(BQ) Part 1 book Keelings fetal and neonatal pathology presentation of content: The perinatal postmortem from a clinician’s viewpoint, the perinatal necropsy, genetic and epigenetic basis of development and disease, the placenta and umbilical cord, perinatal imaging, epidemiology of fetal and neonatal death,...and other contents.
T Yee Khong Roger D.G Malcomson Editors Keeling’s Fetal and Neonatal Pathology Fifth Edition 123 Keeling's Fetal and Neonatal Pathology T Yee Khong • Roger D.G Malcomson Editors Keeling's Fetal and Neonatal Pathology Fifth Edition Editors T.Yee Khong Department of Pathology Department of Obstetrics and Gynaecology University of Adelaide North Adelaide South Australia Australia Roger D.G Malcomson Department of Histopathology University Hospitals of Leicester NHS Trust Leicester Royal Infirmary Leicester United Kingdom Department of Histopathology Women’s & Children’s Hospital North Adelaide South Australia Australia ISBN 978-3-319-19206-2 ISBN 978-3-319-19207-9 DOI 10.1007/978-3-319-19207-9 (eBook) Library of Congress Control Number: 2015947612 Springer Cham Heidelberg New York Dordrecht London © Springer International Publishing 2015 This work is subject to copyright All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed The use of general descriptive names, registered names, trademarks, service marks, etc in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use The publisher, the authors and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication Neither the publisher nor the authors or the editors give a warranty, express or implied, with respect to the material contained herein or for any errors or omissions that may have been made Printed on acid-free paper Springer International Publishing AG Switzerland is part of Springer Science+Business Media (www.springer.com) For my wife Anne, and our sons, Jonathan and Jeremy, for all their love TYK To Karen—for unwavering support (and sustenance), come what may To my parents, Vera and Brian—for their confidence in me RDGM Foreword It is more than 30 years (during a Pathological Society Meeting in Edinburgh) since I approached Michael Jackson, then Medical Editor at Springer, with the suggestion that a textbook of Fetal and Neonatal Pathology would be a useful addition to their list He was a little wary at first, perhaps anticipating much overlap with another title, but, having perused the aims, objectives, and provisional contents of the proposal, became most enthusiastic For several years, I had been conscious of the need for such a text, directed towards the general Histopathologist and trainees It was not until I felt able to pick up any chapter where I couldn’t clearly identify an author or where one pulled out (and there were both) that I felt able to approach a Publisher Preparing the first edition was a very steep learning curve for me The most important lesson from that experience was that should a problem arise, go straight to the Medical Editor! The help and support I received during the process had underpinned my editorial activities ever since Its publication was greeted by a dinner for contributors during the Pathological Society Meeting in Southampton where the dessert was a Springer-blue, book-shaped cake Each new edition has brought changes in chapter, subject, and authorship to accommodate advances in pathology and changes in clinical practice The book’s content has, inevitably, become more detailed over time This, too, is appropriate as changes in the provision of pathology services has moved increasingly towards specialisation and regionalisation, such that, in the UK and many other countries, a much higher proportion of fetal and perinatal necropsies are performed by specialist pathologists to the advantage of both clinicians and parents The role of Editor has become easier with computerisation of the process—no more “cut and paste” (literally) of reference lists, no galley proofs to pore over and much more rapid communication with contributors The introduction of inexpensive colour printing has facilitated production of illustrations and improved quality The decision to move to joint Editorship for the fourth edition was prompted by growth of knowledge and increasing specialisation even within perinatal pathology The choice was not a difficult one, Yee and I had maintained regular contact since Oxford and our interests were complementary I was very happy when he accepted the invitation and his suggestions for both content and authorship have worked well It was Yee’s suggestion that it was time for a fifth edition It was his decision to retain joint Editorship and I was delighted when Roger Malcomson accepted the role With Editors who were former trainees of mine, one in Oxford, the other in Edinburgh, I was comfortable that “my baby” was in safe hands! This fifth edition is again appropriately different from what has gone before I have enjoyed reading contributions as they have come in—the more for having put the blue pencil to one side I am flattered that my name is attached to it I am grateful for the effort put in by many contributors over the years and for the continued support, effort, and expertise of the staff at Springer Edinburgh 2015 Jean W Keeling vii Preface When Dr Keeling conceived the first edition of this book more than 30 years ago, she saw a very real need for a textbook that provided an overview of fetal and perinatal pathology Her book concentrated on the common problems, especially where the anatomical pathology findings guided the direction of further investigations This has not changed The aim of this newly updated edition of Dr Keeling’s book remains to provide general guidance to practicing pathologists, particularly those who are called upon to regularly provide a perinatal pathology service Both of us count ourselves extremely privileged to have been Dr Keeling’s last trainees during her specialist consultant appointments in Oxford and Edinburgh and we feel most honored that she has chosen us to carry on her commission by assuming editorial responsibility for her book We welcome several new authors who bring new concepts, ideas and knowledge, along with their authority on those chapter subjects The format of the book remains the same as previous editions with the first half covering general areas in perinatal pathology The second half is based on organ systems and covers specific pathological entities, now including discussion of the relevant molecular pathology There are several new chapters In the years since the publication of the last edition, imaging techniques have advanced rapidly and are contributing new insights into perinatal disease and its detection The genetic and epigenetic basis of disease is much better understood while improvements in molecular testing have also permitted interrogation of many of the disorders encountered during the perinatal period Community expectations have also changed: techniques of the autopsy have to be adapted to meet these expectations and also to meet the practical challenges in undertaking detailed fetal examinations at increasingly earlier gestations As a further example, in the medicolegal setting, the forensic pathologist may not see sufficient fetal and neonatal deaths, while the pediatric/perinatal pathologist may be less well acquainted with the forensic aspects; communities expect that an expertly conducted necropsy, which may need to be conducted jointly, will provide answers to very high standards of documentation and proof In whatever setting, the pathologist needs to be informed about the most appropriate and cost-effective investigations before, during, and after a meticulously performed autopsy, the last directing further testing, including the use of molecular techniques We sincerely hope that the reader will find this book as incisive and insightful as Dr Keeling always has been We are also hopeful that this 5th edition of her work will live up to and extend her professional legacy for the benefit of another generation of pathologists North Adelaide, SA, Australia Leicester, UK T Yee Khong Roger D.G Malcomson ix 398 Fig 16.8 Chest X-ray showing a large left tension pneumothorax than managing the underlying lung disease and utilizing ventilatory strategies to minimize air leak A pneumopericardium is very rare and generally only happens in ventilated neonates with severe underlying lung disease and air leak Following air tracking into the mediastinum, if the pressure is high enough, it may dissect into the pericardium This condition results in acute cardiovascular compromise from cardiac tamponade with hypotension, bradycardia, and respiratory compromise The acute management is direct pericardial tap under the xiphoid process; however, the mortality rate is high (80–100 %) [170] Pneumoperitoneum related to respiratory air leak results from air tracking from the chest into the peritoneum through the diaphragmatic foramina It does not generally require treatment unless it causes significant respiratory compromise In these circumstances, the peritoneum can be drained by needle aspiration or peritoneal drain Chronic Lung Disease of Prematurity/ Bronchopulmonary Dysplasia Bronchopulmonary dysplasia (BPD) was first named by Northway in 1967 and was described as the interstitial and alveolar edema that occurred after the initial hyaline membrane disease resulting in inflammation and fibrosis of the small airways [174] BPD was initially seen in large preterm babies who received oxygen and mechanical ventilation Despite the introduction of antenatal steroids, surfactant, and better ventilation strategies, the complication of BPD continues in the extremely premature neonate Jobe in 1999 reviewed the pathophysiology of chronic lung disease of preterm neonates and indicated that there was less fibrosis with the predominant feature now being abnormal alveolar and A.L Kent vascular development [175] No longer is it considered an injury/repair concept but one of interference/interruption of the normal developmental signaling process for terminal maturation and alveolarization of the lungs This has now been given the name “new BPD.” The definition of BPD has also changed over the years with the one most clinicians use now being that of oxygen and/or supplementary respiratory support at 36 weeks post menstrual age Up to 52 % of neonates born less than 29 weeks’ gestation develop BPD, despite the majority having been exposed to antenatal steroids and receiving surfactant Interestingly in the 19 % of those who had little or no oxygen requirement in the first few weeks, 17 % still went on to develop BPD [176] Thus, BPD continues to be a complex disorder that is unpredictable in its evolution With increasing survival of extremely premature neonates, the incidence of BPD has increased Antenatal corticosteroid use decreases death and severe intraventricular hemorrhages, but the incidence of BPD in survivors is increased [177] Oxygen and mechanical ventilation are significant contributors to BPD; however, many other factors are also implicated in its pathophysiology From 24 weeks’ gestation to 32 weeks, the saccular terminal structures of the lung are meant to segment at least six times prior to the initiation of alveolarization At the same time, the pulmonary vasculature, airways, lymphatics, and delivery of surfactant to the alveolar surface occur Thus extreme premature delivery interrupts this developmental process A number of antenatal fetal exposures can injure lung development including chorioamnionitis, smoking, and in utero growth restriction Postnatally along with mechanical ventilation and oxygen injury, sepsis and a PDA contribute to ongoing injury and the evolution of BPD [178] The typical presentation of BPD presents as delayed resolution of HMD with an ongoing oxygen requirement and respiratory support (mechanical or CPAP) On chest X-ray, the lungs are initially hazy with progression to a lacy parenchymal pattern with hyperinflation and some large cysts (Fig 16.9) The old BPD resulted in overinflated lungs with cystic emphysema and fibrosis [179] (Fig 16.10) The management of BPD is aimed at minimizing ongoing lung damage by careful monitoring of oxygen saturations and ventilator strategies at reducing lung injury Volume-targeted ventilation in comparison with pressurelimited ventilation appears to reduce the incidence of BPD, death, and duration of ventilation [180] Diuretics are utilized at times when fluid overload exists, but there is no evidence that they reduce BPD and generally have only transient effects [181–183] Corticosteroids have been shown to be harmful when used at less than days of life, and concerns regarding effects on long-term neurodevelopmental outcome have meant that corticosteroids, in much smaller doses than the original studies, are utilized for weaning neonates from high ventilator pressures and oxygen 16 Prematurity 399 Gastrointestinal System Fig 16.9 Chest X-ray of evolving BPD Fig 16.10 Chest X-ray of late bronchopulmonary dysplasia showing cystic and fibrotic changes requirements to enable extubation [184–186] Inhaled corticosteroids have also not been shown to be of benefit in comparison with systemic steroids for the prevention or treatment of BPD [187, 188] There are currently no pharmacologic interventions that have been shown to be effective in preventing or treating BPD [189] Mesenchymal stem cells are now being studied to determine whether they have the potential to prevent and repair impaired alveolar development in neonates with BPD [190] Enteral or Parenteral Nutrition/Feed Intolerance/ Osteopenia of Prematurity Ensuring adequate nutrition and preventing postnatal growth failure is an essential component of contemporary neonatal intensive care However, despite improved provision of parenteral nutrition solutions, early institution of enteral feeds, and fortification of feeds, many extremely premature neonates suffer from postnatal growth failure [191] A number of review articles and international guidelines have been produced aimed at minimizing postnatal growth failure in the extremely preterm neonate, proposing that postnatal growth should be equivalent to that of a normal fetus of the same gestational age [192–195] Amino acids and proteins are essential for normal growth, metabolism, and development They are important for the growth and structure of all cells and tissues and act as metabolic signals for metabolism Amino acids with or without glucose stimulate insulin secretion, augmenting protein synthesis and accretion The normal fetus at midterm in utero requires g/kg/day for adequate growth To prevent catabolic metabolism, a minimum protein intake of g/kg/day is required in combination with 30 kcal/kg/day of carbohydrate/fat [196] Early and aggressive protein intake in the first few days of life (2 g/kg/day) has not been shown to be harmful and is well tolerated, and there is some evidence to suggest that high protein intake during the first week of life promotes early weight gain, increases insulin secretion, improves glucose tolerance, and improves long-term neurodevelopmental outcome [197–199] High-density energy and essential fatty acids are the other important components of parenteral nutrition and are provided in the form of intravenous lipid emulsions The essential fatty acids, polyunsaturated fatty acids (PUFAs), are important in the development of the retina and brain and are implicated in long-term neurodevelopmental outcomes [200, 201] Recent studies have shown that commencing lipids at g/kg/day in the first 24 h is safe and well tolerated, and guidelines suggest at a minimum commencing at g/kg/day increasing to g/kg/day daily [198, 202] Preterm neonates are at risk of reduced bone mineral content due to inadequate reserves and an increased loss of essential minerals The majority of calcium and phosphate accretion occurs throughout the third trimester; thus extremely premature neonates not receive adequate accretion of minerals due to their early delivery The daily in utero requirement of calcium is estimated at 310 mg of calcium and 170 mg of phosphorous [203] Postnatal treatment with medications such as dexamethasone, caffeine, and diuretics can also have detrimental affects on bone mineralization, increasing the risk of osteopenia of prematurity [204–206] Extremely premature neonates receiving nonfortified breast 400 milk have an incidence of rickets of 40 % compared to 16 % in those who receive fortified breast milk [207] The clinical features of osteopenia of prematurity are nonspecific On X-ray, the bones may appear thin or fractures may be evident Increasing respiratory compromise has been associated with severe bone disease due to a soft compliant chest wall Screening for osteopenia of prematurity is difficult as there are currently no accurate serum or urinary markers Suggested guidelines for screening and treatment of those at risk of osteopenia include serum calcium, phosphate, and alkaline phosphatase If the serum phosphate is below 1.8 mmol/L and/or the alkaline phosphatase is greater than 500 IU/L, then phosphate supplementation should be commenced Vitamin D supplementation may also be required if there is no response to phosphate supplementation [208] Dual-energy X-ray absorptiometry and quantitative ultrasound of the tibia have been used to assess osteopenia of prematurity but due to their cost and skill requirement are not considered suitable for screening purposes at this time Serum and urinary markers are not entirely accurate screening tools for metabolic bone disease but continue to be the only ones available [208, 209] Necrotizing Enterocolitis Necrotizing enterocolitis (NEC) occurs in % of all very preterm/very low birthweight infants [210] It is a major cause of morbidity and mortality with one-third of infants dying from the disease [211] It is estimated that this disease annually costs the USA billion dollars [212] The condition is not confined just to premature neonates with 10 % of neonates affected being term or near-term Clusters of cases of NEC continue to occur in units in all countries, and as such, surveillance for possible nosocomial causes should always be considered [213, 214] NEC generally presents with abdominal distension, bilious nasogastric aspirates/vomiting, blood-stained stools, temperature instability, and apneic and bradycardic episodes The severity of the disease can vary from mild to severe where the neonate becomes hypotensive and shocked with a consumptive coagulopathy The mortality rate for NEC is reported to be about 30 % and is related to bacteremia, coagulopathy, ascites, and very low birthweight [215, 216] NEC frequently affects the terminal ileum and ascending colon, transverse colon, and descending colon Long-term sequelae include stricture formation, which occurs in 10–20 % of cases Where large areas of bowel resection (particularly the small bowel) have been required, neonates may suffer from short bowel syndrome and require prolonged parenteral nutrition Severe cases may require bowel and potentially liver transplants for hepatic failure secondary to prolonged parenteral nutrition Confirmed NEC is a radiological diagnosis where pneumatosis intestinalis, free peritoneal gas, or portal venous gas A.L Kent Fig 16.11 Necrotizing enterocolitis with pneumatosis intestinalis is documented (Fig 16.11) However, it is frequently nonspecific with bowel dilatation and thickened bowel wall Treatment of NEC involves cessation of enteral feeds, commencement of intravenous antibiotics, circulatory support where there is compromise, and parenteral nutrition and surgery where there is evidence of perforation or gangrenous bowel The acute surgical management of NEC remains controversial with no clear evidence to support peritoneal drainage versus laparotomy and little evidence to support stoma formation versus primary anastomosis [217] The pathogenesis of NEC is largely still not understood and is generally considered to be multifactorial The risk factors for preterm NEC and late preterm/term NEC are provided in Table 16.4 An inflammatory cascade is thought to be involved with tumor necrosis factor-α and platelet activating factor contributing to mucosal damage after a precipitating event In late preterm/term neonates, there has generally been a history of perinatal asphyxia, sepsis, growth restriction, polycythemia, hypoglycemia, exchange transfusions, umbilical lines, or congenital defects Maternal risk factors for neonates developing NEC include in utero growth restriction, pregnancy-induced hypertension, maternal HIV, maternal drug use (cocaine), and chorioamnionitis [218] Postnatal factors in premature neonates developing NEC related to early feeding, rate of advancing feeds, and type of feeds (formula) Cochrane reviews have indicated that delaying enteral feeds does not reduce the risk of NEC and potentially increases the risk related to late-onset sepsis related to the requirement for central venous catheters [219] Advancing feeds at faster rates is not associated with an increased risk of NEC and, as with delaying the commencement of enteral feeds, delays the time to full feeds [220] 16 Prematurity 401 Table 16.4 Risk factors for NEC by gestational age Premature infants Birthweight