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Pediatrics_Nelson. Cystinuria is a disorder of renal tubular transport of cystine, lysine, arginine, and ornithine. Although intestinal transport is affected in some genetic forms, the symptoms are largely due to the renal transport abnormality. The concentration of cystine exceeds its solubility product and results in significant renal stones. Evaluation and diagnosis are based on the pattern of amino acid excretion in the urine. Mutation testing can be done. Treatment is based on increasing the solubility of cystine by complexing it with compounds such as penicillamine. Intestinal transport of tryptophan is impaired in Hartnup syndrome; pellagra-like symptoms result from this deficiency. Diagnosis is based on the amino acid pattern in urine. Treatment with tryptophan is successful.


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Pediatrics_Nelson. Organic acid disorders result from a block in the pathways of amino acid catabolism. Occurring after the amino moiety has been removed, they result in the accumulation of specific organic acids in the blood and urine. Treatment is directed at the specific abnormality, with restriction in precursor substrates and administration of enzyme cofactors, when available. Outcome is generally poor for children with neonatal-onset propionic or methylmalonic acidemia but is influenced by frequency and severity of crises and is optimal when diagnosis is made before the onset of the first episode. Liver transplantation has been used in some patients with early indicators of success. Confirmatory testing begins with a urine organic acid profile and plasma amino acid profile. More specific testing often requires enzyme measurements in appropriate tissues. When abnormal results suggest a specific disorder, DNA testing may identify the mutations involved.


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Pediatrics_Nelson. Propionic acidemia and methylmalonic acidemia result from defects in a series of reactions called the propionate pathway (Fig. 54-1). Defects in these steps produce ketosis and hyperglycinemia. Propionic acidemia and methylmalonic acidemia are identified by neonatal screening with tandem mass spectrometry methods. The clinical manifestations of both of these disorders in the neonatal period consist of tachypnea, vomiting, lethargy, coma, intermittent ketoacidosis, hyperglycinemia, neutropenia, thrombocytopenia, hyperammonemia,


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Pediatrics_Nelson. Methionine Valine Threonine (?) Odd-chain fatty acids Cholesterol Pyrimidines and hypoglycemia. If these disorders are not identified by neonatal screening, intermittent episodes of metabolic acidosis occur. Crises occur during periods of catabolic stress, such as fever, vomiting, and diarrhea; they also may occur without an apparent precipitating event. During periods of neutropenia, the risk of serious bacterial infection is increased. Failure to thrive and impaired development are common.


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Pediatrics_Nelson. Propionic acidemia results from deficiency in propionylCoA-carboxylase, an enzyme that has two pairs of identicalsubunits. All forms of propionic acidemia are inherited in anautosomal recessive manner and are due to mutations in one of the subunits. Methylmalonic acidemia results from deficiencyin methylmalonyl mutase; this may be caused by mutations inthe gene for the mutase protein itself or in one of the stepsof the synthesis of the cobalamin cofactors for the enzyme.A complex set of defects in cobalamin metabolism results inother forms of methylmalonic acidemia, some of which are associated with hyperhomocystinemia. Treatment with massive doses of hydroxocobalamin (the active form of vitaminB12) is helpful in some cases of methylmalonic acidemia.


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Pediatrics_Nelson. For propionic acidemia and the vitamin B12–unresponsive forms of methylmalonic acidemia, management includes the restriction of dietary protein and addition of a medical food deficient in the specific amino acid precursors of propionyl-CoA (isoleucine, valine, methionine, and threonine). Carnitine supplementation is often needed because it is lost in the urine as acylcarnitines. Intestinal bacteria produce a significant quantity of propionate; thus, antibacterial treatment to reduce the population of bacteria in the gut has some beneficial effect in propionic acidemia and vitamin B12–unresponsive methylmalonic acidemia. Isovaleric acidemia results from a block in the catabolism of leucine. Its clinical manifestations are similar to those of defects in the propionate pathway. The strong odor of isovaleric acid results in sweaty feet odor in untreated infants. Therapy involves restricting the intake of leucine, and providing glycine Coenzyme A.


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Pediatrics_Nelson. Coenzyme A. Figure 54-2 Metabolism in isovaleric acidemia. (1) Leucine catabolic pathway (transamination and decarboxylation), (2) isovaleryl-CoA dehydrogenase, (3) glycine acyltransferase. CoA, Coenzyme A. as an alternate pathway therapy that conjugates isovaleric acid (Fig. 54-2) and is then excreted in the urine.


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Pediatrics_Nelson. as an alternate pathway therapy that conjugates isovaleric acid (Fig. 54-2) and is then excreted in the urine. Glutaric acidemia I results from a deficiency at the end of thelysine catabolic pathway. It is an autosomal recessive diseaseproduced by deficiency of glutaryl-CoA dehydrogenase activity (Fig. 54-3). Clinical manifestations include macrocephaly, which may be present at birth, with fever and metabolic distress. Before the advent of newborn screening, more than70% of children had metabolic stroke-like episodes associated with infarction of the basal ganglia and dystonia, which characteristically develops after an episode of intercurrent illness, although it may reflect birth stress or prenatal insults. Treatment includes a protein-restricted diet accompanied by amedical food deficient in lysine and aggressive management of intercurrent illness. Despite this treatment as many as onethird of children still develop neurologic symptoms.


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Pediatrics_Nelson. Biotin is a ubiquitous vitamin that is covalently linked to many carboxylases and cannot be recycled from its attachment to Figure 54-3 Scheme of flavoprotein metabolism with reference to glutaric aciduria types I and II. (1) Glutaryl-CoA dehydrogenase (deficient in glutaric aciduria type1), (2) fatty acyl-CoA dehydrogenases, (3) other flavoprotein dehydrogenases, (4) ETF (deficiency results in glutaric aciduria type II), (5) ETF-ubiquinone oxidoreductase (deficiency results in glutaric aciduria type II). CoA, Coenzyme A; ETF, electron transfer flavoprotein. the carboxylases. Thus, inherited biotinidase deficiency greatly increases the dietary requirement for biotin. Affected individuals become biotin deficient while consuming normal diets. Clinical disease can appear in the neonatal period or be delayed until later infancy, depending on the degree of deficiency.


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Pediatrics_Nelson. Clinical manifestations of biotin deficiency vary greatly (seizures, hypotonia, sensory neural deafness, alopecia, skin rash, metabolic acidosis, immune deficits) and depend on which enzymes in which tissues have the most biotin depletion. Carboxylation is a crucial reaction in the metabolism of organic acids; most patients with biotinidase deficiency excrete abnormal amounts of several organic acids, among which β-methyl-crotonylglycine is prominent. In addition to biotinidase deficiency, an inherited deficiency of holocarboxylase synthetase gives rise to severe disease and to similar patterns of organic aciduria. Both conditions respond well to treatment with large doses of biotin (10 to 40 mg/day). Confirmatory testing is accomplished with quantitative measurement of biotinidase activity.


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Pediatrics_Nelson. Fatty acids are derived from hydrolysis of triglycerides and catabolism of fat. The catabolism of fatty acids (Fig. 55-1) proceeds through the serial, oxidative removal of two carbons at a time as acetyl groups (each as acetyl-CoA). The reactions are catalyzed by a group of enzymes that exhibit specificities related to the chain length and other properties of the fatty acids: very long chain acyl-CoA dehydrogenase (VLCAD), long-chain hydroxyacyl-CoA dehydrogenase (LCHAD) or trifunctional protein, medium-chain acyl-CoA dehydrogenase (MCAD), and short-chain acyl-CoA dehydrogenase (SCAD).


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Pediatrics_Nelson. MCAD deficiency is the most common inborn error of β-oxidation. Hypoketotic hypoglycemia is a common manifestation, as is Reye syndrome–like illness with hypoglycemia and elevated liver enzymes. Fatty infiltration of the liver also occurs. True hepatic failure is rare. Episodes may be recurrent in the patient or the family. Sudden infant death syndrome is reported in infants with MCAD deficiency, perhaps related to hypoglycemia. Treatment requires avoidance of fasting and provision of calories with fever or other metabolic stress. Medium-chain triglycerides must be avoided.


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Pediatrics_Nelson. VLCAD deficiency and LCHAD (trifunctional protein) deficiency result in significant myopathy and cardiomyopathy. LCHAD deficiency is accompanied by a retinopathy in later childhood. In all of the disorders of β-oxidation, carnitine depletion can occur through excessive urinary excretion of carnitine esters of the incompletely oxidized fatty acids. Measurement of plasma carnitine is helpful in monitoring for this deficiency, which results in weakness and muscle pain, along with myoglobinuria in some people. Hydroxymethylglutaryl-CoA lyase deficiency, although not a disorder of β-oxidation, interferes profoundly with hepatic adaptation to fasting by impairing ketogenesis (see Fig. 55-1). The clinical manifestations are those of MCAD deficiency, except that carnitine depletion is less prominent.


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Pediatrics_Nelson. The diagnosis of disorders involving a deficiency of β-oxidation is suggested by the clinical picture and by hypoketotic hypoglycemia. The diagnosis is confirmed by analysis of urinary organic acid and acylglycine profiles, along with plasma acylcarnitine and free fatty acid profiles. Enzyme measurements and DNA testing complete the confirmatory testing. The profile of acylcarnitines in cultured skin fibroblasts may be helpful if other testing is not conclusive. In MCAD deficiency, a single mutation 985 A→G accounts for a significant percentage of cases. Treatment includes avoidance of fasting, as well as fluid and calorie supplementation during periods of metabolic stress, such as fever. In MCAD deficiency, medium-chain triglycerides must be avoided. In the long-chain fatty acid metabolic disorders, provision of medium-chain fatty acids improves muscle energy metabolism.


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Pediatrics_Nelson. Glutaric aciduria type II (multiple acyl-CoA dehydrogenase deficiency) is a clinical disease produced by a defect in the transfer of electrons from flavine adenine nucleotides to the electron transport chain (electron transfer flavoprotein [ETF], or ETF dehydrogenase); this defect results in a deficiency of multiple fatty acyl CoA dehydrogenases (see Fig. 55-1). medium-chain fatty acyl-CoA dehydrogenase, short-chain fatty acyl-CoA dehydrogenase, β-ketothiolase, (6) β-hydroxy-β-methylglutaryl-CoA synthase, (7) β-hydroxy-β-methylglutaryl-CoA lyase, (8) β-hydroxybutyrate dehydrogenase. CoA, Coenzyme A.


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Pediatrics_Nelson. It should not be confused with glutaric acidemia type I (see Chapter 54). When the enzyme essentially is nonfunctional, congenital anomalies are common, including renal cysts, facial abnormalities, rocker-bottom feet, and hypospadias. Severely affected infants have nonketotic hypoglycemia, metabolic acidosis, and the odor of sweaty feet soon after birth; these infants may die within the neonatal period. Less severely affected infants may have a more episodic, Reye syndrome–like illness. Skeletal and cardiac myopathy can be prominent in this complex, multisystemic disease. Onset in later childhood may be marked by recurrent hypoglycemia and myopathy. Treatment has not been effective in infants with complete deficiency. Milder forms respond to avoidance of fasting and caloric support during metabolic stress. Some patients respond to administration of riboflavin. Glutaric aciduria type II exhibits autosomal recessive inheritance. Confirmatory testing is similar to that for the other


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Pediatrics_Nelson. metabolic stress. Some patients respond to administration of riboflavin. Glutaric aciduria type II exhibits autosomal recessive inheritance. Confirmatory testing is similar to that for the other fatty acid oxidation disorders.


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Pediatrics_Nelson. Carnitine is a crucial cofactor in the transport of long-chain fatty acids across the mitochondrial inner membrane (see Fig. 55-1). It is synthesized from lysine by humans and is present in dietary red meat and dairy products. Carnitine deficiency is either primary (caused by failure of intake, synthesis, or transport of carnitine) or secondary (caused by the excretion of excessive amounts of carnitine as carnityl esters in patients with other inborn errors of metabolism; treatment with drugs that complex carnitine, such as valproic acid; or as a result of renal replacement therapy). Primary systemic carnitine deficiency is rare and results from inadequate renal reabsorption of carnitine secondary to a mutation in the sodium-dependent carnitine transporter. It responds well to carnitine supplementation. There are numerous examples of secondary carnitine deficiency among the organic acidurias, most prominently in disorders of the propionate pathway and in disorders of the β-oxidation


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Pediatrics_Nelson. supplementation. There are numerous examples of secondary carnitine deficiency among the organic acidurias, most prominently in disorders of the propionate pathway and in disorders of the β-oxidation of long-chain and medium-chain fatty acids. Clinical manifestations of carnitine deficiency include hypoketotic hypoglycemia, lethargy, lassitude, muscle weakness, sudden death, and cardiomyopathy.


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Pediatrics_Nelson. Peroxisomes are subcellular organelles involved in metabolism and biosynthesis of bile acids, membrane phospholipids, and some β-oxidation of long-chain fatty acids. Disorders include conditions caused by abnormal peroxisomal enzyme function and abnormal peroxisomal biogenesis. Clinical symptoms are diverse and frequently include developmental delay and dysmorphic features that can involve the skeleton and the head. Zellweger syndrome, neonatal adrenoleukodystrophy, and infantile Refsum disease are examples of disorders of peroxisome biogenesis. Zellweger syndrome, an autosomal recessive disease (1:100,000 births), is also called cerebrohepatorenal syndrome. Peroxisomes are virtually absent, as are normal peroxisomal functions, which include the oxidation of very long chain fatty acids. Affected infants have high


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Pediatrics_Nelson. Table 56-1 Lysosomal Storage Diseases DISEASE (EPONYM) ENZYME DEFICIENCY CLINICAL ONSET DYSOSTOSIS MULTIPLEX CORNEA RETINA LIVER, SPLEEN CNS FINDINGS STORED MATERIAL IN URINE WBC/BONE MARROW COMMENT MULTIPLE FORMS MUCOPOLYSACCHARIDOSES (MPS) MPS I (Hurler) α-L-Iduronidase ∼1 yr Yes Cloudy — Both enlarged Profound loss of Acid mucopoly-Alder-Reilly Kyphosis Yes— function saccharide bodies (WBC) Scheie and compounds Metachromatic Arylsulfatase A 1–2 yr No Clear Normal Normal Profound loss of No Normal — Yes leukodystrophy Fabry disease α-Galactosidase A Childhood, No Cloudy by — Liver may be Normal No Normal X-linked No (cerebrosidase) adolescence Wolman disease Acid lipase Neonatal No Clear Normal Both enlarged Profound loss of No Inclusion in — Yes function WBC ML II (I-cell Mannosyl Neonatal Yes Clouding — Liver often Profound loss of Oligosaccharides No Gingival No disease) phosphotransferase


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Pediatrics_Nelson. WBC ML II (I-cell Mannosyl Neonatal Yes Clouding — Liver often Profound loss of Oligosaccharides No Gingival No disease) phosphotransferase Table 56-1 Lysosomal Storage Diseases—cont'd DISEASE (EPONYM) ENZYME DEFICIENCY CLINICAL ONSET DYSOSTOSIS MULTIPLEX CORNEA RETINA LIVER, SPLEEN CNS FINDINGS STORED MATERIAL IN URINE WBC/BONE MARROW COMMENT MULTIPLE FORMS Farber lipogranulo-matosis Acid ceramidase 1st 4 mo No Usually clear Cherry-red spots (12%) May be enlarged Normal or impaired Usually not — Arthritis, nodules Yes MUCOLIPIDOSES (ML) AND CLINICALLY RELATED DISEASE Multiple sulfatase Many sulfatases 1–2 yr Yes Usually Usually Both enlarged Profound loss of Acid mucopoly-Alder-Reilly Ichthyosis Yes deficiency Aspartylglyco-Aspartylglucos-6 mo Mild Clear Normal Early, not late Profound loss of Aspartylgluco-Inclusions in Develop No saminuria aminidase Mannosidosis α-Mannosidase 1st mo Yes Cloudy — Liver enlarged Profound loss of Generally no Inclusions in Cataracts Yes function


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Pediatrics_Nelson. Mannosidosis α-Mannosidase 1st mo Yes Cloudy — Liver enlarged Profound loss of Generally no Inclusions in Cataracts Yes function Fucosidosis α-L-Fucosidase 1st mo Yes Clear May be Both enlarged Profound loss of Oligosaccharides Inclusions in — Yes pigmented commonly function CNS, Central nervous system; WBC, white blood cell.


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Pediatrics_Nelson. CNS, Central nervous system; WBC, white blood cell. foreheads, flat orbital ridges, widely open fontanelles, hepatomegaly, and hypotonia. Other anomalies are common. Failure to thrive, seizures, and nystagmus develop early, and death occurs within the first year. Refsum disease, neonatal adrenoleukodystrophy, and malonic aciduria are examples of peroxisomal single-enzyme disorders. Diagnostic testing includes measurement of very long chain fatty acids in plasma and pipecolic acid in urine. Specific molecular testing, particularly for the disorders involving one in the series of PEX genes, is available for some disorders. Most of these conditions are untreatable; however, bone marrow transplant can be helpful in X-linked adrenoleukodystrophy before the onset of severe symptoms.


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Pediatrics_Nelson. Lysosomes are subcellular organelles that contain degradative enzymes for complex glycosaminoglycans, also called mucopolysaccharides. Glycosaminoglycans are macromolecules that play a number of roles within cells. Genetic disorders result from abnormal formation of the lysosome itself or from deficiency in specific hydrolytic enzymes, in the mechanisms that protect intralysosomal enzymes from hydrolytic destruction, or in the transport of materials into the lysosome and of metabolites out of the lysosome. These materials are stored in cells and ultimately result in their destruction, especially in the nervous system. The clinical disorders are diverse, reflecting tissue specificity of lysosomal function and the intrinsic turnover rates of the compounds whose cycling is affected (Table 56-1). Some disorders affect many tissues but spare the brain. Some are apparent only during adult life. Storage in solid organs results in organomegaly. In many of these disorders, developmental delay,


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Pediatrics_Nelson. Some disorders affect many tissues but spare the brain. Some are apparent only during adult life. Storage in solid organs results in organomegaly. In many of these disorders, developmental delay, corneal clouding, and limitation of joint mobility are common features. Storage in tissues of the upper and lower airways may result in respiratory compromise. Non-immune hydrops fetalis occurs in several lysosomal disorders.


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Pediatrics_Nelson. Diagnostic testing includes measurement of glycosaminoglycans in urine and specific assays for lysosomal enzyme activity in white blood cells. If the urine test is positive, it helps direct specific enzyme measurement. If it is negative, it does not exclude a lysosomal storage disorder, and other testing modalities are needed if clinical signs are convincing. In disorders in which specific mutations are known, molecular testing refines the diagnosis. Specific diagnosis, carrier testing, and evaluation of at-risk family members require one of these approaches. Making a specific diagnosis is assuming increasing importance because specific treatment for some lysosomal disorders is very effective.


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Pediatrics_Nelson. Specific treatment directed at the metabolic abnormality isavailable for some lysosomal disorders. In specific disorders (Gaucher disease) oral medication may be successfulin reducing the accumulation of the metabolite that cannotbe catabolized. For some disorders, bone marrow (stem cell)transplantation can restore lysosomal function. For others, replacement of the missing hydrolytic enzyme by systemic administration of the enzyme allows degradation of stored material. The disorders caused by deficient α-l-iduronidase (Hurler syndrome, Scheie syndrome, and theirvariants) respond to treatment with intravenous humanrecombinant α-l-iduronidase (laronidase). Other disorders for which enzyme therapy is available include MPS VI(Maroteaux-Lamy syndrome), Gaucher disease, Fabry disease, and MPS II (Hunter syndrome). Stem cell transplantation has been helpful or is under investigation in the followingdisorders: MPS type IH (Hurler syndrome), MPS type VI(Maroteaux-Lamy syndrome), MPS type VII


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Pediatrics_Nelson. II (Hunter syndrome). Stem cell transplantation has been helpful or is under investigation in the followingdisorders: MPS type IH (Hurler syndrome), MPS type VI(Maroteaux-Lamy syndrome), MPS type VII (Sly syndrome),Krabbe disease, metachromatic leukodystrophy, alpha-fucosidosis, alpha-mannosidosis, Gaucher disease, and Nie-mann-Pick disease type B. However, treatment for many ofthese conditions is supportive, with careful attention to respiratory status and physical therapy. As a result of the rapidlychanging therapeutic options, geneticists with a special interest in these disorders should be consulted when a diagnosis issuspected. Treatment decisions should be made by the familyin the light of the potential therapeutic benefits and burdensof therapy and typically should be resolved before the onset ofcentral nervous system manifestations, which are typically notimproved by these approaches.


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Pediatrics_Nelson. Mitochondria are very complex organelles located in virtually all cells of the body. They perform a variety of functions such as intracellular signaling of oxygen tension and key roles in programmed cell death. From a biochemical perspective, mitochondria are the key site of energy production in the cell. Indeed they are the site of beta oxidation (see Chapter 55), the Krebs cycle, and parts of the urea cycle (see Figure 53-4). This complexity requires more than 1000 proteins localized specifically to the mitochondrion. Only 13 of these are encoded by the mitochondrial DNA (mtDNA); the remainder are nuclear encoded (on the chromosomes) and require import into the mitochondrion. In addition, the mitochondrial DNA needs its own set of proteins to allow for its maintenance, transcription, and translation.


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Pediatrics_Nelson. Mitochondrial disorders are typically defined as defects in the ability to generate energy from oxidative phosphorylation to produce ATP by transferring electrons formed by glycolysis and the Krebs cycle to a cascade that generates NADH and FADH2 (Fig. 57-1) and are also known as phosphorylation disorders or respiratory chain disorders. The more dependent on energy production an organ is, the more profound the symptoms of deficiency of mitochondrial function in that organ. Certain proteins are only expressed in specific tissues, and defects in these will lead to differing patterns of disease. Taken together, mitochondrial disorders may affect as many as 1 in 2500 people. Figure 57-1 The mammalian mitochondrial genome and its protein-coding gene repertoire involved in the oxidative phosphorylation pathway.


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Pediatrics_Nelson. (A) Schematic representation of genes within mammalian mitochondrial genome (∼7000 bp). Genes on the outer circle are transcribed from the light strand. Location of the tRNAs (red boxes) conforms to the canonical placental mammalian arrangement. (B) Simplified view of the mitochondrial oxidative phosphorylation machinery. Complexes I (NADH dehydrogenase) and II (succinate dehydrogenase) receive electrons from either NADH or FADH2. Electrons are then carried between complexes by the carrier molecules coenzyme Q/ubiquinone (UQ) and cytochrome c (CYC). The potential energy of these electron transfer events is used to pump protons against the gradient, from the mitochondrial matrix into the intermembrane space [complexes I and III (cytochrome bc1) and IV (cytochrome c oxidase)]. ATP synthesis by complex V (ATP synthase) is driven by the proton gradient and occurs in the mitochondrial matrix. HSP, Putative heavy-strand promoter; IM, intermembrane space; MM, mitochondrial matrix; OHR,


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Pediatrics_Nelson. by complex V (ATP synthase) is driven by the proton gradient and occurs in the mitochondrial matrix. HSP, Putative heavy-strand promoter; IM, intermembrane space; MM, mitochondrial matrix; OHR, origin of heavy-strand replication; OLR, origin of light-strand replication. (From da Fonseca RR, Johnson WE, O’Brien SJ, et al: The adaptive evolution of the mammalian mitochondrial genome, BMC Genomics 9:119, 2008.)


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Pediatrics_Nelson. The signs and symptoms of mitochondrial disorders are varied. Symptoms depend on how an organ is affected by energy deficiency. Muscle function that is compromised will result in muscle fatigue and weakness. Myopathy is common and may show ragged red fibers on a muscle biopsy. Rhabdomyolysis can occur. Brain dysfunction may be expressed as seizures, loss of intellectual function, headache, or signs consistent with stroke. Spastic paraplegia may occur. Ataxia and basal ganglia symptoms are features of some disorders. Vision and eye muscle movement may be compromised, with progressive external ophthalmoplegia being almost diagnostic of an oxidative phosphorylation defect. Cardiomyopathy is frequent, and cardiac rhythm disturbances occur. Liver dysfunction may be expressed as both synthetic deficiencies and liver failure. Diabetes may signal pancreatic involvement. Renal tubular abnormalities and renal failure both occur. Gastrointestinal symptoms include both diarrhea and constipation


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Pediatrics_Nelson. deficiencies and liver failure. Diabetes may signal pancreatic involvement. Renal tubular abnormalities and renal failure both occur. Gastrointestinal symptoms include both diarrhea and constipation that are difficult to treat. Alper disease (cerebral degeneration and liver disease) and Leigh disease (subacute necrotizing encephalomyelopathy) show similar brain lesions but in distinctly different areas of the brain. Because the signs and symptoms may involve multiple organs and may seem nonspecific, physicians may not suspect a mitochondrial disorder until significant progression has occurred.


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Pediatrics_Nelson. Defects in the mitochondrial respiratory chain may produce lactic acidosis. Given the complexity of the respiratory chain, it is not surprising that the described defects are varied as to cause, intensity, and tissues affected. The metabolism of glucose to carbon dioxide and water, with pyruvate as an intermediate (Fig. 57-2), occurs as part of the energy cycle in many tissues. Interference with mitochondrial oxidative metabolism may result in the accumulation of pyruvate. Because lactate dehydrogenase is ubiquitous, and because the equilibrium catalyzed by this enzyme greatly favors lactate over pyruvate, the accumulation of pyruvate results in lactic acidosis. The most common cause of such lactic acidosis is oxygen deficiency caused by hypoxia or poor perfusion. Lactic acidosis also occurs when specific reactions of pyruvate are impaired. In the liver, pyruvate undergoes carboxylation to form oxaloacetate using the enzyme pyruvate carboxylase; deficiency in this enzyme causes severe


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Pediatrics_Nelson. when specific reactions of pyruvate are impaired. In the liver, pyruvate undergoes carboxylation to form oxaloacetate using the enzyme pyruvate carboxylase; deficiency in this enzyme causes severe lactic acidosis. In many tissues, lactate is catabolized to form acetyl coenzyme A (CoA) by the pyruvate dehydrogenase complex; deficiency in pyruvate dehydrogenase also can cause lactic acidosis. Because these reactions also play a role in gluconeogenesis, hypoglycemia can be a feature of these disorders. These disorders comprise forms of primary lactic acidosis. They frequently present as intractable, lethal acidosis in the first days or weeks of life and are difficult to treat. Some of the enzymes in this pathway can be measured


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Pediatrics_Nelson. Figure 57-2 Metabolism of pyruvate and lactate. (1) Alanine aminotransferase, (2) lactate dehydrogenase, (3) pyruvate dehydrogenase, (4) pyruvate carboxylase, (5) Krebs cycle, (6) phosphoenolpyruvate carboxykinase, (7) reverse glycolysis. CoA, Coenzyme A. and specific diagnosis can be made. This may require white blood cells or tissue biopsy.


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Pediatrics_Nelson. Mitochondrial function is carried out by proteins that are coded for by both nuclear and mitochondrial genes. These enzymes are extremely complicated, and several are quite large. The mitochondrial genome encodes 13 subunits of the enzymes involved in mitochondrial oxidative phosphorylation. More than 85 autosomal genes code for the rest of the subunits of these enzymes. In children, only about 15% of cases of mitochondrial disease are caused by mutations in mitochondrial DNA (mtDNA); the rest are due to mutations in nuclear genes. The most frequent cases in several large series have been mutations that lead to a reduction in the ability of the mtDNA to maintain itself. Large population studies show carrier rates of about 2% of the population for mutations in polymerase (DNA directed), gamma (POLG), and deoxyguanosine kinase (DGUOK). Most disorders show autosomal recessive inheritance. A few are X linked or passed on by maternal mtDNA mutations, such as mitochondrial encephalopathy


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Pediatrics_Nelson. gamma (POLG), and deoxyguanosine kinase (DGUOK). Most disorders show autosomal recessive inheritance. A few are X linked or passed on by maternal mtDNA mutations, such as mitochondrial encephalopathy with lactic acidosis (MELAS) and mitochondrial encephalopathy with ragged red fibers (MERRF), or deletions such as maternally inherited diabetes and deafness (MIDD).


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Pediatrics_Nelson. Repairing the basic energy deficit and getting the appropriate drugs and cofactors to the appropriate location within the mitochondrion are difficult. Nevertheless, a number of strategies are used, including judicious physical therapy and exercise with adequate rest, adequate nutrition, and cofactors for the deficient pathway. Specific treatment is limited for most mitochondrial defects. Vitamin cofactors for the respiratory chain, such as riboflavin and pharmaceutical forms of coenzyme Q, are often used. When a single organ bears most of the damage, organ transplant may be effective. Identification of family members at risk may allow earlier diagnosis and treatment. The author would like to acknowledge Dr. Margretta R. Seashore for her superb work in the last edition. Hers was an excellent analysis of the topic and has informed much of the present discussion.


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Pediatrics_Nelson. The author would like to acknowledge Dr. Margretta R. Seashore for her superb work in the last edition. Hers was an excellent analysis of the topic and has informed much of the present discussion. de Baulny HO, Benoist JF, Rigal O, et al: Methylmalonic and propionic acidaemias: management and outcome, J Inherit Metab Dis 28(3):415–423, Heese BA: Current strategies in the management of lysosomal storage dis eases, Semin Pediatr Neurol 15(3):119–126, 2008 Kayser MA: Inherited metabolic diseases in neurodevelopmental and neuro behavioral disorders, Semin Pediatr Neurol 15(3):127–131, 2008 Kliegman RM, Stanton BF, St. Geme JW, et al: Nelson Textbook of Pediatrics, ed 19, Philadelphia, 2011, Elsevier Science Koeberl DD, Kishnani PS, Chen YT: Glycogen storage disease types I and II: treatment updates, J Inherit Metab Dis 30(2):159–164, 2007 Kompare M, Rizzo WB: Mitochondrial fatty-acid oxidation disorders, Semin Pediatr Neurol 15(3):140–149, 2008


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Pediatrics_Nelson. Kompare M, Rizzo WB: Mitochondrial fatty-acid oxidation disorders, Semin Pediatr Neurol 15(3):140–149, 2008 Tuchman M, Lee B, Lichter-Konecki U, et al: Cross-sectional multicenter study of patients with urea cycle disorders in the United States, Mol Genet Metab 94(4):397–402, 2008 Clarence W. Gowen, Jr. ASSESSMENT OF THE MOTHER, FETUS, AND NEWBORN


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Pediatrics_Nelson. Pregnancies associated with perinatal morbidity or mortality are considered high risk. Identification of high-risk pregnancies is essential to the care of the infant because they may result in intrauterine fetal death, intrauterine growth restriction (IUGR), congenital anomalies, excessive fetal growth, birth asphyxia and trauma, prematurity (birth at <38 weeks) or postmaturity (birth at ≥42 weeks), neonatal disease, or longterm risks of cerebral palsy, mental retardation, and chronic sequelae of neonatal intensive care. Ten percent to 20% of women may be high risk at some time during their pregnancy. Although some obstetric complications are first seen during labor and delivery and cannot be predicted, more than 50% of perinatal mortality and morbidity results from problems identified before delivery as high risk. After a high-risk pregnancy is identified, measures can be instituted to prevent complications, provide intensive fetal surveillance, and initiate appropriate treatments of


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Pediatrics_Nelson. delivery as high risk. After a high-risk pregnancy is identified, measures can be instituted to prevent complications, provide intensive fetal surveillance, and initiate appropriate treatments of the mother and fetus.


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Pediatrics_Nelson. A history of previous premature birth, intrauterine fetal death, multiple gestation, IUGR, congenital malformation, explained or unexplained neonatal death (e.g., group B streptococcal sepsis), birth trauma, preeclampsia, gestational diabetes, grand multipara status (five or more pregnancies), or cesarean section is associated with additional risk in subsequent pregnancies.


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Pediatrics_Nelson. Pregnancy complications that increase the risk of a poor outcome can be secondary to maternal or fetal causes or both. Complications include placenta previa; abruptio placentae; preeclampsia; diabetes; oligohydramnios or polyhydramnios; multiple gestation; blood group sensitization; abnormal levels of unconjugated estriols, chorionic gonadotropin, or alpha-fetoprotein; abnormal fetal ultrasound; hydrops fetalis; maternal trauma or surgery; abnormal fetal presentation (breech); exposure to prescribed or illicit drugs; prolonged labor; cephalopelvic disproportion; prolapsed cord; fetal distress; prolonged or premature rupture of membranes; short cervical length (<25 mm) and the presence of fetal fibronectin in cervical secretions at less than 35 weeks’ gestation (a predictor of preterm labor); cervical infections and vaginosis; and congenital infections, including rubella, cytomegalovirus, herpes simplex, human immunodeficiency virus (HIV), toxoplasmosis, syphilis, and gonorrhea.


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Pediatrics_Nelson. Maternal medical complications associated with increased risk of maternal and fetal morbidity and mortality include diabetes, chronic hypertension, congenital heart disease (especially with right-to-left shunting and Eisenmenger complex), glomerulonephritis, collagen vascular disease (especially systemic lupus erythematosus with or without antiphospholipid antibodies), lung disease (cystic fibrosis), severe anemia (sickle cell anemia), hyperthyroidism, myasthenia gravis, idiopathic thrombocytopenic purpura, inborn errors of metabolism (maternal phenylketonuria), and malignancy.


Pediatrics_Nelson

Pediatrics_Nelson. Obstetric complications often are associated with increased fetal or neonatal risk. Vaginal bleeding in the first trimester or early second trimester may be caused by a threatened or actual spontaneous abortion and is associated with increased risk of congenital malformations or chromosomal disorders. Painless vaginal bleeding that is not associated with labor and occurs in the late second or (more likely) third trimester often is the result of placenta previa. Bleeding develops when the placental mass overlies the internal cervical os; this may produce maternal hemorrhagic shock, necessitating transfusions. Bleeding also may result in premature delivery. Painful vaginal bleeding is often the result of retroplacental hemorrhage or placental abruption. Associated findings may be advanced maternal age and parity, maternal chronic hypertension, maternal cocaine use, preterm rupture of membranes, polyhydramnios, twin gestation, and preeclampsia. Fetal asphyxia ensues as the retroplacental


Pediatrics_Nelson

Pediatrics_Nelson. age and parity, maternal chronic hypertension, maternal cocaine use, preterm rupture of membranes, polyhydramnios, twin gestation, and preeclampsia. Fetal asphyxia ensues as the retroplacental hematoma causes placental separation that interferes with fetal oxygenation. Both types of bleeding are associated with fetal blood loss. Neonatal anemia may be more common with placenta previa.


Pediatrics_Nelson

Pediatrics_Nelson. Abnormalities in the volume of amniotic fluid, resulting in oligohydramnios or polyhydramnios, are associated with increased fetal and neonatal risk. Oligohydramnios (amniotic ultrasound fluid index ≤2 cm) is associated with IUGR and major congenital anomalies, particularly of the fetal kidneys, and with chromosomal syndromes. Bilateral renal agenesis results in diminished production of amniotic fluid and a specific deformation syndrome (Potter syndrome), which includes clubfeet, characteristic compressed facies, low-set ears, scaphoid abdomen, and diminished chest wall size accompanied by pulmonary hypoplasia and, often, pneumothorax. Uterine compression in the absence of amniotic fluid retards lung growth, and patients with this condition die of respiratory failure rather than renal insufficiency. Twin-to-twin transfusion syndrome (donor) and complications from amniotic fluid leakage also are associated with oligohydramnios. Oligohydramnios increases the risk of fetal distress


Pediatrics_Nelson

Pediatrics_Nelson. insufficiency. Twin-to-twin transfusion syndrome (donor) and complications from amniotic fluid leakage also are associated with oligohydramnios. Oligohydramnios increases the risk of fetal distress during labor (meconium-stained fluid and variable decelerations); the risk may be reduced by saline amnioinfusion during labor.


Pediatrics_Nelson

Pediatrics_Nelson. Polyhydramnios may be acute and associated with premature labor, maternal discomfort, and respiratory compromise. More often, polyhydramnios is chronic and is associated with diabetes, immune or nonimmune hydrops fetalis, multiple gestation, trisomy 18 or 21, and major congenital anomalies. Anencephaly, hydrocephaly, and meningomyelocele are associated with reduced fetal swallowing of amniotic fluid. Esophageal and duodenal atresia as well as cleft palate interfere with swallowing and gastrointestinal fluid dynamics. Additional causes of polyhydramnios include Werdnig-Hoffmann and Beckwith-Wiedemann syndromes, conjoined twins, chylothorax, cystic adenomatoid lung malformation, diaphragmatic hernia, gastroschisis, sacral teratoma, placental chorioangioma, and myotonic dystrophy. Hydrops fetalis may be a result of Rh or other blood group incompatibilities and anemia caused by intrauterine hemolysis of fetal erythrocytes by maternal IgG-sensitized antibodies crossing the placenta.


Pediatrics_Nelson

Pediatrics_Nelson. fetalis may be a result of Rh or other blood group incompatibilities and anemia caused by intrauterine hemolysis of fetal erythrocytes by maternal IgG-sensitized antibodies crossing the placenta. Hydrops is characterized by fetal edema, ascites, hypoalbuminemia, and congestive heart failure. Causes of nonimmune hydrops include fetal arrhythmias (supraventricular tachycardia, congenital heart block), fetal anemia (bone marrow suppression, nonimmune hemolysis, or twin-to-twin transfusion), severe congenital malformation, intrauterine infections, congenital neuroblastoma, inborn errors of metabolism (storage diseases), fetal hepatitis, nephrotic syndrome, and pulmonary lymphangiectasia. Twin-to-twin transfusion syndrome (recipient) also may be associated with polyhydramnios. Polyhydramnios is often the result of unknown causes. If severe, polyhydramnios may be managed with bed rest, indomethacin, or serial amniocenteses.


Pediatrics_Nelson

Pediatrics_Nelson. Premature rupture of the membranes, which occurs in the absence of labor, and prolonged rupture of the membranes(>24 hours) are associated with an increased risk of maternal or fetal infection (chorioamnionitis) and preterm birth. In the immediate newborn period, group B streptococcus and Escherichia coli are the two most common pathogens associated with sepsis. Listeria monocytogenes is a less common cause. Mycoplasma hominis, Ureaplasma urealyticum, Chlamydia trachomatis, and anaerobic bacteria of the vaginal flora also have been implicated in infection of the amniotic fluid. Infection with community-acquired methicillin-resistant Staphylococcus aureus must be considered for infants with skin infections or with known exposures. The risk of serious fetal infection increases as the duration between rupture and labor (latent period) increases, especially if the period is greater than 24 hours. Intrapartum antibiotic therapy decreases the risk of neonatal sepsis.


Pediatrics_Nelson

Pediatrics_Nelson. Multiple gestations are associated with increased risk resulting from polyhydramnios, premature birth, IUGR, abnormal presentation (breech), congenital anomalies (intestinal atresia, porencephaly, and single umbilical artery), intrauterine fetal demise, birth asphyxia, and twin-to-twin transfusion syndrome. Twin-to-twin transfusion syndrome is associated with a high mortality and is seen only in monozygotic twins who share a common placenta and have an arteriovenous connection between their circulations. The fetus on the arterial side of the shunt serves as the blood donor, resulting in fetal anemia, growth retardation, and oligohydramnios for this fetus. The recipient, or venous-side twin, is larger or discordant in size, is plethoric and polycythemic, and may show polyhydramnios. Weight differences of 20% and hemoglobin differences of 5 g/dL suggest the diagnosis. Ultrasonography in the second trimester reveals discordant amniotic fluid volume with oliguria/oligohydramnios and


Pediatrics_Nelson

Pediatrics_Nelson. differences of 20% and hemoglobin differences of 5 g/dL suggest the diagnosis. Ultrasonography in the second trimester reveals discordant amniotic fluid volume with oliguria/oligohydramnios and hypervolemia/polyuria/polyhydramnios with a distended bladder, with or without hydrops and heart failure. Treatment includes amniocentesis and attempts to ablate the arteriovenous connection (using a laser). The birth order of twins also affects morbidity by increasing the risk of the second-born twin for breech position, birth asphyxia, birth trauma, and respiratory distress syndrome.


Pediatrics_Nelson

Pediatrics_Nelson. Overall, twinning is observed in 1 of 80 pregnancies; 80% of all twin gestations are dizygotic twins. The diagnosis of the type of twins can be determined by placentation, sex, fetal membrane structure, and, if necessary, tissue and blood group typing or DNA analysis. Toxemia of pregnancy, or preeclampsia/eclampsia, is a disorder of unknown but probably vascular etiology that may lead to maternal hypertension, uteroplacental insufficiency, IUGR, intrauterine asphyxia, maternal seizures, and maternal death. Toxemia is more common in nulliparous women and in women with twin gestation, chronic hypertension, obesity, renal disease, positive family history of toxemia, or diabetes mellitus. A subcategory of preeclampsia, the HELLP syndrome (hemolysis, elevated liver enzyme levels, low platelets), is more severe and is often associated with a fetal inborn error of fatty acid oxidation (long-chain hydroxyacyl–coenzyme A dehydrogenase of the trifunctional protein complex).


Pediatrics_Nelson

Pediatrics_Nelson. The late fetal–early neonatal period has the highest mortality rate of any age interval. Perinatal mortality refers to fetal deaths occurring from the 20th week of gestation until the 28th day after birth and is expressed as number of deaths per 1000 live births. Intrauterine fetal death accounts for 40% to 50% of the perinatal mortality rate. Such infants, defined as stillborn, are born without a heart rate and are apneic, limp, pale, and cyanotic. Many stillborn infants exhibit evidence of maceration; pale, peeling skin; corneal opacification; and softcranial contents.


Pediatrics_Nelson

Pediatrics_Nelson. Mortality rates around the time of birth are expressed as number of deaths per 1000 live births. The neonatal mortality rate includes all infants dying during the period from after birth to the first 28 days of life. Modern neonatal intensive care allows many newborns with life-threatening diseases to survive the neonatal period, only to die of their original diseases or of complications of therapy after 28 days of life. This delayed mortality and mortality caused by acquired illnesses occur during the postneonatal period, which begins after 28 days of life and extends to the end of the first year of life. The infant mortality rate encompasses the neonatal and the postneonatal periods. In the United States, it declined to 6.15:1000 in 2010. The rate for African American infants was approximately 11.6:1000. The most common causes of


Pediatrics_Nelson

Pediatrics_Nelson. Abruptio placentae Chromosomal anomalies Congenital malformations (heart, CNS, renal) Hydrops fetalis Intrauterine asphyxia* Intrauterine infection* Maternal underlying disease (chronic hypertension, autoimmune disease, diabetes mellitus) Multiple gestation* Placental insufficiency* Umbilical cord accident CNS, Central nervous system. *Common. perinatal and neonatal death are listed in Table 58-1. Overall, congenital anomalies and diseases of the premature infant are the most significant causes of neonatal mortality. Low birth weight (LBW) infants, defined as infants having birth weights of less than 2500 g, represent a disproportionately large component of the neonatal and infant mortality rates. Although LBW infants make up only about 6% to 7% of all births, they account for more than 70% of neonatal deaths. IUGR is the most common cause of LBW in developing countries, whereas prematurity is the cause in developed countries.


Pediatrics_Nelson

Pediatrics_Nelson. Very low birth weight (VLBW) infants, weighing less than 1500 g at birth, represent about 1% of all births but account for 50% of neonatal deaths. Compared with infants weighing 2500 g or more, LBW infants are 40 times more likely to die in the neonatal period; VLBW infants have a 200-fold higher risk of neonatal death. The LBW rate has not improved in recent years and is one of the major reasons that the U.S. infant mortality rate is high compared with other large, modern, industrialized countries.


Pediatrics_Nelson

Pediatrics_Nelson. Maternal factors associated with a LBW caused by premature birth or IUGR include a previous LBW birth, low socioeconomic status, low level of maternal education, no antenatal care, maternal age younger than 16 years or older than 35 years, short interval between pregnancies, cigarette smoking, alcohol and illicit drug use, physical (excessive standing or walking) or psychological (poor social support) stresses, unmarried status, low pre-pregnancy weight (<45 kg), poor weight gain during pregnancy (<10 lb), and African American race. LBW and VLBW rates for African American women are twice the rates for white women. The neonatal and infant mortality rates are nearly twofold higher among African American infants. These racial differences are only partly explained by poverty.


Pediatrics_Nelson

Pediatrics_Nelson. Fetal size can be determined accurately by ultrasound techniques. Fetal growth can be assessed by determining the fundal height of the uterus through bimanual examination of the gravid abdomen. Ultrasound measurements of the fetal biparietal diameter, femur length, and abdominal circumference are used to estimate fetal growth. A combination of these measurements predicts fetal weight. Deviations from the normal fetal growth curve are associated with high-risk conditions.


Pediatrics_Nelson

Pediatrics_Nelson. IUGR is present when fetal growth stops and, over time, declines to less than the 5th percentile of growth for gestational age or when growth proceeds slowly, but absolute size remains less than the 5th percentile. Growth restriction may result from fetal conditions that reduce the innate growth potential, such as fetal rubella infection, primordial dwarfing syndromes, chromosomal abnormalities, and congenital malformation syndromes. Reduced fetal production of insulin and insulin-like growth factor I is associated with fetal growth restriction. Placental causes of IUGR include villitis (congenital infections), placental tumors, chronic abruptio placentae, twin-to-twin transfusion syndrome, and placental insufficiency. Maternal causes include severe peripheral vascular diseases that reduce uterine blood flow (chronic hypertension, diabetic vasculopathy, and preeclampsia/eclampsia), reduced nutritional intake, alcohol or drug abuse, cigarette smoking, and uterine constraint (noted


Pediatrics_Nelson

Pediatrics_Nelson. uterine blood flow (chronic hypertension, diabetic vasculopathy, and preeclampsia/eclampsia), reduced nutritional intake, alcohol or drug abuse, cigarette smoking, and uterine constraint (noted predominantly in mothers of small stature with a low prepregnancy weight) and reduced weight gain during pregnancy. The outcome of IUGR depends on the cause of the reduced fetal growth and the associated complications after birth (Table 58-2). Fetuses subjected to chronic intrauterine hypoxia as a result of uteroplacental insufficiency are at an increased risk for the comorbidities of birth asphyxia, polycythemia, and hypoglycemia. Fetuses with reduced tissue mass due to chromosomal, metabolic, or multiple congenital anomaly syndromes have poor outcomes based on the prognosis for the particular syndrome. Fetuses born to small mothers and fetuses with poor nutritional intake usually show catch-up growth after birth.


Pediatrics_Nelson

Pediatrics_Nelson. Fetal size does not always correlate with functional or structural maturity. Determining fetal maturity is crucial when making a decision to deliver a fetus because of fetal or maternal disease. Fetal gestational age may be determined accurately on the basis of a correct estimate of the last menstrual period. Clinically relevant landmark dates can be used to determine gestational age; the first audible heart tones by fetoscope are detected at 18 to 20 weeks (12 to 14 weeks by Doppler methods), and quickening of fetal movements usually is perceived at 18 to 20 weeks. However, it is not always Intrauterine fetal Placental insufficiency, hypoxia, acidosis, demise infection, lethal anomaly Temperature Cold stress, ↓ fat stores, hypoxia, instability hypoglycemia Perinatal asphyxia ↓ Uteroplacental perfusion during labor with or without chronic fetal hypoxia-acidosis, meconium aspiration syndrome


Pediatrics_Nelson

Pediatrics_Nelson. Perinatal asphyxia ↓ Uteroplacental perfusion during labor with or without chronic fetal hypoxia-acidosis, meconium aspiration syndrome Hypoglycemia ↓ Tissue glycogen stores; ↓ gluconeogenesis, hyperinsulinism, ↑ glucose needs of hypoxia, hypothermia, relatively large brain Polycythemia-Fetal hypoxia with ↑ erythropoietin production hyperviscosity Reduced oxygen Hypoxia, hypoglycemia, starvation effect, poor consumption/ subcutaneous fat stores hypothermia Dysmorphology Syndrome anomalads, chromosomal-genetic disorders, oligohydramnios-induced deformations Pulmonary Hypothermia, polycythemia, hypoxia hemorrhage Modified from Carlo WA: The high-risk infant. In Kliegman RM, Stanton BF, St. Geme JW, et al, editors: Nelson Textbook of Pediatrics, ed 19, Philadelphia, 2011, Elsevier Science. *Other problems are common to the gestational age–related risks of prematurity if born before 37 weeks.


Pediatrics_Nelson

Pediatrics_Nelson. *Other problems are common to the gestational age–related risks of prematurity if born before 37 weeks. possible to determine fetal maturity by such dating, especially in a high-risk situation, such as preterm labor or a diabetic pregnancy. Surfactant, a combination of surface-active phospholipids and proteins, is produced by the maturing fetal lung and eventually is secreted into the amniotic fluid. The amount of surfactant in amniotic fluid is a direct reflection of surface-active material in the fetal lung and can be used to predict the presence or absence of pulmonary maturity. Because phosphatidylcholine, or lecithin, is a principal component of surfactant, the determination of lecithin in amniotic fluid is used to predict a mature fetus. Lecithin concentration increases with increasing gestational age, beginning at 32 to 34 weeks.


Pediatrics_Nelson

Pediatrics_Nelson. Methods used to assess fetal well-being before the onset of labor are focused on identifying a fetus at risk for asphyxia or a fetus already compromised by uteroplacental insufficiency. The oxytocin challenge test simulates uterine contractions through an infusion of oxytocin sufficient to produce three contractions in a 10-minute period. The development of periodic fetal bradycardia out of phase with uterine contractions (late deceleration) is a positive test result and predicts an at-risk fetus.


Pediatrics_Nelson

Pediatrics_Nelson. The nonstress test examines the heart rate response to fetal body movements. Heart rate increases of more than 15 beats/min lasting 15 seconds, are reassuring. If two such episodes occur in 30 minutes, the test result is considered reactive (versus nonreactive), and the fetus is not at risk. Additional signs of fetal well-being are fetal breathing movements, gross body movements, fetal tone, and the presence of amniotic fluid pockets more than 2 cm in size, detected by ultrasound. The biophysical profile combines the nonstress test with these four parameters and offers the most accurate fetal assessment.


Pediatrics_Nelson

Pediatrics_Nelson. Doppler examination of the fetal aorta or umbilical arteries permits identification of decreased or reversed diastolic blood flow associated with increased peripheral vascular resistance, fetal hypoxia with acidosis, and placental insufficiency. Cordocentesis (percutaneous umbilical blood sampling) can provide fetal blood for Po2, pH, lactate, and hemoglobin measurements to identify a hypoxic, acidotic, or anemic fetus who is at risk for intrauterine fetal demise or birth asphyxia. Cordocentesis also can be used to determine fetal blood type, platelet count, microbial testing, antibody titer, and rapid karyotype.


Pediatrics_Nelson

Pediatrics_Nelson. In a high-risk pregnancy, the fetal heart rate should be monitored continuously during labor, as should uterine contractions.Fetal heart rate abnormalities may indicate baseline tachycardia (>160 beats/min as a result of anemia, β-sympathomimeticdrugs, maternal fever, hyperthyroidism, arrhythmia, or fetal distress), baseline bradycardia (<120 beats/min as a result of fetaldistress, complete heart block, or local anesthetics), or reducedbeat-to-beat variability (flattened tracing resulting from fetalsleep, tachycardia, atropine, sedatives, prematurity, or fetaldistress). Periodic changes of the heart rate relative to uterinepressure help determine the presence of hypoxia and acidosiscaused by uteroplacental insufficiency or maternal hypotension(late or type II decelerations) or by umbilical cord compression(variable decelerations). In the presence of severe decelerations (late or repeated prolonged variable), a fetal scalp bloodgas level should be obtained to assess fetal acidosis. A


Pediatrics_Nelson

Pediatrics_Nelson. cord compression(variable decelerations). In the presence of severe decelerations (late or repeated prolonged variable), a fetal scalp bloodgas level should be obtained to assess fetal acidosis. A scalppH of less than 7.20 indicates fetal hypoxic compromise. A pHbetween 7.20 and 7.25 is in a borderline zone and warrants repeat testing.


Pediatrics_Nelson

Pediatrics_Nelson. Fetal anomalies may be detected by ultrasonography. Emphasis should be placed on visualization of the genitourinary tract; the head (for anencephaly or hydrocephaly), neck (for thickened nuchal translucency), and back (for spina bifida); skeleton; gastrointestinal tract; and heart. Four-chamber and great artery views are required for detection of heart anomalies. Chromosomal anomaly syndromes are often associated with an abnormal “triple test” (low estriols, low maternal serum alpha-fetoprotein levels, and elevated placental chorionic gonadotropin levels). If a fetal abnormality is detected, fetal therapy or delivery with therapy in the neonatal intensive care unit may be lifesaving.


Pediatrics_Nelson

Pediatrics_Nelson. The approach to the birth of an infant requires a detailed history (Table 58-3). Knowing the mother’s risk factors enables the delivery room team to anticipate problems that may occur after birth. The history of a woman’s labor and delivery can reveal events that might lead to complications affecting either the mother or the neonate, even when the pregnancy was previously considered low risk. Anticipating the need to resuscitate a newborn as a result of fetal distress increases the likelihood of successful resuscitation.


Pediatrics_Nelson

Pediatrics_Nelson. The transition from fetal to neonatal physiology occurs at birth. Oxygen transport across the placenta results in a gradient between the maternal and fetal Pao2. Although fetal oxygenated blood has a low Pao2 level compared with that of adults and infants, the fetus is not anaerobic. Fetal oxygen uptake and consumption are similar to neonatal rates, even though the thermal environments and activity levels of fetuses and neonates differ. The oxygen content of fetal blood Age Race Sexually transmitted infections, hepatitis, AIDS Illicit drugs, cigarettes, ethanol, cocaine Immune status (syphilis, rubella, hepatitis B, HIV, blood group) Occupational exposure Chronic hypertension Heart disease Diabetes mellitus Thyroid disorders Hematologic/malignancy Collagen-vascular disease (SLE) Genetic history—inborn errors of metabolism, bleeding, jaundice Drug therapy Current gestational age Method of assessing gestational age


Pediatrics_Nelson

Pediatrics_Nelson. Current gestational age Method of assessing gestational age Fetal surveillance (OCT, NST, biophysical profile) Ultrasonography (anomalies, hydrops) Amniotic fluid analysis (L/S ratio) Oligohydramnios-polyhydramnios Vaginal bleeding Preterm labor Premature (prolonged) rupture of membranes (duration) Preeclampsia Urinary tract infection Colonization status (herpes simplex, group B streptococcus) Medications/drugs Acute medical illness/exposure to infectious agents Fetal therapy Duration of labor Presentation—vertex, breech Vaginal versus cesarean section Spontaneous labor versus augmented or induced with oxytocin (Pitocin) Forceps delivery Presence of meconium-stained fluid Maternal fever/amnionitis Fetal heart rate patterns (distress) Scalp pH Maternal analgesia, anesthesia Nuchal cord Apgar score/methods of resuscitation Gestational age assessment Growth status (AGA, LGA, SGA)


Pediatrics_Nelson

Pediatrics_Nelson. AGA, Average for gestational age; AIDS, acquired immunodeficiency syndrome; LGA, large for gestational age; L/S, lecithin-to-sphingomyelin ratio; NST, nonstress test; OCT, oxytocin challenge test; SGA, small for gestational age; SLE, systemic lupus erythematosus. is almost equal to the oxygen content in older infants and children because fetal blood has a much higher concentration of hemoglobin.


Pediatrics_Nelson

Pediatrics_Nelson. Fetal hemoglobin (two alpha and two gamma chains) has a higher affinity for oxygen than adult hemoglobin, facilitating oxygen transfer across the placenta. The fetal hemoglobin-oxygen dissociation curve is shifted to the left of the adult curve (Fig. 58-1); at the same Pao2 level, fetal hemoglobin is more saturated than adult hemoglobin. Because fetal hemoglobin functions on the steep, lower end of the oxygen saturation curve (Pao2, 20 to 30 mm Hg), however, oxygen unloading to the tissue is not deficient. In contrast, at the higher oxygen concentrations present in the placenta, oxygen loading is enhanced. In the last trimester, fetal hemoglobin production begins to decrease as adult hemoglobin production begins to increase, becoming the only hemoglobin available to the infant by 3 to 6 months of life. At this time, the fetal hemoglobin dissociation curve has shifted to the adult position.


Pediatrics_Nelson

Pediatrics_Nelson. A portion of well-oxygenated umbilical venous blood returning to the heart from the placenta perfuses the liver. The remainder bypasses the liver through a shunt (the ductus venosus) andenters the inferior vena cava. This oxygenated blood in the venacava constitutes 65% to 70% of venous return to the right atrium.The crista dividens in the right atrium directs one third of thisblood across the patent foramen ovale to the left atrium, whereit subsequently is pumped to the coronary, cerebral, and upperextremity circulations by the left ventricle. Venous return from the upper body combines with the remaining two thirds of thevena caval blood in the right atrium and is directed to the rightventricle. This mixture of venous low-oxygenated blood fromthe upper and lower body enters the pulmonary artery. Only 8%to 10% of it is pumped to the pulmonary circuit; the remaining80% to 92% of the right ventricular output bypasses the lungsthrough a patent ductus arteriosus and enters the


Pediatrics_Nelson

Pediatrics_Nelson. pulmonary artery. Only 8%to 10% of it is pumped to the pulmonary circuit; the remaining80% to 92% of the right ventricular output bypasses the lungsthrough a patent ductus arteriosus and enters the descendingaorta. The amount of blood flowing to the pulmonary systemis low because vasoconstriction produced by medial muscle


Pediatrics_Nelson

Pediatrics_Nelson. Figure 58-1 Hemoglobin-oxygen dissociation curves. The position of the adult curve depends on the binding of adult hemoglobin to 2,3-diphosphoglycerate (DPG), temperature, PCO2, and hydrogen ion concentration (pH). hypertrophy of the pulmonary arterioles and fluid in the fetallung increases resistance to blood flow. Pulmonary artery tonealso responds to hypoxia, hypercapnia, and acidosis with vasoconstriction, a response that may increase pulmonary vascularresistance further. The ductus arteriosus remains patent in thefetus because of low Pao2 levels and dilating prostaglandins. Inutero, the right ventricle is the dominant ventricle, pumping65% of the combined ventricular output, which is a high volume (450 mL/kg/min) compared with that pumped by an olderinfant’s right ventricle (200 mL/kg/min).


Pediatrics_Nelson

Pediatrics_Nelson. The transition of the circulation, occurring between the fetal and neonatal periods, involves the removal of the low-resistance circulation of the placenta, the onset of breathing, reduction of pulmonary arterial resistance, and closure of in utero shunts. Clamping the umbilical cord eliminates the low-pressure system of the placenta and increases systemic blood pressure. Decreased venous return from the placenta decreases right atrial pressure. As breathing begins, air replaces lung fluid, maintaining the functional residual capacity. Fluid leaves the lung, in part, through the trachea; it is either swallowed or squeezed out during vaginal delivery. The pulmonary lymphatic and venous systems reabsorb the remaining fluid.


Pediatrics_Nelson

Pediatrics_Nelson. Most normal infants require little pressure to spontaneously open the lungs after birth (5 to 10 cm H2O). With the onset of breathing, pulmonary vascular resistance decreases, partly a result of the mechanics of breathing and partly a result of the elevated arterial oxygen tensions. The increased blood flow to the lungs increases the volume of pulmonary venous blood returning to the left atrium; left atrial pressure now exceeds right atrial pressure, and the foramen ovale closes. As the flow through the pulmonary circulation increases and arterial oxygen tensions rise, the ductus arteriosus begins to constrict. In a term infant, this constriction functionally closes the ductus arteriosus within 1 day after birth. A permanent closure requires thrombosis and fibrosis, a process that may take several weeks. In a premature infant, the ductus arteriosus is less sensitive to the effects of oxygen; if circulating levels of vasodilating prostaglandins are elevated, the ductus arteriosus may


Pediatrics_Nelson

Pediatrics_Nelson. several weeks. In a premature infant, the ductus arteriosus is less sensitive to the effects of oxygen; if circulating levels of vasodilating prostaglandins are elevated, the ductus arteriosus may remain patent. This patency is a common problem in a premature infant with respiratory distress syndrome.


Pediatrics_Nelson

Pediatrics_Nelson. Ventilation, oxygenation, and normal pH and Pco2 levels immediately reduce pulmonary artery vasoconstriction bycausing smooth muscle relaxation. Remodeling of the medialmuscle hypertrophy begins at birth and continues for thenext 3 months, resulting in a further reduction of pulmonary vascular resistance and a further increase of pulmonaryblood flow. Persistence or aggravation of pulmonary vasoconstriction caused by acidosis, hypoxia, hypercapnia, hypothermia, polycythemia, asphyxia, shunting of blood from thelungs, or pulmonary parenchymal hypoplasia results in persistent pulmonary hypertension of the newborn (PPHN). Failure to replace pulmonary alveolar fluid completely withair can lead to respiratory distress (transient tachypnea of the newborn).


Pediatrics_Nelson

Pediatrics_Nelson. Silver nitrate (1%) instilled into both eyes without being washed out is an indicated effective therapy for the prevention of neonatal gonococcal ophthalmia, which can result in severe panophthalmitis and subsequent blindness. Silver nitrate may produce a chemical conjunctivitis with a mucopurulent discharge and is not effective against C. trachomatis. Many hospitals use erythromycin drops to prevent neonatal gonococcal and chlamydial eye disease.


Pediatrics_Nelson

Pediatrics_Nelson. Bacterial colonization of a newborn may begin in utero if the fetal membranes have been ruptured. Most infants undergo colonization after birth and acquire the bacteria present in the mother’s genitourinary system, such as group B streptococci, staphylococci, E. coli, and clostridia. Antiseptic skin or cord care is routine in most nurseries to prevent the spread of pathologic bacteria from one infant to another and to prevent disease in the individual infant. Staphylococcal bullous impetigo, omphalitis, diarrhea, and systemic disease may result from colonization with virulent S. aureus. Triple antibiotic ointment (polymyxin B, neomycin, and bacitracin) or bacitracin may be applied to the umbilical cord to reduce its colonization with gram-positive bacteria. Epidemics of S. aureus nursery infections are managed with strict infectious disease control measures (cohorting, hand washing, and monitoring for colonization).


Pediatrics_Nelson

Pediatrics_Nelson. S. aureus nursery infections are managed with strict infectious disease control measures (cohorting, hand washing, and monitoring for colonization). Vitamin K prophylaxis (intramuscular) should be given to all infants to prevent hemorrhagic disease of the newborn. Before discharge, infants should receive the hepatitis B vaccine and be screened for various diseases (Tables 58-4 and 58-5).


Pediatrics_Nelson

Pediatrics_Nelson. Fetal or neonatal hypoxia, hypercapnia, poor cardiac output, and a metabolic acidosis can result from numerous conditions affecting the fetus, the placenta, or the mother. Whetherin utero or after birth, asphyxia-caused hypoxic-ischemic brain injury is the result of reduced gaseous exchange through the placenta or through the lungs. Asphyxia associated with severe bradycardia or cardiac insufficiency reduces or eliminates tissue blood flow, resulting in ischemia. The fetaland neonatal circulatory systems respond to reduced oxygenavailability by shunting the blood preferentially to the brain,heart, and adrenal glands and away from the intestine, kidneys, lungs, and skin. Beta-ketothiolase deficiency (mitochondrial acetoacetyl CoA thiolase deficiency) BKT C5:1/C5OH Cobalamin defects A, B CBL (A,B) C3 Long-chain hydroxyacyl-CoA dehydrogenase deficiency* LCHAD/D C16OH/C18:1OH Trifunctional protein deficiency* TFP C16OH/C18:1OH


Pediatrics_Nelson

Pediatrics_Nelson. Cobalamin defects A, B CBL (A,B) C3 Long-chain hydroxyacyl-CoA dehydrogenase deficiency* LCHAD/D C16OH/C18:1OH Trifunctional protein deficiency* TFP C16OH/C18:1OH Very long chain acyl-CoA dehydrogenase deficiency VLCAD/D C14:1/C14 Galactosemia* GALT Total galactose, GALT activity Congenital hypothyroidism CH T4, TSH HEMOGLOBIN DISORDERS From Sahai I, Levy H: Newborn screening. In Gleason C, Devasker D editors: Avery’s diseases of the newborn, ed 9, Philadelphia, 2012, Saunders. *Can manifest acutely in the first week of life.


Pediatrics_Nelson

Pediatrics_Nelson. From Sahai I, Levy H: Newborn screening. In Gleason C, Devasker D editors: Avery’s diseases of the newborn, ed 9, Philadelphia, 2012, Saunders. *Can manifest acutely in the first week of life. Metabolic acidosis during asphyxia is caused by the combined that interfere with uteroplacental perfusion (chronic hyper-effects of poor cardiac output secondary to hypoxic depression tension, preeclampsia, and diabetes mellitus) place the fetus of myocardial function, systemic hypoxia, and tissue anaerobic at risk for intrauterine asphyxia. Maternal epidural anesthesia metabolism. With severe or prolonged intrauterine or neonatal and the development of the vena caval compression syndrome asphyxia, multiple vital organs are affected (Table 58-6). may produce maternal hypotension, which decreases uterine


Pediatrics_Nelson

Pediatrics_Nelson. Many conditions that contribute to fetal or neonatal perfusion. Maternal medications given to relieve pain during asphyxia are the same medical or obstetric problems associ-labor may cross the placenta and depress the infant’s respiraated with high-risk pregnancy (Table 58-7). Maternal diseases tory center, resulting in apnea at the time of birth. Table 58-5 Abnormal Newborn Screening Results: Possible Implications and Initial Action to Be Taken NEWBORN SCREENING FINDING DIFFERENTIAL DIAGNOSIS INITIAL ACTION ↑ Phenylalanine PKU, non-PKU hyperphenylalaninemia, pterin defect, galactosemia, transient hyperphenylalaninemia Repeat blood specimen T4, ↑ TSH Congenital hypothyroidism, iodine exposure Repeat blood specimen or thyroid function testing, begin thyroxine treatment T4, normal TSH Maternal hyperthyroidism, thyroxine-binding globulin Repeat blood specimen deficiency, secondary hypothyroidism, congenital hypothyroidism with delayed TSH elevation


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Pediatrics_Nelson. T4, normal TSH Maternal hyperthyroidism, thyroxine-binding globulin Repeat blood specimen deficiency, secondary hypothyroidism, congenital hypothyroidism with delayed TSH elevation Methionine Homocystinuria, isolated liver dysfunction, tyrosinemia Repeat blood and urine specimen type I, transient hypermethioninemia Leucine Maple syrup urine disease, transient elevation Clinical evaluation including urine for ketones, acid-base status, amino acid studies, immediate neonatal ICU care if urine ketones positive Tyrosine Tyrosinemia type I or type II, transient tyrosinemia, liver Repeat blood specimen disease S-hemoglobin Sickle cell disease, sickle cell trait Hemoglobin electrophoresis Trypsinogen Cystic fibrosis, transient, intestinal anomalies, perinatal Repeat blood specimen, possible sweat test stress, trisomies 13 and 18, renal failure and DNA testing


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Pediatrics_Nelson. Trypsinogen Cystic fibrosis, transient, intestinal anomalies, perinatal Repeat blood specimen, possible sweat test stress, trisomies 13 and 18, renal failure and DNA testing Creatinine phosphokinase Duchenne muscular dystrophy, other type of muscular Repeat blood test dystrophy, birth trauma, invasive procedure Biotinidase Biotinidase deficiency Serum biotinidase assay, biotin therapy G6PD G6PD deficiency Complete blood count, bilirubin determination HIV antibody (IgG) Maternally transmitted HIV, possible AIDS Infectious disease consultation From Kim SZ, Levy HL: Newborn screening. In Taeusch HW, Ballard RA, editors: Avery’s Diseases of the Newborn, ed 7, Philadelphia, 1998, Saunders. AIDS, Acquired immunodeficiency syndrome; G6PD, glucose-6-phosphate dehydrogenase; HIV, human immunodeficiency virus; ICU, intensive care unit; PKU, phenylketonuria; T4, thyroxine; TSH, thyroid-stimulating hormone.


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Pediatrics_Nelson. Table 58-6 Effects of Asphyxia SYSTEM EFFECT Central nervous system Hypoxic-ischemic encephalopathy, IVH, PVL, cerebral edema, seizures, hypotonia, hypertonia Cardiovascular Myocardial ischemia, poor contractility, tricuspid insufficiency, hypotension Pulmonary Persistent pulmonary hypertension, respiratory distress syndrome Gastrointestinal Perforation, ulceration, necrosis Metabolic Inappropriate ADH, hyponatremia, hypoglycemia, hypocalcemia, myoglobinuria ADH, Antidiuretic hormone; IVH, intraventricular hemorrhage; PVL, periventricular leukomalacia. Table 58-7 Etiology of Birth Asphyxia TYPE EXAMPLE INTRAUTERINE Hypoxia-ischemia Uteroplacental insufficiency, abruptio placentae, prolapsed cord, maternal hypotension, unknown Anemia-shock Vasa previa, placenta previa, fetomaternal hemorrhage, erythroblastosis Birth trauma Cephalopelvic disproportion, shoulder dystocia, breech presentation, spinal cord transection


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Pediatrics_Nelson. Anemia-shock Vasa previa, placenta previa, fetomaternal hemorrhage, erythroblastosis Birth trauma Cephalopelvic disproportion, shoulder dystocia, breech presentation, spinal cord transection Hypoxia-ischemia Umbilical cord compression, tetanic contraction, abruptio placentae POSTPARTUM Central nervous system Maternal medication, trauma, previous episodes of fetal hypoxia-acidosis Congenital neuromuscular disease Congenital myasthenia gravis, myopathy, myotonic dystrophy Infection Consolidated pneumonia, shock Airway disorder Choanal atresia, severe obstructing goiter or tumor, laryngeal webs Pulmonary disorder Severe immaturity, pneumothorax, pleural effusion, diaphragmatic hernia, pulmonary hypoplasia Renal disorder Pulmonary hypoplasia, pneumothorax


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Pediatrics_Nelson. Pulmonary disorder Severe immaturity, pneumothorax, pleural effusion, diaphragmatic hernia, pulmonary hypoplasia Renal disorder Pulmonary hypoplasia, pneumothorax Fetal conditions associated with asphyxia usually do not become manifested until delivery, when the infant must initiate and sustain ventilation. In addition, the upper and lower airways must be patent and unobstructed. Alveoli must be free from foreign material, such as meconium, amniotic fluid debris, and infectious exudates, which increases airway resistance, reduces lung compliance, and leads to respiratory distress and hypoxia. Some extremely immature infants weighing less than 1000 g at birth may be unable to expand their lungs, even in the absence of other pathology. Their compliant chest walls and surfactant deficiency may result in poor air exchange, retractions, hypoxia, and apnea.


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Pediatrics_Nelson. The newborn (particularly a preterm infant) responds paradoxically to hypoxia with apnea rather than tachypnea as occurs in adults. Episodes of intrauterine asphyxia also may depress the neonatal central nervous system. If recovery of the fetal heart rate occurs as a result of improved uteroplacental perfusion, fetal hypoxia and acidosis may resolve. Nonetheless, if the effect on the respiratory center is more severe, a newborn may not initiate an adequate ventilatory response at birth and may undergo another episode of asphyxia.


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Pediatrics_Nelson. The Apgar examination, a rapid scoring system based on physiologic responses to the birth process, is a good method for assessing the need to resuscitate a newborn (Table 58-8).At intervals of 1 minute and 5 minutes after birth, each of the five physiologic parameters is observed or elicited by a qualified examiner. Full-term infants with a normal cardiopulmonary adaptation should score 8 to 9 at 1 and 5 minutes. Apgar scores of 4 to 7 warrant close attention to determine whether the infant’s status will improve and to ascertain whether any pathologic condition is contributing to the low Apgar score.


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Pediatrics_Nelson. By definition, an Apgar score of 0 to 3 represents either a cardiopulmonary arrest or a condition caused by severe bradycardia, hypoventilation, or central nervous system depression. Most low Apgar scores are caused by difficulty in establishing adequate ventilation and not by primary cardiac pathology. In addition to an Apgar score of 0 to 3, most infants with asphyxia severe enough to cause neurologic injury also manifest fetal acidosis (pH <7); seizures, coma, or hypotonia; and multiorgan dysfunction. Low Apgar scores may be caused by fetal hypoxia or other factors listed in Table 58-7. Most infants with low Apgar scores respond to assisted ventilation by face mask or by endotracheal intubation and usually do not need emergency medication.


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Pediatrics_Nelson. Resuscitation of a newborn with a low Apgar score follows the same systematic sequence as that for resuscitation of older patients, but in the newborn period this simplified ABCD approach requires some qualification (Fig. 58-2). In the ABCD approach, A stands for securing a patent airway by clearing amniotic fluid or meconium by suctioning; A is also a reminder of anticipation and the need for knowing the events of pregnancy, labor, and delivery. Evidence of a diaphragmatic hernia and a low Apgar score indicate that immediate endotracheal intubation is required. If a mask and bag are used, gas enters the lung and the stomach, and the latter may act as an expanding mass in the chest that compromises respiration. If fetal hydrops has occurred with pleural effusions, bilateral thoracentesis to evacuate the pleural effusions may be needed to establish adequate ventilation.


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Pediatrics_Nelson. B represents breathing. If the neonate is apneic or hypoventilating and remains cyanotic, artificial ventilation should be initiated. Ventilation should be performed with a well-fitted mask attached to an anesthesia bag and a manometer to prevent extremely high pressures from being given to the newborn; 100% oxygen should be administered through the mask. Yes, stay Term gestation? Routine care Breathing or crying? Good tone?  Clear airway if necessary  Dry  Ongoing evaluation Warm, clear airway if necessary, dry, stimulate NoHR below 100,30 sec gasping, or apnea? Yes Labored breathing or persistent cyanosis? Yes No Clear airway SpO2 monitoringPPV, Consider CPAP Postresuscitation care HR below 100? Take ventilation corrective steps SpO2 monitoring No HR below 60? Consider intubation Chest compressions Coordinate with PPV Take ventilation corrective steps Intubate if no chest rise! HR below 60? IV epinephrine


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Pediatrics_Nelson. No HR below 60? Consider intubation Chest compressions Coordinate with PPV Take ventilation corrective steps Intubate if no chest rise! HR below 60? IV epinephrine Figure 58-2 New Guidelines and Algorithm for Neonatal Resuscitation. CPAP, Continuous positive airway pressure; PPV, positive-pressure ventilation. (From Kattwinkel J, Perlman JM, Aziz K, et al: Special Report—Neonatal Resuscitation: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care, Pediatrics 126(5):e1400–e1413, 2010. Erratum in Neoreviews 128(1):176, Consider: 2011. doi: 10.1542/peds.2011-1260.)


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Pediatrics_Nelson. Consider: 2011. doi: 10.1542/peds.2011-1260.) If the infant does not revive, an endotracheal tube should be placed, attached to the anesthesia bag and manometer, and 100% oxygen should be administered. The pressure generated should begin at 20 to 25 cm H2O, with a rate of 40 to 60 breaths/minute. An adequate response to ventilation includes good chest rise, return of breath sounds, well-oxygenated color, heart rate returning to the normal range (120 to 160 beats/minute), normal end-tidal carbon dioxide, and, later, increased muscle activity and wakefulness. The usual recovery after a cardiac arrest first involves a return to a normal heart rate, followed by disappearance of cyanosis and noticeably improved perfusion. An infant may remain limp and be apneic for a prolonged time after return of cardiac output and correction of acidosis.


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Pediatrics_Nelson. Breathing initially should be briefly delayed if meconium-stained amniotic fluid is present to avoid dissemination of meconium into the lungs, producing severe aspiration pneumonia. If meconium is noted in the amniotic fluid, the oropharynx should be suctioned when the head is delivered. After the birth of a depressed infant, the oral cavity should be Table 58-9 Life-Threatening Congenital Anomalies NAME MANIFESTATIONS Choanal atresia (stenosis) Respiratory distress in delivery room, apnea, unable to pass nasogastric tube through nares Pierre Robin syndrome Micrognathia, cleft palate, airway obstruction Diaphragmatic hernia Scaphoid abdomen, bowel sounds present in left chest, heart shifted to right, respiratory distress, polyhydramnios Tracheoesophageal fistula Polyhydramnios, aspiration pneumonia, excessive salivation, unable to place nasogastric tube in stomach


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Pediatrics_Nelson. Tracheoesophageal fistula Polyhydramnios, aspiration pneumonia, excessive salivation, unable to place nasogastric tube in stomach Intestinal obstruction: volvulus, Polyhydramnios, bile-stained emesis, abdominal distention duodenal atresia, ileal atresia Renal agenesis/Potter syndrome Oligohydramnios, anuria, pulmonary hypoplasia, pneumothorax Neural tube defects: anencephaly, Polyhydramnios, elevated α-fetoprotein; decreased fetal activity meningomyelocele Down syndrome (trisomy 21) Hypotonia, congenital heart disease, duodenal atresia Ductal-dependent congenital heart Cyanosis, murmur, shock disease suctioned again; the vocal cords should be visualized and the infant intubated.


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Pediatrics_Nelson. Ductal-dependent congenital heart Cyanosis, murmur, shock disease suctioned again; the vocal cords should be visualized and the infant intubated. C represents circulation and external cardiac massage. Ifartificial ventilation does not improve bradycardia, if asystole is present, or if peripheral pulses cannot be palpated,external cardiac massage should be performed at a rate of 120 compressions/minute with compressions and breathsgiven at a ratio of 3:1. External cardiac massage usually is notneeded because most infants in the delivery room respondto ventilation.


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Pediatrics_Nelson. D represents the administration of drugs. If bradycardia is unresponsive to ventilation or if asystole is present, epinephrine should be administered. Intravenous (IV) epinephrine (1:10,000), 0.1 to 0.3 mL/kg, should be given through an umbilical venous line or injected into the endotracheal tube. However, when epinephrine is administered through the endotracheal tube, the result is often unpredictable. Before medications are administered in the presence of electrical cardiac activity with poor pulses, it is important to determine whether there is a pneumothorax. Transillumination of the thorax, involving the use of a bright light through each side of the thorax and over the sternum, may suggest pneumothorax if one side transmits more light than the other. Breath sounds may be decreased over a pneumothorax and there may be a shift of the heart tones away from the side of a tension pneumothorax.


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Pediatrics_Nelson. If central nervous system depression in the infant may be due to a narcotic medication given to the mother, 0.1 mg/kg of naloxone (Narcan) can be given to the infant intravenously or endotracheally. Before this drug is administered, the ABCs should be followed carefully. Naloxone should not be given to a newborn of a mother who is suspected of being addicted to narcotics or is on methadone maintenance because the newborn may experience severe withdrawal seizures. In babies of more than 35 weeks’ gestation suffering hypoxic ischemic injury at birth, induced therapeutic hypothermia(33.0°C to 34.0°C) for 72 hours has been shown in clinical studies to be efficacious in reducing the severity of brain injury. Brain hypothermia, whether induced by whole-body or selective head cooling, provides neuroprotection against encephalopathy presumably due to hypoxic ischemia.


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Pediatrics_Nelson. The first physical examination of a newborn may be a general physical examination of a well infant or an examination to confirm fetal diagnoses or to determine the cause of various manifestations of neonatal diseases. Problems in the transition from fetal to neonatal life may be detectable immediately in the delivery room or during the first day of life. Physical examination also may reveal effects of the labor and delivery resulting from asphyxia, drugs, or birth trauma. The first newborn examination is an important way to detect congenital malformations or deformations (Table 58-9). Significant congenital malformations may be present in 1% to 3% of all births.


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Pediatrics_Nelson. Signs such as cyanosis, nasal flaring, intercostal retractions, and grunting suggest pulmonary disease. Meconium staining of the umbilical cord, nails, and skin suggest fetal distress and the possibility of aspiration pneumonia. The level of spontaneous activity, passive muscle tone, quality of the cry, and apnea are useful screening signs to evaluate the state of the nervous system. The examination should proceed with an assessment of vital signs, particularly heart rate (normal rate, 120 to 160 beats/min); respiratory rate (normal rate, 30 to 60 breaths/min); temperature (usually done per rectum and later as an axillary measurement); and blood pressure (often reserved for sick infants). Length, weight, and head circumference should be measured and plotted on growth curves to determine whether growth is normal, accelerated, or retarded for the specific gestational age.


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Pediatrics_Nelson. Figure 58-3 Physical criteria for assessment of maturity and gestational age. Expanded New Ballard Score (NBS) includes extremely premature infants and has been refined to improve accuracy in more mature infants. (From Ballard JL, Khoury JC, Wedig K, et al: New Ballard Score, expanded to include extremely premature infants, J Pediatr 119:417-423, 1991.)


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Pediatrics_Nelson. Gestational age is determined by an assessment of various physical signs (Fig. 58-3) and neuromuscular characteristics (Fig. 58-4) that vary according to fetal age and maturity. Physical criteria mature with advancing fetal age, including increasing firmness of the pinna of the ear; increasing size of the breast tissue; decreasing fine, immature lanugo hair over the back; and decreasing opacity of the skin. Neurologic criteria mature with gestational age, including increasing flexion of the legs, hips, and arms; increasing tone of the flexor muscles of the neck; and decreasing laxity of the joints. These signs are determined during the first day of life and are assigned scores. The cumulative score is correlated with a gestational age, which is usually accurate to within 2 weeks (Fig. 58-5).


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Pediatrics_Nelson. Gestational age assessment permits the detection of abnormal fetal growth patterns, aiding in predicting the neonatal complications of largeness or smallness for gestational age (Fig. 58-6). Infants born at a weight greater than the 90th percentile for age are considered large for gestational age. Among therisks associated with being large for gestational age are all the risks of the infant of a diabetic mother and risks associated with postmaturity. Infants born at a weight less than 10th percentile for age (some growth curves use <2 standard deviations or the 5th percentile) are small for gestational age and have IUGR. Problems associated with small for gestational age infants include congenital malformations, in addition to the problems listed in Table 58-2.


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Pediatrics_Nelson. The skin should be evaluated for pallor, plethora, jaundice, cyanosis, meconium staining, petechiae, ecchymoses, congenital nevi, and neonatal rashes. Vasomotor instability with cutis marmorata, telangiectasia, phlebectasia (intermittent mottling with venous prominence), and acrocyanosis (feet and hands) is normal in a premature infant. Acrocyanosis also may be noted in a healthy term infant in the first days after birth.


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Pediatrics_Nelson. The skin is covered with lanugo hair, which disappears by term gestation. Hair tufts over the lumbosacral spine suggest a spinal cord defect. Vernix caseosa, a soft, white, creamy layer covering the skin in preterm infants, disappears by term. Post-term infants often have peeling, parchment-like skin. Mongolian spots are transient, dark blue to black pigmented macules seen over the lower back and buttocks in 90% of African American, Indian, and Asian infants. Nevus simplex (salmon patch), or pink macular hemangioma, is common, usually transient, and noted on the back of the neck, eyelids, and forehead. Nevus flammeus, or port-wine stain, is seen on the face and should cause the examiner to consider Sturge-Weber syndrome (trigeminal angiomatosis, convulsions, and ipsilateral intracranial tram-line calcifications).


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Pediatrics_Nelson. Figure 58-4 Neuromuscular criteria for assessment of maturity and gestational age. Expanded New Ballard Score (NBS) includes extremely premature infants and has been refined to improve accuracy in more mature infants. (From Ballard JL, Khoury JC, Wedig K, et al: New Ballard Score, expanded to include extremely premature infants, J Pediatr 119:417-423, 1991.)


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Pediatrics_Nelson. Congenital melanocytic nevi are pigmented lesions of varying size noted in 1% of neonates. Giant pigmented nevi are uncommon but have malignant potential. Capillary hemangiomas are raised, red lesions, whereas cavernous hemangiomas are deeper, blue masses. Both lesions increase in size after birth, then resolve when the child is 1 to 4 years of age. When enlarged, these hemangiomas may produce high-output heart failure or platelet trapping and hemorrhage. Erythema toxicum is an erythematous, papular-vesicular rash common in neonates that develops after birth and involves eosinophils in the vesicular fluid. Pustular melanosis, more common in African American infants, may be seen at birth and consists of a small, dry vesicle on a pigmented brown macular base. Erythema toxicum and pustular melanosis are benign lesions but may mimic more serious conditions, such as the vesicular rash of disseminated herpes simplex or the bullous eruption of S. aureus impetigo. Tzanck smear, Gram stain,


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Pediatrics_Nelson. melanosis are benign lesions but may mimic more serious conditions, such as the vesicular rash of disseminated herpes simplex or the bullous eruption of S. aureus impetigo. Tzanck smear, Gram stain, Wright stain, direct fluorescent antibody stain, polymerase chain reaction for herpes DNA, and appropriate cultures may be needed to distinguish these rashes. Other common characteristic rashes are milia (yellow-white epidermal cysts of the pilosebaceous follicles that are noted on the nose) and miliaria (prickly heat), which is caused by obstructed sweat glands. Edema maybe present in preterm infants, but also suggests hydrops fetalis, sepsis, hypoalbuminemia, or lymphatic disorders.


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Pediatrics_Nelson. Figure 58-5 Maturity rating as calculated by adding the physical and neurologic scores, calculating the gestational age. (From Ballard JL, Khoury JC, Wedig K, et al: New Ballard Score, expanded to include extremely premature infants, J Pediatr 119:417-423, 1991.). The skull may be elongated and molded after a prolonged labor; this resolves 2 to 3 days after birth. The sutures should be palpated to determine the width and the presence of premature fusion or cranial synostosis. The anterior and posterior 4.5 3.5 2.5 1.5 0.5 0 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41


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Pediatrics_Nelson. Figure 58-6 Birth weight–specific and estimated gestational age–specific mortality rates. The dashed lines of the figure represent the 10th and 90th percentile weights. The grid lines are plotted by each gestational age and in 250-g weight increments. Each number in the box is the percent mortality rate for the grid defined by gestational age and birth weight range. (From Thomas P, Peabody J, Turnier V, et al: A new look at intrauterine growth and impact of race, attitude, and gender, Pediatrics 106:E21, 2000.) fontanelles should be soft and nonbulging, with the anterior larger than the posterior. A large fontanelle is associated with hydrocephalus, hypothyroidism, rickets, and other disorders. Soft areas away from the fontanelle are craniotabes; these lesions feel like a Ping-Pong ball when they are palpated. They may be a result of in utero compression. The skull should be examined carefully for signs of trauma or lacerations from internal fetal electrode sites or fetal scalp pH


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Pediatrics_Nelson. when they are palpated. They may be a result of in utero compression. The skull should be examined carefully for signs of trauma or lacerations from internal fetal electrode sites or fetal scalp pH sampling; abscesses may develop in these areas.


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Pediatrics_Nelson. Face, Eyes, and Mouth The face should be inspected for dysmorphic features, such as epicanthal folds, hypertelorism, preauricular tags or sinuses, low-set ears, long philtrum, and cleft lip or palate. Facial asymmetry may be a result of seventh nerve palsy; head tilt may be caused by torticollis.


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Pediatrics_Nelson. The eyes should open spontaneously, especially in an uprightposition. Before 28 weeks’ gestational age, the eyelids may befused. Coloboma, megalocornea, and microphthalmia suggestother malformations or intrauterine infections. A cloudy corneagreater than 1 cm in diameter also may be seen in congenitalglaucoma, uveal tract dysgenesis, and storage diseases. Conjunctival and retinal hemorrhages are common and usually of no significance. The pupillary response to light is present at 28weeks of gestation. The red reflex of the retina is shown easily. A white reflex, or leukokoria, is abnormal and may be the result ofcataracts, ocular tumor, severe chorioretinitis, persistent hyper-plastic primary vitreous, or retinopathy of prematurity.


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Pediatrics_Nelson. The mouth should be inspected for the presence of natal teeth, clefts of the soft and hard palate and uvula, and micrognathia. A bifid uvula suggests a submucosal cleft. White, shiny, multiple transient epidermal inclusion cysts (Epstein pearls) on the hard palate are normal. Hard, marble-sized masses in the buccal mucosa are usually transient idiopathic fat necrosis. The tympanic membranes are dull, gray, opaque, and immobile in the first 1 to 4 weeks. These findings should not be confused with otitis media.


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Pediatrics_Nelson. The neck appears short and symmetrical. Abnormalities include midline clefts or masses caused by thyroglossal duct cysts or by goiter and lateral neck masses (or sinuses), which are the result of branchial clefts. Cystic hygromas and hemangiomas may be present. Shortening of the sternocleidomastoid muscle with a fibrous tumor over the muscle produces head tilt and asymmetrical facies (neonatal torticollis). Arnold-Chiari malformation and cervical spine lesions also produce torticollis. Edema and webbing of the neck suggest Turner syndrome. Both clavicles should be palpated for fractures.


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Pediatrics_Nelson. Examination of the chest includes inspection of the chest wall to identify asymmetry resulting from absence of the pectoralis muscle and inspection of the breast tissue to determine gestational age and detect a breast abscess. Boys and girls may have breast engorgement and produce milk; milk expression should not be attempted. Supernumerary nipples may be bilateral and may be associated with renal anomalies.


Pediatrics_Nelson

Pediatrics_Nelson. Examination of the lungs includes observations of the rate, depth, and nature of intercostal or sternal retractions. Breath sounds should be equal on both sides of the chest, and rales should not be heard after the first 1 to 2 hours of life. Diminished or absent breath sounds on one side suggest pneumothorax, collapsed lung, pleural effusion, or diaphragmatic hernia. Shift of the cardiac impulse away from a tension pneumothorax and diaphragmatic hernia and toward the collapsed lung is a helpful physical finding for differentiating these disorders. Subcutaneous emphysema of the neck or chest also suggests a pneumothorax or pneumomediastinum, whereas bowel sounds auscultated in the chest in the presence of a scaphoid abdomen suggest a diaphragmatic hernia.