Saving lives with 4.

0% chlorhexidine cleansing of the umbilical cord

Luke C. Mullany, PhD, MHS Associate Professor, Johns Hopkins University (lmullany@jhsph.edu) Johannesburg, - April 2013

Infection and umbilical cord

Infection represents a significant cause of neonatal mortality in low resource settings Exposure to pathogens is high at birth and immediate postpartum Umbilical cord vessels are open for 2448 hours after birth Stump is rapidly colonized

Topical Antiseptics and the Cord

~50 years ago: nearly universal use of topical antiseptics in facilities of high income countries ~25-40 years ago: MANY studies on topical antiseptics to examine:

Topical antiseptics reduce exposure to pathogens Less direct evidence for reduction in infection / death

By late 1990s, large literature, but almost NONE from places with high infection risk

WHO Guidelines

Recognizing a lack of clear evidence, WHO provided 3 key recommendations: 1. Promote keeping the cord clean / dry 2. Topical antiseptic could be used where infection/exposure risk is high 3. Research needed for optimal guidelines for high risk settings

*WHO. Care of the umbilical cord. WHO. Geneva, 1998. WHO/RHT/MSM 98.4

Why Chlorhexidine?

Broad spectrum antiseptic solution Readily available, worldwide Excellent safety record Superior to many other choices for reducing cord pathogens WHO Model List of Essential Medicines for cord cleansing Evidence for reduction of mortality

Overview and Pooled Analysis of CHX Trials

S Asia CHX Cord Cleansing Trials

Sarlahi District, Nepal: 2002-2006

Mullany et al, Lancet 2006

Sylhet District, Bangladesh: 2007-2009

Arifeen et al, Lancet 2012

Sindh Province, Pakistan: 2008-2009

Soofi et al, Lancet 2012

Overall Design and Context

In study area, at time of study

Nepal 32 / 1000 92% 413 (700) All live births in study area 133 (4000) All live births in study area 88% 36 / 1000

Bangladesh

Pakistan 30 / 1000 80% 187 (1000) All live births in study area

Overall NMR

% Home Births

No. Clusters (avg size)

Eligibility

Exclusion

Not met within 10 days after birth

Not met within 7 days after birth

Not met within 3 days after birth Con. anomalies

Intervention Provided
Nepal Dry Cord Care Dry Cord Care Bangladesh Pakistan Dry Cord Care

Comparison Group

Intervention Groups

1. Multiple CHX 2. Soap/H2O 4.0% 1,2,3,4,6,8,10 4.0%

1. Multiple CHX 2. Single CHX

1. Multiple CHX 2. Hand Washing 3. HW + CHX 4.0%

CHX Concentration

Freq of Multiple App

1,2,3,4,5,6,7

Daily for 14 days

Intervention Provider

Local project staff

Local project staff

TBA to caretaker

Co-interventions, Outcomes, SS, FU

Nepal Bangladesh Pakistan

Basic interventions to all babies/mothers

CDK, Fe/FA, TT, promotion of ANC/ENC Mortality Omphalitis 15,123 ~5050 1,2,3,4,6,8,10,12, 14,21,28 Mortality Omphalitis 29,760 ~9,900 1,3,6,9,15,28

CDK, FeFA, promotion of TT, ANC, ENC

Basic comp of ENC as promoted by MoH Mortality Omphalitis 9,741 ~4,850 1,3,5,7,14,28

Primary Outcomes

Sample Size Total

Sample Size Per Group

Follow Up Days

Impact on All-Cause Mortality

Nepal 24% lower mortality at 28 days (multiple CHX) 34% lower mortality if initiated within 24 hours No impact of Soap/H2O cleansing

Bangladesh 20% lower mortality at 28 days (single CHX) 6% lower mortality at 28 days (multiple CHX, NS) Strong evidence of impact among preterm babies

Pakistan 38% lower mortality at 28 days (CHX groups)

Preliminary Pooled Analysis

MORTALITY: MORTALITY:Any AnyCHX CHXvs. vs.No NoCHX CHX

RR (95% CI)

Study

Nepal reduction in mortality 0.76 (0.58, 1.00) 23% among Bangladesh 0.88 (0.74, 1.04) those receiving intervention Pakistan 0.62 (0.45, 0.85) 0.77 (0.63, 0.94)

Overall

.5

.75

1.2

Impact on Cord Infection

In all studies Multiple CHX reduced cord infection Nepal: 33% 75% reduction Bangladesh: 15% 45% reduction Pakistan: 40% 50% reduction

Pooled Analysis Cord Infection

Severe Infection: Any Any CHX CHX vs. vs. No No CHX CHX Cord Infection:
RR (95% CI)

Study

0.25 (0.13, 0.51) 59% reduction in serious cord Bangladesh 0.55 (0.30, 1.01) infection among those 0.51 receiving Pakistan (0.18, 1.45) Overall chlorhexidine0.41 (0.24, 0.69)

Nepal

.1

.25

.5

1.5

Cord exposure and causal pathways

Exposure of the cord stump

No local signs of infection

Local signs of infection

Bloodstream infection

No bloodstream infection

Survival

Death

Survival

Mullany et al, PIDJ, 2009

Summary of Mode of Action

CHX Application

Day
HIGH MEDIUM LOWER

14

Mortality Risk

Early applications protect during patent period

Colonization of the patent vessels Sepsis Death

Primary benefit of early CHX cleansings

Prevent continued exposure with repeat applications

Visible infection

Sepsis

Death

Additional benefit of multiple cleansing

Segre J, September 2011

Common Questions / Thoughts

Is chlorhexidine safe?

Yes, chx has been in common use for 60 years, and has excellent safety record. No reported adverse events when used on umbilical cord

Is chlorhexidine readily available?

Yes, one of the most commonly used topical antiseptics in the world

Common Questions / Thoughts

Putting chlorhexidine on the cord might delay separation time

TRUE any action that keeps the cord cleaner, will delay cord separation time This is important from a programmatic experience and for shaping acceptance What is more important?

saving lives and reducing infection OR Have cord fall off on day 5 instead of day 6?

Common Questions / Thoughts

Doesnt clean and dry cord care work just as well?

All three of the big trials tell us the opposite There are no community-based randomized trials of promotion of dry and clean cord practices showing impact on mortality Why not? Because keeping cord clean and avoiding pathogens is very difficult (~80%90% of cords colonized immediately)

Common Questions / Thoughts

We wont benefit from chlorhexidine because harmful practices are no longer common

Not necessarily true. The cord stump is still exposed to pathogens through routine home and facility practices Among babies where caretakers followed suggested cleaned cord practices, chlorhexidine still reduced infection and mortality

Common Questions / Thoughts

This intervention would only help babies born at home

Not true. Facility born babies in the Bangladesh and Nepal trials had:

Lower mortality if they got chlorhexidine Lower risk of cord infection Reduced colonization of the cord and same relationship between cord separation time and cord care, as seen in home births

facilities also struggle to achieve hygienic practices babies are discharged into same environment as home-born babies

Common Questions/Points

Cant we just use alcohol, gentian violet, or iodine?

Alcohol not good for preterm skin Gentian violet not sufficiently bacteriocidal Iodine too easily absorbed through skin All high quality evidence from communitysettings is based on chlorhexidine

Common Questions / Thoughts

The prior WHO recommendation was clean/dry cord care!

When making the recommendation, WHO recognized that:

Evidence from higher-risk populations was not available More research was needed to define optimal cord care Topical antiseptic such as chlorhexidine could be used if exposure to the cord was likely

As public health professionals we are obligated to update recommendations and policies if evidence emerges that warrants change

Common Questions / Thoughts

Promotion of chlorhexidine conflicts with our previous messages..

Messages can be shaped to fit consistently with promotion of clean cord care Topical chlorhexidine can be promoted as a tool to help caretakers achieve a clean cord

Even if conflict, this is NOT a valid reason for INACTION, if the evidence exists.

Final Thoughts

CHX is safe, acceptable CHX can have various formulations, packaging, distribution models Cleansing should begin as early as possible after birth CHX cord cleansing can save hundreds of thousands of lives, at very low cost

Partners and Support

Nepal: NNIPS, JHU, IOM-Tribhuvan University, NICHD, Bill & Melinda Gates Foundation, USAID, Proctor and Gamble, MoHP, Nepal Family Health Project

Bangladesh: MoHFW, ICDDR,B, JHU, Shimantik, DSH, SNL/Save The Children (USA), USAID, Thrasher Research Fund

Pakistan: Aga Khan University, John Snow Inc, Pakistan MoH

CHX reduces colonization

Large reductions in colonization during the period of open, patent blood vessels Multiple cleansing sustains the reduction through first week of life