Long-term effects of severe acute malnutrition on growth, body composition, and function

293 Pages·2016·14.02 MB·English

Long-term effects of severe acute malnutrition on
growth, body composition, and function; a
prospective cohort study in Malawi

Natasha Lelijveld
Institute for Global Health

Thesis submitted for degree of Doctor of Philosophy

University College London
2013-2016

I
Declaration

I, Natasha Lelijveld, confirm that the work presented in this thesis is my own. Where information
has been derived from other sources, I confirm that this has been indicated in the thesis.

Signed…………………………………… Date………………………………………
II
III
I. Abstract
Background: Tackling severe acute malnutrition (SAM) is a global health priority. Whilst SAM-
related mortality is well described, little is known about long-term effects on survivors. Given
extensive evidence from developed countries that early nutritional insults have enduring
detrimental effects, particularly heightened risk of non-communicable disease (NCD) in
adulthood, it is plausible that SAM survivors could share some of these traits. Applying the
DOHaD (Developmental Origins of Health and Disease) concept to a novel group, this study
aimed to explore the long-term impacts of SAM on growth, body composition, and functional
outcomes.

Methods and Findings: From August 2013 to February 2014 I followed-up the 352/1024
Malawian children who were still alive following SAM treatment in 2006-2007, comparing them
to siblings and age/sex matched community controls. Compared to community controls, SAM-
survivors had significantly lower height-for-age z-score (HAZ) (-0.4, CI -0.2 to -0.6) and limb
length (-2.0cm, CI -1.0 to -3.0) although there was evidence of some catch-up growth. They also
had smaller mid-upper arm, calf and hip circumferences and less lean mass. Functional deficits
included: weaker hand-grip (-1.68kg, CI -0.9 to -2.4) and fewer minutes completed of an exercise
test (-1.59 minutes, CI -1.0 to -2.5). There was no statistically significant impact on lung function,
skinfold thickness, sitting height and head circumference.

Conclusions: These results show that there are long-term implications of an episode of SAM in
the areas of growth, body composition, and physical function. Most notable are deficits in HAZ,
lean mass, grip strength, and preservation of sitting height and head circumference at the expense
of leg length, a pattern consistent with ‘thrifty growth’ which is associated with increased future
cardiometabolic disease risk. Some catch-up of linear growth has occurred, suggesting that
interventions post-“first 1000 days” could still be effective. Children who experienced SAM at an
older age had greater detrimental effects, emphasising the need for early intervention and better
prevention. Further follow-up is required to establish the full impact of puberty, and societal
transition such as greater access to high fat/sugar diets. Intervention studies are also needed to
determine whether earlier SAM treatment, improved post-SAM care such as nutrition
supplementation and/or physical fitness interventions, could minimise or reverse some of these
long-term effects.

IV
II. Table of Contents

I. Abstract .................................................................................................................................. IV
II. Table of Contents .................................................................................................................... V
III. List of Tables ........................................................................................................................ X
IV. List of Figures .................................................................................................................... XII
V. List of Images ....................................................................................................................... XIII
VI. List of Appendixes ............................................................................................................ XIV
VII. List of Acronyms ................................................................................................................ XV
VIII. List of Publications and Presentations ............................................................................ XVII
IX. Acknowledgements ........................................................................................................ XVIII
Chapter 1: Introduction ................................................................................................................... 2
1.1 Background ..................................................................................................................... 2
1.1.1 Severe Acute Malnutrition ...................................................................................... 2
1.1.2 Early Life Nutrition and Long-term Health .............................................................. 7
1.1.3 Long-term Effects of SAM ..................................................................................... 12
1.1.4 Study Outcomes: Growth, Body Composition, Physical Function and Lung Function
13
1.2 Hypotheses, Aims and Objectives ................................................................................. 25
1.2.1 Aim and Objectives ................................................................................................ 25
1.2.2 Hypotheses ............................................................................................................ 25
2 Chapter 2: Settings, Participants and General Methods ....................................................... 26
2.1 Study Design .................................................................................................................. 26
2.2 Setting ........................................................................................................................... 27
2.3 Study Participants ......................................................................................................... 29
2.3.1 Eligibility Criteria: .................................................................................................. 29
2.3.2 SAM Admission Criteria and Treatment ................................................................ 29
2.3.3 PRONUT and FuSAM Studies ................................................................................. 31
2.3.4 Locating Participants ............................................................................................. 32
2.3.5 Informed Consent Process .................................................................................... 33
2.4 Ethical Approval: ........................................................................................................... 34
V
2.5 Sample Size .................................................................................................................... 34
2.6 Data Collection Overview .............................................................................................. 35
2.6.1 Staff Training .......................................................................................................... 36
2.6.2 Pilot Phase ............................................................................................................. 38
2.6.3 Data Recording and Management ......................................................................... 38
2.6.4 Demographic Questionnaires ................................................................................ 41
2.6.5 Maternal Mental Health SRQ ................................................................................. 41
2.6.6 Disability Screening Questionnaire ........................................................................ 42
2.6.7 Assessing HIV Status .............................................................................................. 42
2.6.8 Assessing Puberty .................................................................................................. 42
2.6.9 Gestures of Thanks/Incentives .............................................................................. 43
2.6.10 Quality Control Systems: ....................................................................................... 43
2.7 Data Analysis .................................................................................................................. 46
2.7.1 Potential Confounders ........................................................................................... 46
2.7.2 Linear Regression Analysis ..................................................................................... 50
2.7.3 Principle Component Analysis (PCA) ...................................................................... 51
3 Chapter 3: Cohort Profile ....................................................................................................... 52
3.1 Sample Description ........................................................................................................ 52
3.1.1 Missing data ........................................................................................................... 54
3.1.2 Other Bias .............................................................................................................. 55
3.1.3 Study group Demographic and Health Characteristics .......................................... 56
3.1.4 HIV ......................................................................................................................... 59
3.2 Mortality ........................................................................................................................ 60
3.3 Original Synbiotic/Control groups ................................................................................. 63
3.4 Questionnaire Repeatability .......................................................................................... 64
4 Chapter 4: Growth and Anthropometric Status .................................................................... 65
4.1 Chapter-specific Hypotheses ......................................................................................... 65
4.2 Specific Methods ........................................................................................................... 66
4.2.1 Anthropometry ...................................................................................................... 66
4.2.2 Sample Size Calculations ........................................................................................ 70
4.3 Analysis .......................................................................................................................... 71
VI
4.3.1 Data Cleaning & Z scores ....................................................................................... 72
4.3.2 Calculations and Statistics ..................................................................................... 73
4.4 Results ........................................................................................................................... 74
4.4.1 Missing Data .......................................................................................................... 74
4.4.2 Growth: Whole Cohort .......................................................................................... 74
4.4.3 Growth of Controls vs Cases .................................................................................. 76
4.4.4 Longitudinal Growth Data ..................................................................................... 79
4.4.5 Longitudinal Data: Comparing Growth of Cases with Sibling Controls ................. 82
4.4.6 Impact of HIV on Growth ...................................................................................... 83
4.4.7 Predictors of Growth Outcomes ............................................................................ 84
4.4.8 Summary ............................................................................................................... 91
5 Chapter 5: Body Composition ............................................................................................... 92
5.1 Chapter-specific Hypotheses ......................................................................................... 92
5.2 Measuring Body Composition ....................................................................................... 93
5.3 Specific Methods ........................................................................................................... 96
5.3.1 Anthropometry ...................................................................................................... 96
5.3.2 Bioelectrical Impedance (BIA) ............................................................................... 97
5.3.3 Skinfold Thickness ................................................................................................. 98
5.4 Analysis ........................................................................................................................ 100
5.4.1 Data Cleaning ...................................................................................................... 100
5.4.2 Calculations and Statistics ................................................................................... 101
5.5 Results ......................................................................................................................... 103
5.5.1 Missing Data ........................................................................................................ 103
5.5.2 BIA repeatability .................................................................................................. 103
5.5.3 Body Composition of Controls vs Cases .............................................................. 105
5.5.4 Impact of HIV on Body composition .................................................................... 111
5.5.5 Body composition and Sex .................................................................................. 112
5.5.6 Predictors of adverse Body composition in cases ............................................... 113
5.5.7 Summary ............................................................................................................. 116
6 Chapter 6: Physical Function ............................................................................................... 117
6.1 Chapter-specific Hypotheses ....................................................................................... 117
VII
6.2 Specific Methods ......................................................................................................... 118
6.2.1 Hand Grip Strength .............................................................................................. 118
6.2.2 Physical Activity: Accelerometers ........................................................................ 118
6.2.3 Physical Capacity: iStep Exercise Test .................................................................. 119
6.2.4 Sample Size Calculations ...................................................................................... 121
6.3 Analysis ........................................................................................................................ 122
6.3.1 Calculations .......................................................................................................... 122
6.4 Results ......................................................................................................................... 123
6.4.1 Missing Data & Data Quality ................................................................................ 123
6.4.2 Physical function of Controls vs Cases ................................................................. 124
6.4.3 HIV and Physical Function .................................................................................... 128
6.4.4 Effect of Body Size and Composition on Physical Function ................................. 129
6.4.5 Associations between Physical Function Measures ............................................. 131
6.4.6 Predictors of Poor Physical Function in Cases ..................................................... 131
6.5 Summary ...................................................................................................................... 133
7 Chapter 7: Lung function ..................................................................................................... 134
7.1 Chapter-specific Hypotheses ....................................................................................... 134
7.2 Measuring Lung Function ............................................................................................ 135
7.3 Specific Methods ......................................................................................................... 136
7.3.1 Anthropometry .................................................................................................... 136
7.3.2 Spirometry ........................................................................................................... 136
7.3.3 Sample Size Calculations ...................................................................................... 140
7.4 Analysis ........................................................................................................................ 141
7.4.1 Data Cleaning ....................................................................................................... 141
7.4.2 Calculations and Statistics .................................................................................... 141
7.4.3 Adjusting for Potential Confounders ................................................................... 142
7.5 Results ......................................................................................................................... 144
7.5.1 Missing Data ........................................................................................................ 144
7.5.2 Data Quality ......................................................................................................... 146
7.5.3 Anthropometry .................................................................................................... 148
7.5.4 Spirometry ........................................................................................................... 149
VIII
7.5.5 Predictors of Lung Function in Case Group ......................................................... 157
7.5.6 Summary ............................................................................................................. 159
8 Chapter 8: Discussion .......................................................................................................... 160
8.1 Summary of Hypotheses and Results .......................................................................... 161
8.2 Growth ........................................................................................................................ 162
8.3 Body Composition ....................................................................................................... 165
8.4 Physical Function ......................................................................................................... 167
8.5 Lung Function .............................................................................................................. 169
8.6 HIV ............................................................................................................................... 172
8.7 Kwashiorkor vs Marasmas ........................................................................................... 174
8.8 Age at Admission ......................................................................................................... 175
8.9 The Overall Picture ...................................................................................................... 177
8.9.1 Strengths and Limitations .................................................................................... 179
8.9.2 Causality .............................................................................................................. 180
8.9.3 Generalisability .................................................................................................... 180
8.10 Study Implications ....................................................................................................... 181
8.10.1 Scientific & Programme Implications .................................................................. 181
8.10.2 Policy Implications ............................................................................................... 182
8.11 Conclusions ................................................................................................................. 183
References .................................................................................................................................. 184

IX
III. List of Tables
Table 1: summary of the evidence and references from human studies linking early nutritional insults to
later health, including a list of long-term outcomes as well as the nature and timing of the insult .............. 10
Table 2: Intra-observer technical error of measurement (TEM) for anthropometry standardisation session
conducted during ChroSAM team training, as well as “Gold Standard” TEM from WHO Multicentre
Reference Study and mean standard deviation (SD) between operators across each child. ......................... 38
Table 3: Maximum allowable differences between measurements conducted by independent data
collectors; a quality control system developed by WHO Multicentre Reference Study. ............................. 44
Table 4: Outcomes used in Principle Component Analysis (PCA) to generate wealth score .............................. 51
Table 5: Number of participants included in analysis for each of the main outcomes ......................................... 54
Table 6: characteristics of cases recruited, cases that have died since 1 year follow-up, sibling controls,
community controls and cases lost to follow up. ~ parity defined as number of children in family
alive; ¥ poor maternal mental health defined as SRQ score ≥7; * cooking smoke defined as cooking
with wood or charcoal inside the home; Ф unsanitary toilet defined as open pit latrine or field or bush.
/// indicates no data, largely because family characteristics for siblings were presumed to be the same
as cases .......................................................................................................................................................... 58
Table 7: means and differences for WAZ, HAZ and BAZ for the original controls and case groups in the
PRONUT study. Adjusted differences include HIV status and SES in the regression model. No
differences have a p value <0.05. .................................................................................................................. 63
Table 8: results of questionnaire validity analysis, including means for each repeat, Cohen’s kappa and
kappa interpretation as published by Landis and Koch[201]. ....................................................................... 64
Table 9: WHO standards for flag of extreme z score results ................................................................................ 73
Table 10: proportion of children with low (<-2) WAZ, HAZ and BAZ in each study group .............................. 75
Table 11: Results of simple and multivariable linear regression analysis, comparing siblings and
community controls to cases for each growth variable at 7 years post-discharge. Adjusted difference
includes age, sex, HIV status, SES and puberty in regression model. * indicates p value less than 0.05.
Sitting height % = sitting height/height*100; Relative leg length = regression residuals for leg length
by sitting height; Lower limb length ratio = lower limb length/height ......................................................... 77
Table 12: shows mean (SD) of WAZ HAZ and BAZ across 4 time points (on the ward, at discharge from
OTP, at 1 year post-discharge and at 7 years post-discharge) (p.d = post-discharge). Difference in z
score between discharge and 1 year post-discharge, and difference in z score between 1 year post-
discharge and 7 years post-discharge are also presented. ............................................................................. 79
Table 13: Mean values and SD scores for growth variables by study group and HIV status. Those with
unknown HIV status are not included. Sitting height % = sitting height/height*100. Lower limb ratio
= lower limb length/height. ........................................................................................................................... 83
Table 14: means and standard deviations for main growth outcomes stratified by characteristics at
admission ...................................................................................................................................................... 84
Table 15: results of linear regression analysis assessing associations between nutritional z scores at the
point of minimum weight during admission and growth outcomes at 7 years post-discharge. Outcome
at 7 years post-discharge is the dependant variable. Regression has been adjusted for HIV status, age,
sex and SES. * indicates p<0.05. Sitting height % = sitting height/ height *100. ........................................ 85
Table 16: results of linear regression analysis for growth outcomes at 7 years post-discharge comparing
cases who had oedema at admission and those who didn’t, with controls (siblings and community
combined), adjusted for HIV and SES. * indicates significant difference. Sitting height % = sitting
height/height*100. ........................................................................................................................................ 86
Table 17: shows results of linear regression analysis comparing growth outcomes of those who were
admitted before or at 24 months and those who were admitted after 24 months to controls, adjusted for
HIV status, ahe, sex, SES and physical disability. ........................................................................................ 89
Table 18: results of linear regression analysis for growth outcomes at 7 years post-discharge comparing
cases that were reportedly small or very small at birth with those who were normal or large size at
birth, with controls (siblings and community combined), adjusted for HIV, age, sex and SES. *
indicates p<0.05. Sitting height % = sitting height/height*100. .................................................................. 90
Table 19: Results of paired t-test comparing repeat BIA readings in order to assess BIA reading
consistency. 2nd BIA reading was taken at least 2 hours after the first reading on a subset of children
(n=23). ......................................................................................................................................................... 104
X