Modern neonatology is still a relatively new specialty: the first positive pressure ventilation for respiratory distress syndrome was practiced in the 1960s. In the 1970s and 1980s the focus was on survival of increasingly preterm infants and exogenous surfactant therapy began. The first edition of this book was published 25 years ago, at a time of great excitement about the new therapeutic options available. In the 1990s survival began to be the norm and increasingly neonatologists started to consider the evidence for therapies: antenatal steroids became a standard of care and the first concerns were expressed about the effect of post natal steroids on the developing brain.

The fifth edition of this book is published in a new era where survival of even the most preterm infants has come to be expected, and the focus now is on the quality of care and achieving the best long term outcomes with the least invasive therapy. The importance of family-centred developmental care and supporting breastfeeding and attachment are now regarded as equally important standards of care.

This book is also developing and maturing: we have tried to present complex information in a visually appealing format and we now have full colour diagrams and photographs. The authors offer the benefit of their clinical expertise with a series of “clinical tips” throughout the text and there are links to our sister title, Nursing the Neonate. Self-assessment questions for each chapter are available online. We have tried to present the latest evidence and therapies and addressed modern controversies and changes in practice. The result is a comprehensive text that provides an international insight into the current practice of neonatal care in a user-friendly format.

We believe this book offers an excellent introduction to state-of-the-art neonatal medicine for trainee doctors, nurses, midwives and allied health professionals. We would also like to pay tribute to two of the original authors of the first edition, Malcolm Levene and David Tudehope who have recently retired and handed over the baton of Essential Neonatal Medicine to a new generation of neonatologists.

Sunil Sinha
Lawrence Miall
Luke Jardine

Acknowledgements

We would like to thank Dr Michael Griksaitis for help with revising and updating the chapter on practical procedures, Dr Fiona Wood, Dr Shalabh Garg, Dr Sam Richmond and Dr Jonathan Wyllie for various images, Dr Tracey Glanville for reviewing the obstetric chapter, and Dr Jayne Shillito, Dr Mike Weston and Dr Liz McKechnie for providing clinical images.

This edition of the book would also not have been possible without the efforts of many “behind the scenes” individuals, including – Madeleine Hurd (Associate Editor, Medical Education, Wiley) and Elizabeth Norton (Production Editor, Medical Education, Wiley) and the editors are grateful to them for their patience and guidance.

We would especially like to thank our families for their patience and understanding during the many evenings we spent writing this book.

And finally we are indebted to the babies and their families that it has been our privilege to treat, who have taught us so much over the years.

Preface to the First Edition

There has been an explosion of knowledge over the last decade in fetal physiology, antenatal management and neonatal intensive care. This has brought with it confusion concerning novel methods of treatment and procedures as well as the application of new techniques for investigating and monitoring high-risk neonates. The original idea for this book was conceived in Brisbane, and a Primer of Neonatal Medicine was produced with Australian conditions in mind. We have now entirely rewritten the book, and it is the result of cooperation between Australian and British neonatologists with, we hope, an international perspective.

We are aware of the need for a short book on neonatal medicine which gives more background discussion and is less dogmatic than other works currently available. We have written this book to give more basic information concerning physiology, development and a perspective to treatment which will be of value equally to neonatal nurses, paediatricians in training, medical students and midwives. Whilst collaborating on a project such as this we are constantly aware of the variety of ways for managing the same condition. This is inevitable in any rapidly growing acute speciality, and we make no apologies for describing alternative methods of treatment where appropriate. Too rigid an approach will be to the detriment of our patients!

A detailed account of all neonatal disorders is not possible but common problems and their management are outlined giving an overall perspective of neonatology. Attention has been given to rare medical and surgical conditions where early diagnosis and treatment may be lifesaving. It is easy to be carried away with the excitement of neonatal intensive care and forget the parents sitting at the cotside. Our approach is to care for the parents as well as their baby, and we have included two chapters on parent–infant attachment as well as death and dying. The final chapter deals with practical procedures and gives an outline of the commonly performed techniques used in the care of the high-risk newborn. We have also provided an up-to-date neonatal Pharmacopoeia as well as useful tables and charts for normal age-related ranges.

Malcolm I. Levene
David I. Tudehope
M. John Thearle

Abbreviations

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CHAPTER 1

Fetal Well-Being and Adaptation at Birth

Introduction

The discipline of ‘perinatal medicine’ spans the specialties of fetal medicine and neonatology. The obstetrician must have a thorough knowledge of pregnancy and its effects on the mother and fetus, as well as fetal development and physiology. The neonatologist specializes in the medical care of the infant immediately after birth but must also have a thorough understanding of fetal development and physiology. This chapter reviews fetal assessment and physiology to provide the paediatrician and neonatal nurse with a better understanding of normal perinatal adaptation and the adverse consequences arising from maladaptation.

Placental Function

The placenta is a fetal organ that has three major functions: transport, immunity and metabolism.

The uterus is supplied with blood from the uterine arteries, which dilate throughout pregnancy, increasing blood supply 10-fold by term. Maternal blood bathes the intervillous space and is separated from fetal blood by the chorionic plate. Transport of nutrients and toxins occurs at this level. Oxygenated fetal blood in the capillaries of the chorionic plate leaves the placenta via the umbilical vein to the fetus (Fig. 1.1).

Figure 1.1 Diagram of placental structures showing blood perfusion.

Transport

The placenta transports nutrients from the mother to the fetus, and waste products in the other direction. This occurs in a number of ways, including simple diffusion (for small molecules) and active transport, which is used for larger molecules. The placenta is crucially also responsible for gaseous exchange of oxygen and carbon dioxide. Oxygen diffuses from the mother (PO₂ = 10–14 kPa, 75–105 mmHg) to the fetus (PO₂ = 2–4 kPa, 15–30 mmHg) where it binds to fetal haemoglobin. This has a higher affinity for oxygen than maternal haemoglobin for a given PO₂. This off-loading of maternal haemoglobin is also facilitated by a change in maternal blood pH.

Immunity

The placenta trophoblast prevents the maternal immune system from reacting against ‘foreign’ fetal antigens. Rejection does not occur because the trophoblastic cells appear to be non-antigenic, although it is known that fetal cells can cross into the maternal circulation where they can trigger an immune reaction (e.g. rhesus haemolytic disease). Maternal IgG antibody, the smallest of the immunoglobulins, can cross the placenta where it provides the newborn with innate immunity to infectious diseases. These IgG antibodies can also cause perinatal disease such as transient hyperthyroidism (see Chapter 21).

Metabolism

The placenta is metabolically active and produces hormones, including human chorionic gonadotropin (hCG) and human chorionic thyrotropin (hCT). It also detoxifies drugs and metabolites. Oestriol cannot be produced by the placenta alone. This is done by the fetal liver and adrenal glands. The metabolites are then sulphated by the placenta to form oestrogens, one of which is oestriol.

Because of its metabolic activity, the placenta has very high energy demands and consumes over 50% of the total oxygen and glucose transported across it.

Fetal Homeostasis

The placenta is an essential organ for maintaining fetal homeostasis but the fetus is capable of performing a variety of physiological functions:

• The liver produces albumin, coagulation factors and red blood cells.
• The kidney excretes large volumes of dilute urine from 10–11 weeks’ gestation, which contributes to amniotic fluid.
• Fetal endocrine organs produce thyroid hormones, corticosteroids, mineralocorticoids, parathormone and insulin from 12 weeks’ gestation.
• Some immunoglobulins are produced by the fetus from the end of the first trimester.

Fetal Circulation

The fetal circulation is quite different from the newborn or adult circulation. The umbilical arteries are branches of the internal iliac arteries. These carry deoxygenated blood from the fetus to the placenta where it is oxygenated as it comes into close apposition with maternal blood in the intervillous spaces. Oxygenated fetal blood is carried in the single umbilical vein which bypasses the liver via the ductus venosus to reach the inferior vena cava. It then passes into the inferior vena cava and enters the right atrium as a ‘jet’, which is shunted to the left atrium across the foramen ovale (Fig. 1.2). From here it passes into the left ventricle and is pumped to the coronary arteries and cerebral vessels. In this way the fetal brain receives the most oxygenated blood. Some deoxygenated blood is pumped by the right ventricle into the pulmonary artery, but the majority bypasses the lungs via the ductus arteriosus to flow into the aorta where it is carried back to the placenta. Only 7% of the combined ventricular output of blood passes into the lungs. The right ventricle is the dominant ventricle, ejecting 66% of the combined ventricular output.

Figure 1.2 Diagram of the fetal circulation through the heart and lungs, showing the direction of flow through the foramen ovale and ductus arteriosus (DA).

In summary, there are three shunts:

The last two shunts only occur because of the very high fetal pulmonary vascular resistance and the high pulmonary artery pressure that is characteristic of fetal circulation.

Umbilical Vessels

There are two umbilical arteries and one umbilical vein, surrounded by protective ‘Wharton’s jelly’. In 1% of babies there is only one umbilical artery, and this may be associated with growth retardation and congenital malformations, especially of the renal tract. Chromosomal anomalies are also slightly more common.

Assessment of Fetal Well-Being

Assessment of fetal well-being is an integral part of antenatal care. It includes diagnosis of fetal abnormality, assessment of the fetoplacental unit and fetal maturity, monitoring of growth and well-being monitoring in the third trimester and during labour (Fig. 1.3).

Figure 1.3 A timeline for fetal assessment and monitoring during pregnancy.

Assessment of Maturity

Clinical Assessment

Assessment of gestational age depends on the date of the last menstrual period (LMP) and clinical measurement of fundal height: fundal height (cm) = gestational age (weeks). This is most accurate in early pregnancy. Fetal ‘quickening’ can help in dating the duration of pregnancy: in primiparas movements are first felt at about 20–21 weeks, and in multiparas at 18 weeks.

Ultrasound

Early measurement of fetal size is the most reliable way to estimate gestation and is considered to be even more reliable than calculation from the date of the LMP. Ultrasound measurements that correlate well with gestational age include crown–rump length (until 14 weeks), biparietal diameter (BPD) and femur length. The BPD measurement at 14–18 weeks appears to be the best method for assessing the duration of pregnancy.

Assessment of Fetal Growth and Well-Being

Clinical Assessment

Monitoring fundal height is a time-honoured method of assessing fetal growth. Unfortunately, up to 50% of growth-restricted infants are not detected clinically.

Ultrasound

Serial estimates of BPD, head circumference, abdominal circumference and femur length are widely used to monitor growth, often on customized fetal growth charts. In fetuses suffering IUGR, head growth is usually the last to slow down. Estimating fetal weight by ultrasound has become very accurate and provides critical information for perinatal decision-making about the timing of delivery.

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Link to Nursing the Neonate: Obstetric issues relating to neonatal care. Chapter 2, pp.14–19.

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Ultrasound Imaging and Doppler Blood Flow

The location of the placenta can be confidently established by ultrasound. Doppler flow velocity waveforms of the umbilical artery are now used as a major determinant of fetal well-being. In IUGR fetuses, abnormal Doppler waveforms are a reliable prognostic feature. As fetal blood flow become compromised there is reduced, then absent or reversed flow during diastole. Reversed diastolic flow is an ominous sign and is associated with a high risk of imminent fetal demise (see Fig. 1.4). If end-diastolic flow (EDF) is absent, detailed Doppler studies of the middle cerebral artery (MCA) and ductus venosus are indicated. Evidence of cerebral redistribution should trigger intensive regular monitoring. Timing of delivery will be based on Dopplers, gestation and estimated fetal weight. Recently, Doppler measurement of peak systolic blood flow velocity in the MCA has become a part of the assessment of fetal anaemia and isoimmunization. As anaemia becomes severe the velocity increases (see Chapter 20).

Figure 1.4 Doppler measurement of blood flow in the fetal umbilical artery. Left hand panel shows normal forward flow throughout the cardiac cycle. Right hand panel shows pathological reversed flow during diastole.

Amniotic Fluid Volume

Amniotic fluid is easily seen on ultrasound and the maximum pool size in four quadrants is measured (amniotic fluid index). This is often combined with non-stress testing (NST), counting movement and breathing. Both excess (polyhydramnios) and reduced (oligohydramnios) amniotic fluid volumes can be associated with adverse fetal outcome. See Table 1.1.

Table 1.1 Fetal problems associated with abnormal amniotic fluid volumes

Fetal Breathing Movements

The breathing movements of the fetus show marked variability. The fetus breathes from about 11 weeks’ gestation, but this is irregular until 20 weeks. Fetal breathing promotes a tracheal flux of fetal lung fluid into the amniotic fluid. An absence of amniotic fluid (oligohydramnios) can lead to pulmonary hypoplasia. Abnormal gasping respiration, extreme irregularity of breathing in a term fetus and complete cessation of breathing are visible by ultrasound.

Fetal Heart Rate Monitoring, Non-Stress Test and Biophysical Profile

The response of the fetal heart to naturally occurring Braxton Hicks contractions or fetal movements provides information on fetal health during the third trimester. A normal fetal heart trace is reactive (≥2 accelerations) in response to fetal movements. If it is not reactive, further assessment with ultrasound is indicated.

In late pregnancy the biophysical profile combines the NST and ultrasound assessment of fetal movements. A score (2) is given for each of heart rate accelerations, fetal breathing movements, fetal limb movements, movement of the trunk and adequate amniotic fluid depth. A normal well fetus will score 10/10 and a score of less than 8 is abnormal.

Screening During Pregnancy

Maternal Blood Screening

Screening programmes vary from country to country. In the UK all pregnant women are routinely screened for syphilis, hepatitis B, immunity to rubella and haemoglobinopathies (sickle cell disease, thalassaemia), and HIV screening is strongly encouraged.

Fetal Imaging

Ultrasound examination of the fetus for congenital abnormalities is now offered as a routine procedure. Major malformations of the central nervous system, bowel, heart, genitourinary system and limbs should be detected. Some disorders, such as twin-to-twin transfusion, pleural effusion and posterior urethral valves are amenable to fetal ‘surgery’. Advanced ‘4D’ (3D seen in real time) ultrasonography allows visualization of the external features of the fetus, such as the presence of cleft lip (see Fig. 1.5).

Figure 1.5 Cleft lip.

Courtesy of Dr Jason Ong.

Fetal MRI is now feasible and appears safe in pregnancy. The large field of view, excellent soft tissue contrast and multiple planes of construction make MRI an appealing imaging modality to overcome the problems with ultrasound in cases such as maternal obesity and oligohydramnios, but MRI cannot be used for routine screening. It is useful in the assessment of complex anomalies such as urogenital and spinal anomalies, complex brain malformation and congenital diaphragmatic hernia as well as for some fetal cardiac disorders (Fig 1.6).

Figure 1.6 Fetal MRI scan (coronal view) showing large cystic hygroma on the left side of the neck (arrow) and an associated pleural effusion (arrow).

Courtesy of Dr Mike Weston.

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Link to Nursing the Neonate: Obstetric issues relating to neonatal care. Chapter 2, pp. 14–19.

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Down’s Syndrome Screening

Trisomy 21 affects 1 in 600 fetuses and 1 in 1000 live births. Incidence rises with maternal age (1 in 880 at 30 years to 1 in 100 at 40 years) but as more younger women are pregnant, in the UK screening is offered to all pregnant women regardless of age. The screening tests vary and are summarized in Table 1.2. If the risks after screening are high then a diagnostic test (amniocentesis or chorionic villus sampling, CVS) is offered.

Table 1.2 Screening tests for Down’s syndrome in UK

AFP, alpha-fetoprotein; hCG, human chorionic gonadotropin; PAPP, pregnancy-associated plasma protein A.

Amniocentesis

Amniocentesis is valuable for the diagnosis of a variety of fetal abnormalities. Trisomy 13, 18 and 21 can be detected by PCR within 48 h and the cells cultured for chromosome analysis (14 days) or to study enzyme activity. Ultrasound-guided amniocentesis is undertaken by passing a needle through the anterior abdominal wall into the uterine cavity. The risk of miscarriage is less than 1%. Larger volumes of amniotic fluid may be removed (amnioreduction) as a treatment for polyhydramnios, although this treatment normally needs to be repeated weekly.

Chorionic Villus Sampling

CVS involves the transcervical or transabdominal passage of a needle into the chorionic surface of the placenta after 11 weeks’ gestation to withdraw a small sample of tissue. Because of the 1% risk of miscarriage, the test is reserved for detection of genetic or chromosomal abnormalities in at-risk pregnancies, rather than as a mere screening test. Preliminary chromosomal results can be obtained within 24–48 hours by fluorescent in situ hybridization (FISH) or PCR. Direct analysis requires cell culture (14 days)

Fetal Blood Sampling (Cordocentesis)

Fetal blood sampling is an ultrasound-guided technique for sampling blood from the umbilical cord to assist in the diagnosis of chromosome abnormality, intrauterine infection, coagulation disturbance, haemolytic disease or severe anaemia. It can also be used for treatment, with in utero transfusion of packed red blood cells during the same procedure. There is a 1% risk of fetal death.

Fetal Monitoring During Labour

Intrapartum Monitoring

In low-risk pregnancies intermittent auscultation of the fetal heart rate (FHR) is all that is required. Continuous electronic monitoring of the FHR can be performed non-invasively with a cardiotocograph (CTG) strapped to the abdominal wall, or invasively with a fetal scalp electrode.

The CTG trace allows observation of four features:

• Baseline heart rate
• Beat to beat variability
• Decelerations:
  • Early: slowing of the FHR early in the contraction with return to baseline by the end of the contraction
  • Late: repetitive, periodic slowing of FHR with onset at middle to end of the contraction
  • Variable: variable, intermittent slowing of FHR with rapid onset and recovery
  • Prolonged: abrupt fall in FHR to below baseline lasting at least 60–90 s; pathological if last >3 min
• Accelerations: transient increases in FHR >15 bpm lasting 15 s or more. These are normal and are reassuring. The significance of absent accelerations as a single feature is not known.

The interpretation of the CTG must then be classified as normal, suspicious or pathological (Box 1.1; see also Table 1.3 and Fig. 1.7).

Table 1.3 Features of a CTG

Figure 1.7a CTG showing fetal heart rate accelerations.

Figure 1.7b CTG showing late decelerations.

Figure 1.7c CTG showing normal heart rate followed by severe prolonged fetal bradycardia.

Figure 1.7d CTG showing loss of beat to beat variability.

Although FHR monitoring has been in widespread use of for over 30 years it has not been shown to reduce morbidity in term infants. It has, however, increased the rate of instrumental and caesarean section delivery. There is no evidence that routine FHR monitoring in the low-risk fetus improves outcome. Intermittent auscultation seems to be acceptable in these cases.

Fetal Scalp pH

Used in conjunction with CTG monitoring. In the presence of abnormal FHR, fetal scalp pH measurement may be helpful. Clinical decisions are made on the severity of the blood acidosis (Table 1.4).

Table 1.4 Clinical decisions based on blood acidosis

Fetal Electrocardiogram

Direct measurement of fetal ECG via a fetal scalp electrode, in conjunction with a CTG allows S-T waveform analysis (STAN). This has been shown to reduce fetal blood sampling and operative delivery and improve fetal condition at birth compared with CTG alone.

Fetal Compromise

‘Fetal distress’ is a commonly used but emotive clinical term which usually refers to a stressed fetus showing signs of compromise due to lack of oxygen. ‘Fetal compromise’ may be used to describe the ‘at-risk’ fetus, e.g. evidence of severe IUGR or abnormal Doppler flow. Factors causing fetal compromise are listed in Table 1.5.

Table 1.5 Causes of fetal compromise

Fetal compromise may lead to

• reduction in fetal movements
• passage of thick meconium into the amniotic fluid (this can be normal at term)
• FHR abnormality on CTG or fetal scalp electrode as described above
• metabolic acidosis (pH <7.20) on fetal scalp sample or arterial umbilical cord blood gas sample.

Physiological Changes at Birth

At birth the baby changes from being in a fluid environment, with oxygen provided via the umbilical vein, to an air environment, with oxygenation dependent on breathing. This remarkable adaptation requires considerable changes to the respiratory and cardiovascular systems within the first minutes after delivery. Other adaptations required include maintenance of glucose homeostasis (see Chapter 21) and thermoregulation (see Chapter 24).

While the fetus is in utero the lungs are filled with lung fluid, which is produced at up to 5 mL/kg per hour in response to secretion of chloride ions in pulmonary epithelium. During labour rising adrenaline levels ‘switch off’ lung fluid secretion and reabsorption begins. At birth the baby generates enormous negative pressures (−60 cmH₂O) which fill the lungs with air. With the first two or three breaths much of the fetal lung fluid is expelled. The remainder is absorbed into pulmonary lymphatics and capillaries over the first 6–12 h. Sometimes these clearance mechanisms fail and the lungs remain ‘wet’. This is known as transient tachypnoea of the newborn (see Chapter 13). The stimulus for the first breath is a combination of cold, physical touch, rising carbon dioxide levels and cessation of placental adenosine. It is also in part a reflex reaction to the emptying of the lungs of fluid (Hering–Breuer deflation reflex).

With the first few breaths the arterial oxygen tension (P_aO₂