ANEMIA IN NEONATES:Dr Sabih S AL-FETLAWI MRCP(UK)
Definition:Hb<12gm/dl in the first week or 10 gm/dl after the first week,or Hb.the normal range for age and sex .
Causes:Early onset anemia,<7days of age.:
1-Impaired red cell production:
a-congenital infection.
b-Diamond-Blackfan disease.
c-congenital leukemia
d-transient erythroblastopenia of childhood.
e-folic acid deficiency.
2-Increased RBCsdestruction like HDN.
3-Infection.
4-RBC membrane disorders like spherocytosis.
5-RBC enzyme problems like G6PD deficiency.
6-Hb pathies like Thalasemia.
7-blood loss: a-fetal hemorrhage,placenta previa,abraptio placntae,incision of placenta during CS.
b-fetomaternal transfusion ,occurs in 5-15% but not all are severe.
c-twin to twin transfusion.
d-fetoplacental transfusion(if baby held above placenta).
e-neonatal hemorrhage like ruptured liver or spleen,fractures,intracranial,pulmonary,GI hemorrhage.
f-repeated blood sampling.
8- anemia of prematurity(impaired red cell production and reduced red cell life span..
Late onset anemia:it occurs after the first week of life.
causes:
1-hemorrhage:
a-small perinatal hemorrhage.
b-excessive blood sampling.
c-hemorrhagic disease of the newborn.
d-IVH.
e-chronic GIT bleeding.
2-hemolysis:
a-Rh,ABO incompatibility.
b-sepsis.
c-Hb pathies
d-red cell defects like spherocytosis.
e-vitamin E deficiency.
3-decreased red cell production:
a-anemia of prematurity.
b-infection.
c-folic acid deficienc
d-congenital marrow aplasia.
e-congenital leukemia.
Management:1-treat underlying cause.
2-give iron ,folate,vitamin E.
3-transfuse with packed cells if Hb is <8gm/dl.
ANEMIA OF PREMATURITY:
Hb might drop to 6.5-9gm/dl at the age 4-8 weeks,with low retic count 0.2% but there is no pathological cause, contributory factors include:
1-Reduced RBC life span.
2-Low erythropoiten level.
3-Nutritional deficiency.
4-Rapid growth.
Management:
Blood transfusion protocol:
a-PCV<35%+infant requiring mechanical ventilation.
b-PCV<30+infant requiring minimal resp.support.
c-PCV<25,infant has tachycardia,tachypnea,increased oxygen requirement,weight gain<10gm/day while receiving good nutrition,apnea,surgery,acute blood loss.
PREVENTION:
1-Proper use of blood tests.
2-Iron supplements+folic acid..
3-Erythepoiten.
4-Vitamin E.
NEONATAL SEPSIS:
Definition:a clinical syndrome of systemic illness accompanied by bacteremia occurring in the first month of life.
Sepsis is the commonest cause of neonatal mortality and is responsible for 30-50% of total neonatal deaths each year in developing countries .
The term neonatal sepsis, refers to a systemic infection of neonates including septicemia, pneumonia, meningitis, arthritis, osteomyelitis, and urinary tract infection.Incidence is 10-30%.Premature and VLBW neonates have 3-10 folds risk of getting infection.
Intra-amniotic infection (chorioamnionitis) is a risk factor for neonatal sepsis, the diagnosis is typically based on the presence of maternal fever of greater than 38°C (100.4°F) and at least two of the following criteria: maternal leukocytosis (greater than 15000 cells/mm3), maternal tachycardia(greaterthan 100 beats/minute), fetal tachycardia (greater than 160 beats/minute),uterine tenderness, and/or foul odor of the amniotic fluid.
. Lymphocytes
Lymphocytes control the immune response. B lymphocytes produce antibodies. T lymphocytes have multiple functions including:
- helping B cells to make antibodies;
- recognizing and destroying infected cells;
- activating phagocytes to destroy the pathogens which they have ingested; and
controlling the level of the immune response
Pathogenesis of infection: Once an organism enters the body, it is quickly recognized and taken up by macrophages and other phagocytes and is lysed, releasing toxins such as lipopolysaccharide A. This activates the so- called ‘sepsis cascade’ ).
- . Activated macrophages stimulate the release of arachidonic acid metabolites like prostaglandins. They also initiate the release of proinflammatory cytokines which in turn switch on the release of anti-inflammatory cytokines. Lipopolysaccharides also activate the complement and coagulation cascades. All the above events working in combination or individually cause endothelial damage. As a consequence, systemic sepsis becomes a multisystem disorder. Effects on the cardiovascular system lead to hypotension. Effects on the hemopoietic system lead to neutropenia, anemia and disseminated intravascular coagulation. There are metabolic effects and apoptosis is accelerated. Left unchecked, sepsis proceeds to septic shock and death.Cytokins are glycoproteins secreted mainly by macrophages they regulate inflammatory mediators and modulate immune response.
Whey neonates are more liable to get infection?
1- because of the immaturity of the immune system and slow immune response .
2-the infant has low level of complement(50-70%) of adult level.
3-impaired function of neutrophils,monocytes,macrophages.
4-K.cells(killer cells) have diminished cytotoxic effect.
5-IgM,IgA do not cross the placenta. Levels of IgA are usually not detected until the infant is around 2-3 weeks.
Types of sepsis:
A-Early onset(EOS)
( sepsis:usually occurs in the first week of life,characterised by multisystem ,fulminant illness with prominent respiratory symptoms, the infection occurs in the perinatal period.Organisms like:group B streptococci, treponemes,viruses,listeria,HIV,HbS,CMV.Candida can be acquired transplacentally or through the birth canal. Aspiration of amniotic fluid by the fetus causes aspiration pneumonia–EOS can manifest as asymptomatic bacteremia.Ninty percent of neonates with EOS present in the first 24 hours. Respiratory distress is the most prominent symptom which proceeds to respiratory failure. Persistent pulmonary hypertension of the newborn can follow sepsis.
The primary sites of infection are: Skin,nasopharynx,oropharynx,conjunctiva,umbilicus.
.
Pneumonia is the commonest disease.
B-Late onset: usually presents after the first week, commonly by meningitis which presents by 2-3 weeks, the cause of delay and predilection for CNS involvement is unclear.Mortality from meningitis is about 20-25%.Group B streptococcus is the commonest organism but Listeria monocytogenes acconts for up to20%.
C-Nosocomial: usually occurs in neonatal intensive care units (NICU) and in ill infants. It depends on NICU environment, invasive monitoring and technique.
common organisms in nosocomial sepsis are staph epidermidis,G-ve rods,like pseudomonas,klebsiella,serratia,proteus and fungi.
Risk factors for neonatal sepsis:
1-prematurity(<37 weeks gestation).
2-prolonged rupture of membranes(more than 24hours).
3-maternal fever(>37.5 c).
4-maternal UTI or genital infection.
5-meconium stained or foul smellingamniotic fluid.
6-ressuscitation at birth with low APGAR(<6 at 1,5 minutes).
7-multiple gestation.
8-invasive procedures.
9-artificial feeding.
CLINICAL PRESENTATION:
Clinical symptoms are non specific and a high index of suspicion is the corner stone for early diagnosis, blood culture is a late diagnostic tool if it is+ve.
a-Reluctance to feed..
b-Respiratory distress,grunting and apnea.
c-lethargy,blank look,bulging anterior fontannelle.
d-hypo or hyperthermia.Only 50% of infected neonates have high temp.
e-jaundice.
f-vomiting,diarrhea,abdominal distension.
g-skin rash,skin mottling(cutis marmorata),ecthyma gangrenosum(deep ulcers with ecchymotic margins commonly seen in klebsiella infection),empetigo,cellulitis,omphalitis.
h-tachycardia,ECG changes.
i-poor peripheral perfusion,delayed capillary refill(more than 2 seconds).
j-hypotension.
k-hypoglycemia or hyperglycemia.
l-sclerema,petichie,purpura.
j-edema.
k-hepatosplenomegaly,jaundice
l-convulsions .
30% of women have asymptomatic GBS colonization.
WHO Criteria of severe sepsis:
1-Feeding ability reduced.
2-No spontaneous movement.
3-Temp.>38 degree.
4-Prolonged capillary refill time.
5-Lower chest wall indrawing.
6-Resp.rate>60/min.
7-Grunting.
8-Cyanosis.
9-History of convulsions.
D.D:respiratory distress syndrome,metabolic disorders,Perinatal asphyxia,intracranial hemorrhage,hypoplastic left heart syndrome,inborn error of metabolism.
BLOOD FINDINGS:Blood tests should be done 6-12 hours after birth
1-Thrombocytopenia(<100000/c,mm) is seen in 10-60%,
2-Total WBC count(increase or decrease) is less sensitive than neutrophil count and immature neutrophils it can increase in haemorrhage,asphyxia,convulsion..Abnormal neutrophil count is seen in 2/3 of cases,so it is not a good indicator of sepsis,Neutropenia <1500 is commonly seen.The immature neutrophil to total ratio is more sensitive(I/T ratio) a figure of 0.16 is normal,sensitivity of I/T ratio is 60-90%.When the I/T ratio is greater than 0.2,this indicates that there is a left shift(there are more immature neutrophils than mature neutrophils in the peripheral blood). The I/T ratio may be elevated in 25% to 50% of uninfected infants
I/T ratio=immature/Total(mature+immature neutrophils).
Immature cells appear when there is excessive use of mature cells.
Despite the frequency of low platelet counts in infected infants, they are a
nonspecific, insensitive, and late indicator of sepsis
LABARATORY STUDIES:There is no Lab test with 100% specificity and sensitivity .
1-Blood,CSF,Urine cultures..
Blood culture
Although essential for diagnosis and appropriate management, blood culture results are not immediately available and their yield is low (6–32%). The yield depends on skin disinfection, sample volume and sampling site. Ideally 3 ml of blood is collected for both aerobic and anaerobic cultures. Samples less than 1 ml may produce false negative results. A Gram stain on buffy coat smear may give earlier information, and sending several blood cultures.
CSF culture
Because meningitis may accompany neonatal sepsis in up to one-third of cases a lumbar puncture should rarely be omitted from the ‘septic screen’. Some question the wisdom of routine lumbar puncture with septic screens but if CSF examination is omitted the diagnosis of meningitis may be delayed or missed. Interpretation of cerbrospinal fluid tests in the newborn differs from that in older children .
CSF should be performed for infants with signs of sepsis who can safely undergo the procedure, for infants with a positive blood culture, for infants likely to be bacteremic (on the basis of laboratory data), and infants who do not respond to antimicrobial therapy .
. With a delay in analysis(2 hours), white blood cell counts and glucose concentrations decrease significantly
2-FBC:Platelets,low platelet count is an indicator of infection and the presence of large platelets has a poor prognostic value.,neutrophil count,I/T ratio.
50% of+ve blood culture patients have normal WBC count.2/3 of cases have abnormal neutrophil count.Micro ESR(done by using PCV tube) is suggestive of infection if it is more than 15 mm in the first hour.
3-Elevated I/T ratio.
4-Elevated C-reactive protein(CRP) in 50-90%.Increase to 10 times is significant. The sensitivity improves dramatically if the first determination is made 6to12hours after birth. If CRP determinations remain persistently normal, it is strong evidence that bacterial sepsis is unlikely, and antimicrobial agents can be safely discontinued.
5-Elevated IgM level in congenital infection.
6-Imaging,CT scan,ultrasound,CXR.
7-Cord Interleukin 6&8 measurement are predictive of sepsis
8-Increase in Procalcitonin level,it is produced by hepatocytes and monocytes,it increases by 6-8 hours after bacterial infection,a level of 2.3ng/ml is abnormal
Procalcitonin concentration has a bettersensitivity than does CRP concentrationbut is less specific.
9-Iterleukin-6(induces CRP) and TNF alpha
10-PCR
11-Gram stains of gastric aspirates to identify bacteria are of limited value
and are not routinely recommended.
12-Cultures and Gram stains of tracheal aspirate specimens may be of value if obtained immediately after endotra-
cheal tube placement.
Cultures of superficial body sites,gastric aspirates, and urine are of
no value in the diagnosis of early-onset sepsis
TREATMENT:
Early treatment is very important,no delay should be made,waiting for Lab. Results.
1-Antibiotics should be given by IV route,IM is painful,Oral absorption is irratic,transdermal application is being studied in prem. Antibiotics take 12-24 hours to show effect.
Duration:clinical sepsis,based on clinical suspicion :7-10 days , meningitis,14-21 days ,Osteomyelitis:4-6 weeks,..
a- Ampicillin(150mg/kg per dose twice daily+gentamicin(3-4mg/kg/24 hours).
(Third generation cephalosporins like cephotaxime.
Vancomycin may be added.
Ceftriaxone is contraindicated in neonates because it is highly protein bound and may displace bilirubin, leading to a risk of kernicterus.
b-Granulocyte transfusion.
C-Granulocyte Macrophage Colony Stimulating Factor(GM-CSF) and Granulocyte Colony Stimulating Factor(G-CSF) have been used,the evidence is not strong .
D-TPN.
F-IPPV.
G-Double volume blood exchange with adult whole blood has not been shown to be beneficial, It may reduce mortality to 50%.
H-Supportive care:Incubator care,correction of acid base abnormalities,oxygen,dopamine,fluid and electrolytes correction..
GCSF is a glycoprotein stimulates proliferation and differentiation of neutrophil granulocytes precursors and activates mature neutrophils,it is prepared by recombinant DNA technology.
J-FFP:There is no evidence that infusion of FFP has any beneficial effect on humoral immunity of the newborn ,it’s routine use is unjustified.
k-Pentoxiphylline:xanthine derivative,it inhibits TNF(Tissue Necrosis Factor) production,preserve microvascular blood flow,inhibits Neutrophil deformability and by this way it reduces tissue injury.
J-Metronidazole for anaerobic infections,for 7-10 days.
(Intravenous immunoglobulin)IVIGs have multiple mechanisms of action which promote host defenses. IVIGs bind to cell surface receptors, provide opsonic activity, activate complement, promote antibody dependent cytotoxicity,and phagocytosis and can improve neutropenia by enhancing the release of stored neutrophils.
Vit.K
Complications:
Septic emboli,abscesses,septic arthritis,osteomyelitis,septic shock,DIC.Meningitis is present in 1/3 rd of cases.Mortality is about 50%.
PROGNOSIS
Mortality from neonatal sepsis has not fallen for many years. Serious morbidity can also result.
Congenital infection
Incidence 0.5-2.5%
Common organisms:Rubella,Toxoplasma,CMV,Herpes,Treponema,HIV,Ebestein bar virus,Hepatitis B virus.
Prevention of neonatal sepsis:
1-Hand washing by caregivers.
2-Breast feeding.
3-Tetanus immunization of mothers.
4-Umbilical stump should be kept clean.
5-Keep interventions to the lower limit.
6-Treat infected mothers. Maternal treatment with intrapartum intravenous antimicrobial agents for the prevention of GBS infections.
Use of group B streptococcal vaccine administered to susceptible women in the child bearing age show promise.
7-Avoid overcrowding in NICU.
8-Good ventilation.
10-No prophylactic antibiotics for nosocomial infections.
NEONATAL CONVULSIONS
Neonates are at particular risk to get convulsions because of the immaturity of the brain.About 80% present in the first 48 hours of life.
Types:1-focal(The commonest type) 2-multi-focal:many muscle groups are involved. 3-tonic:rigid presentation with deviation of the eyes(The tonic seizures have a poor prognosis because they frequently accompany periventricular haemorrhage). 4-myoclonic:brief focal or generalized jerks of the extremities or body(They may mimic the Moro reflex and startling responses) Myoclonic seizures are associated with the most severe brain damage,however, healthy pre-term and rarely full-term neonates may have abundant myoclonic movements during sleep .5-subtle seizures:chewing,excessive salivation.blinking,apnea,nystagmus
Pathophysiology:
1-Excessive,synchronized depolarization.
2-Distruption of ATP-dependent resting membrane potentials,which causes Na to enter cells and K to leave the cells.
Jitterness:abnormal movement,simulates tremor,stimulus dependent(stopped by gripping the limb),no ocular deviation.
Normal Behaviours
Amongst normal behaviours neonates may stretch, exhibit spontaneous sucking movements and have random and non-specific movements of the limbs. Intense physiological myoclonus may occur during rapid eye movement sleep. Jitteriness or tremulousness of the extremities or facial muscles is frequent in normal or abnormal neonates.
Tremor has a symmetrical ‘to and fro’ motion, is faster than clonic seizures, mainly affects all four limbs and will stop when the limb is restrained or repositioned.
Causes of convulsions:
1-Hypoglycemia.
2-Hypocalcemia and or hypomagnesemia.
3-Hypo/hypernatremia.
4-Meningitis.
5-Intracanial bleeding(15%).
6-Hypoxia.
7-Perinatal asphyxia
8-Birth trauma.
9-Kernicterus.
10-Pyridoxine dependency.(a rare disorder with an autosomal recessive inheritance,pyridoxine is required in the synsethesis of glutamic acid decarboxylase which is required for the formation of GABA.pyridoxine is needed in a large amount,100-200mgm IV.
11-Inborn error of metabolismlike Galactossemia,Acidemias.
12-Developmental defects.
13-Drug withdrawal like phenobarbitone,diazepam,heroin,.
14-No cause found in 10%.
15-Benign familial neonatal seizures(an autosomal dominant condition begins on the 2-3rd day of life,patients are normal between fits,resolves within 1-6 months,a family history is usual,development is normal...
16-Infection like TORCH infection.
17-Benign idiopathic neonatal seizures typically present at day 5 of life(fifth day fits)The diagnosis can be made only after other causes of neonatal seizures have been excluded. A single episode of repetitive clonic seizures that are mainly unilateral, often of alternating side and lasting for around 20 h in a full-term neonate that was normal up to that stage. All relevant investigations other than EEG are normal
Labaratory studies:EEG and video EEG is recommended to capture abnormal movement for follow-up treatment.
1-Blood sugar
2-Electrolytes
3-CSF
4-Plasma and urine amino acid chromatography.
5-Brain ultrasound
6-Brain CT scan
7-MRI
Complications
-Cerebral palsy
Cerebral atrophy
Hydrocephalus
Epilepsy
Feeding difficulties.
TREATMENT:Stabilize vital functions.
1-Stop convulsions by:
A-Diazepam 0.3mgm/kg iv or 0.5mgm rectally after dilution with normal saline, can be repeated. Lorazepam can be used in a dose of 0.05mg/kg IV can be repeated.
B-Phenobarbital 20mgm/kg loading dose then 5mgm/kg/day.It acts on sodium current and GABA receptors.It can be repeated in a loading dose after 10 minutes.
C-Phenytoin 20mgm/kg stat then 5mgm/kg/24hours..(fosphenytoin,a pro-drug of phenytoin can be used in a loading dose of 10mg/kg
E-Sodium valproate,it can be given rectally or IV.
F-Treat the cause and correct metabolic abnormalities(Hypocalcemia,hypoglycemia,hypomagnesemia)
G-Lidocaine have been used in some centers.
H-Respiratory support.
If convulsions have resolved, if neurological findings are normal and if the EEG is normal,the anticonvulsants can be stopped within the first 14 days of life,otherwise it should be continued for 1-3 months.
Prognosis:
This is cause dependent because the main factor that determines outcome is the underlying cause and not the seizures themselves.
.
Neonatal reflexes;
1-Moro response: The baby is put supine, head is lifted a little off table and then dropped suddenly supported by the examiner's hand. There is abduction and extension of arms with opening of hands followed by adduction. It disappears by the age of 3-4 months.
Asymmetrical Moro ReflexHemiplegia
Fracture Humerus
Fracture Clavicle
Dislocation of the Shoulder
Erbs Palsy
Klumpke's Paralysis
2-Rooting reflex: When the corner of the mouth is touched, the lower lip is lowered and the tongue moves toward the stimulus.