Utility of Early Onset Neonatal Sepsis Calculator

Dr. R. Adhi Teguh Perma Iskandar Sp.A(K)

Child Health Department of Ciptomangunkusumo Hospital
Medical Faculty Of University of Indonesia
 Objective

• Mother and Newborn risk factor for EONs

• Current AAP Guideline for EONs
• Sepsis Calculator for EONs
• Evidence of using Sepsis Calculator for EONs
• Problem for sepsis calculator implementation
in Indonesia
 Introduction
Neonatal Sepsis

Early Onset Neonatal Sepsis (EONS) Late Onset Neonatal Sepsis (LONS)
<72 hour >72 hour

• Transplacental Infection
• Ascending infection Hospital environment or
from the cervix caused the community
by microorganisms
colonizing the maternal
genitourinary tract or
birth canal

Selimovic A, Skokic F, Bazardzanovic M, Selimovic Z. The predictive score for early onset neonatal sepsis. The Turkish Journal of Pediatrics. 2010;52:139-44
Mortality Cause in the NICU
Pulmonary
Renal Failure % CDH
Hypertension %
Shock/anemia % Other %

Major Heart Defects, 3%

Genetic Syndrome, 5%

SIP, 1.1%
Sepsis ≤ 7 days, 5%

Sepsis > 7 days, 7%

Air leak, 0.6%

BPD 3%

Pulmonary hemorrhage, 2%

Jacob et al. Etiologies of NICU Deaths. Pediatrics. 2015;135(1):e59–e65

 Epidemiology of EONS
• Sepsis in neonatal is rare (0.5-1.0 : 1000 live births)
• Incidence of early onset sepsis (EOS) is as low as
1:25.000 in well-appearing term and late-preterm
infants
• Incidence of sepsis in very low birth weight (VLBW)
infant is 20x higher than term infants.
• Sepsis work ups were done 30-200x times more than
sepsis-proven infants.
• Clinical symptoms set up half of all sepsis workup,
while most infants suffer from non-infectious diseases.

Polin RA. Evidence-Based approach to early-onset sepsis: finding needle in a haystack. Columbia
University.
Chorioamnionitis Mother (CAM)
Acute inflammation
membranes and chorion
of the placenta

Chorioamnionitis
or Ascending polymicrobial
Intraamniotic bacterial infection
infection

Intact membranes
or
Rupture membranes
 Chorioamnionitis
• Maternal fever of greater
than 38°C (100.4°F) and at
least two of the following
criteria:
– Maternal leukocytosis
(greater than 15 000
cells/mm3),
– Maternal tachycardia (greater
than 100 beats/minute),
– Fetal tachycardia (greater
than 160 beats/minute),
– Uterine tenderness, and/or
– Foul odor of the amniotic
fluid.

Intrauterine infection and preterm delivery. N Engl J Med. 2000;342:1500-1507

Clinical Diagnosis of Chorioamnionitis

Result Suggesting
Test Chorioamnionitis Comments
Clinical Parameters Generally nonspesific

Fever Temperature > 100.4° F 95%-100% sensitive

twice or > 101° F once

Maternal tachycardia > 100/min 50%-80% sensitive

Fetal tachycardia > 160/min 40%-70% sensitive

Fundal tenderness Tenderness on palpation 4%-25% sensitive

Vaginal discharge Foul-smelling discharge 5%-22% sensitive

Clin Perinatol 37 (2010) 339–354

Amniotic Fluid Laboratory Diagnosis of
Chorioamnionitis
Result Suggesting
Test Chorioamnionitis Comments
Amniotic fluid parameter
Culture Microbial growth Diagnostic gold standart
Gram stain Bacteria or white blood 24% sensitive, 99% spesific
cells (> 6/high power field)
Glucose level < 15 mg/dL Affected by maternal
hyperglycemia 57%
sensitive, 74% spesific
IL-6 > 7.9 ng/mL 81% sensitive, 75% spesific
Matrix metalloproteinase Positive result 90% sensitive and 80%
spesific
White blood cell count > 30/cubic mm 57% sensitive, 78% spesific
Leukocyte esterase Positive (dipsticks) 85%-91% sensitive, 95%-
100% spesific
Clin Perinatol 37 (2010) 339–354
Chorioamnionitis  Early Onset Sepsis

Elevated Histological Polymorphonuclear

infiltration of placenta,
cytokines or membranes and
amniotic fluid Biochemical umbilical cord

Microbiological

Clinical
Maternal fever Positive
tachycardia,
culture
leukocytosis, CRP,
vaginal discharge, Positive PCR
uterine tenderness. Fetal
Fetal tachycardia vasculitis
(funisitis)

Neonatal Sepsis
 • CAM is an unreliable predictor of EOS due to
variability in its clinical diagnosis among
obstetricians.
• The rate of EOS in infants born to mothers
with CAM is lower.
• 3 studies of late preterm and term infants
born to mothers with CAM report EOS rates of
4/554 (0.7%), 1/698 (0.14%) and 5/1243
(0.4%), respectively.

Money N, Newman J, Demissie S, Roth P, Blau J. Anti-microbial stewardship:antibiotic use in well-appearing term neonates born to mothers
with chorioamnionitis. J Perinatol.2017;00:1-6
 Other Major Risk Factor For EONS

• Preterm birth
• Maternal colonization with GBS
• Rupture of membranes > 18 hours

PEDIATRICS Volume 129, Number 5, May 2012

Initial signs and symptoms of infection
in newborn infants
General Fever, temperature instability, “not doing well”, poor
feeding, or oedema
Gastrointestinal system Abdominal distention, vomiting, diarrhoea, or hepatomegaly
Respiratory system Apnoea, dyspnoea, tachypnoea, retractions, flaring,
grunting, or cyanosis
Renal system Oliguria
Cardiovascular system Pallor, mottling, cold, clammy skin, tachycardia, hypotension,
or bradycardia
CNS Irritability, lethargy, tremors, seizures, hyporeflexia,
hypotonia, abnormal Moro reflex, irregular respiration, full
fontanel, or high-pitched cry
Haematological system Jaundice, splenomegaly, pallor, petechiae, purpura, or
bleeding

Shane A.L, Sanchez P, Stoll B.J. Neonatal sepsis. The Lancet.2017;390;10104:1770-80

Well Appearing Baby
 Yes

No
Yes

No
No

Yes
Yes

No
Yes

No
Yes
Evaluation of Asymptomatic Infants ≥ 37 weeks’
Gestation with Risk Factors for Sepsis

Pediatr. 2012;129(5).
Evaluation of Asymptomatic Infants < 37 weeks’
Gestation with Risk Factors for Sepsis

Pediatr. 2012;129(5).
Evaluation of Asymptomatic Infants ≥ 37 weeks’ Gestation with
Risk Factors for Sepsis (No Chorioamnionitis)

Pediatr. 2012;129(5).
• Under current CDC guidelines, 200 neonates a re-
treated with antibiotics for each episode of EOS
• It against antibiotic stewardship advice that we
should reduced using inappropriate antibiotic.
• Skin-breaking procedures for blood sampling and
peripheral intravenous (PIV) catheter placement
• Avoiding separation of mother and neonate after
delivery could improve maternal-infant bonding
and increase breastfeeding success

Jt Comm J Qual Patient Saf. 2016;42:232-239

 Chances to reduce antibiotics exposure

• Well-appearing infants (≥ 35 weeks GA) with

sepsis risk factors (including chorioamnionitis)
• Symptomatic infants with non-infectious
diseases (RDS or TTN) without sepsis risk
factors (who are not critically ill)
• Well-appearing infants with sepsis risk factors
other than chorioamnionitis.

Polin RA. Evidence-Based approach to early-onset sepsis: finding needle in a haystack. Columbia
University.
 Is there any way to solve this problem?

Nested case control study

608 014 Infants born > 34 weeks at 12 kesier permanate medical care program hospital
305 culture proven as case and 915 as controlled
Predictive model based on mother and neonate characteristic
Rather than using cut of value, risk factor are treated as continuous variable

Pediatrics. 128;2011:1555-59
Most Common Causative Organism of EOS

Percentage of positive blood cultures in EOS

Pathogen
UK USA

Gram-positive

Group B streptococcus (GBS) 58% 43%

Coagulase-negative staphylococci (CoNS)
frequently considered as contaminant 20% 24%

Gram-negative

Escherichia coli (E. coli) 18% 29%

Herk W. V, Stocker M, Rossum A. M. Recognising early onset nepnatal sepsis: an essential step in appropriate antimicrobial use. Elsevier.2016;72:S77-82
Estimating the Probability of Neonatal Early Onset
Infection on the Basis of Maternal Risk Factors

20

15
Cases per 1000 live births

10

97 98 99 100 101 102 103

Highest maternal temperature, ̊F

Puopolo K.M, Draper D, Wi S, Newman T.B, Zupancic J, et al. Pediatr. 2011;128(5).

 Estimating the Probability of Neonatal Early Onset
Infection on the Basis of Maternal Risk Factors (2)

4
Cases per 1000 live births

0 10 20 30 40 50

Duration of ROM, h

Puopolo K.M, Draper D, Wi S, Newman T.B, Zupancic J, et al. Pediatr. 2011;128(5).

 Estimating the Probability of Neonatal Early Onset
Infection on the Basis of Maternal Risk Factors (3)

3
v
Cases per 1000 live births

0
34 36 38 40 42
Gestational age, wk

Puopolo K.M, Draper D, Wi S, Newman T.B, Zupancic J, et al. Pediatr. 2011;128(5).

 Estimating the Probability of Neonatal Early Onset
Infection on the Basis of Maternal Risk Factors
Variable Adjusted OR (95% CI)
Gestational age 0.001 (0.0001-0.014)
Gestational age squared 1.09 (1.05-1.13)
GBS carrier status
Negative Reference
Positive 1.78 (1.11-2.85)
Unknown 1.04 (0.76-1.44)
Duration of ROM 3.41 (2.23-5.20)
Highest intrapartum temperature 2.38 (2.05-2.77)
Intrapartum antibiotic treatment
None Reference
GBS IAP given on time or any antibiotic not given on 0.35 (0.23-0.53)
Broad spectrum antibiotics given on time 0.31 (0.13-0.71)
Multivariate Model for EOS Based on Maternal Predictors
Puopolo K.M, Draper D, Wi S, Newman T.B, Zupancic J, et al. Estimating the Probability of Neonatal Early Onset Infection on the Basis of
Maternal Risk Factors. Pediatr. 2011;128(5).
 Bayesian analysis

Pretest Probability (risk of sepsis based on historical data)

infant clinical presentation during 6-12 hours of life

Post test Probability

Neonatal Early Onset Sepsis Calculator

The calculator was developed using a nested

case-control study of infants ⩾34 weeks
gestational age for whom risk factors were
compared between 350 culture-positive cases
and 1063 controls, matched according to birth year
and hospital site from a total cohort of 4600,000
infants
Kaiser Permante Research
 Clinical Illness:
• Persistent need for NCPAP/HFNC/mechanical
ventilation (outside of the delivery room)
• Hemodynamic instability requiring vasoactive drugs
• Neonatal encephalopathy/Perinatal depression
– Seizure
– Apgar Score @ 5 minutes < 5
• Need for supplemental O2 ≥ 2 hours to maintain
oxygen saturation > 90% (outside of the delivery room)
 Equivocal:
1. One Persistent physiologic abnormallyy ≥4 h
-----Tachycardia (HR ≥ 160)
-----Tachypnea (RR ≥ 60)
-----Temperature instability (≥ 100.4°F or < 97.5°F)
-----Respiratory distress (grunting, flaring, or retracting) not requiring
supplemental O2
2.Two or more physiologic abnormalities lasting for ≥ 2 h
-----Tachycardia (HR≥ 160)
-----Tachypnea (RR ≥ 60)
-----Temperature instability (≥ 100.4°F or < 97.5°F)
-----Respiratory distress (grunting, flaring, or retracting) not requiring
supplemental O2
A Quantitative, Risk-Based Approach to The
Management of Neonatal Early Onset Sepsis

Kuzniewicz M.W, Puopolo K.M, Fischer A, Walsh E.M, Li S, et all. Jama Paed.2017
 Impact of Neonatal Early-Onset Sepsis Calculator on
Antibiotic Use Within Two Tertiary Healthcare Centers
Characteristics

Gestational age, weeks+days (s.d. in days) 39+4 (±11)

Birth weight, kg (s.d.) 3.37 (±0.5)

Risk Calculator
Admitted to NICU, n (%) 44 (21) Start Watchful
Total
antibiotics waiting
Suspected maternal chorioamnionitis, n (%) 161 (78.5)
CDC/AAP Start
47 141 188 (93%)
Maternal Tmax, ∘C (s.d.) 382.2 (±0.7) antibiotics
Watchful
Duration of ruptured membranes, hours (s.d.) 18 (±43) - 14 14 (7%)
waiting

Positive Group B Streptococcus status, n (%) 39 (19) Total 47 (23%) 155 (77%) 202

1 min Apgar, median (range) 8 (1-9) Abbreviations: AAP, American Academy of Pediatrics; CDC, Centers for
Disease Control. Statistically significant difference between proportion
of antibiotics recommended (P<0.001). Three of 205 patients removed
5 min Apgar, median (range) 9 (2-10)
due to missing information
Neonatal WBC count, cells x109 L-1 (s.d.) 21.5 (±6.8)

Neonatal immature to total neutrophil ratio (s.d.) 0.22 (±0.15)

Abbreviations: n, number of subjects; NICU, neonatal intensive care

unit; Tmax, maximum intrapartum temperature; WBC, white blood
cell.
J Perinatol.2016;00:1-6
 Implementation and Evaluation of The Early-Onset
Sepsis Risk Calculator in a High-Risk University Nursery
Before Implementation After Implementation
p
(N=180) (N=76)
NICU admission, n (%) <.001
No 16 (9) 48 (63)
Yes 163 (91) 28 (37)
Missing 1 0
Antibiotic usage rate, n (%) <.001
Total patients 179 76
Received antibiotics 168 (94) 28 (37)
Did not received antibiotics 11 (6) 48 (63)
Total charges, thousand dollars .005
n 179 76
Mean (SD) 14.7 (16.4) 11.6 (14.9)
Total bed charges, thousand dollars <.001
n 179 76
Mean (SD) 12.6 (10.7) 7.7 (7.6)
Length of stay, days <.001
n 179 76
Mean (SD) 6.1 (5.0) 4.5 (3.3)
Abbreviations: EOS, early-onset sepsis; N, number; NICU, neonatal intensive care unit; SD, standart deviation. P values are
calculated from chi-square test for NICU admission and Wilcoxon-Mann-Whitney test for all other outcomes
Beavers J.B, Bai S, Perry J, Simpson J, Peeples S. Clin Paed.2018;1-6
 Sepsis calculator to support antibiotic stewardship in
early-onset neonatal sepsis: a meta-analysis
Rinawati Rohsiswatmo¹, Hardya G. Hikmahrachim², Dinarda U. Nadobudskaya²,
Sonia M. Anjani², Albert You³

Study Name RR LCL UCL

Dhudasia, et al 2018 0.58 0.5 0.69

Strunk, et al 2018 0.55 0.42 0.71

Achten, et al 2018 0.46 0.18 0.88

0.39 0.29 0.52

Beavers, et al 2018
0.25 0.19 0.31
Warren, et al 2016
0.46 0.41 0.51
Overall: P,0.001, I² = 87.5%

0.1 0.25 0.5 0.75 1.1

0.1
Less antibiotic use More antibiotic use
1
Study Name RR LCL UCL

Dhudasia, et al 2018
0.24 0.19 0.39

Strunk, et al 2018
0.67 0.55 0.82

Beavers, et al 2018
0.54 0.43 0.78

Overall: P 0.001, I² = 95.7% 0.46 0.4 0.52

0.1 0.25 0.5 0.75 1.1

0.46

Less blood culture 1 More blood culture

Study Name RR LCL UCL

Strunk, et al 2018 0.79 0.67 0.92

Beavers, et al 2018 0.4 0.3 0.54

Overall: P 0.001, I² = 93.7% 0.68 0.59 0.78

0.1 0.25 0.5 0.75 1.1

0.68

Less admission
 Some Problem for implementing
sepsis calculator in Indonesia

• We still don’t have national Insiden rate of EONs.

• EONs in Indonesia mostly caused by gram negative
rods  might had different characteristics.
• Antenatal care rate is low  inaccurate estimation
of gestational age & Maternal GBS status
• Small gestational age for babies born > 34 weeks is
higher than original stadies
Neonatal Sepsis Surabaya

Mobile app
Data Registry with link to neonatal sepsis calculator
Latest RSCM Study of EONs
 Summary
• Calculator sepsis in not diagnosis tools
• It is only an EONs predictive tools for baby
born > 34 weeks
• Sepsis calculator could reduced both
laboratory and antibiotic overuse in NICU and
reduced long of stays babies in hospital
• We need more study from indonesian
population to implement this tool.
Thank You