Nutrition and Infection Wafaie Fawzi, MBBS, DrPH Harvard T.H. Chan School of Public Health

Nutrition and Infection

Wafaie Fawzi, MBBS, DrPHHarvard T.H. Chan School

of Public Health

Outline

• Big picture –nutrition and infections

• Nutrition and malaria

• Nutrition, HIV infection and TB

• Infant feeding practices and MCH

Child stunting is …

A. Low weight-for-height

B. Low height-for-ageC. Low weight-for-ageD. Low body mass

index (BMI)

Low w

eight-f

or-height

Low heigh

t-for-a

ge

Low w

eight-f

or-age

Low body m

ass index (B

MI)

25% 25%25%25%

Which world region has the highest number of stunted children?

A. South AmericaB. Sub-Saharan AfricaC. South AsiaD. North Africa

South Americ

a

Sub-Sahara

n Africa

South Asia

North Afri

ca

0% 0%0%0%

Why are we interested in Nutrition and Infection?

What are the most common nutritional problems globally?

Globally, is the burden of undernutrition higher, the same, or lower than the burden of overnutrition?

A. About the sameB. LowerC. Higher

About the sa

meLo

wer

Higher

33% 33%33%

Global child malnutrition trends (1990-2013)

Stunting

Overweight

UNICEF, WHO, World Bank, Joint child malnutrition estimates for 2013, released in September 2014

Underweight

Morbidity and mortality

Percent distribution of age at death by region, 2005 - 2010

Which country has the lowest life expectancy at birth, according to latest WHO and WB estimates

A. AfghanistanB. BotswanaC. Sierra LeoneD. SwazilandE. India

Afghanist

an

Botswana

Sierra Le

one

Swazila

ndIndia

20% 20% 20%20%20%

Deaths of children younger than 5 years

UN Inter-agency Group for Child Mortality Estimation, UNICEF 2014

U-5 mortality rates (deaths/1000 live births) by MDG region, 1990 and 2013


Neonatal mortality rate (deaths/1000 live births) by MDG region, 1990 and 2013


Infant mortality rates (deaths/1000 live births), 1990 to 2013

UNICEF, WHO, World Bank, UN DESA/Population Division. Levels and Trends in Child Mortality 2014. UNICEF, 2014

Decline in neonatal and post-neonatal mortality rates, by MDG region, 1990–2013 (%)


Distribution of global deaths by leading cause , 2012 data

WHO 2014

Causes of death by WHO Region and World Bank income categories, 2000 and 2012

WHO 2014

WHO 2014: 6.3 million children under age five years died in 2013, nearly 17,000 every day

WHO facts, 2013

• More than half of early child deaths are from preventable or easily treated conditions

• Leading causes are pneumonia, preterm birth complications, birth asphyxia, diarrhea and malaria

• About 45%, or 3.1 million child deaths annually are linked to undernutrition (fetal growth restriction, suboptimum breastfeeding, stunting, wasting, and deficiencies of vitamin A and zinc).

• Over 70% of all under-five deaths occur in WHO African and South-East Asia regions.

Under-5 mortality attributed to nutritional causes

Black et al. Lancet 2013

Prevalence of HIV among 15 to 49 year olds

Progress toward eliminating nutritional problems (contd.)

Scaling Up Nutrition (SUN): 54 countries and counting

• A movement founded on the principle that all people have a right to food and good nutrition

• Unites people - from governments, civil society, the United Nations, donors, businesses and researchers - in a collective effort to improve nutrition

• National leaders prioritizing efforts to address malnutrition - the right policies, collaborating with partners on programs, mobilizing resources, a core focus on empowering women

New: Global Nutrition Targets 2025

• “Recognizing that accelerated global action is needed to address the pervasive and corrosive problem of the double burden of malnutrition, in 2012 the World Health Assembly Resolution 65.6 endorsed a Comprehensive implementation plan on maternal, infant and young child nutrition, which specified a set of six global nutrition targets, that by 2025 aim to achieve:”

Global Nutrition Targets 2025

Which micronutrient deficiency affects the most people globally?

A. Vitamin A deficiencyB. Iodine deficiencyC. Iron deficiencyD. Vitamin C deficiency

Vitamin A

deficiency

Iodine deficiency

Iron deficie

ncy

Vitamin C deficie

ncy

25% 25%25%25%

Latest anemia prevalence, women of reproductive age

www.who.int/nutrition/trackingtool WHO 2014

http://www.who.int/nutrition/trackingtool

Average prevalence of anemia in women of reproductive age by UN sub-region (%)

Source: Stevens et al. 2013, based on modeled estimates for 2011

Prevalence of vitamin A deficiency in children under 5 years. Black et al. Lancet 2008

National risk of zinc deficiency in children under 5 years.


Investing in the future: A united call to action on vitamin and mineral deficiencies.

The 3 major infectious causes of death in childhood worldwide, in order of frequency:

A. HIV/AIDS, pneumonia, measlesB. HIV/AIDS, malaria, diarrheal

diseasesC. Pneumonia, diarrheal diseases,

HIV/AIDSD. Pneumonia, diarrheal diseases,

malariaE. Diarrheal diseases, HIV/AIDS,

pneumoniaHIV

/AID

S, pneumonia, m

...

HIV/A

IDS,

malaria, d

iarrh...

Pneumonia, diarrh

eal dis.

..

Pneumonia, diarrh

eal di...

Diarrheal d

isease

s, HIV/A

...

20% 20% 20%20%20%

Respiratory infections• Acute respiratory infection (ARI): Infections of

the upper or lower respiratory tract, as defined by the International Classification of Diseases

• Upper respiratory tract infection e.g. common cold, pharyngitis, sinusitis

• Acute lower respiratory infection (ALRI) affect the airway below the epiglottis e.g. pneumonia, bronchiolitis, bronchitis

Definitions and causes continued…• WHO, Non-severe pneumonia: cough ± difficulty

breathing, fast breathing (tachypnea)

• WHO, Severe pneumonia: same criteria + lower chest wall indrawing ± stridor in calm child. Very severe pneumonia if any general danger sign

• Causes of pneumonia globally: - Bacteria: No.1 in children: Streptococcus pneumonia, No.2: Haemophilus influenzae type b - Viruses: Respiratory syncytial virus, Influenza virus - Fungi: Pneumocystis jiroveci (No.1 in HIV infected infants)

Incidence of childhood clinical pneumonia

Rudan et al. Bull World Health Organ 2008; Walker et al. Lancet 2013

In 2011, 15 Asian and African countries

responsible for 2/3rd of cases: Afghanistan,

Angola, Burkina Faso, China, DRC,

Ethiopia, India, Indonesia, Kenya,

Mali, Niger, Nigeria, Pakistan,

Tanzania and Uganda

Pneumonia incidence and mortality, children under-5 years

• Pneumonia is the 2nd leading cause of under-5 deaths globally - 935,000 deaths in 2013 (95% CI: 817,000 – 1.06 million)

• Burden is mainly in younger age groups - 81% of deaths from pneumonia are in children younger than 2 years - but pneumonia incidence falls less rapidly with age than mortality from the disease

• Pneumonia mortality rates declining (5% reduction per year overall, > 24% reduction per year in some regions)

Nutrition-related mechanisms• Undernutrition: associated with acquired immune

suppression

• Suboptimal breastfeeding: breast milk contains antibodies that confer passive immunity

• Zinc deficiency: Zinc is important for cell mediated immunity and has antioxidant and anti-inflammatory functions

• Vitamin A and ARI: a paradox

Undernutrition-infection cycle

Inadequate dietary intake

anorexianutrient loss

malabsorptionaltered metabolism

weight lossgrowth faltering

impaired immunity

mucosal damage

Disease: - incidence

- duration- severity

Nutrition and Malaria

Malaria• An entirely preventable and treatable

mosquito-borne illness• 3.2 billion people in 97 countries are at risk

of malaria - 1.2 billion at high risk• In 2013, about 198 million malaria cases

(95%CI 124 – 283 million), with 584,000 deaths (95% CI 367,000-755,000)

• 90% of malaria deaths occur in sub-Saharan Africa, > 80% in children < 5 years

World malaria report, December 2014

Malaria

• Children under five years of age and pregnant women most severely affected

• Others are people with HIV/AIDS; non-immune populations (travelers, displaced peoples, trans-migrants)

Causes of malaria in humans• Plasmodium falciparum

– Occurs worldwide– Responsible for greatest morbidity + mortality

• P. vivax– Occurs in Latin America, Asia, Middle East, North and

East Africa• P. ovale

– Only found in Central-West Africa• P. malariae

– Limited worldwide distribution• P. knowlesi

– Newly identified cause of human malaria in Malaysia and Borneo

Global P. falciparum endemicity

Gething et al. Malaria Journal 2011

PfPR: P. falciparum parasite rate

Pathogenesis of malaria

Malaria and undernutrition

• Recurrent malaria attacks associated with increased risk of impaired weight and height gain

• Undernutrition increases risk of malaria, including severity of episodes and death

• Children with PEM undergoing nutritional rehabilitation should be monitored closely for malaria and treated aggressively

• Children with severe malaria and PEM should be given appropriate nutritional interventions (food, vitamins, minerals) in addition to antimalarials

Malaria, anemia, and iron deficiency

Malaria and anemia• Prevalence of anemia (Hb < 11 g/dL) is high in

children under the age of 5 years in sub-Saharan Africa; children under the age of 2 years most greatly affected

• Contributing factors (besides malaria):– Intestinal nematodes (esp. hookworms)– Schistosomiasis– Sickle cell disease– Inadequate dietary iron intake of child or mother during

pregnancy/breastfeeding

Negative consequences of iron deficiency anemia

• Impaired height and weight gain• Low birth weight

– if anemia occurs during pregnancy• Impaired cognitive development• Decreased physical exercise tolerance

Iron and infection

Prentice J Nutr. 2008

Iron, folate and malaria: The Pemba trial

• RCT of children aged 1-35 months in Zanzibar• Children received one of:

• Iron (12.5 mg) and folic acid (50 µg)• Zinc (10 mg)• Iron, folic acid and zinc• Placebo• Half doses given to children aged 1-11 mo

• Iron and folic acid component of trial stopped early by DSMB because of increased hospitalizations and death

Sazawal et al. Lancet 2006

Iron, folate and malaria: The Pemba trial


Children “who received iron and folic acid with or without zinc were 12% (95% CI 2–23, p=0·02) more likely to die or need treatment in hospital for an adverse event and 11% (1–23%, p=0·03) more likely to be admitted to hospital”

Iron, folate and malaria: The Pemba trial sub-study


Summary of the effects of iron supplementation on malaria morbidity

(Cochrane Review)• In trials where malaria surveillance and malaria

treatment offered, no significant difference in malaria risk between iron and control groups (RR 0.94, 95% CI 0.85 to 1.04)

• Otherwise, there was significantly increased risk of malaria (RR 1.16, 95% CI 1.03 to 1.31), P = 0.009 for the subgroup difference

Okebe et al. Cochrane Database Syst Rev. 2011

The role of nutrition in HIV disease progression and tuberculosis

At its emergence, HIV infection was described as:

A. ConsumptionB. Slim diseaseC. PhthisisD. Graves’ disease

Consumption

Slim dise

ase

Phthisi

s

Grave

s’ dise

ase

25% 25%25%25%

HIV/AIDS• Human immunodeficiency virus (HIV) is a virus

spread through body fluids • It affects cells of the immune system - CD4 T

lymphocytes - potentially destroying so many of these cells the body is unable to fight off infections and disease. When this happens, HIV infection leads to acquired immunodeficiency syndrome (AIDS)

• A chronic infection - the human body cannot get rid of HIV

Clinical progression of HIVUntreated HIV infection is almost universally fatal - it eventually overwhelms the immune system i.e. progression to AIDS

Figure courtesy of Annenberg Learner, Annenberg Foundation

“19 million of the ~35 million people living with HIV globally do not know that they have the virus”

People living with HIV: 35 million in 2013 [33.2 million–37.2 million] Since the start of the epidemic, around 78 million [71

million–87 million] people have become infected with HIV and 39 million [35 million–43 million] have died of AIDS-related illnesses

New HIV infections: have fallen by 38% since 2001 Worldwide, 2.1 million [1 .9 million–2.4 million] people

became newly infected with HIV in 2013, down from 3.4 million [3.3 million–3.6 million] in 2001

UNAIDS 2014

Global HIV prevalence among adults in 2013

UNAIDS: aidsinfo 2015, CDC 2014

More than 1.2 million people aged 13 years and older in the United States are living with HIV infection, and almost 1 in 7 (14%) are unaware of their infection

Management of HIV• Currently no safe and effective cure, but

can be controlled with antiretroviral therapy (ARVs, ART) - slower progression to AIDS and death, reduced transmission from person to person

• Nutrition is important in management of HIV

13.6 million accessed antiretroviral therapy by June 2014

UNAIDS: aidsinfo 2015

38% of adults and 24% of children with HIV had access to ART in 2013

Tuberculosis: time trends in deaths

Whalen C and Semba R. 2000

What is the main reason for the uptick in TB cases on the previous slide?

A. Improved tuberculosis surveillance

B. Reduced BCG vaccination (to prevent tuberculosis)

C. The HIV epidemicD. Time trends

Impro

ved tubercu

losis su

...

Reduced BCG vacci

nation...

The HIV epidemic

Time tr

ends

25% 25%25%25%

Global incidence of tuberculosis

Global Tuberculosis Report, WHO 2014

9 million people fell ill with TB in 2013, and 1.5 million people died from TB

Global Tuberculosis Report, WHO 2014

Estimated HIV prevalence in new TB cases, 20139 million people fell ill with TB in 2013, including 1.1 million people living with HIV

1.5 million people died from TB, including 360,000 who were HIV positive

Transmission and pathogenesis of tuberculosis

CDC self study modules on tuberculosis

Tuberculosis Malnutrition

Cytokine activation

Abnormal protein metabolism

Loss of lean tissue

Loss of fat reserves

Increased Morbidity

Increased Susceptibility

Impaired Immune Function

+

+

TB: Bi-directional interaction of tuberculosis and malnutrition and some putative mechanisms

Macallan Diagn Microbiol Infect Dis 1999

B vitamins may reduce HIV mortality• Vitamin B1 (quartile 4: >5.3 mg/d)

• RR=0.60, 95% CI: 0.38-0.95

• Vitamin B2 (quartile 4: >6.3 mg/d)• RR=0.59, 95% CI: 0.38-0.93

• Vitamin B6 (quartile 4: >5.9 mg/d)• RR=0.45, 95% CI: 0.28-0.73

• Niacin (quartile 4: >64 mg/d)• RR=0.57, 95% CI: 0.36-0.91

Tang et al. AJE 1996

Multicenter AIDS cohort study, Maryland USA

• For many nutrients previous observational studies had suggested better outcomes at multiples of the RDA

• RDA: daily dietary nutrient intake sufficient to meet requirements of 97.5% of healthy individuals


B Vitamins in multiples of RDA may reduce HIV mortality

• Vitamin B1 (>=5 x RDA) • RR=0.61, 95% CI: 0.38-0.98

• Vitamin B2 (>=5 x RDA)• RR=0.60, 95% CI: 0.37-0.97

• Vitamin B6 (>=2 x RDA)• RR=0.60, 95% CI: 0.39-0.93


Supplemental B vitamins may have delayed progression to AIDS and death in an observational study

• Matched case-control study, N=175 pairs• Black HIV+ patients in Johannesburg 1985-1997• Self reported intakes of vitamin supplements• Median time to progression 32.0 weeks for those

without vitamins versus 72.7 weeks for those who took B vitamins (p=0.004)

• Median survival 144.8 weeks for patients without vitamins, 264.6 weeks for those who took B vitamins (p=0.001)

Kanter et al. JAIDS 1999

Randomized controlled trials

Vitamin E and C supplementation and HIV viral loads

• Double blind RCT, N=49, duration=3 months• 800 IU α-tocopherol and 1000 mg vitamin C, or

placebo, daily• Significant increase in plasma levels vitamins E, C• Significant decrease in lipid peroxidation markers• Trend toward reduction in viral load: • Mean: -0.45 (SD=0.39) vs +0.50 (SD=0.40) log

copies/ml, p=0.10

Allard et al. AIDS 1998

Multiple micronutrients reduce mortality among some HIV positive Thai patients

• RCT, N=481, duration=48 weeks

• Daily placebo vs. micronutrient (Vit A 3000μg, betacarotene 6 mg, Vit D3 20μg, Vit E 80 mg, Vit K 180μg, Vit C 400 mg, Vit B1 24 mg, Vit B2 15 mg, Vit B6 40 mg, Vit B12 30μg, folacin 100μg, pantothenic acid 40 mg, iron 10 mg, magnesium 200 mg, manganese 8 mg, zinc 30 mg, iodine 300μg, copper 3 mg, selenium 400μg, chromium 150μg, cystine 66 mg)

• Overall death: RR=0.53 (95%CI 0.22-1.25), p=0.10

• Among those with CD4 <200: RR=0.37, p=0.05

• Among those with CD4 <100: RR=0.26, p=0.03

Jiamton et al. AIDS 2003

Trial of Vitamins, Tanzania

• Women enrolled during pregnancy and followed-up for median of 6 years

• Monthly assessment of clinical signs, regular assessment of CD4+ count, hemoglobin concentration, and viral load

• High compliance with assigned regimen

Fawzi et al. NEJM 2004

Tanzanian randomized controlled trial 1. VITAMIN A ALONE (n=272)

2. MULTIVITAMINS EXCLUDING VIT A (n=271)

3. MULTIVITAMINS INCLUDING VIT A (n=268)

4. PLACEBO (n=267)

• PREFORMED VIT A : 5000 IU

• β-CAROTENE : 30 mg

• B1 : 20 mg

• B2 : 20 mg

• B6 : 25 mg

• NIACIN : 100 mg

• B12 : 50 µg

• C : 500 mg

• E : 30 mg

• FOLATE: 0.8 mg

1. & 3. VITAMIN A 200,000 IU

2. & 4. PLACEBO

DAILY

Fawzi et al. NEJM 2004@D

ELIV

ERY

Composition of the supplementNutrient FAO/WHO RNI for a

lactating adultTanzanian supplementation studies

Vitamin A 2,800 IU (850 μg) 5,000 IU (1500 μg)

β-Carotene 5.1 mg 30 mg

Thiamin 1.5 mg 20 mg

Riboflavin 1.6 mg 20 mg

Vitamin B-6 2.0 mg 25 mg

Niacin 17 mg 100 mg

Vitamin B-12 2.8 μg 50 mg

Vitamin C 70 mg 500 mgVitamin E 5 mg 30 mg

Folic acid 260 μg 5 mg

Ferrous Iron 10-30 mg 120 mg

Copper 1.5mg

Selenium 35 μg

Zinc 5.8-19 mg

Iodine 200 μg

Patient careWhile pregnant, all women received:

• Daily ferrous sulphate (400 mg equivalent to 120 mg ferrous iron)

• Daily folate (5 mg)

• Weekly chloroquine phosphate (500 mg ≈ 300 mg base)

• Standard prenatal care services including:– Regular visits, clinical assessments, laboratory

investigations, and appropriate treatment– Continued psychosocial assessment, counseling and support– ART not standard of care at time of study


Characteristic Multivitamins [N=539]

No Multivitamins [N=539]

Vitamin A [N= 540]

No Vitamin A [N=538]

CD4+ cell count Mean (SD) 444 (249) 453 (289) 438 (255) 459 (284)

Median 415 407 404 419 CD4+ categories (%)

<200 11.8 12.2 12.1 11.8 200-499 51.0 51.9 53.1 49.7

500+ 29.7 29.0 2739 30.7 Unknown 7.6 7.0 6.8 7.8

Baseline CD4+ T cell counts of women in intervention and control groups


Effect of multivitamins on HIV viral load andCD4 + T cell counts


Multivitamins and HIV-related complications


Effect of multivitamins on progression to stage 4 disease or AIDS-related death


No. of Events

Relative Risk(95% CI) p

Whole Period

Multivitamins B, C and E 67 0.71 (0.51, 0.98) 0.04

Multivitamins and vitamin A 70 0.80 (0.58, 1.10) 0.17

Vitamin A alone 79 0.88 (0.64 1.19) 0.40

Placebo 83 1.0

Kaplan-Meier curves of progression to WHO stage 4 disease or death, by regimen

0.6

0.7

0.8

0.9

1.0

0 12 24 36 48 60 72

Months after randomization

Fra

ctio

n al

ive

with

sta

ge <

4

Multivitamins B, C, and EMultivitamins and Vitamin AVitamin A alonePlacebo

No. at risk Multivitamins B, C, and E 271 195 157 119 Multivitamins and Vitamin A

267 181 143 102

Vitamin A alone 272 190 147 104 Placebo 267 173 145 101


Multiple micronutrients reduce risk of immune decline, Botswana

Baum et al. JAMA 2013

Infant Feeding Practices and Child and Maternal Health

Most DALYs lost due to underweight occur in infants and young children – first 2 years are critical

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-1

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Africa Asia Latin America and Caribbean

Age (months)

Z-s

core

(N

CH

S)

Shrimpton et al. Pediatrics 2001

Breast milk is a major source of nutrients in diets of 6-11 month old infants in developing countries…

Protein

Vitamin A

Folat

e

Riboflavin

Vitamin B6

Vitamin C

Calcium

Iron

Zinc

020406080

100

% contribution of BM to total intake of nutrients by Bangladeshi infants (at 6-8mo, at 9-11mo)

6-8 mo 9-11 mo

% c

ontr

ibuti

on o

f BM

Adapted from Kimmons et al. J Nutr 2005

BF initiation timing and pattern are independently associated with risk of neonatal mortality, Ghana (day 2-28) Edmond et al. Pediatrics, 2006

• Study included 10,947 infants alive on day 2 w/ FU data– 145 neonatal deaths (NN)

• Late BF initiation (> day 1) ~ 2.4-fold increased risk of NN mortality (95% CI: 1.69-3.4; p<0.001)– Adj. for gender, birth size,

gestational age, infant & maternal health at birth, maternal age, parity, education, income, hygiene & sanitation, ANC, place of birth, and birth attendant

– Finding similar w/in BF patterns

BF pattern (median: 14 d)

Adj. OR(95% CI)

Exclusive BF 1.00

Predominant BF 1.30(0.90-1.87)

Partial BF 3.82 (1.99-7.34)

Adjusted for timing of initiation & factors described here; P<0.0001 trend

Early initiation could prevent 16-22% of all NN deaths (PAF)

Early BF initiation reduces neonatal mortality

Infection-related neonatal mortalityAll-cause neonatal mortality

Debes et al. BMC Public Health. 2013

Suboptimal feeding practices play a major role in early underweight and associated mortality

Breastfeeding Complementary Feeding0

5

10

15 13

6

Proportion of all deaths < 5 yrs that could be prevented with infant feeding interventions

Jones et al. Lancet 2003

Multi-center cohort analysis of relationships between infant feeding patterns and risk of death, hospitalization

• Secondary analysis of data from studies on vitamin A and immunization• N=9424 infants and mothers

– Ghana: n=2919, India: n=4000, Peru: n=2505• Home visits to collect data on infant feeding (preceding week),

morbidity, hospitalizations and death• Primary outcomes:

– All-cause mortality, disease-specific mortality, hospital admissions, from 6 wks-6 months of age

– Infants not breastfed or those exposed to early “mixed” feeding at higher mortality risk from 6 weeks - 6 months compared with predominantly or exclusively breastfed

Bahl et al. Bull WHO 2005


Mortality relative risks, suboptimal BF vs. Exclusive BF from 0-5 m and any BF 6-23 m

random effects meta-analysis

Greatest protection from Non-HIV infectious mortality for breastfeed infants is during first 6-8 months of life

0-1 2-3 4-5 6-8 9-110

2

4

6

85.8

(3.4-9.8)4.1

(2.7-6.4) 2.6(1.6-3.9) 1.8

(1.2-2.8) 1.4(0.8-2.6)

Age in months

Odd

s Ra

tio

Pooled Odds Ratio for Mortality if Not Breastfeeding

WHO Collaborative Study Team. Lancet 2000

Breast feeding associated with reduced occurrence of:

• Ear infections*: acute otitis media 23% reduction if any breastfeeding, 50% (CI 30% to 64%) if exclusive breastfeeding (EBF)

• Gastrointestinal infections*• Lower respiratory tract infections*: 72% (CI 46%

to 86%) lower risk of hospitalizations for EBF infants

• Necrotizing enterocolities (NEC): 4% to 82% reduction for preterm infants fed breastmilk

*Evidence from studies conducted in both developed and developing countries

Frequency of acute otitis media in relation to feeding pattern and age, Sweden

1-3 4-7 8-120

5

10

15

20

145

7

13

6

14

20

breastfed mixed fed weaned

months

Perc

ent w

ith a

cute

otiti

s m

edia

Adapted from Aniansson et al. Pediat Infect Dis J. 1994

Relative risks of death from diarrhea or ARI by age and breastfeeding category in Latin America

Diarrhoea 0-3 mo Diarrhoea 4-11 mo0

2

4

6

8

10

12

14

16

10

4.1

1

15.1

2.2

exclusive breastfeeding

partial breastfeeding

no breastfeeding

Adapted from: Betran et al. BMJ 2001

ARI 0-3 mo 4-11 mo0

0.5

1

1.5

2

2.5

3

3.5

4

4.5

1

0

2.9

1

4

2.1

Diarrhea

ARI

Breast feeding has benefits apart from reducing infections

• Allergic conditions: 42% lower risk of atopic dermatitis if EBF ≥ 3 months versus not

• Diabetes mellitus (possible 19% reduction in childhood Type 1 DM, 39% (CI 15 to 56%) reduced risk Type 2 DM in later life)

• Obesity reduction?• Cognitive development?

May decrease risk of allergic disorders: prospective birth cohort study, 4089 children in Sweden

Type of feeding Asthma Atopic dermatitis

Allergic rhinitis

Children exclusively breastfed 4 months or more

7.7% 24% 6.5%

Children breastfed for a shorter period

12% 27% 9%

Adapted from Kull et al. Archives of Dis Child 2002

May decrease prevalence of childhood obesity, (German study)

months breastfeeding0

0.51

1.52

2.53

3.54

4.55 4.5

3.8

2.31.7

0 months2 months3-5 months6-12 months

Prev

alen

ce (%

)

Adapted from: von Kries et al. BMJ 1999

Suggested mechanisms• Breastfed infants control amount of milk

consumed, self-regulating energy intake in response to internal hunger and not external cues to finish feeding

• Formula-fed infants have higher plasma insulin levels; insulin encourages fat deposition

• Breastfeeding may influence leptin ** More recent studies suggest no effect of BF versus modern formula feeds on obesity

Duration of breastfeeding associated with higher IQ scores in young adults, Denmark

Duration of breastfeeding in months96

98

100

102

104

106

108

99.4

101.7102.3

106

104 < 1 months2-3 months4-6 months7-9 months> 9 months

Adapted from: Mortensen et al. JAMA 2002

Did not adjust for mother’s intelligence, which could be a confounder

Breastfeeding and maternal health

Benefits of breastfeeding for the mother

• Protects mother’s health

– Helps reduce risk of uterine bleeding and helps the uterus return to its previous size

– Mildly reduced risk of type 2 DM

– Reduces risk of breast and ovarian cancer

• Helps delay a new pregnancy

• May help a mother return to pre-pregnancy weight (results unclear)

Correlation between duration of breastfeeding and postpartum amenorrhea (in months)

Adapted from: Saadeh & Benbouzid Bulletin of the WHO 1990

Breast cancer and breastfeeding:data from 47 epidemiological studies in 30 countries

Adapted from: Beral et al. Lancet 2002

Theories

• Reduced lifetime exposure to estrogen (fewer menstrual cycles as a result of lactation)

• Breastfeeding may cause breast cell changes that make them more resistant to carcinogenesis

Meta-analyses of breastfeeding associations with breast cancer (BC) and ovarian cancer (OC)

Ip et al. Evidence Report/Technology Assessment 2007

Distribution of maternal work absences due to child’s illness

0 1 2-4 > 4

Lawrence and Lawrence. Breastfeeding, 7th edition, 2011

Risks of artificial feeding Interferes with bonding

More diarrhea and respiratory infections

Persistent diarrhea

Malnutrition vitamin A deficiency

More likely to die

More allergy and milk intolerance

Increased risk of some chronic diseases

Lower scores on intelligence tests

May become pregnant sooner

Increased risk of anemia, ovarian & breast cancer

Adapted from: Breastfeeding counseling: A training course. Geneva, World Health Organization, 1993 (WHO/CDR/93.6).

Most DALYs lost due to underweight occur in infants and young children – first 2 years are critical

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40

41

42

43

44

45

46

47

48

49

50

51

52

53

54

55

56

57

58

59

60

-2

-1.5

-1

-0.5

0

0.5

Africa Asia Latin America and Caribbean

Age (months)

Z-s

core

(N

CH

S)

Shrimpton et al. Pediatrics 2001


Distribution of children by breastfeeding pattern, age group and region (%)

Coverage of interventions in 75 countries (median, Q1, Q3)

Bhutta et al. Lancet 2013

Infant Feeding Practices and mother-to-child HIV transmission

Timing of mother-to-child HIVtransmission: no preventive intervention

Early Antenatal(<36 wks)

Late Antenatal(36 wks to

labor)

Late Postpartum

(6-24 months)

Early Postpartum

(0-6 months)

Adapted from CDC document

5-10% 10-20% 5-20%

Labor and Delivery BreastfeedingPregnancy

Average MTCT in 100 HIV+ mothers, by timing of transmission

Series10

10

20

30

40

50

60

70

80

90

100

Uninfected: 63

Breastfeeding: 15

Delivery: 15

Pregnancy: 7

MTCT risk factor: duration of breastfeeding BHITS meta-analysis

0 6 12 1802468

1012141618

Age (months)

%

Risk of postnatal transmission is cumulative and relatively constant over time

BHITS JID 2004

Transmission = ~ 8.9/100 child years of BF

Most postnatal infections occur after 6 months in populations where breastfeeding is prolonged… (excludes first 4-6 weeks)

WestAfrica Malawi Tanzania Kenya0

20

40

60

80 7666 62

52

Proportion of late PN HIV infections occuring after 6 mo

Estimated from Leroy et al, 2002; Miotti et al, 1999; Fawzi et al, 2002; Nduati et al, 2000

MTCT risk factor: early mixed breastfeeding

Birth 3 mo 6 mo 15 mo0

5

10

15

20

25

30

35

40

EBF to 3 moPartial BF%

Coutsoudis et al. 1999; 2001

Cumulative HIV transmission, Durban, SA

Mother to child HIV transmission

• Risk < 5% with ARV’s during pregnancy and to infant, cesarean section, avoidance of breastfeeding

Source: WHO 2015

PMTCT: An integrated approach is required

1.Focus on maternal health & nutrition

• Keeping HIV-infected mothers well may be among the most important things we can do to prevent postnatal HIV transmission

• BF transmission ~ 2-6% in women with CD4 >500

• Keeping mothers alive will improve child’s chances for survival (Nduati et al. 2001; Nakiyingi et al. 2003)

RR of infant death if mother

dies

5.66.6

0

4

8

Kenya Uganda

2. Expand coverage of PMTCT programs and use of ARV drugs

• Expanding access to treatment will reduce PNT since women with advanced disease are the ones most likely to infect their infants

• “Current WHO 2013 guidelines recommend Option B/B+ regimens for prevention of mother-to-child transmission of HIV and for the health of the mother. Option A is no longer recommended.”

• WHO: All HIV-infected women, irrespective of CD4 T-cell count or clinical stage should initiate first-line ART to reduce risks of HIV transmission to the child and to uninfected partners. For programmatic and operational reasons, all pregnant and breastfeeding women with HIV should initiate ART as lifelong treatment (option B+); women ineligible for ART for their own health (country-specific criteria) may stop ART after the period of MTCT risk ends (option B)

• Prolonging infant ARV prophylaxis during BF to reduce PN transmission shows promise but more data needed

3. Strengthen approaches for making breastfeeding safer for ALL women

• Provide adequate breastfeeding counseling and support, involving families/communities – breastfeeding IS food security for many infants– increase adherence to Exclusive BF and reduce early Mixed BF– promote good breastfeeding techniques to prevent cracked nipples, maintain

breast health• Immediate treatment for mastitis, other infections • Safe sex for prevention These interventions could prevent a sizeable fraction of PN HIV

transmission, particularly because many HIV+ do not know their HIV status

4. Make breastfeeding safer for HIV+ women

• Assist families with decisions about early breastfeeding cessation– assess health status of mother and infant– consider non-HIV related risks– prepare for the process so that the transition is safe

• Provide adequate infant nutrition after breastfeeding ends (for all women)– Animal milk, fortified complementary foods or MN supplements are

needed to prevent malnutrition and malnutrition-associated child deaths

5. Make replacement feeding safer for HIV+ women who choose to avoid BF or stop early

• Screen mothers, target use to those most at risk – Transmission risk highest in those with CD4 < 200

• Safe water & environmental conditions• Family support, community understanding• Postnatal follow-up and enhanced care

– Essential child health and nutrition interventions are critical• Take measures to prevent unnecessary use of replacement

feeding (spillover)

Documents

Nutrition and Infection Wafaie Fawzi, MBBS, DrPH Harvard T.H. Chan School of Public Health