propagation of the cardiac rhythm by their actions on one or several ion channel currents and/or the autonomous nervous system. This chapter focuses on five antiarrhythmic agents: digoxin, flecainide, sotalol, amiodarone and adenosine. Due to their relative safety and efficacy, these agents are considered the foundation of transplacental and/or direct pharmacological therapy of fetal supraventricular tachyarrhythmias (SVT). SVT itself can be produced by four different mechanisms, namely: atrioventricular reentry (AVRT), atrial flutter (AF), atrial ectopic tachycardia (AET), and permanent junctional reciprocating tachycardia (PJRT). AVRT and PJRT involve the atrial and ventricular myocardium, the AV node, and accessory pathway(s) in the reentrant circuit. Suppression of AET and AF is possible by drugs like flecainide, sotalol, and amiodarone that directly act on atrial cells. The fetal response to antiarrhythmic therapy not unexpectedly is affected by fetal hemodynamics, arrhythmia mechanism, and the choice of drug management.
  • Chapter 8.2 - Fetal dysrhythmias
    pp 87-99
  • Clinical management
  • View abstract

    Summary

    This chapter provides a logical approach to diagnosis of fetal dysrhythmias and discusses the current management of fetal dysrhythmias. Echocardiography, the main diagnostic tool in the fetus, allows recording of the mechanical consequences of the electrical stimulation, registered as myocardial wall movement and blood flow signals. Other techniques such as fetal electrocardiography (f-ECG) or fetal magnetocardiography (f-MCG) allow recording of the electrical cardiac impulses. Rhythm irregularities are common and often associated with premature contraction of the atrium. The most frequent tachycardias are supraventricular tachyarrhythmias including supraventricular tachycardia (SVT) and atrial flutter (AF). Neither heart rate nor fetal heart rate (FHR) variability allows clear distinction among the various types although they may aid diagnosis. Fetal bradycardia may be a manifestation of fetal distress and require emergency Cesarean section. Hydrops increases morbidity and mortality for both tachycardias and bradycardias.
  • Chapter 9.1 - Structural heart disease
    pp 100-112
  • Embryology
  • View abstract

    Summary

    In essence cardiac development shows basic similarities of the major processes involved in between species; therefore, mechanisms unraveled in animal models can be reliably used in understanding normal human cardiac development and congenital heart disease (CHD). This chapter provides an update on recent advances in heart development in which it is important to distinguish a first heart field (FHF) and a second heart field (SHF). It provides a general introduction into embryology and then talks about the most common heart malformations in a developmental context. This is followed by a discussion on each specific malformation. The chapter explains the separation of the SHF in an anterior/secondary (arterial pole) and posterior (venous pole) population. It then introduces a number of processes that are essential in the formation of the four-chambered heart with a proper alignment of the atria, ventricles, and great arteries.
  • Chapter 9.2 - Structural heart disease
    pp 113-122
  • Genetic influences
  • View abstract

    Summary

    Congenital heart disease (CHD) is one of the commonest human birth defects, with a widely reported birth incidence of just less than 1%, and it accounts for one-third of infant deaths that result from congenital malformation. Epidemiological studies have long suggested that genetic factors may have a contribution to cardiac maldevelopment in humans. Mapping genes by linkage seeks to identify which DNA sequences have been inherited in common by affected individuals in families with multiple members suffering from the genetic disease. Many disease genes have also been identified by studying individuals with a chromosomal rearrangement, such as a translocation, where a piece of chromosomal material breaks of and rejoins to another chromosome. The first draft of human genome sequence was published in 2001 and in 2003 the International Human Genome Sequencing Consortium announced a finished version which detailed the entire DNA sequence of each chromosome.
  • Chapter 9.3 - Structural heart disease
    pp 123-127
  • Fetal cardiac interventions
  • View abstract

    Summary

    This chapter summarizes the current state of trans-catheter fetal cardiac interventions (FCI) for a select group of congenital heart defects (CHDs). The ethical issues and risks that pertain to the mother, as the healthy patient and innocent bystander are non-trivial. However, there are other situations in medical therapy that involve procedures to a healthy patient for the sake of another. Therapy for FCI involves ultrasound-guided uterine and fetal cardiac puncture with an 18- or 19-gauge cannula, predominantly percutaneous, and can be performed with the mother awake. The fetal cardiac lesion that has been the main focus of FCI over the past two decades is severe aortic stenosis (AS) in early and mid-gestation that has been shown in several publications to evolve into HLHS at birth. Hypoplastic left heart syndrome (HLHS) with highly restrictive or intact atrial septum (IAS) is one of the most challenging lesions in managing patients with CHD.
  • Chapter 10.1 - Manipulation of amniotic fluid volume
    pp 128-136
  • Homeostasis of fluid volumes in the amniotic cavity
  • View abstract

    Summary

    Human pregnancies contain large amounts of water in several compartments, including the fetal body, the placenta and membranes, and the amniotic fluid (AF). This chapter reviews the current understanding of water flow into the gestation and into and out of the amniotic cavity. It reviews evidence suggesting that the fetus may regulate the AF volume. Decreases in fetal urine flow are associated with a decrease in AF volume. The mature fetus can reduce urine flow to achieve homeostasis; in the near-term ovine fetus increased plasma osmolality is associated with fetal vasopressin secretion, urinary concentration, and reduced urine flow. Water permeability in the placenta appears to be regulated at the level of the syncytiotrophoblast, and to vary with gestational age. A variety of influences can alter AF volume by affecting one of the factors associated with AF formation and resorption.
  • Chapter 10.2 - Manipulation of amniotic fluid volume
    pp 137-144
  • Oligohydramnios and polyhydramnios
  • View abstract

    Summary

    This chapter first discusses the measurement of amniotic fluid and the technique of measuring the depth of amniotic pool. It then describes the causes, diagnosis, and treatment of both polyhydramnios and oligohydramnios. Amniotic fluid can be semi-quantified reliably using two-dimensional ultrasound measurement of the depth of amniotic pocket and presented with amniotic fluid index (AFI) or maximum vertical pool or pocket (MVP). Combination of clinical and ultrasound assessment often allows accurate diagnosis of the underlying causes of oligohydramnios and polyhydramnios, which are heterogeneous and are usually not treatable or reversible prenatally. The aim of management is to prevent the adverse consequences resulting from extreme deviations of amniotic fluid volume. In polyhydramnios, serial amnioreduction may help to relieve the maternal pressure symptoms. In oligohydramnios caused by ruptured membranes, serial amnioinfusion may be considered to prevent pulmonary hypoplasia. Both interventions are only supported by small and uncontrolled observational studies.
  • Chapter 11.1 - Twin-to-twin transfusion syndrome
    pp 145-155
  • Scientific basis
  • View abstract

    Summary

    Twin-to-twin transfusion syndrome (TTTS) is a relatively unusual condition as genetically concordant twins develop phenotypically discordant features as a consequence of monochorionic placentation and the conjoined angioarchitecture. This chapter describes the underlying scientific basis for the development of the clinical picture of TTTS and discusses the interplacental vascular connections. Human hemochorial placentation involves vasculogenesis, the formation of blood vessels from non-vascular (hemangioblastic) precursors, in combination with angiogenesis, the remodeling of existing blood vessels to create new ones. The chapter provides the specific placental angioarchitecture in TTTS and explains the role angiogenic growth factors. Vascular endothelial growth factor (VEGF)-A and placental growth factor (PlGF) are shown to be potent angiogenic factors, being critical for placental angiogenesis, and also as permeability factors leading to vascular leakage. Objective ultrasound measurements of fetal cardiac function include: cardiothoracic ratio; ventricular chamber dimensions and freewall thickness; valvular regurgitation; and assessment of systolic and diastolic function.
  • Chapter 11.2 - Twin-to-twin transfusion syndrome
    pp 156-165
  • placental circulation
  • View abstract

    Summary

    Monochorionic (MC) twin and triplet pregnancies pose complex clinical problems and high risks of types that are not seen in dichorionic (DC) twin pregnancies. Fetal growth discordance (FGD) and twin-to-twin transfusion syndrome (TTTS) are the most common problems. The MC twin placenta is usually a truly single, not fused, placenta that is produced by a single zygote and intended for the metabolic support of a singleton fetus. There are three vascular consequences of the insertion of two or more umbilical cords into an MC placenta: cord insertions, single umbilical artery, and interfetal vascular connections. TTTS is usually caused by a relatively low number of small diameter arteriovenous connections (AVCs) in combinations that result in net chronic blood seepage into the recipient twin. All types of vascular connections are involved in major complications in MC twins, including TTTS, donor/recipient role reversal after treatment, and neurological damage of a single surviving fetus.
  • Chapter 11.3 - Twin-to-twin transfusion syndrome
    pp 166-172
  • Cardiovascular manifestations
  • View abstract

    Summary

    This chapter demonstrates the role of the cardiovascular system as a contributor to the mechanisms of twin-to-twin transfusion syndrome (TTTS) and the essential role that cardiovascular characterization plays in diagnosing and monitoring the condition. It reviews the pathophysiology of TTTS and its impact on the cardiovascular system. The chapter discusses current methods for cardiovascular assessment, treatment strategies and the impact these have on the progression of cardiovascular disease and long-term implications. The longitudinal assessment of TTTS demonstrated that the circulatory derangement results in cardiac deterioration in a subset of patients. TTTS is believed to result from unidirectional flow across arteriovenous anastomoses within the shared placental mass with a paucity of bidirectional venovenous and arterioarterial anastomoses. The scoring system incorporates features unique to TTTS that quantify the cardiovascular burden of the disease. In TTTS, the twin pair is composed of the same genetic make-up suggesting that additional prenatal factors are involved.
  • Chapter 11.4 - Twin-to-twin transfusion syndrome
    pp 173-183
  • treatment by fetoscopic laser ablation
  • View abstract

    Summary

    This chapter discusses the twin-to-twin transfusion syndrome (TTTS) treatment options focusing on fetoscopic laser ablation of anastomoses. It also explains the benefits and risks associated with this treatment. Fetoscopic laser coagulation of placental vessels (FLCPV) is the only treatment addressing the pathophysiology of the syndrome as proven through a randomized controlled study against amnioreduction. Septostomy is based on a deliberate opening of the intertwin membrane with the needle in order to let the amniotic fluid flow freely between the two amniotic sacs. Even though two randomized trials have yielded similar survival rates between amnioreduction and septostomy, it has been abandoned by most teams. The superiority of laser treatment over amnioreduction was established through a randomized controlled study. The type of anesthesia has also evolved with time since the first interventions. Some teams still operate under general anesthesia although it is significantly associated with significant maternal morbidity.
  • Chapter 11.5 - Twin-to-twin transfusion syndrome
    pp 184-186
  • management of stage I disease
  • View abstract

    Summary

    Twin-to-twin transfusion syndrome (TTTS) is a complication that affects approximately 10% of all monochorionic twin pregnancies. O'Donoghue et al. reported that majority of stage I cases (67.4%) were managed by amnioreduction, with 39.1% treated at the time of first presentation. Serial amnioreductions may be offered as a treatment for stage I disease for the treatment of patients who are symptomatic from polyhydramnios or have a shortened cervix. In 20% of TTTS cases, amnioreduction may lead to stabilization or regression of the stage. Laser therapy for stage I disease has been offered by many centers due to the risk of progression and the eventual need for a definitive treatment. There are few studies that report outcomes for laser treatment specifically for stage I disease. A consensus conference was sponsored by the North American Fetal Therapy Network to evaluate the available information regarding management of Quintero stage I TTTS.
  • Chapter 12.1 - Twin reversed arterial perfusion (TRAP) sequence
    pp 187-192
  • Pathophysiology
  • View abstract

    Summary

    This chapter discusses the pathophysiological basis and pathology of twin reversed arterial perfusion (TRAP) sequence, briefly discussing prenatal diagnosis and treatment in relation to our understanding of the pathophysiology of the condition and largely focusing on the treatment options. Numerous pregnancy complications may develop, either due to consequences of the abnormal development of the acardiac fetus, or due to secondary effects on the pump twin. The abnormalities present in the affected acardiac twin represent a wide spectrum, ranging from the fetus comprising an amorphous mass of tissue through to a relatively well-formed fetus with trunk, arms, and legs. TRAP sequence is essentially a defect of monozygotic duplication requiring the presence of interfetal placental vascular anastomoses; it is therefore a complication affecting monochorionic multiple pregnancies. Since "pump" twin mortality and morbidity is well reported, several strategies have been described for antenatal intervention in TRAP sequence to improve the outcome.
  • Chapter 12.2 - Twin reversed arterial perfusion (TRAP) sequence
    pp 193-199
  • In-Utero treatment
  • View abstract

    Summary

    This chapter describes the diagnosis, pathophysiology, treatments, and diagnosis of twin reversed arterial perfusion (TRAP). Existence of TRAP requires two conditions: pump or forward flow failure in the acardiac twin and a set of arterioarterial and venovenous placental anastomoses connecting the acardiac and pump twins' circulatory systems. Ultrasonography with color Doppler is the primary method for diagnosing TRAP. The added benefits of color Doppler sonography include ability to trace fetal vessels and document reversed flow through an arterioarterial anastomosis confirming diagnosis of TRAP. MRI has also been used as an adjunct modality in the diagnosis of TRAP. Using MRI, one can determine the extent of blood flow in the umbilical cord of the acardiac, as well as evaluate the pump twin for anomalies, cardiac decompensation, and signs of chronic hypoxia such as brain ischemia. However, no single surgical technique has been found to be unequivocally superior.
  • Chapter 13.1 - Fetal infections
    pp 200-207
  • Immune responses to congenital infections
  • View abstract

    Summary

    This chapter reviews the immune system and describes the current knowledge of its development during fetal life. It summarizes the capacity of the fetal immune system to respond to infectious pathogens and focuses on congenital infections. In tissues, immune cells like macrophages and dendritic cells (DCs) express specific receptors, such as toll-like receptors (TLRs), allowing them to recognize molecules called pathogen-associated molecular-patterns (PAMPs) that are specifically expressed by pathogens. The immune system develops during fetal life in order to be ready to control infectious microorganisms to which the infant will be exposed after birth. Immune effector functions are required to control pathogens but may lead to inflammatory responses that are potentially harmful to the fetus and to the placenta. Recent studies of the immune responses to some pathogens infecting the fetus have indicated that fetal T lymphocytes can develop effector functions similar to those of older children or adults.
  • Chapter 13.2 - Fetal infections
    pp 208-237
  • Clinical management
  • View abstract

    Summary

    This chapter focuses on pathogenic organisms that may be responsible for fetal infection during pregnancy and may have significant effects on outcome. Many infections have associated serious consequences including fetal/perinatal mortality and significant morbidity. Infection with parvovirus can cause fetal hydrops and/or cardiac involvement. Prenatal diagnosis of fetal parvovirus infection requires samples of fetal blood, serous body effusions, and amniotic fluid to be sent to recognized reference laboratories. Chickenpox in adults is often more symptomatic and leads to the risk of varicella pneumonia, which carries a significant mortality. Diagnosis of primary cytomegalovirus (CMV) infection in pregnant women is based on serological testing with the appearance of specific IgG. The main host cells infected by CMV are the endothelial cells and the polymorphic nuclear leukocytes. CMV can be detected in the amniotic fluid by conventional viral isolation, rapid culture, or molecular assays.

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