Neonatology

VOLUME II

First Edition
2015-2016

by

Dr Maged Zakaria IBRAHIM

Neonatologist and Pediatrician
MRCPCH, MSc. Pediatrics, IBCLC

Keynotes
Keynotes Neonatology-Volume II

Copyright 2015 by Maged Zakaria Mahmoud.

All rights reserved. No part of this publication may be reproduced
or transmitted in any form or by any means, electronic or
mechanical, including photocopying, recording, or any information
storage and retrieval system, without permission in writing from the
author. Queries on how to seek permission, and arrangements can be
sent to the authors email: maged.zakaria@yahoo.com

Knowledge and best practice in this field are constantly changing. As new research and
experience broaden our understanding, changes in research methods, professional
practices, or medical treatment may become necessary. Practitioners and researchers must
always rely on their own experience and knowledge in evaluating and using any
information, methods, compounds, or experiments described herein. In using such
information or methods they should be mindful of their own safety and the safety of others,
including parties for whom they have a professional responsibility. With respect to any drug
or pharmaceutical products identified, readers are advised to check the most current
information provided (i) on procedures featured or (ii) by the manufacturer of each product
to be administered, to verify the recommended dose or formula, the method and duration of
administration, and contraindications. It is the responsibility of practitioners, relying on
their own experience and knowledge of their patients, to make diagnoses, to determine
dosages and the best treatment for each individual patient, and to take all appropriate safety
precautions. To the fullest extent of the law, the author does not assume any liability for any
injury and/or damage to persons or property as a matter of products liability, negligence or
otherwise, or from any use or operation of any methods, products, instructions, or ideas
contained in the material herein.

ISBN 978-977-94-3567-2
Printed in EGYPT

maged.zakaria@yahoo.com

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Chapter 6

Neonatal Infections

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Candida Infections in Neonates

- Candida albicans is the major species isolated from neonates with candidal infection.

- Presentations of Candida infections in the newborn can be separated into:

Mucocutaneous (oropharyngeal thrush, diaper dermatitis, or congenital candidacies).
Systemic (due to catheter-related or localized infections that progress to disseminated
infections and multiorgan involvement).
Catheter-related infections without multiorgan involvement.
Invasive focal infection (meningitis, UTIs, peritonitis, osteomyelitis, and septic
arthritis):
o Risk factors for invasive candidiasis:
Immunocompromised host including prematurity and prolonged steroids use
Length of NICU stay > 7 days and total parenteral nutrition for > 5 days
Invasive procedures e.g. endotracheal intubation and central venous catheter
Factors Candida overgrowth e.g. broad-spectrum antimicrobials and H2 blockers

o In infants with culture positive for Candida, further evaluation is recommended:

Cultures of the blood, urine, and CSF
Dilated eye examination
Echocardiogram to detect cardiac thrombi or vegetations
Diagnostic imaging of the brain, liver, spleen, and kidney

o Prevention of systemic candidal disease in preterm infants:

Prophylactic IV fluconazole for 6 wks at a dose of 3 mg/kg every 3rd day for the 1st 2
wks, every other day during the 3rd and 4th wks, and daily during the 5th and 6th wks
Limitation of the use of broad-spectrum antibiotics (cephalosporins and
carbapenems) and H2 blockers
Early introduction of enteral feedings may lessen the duration of parenteral nutrition
and the need for intravascular catheters
Changing infusions of lipid suspensions every 12 hrs microbial contamination; as
well as changing solutions of parenteral nutrition and lipid mixtures every 24 hrs.

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- Treatment:
Amphotericin B (Fungizone) is the mainstay of therapy (0.5-1 mg/kg/day over 4-6
hours for 14 days to 6 weeks depending on disease severity and site). Side effects include
nephrotoxicity, hypokalemia, hepatotoxicity, and bone marrow suppression.
Amphotericin B lipid complex (AmBisome) (5 mg/kg/day over 2 hrs) eliminates the
severe adverse effects of conventional amphotericin with good CNS penetration.
5-Flucytosine (Ancobon) (50-150 mg/kg/day PO) inhibits DNA replication in Candida. It
may be used as adjunctive synergistic therapy for candidal meningitis or persistent
fungemia because amphotericin B penetrates the spinal fluid poorly.
Fluconazole (Diflucan) is an alternative agent that affects fungal membrane integrity
(should not be used primarily until candida speciation is completed, because C. krusei and C.
glabrata are frequently resistant to fluconazole).
Removal of central catheters in place, when candidemia is identified.

Congenital Candidiasis (acquired in utero or during delivery)

Erythematous macules and/or papules

Involve palms and soles Yellow-white papules on umbilical cord
on erythematous base

- Risk is by ruptured membranes, uterine or cervical foreign body, and vaginal candidiasis.
- Presentation:
Usually on the 1st day of life with generalized 2-4 mm erythematous macules and/or
papules on erythematous base that evolve into pustules, vesicles, or even bullae
Frequently involve palms and soles (unlike erythema toxicum neonatorum or miliaria)
Oral thrush
Yellow-white papules on umbilical cord

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In term infants, lesions resolve with desquamation by the 1st week.
In preterm infants, rash is variable including pustular and vesicular lesions, diffuse
erythematous macular patches resembling a burn, skin crusting.
- Diagnosis:
Cultures for fungus should be obtained of blood, urine, and/or CSF.
Demonstration of budding yeast and pseudohyphae on a potassium hydroxide preparation of
scrapings from skin lesions is helpful.
- Treatment:
The disease in term infants is usually limited to skin, so it can be treated successfully with
topical antifungal agents (e.g., nystatin) and close surveillance. Occasionally, term babies have
systemic infection, such as pneumonia which requires systemic antifungal therapy.
Premature infants have a greater risk for systemic infection and should be treated systemic
antifungal therapy until culture results are available.
Amphotericin B (Fungizone) is the preferred initial systemic therapy. Alternate therapy
includes fluconazole (Diflucan) as monotherapy or in combination with amphotericin B.

Candidal Diaper Dermatitis

- Erythematous rash in the inguinal region.
- The rash has areas of confluent erythema with multiple tiny
pustules or discrete erythematous papules and plaques with
superficial scales.
- Satellite lesions are typically noted.
- Topical (2% nystatin or 2% miconazole ointment, or 1%
clotrimazole cream) is usually adequate. Simultaneous oral
and topical therapy used for refractory dermatitis.

Oral Candidiasis
- Oral candidiasis in the young infant is treated with a non-absorbable oral antifungal medication
e.g. Nystatin oral suspension (100,000 U/mL) (1 mL is applied to each side of the mouth every 6
hours, for a minimum of 10-14 days).

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Chapter 7

Blood Conditions

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Thrombosis in the Newborn

Thrombophilia
Predisposing Factors

- Neonates have altered concentrations of procoagulant, anticoagulant, and fibrinolytic

factors than adults which put newborns at risk of bleeding or thrombotic complications,
especially in the presence of indwelling catheters.
- Other risk factors including metabolic disease or hematocrit.

- Hereditary predisposition to thrombosis:

Deficiency of inhibitors of activated coagulation factors:
Factor V Leiden (APC resistance):
This mutation causes factor Va to become resistant to inactivation by activated protein C and
is the most common inherited risk factor for thrombosis
Antithrombin III (ATIII) deficiency
Protein C or S deficiency
Impaired clot lysis:
Dysfibrinogenemia
Plasminogen deficiency
Tissue plasminogen activator (TPA) deficiency
Metabolic defect:
Homocystinuria
Abnormality of coagulation cofactors:
Prothrombin mutation (causes levels of prothrombin)

Clinical Manifestations (depend upon location and size of the thrombus)

- The most common predisposing factor for thrombosis is the presence of a catheter.
- In thrombosis unrelated to a catheter, renal vein thrombosis is the most common.
- Venous thrombosis:
Portal vein thrombosis (with UVC) (may progress later to portal hypertension)
Renal vein thrombosis (with central venous catheter)
Right atrial thrombosis

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- Arterial thrombosis:

Umbilical artery catheter

Peripheral artery occlusion
- Purpura fulminans (rare):
Can result from deficiencies of either protein C, protein S, or both.
Can accompany sepsis or DIC (thrombocytopenia, hypofibrinogenemia, and PT and aPTT).
Characterized by microvascular thrombosis in the dermis followed by perivascular
hemorrhage, necrosis, and minimal inflammation. Lesions can progress very quickly into full-
thickness necrotic skin injury that is not reversible.

Peripheral artery occlusion Purpura fulminans

Diagnosis

- Ultrasound with Doppler flow.

- Contrast angiography is considered the gold standard. CT and MR venography.
- Coagulation studies for prothrombotic disorders:
Antithrombin, protein S, and protein C concentrations (abnormal tests repeated in 6-8 weeks).
Factor V Leiden mutation and prothrombin G20210A.
PT (INR), aPTT, platelet count, and fibrinogen (baseline before initiation of any therapy).
Maternal blood should be tested for lupus anticoagulant and anticardiolipin antibody.
Parents should be tested for prothrombotic state if results are abnormal.
Management

- Treatment approach:
For asymptomatic thrombosis:
o Supportive care and close monitoring of the size of the thrombus.
o If the thrombus extends, treatment is indicated.
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For symptomatic thrombosis:
o Treatment with anticoagulation and/or fibrinolytic agents.

Peripheral arterial catheters associated with thrombosis should be removed

promptly. If the thrombosis is symptomatic, anticoagulation therapy should be initiated.

- Anticoagulant therapy:
Low-molecular-weight heparin (LMWH) is preferred because of fewer side effects.
Unfractionated Heparin may also be used
Heparin is an indirect thrombin inhibitor that complexes with antithrombin and converts it from a slow
to a rapid inactivator of thrombin, factor Xa, and, to a lesser extent, factors XIIa, XIa, IXa, and VIIa
Major side effects are bleeding, heparin-induced thrombocytopenia (HIT), and osteoporosis

Duration of anticoagulation therapy would be from 6 weeks to 3 months.

- Thrombolytic agents:
Guidelines suggest AGAINST the use of thrombolytic therapy for neonatal thrombosis
unless thrombus occludes a major vessel causing critical compromise of organs or limbs.

Contraindications:
o Inability to maintain platelets >100,000/L or fibrinogen >1 g/dL before starting treatment
o Major surgery or hemorrhage within the previous 10 days
o Neurosurgery within 3 weeks
o Severe asphyxial event within 7 days
o Invasive procedure within the previous 3 days
o Seizures within 48 hours
o Prematurity <32 weeks gestation
o Systemic septicemia
o Active bleeding

Recombinant tissue-type plasminogen activator (tPA) is the thrombolytic agent of

choice. Streptokinase and urokinase also have been used in newborns.

The activity of these agents may be in newborns because of their plasminogen

concentration that leads to generation of plasmin. Supplementation with plasminogen by
administration of FFP may improve fibrinolytic activity.

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Management of Neonatal Purpura Fulminans

- Heparin and antiplatelet agents are ineffective.

- For infants with protein C deficiency:

Fresh frozen plasma (FFP) is given at a dose of 10-20 mL/kg every 12 hours.
Frequent dosing is necessary because the half-life of protein C is only about 6-16 hours

Protein C concentrate (Ceprotin) is given if available at a starting dose of 100 units/kg IV,
followed by 50 units/kg IV every 6 hours.
The aim is to achieve a trough level of protein C activity of 50 iu/dL. Treatment is continued until lesions
resolve (typically within 6-8 weeks) and infant is transitioned onto other anticoagulants.

- For infants with protein S deficiency:

Fresh frozen plasma (FFP) is given at a dose of 10-20 mL/kg every 12 hours.
Frequent dosing is necessary because the half-life of protein S is only about 36 hours

The aim is to achieve a trough level of protein S activity of 30 iu/dL

- Long-term management:
Infants must be treated indefinitely with anticoagulation to prevent thrombosis.
Options include LMWH (target anti-factor Xa concentration 0.5-1 U/mL), protein C
supplementation (given subcutaneously every third day), or oral warfarin therapy (the
INR should be maintained at 2.5-3.5), or a combination of these drugs.
Liver transplantation can correct homozygous protein C deficiency.

Prevention

- Arterial catheters:
Infused fluids should contain heparin in a concentration of 0.25-1.0 units/mL.

- Central venous catheters:

Infused fluids should contain heparin in a concentration of 0.5 units/mL.

- Obstructed central venous catheters can be cleared with local instillation of tPA (only
0.25-0.50 mg). Infused volume should be limited to catheters dead space to avoid systemic
administration.

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Chapter 8

Nutritional Conditions

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Chapter 9

GIT Conditions

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Chapter 10

Renal Conditions

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Chapter 11

Miscellaneous

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Neonatal Lupus
- Neonatal lupus (NL) is a passively transferred autoimmune disease occurs in 1-2% of
infants born to mothers with autoimmune disease e.g. SLE and Sjgren's syndrome.
- The most serious complication of NL is complete heart block (about 10% have an associated
cardiomyopathy at the initial diagnosis or develop it later).

Pathogenesis
- Transplacental passage of maternal anti-Ro/SSA (Sjgren syndrome type A antigen), anti-
La/SSB (Sjgren syndrome type B antigen) antibodies, and/or maternal antibodies to other
antigens may cause neonatal disease (11).

Clinical Manifestations
- Rash:
Erythematous annular lesions with slight central atrophy and raised active margins
primarily on scalp and periorbital area (sometimes on other body parts).
Can be prese nt at birth, but may not develop until after exposure to ultraviolet light (up to
4 months of age).
Often confused with a fungal skin infection or seborrheic dermatitis.
Usually self-limiting and almost always resolves by 6-8 months of age because the half-life
of IgG antibodies is ~21-25 days.

- Heart block:
Congenital complete heart block is the most serious manifestation of NL (the most common
cause of congenital complete heart block diagnosed in utero or in the neonatal period).
Second-degree block detected in utero and first- or second-degree heart block found in
infants at birth can progress to complete heart block.

- Other cardiac abnormalities:

Other arrhythmias (e.g. sinus bradycardia) and conduction abnormalities.
Structural abnormalities are reported e.g. valvular lesions, VSD, ASD, and L-TGA

(11) Ro and La molecules are thought to form a single particle that is present in all cells.
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Congestive heart failure due to cardiomyopathy that is often associated with endocardial
fibroelastosis (EFE) or myocarditis.

Skin rash Congenital complete heart block

- Other manifestations:
Asymptomatic liver function tests, mild hepatosplenomegaly, cholestasis, and hepatitis.
Anemia, neutropenia, thrombocytopenia and, rarely, aplastic anemia.
Hydrocephalus and macrocephaly.
Stippling of the epiphyses (chondrodysplasia punctata).
Pneumonitis.

Diagnosis
- No specific diagnostic criteria for NL.

- Prenatal screening:
Anti-Ro/SSA and anti-La/SSB antibodies in women with lupus, Sjgren syndrome, or NL in
a previous pregnancy (tested before conception or as early in pregnancy as possible).

- In utero monitoring for heart block:

Women who test positive for Ro/SSA and La/SSB autoantibodies should have frequent fetal
echocardiographic testing during pregnancy (weekly from the 18th through the 26th week of
pregnancy and then every other week until 32 weeks).

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- Postnatal diagnosis:
ECG and echocardiography
Testing for maternal anti-Ro/SSA antibodies should be performed in any neonate with
heart block-absent causal structural abnormalities. A positive test in the child or mother
fulfills the diagnostic criteria for NL.
CBC with differentials, liver enzymes and functions, X-ray on long bones, and neuroimaging.

Treatment
- Prevention of cardiac-NL:
Hydroxychloroquine may decrease the overall risk of cardiac-NL
IVIG, fluorinated corticosteroids are controversial.

- Treating fetal heart block:

Complete heart block is irreversible even with glucocorticoid therapy. Second-degree heart block may be
reversible, but it also may progress to complete heart block despite therapy. The clinical relevance of first-
degree heart block is unclear.

Fluorinated glucocorticoids, such as dexamethasone (4 mg/day oral) and betamethasone

(3 mg/day) is suggested for mothers of fetuses with second-degree heart block, beginning
as soon after detection and continuing through pregnancy.
Treatment of fetal third-degree block with glucocorticoids is generally not advised.
However, there are risks of glucocorticoid therapy to both the mother (e.g., infection,
hypertension, avascular necrosis, insulin resistance, and gestational diabetes) and the
infant (e.g., oligohydramnios and growth restriction).

- Care of neonates at risk for complete heart block:

Some infants with complete heart block will require insertion of a cardiac pacemaker,
especially if the heart rate at delivery is < 55 beats per minute.
ECG should be performed in all neonates born to mothers with anti-Ro/SSA and/or anti-
La/SSB antibodies.
Prolonged in utero exposure to fluorinated glucocorticoids can lead to adrenal hypoplasia.
Neonatal hypotension that potentially results from adrenal insufficiency should be treated
empirically with hydrocortisone in addition to standard supportive care.

- The rash of NL generally does not cause scarring and disappears within 7-8 months.

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Volume II - Index
Neonatal Infection 216
Neonatal Sepsis 217
Maternal Infections Affecting the Fetus or Newborn 221
Overview of TORCH infections 222
Congenital Toxoplasmosis 223
Congenital Rubella Syndrome (CRS) 227
Congenital Cytomegalovirus Infection 230
Perinatal Herpes Simplex Virus Infection 233
Varicella-Zoster Infections 236
Congenital Syphilis 239
Parvovirus B19 infection 245
Neonatal Pertussis 247
Neonatal Pneumonia 250
Neonatal Meningitis 255
Urinary Tract Infections in Neonates 259
Neonatal Tetanus 262
Candida Infections in Neonates 263
Prevention of Nosocomial Infections in NICU 266
Blood Conditions 267
Neonatal Anemia 268
Hydrops Fetalis 275
Neonatal Unconjugated Hyperbilirubinemia 279
Management of Unconjugated Hyperbilirubinemia 295
Kernicterus 301
Neonatal Polycythemia 304
Vitamin K Deficiency Bleeding 306
Thrombosis in the Newborn 311
Nutritional Conditions 315
Assessment of Growth in the Neonate 316
Parenteral Nutrition in Premature Infants 317
Assessment of Hydration Status of the Neonate 322
Neonatal Hypoglycemia 323
Neonatal Hyperglycemia 329
Osteopenia of Prematurity 331
GIT Conditions 335
Necrotizing Enterocolitis (NEC) 336
Neonatal Vomiting 348
Surgical Emergencies in the Newborn 351
Neonatal Intestinal Obstruction 335
Renal Conditions 356
Neonatal Acute Kidney Injury 357
Nephrocalcinosis 361
Abnormalities of Serum Calcium 362
Abnormalities of Serum Magnesium 367
Miscellenaous 368
Neonatal Lupus 369
Congenital Diaphragmatic Hernia 372
Developmental Dysplasia of the Hip 376
Neonatal Dermatology 378
Vascular Disorders 384

Keynotes in Neonatology 386

 1. Pediatric Cardiology 2. Pediatric Gastroenterology 3. Pediatric Hepatology

5. Genetic Disorders of
4. Pediatric Genetics 6. Immunology and Allergy
Metabolism (IEM)

7. Pediatric Endocrinology 8. Pediatric Nephrology 9. Pediatric Nutrition

10. Pediatric Neurology 11. Pediatric Psychiatry 12. Pediatric Rheumatology

15. Neonatologists Pocket

13. Neonatology (Volume I) 14. Neonatology (Volume II)
Drug Reference

18. Pediatric Infections

16. Pediatric Hematology 17. Pediatric Oncology
(coming soon)

Keynotes

Pediatric Postgraduate Series