Triple I (Intrauterine inflammation and infection)

Neonatal perspective

Jagadish Elumalai MD FAAP

Attending Neonatologist
Novant Health UVA Health system Prince William Medical Center, Manassas VA
Novant Health UVA Health system Haymarket Medical Center, Haymarket VA
9/21/2017
Disclosure
No financial relationships with commercial interests

2
Triple I : Neonatal Perspective
Sep 21, 2017
Learning objectives
Brief overview of Triple I
Proposed algorithm for neonatal management
Neonatal Sepsis calculator vs Triple I
Number needed to treat and Number needed to harm
Fetal and neonatal exposure to antibiotics
Antibiotics stewardship program in neonates

3
Triple I : Neonatal Perspective
Sep 21, 2017
Chorioamnionitis
Prior to Triple I classification, chorio diagnosed by fever PLUS 1 or 2 of
the following:
Maternal leukocytosis (>15000)
Maternal tachycardia
Fetal tachycardia
Uterine tenderness
Foul smelling amniotic fluid

However this evolved into fever + clinical suspicion

Lots of pregnant women getting treated

How Neonatal providers think?

Diagnosis of maternal chorioamnionitis (soft call or strong suspicion)

or
OB team started antibiotics for mother

Neonatal provider
If OB team is concerned enough to suspect infection and start antibiotics in
mother, I cant take the risk of not doing a work up/treat the baby

In line with current guidelines

CDC, AAP, NICE
Triple I- the new Chorioamnionitis

At a system level Triple I filters off

Isolated maternal fever, hence
reducing knee jerk reaction of
starting maternal antibiotics in
patients with Isolated maternal
fever.

Take away the soft call for diagnosing Chorioamnionitis

Develop stricter criteria for Intra-uterine inflammation/infection
Triple I
Remember 39 C or 102.2 F
0 0
 Triple I incorporated in delivery note in EPIC

University of Utah
Triple I workshop summary
Proposed algorithm for neonatal management
Variable Score
Well appearing 0
Not well-appearing 1

GA > 34 weeks 0
GA < 34 weeks 1

Isolated maternal fever 0

Suspected Triple I 1
Confirmed Triple I 2

SCORE > 2 = Work-up & treat

Triple I and Neonatal EOS calculator

Independent of Triple I, use of Neonatal Sepsis Calculator at birth

reduces the number of infants exposed to antibiotics when compared
to CDC criteria for management of Chorioamnionitis

If we adopt Triple I, we may be able to reduce maternal and fetal

exposure of antibiotics to some extent
NNT to treat one true case of Early-onset neonatal
sepsis

Using CDC
NNT=823

Using Sepsis
Calculator
NNT=118
Study behind Sepsis calculator: Number needed to treat (NNT)

Pediatrics
January 2014, VOLUME 133 / ISSUE 1
Stratification of Risk of Early-Onset Sepsis in Newborns 34 Weeks Gestation
Gabriel J. Escobar, Karen M. Puopolo, Soora Wi, Benjamin J. Turk, Michael W. Kuzniewicz, Eileen M. Walsh, Thomas B. Newman, John Zupancic, Ellice Lieberman, David Draper
Number needed to treat Number needed to harm

Antibiotic resistance
Exposure of newborn to antibiotics-alters
gut microbiota
Using CDC
NNT=823 NICU admission means
Interference with successful
breastfeeding
Using Sepsis
Calculator
Interference with mother infant bonding
NNT=118 Exposure to multi-resistant microbes
Medical errors
Treatment complications
Increase cost
Increase workload to health care system
Number needed to harm: Antibiotic
resistance
Number needed to harm: Ampicillin resistant E coli neonatal sepsis

16
Fetal exposure to antibiotics

Estimated 40% of pregnant women receive antibiotics

GBS colonization (10-30%)
C-section (30-35%)
Asymptomatic bacteriuria (2-10%)
Pyelonephritis
PPROM
Chorioamnionitis (3-10%)a

a- Higgins RD, Saade G, Polin RA, et al. Chorioamnionitis Workshop Participants. Evaluation and
management of women and newborns with a maternal diagnosis of chorioamnionitis: summary of a workshop.
Obstet Gynecol2016;127:426e36.
Consequences of altering microbiome-prenatally

Intrauterine environment is not sterile

Active maternal-fetal exchange of commensal

micro-organisms a,b.

Maternal antibiotics administered disrupt the

normal colonization of the developing fetal
intestinal microbiome with long-lasting effects.
ORACLE study: Co-amoxiclav was associated with an four
fold increased risk of neonatal necrotizing enterocolitis
(RR 4.72, 95% CI 1.57 to 14.23)

a: Romano-Keeler J, Weitkamp JH. Maternal influences on fetal microbial colonization and immune development. Pediatr
Res 2015;77:189e95.
b: Neu J. The microbiome during pregnancy and early postnatal life. Semin Fetal Neonatal Med 2016;21:373e9.
 GBS prophylaxis

GBS sepsis rate was high

Still antibiotics use high in NICU

More antibiotics use in NICU

GBS sepsis rate has come down

E coli sepsis rate did not increase
during study period 2006-2009

700 women treated to prevent 1 case of GBS

Best we have, No GBS vaccine, No rapid sensitive test

Consequences of altering microbiome-postnatally

Prolonged initial antibiotic therapy in VLBW infants has been associated with
increased risks of necrotizing enterocolitis (NEC) and deatha

Prolonged treatment with broad spectrum

Colonization of infants with antimicrobial-resistant Gram-negative bacteria at the time of
discharge from the NICU, with the potential for dissemination of resistant Gram-negative bacteria
from colonized infants to other medical facilities or to the communityb

a: Cotten CM, Taylor S, Stoll B, et al. NICHD Neonatal Research Network. Prolonged duration of initial empirical
antibiotic treatment is associated with increased rates of necrotizing enterocolitis and death for extremely low birth
weight infants. Pediatrics 2009;123:58e66.

b:Clock SA, Ferng YH, Tabibi S, et al. Colonization with antimicrobial-resistant Gram-negative bacilli at neonatal
intensive care unit discharge. J Pediatr Infect Dis Soc 2016 Mar 28.
Antibiotics in NICU

Birth asphyxia
Maternal chorioamnionitis/Triple I

Respiratory distress Preterm < 28 weeks

Preterm 28-34
Hypotension
weeks

Unexplained Late Preterms

hypoglycemia

Temperature Unexplained illness

instability Apnea
No antibiotic treatment is not the same as no care, and that
close clinical observation, increased monitoring of at-risk
infants and parental education is required to ensure success in
decreasing empiric antibiotic use without adverse effects.
Kuzniewicz MW, Puopolo KM, Fischer A, et al. A quantitative, risk-based approach to the
management of neonatal early-onset sepsis. JAMA Pediatr 2017;171:365e71.

Frequent and reliable monitoring

q1h x 6 hours q3h x 18 hours
Pediatrics 2017 Jul;140(1). pii: e20171155. doi: 10.1542/peds.2017-1155. Epub 2017 Jun 8.
Time to Overhaul the "Rule Out Sepsis" Workup. Hooven TA, Polin RA.
Reliability of blood culture
Reasons quoted for reduced reliability
Small blood volume
Maternal antibiotics

Automated blood culture systems with optimized enriched broths identify most
(>94%) micro-organisms within 48 h of incubation, even with low colony countsa,b

Maternal intrapartum antibiotic treatment does not appear to prolong the time
to positivity of neonatal blood cultures in infants with EOSc

Two blood cultures to increase reliability and confidence

a: Garcia-Prats JA, Cooper TR, Schneider VF, Stager CE, Hansen TN. Rapid detection of microorganisms in blood cultures utilizing an
automated blood culture system. Pediatrics 2000;105:523e7.
b: Lancaster DP, Friedman DF, Chiotos K, Sullivan KV. Blood volume required for detection of low levels and ultralow levels of organisms
responsible for neonatal bacteremia by use of Bactec Peds Plus/F, Plus Aerobic/F medium, and the BD Bactec FX system: an in vitro study. J
Clin Microbiol 2015;53: 3609e13.
c: Mukhopadhyay S, Puopolo KM. Clinical and microbiologic characteristics of early-onset sepsis among VLBW infants: opportunities for
antibiotic stewardship. Pediatr Infect Dis J 2017;36:477e81.
Antibiotic stewardship program for neonates

Based on recommendations of
CDC
Infectious disease society of America
Society of Healthcare Epidemiology of America

Semin Fetal Neonatal Med. 2017 Oct;22(5):278-283. Epub 2017 Jul 21.
Antibiotic stewardship in perinatal and neonatal care. Ramasethu J1, Kawakita T2.
Antibiotic stewardship program for neonates

Based on recommendations of
CDC
Infectious disease society of America
Society of Healthcare Epidemiology of America

Semin Fetal Neonatal Med. 2017 Oct;22(5):278-283. Epub 2017 Jul 21.
Antibiotic stewardship in perinatal and neonatal care. Ramasethu J1, Kawakita T2.
Communication

Relevant to baby management

Maternal team to Neonatal team

Prior to delivery
Isolated maternal fever vs Triple I
Post delivery
Maternal post natal course
Placental pathology report

Neonatal team to Maternal team

Clinical course of baby
Positive blood culture
Triple I incorporated in delivery note in EPIC
Obstet Gynecol. 2016 Mar;127(3):426-36.
Evaluation and Management of Women and Newborns With a
Maternal Diagnosis of Chorioamnionitis: Summary of a Workshop.
Higgins RD1, Saade G, Polin RA, Grobman WA, Buhimschi
IA, Watterberg K, Silver RM, Raju TN; Chorioamnionitis Workshop
Participants
Antibiotic usage metrics

Days of therapy (DOT) is calculated as the aggregate sum of antibiotics used per
patient per day, per 1000 patient-days.

Antibiotic use rate (AUR) is the total number of patient-days on which infants are
exposed to antibiotics (or antifungals) administered intravenously or
intramuscularly per 100 patient-days, expressed as a percentage.

Ensure the safety of reduction of antibiotic usage by monitoring relapse or

readmission rates.
Research directions

An effective vaccine for GBS in pregnant women will reduce the use
of antibiotic prophylaxis in 30% of women at delivery.

Improved diagnostic tests to rule out bacterial infections or confirm

viral infections will reduce antibiotic use in culture-negative sepsis.

Observation with evaluation vs Initiation of antibiotics in

symptomatic babies
In perfect world we like NNT=1

Always on target
 History, exam, labs, ongoing
evaluation, following expected
course of non-sepsis, clinical
In perfect world we like NNT=1 improvement

Always on target Clinical judgement

CDC

Sepsis
calculator
Thank you
Strategies
Systematic evaluation of the need for continued treatment after 48 h, would help to focus efforts
to improve compliance and gradually bring about institutional culture change.

Electronic hard stops may be set to automatically discontinue empirical antibiotic therapy after
36-48 h unless reinstituted by the physician.

Antibiotic restriction guidelines, requiring pre-authorization for select antibiotics, have been used
to prevent indiscriminate use of broad spectrum antibiotics.

Education, dissemination of evidence-based guidelines, audits, regular reporting of antibiotic use

metrics, and resistance patterns maintain the momentum.

Participation in a multicenter collaborative such as the Vermont Oxford Network iNICQ 2017:
Choosing Antibiotics Wisely offers the opportunity to share tools, standardized protocols,
progress, and lessons learned.
Antibiotic usage metrics
Days of therapy (DOT) is calculated as the aggregate sum of antibiotics
used per patient per day, per 1000 patient-days.
A neonate receiving ampicillin and gentamicin daily for 2 days would be measured as
4 DOT (2 DOT for each day). DOT may be applied to all or to select antibiotics, and
measured monthly to monitor trends.

Antibiotic use rate (AUR) is the total number of patient-days on which

infants are exposed to antibiotics (or antifungals) administered
intravenously or intramuscularly per 100 patient-days, expressed as a
percentage.
In NICUs with a significant population of small premature infants with prolonged
lengths of stay, AUR may be low, but measuring usage trends indexed to the patient
population would still provide valuable information.
Practice points
Widespread antibiotic use in neonates may be associated with
development of antibiotic resistance, and through the effect on the
microbiome, long-standing immunological and metabolic
consequences.

Antibiotic use in neonates should be based on evidence-based

guidelines, and monitored, with focus on reducing indiscriminate use.
Monitoring outside NICU
If newborns with a maternal history of chorioamnionitis are to be
monitored for signs of sepsis outside the NICU setting, observations
must be frequent (at least hourly for the first 6 hours of life and then
every 3 hours for the next 18 hours) and performed by adequately
trained medical staff. In the absence of frequent, reliable observation,
there is a possibility that the early signs of sepsis will be missed and go
untreated with potentially severe consequences

Pediatrics. 2017 Jul;140(1). pii: e20171155. doi: 10.1542/peds.2017-1155. Epub 2017 Jun 8.
Time to Overhaul the "Rule Out Sepsis" Workup.
Hooven TA1, Polin RA2.