EE: Going Beyond Nutrition to Understand

Child Growth and Development

Laura Smith Rebecca Stoltzfus,Francis Ngure, Brie Reid,

Gretel Pelto, Mduduzi Mbuya, Andrew Prendergast, Jean Humphrey

Division of Nutritional Sciences

(Victora et al. 2010)

The “Window of Opportunity” for Improving Nutrition is very small… Pre-pregnancy until 18-24 months of age

What is causing all this stunting?

Cause #1: Malnourished Mother

• Malnourished mothers give birth to babies that are smaller and shorter than normal

• 50% of Guatemalan babies are born stunted (Ruel 2001)– Prevalence of stunting at birth not well documented– Good length data on newborns is very hard to get!

Estimates of 30-50% of stunting is due to intra-uterine factors. Effective macronutrient interventions for pregnant women are not

well established.

Cause #2: Poor Diet

• Systematic review of the efficacy and effectiveness of complementary feeding interventions in developing countries– Dewey & Adu-Afarwuah, 2008– 42 studies/programs, most published 1996-2006

• Children who received interventions gained:– 0.0 – 0.76 Z scores weight-for-age– 0.0 – 0.64 Z scores length-for-age

The best studies caused a 0.7 Z score improvement. BUT:the average growth deficit of African and Asian children is -2.0 Z

At best, diet solved 1/3 of the problem.

Cause #3: Diarrhea

• Between 6-18 months of age, children in developing countries have around 9 episodes of diarrhea.

• Many authors reported that diarrhea accounts for 10-80% of growth faltering

• But others contend that children grow at “catch-up rates” between episodes, and thus recover these deficits

The Lancet Nutrition Series (2008) concluded that by implementing sanitation and hygiene interventions with 99% coverage, child malnutrition would be reduced by only 2.4%

However:

Evidence exists that the effect of WASH interventions on linear growth is independent of its effect on diarrhea.

In several studies, WASH had a bigger effect on growth than it did on diarrhea

Peru: (Checkley, et al)

• Children assessed for diarrhea and growth from birth to 2 years

• Household sanitation and water assessed

• What predicted height deficit at 2 years?

16% explained by how much diarrhea the child had experienced

40% explained by the level of sanitation and water in child’s household

Rural Ethiopia: HH Hygiene Index was the variable most strongly associated with

stuntingAlive and Thrive baseline data; F Ngure (2013, in prep)

Cause #4: The Environmental

Enteropathy Hypothesis

• A subclinical condition of the small intestine, called environmental enteropathy (EE)

• Characterized by:– Flattening of the villi of the gut, reducing its surface area– Thickening of the surface through which nutrients must be absorbed– Increased permeability to large molecules and cells (microbes)

• Likely causes:– Too many microbes in the gut– Effects of toxins on the gut

Decreased nutrient absorption + Infiltration of microbes

Microbial translocation

Microbial products cross into blood stream

The lining of the gut is only one cell

thick

If the gut is injured and becomes permeable, gaps open up between cells

Chronic immune activation

Diverts nutrients from growth to infection-

fighting

EE is a major cause of post-natal stunting, anemia and immune competence

EE can be prevented or reduced by preventing infants and young children from ingesting human and animal feces through a package of interventions that improve sanitation and hygiene.

Environmental Enteropathy and Stunting Hypothesis:

Chronic immune activation

↑ pro-inflammatory cytokines

Immunosenescence (premature aging) of adaptive cell-mediated immune system

↑Hepcidin ↓Growth Factor (IGF-1)

Anemia StuntingImpaired response to vaccines and infections

HAZ changes over first 18 months in stunted and non-stunted infants

Birth 6wks 3mo 6mo 12mo 15mo9mo 18mo

IGF-1 and IGFBP3 were lower in stunted infants, beginning at 6 wk

P values for all time points 6 w to 12 mo, p<0.001

Values for healthy European children range from 54-170 ng/mL

P values for all time points 6 w to 18 mo, p<0.001

stunted stunted

Development of the WASH Intervention(Efficacy = “Proof of concept”)

WASH Goal:All infants never ingest any faeces between birth

to 18 months

Conventional WASH formative research (2008-2009)

Sanitation HIGHLY valued don’t have a latrine because lack money; a Blair VIP is a source of status

• Infant stools less offensive than adults’• Handwashing is seldom with soap• Frequently feed cold leftover food

• 6 hour observation of 20 babies, recorded what and how often went in the mouth and if visibly dirty

• Returned and collected samples of most frequent and dirtiest things mouthed for micro analysis

Baby Observation Study (2011)

Findings

Most frequent:38 time in 6 hours75% visiby dirty

DirtiestSoil (3 ate avg 11 bites)chicken faeces, stones

If allowed, toddlers consume poultry feces

Peruvian shantytown families:– Households who owned free-range poultry:

• Average ingestion of poultry feces by toddlers per 12-hour observation period was 3.9 times

– Marquis GM et al., Am J Public Health 1990

Rural Zimbabwe:– Not selected for poultry ownership:

• 3 of 7 toddlers directly ate chicken feces during a 6-hour observation period.

– Ngure F et al., submitted, 2012

% HH with E coli + sample

E coil/Per gram

Average E ColiPer Day

Infant Food 0% 0 0

Drinking Water54% 2 800

Soil in laundry area 60-80% 70 1,400

Chicken feces100% 10,000,000 10,000,000

Clearly, kids must stop eating dirt and chicken poop!

24

Babies are fed on *Ground in the yard (60-80% E coli+) or *Kitchen floor

(81% E coli+)

Source: World Bank, accessed 6.23.11http://web.worldbank.org/WBSITE/EXTERNAL/TOPICS/EXTWAT/EXTTOPSANHYG/

Geophagia, dirty hands

LaundryWater

Nappy Handling

Protective Play Space

for babies!

A new way of thinking about WASH in the first 1000 days

• Protective play space, to protect developing child from contaminated soil and animal feces (especially chickens)

• Infant handwashing with soap, when outside of protective play space.

• Caregiver handwashing with soap after fecal contact and before preparing/serving food

• Safe disposal of feces—especially of children

• Water treatment

• Avoid feeding leftovers, or reheat

BABY WASH

Control

Infant Feeding: Education + Nutributter

WASH:Integrated Water,

Hygiene & Sanitation

WASH+

Infant Feeding

2x2 Factorial Design

ObjectiveTo measure the independent and combined effects of

WASH and infant nutrition on stunting and anemia among children from birth to 18 months of age

And, on a sample of 1600 infants, measure the hypothesized “causal pathway” of EE

1000 HIV- mothers600 HIV+ mothers

Protective play space

Goal: Culturally-acceptable, economical product that could be locally fabricated, which protects babies and toddlers from ingesting soil while allowing physical and cognitive development

Engaged a marketing expert (Malinda Sanna, Spark) for consumer research

Design process led by team from Cornell’s Department of Design and Environmental Analysis and Human Development

Early Childhood

Development

Nutrition

Stimulation Social Protection

Hygiene

Programmatic approaches for nutrition, stimulation and social protection are well developed.

UNICEF 2006 Programming Experiences in Early Childhood Development

Lancet 2011 Child Development Series

Hygiene for babies (Baby WASH)

needs to be further developed and tested

Environmental Protection?

SHINE Investigators:

MoHCWGoldberg Mangwadu – Director of Environmental Health, MoHCW (Co-PI)Cynthia Chasokela – Director of Nursing

ZvitamboJean Humphrey (Co-PI) Mduduzi Mbuya, Naume Tavengwa, Kuda Mutasa, Robert Ntozini

Johns Hopkins Bloomberg School of Public HealthLarry Moulton, Jim Tielsch (J Humphrey)

CornellRebecca Stoltzfus

University of LondonAndrew Prendergast

University of British ColumbiaAmee Manges

FundingGates, DFID, CIDA,

NIH,Wellcome Trust,

UNICEF

Zimbabwe SHINES

Zimbabwe Sanitation Hygiene Infant Nutrition Efficacy Study

Observation: babies with healthier guts and less inflammation grow better.

Biological hypothesis: babies who are protected from fecal ingestion will grow better.

Randomized trial hypotheses: babies whose households receive a comprehensive Water Sanitation & Hygiene (WASH) intervention will grow better.

WASH Intervention

Reduced fecal

ingestion

Better Growth

San & HygBehaviors

Healthier Gut& Less

Inflammation

WASH + Nutrition will have more benefit than either alone.

Community-basedTwo entire rural districts

total popn: 180,000K

Standard Care 1. Revived VHW network2. Strengthened PMTCT care3. EBF Promotion 4. Latrine at end of study

Infant Nutrition1. Standard care 2. Promote optimal use of local foods

for complementary feeding3. 20 g Nutributter daily provided for

infants (6-18 mo)

Sanitation/Hygiene1. Standard care2. VIP latrine 3. 2 Tippy Taps and soap4. Water Guard5. Protected play area6. Promote safe feces disposal hand

washing, water Rx, hygienic infant feeding

Infant Nutrition & Sanitation/Hygiene

1. Standard care2. All Nutrition interventions3. All Sanitation/Hygiene interventions

Implementation

• Enroll 4,800 pregnant women at 10-12 weeks gestation and follow them until their babies are 18 months old.

• Interventions delivered by 360 Village Health Workers on bicycle and Oxfam

• Outcomes measured by 34 Research Nurses on motorbike

Outcomes

• Among all 4800 infants assess growth, anemia, intervention uptake, relevant behaviors

• Among 1600 infants, assess causal pathway (indicators of EE) at 3, 6, 12, 18 months

The context: IO study

Laundry area

Bare soil and animal waste

Micro team

Results: IO phase summary

• Barely no HW for infants:

21 times (in 13/23 HH) in 130 hours

HWWS 6/21: all as part of a bath.• Adult caregivers’ HWWS after contact with stool-

7.5 % (4 HWWS/53 opportunities)• 9/23 (39 %) infants took:

3 infants- active soil ingestion

2 took chicken feces

4 took stones from the dirt

Results: Micro phase summaryA one year old ingesting chicken feces, soil and

400 ml of contaminated water:On average 10 million E. coli counts/g of

Chicken feces

Frequency of E. coli: 22/22 HH (100 %)69 E. coli counts/g of wet shaded area soil:

Frequency: 18/22 HH (82 %)800 E. coli counts from water.

Frequency: 12/ 22 HH (55 %) Other bacteria population

Key messages

• Chicken feces and soil ingestion are predominant pathways

• Exploratory soil ingestion and geophagia could be more prevalent in rural Zimbabwe than observed for 23 HH - 2 FGDs indicated this.

• Water contamination is significant.• Infants HW barely practiced.

Key messages

• Caregiver’s HWWS after fecal contact is not common.

• WASH interventions need to focus more on protecting infants from eating earth and chicken feces

• The idea of a washable mat or playing pen as a WASH intervention input

IYCF Intervention

Promote optimal use of locally available foods, responsive feeding, nutrient density, feeding during illness

Provide 20 g/d Nutributter 6-18 mo

Prior to Trial Launch

Village Health Worker Revitalization

Full complement recruited, trained (8 months) Provide tools (bike, kit, uniforms)

Campaign to promote Exclusive breastfeeding for all to 6 months

1. Health worker training

2. Social marketing

Implement WHO 2010 Prevention of Mother to Child Transmission of HIV and Infant Feeding Guidance

EE is caused by environmental exposure

• Fetuses and newborns do not have it

• People acquire it moving into developing country and lose it moving out

• Widely believed:

Result of high exposure to fecal contamination in an environment of poor sanitation and hygiene

• EE is a major cause of child stunting

• EE can be prevented or reduced by preventing infants and young children from ingesting human and animal feces through a package of interventions that improve sanitation and hygiene.

Environmental Enteropathy and Stunting Hypothesis:

Fecal contaminationEnvironment

Altered bacterial load, composition and/or timing of colonisation

Intestinal inflammation and reduced surface area

Increased intestinal permeability

Microbial translocation

Microbiome

Intestinal pathology

Microbial translocation

StuntingAnemia

Activates innate immune system

proinflammatory cytokines

Immune activation

Activates adaptive immune system

Immunosenescence

Impaired responses to vaccinations and

infections

IGF-1 Hepcidin Erythropoiesis

Iron absorption and mobilization

IGF-1

• 70 amino acid polypeptide• Mostly produced by liver• Mediates the effects of growth hormone • Important in fetal and postnatal growth• Endocrine function (paracrine, autocrine)• Highly protein bound

– 6 binding proteins– Mostly IGFBP3– Acid labile subunit

Inflammatory markers were higher in stunted infants

P values for all time points 6 w to 12 mo, p<0.001

P values from multivariate models that included maternal education, MUAC, sex, birth weight, and mixed feeding.

P=0.007 P=0.064

NSP=0.023

stunted

Mean 95.9 Mean 114.3

P=0.02

R=0.50P<0.001

R=-0.39P<0.001

R=0.52P<0.001

Maternal and infant values were correlated at birth

Intestinal Fatty Acid Binding Protein (I-FABP)

• Very small (15kD) cytoplasmic protein• Found in enterocytes• Involved in intracellular transport of LCFA• Rapidly released into blood after cellular damage• Predominantly expressed in cells at tips of villi in

small intestine• Elevated in celiac disease compared to healthy

contols Derikx JP, J Clin Gastroenterol 2009

High I-FABP levels in stunted and non-stunted Zimbabwean infants

6 months 12 monthsMedian 859 Median 978 Median 1148Median 1070

Healthy controls 172.7 pg/mL (±20.2) – mean age 22 yrs (range 1-61 yrs)Coeliac disease Median 784.7 pg/ml (±145.5)Advanced HIV (adults) 174.4 pg/mL

P=0.36 P=0.13

I-FABP was higher in stunted infants

stunted

P value from multivariate model that included maternal education, MUAC, sex, birth weight, and mixed feeding.

P=0.030

Summary

• Growth hormone axis is perturbed very early in life in apparently healthy Zimbabwean infants with poor linear growth.

• Small intestinal damage and low-grade inflammation are evident post-natally and associated with stunting by 18 mo of age

• Diarrhea (measured by clinic visits) was not associated with stunting.

• Circulating levels of pro-inflammatory mediators and IGF-1 in mother-infant dyad at birth are associated with in utero growth.

Zimbabwe SHINES

Zimbabwe Sanitation Hygiene Infant Nutrition Efficacy Study

Observation: babies with healthier guts and less inflammation grow better.

Biological hypothesis: babies who are protected from fecal ingestion will grow better.

Randomized trial hypothesis: babies whose households receive a comprehensive Water Sanitation & Hygiene (WASH) intervention will grow better.

WASH Intervention

Reduced fecal

ingestion

Better Growth

San & HygBehaviors

Healthier Gut& Less

Inflammation