review of scientific published literature on infant

Study protocol for Review C – Version 1.8 26th July 2013

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Review of scientific published literature on infant feeding and 1

development of atopic and autoimmune disease: 2

Review C – Maternal and infant diet 3

4

Robert Boyle, Clinical Senior Lecturer, Section of Paediatrics, Imperial College London 5

Vanessa Garcia-Larsen, Post-Doctoral Research Associate, Respiratory Epidemiology and 6

Public Health, National Heart and Lung Institute, Imperial College London 7

Jo Leonardi-Bee, Associate Professor of Community Health Sciences, University of 8

Nottingham 9

Tim Reeves, Research Support Librarian, Faculty of Medicine, Imperial College London 10

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Imperial Consultants, 13

58 Princes Gate, 14

Exhibition Road, 15

London 16

SW7 2PG 17

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Introduction ............................................................................................................................ 4 20

Key words .............................................................................................................................. 5 21

Review question(s) ................................................................................................................. 6 22

Inclusion criteria:.................................................................................................................... 6 23

Types of studies to be included .......................................................................................... 6 24

Participants/population ....................................................................................................... 6 25

Context................................................................................................................................ 7 26

Interventions/exposures ...................................................................................................... 7 27

Comparator(s)/control ...................................................................................................... 10 28

Search strategy ..................................................................................................................... 11 29

Study Outcomes [identical to Review A] ............................................................................. 12 30

Atopic outcomes: .............................................................................................................. 12 31

Autoimmune outcomes: .................................................................................................... 14 32

Study selection and Data Extraction .................................................................................... 15 33

Study selection .................................................................................................................. 15 34

Data extraction .................................................................................................................. 16 35

Risk of bias (quality) assessment ......................................................................................... 16 36

Review level bias .............................................................................................................. 16 37

Study level bias ................................................................................................................. 17 38

Strategy for data synthesis.................................................................................................... 17 39

Data extraction .................................................................................................................. 18 40

Planned subgroup analyses ............................................................................................... 19 41

Graphical exploration of heterogeneity ............................................................................ 19 42

Review registration .............................................................................................................. 20 43


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Dissemination of findings .................................................................................................... 20 44

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Introduction 47

This is one of 3 systematic reviews being undertaken as part of a review of the scientific 48

literature on infant feeding and development of atopic and autoimmune diseases 49

commissioned by the UK Food Standards Agency. Atopic conditions such as asthma, 50

eczema, rhinoconjunctivitis and food allergy appear to have increased in prevalence in recent 51

decades in many countries, and are now the leading causes of chronic illness during 52

childhood in the UK 1, 2

. The apparently rapid changes in disease prevalence, combined with 53

data from migration studies, suggest that early life environmental factors may be important 54

modulators of atopic disease risk. Similar findings apply to the autoimmune diseases type I 55

diabetes mellitus and Crohn’s disease, which also appear to have increased in prevalence in 56

some countries 3. Significant attention has focussed on dietary exposures in relation to these 57

immune-mediated atopic and autoimmune diseases for 2 reasons – first the temporal 58

association between rises in atopic/autoimmune conditions and changing dietary exposures in 59

the relevant populations; second the gut associated lymphoid tissue is our largest collection of 60

immune tissue, and our most mature immune organ at the time of birth 4. Hence early enteral 61

exposures are likely to be especially potent modulators of immune development and risk of 62

immune-mediated disease. Although there are a large number of observational studies, some 63

intervention trials and several systematic reviews in this area, they tend to focus on one 64

specific area of diet and a limited number of immune outcomes. The purpose of these 3 65

systematic reviews is to comprehensively assess the existing literature regarding the 66

relationship between maternal and infant dietary exposures and a child’s risk of any of the 67

common atopic and autoimmune disease, in order to inform UK Department of Health 68

feeding guidance for mothers and their infants. These protocols have been developed by the 69

authors, but have been modified after independent expert peer review and reviews and 70


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meetings with members of the UK Food Standards Agency and the UK Scientific Advisory 71

Committee on Nutrition. The specific outcomes of interest for these reviews, chosen due to 72

their high prevalence in the UK population, and described in more detail below, are: Food 73

allergy, Eczema, Asthma, Allergic rhinitis, Allergic conjunctivitis, Allergic sensitisation, 74

Type 1 diabetes mellitus, Coeliac disease, Inflammatory bowel disease, Autoimmune thyroid 75

disease, Juvenile rheumatoid arthritis, Vitiligo, Psoriasis. 76

Key words 77

Infant; diet; maternal; pregnancy; lactation; supplement; nutrient; allergy; atopy; asthma; 78

eczema; food allergy; sensitisation; rhinitis; conjunctivitis; autoimmune; diabetes; crohn; 79

inflammatory bowel disease; coeliac; thyroiditis; juvenile arthritis; vitiligo; psoriasis; 80

systematic review 81

82


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Review question(s) 83

C1. Does exposure to specific dietary patterns, food groups or nutrients during the first year 84

of life, influence children’s future risk of atopic disease, allergic sensitisation or autoimmune 85

disease. 86

C2. Does maternal exposure to specific dietary patterns, food groups or nutrients during 87

pregnancy or lactation, influence children’s future risk of atopic disease, allergic sensitisation 88

or autoimmune disease. 89

90

Inclusion criteria: 91

Types of studies to be included 92

We will include randomised controlled trials (RCT), quasi RCT, and where necessary 93

prospective cohort or longitudinal studies, retrospective cohort studies, nested case-control 94

studies or other case control studies. We will take a hierarchical approach to study design, 95

such that where data are absent or limited from certain types of studies, we will include lower 96

level study designs. So where high quality intervention studies are lacking, we will include 97

prospective cohort studies; where high quality prospective cohort studies are lacking we will 98

include retrospective cohort studies; where high quality retrospective cohort studies are 99

lacking we will include data from nested case-control studies, and where these are lacking we 100

will use other types of case control studies. We will not include non-comparative studies, or 101

non-human studies. 102

Participants/population 103

Infants between the age of 0 and the end of the 12th

postpartum month (question C1) and their 104

mothers during pregnancy and lactation up to the end of the 24th

month postnatally (question 105


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C2). If infants are characterised as high or standard risk for allergic disease based on family 106

history, this information will be recorded so that subgroup analysis can be made. 107

Context 108

Our primary analyses will exclude studies in which participants were defined by a disease 109

state - eg pregnant women with specific nutritional deficiencies, infants born prematurely 110

(<31 weeks gestation) or other groups clearly representing <5% of the UK population, since 111

the results of this review should apply to the general UK population. We will include studies 112

of specific ethnic groups. Studies where subject eligibility is defined on the basis of a family 113

history of allergy will be included, since this applies to a majority of infants in the UK. 114

Studies restricted to populations at specific genetic risk of autoimmune disease (eg by HLA 115

type) will also be included, since it is difficult to undertake studies of autoimmune disease 116

prevention in the general population due to low prevalence. 117

Interventions/exposures 118

Review question #C1: Exposure of infants in the first 12 months, to specific dietary patterns, 119

dietary components (as groups eg vegetables, fruits, nuts; and individually) or nutrients/food 120

supplements (eg. antioxidants, vitamin D, omega-3 and omega-6 fatty acids, vitamin B3, 121

probiotics). For probiotics, we will include studies where they are given as supplements, or in 122

infant formula. Where possible, the exposures will be measured as a continuous variable 123

rather than categorically. Because of the variety in diet, we will in principle, attempt to 124

classify foods according to their nutritional properties and similarities. We will classify the 125

foods following the European Food Consumption Survey Method, recently used by VGL in a 126

large epidemiological survey of dietary risk factors for allergic diseases across Europe 6. We 127

will also consider the UK Department of Health proposed classification for fruits and 128

vegetables (www.nhs.uk/5aday) in our interpretation of the data, and the UK Reference 129

http://www.nhs.uk/5aday


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Nutrient Intake. Whenever possible, foods will be classified as indicated in the list below. 130

This method allows for more ambiguous classifications to be included. 131

Hard fruits- apple, pear, peach 132

Oily fruits- olive, avocado 133

Berries (any) 134

Nectarines- nectarine, apricot 135

Citrus- orange, kiwi, lemon, mandarin, grapefruit 136

Dried fruits- raisin, prune, dates 137

Fresh fruit juice 138

Tropical fruits- mango, pine-apple, banana 139

Tinned fruits 140

Melon/watermelon 141

Other fruits- plum, cherries, grapes, fig, rhubarb 142

‘Any fruits’ (to include studies which only included a general question on fruit intake) 143

Other classifications of fruits: ‘flavanoid-rich fruits’ – these will be included as a 144

separate group if the publication has grouped fruits as such without separating 145

individual intake (e.g. apples, grapes, berries) 146

Leafy vegetables- lettuce, spinach, chard, fenugreek, herb, wild greens 147

Fruity vegetables- artichokes, tomato, cucumber, okra, aubergine, capers 148

Root vegetables- carrot, parsnips, turnip, ginger, radish, taro, beetroot 149

Cabbage- cauliflower, coleslaw, brussel sprouts, broccoli, cabbage 150

Stalk- celery, asparagus 151

Allium vegetables- leek, onion, garlic, shallots, 152

Pickled vegetable 153


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‘any vegetables (as in ‘any fruits’) 154

Specific classifications of vegetables e.g. ‘red coloured vegetables’ 155

Sweet potatoes, parsnips, swedes and turnips 156

Pulses and beans (baked beans, haricot beans, kidney beans, cannellini beans, butter 157

beans or chickpeas) 158

Nuts 159

Red meat 160

Fish and seafood 161

Dairy products and derivatives 162

Cereals 163

For studies of overall dietary pattern, such as Mediterranean or organic diet, we will look in 164

detail at the definition and only consider meta-analysis where at least 50% of the definition is 165

shared across studies. 166

- inclusion criteria - studies where infant dietary exposure is characterised during the first 12 167

months of life, in such a way that it can be classified for determining the exposure(s) of 168

interest as above; or an intervention study. We will classify the exposures according to how 169

they were measured, i.e. what type of dietary questionnaire or assessment. In general, we will 170

not include studies of blood/plasma/serum/urine levels of circulating nutrients without an 171

assessment of dietary intake, since the purpose of this review is to inform dietary advice for 172

pregnant and lactating mothers and their infants. The single exception is vitamin D, since the 173

primary source of vitamin D is sunlight exposure, so that estimation of vitamin D status based 174

on dietary assessment alone is unreliable. We will include studies of vitamin D status in 175

blood, measured as 25-hydroxy vitamin D in nmol/L or ng/ml, where 2.5nmol/L = 1 ng/ml. 176


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Review question #C2: Exposure of mothers during pregnancy and/or lactation, to specific 177

dietary patterns, dietary components (as groups eg vegetables, fruits, nuts; and individually) 178

or nutrients/food supplements (eg. antioxidants, vitamin D, omega-3 and omega-6 fatty acids, 179

vitamin B3, probiotics). Where possible, the exposures will be measured as a continuous 180

variable rather than categorically. We will follow the same classification proposed above to 181

classify the dietary exposure during pregnancy and lactation up to 24 months. 182

- inclusion criteria - studies where maternal dietary exposure is characterised during 183

pregnancy and/or lactation, in such a way that it can be classified for determining the 184

exposure(s) of interest as above; or an intervention study. We will classify the exposures 185

according to how they were measured, i.e. what type of dietary questionnaire or assessment. 186

In general, we will not include studies of blood/plasma/serum/urine levels of circulating 187

nutrients without an assessment of dietary intake, since the purpose of this review is to inform 188

dietary advice for pregnant and lactating mothers and their infants. The single exception is 189

vitamin D, since the primary source of vitamin D is sunlight exposure, so that estimation of 190

vitamin D status based on dietary assessment can be unreliable. We will include studies of 191

vitamin D status in blood, measured as 25-hydroxy vitamin D in nmol/L or ng/ml, where 192

2.5nmol/L = 1 ng/ml. 193

194

Comparator(s)/control 195

All comparators will be included, including studies which compare different doses or forms 196

of an exposure eg different doses/levels of vitamin D, or different probiotic interventions. In 197

the case of studies that only document food intake as reported frequency, we will aim to 198

categorise groups for binary comparisons e.g. ‘at least weekly intake’ vs. ‘never’; ‘at least 199

daily intake’ vs. ‘weekly or less frequently’. 200


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Search strategy 201

We will search for eligible studies in MEDLINE, EMBASE, Cochrane, Web of Science and 202

LILACS with no specified start date. We will include peer reviewed publications, and also 203

include proceedings and abstracts presented in scientific conferences in the last 3 years, if 204

they have not subsequently been published as a peer reviewed publication. We will search for 205

studies in progress, or completed but unpublished studies using 206

http://apps.who.int/trialsearch/, and will contact international experts in the field of 207

nutritional exposures in relation to allergy and autoimmune disorders, including where 208

appropriate pharmaceutical or food industry representatives, to identify important 209

unpublished work. We will review the bibliography of eligible studies for possible additional 210

publications, and will include all eligible publications, regardless of the language. Where 211

necessary, and where feasible within the limited timescale of this project, the authors of 212

eligible or potentially eligible studies will be contacted by the research team to obtain any 213

data that might not be available in the abstract/publication. Potentially eligible studies are 214

studies which have clearly recorded both an exposure and an outcome of interest, but have 215

not reported an analysis of the relationship between these. 216

The MEDLINE search strategy is at the end of this document, as an Appendix. 217

We will separately search for existing systematic reviews which cover any of the same 218

exposure(s)/outcome(s) as these, and were published since 1st January 2011. We will quality 219

assess such existing systematic reviews using the revised AMSTAR criteria 5. We will not 220

duplicate any existing systematic reviews with revised AMSTAR score ≥32, but will instead 221

summarise the findings of such reviews and include the summary in our final report. As far as 222

possible, these data will be presented using Cochrane Summary of Findings tables, generated 223

using GradePro. For these pre-existing, high quality systematic reviews, we will also 224

http://apps.who.int/trialsearch/


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summarise any eligible publications identified in the searches, which were published 225

subsequent to the relevant systematic review, in our final report. 226

Study Outcomes [identical to Review A] 227

We have selected atopic and autoimmune outcomes on the basis of their population 228

prevalence in children and young adults in the UK or other affluent nations. We have 229

included diseases with a prevalence of at least 1 in 1000, in children/adolescents or young 230

adults (aged <40 years), but have not included rarer diseases 6. We have not included 231

pernicious anaemia or adult-onset rheumatoid arthritis despite a high prevalence in middle 232

aged or elderly people, because their prevalence in young people is lower than 1 in 1000, and 233

prospective studies of infant feeding in relation to diseases of older adults are unlikely to 234

have been undertaken. For all outcome measures, age at assessment will be grouped as 1-4 235

years, 5-14 years, 15-24 years, 25-44 years, 45-64 years and ≥65 years. Where studies report 236

the same outcome at different timepoints within one of these frames, we will use the 237

timepoint which has the most complete dataset ie lowest percentage of missing data as the 238

primary assessment point. For each outcome measure in this review, there is more than one 239

possible method of assessment. We have therefore included our preferred method of 240

assessment for each outcome, which is the a priori ‘primary outcome measure’, assessed at 241

the optimal age as defined above. We will however document all relevant outcomes measured 242

using different assessment tools, in each included study. This will allow for meta-analysis of 243

different studies where they have used similar outcome measures. 244

Atopic outcomes: 245

1. Asthma - defined as either ‘asthma’, ‘infantile wheeze’ or similar, using parent/self report, 246

doctor diagnosis, a validated questionnaire, scoring system or objective measure such as 247


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bronchial hyper-reactivity, forced vital capacity, peak expiratory flow rate or reversible 248

airways obstruction using forced expiratory volume in 1 second. 249

Primary assessment: parent or self-report using a validated questionnaire such as the 250

International Study of Asthma and Allergies in Childhood questionnaire 7, at 5-14 years. 251

Where multiple measures are used, cumulative incidence of wheezing will be used 252

preferentially. 253

2. Eczema – defined using parent/self report, doctor diagnosis, a validated questionnaire, 254

scoring system or objective measure. 255

Primary assessment: parent or self-report using a validated questionnaire such as the UK 256

adaptation of Hanifin and Rajka criteria 8 at 1-4 years. Where multiple measures are used, 257

cumulative incidence of eczema will be analysed preferentially, but point prevalence will also 258

be reported. 259

3.Allergic Rhinitis – defined using parent/self report, doctor diagnosis, a validated 260

questionnaire, scoring system or objective measure. 261

Primary assessment: parent or self-report using a validated questionnaire such as the 262

International Study of Asthma and Allergies in Childhood questionnaire 7, at 5-14 years. 263

Where multiple measures are used, cumulative incidence will be analysed preferentially. 264

4. Allergic Conjunctivitis - defined using parent/self report, doctor diagnosis, a validated 265

questionnaire, scoring system or objective measure. 266

Primary assessment: parent or self-report using a validated questionnaire, at 5-14 years. 267


5. Food allergy - defined by double blind placebo controlled food challenge, by open food 269

challenge, by medical diagnosis or by self/parent report. 270


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Primary assessment: challenge-proven food allergy, assessed at 1-4 years. Where multiple 271

measures are used, cumulative incidence will be analysed preferentially. 272

6. Allergic sensitisation – to an inhalant, an ingestant, or both – defined as positive skin prick 273

test and/or specific IgE test to the relevant allergen using recognised methodologies and 274

scoring criteria 9. 275

Primary assessment: sensitisation to at least one inhalant or ingestant, assessed at 5-14 years 276

or older. Where multiple measures are used, point prevalence will be analysed preferentially. 277

7. Total IgE – measured using a recognised technology such as ImmunoCAP (ThermoFisher, 278

Massachusets). 279

Autoimmune outcomes: 280

1. Type I diabetes mellitus – defined as a medical diagnosis, or a surrogate marker such as 281

autoantibodies against insulin, GAD65, IA-2 or the ZnT8 transporter in the first 3 years of 282

life. 283

Primary assessment: medical diagnosis of type 1 diabetes mellitus using the 1999 WHO 284

recommendations for diagnosis and classification of diabetes mellitus 10

or similar. Where 285

multiple measures are used, cumulative incidence will be analysed preferentially. 286

2. Coeliac disease – defined by characteristic histological features (intraepithelial 287

lymphocytes, crypt hyperplasia and villous atrophy) with improvement in symptoms and 288

histology after institution of a gluten free diet, a medical diagnosis, or a surrogate marker 289

such as IgA tissue transglutaminase or IgA endomysial antibodies. 290

Primary assessment: medical diagnosis of coeliac disease using a histological diagnosis. 291


3. Inflammatory bowel disease (Crohn's disease or Ulcerative colitis) – defined as a medical 293

diagnosis. 294


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Primary assessment: medical diagnosis using a histological diagnosis. Where multiple 295

measures are used, cumulative incidence will be analysed preferentially. 296

4. Autoimmune thyroid disease (Graves' disease or Hashimoto's thyroiditis) - defined as a 297

medical diagnosis. 298

Primary assessment: medical diagnosis using serology and thyroid function testing. Where 299

multiple measures are used, cumulative incidence will be analysed preferentially. 300

5. Juvenile rheumatoid arthritis – defined as a medical diagnosis. 301

Primary assessment: medical diagnosis using the 2001 revised International League of 302

Associations for Rheumatology (ILAR) classification criteria 11

. Where different time-points 303

are reported, then the cumulative incidence to the latest reported time-point will be used 304

preferentially. Where multiple measures are used, cumulative incidence will be analysed 305

preferentially. 306

6. Vitiligo - defined as a medical diagnosis. 307

Primary assessment: medical diagnosis using the Vitiligo European Task Force 2007 criteria 308

or similar 12

. Where multiple measures are used, cumulative incidence will be analysed 309

preferentially. 310

7. Psoriasis - defined as a medical diagnosis. 311

Primary assessment: medical diagnosis. Where multiple measures are used, cumulative 312

incidence will be analysed preferentially. 313

314

Study selection and Data Extraction 315

Study selection 316

Two members of the research team (RB and VGL) will independently review titles and 317

abstracts of identified studies. The full text of the paper will also be independently assessed 318


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by RB and VGL, and will be assessed for eligibility against the inclusion criteria. Any 319

discrepancies will be resolved through discussions with the research team and, as appropriate, 320

the study sponsor (UK Food Standards Agency, FSA). Electronic records will be kept 321

regarding included and excluded studies for audit purposes, specifying reasons for any 322

exclusion, and these details will be included in the final report. Full text articles will be 323

reviewed in duplicate (by two research team members - RB and VGL), and studies for 324

inclusion will be selected – any discrepancies will be resolved through discussions with the 325

research team and the FSA, as appropriate. The reasons for the exclusion of any relevant 326

studies will be recorded, however ineligible studies will not be analysed further. 327

Data extraction 328

A pilot of the data extraction form will be undertaken using a minimum of 5 papers, after 329

which the extraction form will be amended/updated as necessary. The data extraction form 330

will be used to extract the relevant data fields from each included study independently (by 331

two research team members - RB and VGL), and where appropriate data will be entered into 332

Stata IC 12 statistical software for meta-analysis. 333

334

Risk of bias (quality) assessment 335

Review level bias 336

Publication bias will be assessed using funnel plots and Egger's test. Where asymmetry is 337

evident on the funnel plot, a trim and fill analysis will be used. Possible causes for asymmetry 338

other than publication bias (eg between study heterogeneity) will also be considered. Where 339

significant population based cohorts or randomised controlled trials have assessed mode of 340

infant feeding but not reported relevant atopic or autoimmune outcomes, we will consider 341


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contacting authors for original datasets if atopic or autoimmune outcome assessments appear 342

to have been made. 343

Study level bias 344

The risk of bias in included RCTs will be assessed using the Cochrane Collaboration Risk of 345

bias tool, which includes sequence generation, allocation concealment, blinding, incomplete 346

outcome data, and selective outcome reporting, and other bias 13

. RCTs will be considered at 347

low risk of bias where the risk of bias is judged to be low for all key domains of the Cochrane 348

Risk of bias tool. The risk of bias in included cohort and case control studies will be assessed 349

using the National Institute for Clinical Excellence methodological checklist for cohort and 350

case-control studies respectively, which includes considerations of subject selection, 351

assessment of exposure and outcome, and measures to assess confounding 14. Studies will be 352

considered at low risk of bias where most of the criteria in the checklist are addressed, and 353

those that are not addressed or not reported are judged unlikely to change the study findings. 354

For both RCTs and cohort studies, a level of <20% loss to follow up for atopic/autoimmune 355

outcomes will generally be accepted as representing low risk of bias from incomplete 356

outcome data, if there are no other features to suggest increased risk of bias. For all studies, a 357

summary Table of Study Characteristics will be presented for each relevant exposure and 358

outcome, which will include a summary of each study's risk of bias, in addition to the 359

population characteristics, methods used for assessing exposure and for outcome assessment. 360

Strategy for data synthesis 361

Where appropriate, meta-analysis will be undertaken. If meta-analysis is deemed 362

inappropriate, individual study results will be summarised and a balanced conclusion made. 363

Separate analyses will be undertaken for each disease outcome, for each group of similar 364

outcome assessment methods for any given disease, and for each intervention/exposure. 365


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Results for randomised or quasi-randomised controlled trials, prospective cohort or 366

longitudinal studies, or where appropriate retrospective cohort studies, nested case-control 367

studies or other case-control studies will be reported separately for each comparison. 368

Data extraction 369

Data will be extracted either using raw values, crude estimates of effect (including odds 370

ratios, risk ratios, incidence rate ratios, hazard ratios, mean differences) or as adjusted 371

estimates of effect. Adjusted estimates of effect will be used in preference, where available. 372

Random effect meta-analyses will be performed to allow for the anticipated heterogeneity 373

between the studies. 374

Heterogeneity 375

Heterogeneity will be quantified using I2. We will explore reasons for heterogeneity using 376

subgroup analyses based on study level factors. Where extreme levels of heterogeneity are 377

detected (I2>75%), we will perform sensitivity analyses to assess the effect of excluding 378

outliers, and re-consider whether quantitative data synthesis is appropriate. Where possible, 379

meta-regression and subgroup analysis will be used to explore sources of heterogeneity 380

arising from study characteristics - ordered forest plots and graphical methods will be used to 381

further investigate potential effects of continuous confounders on study effects. Individual 382

patient data analysis will not be undertaken. 383

Data analysis 384

Data from individual studies will be pooled using the generic inverse variance method. 385

Pooled results for binary outcomes will be presented as relative risks s with 95% confidence 386

intervals and 2-sided p values, and also expressed as risk differences where possible. Pooled 387

results for continuous outcomes measured using similar scales will be presented as mean 388

differences with 95% confidence intervals and 2-sided p values. However, where different 389


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scales are pooled across studies, we will report results using standardised mean differences. 390

P<0.05 will be considered statistically significant. Relevant results will be presented in 391

Summary of Findings tables similar to those used by the Cochrane Collaboration 15

. 392

All analyses will be performed using STATA IC 12. 393

Planned subgroup analyses 394

1. High study quality - high quality RCT or cohort studies as defined above will be separately 395

analysed. 396

2. Increased disease risk - studies of populations at increased risk for atopic or autoimmune 397

disease will be separately analysed - for example infants with a family history of atopic or 398

autoimmune disease. 399

3. Type of data - unadjusted versus adjusted data. Factors that we expect to be adjusted for 400

within studies: siblings (parity or birth order or family size); gender; age at outcome 401

assessment; disease risk based on family history; maternal or household smoking (asthma 402

outcomes); maternal age; maternal education or socioeconomic status; duration of 403

breastfeeding or exclusive breastfeeding. 404

4. Quality of dietary assessment - use of a validated food frequency/nutritional exposure 405

assessment tool, or in the case of intervention studies, documented compliance with the study 406

intervention for over 80% of intended doses. Studies which meet these criteria will be 407

analysed separately. 408

5. Quality of dietary exposure - studies of nutrient intake/supplementation in the natural form 409

of the nutrient, as opposed to specific supplementation, will be analysed separately. Some 410

studies have shown stronger effects for foods in their natural form than when given as 411

specific nutritional supplements 17

. 412

Graphical exploration of heterogeneity 413


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1. Study year (average year of assessment/birth for study population) 414

2. Average age of study population at examination/assessment 415

416

Review registration 417

This systematic review will be registered with the International Prospective Register of 418

Systematic Reviews (www.crd.york.ac.uk/Prospero), prior to selecting any studies from the 419

search results. This review protocol has been revised following peer review by the UK Food 420

Standards Agency, the UK Scientific Advisory Committee on Nutrition, independent experts 421

Professor Graham Devereux and Dr Carina Venter, and the Lancet. 422

423

Dissemination of findings 424

The findings of this review will inform the Food Standards Agency review of infant feeding 425

which will in turn inform the revised Department of Health guidance on infant feeding in the 426

UK. The reviews will be submitted for publication as peer reviewed manuscripts in academic 427

journals, and presented at national and international conferences. A summary of the findings 428

will be sent to relevant stakeholders such as charities, health and educational institutions 429

involved in advising on or supporting infant feeding in the UK. 430

431

http://www.crd.york.ac.uk/Prospero


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