I. Acute Metabolic Disturbances II. Neonatal Infections DR. MAHMOUD MOHAMED OSMAN MBBCH, MSc (Pedia), MRCPCH (UK), FRCP(Edinburgh) Consultant & Head of Neonatal Unites AlYammamah Hospital, MOH 09-02-2017

Objectives: Neonatal Hypoglycemia Neonatal Hypocalcemia Neonatal Hypomagnesemia Neonatal Infections Early-onset infections Late-onset infections Management of Infections

I. NEONATAL HYPOGLYCEMIA

1- BACKGROUND: Glucose is the major energy source for fetus and neonate. Up to 90% of total glucose used is consumed by the brain. The usual rate of glucose utilization is 4-8 mg/kg/min. Glucose regulatory mechanisms are sluggish at birth. The infant is susceptible to hypoglycemia when glucose demands are increased or glucose supply is limited. Severe or prolonged hypoglycemia may result in long term neurologic damage.

Glucose Metabolism after Birth Cessation of maternal glucose supply Increase in glucagon & catecholamine Decrease in insulin Gluconeogenesis Hepatic glycogen, amino acid, fatty acid metabolism Normal blood glucose

2- DEFINITION: Hypoglycemia in the first few days after birth is defined as blood glucose below 40 mg/dL. In preterm infants, repeated blood glucose levels below 50 mg/dL may be associated with neurodevelopmental delay.

3- ETIOLOGY: Conditions associated with an increased risk for neonatal hypoglycemia: 1. Decreased substrate availability: Prematurity Intra-uterine growth retardation Prolonged fasting without IV glucose Glycogen storage disease 2. Hyperinsulinemia: Infant of diabetic mother Islet cell hyperplasia Erythroblastosis fetalis Exchange transfusion Beckwith-Wiedemann Syndrome 3. Other endocrine abnormalities: Pan-hypopituitarism Hypothyroidism Adrenal insufficiency 4. Increased glucose utilization: Cold stress Increased work of breathing Sepsis Perinatal asphyxia 5. Miscellaneous conditions: Polycythemia Congenital heart disease CNS abnormalities

Infant of Diabetic Mother

Premature Infant.

Intra-uterine Growth Retardation

Beckwith–Wiedemann syndrome

4- SIGNS AND SYMPTOMS: Symptomatic Hypoglycemia: Signs and symptoms of hypoglycemia are nonspecific and include: jitteriness, irritability, lethargy, seizures, apnea, grunting and sweating (uncommon). Clinical signs should be alleviated with correction of plasma glucose levels Asymptomatic Hypoglycemia: Hypoglycemic Infants may be asymptomatic. Therefore, routine glucose monitoring for at-risk infants is mandatory. Lack of symptoms does not guarantee absence of long term sequelae.

5- DIAGNOSTIC WORKUP: Specimens for measurement of glucose should be obtained from heel-stick, veni-puncture, or from an indwelling catheter that does not have glucose infusion.

6- SCREENING OF AT RISK INFANTS: Infants at risk for hypoglycemia should be screened by measuring blood sugar by Glucometer at ages 1, 2, 4, 6, 9, 12, and 24hs. However continued surveillance and more frequent measurements may be needed until blood glucose is stable >40 mg/dL in term, or >50 mg/dL in preterm infants. Less frequent measurements are appropriate if blood glucose is stable.

7- MANAGEMENT OF HYPOGLYCEMIA: Early feeding as soon as the infant is ready, preferably within 1 hour of birth. Breast milk (Colostrum) or Dextrose-water. When Glucometer reading is >40 mg/dL and infant is feeding normally; follow usual nursery protocol. When Glucometer reading 20-40 mg/dL, and infant is term and able to feed: - Draw blood for stat blood glucose. - Feed 5 mL/kg of D5W. - Repeat blood glucose or Glucometer 20 min after . feeding.

When Glucometer reading are: < 20 mg/dL < 40 mg/dL and NPO or preterm < 40 mg/dL after feeding < 40 mg/dL and symptomatic - Draw blood for stat glucose measurement. - Give IV bolus of 2-3 mL/kg of D10W. - Begin continuous infusion of D10W at 4-6 mg/kg/min. - If infant of diabetic mother, begin D10W at 8-10 mg/kg/min. - Repeat blood glucose in 20 min with treatment until blood sugar > 40 mg/dL. Weaning IV dextrose infusion: When blood glucose has been stable for 12-24 h, begin decreasing IV infusion gradually if blood glucose remains ≥ 60 mg/dL.

Persistent hypoglycemia despite above measures: Increase rate of glucose infusion stepwise in 2 mg/kg/min increments up to 12-15 mg/kg/min glucose. Use increased volume with caution in infants where volume overload is a concern. Maximal concentration of glucose in peripheral IV is D12.5. (Do not use D25W or D50W IV or large IV volume boluses, As this creates rebound hypoglycemia, and causes dangerous increase in plasma osmolarity. Obtain Endocrine Consultation to guide further diagnostic evaluation and management.

Summary of Management of Symptomatic hypoglycemia Bolus of 2 mL/kg of 10% dextrose Start Glucose infusion @ 6-8mg/kg/min Check Blood sugar at 30-60min BS >50 mg, give IVF for 24 hrs start tapering once reading above 60mg BS <50,increase GIR in steps of 1-2 up-to 12mg/kg/min

II. NEONATAL HYPOCALCEMIA

1. INTRODUCTION: Regulation of serum ionized calcium concentration within a narrow range is critical for many biochemical processes such as: Blood coagulation, Neuromuscular excitability, Cell membrane integrity and function, Cellular enzymatic and secretory activity. Significant aberrations of serum calcium concentrations are frequently observed in the neonatal period

There are three fractions of calcium in serum: Ionized calcium (~ 50% of serum total calcium); Calcium bound to serum proteins, principally albumin (~ 40% ) Calcium complexed to phosphates, citrate, and sulfates (~10%). Ionized calcium is the only biologically available form of calcium. At birth, serum calcium level is (10 -11 mg/dL). Then decline for the first 24 to 48 hours; the nadir is usually 7.5 to 8.5 mg/dL. Thereafter, progressively rise to the mean values observed in older children

2. DEFINITION. Neonatal hypocalcemia is defined as a total serum calcium concentration of < 7 mg/dL (1.8 mmol/L) or an ionized calcium concentration of < 4 mg/dL(1 mmol/L). In very low birth weight (VLBW) infants, ionized calcium values of 0.8 to 1 mmol/L are common and not usually associated with clinical symptoms. In larger infants and in infants of >32 weeks' gestation, symptoms may more readily occur with an ionized calcium concentration of <1 mmol/L.

3. PATHOPHYSIOLOGY: The principal calcium-regulating hormones are: Parathyroid hormone (PTH) and 1,25-dihydroxyvitamin D (Calcitriol). PTH mobilizes calcium from bone, increases calcium resorption in the renal tubule, and stimulates renal production of 1,25-dihydroxyvitamin D. PTH secretion causes the serum calcium level to rise and the serum phosphorus level either to be maintained or to fall. Calcitriol increases intestinal calcium and phosphate absorption and mobilizes them from bone.

4. ETIOLOGY: Early Hypocalcemia (1-4 Days of Age): Prematurity Maternal diabetes Perinatal stress, asphyxia Intrauterine growth restriction Maternal anticonvulsants

2. Late Hypocalcemia (5-15 Days of Age): Hyperphosphatemia (High phosphate load). Hypomagnesemia. Vitamin D deficiency (Acquired or inherited). Parathyroid hormone resistance (Transient neonatal pseudohypoparathyroidism). Hypoparathyroidism: Primary: Parathyroid agenesis, 22q11 deletion. Secondary: Maternal hyperparathyroidism. Neonatal hypocalcemia with skeletal dysplasia. Other causes (Alkalosis, citrated blood transfusions, phototherapy, viral gastroenteritis, lipid infusions).

5. DIAGNOSIS: 1. Clinical presentarlon Early-onset hypocalcemia : The signs are usually nonspecific: apnea, seizures, jitteriness, increased extensor tone, clonus, hyper- reflexia, and stridor. In preterm newborns it is often asymptomatic but may show apnea, seizures, or abnormalities of cardiac function. Late-onset syndromes: May present as hypocalcemic seizures.

2. History For late-onset presentation, mothers may report partial breast feeding or whole cow’s milk may be reported. Abnormal movements and lethargy may precede obvious seizures. Symptoms are usually described beginning from 3-4 days of age. 3. Physical examination: General physical findings associated with seizure disorder in the newborn may be present in some cases. Usually, there are no apparent physical findings.

6. INVESTIGATIONS: Total serum and ionized calcium, magnesium, phosphorus, glucose. Acid-base balance. Chest radiograph (Thymic shadow, aortic arch position). Urinary calcium, magnesium, phosphorus, creatinine, drug screen. Vitamin D metabolites. Parathyroid hormone & Calcitonin. Others (Tests for malabsorption, lymphocyte count, T-cell numbers and function). Genetic studies for chromosome 22q11 deletion.

7. MONITORING Suggested schedule for monitoring calcium levels in infants, such as VLBW, IDM, and birth depression, who are at risk for developing hypocalcemia are as follows: - Total and ionized calcium at 12, 24, and 48 hours. - Total serum phosphorus and total serum magnesium for infants with hypocalcemia. - Serum concentrations of PTH, 25(0H)D, and 1,25(0H)2D are not usually needed.

8. TREATMENT: Therapy with calcium is usually adequate for most cases. In some cases, concurrent therapy with magnesium is indicated. Rapid intravenous infusion of calcium can cause a sudden elevation of serum calcium level, leading to bradycardia or other dysrhythmias. Intravenous calcium should only be "pushed" for treatment of hypocalcemic crisis (seizures), and should be given slowly and diluted with careful cardiovascular monitoring.

Calcium gluconate 10% solution is preferred for intravenous use. Calcium glubionate syrup (Neo-Calglucon) is a convenient oral preparation. If the ionized calcium level drops severely, a continuous intravenous calcium gluconate 10% infusion may be commenced. Monitor heart rate and rhythm and the infusion site are mandatory throughout the infusion.

III. Neonatal Hypomagnesemia

Introduction: Abnormalities of magnesium and calcium metabolism are commonly seen in the neonatal intensive care unit. Infants of diabetic mothers (IDMs) and infants with intrauterine growth restriction (IUGR) may present with hypocalcemia, hypomagnesemia, or both. Abnormalities in serum values for calcium and magnesium are of concern in any infant and warrant further investigation.

Definition: Incidence: Normal serum levels for magnesium are typically 0.66 –1.0 mmol/L. Hypomagnesemia is usually seen as any value < 0.66 mmol/L; however, clinical signs do not manifest until levels drop below 0.5 mmol/L . Incidence: True overall incidence in neonates is not well documented and remains to be determined. However, neonates appear to be more predisposed than other groups of patients, and it tends to follow in infants with hypocalcemia.

Pathophysiology: Magnesium is a key trace element for maintaining skeletal integrity, and it acts as a catalyst for intracellular enzymes for adenosine triphosphate (ATP) activation in skeletal and myocardial contractility. It has an important role in different processes related to cell physiology, hormonal and metabolic pathways, nerve conduction, and blood coagulation. It is also integral to protein synthesis, vitamin D metabolism, parathyroid function, and calcium homeostasis.

Risk factors: 1. Hypocalcemia. 2. Preterm and late-preterm infants. 3. Inadequate intake of magnesium. 4. Infant of diabetic mother (IDM), reflecting maternal magnesium deficiency secondary to diabetes. 5. IUGR, especially if mother had preeclampsia. 6. Inherited renal wasting (Gitelman syndrome). 7. Hypoparathyroidism. 8. Associated hypocalciuria and nephrocalcinosis. 9. Magnesuria secondary to Furosemide or Gentamicin. 10. Citrated blood exchange transfusions.

Clinical presentation: 1. Similar to hypocalcemia ( jitteriness, apnea, feeding intolerance), and may also present as seizures. 2. Clinical signs may be masked as hypocalcemia. If symptoms persist after adequate calcium gluconate therapy, hypomagnesemia should be considered.

Diagnosis: Serum magnesium level. Normal values are 0.6–1.0 mmol/L, although it may vary minimally with gestational age. Total and ionized calcium levels. Usually hypomagnesemia is associated with hypocalcemia, and hypercalcemia may inhibit magnesium reabsorption in the distal loop of Henle and cause hypomagnesemia.

Prevention. Adequate intake of magnesium should be assured in parenteral and enteral nutrition to prevent hypomagnesemia. Recommend dose is 8–15 mg/kg/d.

Management. Acute hypomagnesemia should be treated with intravenous magnesium sulfate. Infusion must be monitored closely for cardiac arrhythmias and hypotension. Maintenance magnesium can be by parenteral nutrition solutions or by oral feeds with magnesium salt solution. Magnesium infusion should be used cautiously if patient has impaired renal function due to its accumulated toxicity

Prognosis. Hypomagnesemia generally has good outcome if diagnosed promptly and treated adequately. The exception is a clinical presentation that includes hypomagnesemia-induced seizures with follow-up studies suggesting 20% incidence of neurologic abnormalities.

IV. Neonatal Infections

Neonatal infection may be acquired: In utero (Congenital). 1. Introduction Neonatal infection may be acquired: In utero (Congenital). During labour and delivery (early onset). After birth (late-onset). Infection can present in many different ways and may involve almost any system in the body. Infection poses a significant risk of mortality and is associated with major morbidity. It is a clinical syndrome of systemic illness accompanied by bacteremia or septicemia.

2. Incidence: The incidence of infection is approximately 5/1000 live births. It is more common in premature infants; 13-27/1000 for infants weighing <1500 gm. Mortality rate is high (13-25%); and higher rates are seen in premature infants and in those with early fulminant disease.

A. Early-onset (Perinatal) Infection

1- INTRODUCTION: Neonatal infections were originally divided arbitrarily into infections occurring before and after 1 wk of life. It is more useful to separate early-onset and late-onset infections according to peripartum pathogenesis. Early-onset infections are acquired before or during delivery (vertical mother-to-child transmission). Late-onset infections develop after delivery from organisms acquired in the hospital or the community. Very-late-onset infections develop after 1 month of life in VLBW preterm or term infants requiring prolonged intensive care.

The age at onset depends on the timing of exposure and virulence of the organism. A newborn infant with early-onset infection may be initially asymptomatic or has any of the clinical signs and symptoms of infection.

2. RISK FACTORS: There are a number of maternal and neonatal risk factors significantly increases the risk of early-onset infection in the newborn period A. Maternal risk factors. B. Neonatal risk factors.

A - Maternal risk factors: • Maternal features of sepsis or chorioamnionitis: Fever ≥38°C. High white cell count. Tender uterus. Offensive or purulent liquor. • Preterm labour <37 weeks’ gestation. • Membranes ruptured for more than 18–24 hs. • Prolonged labour beyond 12 hs. • Frequent vaginal examinations. • Group B streptococcus (GBS) colonization. • Bacteriuria in current pregnancy. • Previous infant with early-onset GBS disease. Amniotic fluid problems: Meconium-stained or foul-smelling amniotic fluid.

B. Neonatal risk factors: Prematurity and low birth weight Resuscitation at birth. Infants who had fetal distress, were born by traumatic delivery or were severely depressed at birth and required intubation and resuscitation. Invasive procedures. Invasive monitoring and respiratory or metabolic support. Other factors. - Males are 4 times more affected than females. - More common in black than in white infants. - Variations in immune function may play a role. - NICU staff and family members are often vectors for the spread of microorganisms, as a result of improper hand washing

3.Clinical Presentation: Initial diagnosis of sepsis is, by necessity, a clinical one because it is imperative to begin treatment before the results of cultures are available. Clinical Presentation of sepsis are nonspecific, and the differential diagnosis is broad.

Common Clinical Presentation of sepsis include: 1. Temperature irregularity. Hypo- or hyperthermia. 2. Change in behavior. Lethargy, irritability, crying or change in tone. 3. Skin. Poor peripheral perfusion, cyanosis, mottling, pallor, petechiae, rashes, sclerema, or jaundice. Feeding problems. Feeding intolerance, vomiting, diarrhea (watery loose stool), or abdominal distention with or without visible bowel loops. Cardiopulmonary. Tachypnea, respiratory distress (grunting, flaring, and retractions), apnea , tachycardia, or hypotension, which tends to be late sign. Metabolic. Hypo-or hyperglycemia or metabolic acidosis.

4. Differential Diagnosis Respiratory distress syndrome (RDS) Metabolic diseases Hematologic disease CNS disease Cardiac disease Other infectious processes (TORCH infections)

Complete blood count (CBC): Abnormal findings can include: 5- Investigations: Blood culture (>1mL): Should be collected before the start of antibiotics. Complete blood count (CBC): Abnormal findings can include: Increased white cell count leucocytosis. Lecuopenia or neutropenia, Increased numbers of immature neutrophils ( Bands, blasts, myelocytes, metamyelocytes ). Toxic granulation, vacuolation, Dohle bodies, intracellular organisms Thrombocytopenia.

An elevated C-reactive protein (CRP): May be a marker of infection. Lumbar puncture: Should be considered and is essential if the blood culture becomes positive or if the baby has signs or symptoms of meningitis. Imaging studies: X-rays, US, CT, or isotopic imaging.

  Mature neutrophil Band cell Toxic granulation

6 - Commenest Agents In Early-onset: 1- Group B β-haemolytic streptococcus 2- Escherichia coli 3- Listeria monocytogenes 4- Herpes simplex virus (HSV) 5- Chlamydia trachomatis 6- Other agents

1-Early-onset group B β-haemolytic streptococcus: Group B β-haemolytic streptococcus (GBS) is the most common cause of early-onset sepsis. Although the prognosis has improved, it is still fatal in10–20% of cases depending on gestational age and age of onset. Vaginal or rectal colonization with GBS is found in 15–30% of pregnant women depending on the local population. About 10–20% of infants born to colonized women will be colonized.

Early-onset GBS infection in the neonate occurs in only 1% of colonized women. In areas that are known to have high rates of colonization (e.g. USA), routine screening for GBS in pregnancy is often undertaken. Intrapartum antibiotics prophylaxis for women with risk factors significantly reduces the risk of early-onset infection, but does not eliminate it.

Early neonatal sepsis with multi-organs failure

E.coli may cause septicemia or meningitis. 2- Escherichia coli E.coli (particularly K1 strain), is associated with perinatal infection. E.coli may cause septicemia or meningitis. The incidence of E.coli infection appears to be increasing, due to the increasing use of antibiotics aimed at preventing GBS. The sensitivity of E.coli to antibiotics is variable.

3- Listeria monocytogenes This is a not uncommon perinatal pathogen and may invade the fetus through intact membranes. Characteristically, infected infants pass meconium in utero, and if this is seen in premature infants listeria should be strongly suspected. The organism has a predilection for the lungs and brain. Hydrocephalus is a common sequel to listeria meningitis. The organism is usually sensitive to Ampicillin.

4- Herpes simplex virus (HSV) Neonatal herpes simplex infection is a rare but devastating condition. It occurs as a result of HSV type1 and 2 in equal proportion. In most babies with neonatal HSV, there is no history of genital herpes and their mothers are asymptomatic Caesarean section reduces the risk of infection if there is active maternal shedding of HSV. The virus enters the baby through skin, eye or mouth and may disseminate to the brain or other organs. The risk of an infant being infected from a parent, nurse or midwife with cold sores is small, but not negligible.

Neonatal HSV presents in one of three ways: • Systemic symptoms. In the first few days of life with signs of major over whelming illness including shock, respiratory failure and often severe hepatitis and coagulation disorders. • Neurological symptoms. Approximately one third of babies present with encephalopathic signs of meningoencephalitis, most commonly at 10–14 days. • Cutaneous symptoms. Include rash and keratoconjunctivitis. These babies present in the second week of life; and rarely become seriously ill.

Facial vesicular rash indicative of neonatal HSV infection

Chlamydia is found in the vagina of 4% of pregnant women. 5- Chlamydia trachomatis Chlamydia is found in the vagina of 4% of pregnant women. Up to 70% of infants born through an infected cervix will acquire chlamydia, but with no symptoms. Chlamydia conjunctivitis and, less commonly, pneumonia occur in a small proportion of infants. The conjunctivitis is purulent and is indistinguishable from that of gonococcal ophthalmia. Specific culture media are necessary for this organism Diagnosis can be made by detecting DNA with PCR. Infants should be treated with tetracycline eye ointment and oral erythromycin.

6- Other Agents: Pneumococcus, and Haemophilus influenzae: They are probably haematogenously spread from maternal septicaemia . They may cause profound shock in the infant, indistinguishable clinically from Group B β-haemolytic streptococcus (GBS) . Anaerobes: are contracted from the birth canal and require special culture media.

B. Late-onset (Postnatal) Infection

1. The definition of late-onset infection: The most common definition is “signs of infection developing at least 7 days after birth”. 2. The risk factors of nosocomial infection: • Direct contamination by the hands of medical staff or parents. • Frequently performed procedures. • Cross-infection.

3. Clinical features - There are no pathognomonic signs of infection or any totally reliable way to make an early diagnosis in the laboratory. - The doctor must have a high level of suspicion for infection and not be too reliant on blood tests to make the diagnosis. - If in doubt, treat the baby

Late-onset group B β-haemolytic streptococcus infection 4. Commenest agents in late-onset: Late-onset group B β-haemolytic streptococcus infection Coagulase-negative staphylococci Staphylococcus aureus Others include: Pseudomonas, Proteus, Klebsiella, Serratia, and Candida.

Lower respiratory tract infection. Urinary tract infection. 5. Common presentation: Meningitis. Lower respiratory tract infection. Urinary tract infection. Conjunctivitis (‘sticky eyes’). Infection of the skin and subcutaneous tissues. Gastroenteritis. Systemic candidiasis.

Late-onset GBS Septicemia, and Meningitis with Convulsion

Late Onset Neonatal Sepsis Pneumoccoci

C. Management of Neonatal Infections

Usually Ampicillin, plus an Aminoglycoside are commonly used. 1. Initial therapy: Treatment is most often begun before a definite causative agent is identified. Usually Ampicillin, plus an Aminoglycoside are commonly used. In nosocomial sepsis: Flora of the NICU must be considered. However, staphylococcal coverage with Vancomycin plus a 3rd Generation cephalosporin are commonly used.

Monitoring of antibiotic levels and toxicity are important. 2. Continuing therapy: It is based on culture and sensitivity results, clinical course, and other serial lab studies (CRP). Monitoring of antibiotic levels and toxicity are important. When GBS is documented as the causative agent. Penicillin is the DOC, Aminoglycoside is often given as well because of documented synergism.

3. Supportive Therapy & Complications: RESPIRATORY: Ensure adequate oxygenation with blood gas monitoring and initiate O2 therapy or ventilator support if needed CARDIOVASCULAR: Support BP and perfusion to prevent shock. - Use volume expanders, 10-20 mL/kg (normal saline, albumin, and blood) - Monitor the intake of fluids and output of urine. - Pressor agents such as dopamine or dobutamine may be needed.

Hematologic: A. Disseminated intravascular coagulation (DIC) : Generalized bleeding at puncture sites, GIT, or CNS. In the skin, large vessel thrombosis  gangrene. Lab. parameters consistent with DIC include: Thrombocytopenia, prolonged PT, and PTT. Measures include: Treating the underlying disease. Fresh-frozen plasma, 10 mL/kg. Vitamin K. Blood and platelet infusion. Possible exchange transfusion.

B. Neutropenia: Studies suggest the use of: Recombinant human granulocyte colony-stimulating factor (rh G-CSF) Recombinant human granulocyte-macrophage colony-stimulating factor (rh GM-CSF) can reduce morbidity and mortality.

CNS Implement seizure control measures: Phenobarbiton 20 mg/kg loading dose METABOLIC - Monitor for and treat hypo- or hyperglycemia. - Metabolic acidosis may accompany sepsis and is treated with bicarbonate and fluid replacement.

IN SUMMARY Infection is a common problem in neonatal medicine. It has significant morbidity and mortality. Signs and symptoms may be present at or shortly after birth or may occur at any time during admission. Staff looking after neonates must have a high suspicion index of infection, as prompt treatment is required. A number of measures have been proven to decrease the risk of nosocomial infection with the most important being careful hand-washing.