Diet during pregnancy and infancy and risk of allergic or autoimmune disease: A systematic review and meta-analysis

<!DOCTYPE html> <html lang="en" > <head > <meta charset="UTF-8" /> <meta http-equiv="X-UA-Compatible" content="IE=edge" /> <meta name="HandheldFriendly" content="True" /> <meta name="MobileOptimized" content="320" /> <meta name="viewport" content="width=device-width, initial-scale=1.0" /> <link rel="stylesheet" href="/static/assets/style-b3a36f11.css" /> <script type="module" crossorigin="" src="/static/assets/base_style-d4f8bd56.js"></script> <link rel="stylesheet" href="/static/assets/style-ef962842.css" /> <link rel="stylesheet" href="/static/assets/style-3ade8b5c.css" /> <script type="module" crossorigin="" src="/static/assets/article_style-d757a0dd.js"></script> <style> @media screen and (min-width: 64em) { div.pmc-wm { background: repeat-y; background-image: url("data:image/svg+xml,%3Csvg xmlns='http://www.w3.org/2000/svg' width='20' height='350' xmlns:xlink='http://www.w3.org/1999/xlink'%3E%3Cdefs%3E%3Cfilter x='-.02' y='0' width='1.05' height='1' id='c'%3E%3CfeFlood flood-color='%23FFF'/%3E%3CfeComposite in='SourceGraphic'/%3E%3C/filter%3E%3Ctext id='b' font-family='Helvetica' font-size='11pt' style='opacity:1;fill:%23005ea2;stroke:none;text-anchor:middle' x='175' y='14'%3E%3C/text%3E%3Cpath id='a' style='fill:%23005ea2' d='M0 8h350v3H0z'/%3E%3C/defs%3E%3Cuse xlink:href='%23a' transform='rotate(90 10 10)'/%3E%3Cuse xlink:href='%23b' transform='rotate(90 10 10)' filter='url(%23c)'/%3E%3C/svg%3E"); padding-left: 3rem; } } </style> <link rel="apple-touch-icon" sizes="180x180" href="/static/img/favicons/apple-touch-icon.png" /> <link rel="icon" type="image/png" sizes="48x48" href="/static/img/favicons/favicon-48x48.png" /> <link rel="icon" type="image/png" sizes="32x32" href="/static/img/favicons/favicon-32x32.png" /> <link rel="icon" type="image/png" sizes="16x16" href="/static/img/favicons/favicon-16x16.png" /> <link rel="manifest" href="/static/img/favicons/site.webmanifest" /> <link rel="mask-icon" href="/static/img/favicons/safari-pinned-tab.svg" color="#0071bc" /> <meta name="msapplication-config" content="/static/img/favicons/browserconfig.xml" /> <meta name="theme-color" content="#ffffff" /> <title> Diet during pregnancy and infancy and risk of allergic or autoimmune disease: A systematic review and meta-analysis - PMC </title>  <meta name="ncbi_app" content="cloudpmc-viewer" /> <meta name="ncbi_db" content="pmc" /> <meta name="ncbi_phid" content="607E67C67EB25E930867C6002F0F51D7.m_1" />  <meta name="ncbi_pdid" content="article" /> <link rel="preconnect" href="https://www.google-analytics.com" /> <link rel="preconnect" href="https://cdn.ncbi.nlm.nih.gov" />  <script src="/static/assets/uswds-init.js"></script> <meta name="ncbi_domain" content="plosmed"> <meta name="ncbi_type" content="fulltext"> <meta name="ncbi_pcid" content="journal"> <meta name="ncbi_feature" content="associated_data"> <link rel="canonical" href="https://pmc.ncbi.nlm.nih.gov/articles/PMC5830033/"> <meta name="robots" content="INDEX,NOFOLLOW,NOARCHIVE"> <meta name="citation_journal_title" content="PLoS Medicine"> <meta name="citation_title" content="Diet during pregnancy and infancy and risk of allergic or autoimmune disease: A systematic review and meta-analysis"> <meta name="citation_author" content="Vanessa Garcia-Larsen"> <meta name="citation_author_institution" content="Department of International Health, Johns Hopkins School of Public Health, Baltimore, Maryland, United States of America"> <meta name="citation_author_institution" content="Respiratory Epidemiology, Occupational Medicine and Public Health, National Heart and Lung Institute, Imperial College London, London, United Kingdom"> <meta name="citation_author" content="Despo Ierodiakonou"> <meta name="citation_author_institution" content="Respiratory Epidemiology, Occupational Medicine and Public Health, National Heart and Lung Institute, Imperial College London, London, United Kingdom"> <meta name="citation_author_institution" content="Section of Paediatrics, Department of Medicine, Imperial College London, London, United Kingdom"> <meta name="citation_author" content="Katharine Jarrold"> <meta name="citation_author_institution" content="Section of Paediatrics, Department of Medicine, Imperial College London, London, United Kingdom"> <meta name="citation_author" content="Sergio Cunha"> <meta name="citation_author_institution" content="Respiratory Epidemiology, Occupational Medicine and Public Health, National Heart and Lung Institute, Imperial College London, London, United Kingdom"> <meta name="citation_author" content="Jennifer Chivinge"> <meta name="citation_author_institution" content="Section of Paediatrics, Department of Medicine, Imperial College London, London, United Kingdom"> <meta name="citation_author" content="Zoe Robinson"> <meta name="citation_author_institution" content="Section of Paediatrics, Department of Medicine, Imperial College London, London, United Kingdom"> <meta name="citation_author" content="Natalie Geoghegan"> <meta name="citation_author_institution" content="Section of Paediatrics, Department of Medicine, Imperial College London, London, United Kingdom"> <meta name="citation_author" content="Alisha Ruparelia"> <meta name="citation_author_institution" content="Section of Paediatrics, Department of Medicine, Imperial College London, London, United Kingdom"> <meta name="citation_author" content="Pooja Devani"> <meta name="citation_author_institution" content="Section of Paediatrics, Department of Medicine, Imperial College London, London, United Kingdom"> <meta name="citation_author" content="Marialena Trivella"> <meta name="citation_author_institution" content="Centre for Statistics in Medicine, University of Oxford, Oxford, United Kingdom"> <meta name="citation_author" content="Jo Leonardi-Bee"> <meta name="citation_author_institution" content="Division of Epidemiology and Public Health, University of Nottingham, Nottingham, United Kingdom"> <meta name="citation_author" content="Robert J Boyle"> <meta name="citation_author_institution" content="Section of Paediatrics, Department of Medicine, Imperial College London, London, United Kingdom"> <meta name="citation_author_institution" content="Centre of Evidence Based Dermatology, University of Nottingham, Nottingham, United Kingdom"> <meta name="citation_publication_date" content="2018 Feb 28"> <meta name="citation_volume" content="15"> <meta name="citation_issue" content="2"> <meta name="citation_firstpage" content="e1002507"> <meta name="citation_doi" content="10.1371/journal.pmed.1002507"> <meta name="citation_pmid" content="29489823"> <meta name="citation_abstract_html_url" content="https://pmc.ncbi.nlm.nih.gov/articles/PMC5830033/"> <meta name="citation_fulltext_html_url" content="https://pmc.ncbi.nlm.nih.gov/articles/PMC5830033/"> <meta name="citation_pdf_url" content="https://pmc.ncbi.nlm.nih.gov/articles/PMC5830033/pdf/pmed.1002507.pdf"> <meta name="description" content="There is uncertainty about the influence of diet during pregnancy and infancy on a child’s immune development. We assessed whether variations in maternal or infant diet can influence risk of allergic or autoimmune disease. Two authors selected ..."> <meta name="og:title" content="Diet during pregnancy and infancy and risk of allergic or autoimmune disease: A systematic review and meta-analysis"> <meta name="og:type" content="article"> <meta name="og:site_name" content="PubMed Central (PMC)"> <meta name="og:description" content="There is uncertainty about the influence of diet during pregnancy and infancy on a child’s immune development. We assessed whether variations in maternal or infant diet can influence risk of allergic or autoimmune disease. Two authors selected ..."> <meta name="og:url" content="https://pmc.ncbi.nlm.nih.gov/articles/PMC5830033/"> <meta name="og:image" content="https://cdn.ncbi.nlm.nih.gov/pmc/cms/images/pmc-card-share.jpg?_=0"> <meta name="twitter:card" content="summary_large_image"> <meta name="twitter:site" content="@ncbi"> </head> <body > <a class="usa-skipnav " href="#main-content"> Skip to main content </a> <section class="usa-banner " aria-label="Official website of the United States government" > <div class="usa-accordion"> <header class="usa-banner__header"> <div class="usa-banner__inner"> <div class="grid-col-auto"> <img aria-hidden="true" class="usa-banner__header-flag" src="/static/img/us_flag.svg" alt="" /> </div> <div class="grid-col-fill tablet:grid-col-auto" aria-hidden="true"> <p class="usa-banner__header-text"> An official website of the United States government </p> <span class="usa-banner__header-action">Here's how you know</span> </div> <button type="button" class="usa-accordion__button usa-banner__button " aria-expanded="false" aria-controls="gov-banner-default" data-testid="storybook-django-banner" > <span class="usa-banner__button-text">Here's how you know</span> </button> </div> </header> <div class="usa-banner__content usa-accordion__content" id="gov-banner-default" hidden> <div class="grid-row grid-gap-lg"> <div class="usa-banner__guidance tablet:grid-col-6"> <img class="usa-banner__icon usa-media-block__img" src="/static/img/icon-dot-gov.svg" alt="" aria-hidden="true" /> <div class="usa-media-block__body"> <p> <strong>Official websites use .gov</strong> <br /> A <strong>.gov</strong> website belongs to an official government organization in the United States. </p> </div> </div> <div class="usa-banner__guidance tablet:grid-col-6"> <img class="usa-banner__icon usa-media-block__img" src="/static/img/icon-https.svg" alt="" aria-hidden="true" /> <div class="usa-media-block__body"> <p> <strong>Secure .gov websites use HTTPS</strong> <br /> A <strong>lock</strong> ( <span class="icon-lock"> <svg xmlns="http://www.w3.org/2000/svg" width="52" height="64" viewBox="0 0 52 64" class="usa-banner__lock-image" role="graphics-symbol" aria-labelledby="banner-lock-description" focusable="false"> <title id="banner-lock-title">Lock</title> <desc id="banner-lock-description"> Locked padlock icon </desc> <path fill="#000000" fill-rule="evenodd" d="M26 0c10.493 0 19 8.507 19 19v9h3a4 4 0 0 1 4 4v28a4 4 0 0 1-4 4H4a4 4 0 0 1-4-4V32a4 4 0 0 1 4-4h3v-9C7 8.507 15.507 0 26 0zm0 8c-5.979 0-10.843 4.77-10.996 10.712L15 19v9h22v-9c0-6.075-4.925-11-11-11z" /> </svg> </span>) or <strong>https://</strong> means you've safely connected to the .gov website. Share sensitive information only on official, secure websites. </p> </div> </div> </div> </div> </div> </section> <div class="usa-overlay"> </div> <header class="usa-header usa-header--extended usa-header--wide" data-testid="header" data-header > <div class="ncbi-header"> <div class="ncbi-header__container"> <a class="ncbi-header__logo-container" href="https://www.ncbi.nlm.nih.gov/"> <img alt=" NCBI home page " class="ncbi-header__logo-image" src="/static/img/ncbi-logos/nih-nlm-ncbi--white.svg" /> </a>  <button type="button" class="usa-menu-btn ncbi-header__hamburger-button " aria-label="Show menu" data-testid="navMenuButton" > <svg aria-hidden="true" class="ncbi-hamburger-icon" fill="none" focusable="false" height="21" viewBox="0 0 31 21" width="31" xmlns="http://www.w3.org/2000/svg"> <path clip-rule="evenodd" d="M0.125 20.75H30.875V17.3333H0.125V20.75ZM0.125 12.2083H30.875V8.79167H0.125V12.2083ZM0.125 0.25V3.66667H30.875V0.25H0.125Z" fill="#F1F1F1" fill-rule="evenodd" /> </svg> </button>  <div class="ncbi-header__desktop-buttons">  <button type="button" class="usa-button usa-button--unstyled ncbi-header__desktop-button " aria-expanded="false" aria-controls="search-field-desktop-navigation" aria-label="Show search overlay" data-testid="toggleSearchPanelButton" data-toggle-search-panel-button > <svg class="usa-icon " role="graphics-symbol" aria-hidden="true" > <use xlink:href="/static/img/sprite.svg#search" /> </svg> Search </button>  <div class="ncbi-header__login-dropdown"> <button type="button" class="usa-button usa-button--unstyled ncbi-header__desktop-button ncbi-header__login-dropdown-button " aria-expanded="false" aria-controls="login-dropdown-menu" aria-label="Show login menu" data-testid="toggleLoginMenuDropdown" data-desktop-login-button > <svg class="usa-icon " role="graphics-symbol" aria-hidden="true" > <use xlink:href="/static/img/sprite.svg#person" /> </svg> <span data-login-dropdown-text>Log in</span>  <svg class="usa-icon ncbi-header__login-dropdown-icon ncbi-header__login-dropdown-icon--expand-less ncbi-header__login-dropdown-icon--hidden" role="graphics-symbol" aria-hidden="true" data-login-dropdown-up-arrow> <use xlink:href="/static/img/sprite.svg#expand_less" /> </svg>  <svg class="usa-icon ncbi-header__login-dropdown-icon ncbi-header__login-dropdown-icon--expand-more ncbi-header__login-dropdown-icon--hidden" role="graphics-symbol" aria-hidden="true" data-login-dropdown-down-arrow> <use xlink:href="/static/img/sprite.svg#expand_more" /> </svg> </button>  <ul class="usa-nav__submenu ncbi-header__login-dropdown-menu" id="login-dropdown-menu" data-desktop-login-menu-dropdown hidden> <li class="usa-nav__submenu-item">  <a href="https://www.ncbi.nlm.nih.gov/myncbi/" class="usa-link " > Dashboard </a> </li> <li class="usa-nav__submenu-item">  <a href="https://www.ncbi.nlm.nih.gov/myncbi/collections/bibliography/" class="usa-link " > Publications </a> </li> <li class="usa-nav__submenu-item">  <a href="https://www.ncbi.nlm.nih.gov/account/settings/" class="usa-link " > Account settings </a> </li> <li class="usa-nav__submenu-item"> <button type="button" class="usa-button usa-button--outline ncbi-header__login-dropdown-logout-button " data-testid="desktopLogoutButton" data-desktop-logout-button > Log out </button> </li> </ul> </div> </div> </div> </div>  <div class="ncbi-search-panel ncbi--show-only-at-desktop" data-testid="searchPanel" data-header-search-panel hidden> <div class="ncbi-search-panel__container"> <form action="https://www.ncbi.nlm.nih.gov/search/all/" aria-describedby="search-field-desktop-navigation-help-text" autocomplete="off" class="usa-search usa-search--big ncbi-search-panel__form" data-testid="form" method="GET" role="search"> <label class="usa-sr-only" data-testid="label" for="search-field-desktop-navigation"> Search… </label> <input class="usa-input" data-testid="textInput" id="search-field-desktop-navigation" name="term" placeholder="Search NCBI" type="search" value="" /> <button type="submit" class="usa-button " data-testid="button" > <span class="usa-search__submit-text"> Search NCBI </span> </button> </form> </div> </div> <nav aria-label="Primary navigation" class="usa-nav"> <p class="usa-sr-only" id="primary-navigation-sr-only-title"> Primary site navigation </p>  <button type="button" class="usa-nav__close ncbi-nav__close-button " aria-label="Close navigation menu" data-testid="navCloseButton" > <img src="/static/img/usa-icons/close.svg" alt="Close" /> </button>  <form class="usa-search usa-search--small ncbi--hide-at-desktop margin-top-6" role="search"> <label class="usa-sr-only" for="search-field"> Search </label> <input class="usa-input" id="search-field-mobile-navigation" type="search" placeholder="Search NCBI" name="search" /> <button type="submit" class="usa-button " >  <img src="data:image/svg+xml;base64,PHN2ZyB4bWxucz0iaHR0cDovL3d3dy53My5vcmcvMjAwMC9zdmciIGhlaWdodD0iMjQiIHZpZXdCb3g9IjAgMCAyNCAyNCIgd2lkdGg9IjI0Ij48cGF0aCBkPSJNMCAwaDI0djI0SDB6IiBmaWxsPSJub25lIi8+PHBhdGggZmlsbD0iI2ZmZiIgZD0iTTE1LjUgMTRoLS43OWwtLjI4LS4yN0E2LjQ3MSA2LjQ3MSAwIDAgMCAxNiA5LjUgNi41IDYuNSAwIDEgMCA5LjUgMTZjMS42MSAwIDMuMDktLjU5IDQuMjMtMS41N2wuMjcuMjh2Ljc5bDUgNC45OUwyMC40OSAxOWwtNC45OS01em0tNiAwQzcuMDEgMTQgNSAxMS45OSA1IDkuNVM3LjAxIDUgOS41IDUgMTQgNy4wMSAxNCA5LjUgMTEuOTkgMTQgOS41IDE0eiIvPjwvc3ZnPg==" class="usa-search__submit-icon" alt="Search" /> </button> </form>   <div class="ncbi-nav__mobile-login-menu ncbi--hide-at-desktop" data-mobile-login-menu hidden> <p class="ncbi-nav__mobile-login-menu-status"> Logged in as: <strong class="ncbi-nav__mobile-login-menu-email" data-mobile-login-email-text></strong> </p> <ul class="usa-nav__primary usa-accordion"> <li class="usa-nav__primary-item"> <a href="https://www.ncbi.nlm.nih.gov/myncbi/" class="usa-link " > Dashboard </a> </li> <li class="usa-nav__primary-item"> <a href="https://www.ncbi.nlm.nih.gov/myncbi/collections/bibliography/" class="usa-link " > Publications </a> </li> <li class="usa-nav__primary-item"> <a href="https://www.ncbi.nlm.nih.gov/account/settings/" class="usa-link " > Account settings </a> </li> </ul> </div> <button type="button" class="usa-button ncbi-nav__mobile-login-button ncbi--hide-at-desktop " data-testid="mobileLoginButton" data-mobile-login-button > Log in </button> </nav> </header> <section class="pmc-header pmc-header--basic" aria-label="PMC Header with search box"> <div class="pmc-nav-container"> <div class="pmc-header__bar"> <div class="pmc-header__logo"> <a href="/" title="Home" aria-label="PMC Home"></a> </div> <button type="button" class="usa-button usa-button--unstyled pmc-header__search__button" aria-label="Open search" data-ga-category="search" data-ga-action="PMC" data-ga-label="pmc_search_panel_mobile" > <svg class="usa-icon width-4 height-4 pmc-icon__open" aria-hidden="true" focusable="false" role="img"> <use xlink:href="/static/img/sprite.svg#search"></use> </svg> <svg class="usa-icon width-4 height-4 pmc-icon__close" aria-hidden="true" focusable="false" role="img"> <use xlink:href="/static/img/sprite.svg#close"></use> </svg> </button> </div> <div class="pmc-header__search"> <form class="usa-search usa-search--extra usa-search--article-right-column pmc-header__search__form" autocomplete="off" role="search"> <label class="usa-sr-only" for="pmc-search">Search PMC Full-Text Archive</label> <span class="autoComplete_wrapper flex-1"> <input class="usa-input width-full maxw-none" required="required" placeholder="Search PMC Full-Text Archive" id="pmc-search" type="search" name="term" data-autocomplete-url="https://pmc.ncbi.nlm.nih.gov/autocomp/search/autocomp/"/> </span> <button class="usa-button" type="submit" formaction="https://www.ncbi.nlm.nih.gov/pmc/" data-ga-category="search" data-ga-action="PMC" data-ga-label="PMC_search_button" > <span class="usa-search__submit-text">Search in PMC</span> <img src="/static/img/usa-icons-bg/search--white.svg" class="usa-search__submit-icon" alt="Search" /> </button> </form> <ul class="pmc-header__search__menu"> <li> <a class="usa-link" href="https://www.ncbi.nlm.nih.gov/pmc/advanced/" data-ga-action="featured_link" data-ga-label="advanced_search"> Advanced Search </a> </li> <li> <a class="usa-link" href="/journals/" data-ga-action="featured_link" data-ga-label="journal list"> Journal List </a> </li> <li> <a class="usa-link" href="/about/userguide/" data-ga-action="featured_link" data-ga-label="user guide"> User Guide </a> </li> </ul> </div> </div> </section> <div class="usa-section padding-top-0 desktop:padding-top-6 pmc-article-section" data-article-db="pmc" data-article-id="5830033"> <div class="grid-container pmc-actions-bar" aria-label="Actions bar" role="complementary"> <div class="grid-row"> <div class="grid-col-fill display-flex"> <div class="display-flex"> <ul class="usa-list usa-list--unstyled usa-list--horizontal"> <li class="margin-right-2 mobile-lg:margin-right-4 display-flex mob"> <button type="button" class="usa-button pmc-sidenav__container__open usa-button--unstyled width-auto display-flex" aria-label="Open resources" data-extra-class="is-visible-resources" data-ga-category="resources_accordion" data-ga-action="click" data-ga-label="mobile_icon" > <svg class="usa-icon width-4 height-4" aria-hidden="true" focusable="false" role="img"> <use xlink:href="/static/img/sprite.svg#more_vert"></use> </svg> </button> </li> <li class="margin-right-2 mobile-lg:margin-right-4 display-flex mob"> <a href="https://doi.org/10.1371/journal.pmed.1002507" class="usa-link display-flex usa-tooltip" role="button" target="_blank" rel="noreferrer noopener" title="View on publisher site" data-position="bottom" aria-label="View on publisher site" data-ga-category="actions" data-ga-action="click" data-ga-label="publisher_link_mobile" > <svg class="usa-icon width-4 height-4" aria-hidden="true" focusable="false" role="img"> <use xlink:href="/static/img/sprite.svg#launch"></use> </svg> </a> </li> <li class="margin-right-2 mobile-lg:margin-right-4 display-flex"> <a href="pdf/pmed.1002507.pdf" class="usa-link display-flex usa-tooltip" role="button" title="Download PDF" data-position="bottom" aria-label="Download PDF" data-ga-category="actions" data-ga-action="click" data-ga-label="pdf_download_mobile" > <svg class="usa-icon width-4 height-4" aria-hidden="true" focusable="false" role="img"> <use xlink:href="/static/img/sprite.svg#file_download"></use> </svg> </a> </li> <li class="margin-right-2 mobile-lg:margin-right-4 display-flex"> <button class="usa-button usa-button--unstyled usa-tooltip collections-dialog-trigger collections-button display-flex collections-button-empty" title="Add to Collections" data-position="bottom" aria-label="Save article in MyNCBI collections." data-ga-category="actions" data-ga-action="click" data-ga-label="collections_button_mobile" data-collections-open-dialog-enabled="false" data-collections-open-dialog-url="https://account.ncbi.nlm.nih.gov/?back_url=https%3A%2F%2Fpmc.ncbi.nlm.nih.gov%2Farticles%2FPMC5830033%2F%23open-collections-dialog" data-in-collections="false" > <svg class="usa-icon width-4 height-4 usa-icon--bookmark-full" aria-hidden="true" focusable="false" role="img" hidden> <use xlink:href="/static/img/action-bookmark-full.svg#icon"></use> </svg> <svg class="usa-icon width-4 height-4 usa-icon--bookmark-empty" aria-hidden="true" focusable="false" role="img" hidden> <use xlink:href="/static/img/action-bookmark-empty.svg#icon"></use> </svg> </button> </li> <li class="margin-right-2 mobile-lg:margin-right-4 display-flex"> <button role="button" class="usa-button usa-button--unstyled usa-tooltip citation-dialog-trigger display-flex" aria-label="Open dialog with citation text in different styles" title="Cite" data-position="bottom" data-ga-category="actions" data-ga-action="open" data-ga-label="cite_mobile" data-all-citations-url="/resources/citations/5830033/" data-citation-style="nlm" data-download-format-link="/resources/citations/5830033/export/" > <svg class="usa-icon width-4 height-4 usa-icon--bookmark-empty" aria-hidden="true" focusable="false" role="img" hidden> <use xlink:href="/static/img/sprite.svg#format_quote"></use> </svg> </button> </li> <li class="pmc-permalink display-flex"> <button type="button" class="usa-button usa-button--unstyled usa-tooltip display-flex" title="Permalink" data-position="bottom" aria-label="Show article permalink" aria-expanded="false" aria-haspopup="true" data-ga-category="actions" data-ga-action="open" data-ga-label="permalink_mobile" > <svg class="usa-icon width-4 height-4" aria-hidden="true" focusable="false" role="img"> <use xlink:href="/static/img/sprite.svg#share"></use> </svg> </button> <div class="pmc-permalink__dropdown" hidden> <div class="pmc-permalink__dropdown__container"> <h2 class="usa-modal__heading margin-top-0 margin-bottom-2">PERMALINK</h2> <div class="pmc-permalink__dropdown__content"> <input type="text" class="usa-input" value="https://pmc.ncbi.nlm.nih.gov/articles/PMC5830033/" aria-label="Article permalink"> <button class="usa-button display-inline-flex pmc-permalink__dropdown__copy__btn margin-right-0" title="Copy article permalink" data-ga-category="save_share" data-ga-action="link" data-ga-label="copy_link"> <svg class="usa-icon" aria-hidden="true" focusable="false" role="img"> <use xlink:href="/static/img/sprite.svg#content_copy"></use> </svg> <span class="margin-left-1">Copy</span> </button> </div> </div> </div> </li> </ul> </div> <button type="button" class="usa-button pmc-sidenav__container__open usa-button--unstyled width-auto display-flex" aria-label="Open article navigation" data-extra-class="is-visible-in-page" data-ga-category="actions" data-ga-action="open" data-ga-label="article_nav_mobile" > <svg class="usa-icon width-4 height-4" aria-hidden="true" focusable="false" role="img"> <use xlink:href="/static/img/sprite.svg#list"></use> </svg> </button> </div> </div> </div> <div class="grid-container desktop:padding-left-6"> <div id="article-container" class="grid-row grid-gap"> <div class="grid-col-12 desktop:grid-col-8 order-2 pmc-layout__content"> <div class="grid-container padding-left-0 padding-right-0"> <div class="grid-row desktop:margin-left-neg-6"> <div class="grid-col-12"> <div class="pmc-layout__disclaimer" role="complementary" aria-label="Disclaimer note"> As a library, NLM provides access to scientific literature. Inclusion in an NLM database does not imply endorsement of, or agreement with, the contents by NLM or the National Institutes of Health.<br/> Learn more: <a class="usa-link" data-ga-category="Link click" data-ga-action="Disclaimer" data-ga-label="New disclaimer box" href="/about/disclaimer/">PMC Disclaimer</a> | <a class="usa-link" data-ga-category="Link click" data-ga-action="PMC Copyright Notice" data-ga-label="New disclaimer box" href="/about/copyright/"> PMC Copyright Notice </a> </div> </div> </div> <div class="grid-row pmc-wm desktop:margin-left-neg-6">  <main id="main-content" class="usa-layout-docs__main usa-layout-docs grid-col-12 pmc-layout pmc-prose padding-0" > <section class="pmc-journal-banner text-center line-height-none" aria-label="Journal banner"><img src="https://cdn.ncbi.nlm.nih.gov/pmc/banners/logo-plosmed.png" alt="PLOS Medicine logo" usemap="#pmc-banner-imagemap" width="500" height="75"><map name="pmc-banner-imagemap"><area alt="Link to PLOS Medicine" title="Link to PLOS Medicine" shape="default" href="https://doi.org/10.1371/journal.pmed.1002507" target="_blank" rel="noopener noreferrer"></map></section><article lang="en"><section aria-label="Article citation and metadata"><section class="pmc-layout__citation font-secondary font-xs"><div> <div class="display-inline-block"><button type="button" class="cursor-pointer text-no-underline bg-transparent border-0 padding-0 text-left margin-0 text-normal text-primary" aria-controls="journal_context_menu">PLoS Med</button></div>. 2018 Feb 28;15(2):e1002507. doi: <a href="https://doi.org/10.1371/journal.pmed.1002507" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">10.1371/journal.pmed.1002507</a> </div> <nav id="journal_context_menu" hidden="hidden"><ul class="menu-list font-family-ui" role="menu"> <li role="presentation"><a href="https://www.ncbi.nlm.nih.gov/pmc/?term=%22PLoS%20Med%22%5Bjour%5D" class="usa-link" role="menuitem">Search in PMC</a></li> <li role="presentation"><a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22PLoS%20Med%22%5Bjour%5D" lang="en" class="usa-link" role="menuitem">Search in PubMed</a></li> <li role="presentation"><a href="https://www.ncbi.nlm.nih.gov/nlmcatalog?term=%22PLoS%20Med%22%5BTitle%20Abbreviation%5D" class="usa-link" role="menuitem">View in NLM Catalog</a></li> <li role="presentation"><a href="?term=%22PLoS%20Med%22%5Bjour%5D" class="usa-link" role="menuitem" data-add-to-search="true">Add to search</a></li> </ul></nav></section><section class="front-matter"><div class="ameta p font-secondary font-xs"> <hgroup><h1>Diet during pregnancy and infancy and risk of allergic or autoimmune disease: A systematic review and meta-analysis</h1></hgroup><div class="cg p"> <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Garcia-Larsen%20V%22%5BAuthor%5D" class="usa-link" aria-describedby="id1"><span class="name western">Vanessa Garcia-Larsen</span></a><div hidden="hidden" id="id1"> <h3><span class="name western">Vanessa Garcia-Larsen</span></h3> <div class="p"> <sup>1</sup>Department of International Health, Johns Hopkins School of Public Health, Baltimore, Maryland, United States of America</div> <div class="p"> <sup>2</sup>Respiratory Epidemiology, Occupational Medicine and Public Health, National Heart and Lung Institute, Imperial College London, London, United Kingdom</div> <div>Conceptualization, Data curation, Funding acquisition, Investigation, Methodology, Project administration, Resources, Supervision, Writing – original draft, Writing – review & editing</div> <div class="p">Find articles by <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Garcia-Larsen%20V%22%5BAuthor%5D" class="usa-link"><span class="name western">Vanessa Garcia-Larsen</span></a> </div> </div> <sup>1,</sup><sup>2,</sup><sup>‡</sup>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Ierodiakonou%20D%22%5BAuthor%5D" class="usa-link" aria-describedby="id2"><span class="name western">Despo Ierodiakonou</span></a><div hidden="hidden" id="id2"> <h3><span class="name western">Despo Ierodiakonou</span></h3> <div class="p"> <sup>2</sup>Respiratory Epidemiology, Occupational Medicine and Public Health, National Heart and Lung Institute, Imperial College London, London, United Kingdom</div> <div class="p"> <sup>3</sup>Section of Paediatrics, Department of Medicine, Imperial College London, London, United Kingdom</div> <div>Data curation, Formal analysis, Investigation, Methodology, Project administration, Software, Writing – original draft, Writing – review & editing</div> <div class="p">Find articles by <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Ierodiakonou%20D%22%5BAuthor%5D" class="usa-link"><span class="name western">Despo Ierodiakonou</span></a> </div> </div> <sup>2,</sup><sup>3,</sup><sup>‡</sup>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Jarrold%20K%22%5BAuthor%5D" class="usa-link" aria-describedby="id3"><span class="name western">Katharine Jarrold</span></a><div hidden="hidden" id="id3"> <h3><span class="name western">Katharine Jarrold</span></h3> <div class="p"> <sup>3</sup>Section of Paediatrics, Department of Medicine, Imperial College London, London, United Kingdom</div> <div>Investigation, Writing – review & editing</div> <div class="p">Find articles by <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Jarrold%20K%22%5BAuthor%5D" class="usa-link"><span class="name western">Katharine Jarrold</span></a> </div> </div> <sup>3</sup>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Cunha%20S%22%5BAuthor%5D" class="usa-link" aria-describedby="id4"><span class="name western">Sergio Cunha</span></a><div hidden="hidden" id="id4"> <h3><span class="name western">Sergio Cunha</span></h3> <div class="p"> <sup>2</sup>Respiratory Epidemiology, Occupational Medicine and Public Health, National Heart and Lung Institute, Imperial College London, London, United Kingdom</div> <div>Formal analysis, Methodology, Writing – review & editing</div> <div class="p">Find articles by <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Cunha%20S%22%5BAuthor%5D" class="usa-link"><span class="name western">Sergio Cunha</span></a> </div> </div> <sup>2</sup>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Chivinge%20J%22%5BAuthor%5D" class="usa-link" aria-describedby="id5"><span class="name western">Jennifer Chivinge</span></a><div hidden="hidden" id="id5"> <h3><span class="name western">Jennifer Chivinge</span></h3> <div class="p"> <sup>3</sup>Section of Paediatrics, Department of Medicine, Imperial College London, London, United Kingdom</div> <div>Data curation, Formal analysis, Methodology, Writing – original draft</div> <div class="p">Find articles by <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Chivinge%20J%22%5BAuthor%5D" class="usa-link"><span class="name western">Jennifer Chivinge</span></a> </div> </div> <sup>3</sup>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Robinson%20Z%22%5BAuthor%5D" class="usa-link" aria-describedby="id6"><span class="name western">Zoe Robinson</span></a><div hidden="hidden" id="id6"> <h3><span class="name western">Zoe Robinson</span></h3> <div class="p"> <sup>3</sup>Section of Paediatrics, Department of Medicine, Imperial College London, London, United Kingdom</div> <div>Data curation, Formal analysis, Methodology, Writing – original draft</div> <div class="p">Find articles by <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Robinson%20Z%22%5BAuthor%5D" class="usa-link"><span class="name western">Zoe Robinson</span></a> </div> </div> <sup>3</sup>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Geoghegan%20N%22%5BAuthor%5D" class="usa-link" aria-describedby="id7"><span class="name western">Natalie Geoghegan</span></a><div hidden="hidden" id="id7"> <h3><span class="name western">Natalie Geoghegan</span></h3> <div class="p"> <sup>3</sup>Section of Paediatrics, Department of Medicine, Imperial College London, London, United Kingdom</div> <div>Data curation, Formal analysis, Methodology, Writing – original draft</div> <div class="p">Find articles by <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Geoghegan%20N%22%5BAuthor%5D" class="usa-link"><span class="name western">Natalie Geoghegan</span></a> </div> </div> <sup>3</sup>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Ruparelia%20A%22%5BAuthor%5D" class="usa-link" aria-describedby="id8"><span class="name western">Alisha Ruparelia</span></a><div hidden="hidden" id="id8"> <h3><span class="name western">Alisha Ruparelia</span></h3> <div class="p"> <sup>3</sup>Section of Paediatrics, Department of Medicine, Imperial College London, London, United Kingdom</div> <div>Formal analysis, Methodology, Writing – original draft</div> <div class="p">Find articles by <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Ruparelia%20A%22%5BAuthor%5D" class="usa-link"><span class="name western">Alisha Ruparelia</span></a> </div> </div> <sup>3</sup>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Devani%20P%22%5BAuthor%5D" class="usa-link" aria-describedby="id9"><span class="name western">Pooja Devani</span></a><div hidden="hidden" id="id9"> <h3><span class="name western">Pooja Devani</span></h3> <div class="p"> <sup>3</sup>Section of Paediatrics, Department of Medicine, Imperial College London, London, United Kingdom</div> <div>Formal analysis, Methodology, Writing – original draft</div> <div class="p">Find articles by <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Devani%20P%22%5BAuthor%5D" class="usa-link"><span class="name western">Pooja Devani</span></a> </div> </div> <sup>3</sup>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Trivella%20M%22%5BAuthor%5D" class="usa-link" aria-describedby="id10"><span class="name western">Marialena Trivella</span></a><div hidden="hidden" id="id10"> <h3><span class="name western">Marialena Trivella</span></h3> <div class="p"> <sup>4</sup>Centre for Statistics in Medicine, University of Oxford, Oxford, United Kingdom</div> <div>Investigation, Methodology, Supervision, Writing – review & editing</div> <div class="p">Find articles by <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Trivella%20M%22%5BAuthor%5D" class="usa-link"><span class="name western">Marialena Trivella</span></a> </div> </div> <sup>4</sup>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Leonardi-Bee%20J%22%5BAuthor%5D" class="usa-link" aria-describedby="id11"><span class="name western">Jo Leonardi-Bee</span></a><div hidden="hidden" id="id11"> <h3><span class="name western">Jo Leonardi-Bee</span></h3> <div class="p"> <sup>5</sup>Division of Epidemiology and Public Health, University of Nottingham, Nottingham, United Kingdom</div> <div>Conceptualization, Formal analysis, Funding acquisition, Investigation, Methodology, Supervision, Writing – review & editing</div> <div class="p">Find articles by <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Leonardi-Bee%20J%22%5BAuthor%5D" class="usa-link"><span class="name western">Jo Leonardi-Bee</span></a> </div> </div> <sup>5</sup>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Boyle%20RJ%22%5BAuthor%5D" class="usa-link" aria-describedby="id12"><span class="name western">Robert J Boyle</span></a><div hidden="hidden" id="id12"> <h3><span class="name western">Robert J Boyle</span></h3> <div class="p"> <sup>3</sup>Section of Paediatrics, Department of Medicine, Imperial College London, London, United Kingdom</div> <div class="p"> <sup>6</sup>Centre of Evidence Based Dermatology, University of Nottingham, Nottingham, United Kingdom</div> <div>Conceptualization, Funding acquisition, Investigation, Methodology, Project administration, Validation, Writing – original draft, Writing – review & editing</div> <div class="p">Find articles by <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Boyle%20RJ%22%5BAuthor%5D" class="usa-link"><span class="name western">Robert J Boyle</span></a> </div> </div> <sup>3,</sup><sup>6,</sup><sup>*</sup> </div> <div class="cg p">Editor: <span class="name western">Sanjay Basu</span><sup>7</sup> </div> <ul class="d-buttons inline-list"> <li><button class="d-button" aria-controls="aip_a" aria-expanded="false">Author information</button></li> <li><button class="d-button" aria-controls="anp_a" aria-expanded="false">Article notes</button></li> <li><button class="d-button" aria-controls="clp_a" aria-expanded="false">Copyright and License information</button></li> </ul> <div class="d-panels font-secondary-light"> <div id="aip_a" class="d-panel p" style="display: none"> <div class="p" id="aff001"> <sup>1</sup>Department of International Health, Johns Hopkins School of Public Health, Baltimore, Maryland, United States of America</div> <div id="aff002"> <sup>2</sup>Respiratory Epidemiology, Occupational Medicine and Public Health, National Heart and Lung Institute, Imperial College London, London, United Kingdom</div> <div id="aff003"> <sup>3</sup>Section of Paediatrics, Department of Medicine, Imperial College London, London, United Kingdom</div> <div id="aff004"> <sup>4</sup>Centre for Statistics in Medicine, University of Oxford, Oxford, United Kingdom</div> <div id="aff005"> <sup>5</sup>Division of Epidemiology and Public Health, University of Nottingham, Nottingham, United Kingdom</div> <div id="aff006"> <sup>6</sup>Centre of Evidence Based Dermatology, University of Nottingham, Nottingham, United Kingdom</div> <div id="edit1"> <sup>7</sup>Stanford University, UNITED STATES</div> <div class="author-notes p"> <div class="fn" id="coi001"><p>I have read the journal's policy and the authors of this manuscript have the following competing interests: RJB, VGL, JLB, SC, and DI received support from the UK Food Standards Agency for the submitted work. MT received a consultation fee from the UK Food Standards Agency for methodological work on this systematic review. No other support was received from any organisation for the submitted work. The authors have no financial relationships with any organisations that might have an interest in the submitted work in the previous three years. RJB was a co-investigator and author of two of the trials included in this systematic review. The authors report no other relationships or activities that could appear to have influenced the submitted work.</p></div> <div class="fn" id="econtrib001"><p>‡ These authors are joint first authors on this work.</p></div> <div class="fn" id="cor001"> <sup>✉</sup><p class="display-inline">* E-mail: <span>r.boyle@imperial.ac.uk</span></p> </div> </div> <h4 class="font-secondary">Roles</h4> <div class="p"> <strong class="contrib"><span class="name western">Vanessa Garcia-Larsen</span></strong>: <span class="role">Conceptualization, Data curation, Funding acquisition, Investigation, Methodology, Project administration, Resources, Supervision, Writing – original draft, Writing – review & editing</span> </div> <div> <strong class="contrib"><span class="name western">Despo Ierodiakonou</span></strong>: <span class="role">Data curation, Formal analysis, Investigation, Methodology, Project administration, Software, Writing – original draft, Writing – review & editing</span> </div> <div> <strong class="contrib"><span class="name western">Katharine Jarrold</span></strong>: <span class="role">Investigation, Writing – review & editing</span> </div> <div> <strong class="contrib"><span class="name western">Sergio Cunha</span></strong>: <span class="role">Formal analysis, Methodology, Writing – review & editing</span> </div> <div> <strong class="contrib"><span class="name western">Jennifer Chivinge</span></strong>: <span class="role">Data curation, Formal analysis, Methodology, Writing – original draft</span> </div> <div> <strong class="contrib"><span class="name western">Zoe Robinson</span></strong>: <span class="role">Data curation, Formal analysis, Methodology, Writing – original draft</span> </div> <div> <strong class="contrib"><span class="name western">Natalie Geoghegan</span></strong>: <span class="role">Data curation, Formal analysis, Methodology, Writing – original draft</span> </div> <div> <strong class="contrib"><span class="name western">Alisha Ruparelia</span></strong>: <span class="role">Formal analysis, Methodology, Writing – original draft</span> </div> <div> <strong class="contrib"><span class="name western">Pooja Devani</span></strong>: <span class="role">Formal analysis, Methodology, Writing – original draft</span> </div> <div> <strong class="contrib"><span class="name western">Marialena Trivella</span></strong>: <span class="role">Investigation, Methodology, Supervision, Writing – review & editing</span> </div> <div> <strong class="contrib"><span class="name western">Jo Leonardi-Bee</span></strong>: <span class="role">Conceptualization, Formal analysis, Funding acquisition, Investigation, Methodology, Supervision, Writing – review & editing</span> </div> <div> <strong class="contrib"><span class="name western">Robert J Boyle</span></strong>: <span class="role">Conceptualization, Funding acquisition, Investigation, Methodology, Project administration, Validation, Writing – original draft, Writing – review & editing</span> </div> <div class="p"> <strong class="contrib"><span class="name western">Sanjay Basu</span></strong>: <span class="role">Academic Editor</span> </div> </div> <div id="anp_a" class="d-panel p" style="display: none"><div class="notes p"><section id="historyarticle-meta1" class="history"><p>Received 2017 Jul 24; Accepted 2018 Jan 15; Collection date 2018 Feb.</p></section></div></div> <div id="clp_a" class="d-panel p" style="display: none"> <div>© 2018 Garcia-Larsen et al</div> <p>This is an open access article distributed under the terms of the <a href="http://creativecommons.org/licenses/by/4.0/" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">Creative Commons Attribution License</a>, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.</p> <div class="p"><a href="/about/copyright/" class="usa-link">PMC Copyright notice</a></div> </div> </div> <div>PMCID: PMC5830033 PMID: <a href="https://pubmed.ncbi.nlm.nih.gov/29489823/" class="usa-link">29489823</a> </div> </div></section></section><section aria-label="Article content"><section class="body main-article-body"><section class="abstract" id="abstract1"><h2>Abstract</h2> <section id="sec001"><h3 class="pmc_sec_title">Background</h3> <p>There is uncertainty about the influence of diet during pregnancy and infancy on a child’s immune development. We assessed whether variations in maternal or infant diet can influence risk of allergic or autoimmune disease.</p></section><section id="sec002"><h3 class="pmc_sec_title">Methods and findings</h3> <p>Two authors selected studies, extracted data, and assessed risk of bias. Grading of Recommendations Assessment, Development and Evaluation (GRADE) was used to assess certainty of findings. We searched Medical Literature Analysis and Retrieval System Online (MEDLINE), Excerpta Medica dataBASE (EMBASE), Web of Science, Central Register of Controlled Trials (CENTRAL), and Literatura Latino Americana em Ciências da Saúde (LILACS) between January 1946 and July 2013 for observational studies and until December 2017 for intervention studies that evaluated the relationship between diet during pregnancy, lactation, or the first year of life and future risk of allergic or autoimmune disease. We identified 260 original studies (964,143 participants) of milk feeding, including 1 intervention trial of breastfeeding promotion, and 173 original studies (542,672 participants) of other maternal or infant dietary exposures, including 80 trials of maternal (<em>n</em> = 26), infant (<em>n</em> = 32), or combined (<em>n</em> = 22) interventions. Risk of bias was high in 125 (48%) milk feeding studies and 44 (25%) studies of other dietary exposures. Evidence from 19 intervention trials suggests that oral supplementation with nonpathogenic micro-organisms (probiotics) during late pregnancy and lactation may reduce risk of eczema (Risk Ratio [RR] 0.78; 95% CI 0.68–0.90; I<sup>2</sup> = 61%; Absolute Risk Reduction 44 cases per 1,000; 95% CI 20–64), and 6 trials suggest that fish oil supplementation during pregnancy and lactation may reduce risk of allergic sensitisation to egg (RR 0.69, 95% CI 0.53–0.90; I<sup>2</sup> = 15%; Absolute Risk Reduction 31 cases per 1,000; 95% CI 10–47). GRADE certainty of these findings was moderate. We found weaker support for the hypotheses that breastfeeding promotion reduces risk of eczema during infancy (1 intervention trial), that longer exclusive breastfeeding is associated with reduced type 1 diabetes mellitus (28 observational studies), and that probiotics reduce risk of allergic sensitisation to cow’s milk (9 intervention trials), where GRADE certainty of findings was low. We did not find that other dietary exposures—including prebiotic supplements, maternal allergenic food avoidance, and vitamin, mineral, fruit, and vegetable intake—influence risk of allergic or autoimmune disease. For many dietary exposures, data were inconclusive or inconsistent, such that we were unable to exclude the possibility of important beneficial or harmful effects. In this comprehensive systematic review, we were not able to include more recent observational studies or verify data via direct contact with authors, and we did not evaluate measures of food diversity during infancy.</p></section><section id="sec003"><h3 class="pmc_sec_title">Conclusions</h3> <p>Our findings support a relationship between maternal diet and risk of immune-mediated diseases in the child. Maternal probiotic and fish oil supplementation may reduce risk of eczema and allergic sensitisation to food, respectively.</p></section></section><section class="abstract" id="abstract2"><hr class="headless"> <p>Robert Boyle and colleagues reveal the importance of a pregnant woman's diet. Diets supplemented with probiotics and fish oils may reduce the likelihood of eczema and other autoimmune conditions in children.</p></section><section class="abstract" id="abstract3"><h2>Author summary</h2> <section id="sec004"><h3 class="pmc_sec_title">Why was this study done?</h3> <ul class="list" style="list-style-type:disc"><li><p>There is uncertainty about the effects of specific dietary variations in early life on risk of immune-mediated disease.</p></li></ul></section><section id="sec005"><h3 class="pmc_sec_title">What did the researchers do and find?</h3> <ul class="list" style="list-style-type:disc"> <li><p>We undertook a systematic review of observational and intervention studies of maternal diet during pregnancy and lactation and infant diet during the first year of life to evaluate whether dietary exposures in early life influence risk of allergic or autoimmune disease.</p></li> <li><p>We found that supplementation with micro-organisms (probiotics) during late pregnancy and breastfeeding may reduce risk of eczema, and fish oil supplementation during pregnancy and breastfeeding may reduce risk of sensitisation to food allergens.</p></li> <li><p>We found more limited data that longer duration of breastfeeding may reduce risk of eczema and type 1 diabetes mellitus.</p></li> </ul></section><section id="sec006"><h3 class="pmc_sec_title">What do these findings mean?</h3> <ul class="list" style="list-style-type:disc"><li><p>A mother’s diet during pregnancy and lactation may influence her child’s risk of developing allergic disease.</p></li></ul></section></section><section id="sec007"><h2 class="pmc_sec_title">Introduction</h2> <p>Immune-mediated health conditions such as allergic and autoimmune diseases appear to have increased in prevalence in many countries and are leading causes of chronic illness in young people [<a href="#pmed.1002507.ref001" class="usa-link" aria-describedby="pmed.1002507.ref001">1</a>]. There is evidence that early dietary exposures may influence the development of these diseases, but a comprehensive analysis of the relationship between all dietary exposures during pregnancy, lactation, or the first year of life and risk of allergic or autoimmune disease has not been undertaken [<a href="#pmed.1002507.ref001" class="usa-link" aria-describedby="pmed.1002507.ref001">1</a>]. Relevant dietary exposures may include intake of individual foods or food groups, nutrients or nutrient groups, dietary supplements, avoidance of specific allergenic foods, timing of introduction of specific foods or food groups to the infant diet, overall dietary pattern, and duration of breastfeeding. A recent World Allergy Organization guideline recommended probiotic and prebiotic supplements for eczema prevention [<a href="#pmed.1002507.ref002" class="usa-link" aria-describedby="pmed.1002507.ref002">2</a>,<a href="#pmed.1002507.ref003" class="usa-link" aria-describedby="pmed.1002507.ref003">3</a>], but European, North American, and Australasian guidelines do not support this [<a href="#pmed.1002507.ref004" class="usa-link" aria-describedby="pmed.1002507.ref004">4</a>–<a href="#pmed.1002507.ref006" class="usa-link" aria-describedby="pmed.1002507.ref006">6</a>]. Several guidelines recommend exclusive breastfeeding for at least 4 to 6 months to reduce risk of eczema, food allergy, and wheezing [<a href="#pmed.1002507.ref004" class="usa-link" aria-describedby="pmed.1002507.ref004">4</a>,<a href="#pmed.1002507.ref005" class="usa-link" aria-describedby="pmed.1002507.ref005">5</a>,<a href="#pmed.1002507.ref007" class="usa-link" aria-describedby="pmed.1002507.ref007">7</a>], and a recent Australasian guideline recommends oily fish or omega-3 fatty acid supplements during pregnancy to reduce eczema [<a href="#pmed.1002507.ref006" class="usa-link" aria-describedby="pmed.1002507.ref006">6</a>]. Recent focused systematic reviews support a relationship between breastfeeding and reduced asthma risk [<a href="#pmed.1002507.ref008" class="usa-link" aria-describedby="pmed.1002507.ref008">8</a>,<a href="#pmed.1002507.ref009" class="usa-link" aria-describedby="pmed.1002507.ref009">9</a>] and between probiotics and prebiotics and reduced eczema risk [<a href="#pmed.1002507.ref002" class="usa-link" aria-describedby="pmed.1002507.ref002">2</a>,<a href="#pmed.1002507.ref010" class="usa-link" aria-describedby="pmed.1002507.ref010">10</a>,<a href="#pmed.1002507.ref011" class="usa-link" aria-describedby="pmed.1002507.ref011">11</a>]. In order to inform United Kingdom dietary recommendations for infants and their pregnant or lactating mothers, we undertook an updated and comprehensive systematic review of diet during pregnancy and infancy and risk of allergic sensitisation, allergic disease, or autoimmune disease.</p></section><section id="sec008"><h2 class="pmc_sec_title">Methods</h2> <p>This review is reported in accordance with PRISMA guidance. The review is part of a series of systematic reviews commissioned by the UK Food Standards Agency in order to inform UK dietary recommendations for infants and their pregnant or lactating mothers, under the title ‘Review of scientific published literature on infant feeding and development of atopic and autoimmune disease'. The protocols for the systematic reviews were registered with the International Prospective Register of Systematic Reviews (PROSPERO CRD42013003802 ‘Review A:milk feeding’; CRD42013004239 ‘Review B:timing of allergenic food introduction’; CRD42013004252 ‘Review C:maternal and infant diet’) on 5 August 2013, prior to title screening or selecting any studies from the search results. This manuscript reports findings from the majority of the project, comprising Reviews A and C, ‘milk feeding’ and ‘maternal and infant diet’. Review B, regarding timing of introduction of allergenic foods, and one part of Review C, regarding use of hydrolysed infant formula, have been published separately [<a href="#pmed.1002507.ref012" class="usa-link" aria-describedby="pmed.1002507.ref012">12</a>,<a href="#pmed.1002507.ref013" class="usa-link" aria-describedby="pmed.1002507.ref013">13</a>]. Thus, this manuscript describes outcomes for maternal or infant intake of individual foods or food groups, nutrients or nutrient groups, dietary supplements, maternal allergenic food avoidance, timing of introduction of solid foods or nonallergenic foods to the infant diet, overall dietary pattern and duration of breastfeeding. This manuscript does not include timing of introduction of allergenic foods (milk, soya, egg, peanuts, tree nuts, fish, seafood, wheat) to the infant diet or use of hydrolysed formula in infants. Measures of dietary diversity and objective measures of nutritional status (with the exception of blood vitamin D level) were not included in these systematic reviews. These measures were considered to be too indirect as indicators of dietary intake to be used to inform public health guidance in the UK. As part of this project, we also searched for other systematic reviews covering the same topic published since 1 January 2011.</p> <section id="sec009"><h3 class="pmc_sec_title">Study interventions and comparators</h3> <p>Studies of total breastfeeding duration, exclusive breastfeeding duration [<a href="#pmed.1002507.ref014" class="usa-link" aria-describedby="pmed.1002507.ref014">14</a>], and timing of solid food introduction were included in Review A ‘milk feeding’. Studies of any other nutritional exposure, ranging from dietary pattern to specific micronutrient supplementation and from single to multifaceted interventions, were included in Review C ‘maternal and infant diet’. For observational studies, data on dietary exposures were acquired from interviews, health records, diaries, and questionnaires. With the exception of blood vitamin D level, we did not include assessments of nutrient status as an exposure, and we did not include measures of dietary diversity as an exposure.</p></section><section id="sec010"><h3 class="pmc_sec_title">Study designs and populations</h3> <p>We included all intervention trials, and observational studies described as cohort, case control or cross-sectional analytic studies. Intervention trials were classified as randomised controlled trials (RCTs), where the method of treatment allocation was random, and as controlled clinical trials (CCTs), where treatment allocation was nonrandom and likely to lead to significant imbalance between treatment groups. CCTs were analysed separately from RCTs. Prospective and retrospective observational studies were analysed separately. We included studies of diet during pregnancy or lactation and of infant feeding between birth and 12 months of age. We excluded studies in which participants or their mothers were defined by the presence of a preexisting disease state, including very low birth weight or very premature infants.</p></section><section id="sec011"><h3 class="pmc_sec_title">Study outcomes</h3> <p>Allergic and autoimmune outcomes were selected on the basis of their population prevalence in children and young adults [<a href="#pmed.1002507.ref015" class="usa-link" aria-describedby="pmed.1002507.ref015">15</a>]. We included diseases with a prevalence of at least 1 in 1,000 in children/adolescents or young adults (aged <40 years) but did not include rarer diseases. We did not include pernicious anaemia or adult-onset rheumatoid arthritis despite a high prevalence in middle-aged and elderly people because their prevalence in young people is lower than 1 in 1,000, and prospective studies of infant feeding in relation to diseases of older adults were thought unlikely to have been reported. Allergic outcomes that met our inclusion criteria were asthma or wheeze, eczema, allergic rhinitis and/or conjunctivitis, food allergy (defined by food challenge, medical diagnosis, or self/parent report), allergic sensitisation, i.e., skin prick or specific immunoglobulin E (sIgE) assessment, and total immunoglobin E (IgE) level. We categorised asthma as wheeze, recurrent wheeze, or atopic wheeze depending on the definition used in the original publication, and we included measures of lung function, specifically bronchial hyper-reactivity, forced vital capacity, peak expiratory flow rate, and forced expiratory volume in 1 second. Physician-diagnosed asthma was included within the category ‘recurrent wheeze’, unless defined as a single episode of wheeze. Autoimmune diseases that met our inclusion criteria were type 1 diabetes mellitus (TIDM) (doctor diagnosed or serological diagnosis), coeliac disease defined serologically or clinically (positive Immunoglobulin A tissue Transglutaminase antibodies on one or more visits or a positive small bowel biopsy), inflammatory bowel disease, autoimmune thyroid disease, juvenile rheumatoid arthritis, vitiligo, and psoriasis, all as doctor diagnosis. For clinical allergic outcomes, we grouped age at assessment as 0–4 years, 5–14 years, and ≥15 years. Allergic sensitisation and autoimmune diseases were not stratified by age at outcome assessment.</p></section><section id="sec012"><h3 class="pmc_sec_title">Data sources</h3> <p>We searched The Cochrane Library (2013, Issue 7), Excerpta Medica dataBASE (EMBASE) (1947 to July 2013), Literatura Latino Americana em Ciências da Saúde (LILACS) (1982 to July 2013), Medical Literature Analysis and Retrieval System Online (MEDLINE) (1946 to July 2013), and Web of Science (1970 to July 2013) on 25 July 2013. We reran the searches for intervention trials and systematic reviews on 26 February 2017 and for intervention trials again on 15 December 2017. We included all studies published up to that date and studies in progress or completed but unpublished studies identified through <a href="http://apps.who.int/trialsearch/" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">http://apps.who.int/trialsearch/</a>. Both peer-reviewed publications and abstract publications were included. We reviewed the bibliography of eligible studies for possible additional publications and included all eligible publications, regardless of the language. Study authors were not contacted for original data. The search strategies were extensively piloted and refined to optimise sensitivity, comparing search results with those of other systematic reviews. The search strategies are shown in <a href="#pmed.1002507.s002" class="usa-link">S1 Text</a>.</p></section><section id="sec013"><h3 class="pmc_sec_title">Study selection</h3> <p>Title and abstract screening was undertaken by a team of 9 trained researchers (RJB, VGL, DI, NG, KJ, JC, ZR, AR, PD). Two researchers undertook title screening independently and met to agree upon included and excluded titles. Their screening was checked by a third person, and uncertainties were resolved at a weekly team meeting between February and April 2014, 2015, and 2017 (RB, SC, VGL). The full texts of all potentially eligible studies were reviewed.</p></section><section id="sec014"><h3 class="pmc_sec_title">Risk of bias assessment</h3> <p>Risk of bias assessment was undertaken in duplicate, using modified versions of the Cochrane Collaboration Risk of Bias tool for intervention trials and the National Institute for Clinical Excellence methodological checklist for cohort and case–control studies [<a href="#pmed.1002507.ref016" class="usa-link" aria-describedby="pmed.1002507.ref016">16</a>]. Risk of bias domains for intervention trials were Selection bias (sequence generation and allocation concealment), Assessment bias (blinding of outcome assessors and validity of the outcome assessment tool), and Attrition bias (considered high when <70% of randomised participants had outcome data). Risk of bias domains for observational studies were Selection bias (low if cases and controls came from similar populations and participation rate ≥80%), Assessment bias (the validity of exposure and outcome assessment tools), and Confounding bias (whether study design and analysis accounted for most potential confounders). We separately included an assessment of Conflict of Interest for each study, judged as low where there was no evidence of industry involvement in study design, analysis, interpretation, or publication and no evidence that study authors received remuneration from relevant industry partners for other activities.</p></section><section id="sec015"><h3 class="pmc_sec_title">Data extraction</h3> <p>Data extraction was undertaken in duplicate. Disagreements and uncertainties about data coding and risk of bias were discussed within the team. For foreign language studies, data were extracted by VGL together with a native speaker of the relevant language (see Acknowledgemnts section). We extracted all relevant data from included studies, including data not able to be meta-analysed. Data were extracted using either raw frequencies or crude or adjusted effect estimates. Random effects meta-analysis was undertaken, and where this was not possible, study results were summarised in a narrative table.</p></section><section id="sec016"><h3 class="pmc_sec_title">Data selection for analysis</h3> <p>For intervention trials, we extracted outcome data that adhered to the intention-to-treat principle in preference to data based on per protocol analyses. Where studies included multiple intervention groups, we performed pairwise comparisons where we split the number of events and no events in the unexposed/control group to prevent double counting. Where studies reported data at multiple timepoints, we extracted the most complete dataset available beyond the intervention period (i.e., from 1 year of age onwards); this is the dataset with the largest denominator or, where the denominator is identical for multiple time points, the largest numerator (number of events). Where studies reported multiple assessments of the same outcome at the same timepoint, clinical assessments were selected in preference to serological assessments, and skin prick in preference to sIgE assessment of allergic sensitisation. For observational studies of breastfeeding or timing of solid or other food introduction to the infant diet, data were only included in meta-analysis where the reference group was complete, i.e., ‘less than’ a certain duration or, in some cases, ‘never’. Where more than one exposure group was compared with the reference group, we analysed data for the latest exposure group. For all observational studies, adjusted effect estimates were used in preference to unadjusted estimates for meta-analysis if both were reported.</p></section><section id="sec017"><h3 class="pmc_sec_title">Data synthesis</h3> <p>Pooled results for binary outcomes were presented as Risk Ratio (RR) calculated using the Mantel–Haenszel method, with continuity correction of 0.5 for zero cell frequencies, and odds ratios (ORs) were pooled using the generic inverse variance method using R (version 3.1.0 2014-04-10, <a href="https://web.nhs.net/OWA/redir.aspx?SURL=m2cp-MJbiKfUkGSQTo7nucodRZr2YgoWc1vtbToOC5G6qOvA2NPSCGgAdAB0AHAAOgAvAC8AdwB3AHcALgByAC0AcAByAG8AagBlAGMAdAAuAG8AcgBnAA..&URL=http%3a%2f%2fwww.r-project.org" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">www.r-project.org</a>). For continuous outcomes measured using similar scales, data were summarised as mean differences with 95% CI. Key findings are presented in a Summary of Findings table with Grading of Recommendations Assessment, Development and Evaluation (GRADE) assessment of certainty of findings [<a href="#pmed.1002507.ref017" class="usa-link" aria-describedby="pmed.1002507.ref017">17</a>]. Heterogeneity was quantified using I<sup>2</sup> and classified as low (I<sup>2</sup> < 25%), moderate (I<sup>2</sup> 25%<em>–</em>50%), high (I<sup>2</sup> 50%<em>–</em>75%) or extreme (I<sup>2</sup> > 75%). Data were not pooled where I<sup>2</sup> ≥ 80%. We assessed for publication bias using Funnel plots and Egger asymmetry tests where there were ≥ 10 studies in a meta-analysis. We undertook a priori defined subgroup analyses for meta-analyses with > 5 studies according to overall risk of bias; disease risk; study design; conflict of interest; for some analyses, by features of the intervention or exposure assessment; and method of outcome assessment. Data that could not be included in meta-analysis were reported narratively, and the outcomes of both meta-analyses and narrative reports were considered when interpreting data and making conclusions. Trial sequential analysis (TSA) was used to quantify the statistical reliability of moderate or high certainty findings using 2-sided 5% significance and 80% power to estimate optimum heterogeneity-adjusted information sizes needed to identify relative risk reductions of 20% and 30%. Control event rates were estimated using random effects meta-analyses of the pooled proportions from the largest studies included in the meta-analysis and compared with event rates from large population-based studies. TSA quantifies the statistical reliability of data in a cumulative meta-analysis in a similar way to an interim analysis in a single randomised clinical trial.</p></section></section><section id="sec018"><h2 class="pmc_sec_title">Results</h2> <p>Our original search identified 16,289 original titles. Title, abstract, and full text screening yielded a total of 343 titles (260 original studies; 964,143 participants) of milk feeding and 281 titles (173 original studies; 542,672 participants) of maternal and infant diet, including 80 trials of maternal (<em>n</em> = 26), infant (<em>n</em> = 32), or combined (<em>n</em> = 22) interventions. Full details of the search results are shown in <a href="#pmed.1002507.g001" class="usa-link">Fig 1</a> (PRISMA flow chart), and characteristics of included studies and risk of bias are summarised in <a href="#pmed.1002507.s005" class="usa-link">S1 Appendix</a>. Risk of bias was high in 125 (48%) studies of milk feeding and 44 (25%) studies of maternal and infant diet (most commonly due to attrition bias in intervention studies and confounding bias in observational studies). Key findings are shown in <a href="#pmed.1002507.t001" class="usa-link">Table 1</a>, which includes a GRADE assessment of certainty for each finding [<a href="#pmed.1002507.ref018" class="usa-link" aria-describedby="pmed.1002507.ref018">18</a>], and in Figs <a href="#pmed.1002507.g002" class="usa-link">2</a>–<a href="#pmed.1002507.g009" class="usa-link">9</a>. The full report, with a detailed description of the methodology used and all review findings, is available on the Food Standards Agency website (<a href="https://www.food.gov.uk/science/research/allergy-research/fs305005ac" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">https://www.food.gov.uk/science/research/allergy-research/fs305005ac</a>). Summary reports to the Food Standards Agency for studies of milk feeding and studies of maternal and infant diet are in <a href="#pmed.1002507.s003" class="usa-link">S2 Text</a> and <a href="#pmed.1002507.s004" class="usa-link">S3 Text</a>, respectively. Detailed appraisal of findings underlying the 2 reports are in <a href="#pmed.1002507.s006" class="usa-link">S1 Data</a> and <a href="#pmed.1002507.s007" class="usa-link">S2 Data</a>, respectively, and all data used for meta-analyses are in <a href="#pmed.1002507.s008" class="usa-link">S3 Data</a>. An associated statement by the Committee on Toxicity is available on the Food Standards Agency website (<a href="https://cot.food.gov.uk/cotstatements/cotstatementsyrs/cot-statements-2017/statementonrevsaandc" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">https://cot.food.gov.uk/cotstatements/cotstatementsyrs/cot-statements-2017/statementonrevsaandc</a>).</p> <figure class="fig xbox font-sm" id="pmed.1002507.g001"><h3 class="obj_head">Fig 1. PRISMA flow chart.</h3> <p class="img-box line-height-none margin-x-neg-2 tablet:margin-x-0 text-center"><a class="tileshop" target="_blank" href="https://www.ncbi.nlm.nih.gov/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Click%20on%20image%20to%20zoom&p=PMC3&id=5830033_pmed.1002507.g001.jpg"><img class="graphic zoom-in" src="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c8b9/5830033/ed8f075d6228/pmed.1002507.g001.jpg" loading="lazy" height="422" width="615" alt="Fig 1"></a></p> <div class="p text-right font-secondary"><a href="figure/pmed.1002507.g001/" class="usa-link" target="_blank" rel="noopener noreferrer">Open in a new tab</a></div> <figcaption><p>CENTRAL, Central Register of Controlled Trials; EMBASE, Excerpta Medica dataBASE; LILACS, Literatura Latino Americana em Ciências da Saúde; MEDLINE, Medical Literature Analysis and Retrieval System Online.</p></figcaption></figure><section class="tw xbox font-sm" id="pmed.1002507.t001"><h3 class="obj_head">Table 1. GRADE assessment and summary of key findings.</h3> <div class="tbl-box p" tabindex="0"><table class="content" frame="hsides" rules="groups"> <colgroup span="1"> <col align="left" valign="middle" span="1"> <col align="left" valign="middle" span="1"> <col align="left" valign="middle" span="1"> <col align="left" valign="middle" span="1"> <col align="left" valign="middle" span="1"> <col align="left" valign="middle" span="1"> <col align="left" valign="middle" span="1"> <col align="left" valign="middle" span="1"> <col align="left" valign="middle" span="1"> <col align="left" valign="middle" span="1"> <col align="left" valign="middle" span="1"> </colgroup> <thead> <tr> <th align="center" colspan="7" style="background-color:#F2F2F2" rowspan="1">GRADE of evidence assessment</th> <th align="center" colspan="2" style="background-color:#F2F2F2" rowspan="1">Summary of findings</th> <th align="center" colspan="2" style="background-color:#F2F2F2" rowspan="1">Absolute Risk Reduction<a href="#t001fn001" class="usa-link"><sup>*</sup></a> </th> </tr> <tr> <th align="center" rowspan="2" style="background-color:#F2F2F2" colspan="1">No of studies and design</th> <th align="center" rowspan="2" style="background-color:#F2F2F2" colspan="1">Risk of bias</th> <th align="center" rowspan="2" style="background-color:#F2F2F2" colspan="1">Inconsistency</th> <th align="center" rowspan="2" style="background-color:#F2F2F2" colspan="1">Indirectness</th> <th align="center" rowspan="2" style="background-color:#F2F2F2" colspan="1">Imprecision</th> <th align="center" rowspan="2" style="background-color:#F2F2F2" colspan="1">Publication bias</th> <th align="center" rowspan="2" style="background-color:#F2F2F2" colspan="1">Other considerations</th> <th align="center" rowspan="2" style="background-color:#F2F2F2" colspan="1">Relative risk</th> <th align="center" rowspan="2" style="background-color:#F2F2F2" colspan="1">GRADE of evidence</th> <th align="center" style="background-color:#F2F2F2" rowspan="1" colspan="1">Control Risk</th> <th align="center" style="background-color:#F2F2F2" rowspan="1" colspan="1">Risk Difference</th> </tr> <tr> <th align="center" style="background-color:#F2F2F2" rowspan="1" colspan="1">Cases per 1,000 population</th> <th align="center" style="background-color:#F2F2F2" rowspan="1" colspan="1">Cases per 1,000 population</th> </tr> </thead> <tbody> <tr><td align="left" colspan="11" style="background-color:#F2F2F2" rowspan="1"> <strong>Intervention: Breastfeeding promotion intervention vs no intervention</strong><br><strong>Outcome: Eczema at age 0–4</strong><br><strong>Study design: RCT</strong> </td></tr> <tr> <td align="left" rowspan="1" colspan="1">1 RCT<br> </td> <td align="center" rowspan="3" colspan="1">Not Serious<br>Unblinded outcome assessment</td> <td align="center" rowspan="3" colspan="1">Serious<br>No effect seen at age 6–7 years, and no clear evidence for an effect seen at age 16 years. No association seen in observational studies.</td> <td align="center" rowspan="3" colspan="1">No</td> <td align="center" rowspan="3" colspan="1">Serious<br>Wide CIs</td> <td align="center" rowspan="3" colspan="1">No</td> <td align="center" rowspan="3" colspan="1">No association found between exclusive breastfeeding duration and eczema in an observational analysis of this trial</td> <td align="center" rowspan="3" colspan="1"><strong>OR 0.54 95% CI 0.31–0.95</strong></td> <td align="center" rowspan="3" colspan="1"> <strong>⨂⨂○○</strong><br><strong>Low</strong> </td> <td align="left" rowspan="1" colspan="1"> <strong>200</strong><br><strong>(low risk)</strong><br> </td> <td align="left" rowspan="1" colspan="1"> <strong>81 cases</strong><br><strong>95% CI</strong><br><strong>8–128</strong> </td> </tr> <tr> <td align="left" rowspan="2" colspan="1">Eczema<br> </td> <td align="left" rowspan="1" colspan="1"> <br><strong>300</strong><br><strong>(high risk)</strong><br> </td> <td align="left" rowspan="1" colspan="1"> <br><strong>112 cases</strong><br><strong>95% CI</strong><br><strong>11–183</strong> </td> </tr> <tr> <td align="left" rowspan="1" colspan="1"> <br><strong>400</strong><br><strong>(very high risk)</strong> </td> <td align="left" rowspan="1" colspan="1"> <br><strong>135 cases</strong><br><strong>95% CI</strong><br><strong>12–229</strong><br> </td> </tr> <tr><td align="left" colspan="11" style="background-color:#F2F2F2" rowspan="1"> <strong>Exposure: Total breastfeeding duration—Breastfed ever versus never</strong><br><strong>Outcome: Recurrent wheeze at age 5–14 and Type 1 Diabetes Mellitus</strong><br><strong>Study design: Prospective or retrospective studies</strong> </td></tr> <tr> <td align="left" rowspan="3" colspan="1">14 prospective<br>(13 PC, 1 NCC all in meta-analysis)<br>13 retrospective<br>(2 RC, 4 CC, 7 CS, 1 RC, and 1 CS not in meta-analysis)<br>Recurrent wheeze</td> <td align="center" rowspan="3" colspan="1">Not serious<br>4 prospective studies, and 7 retrospective studies, at high risk of bias, but no subgroup difference according to risk of bias</td> <td align="center" rowspan="3" colspan="1">Not serious<br>I<sup>2</sup> = 29% prospective, 47% retrospective.<br>Study estimates vary from 0.38 to 1.15 prospective; 0.51 to 1.28 retrospective.<br>Similar findings not consistently seen for wheeze at age 5–14 years, nor for wheeze or recurrent wheeze at ages 0–4 or 15+ years.</td> <td align="center" rowspan="3" colspan="1">Not serious<br>Mixed study populations, but several studies included large numbers of participants from representative populations</td> <td align="center" rowspan="3" colspan="1">No<br>Large numbers of participants and events, with relatively narrow CIs</td> <td align="center" rowspan="3" colspan="1">Serious<br>Asymmetrical Funnel plot for all studies combined<br>Egger <em>P</em> = 0.012</td> <td align="center" rowspan="3" colspan="1">Analysis of other cut-offs for duration of total breastfeeding showed a similar association between longer BF duration and reduced risk of recurrent wheeze at age 5–14, but with evidence of publication bias; no evidence of subgroup differences by adjustment of analysis; by disease risk; by risk of bias; or by prospective versus retrospective study design</td> <td align="center" rowspan="3" colspan="1"> <strong>ProspectiveOR = 0.85</strong><br><strong>(0.76, 0.95)</strong><br><strong>Retrospective</strong><br><strong>OR = 0.90</strong><br><strong>(0.81, 1.00)</strong><br><strong>Pooled effect</strong><br><strong>OR = 0.88</strong><br><strong>(0.82, 0.94)</strong><br> </td> <td align="center" rowspan="3" colspan="1"> <strong>⨂○○○</strong><br><strong>Very Low</strong><br> </td> <td align="left" rowspan="1" colspan="1"> <strong>50</strong><br><strong>(low risk)</strong><br> </td> <td align="left" rowspan="1" colspan="1"> <strong>6 cases</strong><br><strong>95% CI</strong><br><strong>3–9</strong> </td> </tr> <tr> <td align="left" rowspan="1" colspan="1"> <br><strong>100</strong><br><strong>(high risk)</strong><br> </td> <td align="left" rowspan="1" colspan="1"> <br><strong>11 cases</strong><br><strong>95% CI</strong><br><strong>5–16</strong><br> </td> </tr> <tr> <td align="left" rowspan="1" colspan="1"> <br><strong>150</strong><br><strong>(very high risk)</strong><br> </td> <td align="left" rowspan="1" colspan="1"> <br><strong>16 cases</strong><br><strong>95% CI</strong><br><strong>8–24</strong> </td> </tr> <tr> <td align="left" rowspan="3" colspan="1">7 prospective<br>(4 PC, 3 in meta-analysis; 3 NCC, all in meta-analysis)<br>28 retrospective<br>(27 CC, 24 in meta-analysis; 1 CS in meta-analysis)<br>TIDM</td> <td align="center" rowspan="3" colspan="1">Not serious<br>4 prospective studies, and 11 retrospective studies, at high risk of bias</td> <td align="center" rowspan="3" colspan="1">Serious<br>I<sup>2</sup> = 0% prospective, 55% retrospective.<br>Study estimates vary from 0.76 to 1.67 prospective; 0.14 to 2.44 retrospective.<br>Significant difference between prospective studies, with no association seen, and retrospective studies, where breastfeeding was associated with reduced TIDM.</td> <td align="center" rowspan="3" colspan="1">Not serious<br>3 studies used serological diagnosis in populations at high inherited risk of TIDM, others used clinical diagnosis in more representative populations</td> <td align="center" rowspan="3" colspan="1">No<br>Large numbers of studies and events</td> <td align="center" rowspan="3" colspan="1">No<br>Symmetrical funnel plot for all studies combined<br>Egger <em>P</em> = 0.81</td> <td align="center" rowspan="3" colspan="1">Analysis of other cut-offs for duration of total breastfeeding showed a similar pattern of a significant association between longer BF duration and reduced odds of TIDM in retrospective studies, where clinical TIDM was used for outcome assessment; but no consistent evidence of a relationship seen in prospective studies, where serological TIDM was usually used for outcome assessment<br> </td> <td align="center" rowspan="3" colspan="1"> <strong>ProspectiveOR = 1.12</strong><br><strong>(0.77, 1.61)</strong><br><strong>Retrospective</strong><br><strong>OR = 0.75</strong><br><strong>(0.65, 0.87)</strong><br><strong>Pooled effect</strong><br><strong>OR = 0.78 (0.68, 0.89)</strong><br> </td> <td align="center" rowspan="3" colspan="1"> <strong>⨂○○○</strong><br><strong>Very Low</strong><br> </td> <td align="left" rowspan="1" colspan="1"> <strong>1</strong><br><strong>(low risk)</strong><br> </td> <td align="left" rowspan="1" colspan="1"> <strong>Prospective0.2 cases</strong><br><strong>95% CI</strong><br><strong>0.1–0.3</strong> </td> </tr> <tr> <td align="left" rowspan="1" colspan="1"> <br><strong>10</strong><br><strong>(high risk)</strong><br> </td> <td align="left" rowspan="1" colspan="1"> <br><strong>2 cases</strong><br><strong>95% CI</strong><br><strong>1–3</strong><br> </td> </tr> <tr> <td align="left" rowspan="1" colspan="1"> <strong>100</strong><br><strong>(very high risk)</strong><br> </td> <td align="left" rowspan="1" colspan="1"> <br><strong>20 cases</strong><br><strong>95% CI</strong><br><strong>10–30</strong> </td> </tr> <tr><td align="left" colspan="11" style="background-color:#F2F2F2" rowspan="1"> <strong>Exposure: Exclusive breastfeeding duration greater than 3–4 months versus less than 3–4 months</strong><br><strong>Outcome: Type 1 Diabetes Mellitus</strong><br><strong>Study design: Prospective or retrospective studies</strong> </td></tr> <tr> <td align="left" rowspan="1" colspan="1">5 prospective<br>(5 PC, 4 in meta-analysis)<br>5 retrospective<br>(5 CC, all in meta-analysis)<br>TIDM</td> <td align="center" rowspan="1" colspan="1">Not serious<br>2 prospective studies, and 3 retrospective studies, at high risk of bias; no subgroup difference according to risk of bias</td> <td align="center" rowspan="1" colspan="1">Not serious<br>I<sup>2</sup> = 21% prospective, 31% retrospective.<br>Study estimates vary from 0.35 to 1.00 prospective; 0.18 to 1.08 retrospective.<br>Nonsignificant difference between prospective studies, with no association seen, and retrospective studies, where longer exclusive breastfeeding was associated with reduced TIDM.</td> <td align="center" rowspan="1" colspan="1">Not serious<br>Prospective studies used serological diagnosis in populations at high inherited odds of TIDM, retrospective studies used clinical diagnosis in more representative populations</td> <td align="center" rowspan="1" colspan="1">Not serious<br>Reasonable numbers of studies and events.</td> <td align="center" rowspan="1" colspan="1">Not tested<br>(<em>n</em> < 10)<br> </td> <td align="center" rowspan="1" colspan="1">Analysis of other cut-offs for duration of exclusive breastfeeding showed a similar pattern of a significant association between longer duration and reduced odds of TIDM in retrospective studies, where clinical TIDM was used for outcome assessment; but no consistent evidence of a relationship seen in prospective studies, where serological TIDM was used for outcome assessment<br> </td> <td align="center" rowspan="1" colspan="1"> <strong>ProspectiveOR = 0.77</strong><br><strong>(0.56, 1.05)</strong><br><strong>Retrospective</strong><br><strong>OR = 0.62</strong><br><strong>(0.48, 0.81)</strong><br><strong>Pooled effect</strong><br><strong>OR = 0.68 (0.55, 0.83)</strong><br> </td> <td align="center" rowspan="1" colspan="1"> <strong>⨂⨂○○</strong><br><strong>Low</strong><br> </td> <td align="left" rowspan="1" colspan="1"> <strong>1</strong><br><strong>(low risk)</strong><br><strong>10</strong><br><strong>(high risk)</strong><br><strong>100</strong><br><strong>(very high risk)</strong> </td> <td align="left" rowspan="1" colspan="1"> <strong>0.3 cases</strong><br><strong>95% CI</strong><br><strong>0.2 to 0.4</strong><br><strong>3 cases</strong><br><strong>95% CI</strong><br><strong>2 to 4</strong><br><strong>30 cases</strong><br><strong>95% CI</strong><br><strong>16 to 42</strong> </td> </tr> <tr><td align="left" colspan="11" style="background-color:#F2F2F2" rowspan="1"> <strong>Intervention: Maternal or infant probiotic supplement vs no probiotic supplement</strong><br><strong>Outcome: Eczema, atopic eczema or cow’s milk sensitisation at age 0–4</strong><br><strong>Study design: RCT</strong> </td></tr> <tr> <td align="left" rowspan="3" colspan="1">23 RCT<br>(19 in meta-analysis)<br>1 CCT<br>Eczema<br> </td> <td align="center" rowspan="3" colspan="1">Not Serious<br><20% of studies had a high risk of bias</td> <td align="center" rowspan="3" colspan="1">Serious<br>I<sup>2</sup> = 61% Eczema<br>Study estimates vary from 0.14 to 1.34; subgroup analysis suggests greatest effect if postnatal component includes maternal supplementation<br> </td> <td align="center" rowspan="3" colspan="1">No</td> <td align="center" rowspan="3" colspan="1">No</td> <td align="center" rowspan="3" colspan="1">No</td> <td align="center" rowspan="3" colspan="1">Most RCTs were undertaken in populations at high risk of eczema due to family history of allergic disease.<br>No evidence of an effect on eczema beyond age 0–4.</td> <td align="center" rowspan="3" colspan="1"> <strong>RR = 0.78</strong><br><strong>(0.68, 0.90)</strong><br> </td> <td align="center" rowspan="3" colspan="1"> <strong>⨂⨂⨂○</strong><br><strong>Moderate</strong><br> </td> <td align="left" rowspan="1" colspan="1"> <strong>200</strong><br><strong>(low risk)</strong><br> </td> <td align="left" rowspan="1" colspan="1"> <strong>44 cases</strong><br><strong>95% CI</strong><br><strong>20–64</strong> </td> </tr> <tr> <td align="left" rowspan="1" colspan="1"> <br><strong>300</strong><br><strong>(high risk)</strong><br> </td> <td align="left" rowspan="1" colspan="1"> <br><strong>66 cases</strong><br><strong>95% CI</strong><br><strong>30–96</strong> </td> </tr> <tr> <td align="left" rowspan="1" colspan="1"> <br><strong>400</strong><br><strong>(very high risk)</strong> </td> <td align="left" rowspan="1" colspan="1"> <br><strong>88 cases</strong><br><strong>95% CI</strong><br><strong>40–128</strong> </td> </tr> <tr> <td align="left" rowspan="1" colspan="1">11 RCT<br>Atopic Eczema</td> <td align="center" rowspan="1" colspan="1">Not Serious<br><20% of studies had a high risk of bias</td> <td align="center" rowspan="1" colspan="1">Serious<br>I<sup>2</sup> = 0% Study estimates vary from 0.47 to 1.36.<br>But no beneficial effect seen at age 5–14 years RR 0.99 (0.80, 1.22; I<sup>2</sup> = 0%).<br> </td> <td align="center" rowspan="1" colspan="1">No</td> <td align="center" rowspan="1" colspan="1">No</td> <td align="center" rowspan="1" colspan="1">No<br>Egger <em>P</em> = 0.70</td> <td align="center" rowspan="1" colspan="1">Most RCTs were undertaken in populations at high risk of eczema due to family history of allergic disease.</td> <td align="center" rowspan="1" colspan="1"><strong>RR = 0.78 (0.65, 0.92)</strong></td> <td align="center" rowspan="1" colspan="1"> <strong>⨂⨂⨂○</strong><br><strong>Moderate</strong><br> </td> <td align="left" rowspan="1" colspan="1"> <strong>100</strong><br><strong>(low risk)</strong><br><strong>150</strong><br><strong>(high risk)</strong><br><strong>200</strong><br><strong>(very high risk)</strong> </td> <td align="left" rowspan="1" colspan="1"> <strong>22 cases</strong><br><strong>95% CI</strong><br><strong>8–35</strong><br><strong>33 cases</strong><br><strong>95% CI</strong><br><strong>12–53</strong><br><strong>44 cases</strong><br><strong>95% CI</strong><br><strong>16–70</strong> </td> </tr> <tr> <td align="left" rowspan="1" colspan="1">97 RCT<br>(8 in meta-analysis)<br>Cow’s milk sensitisation</td> <td align="center" rowspan="1" colspan="1">Not Serious<br><20% of studies had a high risk of bias</td> <td align="center" rowspan="1" colspan="1">Not Serious<br>I<sup>2</sup> = 0% Study estimates vary from 0.14 to 0.98.<br>No beneficial effect seen for allergic sensitisation to other allergens.</td> <td align="center" rowspan="1" colspan="1">Serious<br>Milk sensitisation is a surrogate measure of clinical food allergy. No effect of the intervention was seen on clinical food allergy.<br> </td> <td align="center" rowspan="1" colspan="1">Serious<br>Low event numbers and borderline statistical significance</td> <td align="center" rowspan="1" colspan="1">Not tested<br>(<em>n</em> < 10)<br>No evidence of publication bias in Funnel plots for other forms of allergic sensitisation</td> <td align="center" rowspan="1" colspan="1">Most RCTs were undertaken in populations at high risk of eczema due to family history of allergic disease</td> <td align="center" rowspan="1" colspan="1"><strong>RR = 0.60 (0.37, 0.96)</strong></td> <td align="center" rowspan="1" colspan="1"> <strong>⨂⨂○○</strong><br><strong>Low</strong> </td> <td align="left" rowspan="1" colspan="1"> <strong>30</strong><br><strong>(low risk)</strong><br><strong>100</strong><br><strong>(high risk)</strong><br><strong>300</strong><br><strong>(very high risk)</strong> </td> <td align="left" rowspan="1" colspan="1"> <strong>12 cases</strong><br><strong>95% CI</strong><br><strong>1–19</strong><br><strong>40 cases</strong><br><strong>95% CI</strong><br><strong>4–63</strong><br><strong>120 cases</strong><br><strong>95% CI</strong><br><strong>12–189</strong> </td> </tr> <tr><td align="left" colspan="11" style="background-color:#F2F2F2" rowspan="1"> <strong>Intervention: Infant prebiotic supplement versus no prebiotic supplement</strong><br><strong>Outcome: Eczema at age 0–4</strong><br><strong>Study design: RCT</strong> </td></tr> <tr> <td align="left" rowspan="1" colspan="1">9 RCT<br>(7 in meta-analysis)<br>Eczema</td> <td align="center" rowspan="1" colspan="1">Serious<br>4 studies with high risk of attrition bias, 5 with high risk of conflict of interest</td> <td align="center" rowspan="1" colspan="1">Serious<br>I<sup>2</sup> = 57%<br>Study estimates vary from 0.14 to 1.64</td> <td align="center" rowspan="1" colspan="1">Serious<br>6 studies restricted inclusion to infants fully formula fed from birth, 3 days, < 2 weeks, <6 weeks (n = 2) and <8 weeks; 3 other studies used co-interventions–hydrolysed formula and probiotics<br> </td> <td align="center" rowspan="1" colspan="1">Serious<br>Wide CIs, borderline statistical significance</td> <td align="center" rowspan="1" colspan="1">Not tested<br>(n<10)<br> </td> <td align="center" rowspan="1" colspan="1">3 RCTs were undertaken in populations at high risk due to family history of allergic disease, 4 at normal risk, and 1 at low risk due to absence of family history of allergic disease.<br>All studies used galactooligosaccharides, usually combined with other oligosaccharides; 2 studies combined the intervention with probiotic(s).</td> <td align="center" rowspan="1" colspan="1"> <strong>RR = 0.75</strong><br><strong>(0.56, 1.01)</strong> </td> <td align="center" rowspan="1" colspan="1"> <strong>○○○○</strong><br><strong>No evidence</strong><br> </td> <td align="center" rowspan="1" colspan="1"> <strong>-</strong><br> </td> <td align="center" rowspan="1" colspan="1"><strong>-</strong></td> </tr> <tr><td align="left" colspan="11" style="background-color:#F2F2F2" rowspan="1"> <strong>Intervention: Maternal fish oil (n-3 PUFA) vs no fish oil</strong><br><strong>Outcome: Allergic sensitisation to egg</strong><br><strong>Study design: RCT</strong> </td></tr> <tr> <td align="left" rowspan="1" colspan="1">6 RCT<br>Allergic sensitisation to egg</td> <td align="center" rowspan="1" colspan="1">Not Serious<br>2 studies with unclear overall risk of bias and 2 studies with unclear risk of conflict of interest</td> <td align="center" rowspan="1" colspan="1">Not Serious<br>I<sup>2</sup> = 15%<br>Study estimates vary from 0.45 to 1.02.<br>No significant effect seen for allergic sensitisation to other allergens, but direction of effect is inconsistent with that seen for egg.<br> </td> <td align="center" rowspan="1" colspan="1">Serious<br>Egg sensitisation is a surrogate measure of clinical food allergy. No effect of the intervention was seen on clinical food allergy.</td> <td align="center" rowspan="1" colspan="1">Not serious<br>Limits of 95% CI are all important effects at a population level.</td> <td align="center" rowspan="1" colspan="1">Not tested<br>(<em>n</em> < 10)<br> </td> <td align="center" rowspan="1" colspan="1">All RCTs were undertaken in populations at high risk of allergy due to family history of allergic disease.<br>Subgroup analysis suggests effect is greatest if treatment is given during pregnancy.</td> <td align="center" rowspan="1" colspan="1"> <strong>RR = 0.69</strong><br><strong>(0.53, 0.90)</strong> </td> <td align="center" rowspan="1" colspan="1"> <strong>⨂⨂⨂○</strong><br><strong>Moderate</strong> </td> <td align="left" rowspan="1" colspan="1"> <strong>100</strong><br><strong>(low risk)</strong><br><strong>150</strong><br><strong>(high risk)</strong><br><strong>200</strong><br><strong>(very high risk)</strong> </td> <td align="left" rowspan="1" colspan="1"> <strong>31 cases</strong><br><strong>95% CI</strong><br><strong>10–47</strong><br><strong>46 cases</strong><br><strong>95% CI</strong><br><strong>15–71</strong><br><strong>62 cases</strong><br><strong>95% CI</strong><br><strong>20–94</strong> </td> </tr> <tr><td align="left" colspan="11" style="background-color:#F2F2F2" rowspan="1"> <strong>Intervention: Multifaceted interventions vs control</strong><br><strong>Outcome: Allergic rhinitis at age 0–4</strong><br><strong>Study design: RCT</strong> </td></tr> <tr> <td align="left" rowspan="1" colspan="1">3 RCT<br>(2 in meta-analysis)<br>Allergic rhinitis</td> <td align="center" rowspan="1" colspan="1">Not serious<br>No study with high risk of bias or high risk of conflict of interest</td> <td align="center" rowspan="1" colspan="1">Not serious<br>I<sup>2</sup> = 0%<br>Study estimates vary from 0.58 to 0.61</td> <td align="center" rowspan="1" colspan="1">Serious<br>Both studies in meta-analysis included environmental control measures such as dust mite and tobacco smoke avoidance</td> <td align="center" rowspan="1" colspan="1">Serious<br>Sparse data, inconsistent with data for ages 5–14 years, where no effect was seen. Study not included in meta-analysis found no effect.<br> </td> <td align="center" rowspan="1" colspan="1">Not tested<br>(<em>n</em> < 10)<br> </td> <td align="center" rowspan="1" colspan="1">All RCTs were undertaken in populations at high risk due to family history of allergic disease.<br>All studies included delayed introduction of allergenic foods and maternal allergenic food avoidance</td> <td align="center" rowspan="1" colspan="1"> <strong>RR = 0.61</strong><br><strong>(0.44, 0.84)</strong> </td> <td align="center" rowspan="1" colspan="1"> <strong>⨂⨂○○</strong><br><strong>Low</strong><br> </td> <td align="left" rowspan="1" colspan="1"> <strong>50</strong><br><strong>(low risk)</strong><br><strong>100</strong><br><strong>(high risk)</strong><br><strong>150</strong><br><strong>(very high risk)</strong><br> </td> <td align="left" rowspan="1" colspan="1"> <strong>20 cases</strong><br><strong>95% CI</strong><br><strong>8–28</strong><br><strong>39 cases</strong><br><strong>95% CI</strong><br><strong>16–56</strong><br><strong>59 cases</strong><br><strong>95% CI</strong><br><strong>24–84</strong> </td> </tr> <tr><td align="left" colspan="11" style="background-color:#F2F2F2" rowspan="1"> <strong>Intervention: Multifaceted interventions vs control</strong><br><strong>Outcome: Wheeze or recurrent wheeze at age 5–14</strong><br><strong>Study design: RCT</strong> </td></tr> <tr> <td align="left" rowspan="1" colspan="1">2 RCT<br>Wheeze</td> <td align="center" rowspan="1" colspan="1">Not serious<br>No study with high risk of attrition bias or high risk of conflict of interest</td> <td align="center" rowspan="1" colspan="1">Not serious<br>I<sup>2</sup> = 0%<br>Study estimates vary from 0.50 to 0.59</td> <td align="center" rowspan="1" colspan="1">Serious<br>Both studies included environmental control measures such as dust mite and tobacco smoke avoidance, which are known to reduce respiratory symptoms<br> </td> <td align="center" rowspan="1" colspan="1">Serious<br>Sparse data, inconsistent with data for age 0–4 and lung function data, where no effect was seen</td> <td align="center" rowspan="1" colspan="1">Not tested<br>(<em>n</em> < 10)<br> </td> <td align="center" rowspan="1" colspan="1">All RCTs were undertaken in populations at high risk due to family history of allergic disease.<br>Both studies included delayed introduction of allergenic foods and maternal allergenic food avoidance</td> <td align="center" rowspan="1" colspan="1"> <strong>RR = 0.57</strong><br><strong>(0.41, 0.81)</strong> </td> <td align="center" rowspan="1" colspan="1"> <strong>⨂⨂○○</strong><br><strong>Low</strong><br> </td> <td align="left" rowspan="1" colspan="1"> <strong>100</strong><br><strong>(low risk)</strong><br><strong>150</strong><br><strong>(high risk)</strong><br><strong>200</strong><br><strong>(very high risk)</strong><br> </td> <td align="left" rowspan="1" colspan="1"> <strong>43 cases</strong><br><strong>95% CI</strong><br><strong>19–59</strong><br><strong>65 cases</strong><br><strong>95% CI</strong><br><strong>29–89</strong><br><strong>86 cases</strong><br><strong>95% CI</strong><br><strong>38–118</strong> </td> </tr> <tr> <td align="left" rowspan="1" colspan="1">4 RCT<br>Recurrent wheeze</td> <td align="center" rowspan="1" colspan="1">Not serious<br>1 study high risk of attrition bias, and no study with high risk of conflict of interest</td> <td align="center" rowspan="1" colspan="1">Not serious<br>I<sup>2</sup> = 0%<br>Study estimates vary from 0.64 to 1.41</td> <td align="center" rowspan="1" colspan="1">Serious<br>3 studies included environmental control measures such as dust mite and tobacco smoke avoidance, which are known to reduce respiratory symptoms<br> </td> <td align="center" rowspan="1" colspan="1">Serious<br>Sparse data, inconsistent with data for age 0–4 and lung function data, where no effect was seen</td> <td align="center" rowspan="1" colspan="1">Not tested<br>(<em>n</em> < 10)<br> </td> <td align="center" rowspan="1" colspan="1">All RCTs were undertaken in populations at high risk due to family history of allergic disease.<br>All studies included delayed introduction of allergenic foods; three also included maternal allergenic food avoidance.</td> <td align="center" rowspan="1" colspan="1"> <strong>RR = 0.77</strong><br><strong>(0.61, 0.97)</strong> </td> <td align="center" rowspan="1" colspan="1"> <strong>⨂⨂○○</strong><br><strong>Low</strong><br> </td> <td align="left" rowspan="1" colspan="1"> <strong>50</strong><br><strong>(low risk)</strong><br><strong>100</strong><br><strong>(high risk)</strong><br><strong>150</strong><br><strong>(very high risk)</strong> </td> <td align="left" rowspan="1" colspan="1"> <strong>12 cases</strong><br><strong>95% CI</strong><br><strong>2–20</strong><br><strong>23 cases</strong><br><strong>95% CI</strong><br><strong>3–39</strong><br><strong>35 cases</strong><br><strong>95% CI</strong><br><strong>5–59</strong> </td> </tr> <tr><td align="left" colspan="11" style="background-color:#F2F2F2" rowspan="1"> <strong>Intervention: Maternal vitamin A vs no vitamin A</strong><br><strong>Outcome: Lung function at age 11 years</strong><br><strong>Study design: RCT</strong> </td></tr> <tr> <td align="left" rowspan="1" colspan="1">1 RCT<br>Lung function</td> <td align="center" rowspan="1" colspan="1">Not serious<br>Low risk of bias</td> <td align="center" rowspan="1" colspan="1">Very serious<br>Supplementation with the vitamin A precursor beta carotene in the same trial had no effect on lung function. Neither vtamin A nor beta carotene had an effect on risk of wheeze. Separate trial with similar design but lower vitamin A dose as part of a multivitamin intervention found no effect on FEV1 or FVC at age 8.</td> <td align="center" rowspan="1" colspan="1">Serious<br>Study population was a poor rural Nepalese population at risk of vitamin A deficiency</td> <td align="center" rowspan="1" colspan="1">Serious<br>Single study, with wide CIs</td> <td align="center" rowspan="1" colspan="1">Not tested<br>(<em>n</em> < 10)<br> </td> <td align="center" rowspan="1" colspan="1">Dose response relationship between maternal postpartum serum retinol levels and lung function outcomes</td> <td align="center" rowspan="1" colspan="1"> <strong>Mean Difference</strong><br><strong>FEV</strong><sub><strong>1</strong></sub> <strong>46mls (6, 86)</strong><br><strong>FVC 46mls (8, 84)</strong> </td> <td align="center" rowspan="1" colspan="1"> <strong>○○○○</strong><br><strong>No evidence</strong> </td> <td align="center" rowspan="1" colspan="1"><strong>-</strong></td> <td align="center" rowspan="1" colspan="1"><strong>-</strong></td> </tr> </tbody> </table></div> <div class="p text-right font-secondary"><a href="table/pmed.1002507.t001/" class="usa-link" target="_blank" rel="noopener noreferrer">Open in a new tab</a></div> <div class="tw-foot p"><div class="fn" id="t001fn001"><p>* Absolute risk reduction is expressed per 1,000 people treated. Control risks were derived from control event rates in included studies or, where data were sparse or unrepresentative from included studies, from large international surveys such as the ISAAC survey [<a href="#pmed.1002507.ref019" class="usa-link" aria-describedby="pmed.1002507.ref019">19</a>]. Abbreviations: BF, breastfeeding; CC case control; CS, cross-sectional; NCC, nested case control; OR, odds ratio; PC, prospective cohort; RC, retrospective cohort; RCT, randomised controlled trial; RR, Risk Ratio; TIDM, type 1 diabetes mellitus</p></div></div></section><figure class="fig xbox font-sm" id="pmed.1002507.g002"><h3 class="obj_head">Fig 2.</h3> <p class="img-box line-height-none margin-x-neg-2 tablet:margin-x-0 text-center"><a class="tileshop" target="_blank" href="https://www.ncbi.nlm.nih.gov/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Click%20on%20image%20to%20zoom&p=PMC3&id=5830033_pmed.1002507.g002.jpg"><img class="graphic zoom-in" src="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c8b9/5830033/4ac466c79770/pmed.1002507.g002.jpg" loading="lazy" height="358" width="709" alt="Fig 2"></a></p> <div class="p text-right font-secondary"><a href="figure/pmed.1002507.g002/" class="usa-link" target="_blank" rel="noopener noreferrer">Open in a new tab</a></div> <figcaption><p>Observational study findings for a relationship between breastfeeding ever and recurrent wheeze at age 5–14 years (A) and a Funnel plot for this analysis showing evidence of publication bias (B). Egger test <em>P</em> = 0.012. CI, confidence interval; OR, odds ratio; W, weight.</p></figcaption></figure><figure class="fig xbox font-sm" id="pmed.1002507.g009"><h3 class="obj_head">Fig 9.</h3> <p class="img-box line-height-none margin-x-neg-2 tablet:margin-x-0 text-center"><a class="tileshop" target="_blank" href="https://www.ncbi.nlm.nih.gov/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Click%20on%20image%20to%20zoom&p=PMC3&id=5830033_pmed.1002507.g009.jpg"><img class="graphic zoom-in" src="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c8b9/5830033/c49abd85e924/pmed.1002507.g009.jpg" loading="lazy" height="1298" width="702" alt="Fig 9"></a></p> <div class="p text-right font-secondary"><a href="figure/pmed.1002507.g009/" class="usa-link" target="_blank" rel="noopener noreferrer">Open in a new tab</a></div> <figcaption><p>RCT findings for vitamin supplementation compared with no vitamin supplementation and risk of wheeze (A), recurrent wheeze (B), or eczema (C) at age ≤4 years. CI, confidence interval; RCT, randomised controlled trial; RR, risk ratio; W, weight.</p></figcaption></figure><section id="sec019"><h3 class="pmc_sec_title">Breastfeeding duration and timing of solid food introduction</h3> <p>One intervention trial (17,046 participants) and 259 observational studies (947,097 participants) reported the association between total breastfeeding, exclusive breastfeeding or timing of solid food introduction, and allergic or autoimmune diseases. The intervention trial found reduced eczema in the first year of life in centres allocated to deliver a breastfeeding promotion intervention. Meta-analyses of 24 observational studies showed an association between total breastfeeding duration and reduced recurrent wheeze at 5 to 14 years (e.g., <a href="#pmed.1002507.g002" class="usa-link">Fig 2</a>), but we also found evidence of publication bias. Meta-analyses of 31 observational studies showed an association between total and exclusive breastfeeding duration and reduced TIDM (e.g. <a href="#pmed.1002507.g003" class="usa-link">Fig 3</a>). Associations were statistically significant for retrospective studies but not for prospective studies. The GRADE certainty of these breastfeeding findings was low to very low. There was no association found for other allergic outcomes or for the other autoimmune diseases studied (coeliac disease, 12 studies; inflammatory bowel disease, 13 studies; juvenile rheumatoid arthritis, 3 studies; autoimmune thyroid disease, 1 study).</p> <figure class="fig xbox font-sm" id="pmed.1002507.g003"><h4 class="obj_head">Fig 3.</h4> <p class="img-box line-height-none margin-x-neg-2 tablet:margin-x-0 text-center"><a class="tileshop" target="_blank" href="https://www.ncbi.nlm.nih.gov/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Click%20on%20image%20to%20zoom&p=PMC3&id=5830033_pmed.1002507.g003.jpg"><img class="graphic zoom-in" src="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c8b9/5830033/4189738e9bc6/pmed.1002507.g003.jpg" loading="lazy" height="528" width="782" alt="Fig 3"></a></p> <div class="p text-right font-secondary"><a href="figure/pmed.1002507.g003/" class="usa-link" target="_blank" rel="noopener noreferrer">Open in a new tab</a></div> <figcaption><p>Observational study findings for a relationship between breastfeeding ever (A) or exclusive breastfeeding for ≥3–4 months (B) and type 1 diabetes mellitus. CI, confidence interval; OR, odds ratio; W, weight.</p></figcaption></figure></section><section id="sec020"><h3 class="pmc_sec_title">Intervention trials of other maternal or infant dietary exposures</h3> <section id="sec021"><h4 class="pmc_sec_title">Probiotic and prebiotic supplementation</h4> <p>Twenty-eight intervention trials (6,705 participants) evaluated probiotic supplements. These were either single or multiple organisms, given as capsules, powder, or part of a drink or infant formula milk, at a dose of 1 to 10 billion colony-forming units per day. Meta-analysis showed an association between probiotic supplementation and reduced eczema (<a href="#pmed.1002507.g004" class="usa-link">Fig 4</a>; 19 studies; RR 0.78; 95% CI 0.68–0.90; I<sup><em>2</em></sup> = 61%) or ‘atopic’ eczema (<a href="#pmed.1002507.g004" class="usa-link">Fig 4</a>; 11 studies; RR 0.78; 95% CI 0.65–0.92; I<sup><em>2</em></sup> = 0%) at age ≤ 4 years and reduced allergic sensitisation to cow’s milk at age 1 to 2 years (<a href="#pmed.1002507.g005" class="usa-link">Fig 5</a>; 97 studies). No significant association was seen with eczema at age 5 to 14 years, nor with allergic sensitisation to other allergens. The GRADE certainty of these findings was moderate for eczema and low for cow’s milk sensitisation. Subgroup analysis for eczema showed a significant difference between supplementing mothers during the postnatal period (9 interventions, RR 0.64; 95% CI 0.51–0.80; I<sup><em>2</em></sup> = 59%) and studies that just supplemented infants during the postnatal period (11 interventions, RR 0.93; 95% CI 0.81–1.06; I<sup><em>2</em></sup> = 31%; test for subgroup difference <em>P</em> = 0.016). Ten intervention trials (4,242 participants) evaluated prebiotic supplements (always a galacto-oligosaccharide) either alone or combined with other prebiotics or with probiotics. Nine studies involved comparison of an infant formula milk with versus without prebiotic. Meta-analysis showed no clear evidence that prebiotic supplementation reduces eczema at age ≤ 4 years (<a href="#pmed.1002507.g006" class="usa-link">Fig 6</a>; 7 studies; RR 0.75; 95% CI 0.56–1.01; I<sup><em>2</em></sup> = 57%) and no association at age 5 to 14 years. There was no association between probiotics or prebiotics and other allergic outcomes. In our updated search on 15 December 2017, we identified one publication reporting no effect of a perinatal probiotic supplement on risk of coeliac disease at age 13 years from the trial of Kukkonen [<a href="#pmed.1002507.ref020" class="usa-link" aria-describedby="pmed.1002507.ref020">20</a>]. No other studies reported autoimmune outcomes.</p> <figure class="fig xbox font-sm" id="pmed.1002507.g004"><h5 class="obj_head">Fig 4.</h5> <p class="img-box line-height-none margin-x-neg-2 tablet:margin-x-0 text-center"><a class="tileshop" target="_blank" href="https://www.ncbi.nlm.nih.gov/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Click%20on%20image%20to%20zoom&p=PMC3&id=5830033_pmed.1002507.g004.jpg"><img class="graphic zoom-in" src="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c8b9/5830033/cbc27311f0fa/pmed.1002507.g004.jpg" loading="lazy" height="237" width="733" alt="Fig 4"></a></p> <div class="p text-right font-secondary"><a href="figure/pmed.1002507.g004/" class="usa-link" target="_blank" rel="noopener noreferrer">Open in a new tab</a></div> <figcaption><p>RCT findings for probiotic supplementation compared with no probiotics and risk of eczema (A) or atopic eczema (B) at age ≤4 years. CI, confidence interval; RCT, randomised controlled trial; RR, risk ratio; W, weight.</p></figcaption></figure><figure class="fig xbox font-sm" id="pmed.1002507.g005"><h5 class="obj_head">Fig 5.</h5> <p class="img-box line-height-none margin-x-neg-2 tablet:margin-x-0 text-center"><a class="tileshop" target="_blank" href="https://www.ncbi.nlm.nih.gov/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Click%20on%20image%20to%20zoom&p=PMC3&id=5830033_pmed.1002507.g005.jpg"><img class="graphic zoom-in" src="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c8b9/5830033/299dfe057777/pmed.1002507.g005.jpg" loading="lazy" height="267" width="793" alt="Fig 5"></a></p> <div class="p text-right font-secondary"><a href="figure/pmed.1002507.g005/" class="usa-link" target="_blank" rel="noopener noreferrer">Open in a new tab</a></div> <figcaption><p>RCT findings for probiotic supplementation compared with no probiotics and risk of allergic sensitisation to any allergen (A), any inhalant allergen (B), any food allergen (C), egg (D), milk (E), or peanut (F). CI, confidence interval; RCT, randomised controlled trial; RR, risk ratio; W, weight.</p></figcaption></figure><figure class="fig xbox font-sm" id="pmed.1002507.g006"><h5 class="obj_head">Fig 6. RCT findings for prebiotic supplementation compared with no prebiotics and risk of eczema at age ≤4 years.</h5> <p class="img-box line-height-none margin-x-neg-2 tablet:margin-x-0 text-center"><a class="tileshop" target="_blank" href="https://www.ncbi.nlm.nih.gov/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Click%20on%20image%20to%20zoom&p=PMC3&id=5830033_pmed.1002507.g006.jpg"><img class="graphic zoom-in" src="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c8b9/5830033/18ea0c702d01/pmed.1002507.g006.jpg" loading="lazy" height="288" width="792" alt="Fig 6"></a></p> <div class="p text-right font-secondary"><a href="figure/pmed.1002507.g006/" class="usa-link" target="_blank" rel="noopener noreferrer">Open in a new tab</a></div> <figcaption><p>CI, confidence interval; RCT, randomised controlled trial; RR, risk ratio; W, weight.</p></figcaption></figure></section><section id="sec022"><h4 class="pmc_sec_title">Polyunsaturated fatty acid supplementation</h4> <p>Nineteen intervention trials (14,479 participants) evaluated fatty acid supplements. These were given as fish oil supplements in 12 trials, advice to eat oily fish in 1 trial, supplementation of infant formula milk with omega-3 fatty acids in 3 trials, and other oils in 3 trials. Comparators were corn, soya, canola, olive, sunflower, or vegetable oil, or no supplement. Meta-analysis showed an association between omega-3 polyunsaturated fatty acid supplementation using fish oil during pregnancy and lactation and reduced allergic sensitisation to egg at 1 year (<a href="#pmed.1002507.g007" class="usa-link">Fig 7</a>; 6 studies; RR 0.69 95% CI 0.53–0.90; I<sup><em>2</em></sup> = 15%). No significant association was seen with allergic sensitisation to other allergens. The GRADE certainty of this finding was moderate. Subgroup analysis showed a significant difference between studies which supplemented mothers during pregnancy (4 studies; RR 0.55 95% CI 0.40–0.76; I<sup><em>2</em></sup> = 0%) and studies which supplemented during lactation only (2 studies; RR 0.92 95% CI 0.65–1.28; I<sup><em>2</em></sup> = 0%; test for subgroup difference <em>P</em> = 0.032). Similarly, for allergic sensitisation to peanut, there was reduced risk in the subgroup of studies which supplemented mothers during pregnancy (2 studies; RR 0.62 95% CI 0.40–0.96 I<sup><em>2</em></sup> = 0%). There was no association between omega-3 polyunsaturated fatty acid supplementation and other allergic outcomes. Data were sparse and inconclusive for food allergy and for omega-6 supplementation and allergic outcomes. No autoimmune outcomes were reported, and no new trials were identified in our update search on 15 December 2017.</p> <figure class="fig xbox font-sm" id="pmed.1002507.g007"><h5 class="obj_head">Fig 7.</h5> <p class="img-box line-height-none margin-x-neg-2 tablet:margin-x-0 text-center"><a class="tileshop" target="_blank" href="https://www.ncbi.nlm.nih.gov/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Click%20on%20image%20to%20zoom&p=PMC3&id=5830033_pmed.1002507.g007.jpg"><img class="graphic zoom-in" src="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c8b9/5830033/a695de96bb1e/pmed.1002507.g007.jpg" loading="lazy" height="424" width="738" alt="Fig 7"></a></p> <div class="p text-right font-secondary"><a href="figure/pmed.1002507.g007/" class="usa-link" target="_blank" rel="noopener noreferrer">Open in a new tab</a></div> <figcaption><p>RCT findings for omega-3 polyunsaturated fatty acid supplementation compared with no polyunsaturated fatty acids and risk of allergic sensitisation to any allergen (A), any inhalant allergen (B), any food allergen (C), milk (D), egg (E), or peanut (F). CI, confidence interval; RCT, randomised controlled trial; RR, risk ratio; W, weight.</p></figcaption></figure></section><section id="sec023"><h4 class="pmc_sec_title">Maternal allergenic food avoidance and multifaceted interventions</h4> <p>Twelve intervention trials (1,945 participants) evaluated maternal allergenic food avoidance during pregnancy (2 trials), lactation (6 trials), or both (4 trials). The foods excluded were milk alone (2 trials), egg alone (1 trial), milk and egg (3 trials), or multiple foods (6 trials). We did not find that maternal allergenic food avoidance during pregnancy or lactation reduces risk of allergic disease or TIDM development. Nine trials (2,317 participants) evaluated multifaceted interventions—defined as an intervention with more than one category of dietary intervention. Six trials included promotion of prolonged breastfeeding, avoidance of allergenic foods for mother or infant, and delayed solid food introduction; 6 included environmental control measures to reduce dust mite, pet, or tobacco smoke exposure; 7 used an alternative formula milk as part of the intervention. Meta-analysis shown in <a href="#pmed.1002507.g008" class="usa-link">Fig 8</a> found an association between multifaceted interventions and reduced allergic rhinitis at age ≤ 4 years (2 studies; RR 0.61 95% CI 0.44–0.84; I<sup><em>2</em></sup> = 0%), but not at age 5 to 14 years (4 studies). We also found an association between multifaceted interventions and reduced wheeze (2 studies; RR 0.57 95% CI 0.41–0.81; I<sup><em>2</em></sup> = 0%) and recurrent wheeze (4 studies; RR 0.77 95% CI 0.61–0.97; I<sup><em>2</em></sup> = 0%) at age 5–14 years. There was no association at age ≤ 4 years (4 studies), nor with measures of lung function. The GRADE certainty of findings for multifaceted interventions and wheeze or rhinitis was low, there were no autoimmune outcomes reported, and no new trials were identified in our update search on 15 December 2017.</p> <figure class="fig xbox font-sm" id="pmed.1002507.g008"><h5 class="obj_head">Fig 8.</h5> <p class="img-box line-height-none margin-x-neg-2 tablet:margin-x-0 text-center"><a class="tileshop" target="_blank" href="https://www.ncbi.nlm.nih.gov/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Click%20on%20image%20to%20zoom&p=PMC3&id=5830033_pmed.1002507.g008.jpg"><img class="graphic zoom-in" src="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c8b9/5830033/908033dd5207/pmed.1002507.g008.jpg" loading="lazy" height="326" width="740" alt="Fig 8"></a></p> <div class="p text-right font-secondary"><a href="figure/pmed.1002507.g008/" class="usa-link" target="_blank" rel="noopener noreferrer">Open in a new tab</a></div> <figcaption><p>Randomised controlled trial findings for multifaceted dietary interventions compared with no multifaceted intervention and risk of allergic rhinitis at age ≤4 years (A) or 5–14 years (B), wheeze (C) or recurrent wheeze (D) at age 5–14 years, and wheeze (E) or recurrent wheeze (F) at age ≤4 years. CI, confidence interval; RCT, randomised controlled trial; RR, risk ratio; W, weight.</p></figcaption></figure></section><section id="sec024"><h4 class="pmc_sec_title">Vitamin and mineral supplementation</h4> <p>Eleven intervention trials (15,753 participants) evaluated vitamin and mineral supplements. Two trials used vitamin A in infants; 1 used vitamin A or beta carotene in pregnancy; 2 used vitamin C or E during pregnancy; 3 used vitamin D during pregnancy; 1 used vitamin D during pregnancy and infancy; and 2 used multivitamins during pregnancy. Meta-analysis shown in <a href="#pmed.1002507.g009" class="usa-link">Fig 9</a> found no association between vitamin supplementation and risk of wheeze (5 studies), recurrent wheeze (6 studies), or eczema (5 studies) at age 0 to 4 years, nor for these outcomes at other ages or other allergic outcomes. One trial reported an association between vitamin A (but not beta carotene) supplementation during pregnancy and increased lung function in childhood [<a href="#pmed.1002507.ref021" class="usa-link" aria-describedby="pmed.1002507.ref021">21</a>]. This was not consistent with findings from another similar trial [<a href="#pmed.1002507.ref022" class="usa-link" aria-describedby="pmed.1002507.ref022">22</a>]. No autoimmune outcomes were reported, and no new trials were identified in our update search on 15 December 2017.</p></section></section><section id="sec025"><h3 class="pmc_sec_title">Observational studies of other maternal or infant dietary exposures</h3> <p>Ninety-two observational studies (485,733 participants) evaluated other maternal or infant dietary exposures, including fruit and vegetable intake (35 studies), classified as fruits, vegetables, citrus fruits, nuts, or sometimes as individual foods or food groups; fat and fatty acid intake (26 studies), classified as total fat intake, omega 3 or omega 6 poly-unsaturated fatty acids or other types of fatty acids, and specific fatty acids (we also included fish intake and fish oil supplementation in this group); vitamin and mineral intake (50 studies), including antioxidant vitamins A, C, E, and their precursors, vitamin D and folic acid, mineral intake, and blood vitamin D levels; and a wide range of ‘other dietary exposures’ (47 studies), including dietary pattern, maternal allergenic food avoidance, alcohol, tea or coffee intake, and maternal or infant meat, cereal, milk, or egg intake. Opportunities for meta-analysis of these observational studies were very limited due to heterogeneity of exposure assessment methods and reporting—all analyses are described in the full Food Standards Agency report (<a href="https://www.food.gov.uk/science/research/allergy-research/fs305005ac" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">https://www.food.gov.uk/science/research/allergy-research/fs305005ac</a>). Overall, there was no consistent association between these dietary exposures and risk of allergic outcomes or those autoimmune diseases studied (TIDM, 23 studies; coeliac disease, 2 studies; inflammatory bowel disease, 2 studies; juvenile idiopathic arthritis, 1 study). There was insufficient evidence to either support or refute the intervention trial findings for fish oil supplementation and allergic sensitization to foods, in the observational studies of fatty acid intake during pregnancy.</p></section><section id="sec026"><h3 class="pmc_sec_title">Trial sequential analysis of moderate or high certainty findings</h3> <p>We used TSA to evaluate whether probiotics reduce risk of eczema by ≥20% or ≥30%. The heterogeneity-adjusted optimal information size for detection of a 20% relative risk reduction for eczema was 3,780 study participants, and TSA for this outcome is shown in <a href="#pmed.1002507.g010" class="usa-link">Fig 10</a>. The optimal information size has not been reached, but the monitoring boundary has been crossed, suggesting that this treatment reduces eczema risk by ≥20%. Findings were similar for ≥30% risk reduction, for atopic eczema, and for the subgroup of studies that supplemented lactating mothers during the postnatal period (<a href="#pmed.1002507.g010" class="usa-link">Fig 10</a>). TSA for studies that didn’t supplement lactating mothers showed evidence of futility (<a href="#pmed.1002507.g010" class="usa-link">Fig 10</a>). We also used TSA to evaluate whether maternal fish oil supplementation reduces risk of allergic sensitisation to egg by ≥20% or ≥30% (<a href="#pmed.1002507.g011" class="usa-link">Fig 11</a>). The optimal information size for detection of a 20% relative risk reduction was 6,786 participants, which has not been reached, and the monitoring boundary has not been crossed, suggesting that further studies are required to confirm the effect.</p> <figure class="fig xbox font-sm" id="pmed.1002507.g010"><h4 class="obj_head">Fig 10.</h4> <p class="img-box line-height-none margin-x-neg-2 tablet:margin-x-0 text-center"><a class="tileshop" target="_blank" href="https://www.ncbi.nlm.nih.gov/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Click%20on%20image%20to%20zoom&p=PMC3&id=5830033_pmed.1002507.g010.jpg"><img class="graphic zoom-in" src="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c8b9/5830033/c32496fe59e8/pmed.1002507.g010.jpg" loading="lazy" height="1047" width="771" alt="Fig 10"></a></p> <div class="p text-right font-secondary"><a href="figure/pmed.1002507.g010/" class="usa-link" target="_blank" rel="noopener noreferrer">Open in a new tab</a></div> <figcaption><p>TSA of intervention trials evaluating the effect of probiotics on risk of eczema (A) and the subgroups of studies that did (B) or did not (C) supplement lactating mothers during the postnatal period. The vertical red line is the optimal information size, i.e., the cumulative sample size required to establish with 80% power and 5% 2-sided significance whether the intervention reduces risk of the outcome by ≥20%, allowing for repeatedly meta-analysing the accumulating studies. The horizontal green line is a z score of +1.96, equal to two-sided <em>P</em> = 0.05. The cumulative Z-statistic (blue line) does not reach the optimal information size in analysis of all studies (A) or maternal supplementation studies (B) but does cross the trial sequential monitoring boundary (curved red line), showing evidence for ≥20% relative risk reduction. The cumulative Z-statistic (blue line) for studies without maternal supplementation (C) crosses the futility boundary and reaches the optimal information size without crossing ±1.96, indicating evidence of futility such that further trials of this intervention are not required. Findings were similar for ≥30% relative risk reduction and for eczema associated with allergic sensitisation. No., number; TSA, trial sequential analysis.</p></figcaption></figure><figure class="fig xbox font-sm" id="pmed.1002507.g011"><h4 class="obj_head">Fig 11. TSA of intervention trials evaluating the effect of fish oil supplementation on risk of allergic sensitisation to egg.</h4> <p class="img-box line-height-none margin-x-neg-2 tablet:margin-x-0 text-center"><a class="tileshop" target="_blank" href="https://www.ncbi.nlm.nih.gov/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Click%20on%20image%20to%20zoom&p=PMC3&id=5830033_pmed.1002507.g011.jpg"><img class="graphic zoom-in" src="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c8b9/5830033/2f6614a7b633/pmed.1002507.g011.jpg" loading="lazy" height="242" width="615" alt="Fig 11"></a></p> <div class="p text-right font-secondary"><a href="figure/pmed.1002507.g011/" class="usa-link" target="_blank" rel="noopener noreferrer">Open in a new tab</a></div> <figcaption><p>The vertical red line is the optimal information size, i.e., the cumulative sample size required to establish with 80% power and 5% 2-sided significance whether the intervention reduces risk of the outcome by ≥20%, allowing for repeatedly meta-analysing the accumulating studies. The horizontal green line is a z score of +1.96, equal to two-sided <em>P</em> = 0.05. The cumulative Z-statistic (blue line) does not reach the optimal information size and does not cross the trial sequential monitoring boundary (curved red line), indicating no clear evidence for ≥20% relative risk reduction. Findings were similar for ≥30% relative risk reduction. No., number; TSA, trial sequential analysis.</p></figcaption></figure></section></section><section id="sec027"><h2 class="pmc_sec_title">Discussion</h2> <section id="sec028"><h3 class="pmc_sec_title">Principal findings</h3> <p>In this systematic review of diet during pregnancy and infancy and risk of allergic or autoimmune disease, we found a relationship between maternal diet during pregnancy and lactation and eczema or allergic sensitisation to food during childhood. Positive health effects were found for probiotic and fish oil supplements. We found weaker support for the hypotheses that multifaceted interventions reduce risk of allergic rhinitis and wheeze; that longer duration of breastfeeding is associated with reduced eczema, TIDM, and wheezing; and that longer exclusive breastfeeding is associated with reduced TIDM. There was no association between other dietary exposures and risk of allergic or autoimmune diseases, including timing of solid food introduction, prebiotic supplementation, maternal allergenic food avoidance, and vitamin, mineral, fruit, or vegetable intake. Previously, we reported that hydrolysed formula does not appear to influence risk of allergic or autoimmune diseases and that early peanut or egg introduction to the infant diet reduces risk of peanut or egg allergy [<a href="#pmed.1002507.ref012" class="usa-link" aria-describedby="pmed.1002507.ref012">12</a>,<a href="#pmed.1002507.ref013" class="usa-link" aria-describedby="pmed.1002507.ref013">13</a>]. Taken together, our findings suggest that while infant diet may influence immune development through allergen-specific mechanisms, maternal diet during prenatal life and lactation may have broader effects on the developing immune system. Future efforts to promote immune health through the life course should consider maternal dietary interventions during pregnancy and lactation as an important area of investigation. Our finding that probiotic supplements such as <em>Lactobacillus rhamnosus</em> at a dose of 1 to 10 billion colony-forming units per day may reduce risk of eczema is consistent with a recent World Allergy Organization (WAO) systematic review and guideline, although we rated the certainty of findings as stronger than the WAO group, who downgraded the certainty to very low due to risk of selection and attrition bias in the trials, variation in probiotic(s) used, and variation in the timing of the probiotic supplement intervention [<a href="#pmed.1002507.ref003" class="usa-link" aria-describedby="pmed.1002507.ref003">3</a>,<a href="#pmed.1002507.ref010" class="usa-link" aria-describedby="pmed.1002507.ref010">10</a>]. Our subgroup analysis and TSA findings provide new evidence that maternal (rather than infant) supplementation may be important for this intervention. In contrast, we did not find support for the WAO group’s recommendation to use prebiotic supplements such as galacto-oligosaccharides for preventing eczema due to our serious concerns about risk of bias, inconsistency, imprecision, and indirectness, some of which were shared by the WAO group [<a href="#pmed.1002507.ref002" class="usa-link" aria-describedby="pmed.1002507.ref002">2</a>,<a href="#pmed.1002507.ref023" class="usa-link" aria-describedby="pmed.1002507.ref023">23</a>]. Although microbial exposures have long been postulated as influencing risk of allergic disease, a clear mechanism through which probiotics might reduce risk of eczema is currently lacking. Our finding that fish oil supplementation during pregnancy may reduce allergic sensitisation to the most common food allergens affecting young children, hen’s egg and peanut, is new. In contrast to our findings for probiotics, those for fish oil have a plausible mechanistic basis, since fish oil has known anti-inflammatory effects [<a href="#pmed.1002507.ref024" class="usa-link" aria-describedby="pmed.1002507.ref024">24</a>].Further work is required to clarify whether the effect of fish oil on allergic sensitisation leads to reduced risk of clinical food allergy. We did not find support for recent Australasian guidelines or other systematic reviews suggesting that fish or fish oil supplementation may reduce eczema risk [<a href="#pmed.1002507.ref006" class="usa-link" aria-describedby="pmed.1002507.ref006">6</a>,<a href="#pmed.1002507.ref025" class="usa-link" aria-describedby="pmed.1002507.ref025">25</a>,<a href="#pmed.1002507.ref026" class="usa-link" aria-describedby="pmed.1002507.ref026">26</a>]. Other findings were of low or very low GRADE certainty and are not likely to impact infant feeding guidance at present. The findings for multifaceted interventions and reduced risk of rhinitis or wheezing are unlikely to be related to dietary components of the interventions, and the findings that longer breastfeeding or exclusive breastfeeding duration may reduce risk of TIDM, eczema, and wheezing are not likely to change current breastfeeding recommendations [<a href="#pmed.1002507.ref014" class="usa-link" aria-describedby="pmed.1002507.ref014">14</a>]. Others have reported stronger support for an association between breastfeeding duration and reduced risk of wheezing or other allergic outcomes, but only by pooling quite heterogeneous data [<a href="#pmed.1002507.ref008" class="usa-link" aria-describedby="pmed.1002507.ref008">8</a>,<a href="#pmed.1002507.ref009" class="usa-link" aria-describedby="pmed.1002507.ref009">9</a>]. Our meta-analyses of observational studies of breastfeeding duration and wheezing found new evidence of publication bias, which also suggests that previous reports of links between breastfeeding and wheezing may be misleading. We did not find evidence to support a role for vitamin D supplementation in preventing wheezing or other outcomes. This is consistent with a WAO systematic review [<a href="#pmed.1002507.ref027" class="usa-link" aria-describedby="pmed.1002507.ref027">27</a>] that was undertaken prior to the publication of two key vitamin D trials. Two other recent analyses concluded that prenatal vitamin D supplementation may reduce risk of recurrent wheeze. A systematic review of prenatal vitamins and allergic outcomes did not identify one of our included trials and made a data entry error in another trial (Goldring et al. control and active data switched) [<a href="#pmed.1002507.ref028" class="usa-link" aria-describedby="pmed.1002507.ref028">28</a>]. A meta-analysis of the two largest trials, undertaken by their authors, also had positive findings but did not include the other two published studies which we identified [<a href="#pmed.1002507.ref029" class="usa-link" aria-describedby="pmed.1002507.ref029">29</a>]. Overall, we found relatively few opportunities for meaningful meta-analysis in the observational studies, due mainly to variations in exposure definition and assessment. Even when observational study meta-analysis is possible, differences between populations studied or methods of exposure assessment can lead to increased variability of findings and thereby reduce statistical power compared with a single large, well-conducted study. This may partly explain the stronger findings in relation to intervention trials of dietary supplements than for observational studies of dietary pattern or specific nutritional intake.</p></section><section id="sec029"><h3 class="pmc_sec_title">Interpretation</h3> <p>Our key findings suggest that a mother’s diet during pregnancy and lactation may influence the risk that her child develops allergic disease, and this has implications for future research in this field. There are two specific implications for pregnant women. First, a daily probiotic supplement such as <em>L</em>. <em>rhamnosus</em>, taken from around 36 to 38 weeks gestation through the first 3 to 6 months of lactation, may reduce risk of eczema in the child. Although probiotics are generally considered safe, their pro-inflammatory effects may have potential adverse consequences when used earlier in pregnancy, and serious adverse effects in people with intestinal disorders or immune deficiency have been documented [<a href="#pmed.1002507.ref030" class="usa-link" aria-describedby="pmed.1002507.ref030">30</a>][<a href="#pmed.1002507.ref031" class="usa-link" aria-describedby="pmed.1002507.ref031">31</a>]. Second, a fish oil supplement, taken from around 20 weeks gestation through the first 3 to 4 months of lactation, may reduce risk of allergic sensitisation to egg or peanut in the child. In one included trial, the fish oil intervention was administered via advice to consume at least 2 servings per week of low mercury oily fish (farmed salmon), which is consistent with current United States Food and Drug Administration guidance [<a href="#pmed.1002507.ref032" class="usa-link" aria-describedby="pmed.1002507.ref032">32</a>]. It was not possible to reliably assess whether the findings in this small trial differed significantly from the findings in higher dose fish oil supplementation trials.</p></section><section id="sec030"><h3 class="pmc_sec_title">Strengths and limitations of the study</h3> <p>This comprehensive and wide-ranging systematic review has highlighted key dietary interventions that may reduce risk of allergic outcomes, information which will be useful for pregnant women and their healthcare providers. However, for many dietary exposures, data were inconclusive or inconsistent, such that we are unable to exclude the possibility of beneficial or harmful effects. One limitation of this study is the 2013 search date for observational studies, such that review findings that are derived from these studies may benefit from an update in due course. We included abstract publications, since their exclusion can lead to publication bias; however, their inclusion carries a risk of methodological bias due to the lack of peer review. While the list of dietary exposures included was comprehensive, we did not evaluate food diversity during infancy, which has been suggested as an important factor in relation to allergic outcomes, and we did not evaluate objective markers of nutritional status, with the exception of blood vitamin D level [<a href="#pmed.1002507.ref033" class="usa-link" aria-describedby="pmed.1002507.ref033">33</a>]. This means that we may have missed important relationships for food diversity or nutritional markers. Given the volume of titles included in this systematic review, we were unable to contact the corresponding authors of included studies for data verification, as has been recommended by some authors [<a href="#pmed.1002507.ref034" class="usa-link" aria-describedby="pmed.1002507.ref034">34</a>]. Finally, some outcome measures were reported using a wide variety of assessment tools—for example, wheeze and recurrent wheeze were defined in several different ways—and this may have contributed to some of the statistical heterogeneity seen in meta-analyses. There is a need for more well-powered intervention trials of dietary interventions, given the positive findings with some specific dietary supplements identified here.</p></section><section id="sec031"><h3 class="pmc_sec_title">Conclusions and policy implications</h3> <p>These findings, together with our previous findings regarding hydrolysed formula and allergenic food introduction to the infant diet, suggest that current infant feeding guidance needs revision. Guideline committees will need to carefully consider the key findings together with an evaluation of the safety, acceptability, and cost implications of advising probiotic or fish oil supplementation for pregnant and lactating women.</p></section></section><section id="sec032"><h2 class="pmc_sec_title">Supporting information</h2> <section class="sm xbox font-sm" id="pmed.1002507.s001"><div class="caption p"> <span>S1 PRISMA Checklist. PRISMA Checklist.</span><p>(DOC)</p> </div> <div class="media p"><div class="caption"> <a href="/articles/instance/5830033/bin/pmed.1002507.s001.doc" data-ga-action="click_feat_suppl" class="usa-link">Click here for additional data file.</a><sup> (64KB, doc) </sup> </div></div></section><section class="sm xbox font-sm" id="pmed.1002507.s002"><div class="caption p"> <span>S1 Text. Systematic review search strategies.</span><p>(DOCX)</p> </div> <div class="media p"><div class="caption"> <a href="/articles/instance/5830033/bin/pmed.1002507.s002.docx" data-ga-action="click_feat_suppl" class="usa-link">Click here for additional data file.</a><sup> (138.6KB, docx) </sup> </div></div></section><section class="sm xbox font-sm" id="pmed.1002507.s003"><div class="caption p"> <span>S2 Text. Review A (milk feeding) over-arching report.</span><p>(DOC)</p> </div> <div class="media p"><div class="caption"> <a href="/articles/instance/5830033/bin/pmed.1002507.s003.doc" data-ga-action="click_feat_suppl" class="usa-link">Click here for additional data file.</a><sup> (613.5KB, doc) </sup> </div></div></section><section class="sm xbox font-sm" id="pmed.1002507.s004"><div class="caption p"> <span>S3 Text. Review C (maternal and infant diet) over-arching report.</span><p>(DOC)</p> </div> <div class="media p"><div class="caption"> <a href="/articles/instance/5830033/bin/pmed.1002507.s004.doc" data-ga-action="click_feat_suppl" class="usa-link">Click here for additional data file.</a><sup> (673.5KB, doc) </sup> </div></div></section><section class="sm xbox font-sm" id="pmed.1002507.s005"><div class="caption p"> <span>S1 Appendix. Characteristics of included studies and risk of bias tables.</span><p>(DOCX)</p> </div> <div class="media p"><div class="caption"> <a href="/articles/instance/5830033/bin/pmed.1002507.s005.docx" data-ga-action="click_feat_suppl" class="usa-link">Click here for additional data file.</a><sup> (1.6MB, docx) </sup> </div></div></section><section class="sm xbox font-sm" id="pmed.1002507.s006"><div class="caption p"> <span>S1 Data. Review A (milk feeding) report files.</span><p>(ZIP)</p> </div> <div class="media p"><div class="caption"> <a href="/articles/instance/5830033/bin/pmed.1002507.s006.zip" data-ga-action="click_feat_suppl" class="usa-link">Click here for additional data file.</a><sup> (21.1MB, zip) </sup> </div></div></section><section class="sm xbox font-sm" id="pmed.1002507.s007"><div class="caption p"> <span>S2 Data. Review C (maternal and infant diet) report files.</span><p>(ZIP)</p> </div> <div class="media p"><div class="caption"> <a href="/articles/instance/5830033/bin/pmed.1002507.s007.zip" data-ga-action="click_feat_suppl" class="usa-link">Click here for additional data file.</a><sup> (41.1MB, zip) </sup> </div></div></section><section class="sm xbox font-sm" id="pmed.1002507.s008"><div class="caption p"> <span>S3 Data. Data used for meta-analyses.</span><p>(XLSX)</p> </div> <div class="media p"><div class="caption"> <a href="/articles/instance/5830033/bin/pmed.1002507.s008.xlsx" data-ga-action="click_feat_suppl" class="usa-link">Click here for additional data file.</a><sup> (396.9KB, xlsx) </sup> </div></div></section></section><section id="ack1" class="ack"><h2 class="pmc_sec_title">Acknowledgments</h2> <p>We are grateful to the independent experts, Professor Graham Devereux and Dr Carina Venter, and to members of the UK Food Standards Agency, the Committee on Toxicity of Chemicals in Food, Consumer Products and the Environment (COT), and the UK Scientific Advisory Committee on Nutrition (SACN) for their comments on the study protocol and versions of the full report. We are grateful to Dr Yujie Zhao, Mr Szymon Mikolajewski, Dr Andre F Amaral, Dr Mari Kihara, Dr Christian Nielsen, Mr Radoslav Latinovic, Dr Stephanie MacNeill, Dr Andreas Forsters, Dr Daniel Munblit, Dr Sze-Chin Tan, and Dr Claudia Gore for their assistance with translation of foreign language reports. We are grateful to Tim Reeves for writing the search strategy and undertaking the initial literature search and to Jacqueline Cousins of the St. Mary’s library at Imperial College London for assistance with literature search training. We are grateful to Ulugbek Nurmatov and Nara Tagiyeva-Milne for assistance with data extraction, to Evangelia Andreou for assistance with creating tables and figures for the full report, and to Thomas Clark for assistance with manuscript submission.</p></section><section id="glossary1" class="glossary"><h2 class="pmc_sec_title">Abbreviations</h2> <dl class="def-list"> <dt>CCT</dt> <dd><p>controlled clinical trial</p></dd> <dt>CENTRAL</dt> <dd><p>Central Register of Controlled Trials</p></dd> <dt>COT</dt> <dd><p>Committee on Toxicity of Chemicals in Food, Consumer Products and the Environment</p></dd> <dt>EMBASE</dt> <dd><p>Excerpta Medica dataBASE</p></dd> <dt>GRADE</dt> <dd><p>Grading of Recommendations Assessment, Development and Evaluation</p></dd> <dt>LILACS</dt> <dd><p>Literatura Latino Americana em Ciências da Saúde</p></dd> <dt>MEDLINE</dt> <dd><p>Medical Literature Analysis and Retrieval System Online</p></dd> <dt>OR</dt> <dd><p>odds ratio</p></dd> <dt>RCT</dt> <dd><p>randomised controlled trial</p></dd> <dt>RR</dt> <dd><p>Risk Ratio</p></dd> <dt>SACN</dt> <dd><p>Scientific Advisory Committee on Nutrition</p></dd> <dt>sIgE</dt> <dd><p>specific immunoglobulin E</p></dd> <dt>TIDM</dt> <dd><p>type 1 diabetes mellitus</p></dd> <dt>TSA</dt> <dd><p>trial sequential analysis</p></dd> <dt>WAO</dt> <dd><p>World Allergy Organization</p></dd> </dl></section><section id="notes1"><h2 class="pmc_sec_title">Data Availability</h2> <p>All relevant data are within the paper and its Supporting Information files.</p></section><section id="funding-statement1" lang="en"><h2 class="pmc_sec_title">Funding Statement</h2> <p>This work was funded by the Food Standards Agency grant FS305005 to RJB, VGL and JLB <a href="https://www.food.gov.uk/science/research/allergy-research/fs305005" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">https://www.food.gov.uk/science/research/allergy-research/fs305005</a>. The Food Standards Agency commissioned this work, commissioned external peer review of the study protocol, statistical methods and study report, and approved the decision to submit this manuscript for publication.</p></section><section id="ref-list1" class="ref-list"><h2 class="pmc_sec_title">References</h2> <section id="ref-list1_sec2"><ul class="ref-list font-sm" style="list-style-type:none"> <li id="pmed.1002507.ref001"> <span class="label">1.</span><cite>Prescott SL. Early-life environmental determinants of allergic diseases and the wider pandemic of inflammatory noncommunicable diseases. J Allergy Clin Immunol. 2013; 131(1): 23–30. doi: <a href="https://doi.org/10.1016/j.jaci.2012.11.019" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">10.1016/j.jaci.2012.11.019</a> </cite> [<a href="https://doi.org/10.1016/j.jaci.2012.11.019" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">DOI</a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/23265694/" class="usa-link">PubMed</a>] [<a href="https://scholar.google.com/scholar_lookup?journal=J%20Allergy%20Clin%20Immunol&title=Early-life%20environmental%20determinants%20of%20allergic%20diseases%20and%20the%20wider%20pandemic%20of%20inflammatory%20noncommunicable%20diseases&author=SL%20Prescott&volume=131&issue=1&publication_year=2013&pages=23-30&pmid=23265694&doi=10.1016/j.jaci.2012.11.019&" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">Google Scholar</a>]</li> <li id="pmed.1002507.ref002"> <span class="label">2.</span><cite>Cuello-Garcia CA, Fiocchi A, Pawankar R, Yepes-Nunez JJ, Morgano GP, et al. World Allergy Organization-McMaster University Guidelines for Allergic Disease Prevention (GLAD-P): Prebiotics. World Allergy Organ J. 2016; 9: 10 doi: <a href="https://doi.org/10.1186/s40413-016-0102-7" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">10.1186/s40413-016-0102-7</a> </cite> [<a href="https://doi.org/10.1186/s40413-016-0102-7" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">DOI</a>] [<a href="/articles/PMC4772464/" class="usa-link">PMC free article</a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/26962387/" class="usa-link">PubMed</a>] [<a href="https://scholar.google.com/scholar_lookup?journal=World%20Allergy%20Organ%20J&title=World%20Allergy%20Organization-McMaster%20University%20Guidelines%20for%20Allergic%20Disease%20Prevention%20(GLAD-P):%20Prebiotics&author=CA%20Cuello-Garcia&author=A%20Fiocchi&author=R%20Pawankar&author=JJ%20Yepes-Nunez&author=GP%20Morgano&volume=9&publication_year=2016&pages=10&pmid=26962387&doi=10.1186/s40413-016-0102-7&" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">Google Scholar</a>]</li> <li id="pmed.1002507.ref003"> <span class="label">3.</span><cite>Fiocchi A, Pawankar R, Cuello-Garcia C, Ahn K, Al-Hammadi S, et al. World Allergy Organization-McMaster University Guidelines for Allergic Disease Prevention (GLAD-P): Probiotics. World Allergy Organ J. 2015; 8(1): 4 doi: <a href="https://doi.org/10.1186/s40413-015-0055-2" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">10.1186/s40413-015-0055-2</a> </cite> [<a href="https://doi.org/10.1186/s40413-015-0055-2" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">DOI</a>] [<a href="/articles/PMC4307749/" class="usa-link">PMC free article</a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/25628773/" class="usa-link">PubMed</a>] [<a href="https://scholar.google.com/scholar_lookup?journal=World%20Allergy%20Organ%20J&title=World%20Allergy%20Organization-McMaster%20University%20Guidelines%20for%20Allergic%20Disease%20Prevention%20(GLAD-P):%20Probiotics&author=A%20Fiocchi&author=R%20Pawankar&author=C%20Cuello-Garcia&author=K%20Ahn&author=S%20Al-Hammadi&volume=8&issue=1&publication_year=2015&pages=4&pmid=25628773&doi=10.1186/s40413-015-0055-2&" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">Google Scholar</a>]</li> <li id="pmed.1002507.ref004"> <span class="label">4.</span><cite>Muraro A, Halken S, Arshad SH, Beyer K, Dubois AE, et al. EAACI food allergy and anaphylaxis guidelines. Primary prevention of food allergy. Allergy. 2014; 69(5): 590–601. doi: <a href="https://doi.org/10.1111/all.12398" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">10.1111/all.12398</a> </cite> [<a href="https://doi.org/10.1111/all.12398" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">DOI</a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/24697491/" class="usa-link">PubMed</a>] [<a href="https://scholar.google.com/scholar_lookup?journal=Allergy&title=EAACI%20food%20allergy%20and%20anaphylaxis%20guidelines.%20Primary%20prevention%20of%20food%20allergy&author=A%20Muraro&author=S%20Halken&author=SH%20Arshad&author=K%20Beyer&author=AE%20Dubois&volume=69&issue=5&publication_year=2014&pages=590-601&pmid=24697491&doi=10.1111/all.12398&" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">Google Scholar</a>]</li> <li id="pmed.1002507.ref005"> <span class="label">5.</span><cite>Greer FR, Sicherer SH, Burks AW, Comm N. Effects of early nutritional interventions on the development of atopic disease in infants and children: The role of maternal dietary restriction, breastfeeding, timing of introduction of complementary foods, and hydrolyzed formulas. Pediatrics. 2008; 121(1): 183–191. doi: <a href="https://doi.org/10.1542/peds.2007-3022" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">10.1542/peds.2007-3022</a> </cite> [<a href="https://doi.org/10.1542/peds.2007-3022" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">DOI</a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/18166574/" class="usa-link">PubMed</a>] [<a href="https://scholar.google.com/scholar_lookup?journal=Pediatrics&title=Effects%20of%20early%20nutritional%20interventions%20on%20the%20development%20of%20atopic%20disease%20in%20infants%20and%20children:%20The%20role%20of%20maternal%20dietary%20restriction,%20breastfeeding,%20timing%20of%20introduction%20of%20complementary%20foods,%20and%20hydrolyzed%20formulas&author=FR%20Greer&author=SH%20Sicherer&author=AW%20Burks&author=N%20Comm&volume=121&issue=1&publication_year=2008&pages=183-191&pmid=18166574&doi=10.1542/peds.2007-3022&" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">Google Scholar</a>]</li> <li id="pmed.1002507.ref006"> <span class="label">6.</span><cite>Australasian Society of Clinical Immunology and Allergy guidelines for infant feeding and allergy prevention. Available from: <a href="https://www.allergy.org.au/patients/allergy-prevention/ascia-guidelines-for-infant-feeding-and-allergy-prevention" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">https://www.allergy.org.au/patients/allergy-prevention/ascia-guidelines-for-infant-feeding-and-allergy-prevention</a> [Accessed 10th January 2018].</cite> </li> <li id="pmed.1002507.ref007"> <span class="label">7.</span><cite>Fleischer DM, Spergel JM, Assa'ad AH, Pongracic JA. Primary prevention of allergic disease through nutritional interventions. J Allergy Clin Immunol Pract. 2013; 1(1): 29–36. doi: <a href="https://doi.org/10.1016/j.jaip.2012.09.003" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">10.1016/j.jaip.2012.09.003</a> </cite> [<a href="https://doi.org/10.1016/j.jaip.2012.09.003" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">DOI</a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/24229819/" class="usa-link">PubMed</a>] [<a href="https://scholar.google.com/scholar_lookup?journal=J%20Allergy%20Clin%20Immunol%20Pract&title=Primary%20prevention%20of%20allergic%20disease%20through%20nutritional%20interventions&author=DM%20Fleischer&author=JM%20Spergel&author=AH%20Assa'ad&author=JA%20Pongracic&volume=1&issue=1&publication_year=2013&pages=29-36&pmid=24229819&doi=10.1016/j.jaip.2012.09.003&" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">Google Scholar</a>]</li> <li id="pmed.1002507.ref008"> <span class="label">8.</span><cite>Dogaru CM, Nyffenegger D, Pescatore AM, Spycher BD, Kuehni CE. Breastfeeding and childhood asthma: systematic review and meta-analysis. Am J Epidemiol. 2014; 179(10): 1153–1167. doi: <a href="https://doi.org/10.1093/aje/kwu072" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">10.1093/aje/kwu072</a> </cite> [<a href="https://doi.org/10.1093/aje/kwu072" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">DOI</a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/24727807/" class="usa-link">PubMed</a>] [<a href="https://scholar.google.com/scholar_lookup?journal=Am%20J%20Epidemiol&title=Breastfeeding%20and%20childhood%20asthma:%20systematic%20review%20and%20meta-analysis&author=CM%20Dogaru&author=D%20Nyffenegger&author=AM%20Pescatore&author=BD%20Spycher&author=CE%20Kuehni&volume=179&issue=10&publication_year=2014&pages=1153-1167&pmid=24727807&doi=10.1093/aje/kwu072&" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">Google Scholar</a>]</li> <li id="pmed.1002507.ref009"> <span class="label">9.</span><cite>Lodge CJ, Tan DJ, Lau MX, Dai X, Tham R, et al. Breastfeeding and asthma and allergies: a systematic review and meta-analysis. Acta Paediatr. 2015; 104(467): 38–53. doi: <a href="https://doi.org/10.1111/apa.13132" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">10.1111/apa.13132</a> </cite> [<a href="https://doi.org/10.1111/apa.13132" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">DOI</a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/26192405/" class="usa-link">PubMed</a>] [<a href="https://scholar.google.com/scholar_lookup?journal=Acta%20Paediatr&title=Breastfeeding%20and%20asthma%20and%20allergies:%20a%20systematic%20review%20and%20meta-analysis&author=CJ%20Lodge&author=DJ%20Tan&author=MX%20Lau&author=X%20Dai&author=R%20Tham&volume=104&issue=467&publication_year=2015&pages=38-53&pmid=26192405&doi=10.1111/apa.13132&" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">Google Scholar</a>]</li> <li id="pmed.1002507.ref010"> <span class="label">10.</span><cite>Cuello-Garcia CA, Brozek JL, Fiocchi A, Pawankar R, Yepes-Nunez JJ, et al. Probiotics for the prevention of allergy: A systematic review and meta-analysis of randomized controlled trials. J Allergy Clin Immunol. 2015; 136(4): 952–961. doi: <a href="https://doi.org/10.1016/j.jaci.2015.04.031" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">10.1016/j.jaci.2015.04.031</a> </cite> [<a href="https://doi.org/10.1016/j.jaci.2015.04.031" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">DOI</a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/26044853/" class="usa-link">PubMed</a>] [<a href="https://scholar.google.com/scholar_lookup?journal=J%20Allergy%20Clin%20Immunol&title=Probiotics%20for%20the%20prevention%20of%20allergy:%20A%20systematic%20review%20and%20meta-analysis%20of%20randomized%20controlled%20trials&author=CA%20Cuello-Garcia&author=JL%20Brozek&author=A%20Fiocchi&author=R%20Pawankar&author=JJ%20Yepes-Nunez&volume=136&issue=4&publication_year=2015&pages=952-961&pmid=26044853&doi=10.1016/j.jaci.2015.04.031&" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">Google Scholar</a>]</li> <li id="pmed.1002507.ref011"> <span class="label">11.</span><cite>Osborn DA, Sinn JK. Prebiotics in infants for prevention of allergy. Cochrane Database Syst Rev. 2013; 3: CD006474.</cite> [<a href="https://doi.org/10.1002/14651858.CD006474.pub3" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">DOI</a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/23543544/" class="usa-link">PubMed</a>] [<a href="https://scholar.google.com/scholar_lookup?journal=Cochrane%20Database%20Syst%20Rev&title=Prebiotics%20in%20infants%20for%20prevention%20of%20allergy&author=DA%20Osborn&author=JK%20Sinn&volume=3&publication_year=2013&pages=CD006474&pmid=23543544&doi=10.1002/14651858.CD006474.pub3&" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">Google Scholar</a>]</li> <li id="pmed.1002507.ref012"> <span class="label">12.</span><cite>Boyle RJ, Ierodiakonou D, Khan T, Chivinge J, Robinson Z, et al. Hydrolysed formula and risk of allergic or autoimmune disease: systematic review and meta-analysis. BMJ. 2016; 352: i974 doi: <a href="https://doi.org/10.1136/bmj.i974" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">10.1136/bmj.i974</a> </cite> [<a href="https://doi.org/10.1136/bmj.i974" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">DOI</a>] [<a href="/articles/PMC4783517/" class="usa-link">PMC free article</a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/26956579/" class="usa-link">PubMed</a>] [<a href="https://scholar.google.com/scholar_lookup?journal=BMJ&title=Hydrolysed%20formula%20and%20risk%20of%20allergic%20or%20autoimmune%20disease:%20systematic%20review%20and%20meta-analysis&author=RJ%20Boyle&author=D%20Ierodiakonou&author=T%20Khan&author=J%20Chivinge&author=Z%20Robinson&volume=352&publication_year=2016&pages=i974&pmid=26956579&doi=10.1136/bmj.i974&" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">Google Scholar</a>]</li> <li id="pmed.1002507.ref013"> <span class="label">13.</span><cite>Ierodiakonou D, Garcia-Larsen V, Logan A, Groome A, Cunha S, et al. Timing of Allergenic Food Introduction to the Infant Diet and Risk of Allergic or Autoimmune Disease: A Systematic Review and Meta-analysis. JAMA. 2016; 316(11): 1181–1192. doi: <a href="https://doi.org/10.1001/jama.2016.12623" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">10.1001/jama.2016.12623</a> </cite> [<a href="https://doi.org/10.1001/jama.2016.12623" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">DOI</a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/27654604/" class="usa-link">PubMed</a>] [<a href="https://scholar.google.com/scholar_lookup?journal=JAMA&title=Timing%20of%20Allergenic%20Food%20Introduction%20to%20the%20Infant%20Diet%20and%20Risk%20of%20Allergic%20or%20Autoimmune%20Disease:%20A%20Systematic%20Review%20and%20Meta-analysis&author=D%20Ierodiakonou&author=V%20Garcia-Larsen&author=A%20Logan&author=A%20Groome&author=S%20Cunha&volume=316&issue=11&publication_year=2016&pages=1181-1192&pmid=27654604&doi=10.1001/jama.2016.12623&" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">Google Scholar</a>]</li> <li id="pmed.1002507.ref014"> <span class="label">14.</span><cite>World Health Organization. The optimal duration of exclusive breastfeeding. Available from: <a href="http://www.who.int/nutrition/publications/infantfeeding/WHO_NHD_01.09/en/" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">http://www.who.int/nutrition/publications/infantfeeding/WHO_NHD_01.09/en/</a> [Accessed 10th January 2018].</cite> </li> <li id="pmed.1002507.ref015"> <span class="label">15.</span><cite>McGonagle D, McDermott MF. A proposed classification of the immunological diseases. PLoS Med. 2006; 3(8): e297 doi: <a href="https://doi.org/10.1371/journal.pmed.0030297" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">10.1371/journal.pmed.0030297</a> </cite> [<a href="https://doi.org/10.1371/journal.pmed.0030297" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">DOI</a>] [<a href="/articles/PMC1564298/" class="usa-link">PMC free article</a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/16942393/" class="usa-link">PubMed</a>] [<a href="https://scholar.google.com/scholar_lookup?journal=PLoS%20Med&title=A%20proposed%20classification%20of%20the%20immunological%20diseases&author=D%20McGonagle&author=MF%20McDermott&volume=3&issue=8&publication_year=2006&pages=e297&pmid=16942393&doi=10.1371/journal.pmed.0030297&" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">Google Scholar</a>]</li> <li id="pmed.1002507.ref016"> <span class="label">16.</span><cite>National Institute for Health and Care Excellence. Methods for development of NICE public health guidance. Available from: <a href="https://www.nice.org.uk/process/pmg4/chapter/introduction" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">https://www.nice.org.uk/process/pmg4/chapter/introduction</a> [Accessed 10th January 2018].</cite> [<a href="https://pubmed.ncbi.nlm.nih.gov/27905711/" class="usa-link">PubMed</a>]</li> <li id="pmed.1002507.ref017"> <span class="label">17.</span><cite>Guyatt G, Oxman AD, Akl EA, Kunz R, Vist G, et al. GRADE guidelines: 1. Introduction-GRADE evidence profiles and summary of findings tables. J Clin Epidemiol. 2011; 64(4): 383–394. doi: <a href="https://doi.org/10.1016/j.jclinepi.2010.04.026" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">10.1016/j.jclinepi.2010.04.026</a> </cite> [<a href="https://doi.org/10.1016/j.jclinepi.2010.04.026" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">DOI</a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/21195583/" class="usa-link">PubMed</a>] [<a href="https://scholar.google.com/scholar_lookup?journal=J%20Clin%20Epidemiol&title=GRADE%20guidelines:%201.%20Introduction-GRADE%20evidence%20profiles%20and%20summary%20of%20findings%20tables&author=G%20Guyatt&author=AD%20Oxman&author=EA%20Akl&author=R%20Kunz&author=G%20Vist&volume=64&issue=4&publication_year=2011&pages=383-394&pmid=21195583&doi=10.1016/j.jclinepi.2010.04.026&" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">Google Scholar</a>]</li> <li id="pmed.1002507.ref018"> <span class="label">18.</span><cite>Mustafa RA, Santesso N, Brozek J, Akl EA, Walter SD, et al. The GRADE approach is reproducible in assessing the quality of evidence of quantitative evidence syntheses. J Clin Epidemiol. 2013; 66(7): 736–742; quiz 742 e731-735. doi: <a href="https://doi.org/10.1016/j.jclinepi.2013.02.004" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">10.1016/j.jclinepi.2013.02.004</a> </cite> [<a href="https://doi.org/10.1016/j.jclinepi.2013.02.004" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">DOI</a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/23623694/" class="usa-link">PubMed</a>] [<a href="https://scholar.google.com/scholar_lookup?journal=J%20Clin%20Epidemiol&title=The%20GRADE%20approach%20is%20reproducible%20in%20assessing%20the%20quality%20of%20evidence%20of%20quantitative%20evidence%20syntheses&author=RA%20Mustafa&author=N%20Santesso&author=J%20Brozek&author=EA%20Akl&author=SD%20Walter&volume=66&issue=7&publication_year=2013&pages=736-742&pmid=23623694&doi=10.1016/j.jclinepi.2013.02.004&" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">Google Scholar</a>]</li> <li id="pmed.1002507.ref019"> <span class="label">19.</span><cite>Asher MI, Montefort S, Bjorksten B, Lai CK, Strachan DP, et al. Worldwide time trends in the prevalence of symptoms of asthma, allergic rhinoconjunctivitis, and eczema in childhood: ISAAC Phases One and Three repeat multicountry cross-sectional surveys. Lancet. 2006; 368(9537): 733–743. doi: <a href="https://doi.org/10.1016/S0140-6736(06)69283-0" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">10.1016/S0140-6736(06)69283-0</a> </cite> [<a href="https://doi.org/10.1016/S0140-6736(06)69283-0" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">DOI</a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/16935684/" class="usa-link">PubMed</a>] [<a href="https://scholar.google.com/scholar_lookup?journal=Lancet&title=Worldwide%20time%20trends%20in%20the%20prevalence%20of%20symptoms%20of%20asthma,%20allergic%20rhinoconjunctivitis,%20and%20eczema%20in%20childhood:%20ISAAC%20Phases%20One%20and%20Three%20repeat%20multicountry%20cross-sectional%20surveys&author=MI%20Asher&author=S%20Montefort&author=B%20Bjorksten&author=CK%20Lai&author=DP%20Strachan&volume=368&issue=9537&publication_year=2006&pages=733-743&pmid=16935684&doi=10.1016/S0140-6736(06)69283-0&" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">Google Scholar</a>]</li> <li id="pmed.1002507.ref020"> <span class="label">20.</span><cite>Savilahti EM, Ilonen J, Kukkonen AK, Savilahti E, Kuitunen M. Celiac Disease by The Age of 13 Years is Not Associated With Probiotics Administration in Infancy. J Pediatr Gastroenterol Nutr. 2018. (in press). <a href="https://doi.org/10.1097/MPG.0000000000001846" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">https://doi.org/10.1097/MPG.0000000000001846</a>.</cite> [<a href="https://doi.org/10.1097/MPG.0000000000001846" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">DOI</a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/29210921/" class="usa-link">PubMed</a>] [<a href="https://scholar.google.com/scholar_lookup?journal=J%20Pediatr%20Gastroenterol%20Nutr&title=Celiac%20Disease%20by%20The%20Age%20of%2013%20Years%20is%20Not%20Associated%20With%20Probiotics%20Administration%20in%20Infancy&author=EM%20Savilahti&author=J%20Ilonen&author=AK%20Kukkonen&author=E%20Savilahti&author=M%20Kuitunen&publication_year=2018&pmid=29210921&doi=10.1097/MPG.0000000000001846&" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">Google Scholar</a>]</li> <li id="pmed.1002507.ref021"> <span class="label">21.</span><cite>Checkley W, West KP Jr, Wise RA, Baldwin MR, Wu L, et al. Maternal vitamin A supplementation and lung function in offspring. New Engl J Med. 2010; 362(19): 1784–1794. doi: <a href="https://doi.org/10.1056/NEJMoa0907441" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">10.1056/NEJMoa0907441</a> </cite> [<a href="https://doi.org/10.1056/NEJMoa0907441" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">DOI</a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/20463338/" class="usa-link">PubMed</a>] [<a href="https://scholar.google.com/scholar_lookup?journal=New%20Engl%20J%20Med&title=Maternal%20vitamin%20A%20supplementation%20and%20lung%20function%20in%20offspring&author=W%20Checkley&author=KP%20West&author=RA%20Wise&author=MR%20Baldwin&author=L%20Wu&volume=362&issue=19&publication_year=2010&pages=1784-1794&pmid=20463338&doi=10.1056/NEJMoa0907441&" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">Google Scholar</a>]</li> <li id="pmed.1002507.ref022"> <span class="label">22.</span><cite>Devakumar D, Stocks J, Ayres JG, Kirkby J, Yadav SK, et al. Effects of antenatal multiple micronutrient supplementation on lung function in mid-childhood: follow-up of a double-blind randomised controlled trial in Nepal. Eur Resp J. 2015; 45(6): 1566–1575.</cite> [<a href="https://doi.org/10.1183/09031936.00188914" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">DOI</a>] [<a href="/articles/PMC4636045/" class="usa-link">PMC free article</a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/25700386/" class="usa-link">PubMed</a>] [<a href="https://scholar.google.com/scholar_lookup?journal=Eur%20Resp%20J&title=Effects%20of%20antenatal%20multiple%20micronutrient%20supplementation%20on%20lung%20function%20in%20mid-childhood:%20follow-up%20of%20a%20double-blind%20randomised%20controlled%20trial%20in%20Nepal&author=D%20Devakumar&author=J%20Stocks&author=JG%20Ayres&author=J%20Kirkby&author=SK%20Yadav&volume=45&issue=6&publication_year=2015&pages=1566-1575&pmid=25700386&doi=10.1183/09031936.00188914&" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">Google Scholar</a>]</li> <li id="pmed.1002507.ref023"> <span class="label">23.</span><cite>Cuello-Garcia C, Fiocchi A, Pawankar R, Yepes-Nunez JJ, Morgano GP, et al. Prebiotics for the prevention of allergies: A systematic review and meta-analysis of randomized controlled trials. Clin Exp Allergy. 2017; 47(11): 1468–1477. doi: <a href="https://doi.org/10.1111/cea.13042" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">10.1111/cea.13042</a> </cite> [<a href="https://doi.org/10.1111/cea.13042" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">DOI</a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/29035013/" class="usa-link">PubMed</a>] [<a href="https://scholar.google.com/scholar_lookup?journal=Clin%20Exp%20Allergy&title=Prebiotics%20for%20the%20prevention%20of%20allergies:%20A%20systematic%20review%20and%20meta-analysis%20of%20randomized%20controlled%20trials&author=C%20Cuello-Garcia&author=A%20Fiocchi&author=R%20Pawankar&author=JJ%20Yepes-Nunez&author=GP%20Morgano&volume=47&issue=11&publication_year=2017&pages=1468-1477&pmid=29035013&doi=10.1111/cea.13042&" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">Google Scholar</a>]</li> <li id="pmed.1002507.ref024"> <span class="label">24.</span><cite>Dunstan JA, Mori TA, Barden A, Beilin LJ, Taylor AL, et al. Fish oil supplementation in pregnancy modifies neonatal allergen-specific immune responses and clinical outcomes in infants at high risk of atopy: a randomized, controlled trial. J Allergy Clin Immunol. 2003; 112(6): 1178–1184. doi: <a href="https://doi.org/10.1016/j.jaci.2003.09.009" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">10.1016/j.jaci.2003.09.009</a> </cite> [<a href="https://doi.org/10.1016/j.jaci.2003.09.009" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">DOI</a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/14657879/" class="usa-link">PubMed</a>] [<a href="https://scholar.google.com/scholar_lookup?journal=J%20Allergy%20Clin%20Immunol&title=Fish%20oil%20supplementation%20in%20pregnancy%20modifies%20neonatal%20allergen-specific%20immune%20responses%20and%20clinical%20outcomes%20in%20infants%20at%20high%20risk%20of%20atopy:%20a%20randomized,%20controlled%20trial&author=JA%20Dunstan&author=TA%20Mori&author=A%20Barden&author=LJ%20Beilin&author=AL%20Taylor&volume=112&issue=6&publication_year=2003&pages=1178-1184&pmid=14657879&doi=10.1016/j.jaci.2003.09.009&" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">Google Scholar</a>]</li> <li id="pmed.1002507.ref025"> <span class="label">25.</span><cite>Zhang GQ, Liu B, Li J, Luo CQ, Zhang Q, et al. Fish intake during pregnancy or infancy and allergic outcomes in children: a systematic review and meta-analysis. Pediatr Allergy Immunol. 2017; 28(2): 152–161. doi: <a href="https://doi.org/10.1111/pai.12648" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">10.1111/pai.12648</a> </cite> [<a href="https://doi.org/10.1111/pai.12648" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">DOI</a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/27590571/" class="usa-link">PubMed</a>] [<a href="https://scholar.google.com/scholar_lookup?journal=Pediatr%20Allergy%20Immunol&title=Fish%20intake%20during%20pregnancy%20or%20infancy%20and%20allergic%20outcomes%20in%20children:%20a%20systematic%20review%20and%20meta-analysis&author=GQ%20Zhang&author=B%20Liu&author=J%20Li&author=CQ%20Luo&author=Q%20Zhang&volume=28&issue=2&publication_year=2017&pages=152-161&pmid=27590571&doi=10.1111/pai.12648&" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">Google Scholar</a>]</li> <li id="pmed.1002507.ref026"> <span class="label">26.</span><cite>Gunaratne Anoja W, Makrides M, Collins Carmel T. Maternal prenatal and/or postnatal n-3 long chain polyunsaturated fatty acids (LCPUFA) supplementation for preventing allergies in early childhood. Cochrane Database Syst Rev. 2015; 7: CD010085.</cite> [<a href="https://doi.org/10.1002/14651858.CD010085.pub2" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">DOI</a>] [<a href="/articles/PMC8783748/" class="usa-link">PMC free article</a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/26197477/" class="usa-link">PubMed</a>] [<a href="https://scholar.google.com/scholar_lookup?journal=Cochrane%20Database%20Syst%20Rev&title=Maternal%20prenatal%20and/or%20postnatal%20n-3%20long%20chain%20polyunsaturated%20fatty%20acids%20(LCPUFA)%20supplementation%20for%20preventing%20allergies%20in%20early%20childhood&author=W%20Gunaratne%20Anoja&author=M%20Makrides&author=T%20Collins%20Carmel&volume=7&publication_year=2015&pages=CD010085&pmid=26197477&doi=10.1002/14651858.CD010085.pub2&" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">Google Scholar</a>]</li> <li id="pmed.1002507.ref027"> <span class="label">27.</span><cite>Yepes-Nunez JJ, Brozek JL, Fiocchi A, Pawankar R, Cuello-Garcia C, et al. (2018) Vitamin D supplementation in primary allergy prevention: Systematic review of randomized and non-randomized studies. Allergy 73(1): 37–49. doi: <a href="https://doi.org/10.1111/all.13241" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">10.1111/all.13241</a> </cite> [<a href="https://doi.org/10.1111/all.13241" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">DOI</a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/28675776/" class="usa-link">PubMed</a>] [<a href="https://scholar.google.com/scholar_lookup?journal=Allergy&title=Vitamin%20D%20supplementation%20in%20primary%20allergy%20prevention:%20Systematic%20review%20of%20randomized%20and%20non-randomized%20studies&author=JJ%20Yepes-Nunez&author=JL%20Brozek&author=A%20Fiocchi&author=R%20Pawankar&author=C%20Cuello-Garcia&volume=73&issue=1&publication_year=2018&pages=37-49&pmid=28675776&doi=10.1111/all.13241&" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">Google Scholar</a>]</li> <li id="pmed.1002507.ref028"> <span class="label">28.</span><cite>Vahdaninia M, Mackenzie H, Helps S, Dean T. Prenatal Intake of Vitamins and Allergic Outcomes in the Offspring: A Systematic Review and Meta-Analysis. J Allergy Clin Immunol Pract. 2017. 5(3): 771–778. doi: <a href="https://doi.org/10.1016/j.jaip.2016.09.024" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">10.1016/j.jaip.2016.09.024</a> </cite> [<a href="https://doi.org/10.1016/j.jaip.2016.09.024" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">DOI</a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/27888033/" class="usa-link">PubMed</a>] [<a href="https://scholar.google.com/scholar_lookup?journal=J%20Allergy%20Clin%20Immunol%20Pract&title=Prenatal%20Intake%20of%20Vitamins%20and%20Allergic%20Outcomes%20in%20the%20Offspring:%20A%20Systematic%20Review%20and%20Meta-Analysis&author=M%20Vahdaninia&author=H%20Mackenzie&author=S%20Helps&author=T%20Dean&volume=5&issue=3&publication_year=2017&pages=771-778&pmid=27888033&doi=10.1016/j.jaip.2016.09.024&" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">Google Scholar</a>]</li> <li id="pmed.1002507.ref029"> <span class="label">29.</span><cite>Wolsk HM, Chawes BL, Litonjua AA, Hollis BW, Waage J, et al. Prenatal vitamin D supplementation reduces risk of asthma/recurrent wheeze in early childhood: A combined analysis of two randomized controlled trials. PLoS ONE. 2017; 12(10): e0186657 doi: <a href="https://doi.org/10.1371/journal.pone.0186657" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">10.1371/journal.pone.0186657</a> </cite> [<a href="https://doi.org/10.1371/journal.pone.0186657" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">DOI</a>] [<a href="/articles/PMC5659607/" class="usa-link">PMC free article</a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/29077711/" class="usa-link">PubMed</a>] [<a href="https://scholar.google.com/scholar_lookup?journal=PLoS%20ONE&title=Prenatal%20vitamin%20D%20supplementation%20reduces%20risk%20of%20asthma/recurrent%20wheeze%20in%20early%20childhood:%20A%20combined%20analysis%20of%20two%20randomized%20controlled%20trials&author=HM%20Wolsk&author=BL%20Chawes&author=AA%20Litonjua&author=BW%20Hollis&author=J%20Waage&volume=12&issue=10&publication_year=2017&pages=e0186657&pmid=29077711&doi=10.1371/journal.pone.0186657&" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">Google Scholar</a>]</li> <li id="pmed.1002507.ref030"> <span class="label">30.</span><cite>Besselink MG, van Santvoort HC, Buskens E, Boermeester MA, van Goor H, Timmerman HM, et al. Probiotic prophylaxis in predicted severe acute pancreatitis: a randomised, double-blind, placebo-controlled trial. Lancet. 2008; 371(9613): 651–659. doi: <a href="https://doi.org/10.1016/S0140-6736(08)60207-X" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">10.1016/S0140-6736(08)60207-X</a> </cite> [<a href="https://doi.org/10.1016/S0140-6736(08)60207-X" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">DOI</a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/18279948/" class="usa-link">PubMed</a>] [<a href="https://scholar.google.com/scholar_lookup?journal=Lancet&title=Probiotic%20prophylaxis%20in%20predicted%20severe%20acute%20pancreatitis:%20a%20randomised,%20double-blind,%20placebo-controlled%20trial&author=MG%20Besselink&author=HC%20van%20Santvoort&author=E%20Buskens&author=MA%20Boermeester&author=H%20van%20Goor&volume=371&issue=9613&publication_year=2008&pages=651-659&pmid=18279948&doi=10.1016/S0140-6736(08)60207-X&" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">Google Scholar</a>]</li> <li id="pmed.1002507.ref031"> <span class="label">31.</span><cite>Boyle RJ, Robins-Browne RM, Tang ML. Probiotic use in clinical practice: what are the risks? Am J Clin Nutr. 2006; 83(6): 1256–1264. </cite> [<a href="https://doi.org/10.1093/ajcn/83.6.1256" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">DOI</a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/16762934/" class="usa-link">PubMed</a>] [<a href="https://scholar.google.com/scholar_lookup?journal=Am%20J%20Clin%20Nutr&title=Probiotic%20use%20in%20clinical%20practice:%20what%20are%20the%20risks?&author=RJ%20Boyle&author=RM%20Robins-Browne&author=ML%20Tang&volume=83&issue=6&publication_year=2006&pages=1256-1264&pmid=16762934&doi=10.1093/ajcn/83.6.1256&" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">Google Scholar</a>]</li> <li id="pmed.1002507.ref032"> <span class="label">32.</span><cite>Wenstrom KD. The FDA's new advice on fish: it's complicated. Am J Obstet Gynecol. 2014; 211(5): 475–478 doi: <a href="https://doi.org/10.1016/j.ajog.2014.07.048" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">10.1016/j.ajog.2014.07.048</a> </cite> [<a href="https://doi.org/10.1016/j.ajog.2014.07.048" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">DOI</a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/25072735/" class="usa-link">PubMed</a>] [<a href="https://scholar.google.com/scholar_lookup?journal=Am%20J%20Obstet%20Gynecol&title=The%20FDA's%20new%20advice%20on%20fish:%20it's%20complicated&author=KD%20Wenstrom&volume=211&issue=5&publication_year=2014&pages=475-478&pmid=25072735&doi=10.1016/j.ajog.2014.07.048&" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">Google Scholar</a>]</li> <li id="pmed.1002507.ref033"> <span class="label">33.</span><cite>Nwaru BI, Takkinen HM, Kaila M, Erkkola M, Ahonen S, et al. Food diversity in infancy and the risk of childhood asthma and allergies. J Allergy Clin Immunol. 2014; 133(4): 1084–1091. doi: <a href="https://doi.org/10.1016/j.jaci.2013.12.1069" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">10.1016/j.jaci.2013.12.1069</a> </cite> [<a href="https://doi.org/10.1016/j.jaci.2013.12.1069" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">DOI</a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/24472626/" class="usa-link">PubMed</a>] [<a href="https://scholar.google.com/scholar_lookup?journal=J%20Allergy%20Clin%20Immunol&title=Food%20diversity%20in%20infancy%20and%20the%20risk%20of%20childhood%20asthma%20and%20allergies&author=BI%20Nwaru&author=HM%20Takkinen&author=M%20Kaila&author=M%20Erkkola&author=S%20Ahonen&volume=133&issue=4&publication_year=2014&pages=1084-1091&pmid=24472626&doi=10.1016/j.jaci.2013.12.1069&" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">Google Scholar</a>]</li> <li id="pmed.1002507.ref034"> <span class="label">34.</span><cite>Barnard ND, Willett WC, Ding EL. The Misuse of Meta-analysis in Nutrition Research. JAMA. 2017; 318(15): 1435–1436. doi: <a href="https://doi.org/10.1001/jama.2017.12083" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">10.1001/jama.2017.12083</a> </cite> [<a href="https://doi.org/10.1001/jama.2017.12083" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">DOI</a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/28975260/" class="usa-link">PubMed</a>] [<a href="https://scholar.google.com/scholar_lookup?journal=JAMA&title=The%20Misuse%20of%20Meta-analysis%20in%20Nutrition%20Research&author=ND%20Barnard&author=WC%20Willett&author=EL%20Ding&volume=318&issue=15&publication_year=2017&pages=1435-1436&pmid=28975260&doi=10.1001/jama.2017.12083&" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">Google Scholar</a>]</li> </ul></section></section><section id="_ad93_" lang="en" class="associated-data"><h2 class="pmc_sec_title">Associated Data</h2> <p class="font-secondary"><em>This section collects any data citations, data availability statements, or supplementary materials included in this article.</em></p> <section id="_adsm93_" lang="en" class="supplementary-materials"><h3 class="pmc_sec_title">Supplementary Materials</h3> <section class="sm xbox font-sm" id="db_ds_supplementary-material1_reqid_"><div class="caption p"> <span>S1 PRISMA Checklist. PRISMA Checklist.</span><p>(DOC)</p> </div> <div class="media p"><div class="caption"> <a href="/articles/instance/5830033/bin/pmed.1002507.s001.doc" data-ga-action="click_feat_suppl" class="usa-link">Click here for additional data file.</a><sup> (64KB, doc) </sup> </div></div></section><section class="sm xbox font-sm" id="db_ds_supplementary-material2_reqid_"><div class="caption p"> <span>S1 Text. Systematic review search strategies.</span><p>(DOCX)</p> </div> <div class="media p"><div class="caption"> <a href="/articles/instance/5830033/bin/pmed.1002507.s002.docx" data-ga-action="click_feat_suppl" class="usa-link">Click here for additional data file.</a><sup> (138.6KB, docx) </sup> </div></div></section><section class="sm xbox font-sm" id="db_ds_supplementary-material3_reqid_"><div class="caption p"> <span>S2 Text. Review A (milk feeding) over-arching report.</span><p>(DOC)</p> </div> <div class="media p"><div class="caption"> <a href="/articles/instance/5830033/bin/pmed.1002507.s003.doc" data-ga-action="click_feat_suppl" class="usa-link">Click here for additional data file.</a><sup> (613.5KB, doc) </sup> </div></div></section><section class="sm xbox font-sm" id="db_ds_supplementary-material4_reqid_"><div class="caption p"> <span>S3 Text. Review C (maternal and infant diet) over-arching report.</span><p>(DOC)</p> </div> <div class="media p"><div class="caption"> <a href="/articles/instance/5830033/bin/pmed.1002507.s004.doc" data-ga-action="click_feat_suppl" class="usa-link">Click here for additional data file.</a><sup> (673.5KB, doc) </sup> </div></div></section><section class="sm xbox font-sm" id="db_ds_supplementary-material5_reqid_"><div class="caption p"> <span>S1 Appendix. Characteristics of included studies and risk of bias tables.</span><p>(DOCX)</p> </div> <div class="media p"><div class="caption"> <a href="/articles/instance/5830033/bin/pmed.1002507.s005.docx" data-ga-action="click_feat_suppl" class="usa-link">Click here for additional data file.</a><sup> (1.6MB, docx) </sup> </div></div></section><section class="sm xbox font-sm" id="db_ds_supplementary-material6_reqid_"><div class="caption p"> <span>S1 Data. Review A (milk feeding) report files.</span><p>(ZIP)</p> </div> <div class="media p"><div class="caption"> <a href="/articles/instance/5830033/bin/pmed.1002507.s006.zip" data-ga-action="click_feat_suppl" class="usa-link">Click here for additional data file.</a><sup> (21.1MB, zip) </sup> </div></div></section><section class="sm xbox font-sm" id="db_ds_supplementary-material7_reqid_"><div class="caption p"> <span>S2 Data. Review C (maternal and infant diet) report files.</span><p>(ZIP)</p> </div> <div class="media p"><div class="caption"> <a href="/articles/instance/5830033/bin/pmed.1002507.s007.zip" data-ga-action="click_feat_suppl" class="usa-link">Click here for additional data file.</a><sup> (41.1MB, zip) </sup> </div></div></section><section class="sm xbox font-sm" id="db_ds_supplementary-material8_reqid_"><div class="caption p"> <span>S3 Data. Data used for meta-analyses.</span><p>(XLSX)</p> </div> <div class="media p"><div class="caption"> <a href="/articles/instance/5830033/bin/pmed.1002507.s008.xlsx" data-ga-action="click_feat_suppl" class="usa-link">Click here for additional data file.</a><sup> (396.9KB, xlsx) </sup> </div></div></section></section><section id="_adda93_" lang="en" class="data-availability-statement"><h3 class="pmc_sec_title">Data Availability Statement</h3> <p>All relevant data are within the paper and its Supporting Information files.</p></section></section></section><footer class="p courtesy-note font-secondary font-sm text-center"><hr class="headless"> <p>Articles from PLoS Medicine are provided here courtesy of <strong>PLOS</strong></p></footer></section></article> </main> </div> </div> </div>  <div class="pmc-sidenav desktop:grid-col-4 display-flex"> <section class="pmc-sidenav__container" aria-label="Article resources and navigation"> <button type="button" class="usa-button pmc-sidenav__container__close usa-button--unstyled"> <img src="/static/img/usa-icons/close.svg" role="img" alt="Close" /> </button> <div class="display-none desktop:display-block"> <section class="margin-top-4 desktop:margin-top-0"> <h2 class="margin-top-0">ACTIONS</h2> <ul class="usa-list usa-list--unstyled usa-list--actions"> <li> <a href="https://doi.org/10.1371/journal.pmed.1002507" class="usa-button usa-button--outline width-24 font-xs display-inline-flex flex-align-center flex-justify-start padding-left-1" target="_blank" rel="noreferrer noopener" data-ga-category="actions" data-ga-action="click" data-ga-label="publisher_link_desktop" > <svg class="usa-icon width-3 height-3" aria-hidden="true" focusable="false" role="img" hidden> <use xlink:href="/static/img/sprite.svg#launch"></use> </svg> <span class="display-inline-flex flex-justify-center flex-1 padding-right-2">View on publisher site</span> </a> </li> <li> <a href="pdf/pmed.1002507.pdf" class="usa-button usa-button--outline width-24 display-inline-flex flex-align-center flex-justify-start padding-left-1" data-ga-category="actions" data-ga-action="click" data-ga-label="pdf_download_desktop" > <svg class="usa-icon width-3 height-3" aria-hidden="true" focusable="false" role="img" hidden> <use xlink:href="/static/img/sprite.svg#file_download"></use> </svg> <span class="display-inline-flex flex-justify-center flex-1">PDF (25.2 MB)</span> </a> </li> <li> <button role="button" class="usa-button width-24 citation-dialog-trigger display-inline-flex flex-align-center flex-justify-start padding-left-1" aria-label="Open dialog with citation text in different styles" data-ga-category="actions" data-ga-action="open" data-ga-label="cite_desktop" data-all-citations-url="/resources/citations/5830033/" data-citation-style="nlm" data-download-format-link="/resources/citations/5830033/export/" > <svg class="usa-icon width-3 height-3" aria-hidden="true" focusable="false" role="img" hidden> <use xlink:href="/static/img/sprite.svg#format_quote"></use> </svg> <span class="display-inline-flex flex-justify-center flex-1 button-label">Cite</span> </button> </li> <li> <button class="usa-button width-24 collections-dialog-trigger collections-button display-inline-flex flex-align-center flex-justify-start padding-left-1 collections-button-empty" aria-label="Save article in MyNCBI collections." data-ga-category="actions" data-ga-action="click" data-ga-label="collections_button_desktop" data-collections-open-dialog-enabled="false" data-collections-open-dialog-url="https://account.ncbi.nlm.nih.gov/?back_url=https%3A%2F%2Fpmc.ncbi.nlm.nih.gov%2Farticles%2FPMC5830033%2F%23open-collections-dialog" data-in-collections="false"> <svg class="usa-icon width-3 height-3 usa-icon--bookmark-full" aria-hidden="true" focusable="false" role="img" hidden> <use xlink:href="/static/img/action-bookmark-full.svg#icon"></use> </svg> <svg class="usa-icon width-3 height-3 usa-icon--bookmark-empty" aria-hidden="true" focusable="false" role="img" hidden> <use xlink:href="/static/img/action-bookmark-empty.svg#icon"></use> </svg> <span class="display-inline-flex flex-justify-center flex-1">Collections</span> </button> </li> <li class="pmc-permalink"> <button type="button" class="usa-button width-24 display-inline-flex flex-align-center flex-justify padding-left-1 shadow-none" aria-label="Show article permalink" aria-expanded="false" aria-haspopup="true" data-ga-category="actions" data-ga-action="open" data-ga-label="permalink_desktop" > <svg class="usa-icon width-3 height-3" aria-hidden="true" focusable="false" role="img" hidden> <use xlink:href="/static/img/sprite.svg#share"></use> </svg> <span class="display-inline-flex flex-justify-center flex-1 button-label">Permalink</span> </button> <div class="pmc-permalink__dropdown" hidden> <div class="pmc-permalink__dropdown__container"> <h2 class="usa-modal__heading margin-top-0 margin-bottom-2">PERMALINK</h2> <div class="pmc-permalink__dropdown__content"> <input type="text" class="usa-input" value="https://pmc.ncbi.nlm.nih.gov/articles/PMC5830033/" aria-label="Article permalink"> <button class="usa-button display-inline-flex pmc-permalink__dropdown__copy__btn margin-right-0" title="Copy article permalink" data-ga-category="save_share" data-ga-action="link" data-ga-label="copy_link"> <svg class="usa-icon" aria-hidden="true" focusable="false" role="img"> <use xlink:href="/static/img/sprite.svg#content_copy"></use> </svg> <span class="margin-left-1">Copy</span> </button> </div> </div> </div> </li> </ul> </section> </div> <section class="pmc-resources margin-top-6 desktop:margin-top-4" data-page-path="/articles/PMC5830033/"> <h2 class="margin-top-0">RESOURCES</h2> <div class="usa-accordion usa-accordion--multiselectable" data-allow-multiple> <h3 class="usa-accordion__heading"> <button type="button" class="usa-accordion__button" aria-expanded="false" aria-controls="resources-similar-articles" data-ga-category="resources_accordion" data-ga-action="open_similar_articles" data-ga-label="/articles/PMC5830033/" data-action-open="open_similar_articles" data-action-close="close_similar_articles" > Similar articles </button> </h3> <div id="resources-similar-articles" class="usa-accordion__content usa-prose" data-source-url="/resources/similar-article-links/29489823/" > </div> <h3 class="usa-accordion__heading"> <button type="button" class="usa-accordion__button" aria-expanded="false" aria-controls="resources-cited-by-other-articles" data-ga-category="resources_accordion" data-ga-action="open_cited_by" data-ga-label="/articles/PMC5830033/" data-action-open="open_cited_by" data-action-close="close_cited_by" > Cited by other articles </button> </h3> <div id="resources-cited-by-other-articles" class="usa-accordion__content usa-prose" data-source-url="/resources/cited-by-links/29489823/" > </div> <h3 class="usa-accordion__heading"> <button type="button" class="usa-accordion__button" aria-expanded="false" aria-controls="resources-links-to-ncbi-databases" data-ga-category="resources_accordion" data-ga-action="open_NCBI_links" data-ga-label="/articles/PMC5830033/" data-action-open="open_NCBI_links" data-action-close="close_NCBI_link" > Links to NCBI Databases </button> </h3> <div id="resources-links-to-ncbi-databases" class="usa-accordion__content usa-prose" data-source-url="/resources/db-links/5830033/" > </div> </div> </section> <section class="usa-in-page-nav usa-in-page-nav--wide margin-top-6 desktop:margin-top-4" data-title-text="On this page" data-title-heading-level="h2" data-scroll-offset="0" data-root-margin="-10% 0px -80% 0px" data-main-content-selector="main" data-threshold="1" hidden ></section> </section> </div> <div class="overlay" role="dialog" aria-label="Citation Dialog" hidden> <div class="dialog citation-dialog" aria-hidden="true"> <div class="display-inline-flex flex-align-center flex-justify width-full margin-bottom-2"> <h2 class="usa-modal__heading margin-0">Cite</h2> <button type="button" class="usa-button usa-button--unstyled close-overlay text-black width-auto" tabindex="1"> <svg class="usa-icon width-3 height-3" aria-hidden="true" focusable="false" role="img"> <use xlink:href="/static/img/sprite.svg#close"></use> </svg> </button> </div> <div class="citation-text-block"> <div class="citation-text margin-bottom-2"></div> <ul class="usa-list usa-list--unstyled display-inline-flex flex-justify width-full flex-align-center"> <li> <button class="usa-button usa-button--unstyled text-no-underline display-flex flex-align-center copy-button dialog-focus" data-ga-category="save_share" data-ga-action="cite" data-ga-label="copy" tabindex="2"> <svg class="usa-icon width-3 height-3" aria-hidden="true" focusable="false" role="img"> <use xlink:href="/static/img/sprite.svg#content_copy"></use> </svg> <span>Copy</span> </button> </li> <li> <a href="#" role="button" class="usa-button usa-button--unstyled text-no-underline display-flex flex-align-center export-button" data-ga-category="save_share" data-ga-action="cite" data-ga-label="download" title="Download a file for external citation management software" tabindex="3"> <svg class="usa-icon width-3 height-3" aria-hidden="true" focusable="false" role="img"> <use xlink:href="/static/img/sprite.svg#file_download"></use> </svg> <span class="display-none mobile-lg:display-inline">Download .nbib</span> <span class="display-inline mobile-lg:display-none">.nbib</span> </a> </li> <li> <div class="display-inline-flex flex-align-center"> <label class="usa-label margin-top-0">Format:</label> <select aria-label="Format" class="usa-select citation-style-selector padding-1 margin-top-0 border-0 padding-right-4" tabindex="4" > <option data-style-url-name="ama" value="AMA" > AMA </option> <option data-style-url-name="apa" value="APA" > APA </option> <option data-style-url-name="mla" value="MLA" > MLA </option> <option data-style-url-name="nlm" value="NLM" selected="selected"> NLM </option> </select> </div> </li> </ul> </div> </div> </div> <div class="overlay" role="dialog" hidden> <div id="collections-action-dialog" class="dialog collections-dialog" aria-hidden="true"> <div class="display-inline-flex flex-align-center flex-justify width-full margin-bottom-2"> <h2 class="usa-modal__heading margin-0">Add to Collections</h2> </div> <div class="collections-action-panel action-panel"> <form id="collections-action-dialog-form" class="usa-form maxw-full collections-action-panel-form action-panel-content action-form action-panel-smaller-selectors" data-existing-collections-url="/list-existing-collections/" data-add-to-existing-collection-url="/add-to-existing-collection/" data-create-and-add-to-new-collection-url="/create-and-add-to-new-collection/" data-myncbi-max-collection-name-length="100" data-collections-root-url="https://www.ncbi.nlm.nih.gov/myncbi/collections/"> <input type="hidden" name="csrfmiddlewaretoken" value="0QkLavYo7htYvyeq0wgiBl3mrPNTVY5l9kLEtnQ1ES7leaK4qzRlfELpsbOOvYCA"> <fieldset class="usa-fieldset margin-bottom-2"> <div class="usa-radio"> <input type="radio" id="collections-action-dialog-new" class="usa-radio__input usa-radio__input--tile collections-new margin-top-0" name="collections" value="new" data-ga-category="collections_button" data-ga-action="click" data-ga-label="collections_radio_new" /> <label class="usa-radio__label" for="collections-action-dialog-new">Create a new collection</label> </div> <div class="usa-radio"> <input type="radio" id="collections-action-dialog-existing" class="usa-radio__input usa-radio__input--tile collections-existing" name="collections" value="existing" checked="true" data-ga-category="collections_button" data-ga-action="click" data-ga-label="collections_radio_existing" /> <label class="usa-radio__label" for="collections-action-dialog-existing">Add to an existing collection</label> </div> </fieldset> <fieldset class="usa-fieldset margin-bottom-2"> <div class="action-panel-control-wrap new-collections-controls"> <label for="collections-action-dialog-add-to-new" class="usa-label margin-top-0"> Name your collection <abbr title="required" class="usa-hint usa-hint--required text-no-underline">*</abbr> </label> <input type="text" name="add-to-new-collection" id="collections-action-dialog-add-to-new" class="usa-input collections-action-add-to-new" pattern="[^"&=<>/]*" title="The following characters are not allowed in the Name field: "&=<>/" maxlength="" data-ga-category="collections_button" data-ga-action="create_collection" data-ga-label="non_favorties_collection" required /> </div> <div class="action-panel-control-wrap existing-collections-controls"> <label for="collections-action-dialog-add-to-existing" class="usa-label margin-top-0"> Choose a collection </label> <select id="collections-action-dialog-add-to-existing" class="usa-select collections-action-add-to-existing" data-ga-category="collections_button" data-ga-action="select_collection" data-ga-label="($('.collections-action-add-to-existing').val() === 'Favorites') ? 'Favorites' : 'non_favorites_collection'"> </select> <div class="collections-retry-load-on-error usa-input-error-message selection-validation-message"> Unable to load your collection due to an error<br> <a href="#">Please try again</a> </div> </div> </fieldset> <div class="display-inline-flex"> <button class="usa-button margin-top-0 action-panel-submit" type="submit" data-loading-label="Adding..." data-pinger-ignore data-ga-category="collections_button" data-ga-action="click" data-ga-label="add"> Add </button> <button class="usa-button usa-button--outline margin-top-0 action-panel-cancel" aria-label="Close 'Add to Collections' panel" ref="linksrc=close_collections_panel" data-ga-category="collections_button" data-ga-action="click" data-ga-label="cancel"> Cancel </button> </div> </form> </div> </div> </div> </div> </div> </div> <footer class="ncbi-footer ncbi-dark-background " > <div class="ncbi-footer__icon-section"> <div class="ncbi-footer__social-header"> Follow NCBI </div> <div class="grid-container ncbi-footer__ncbi-social-icons-container"> <a href="https://twitter.com/ncbi" class="ncbi-footer__social-icon ncbi-footer__social-icon--gray" target="_blank" rel="noreferrer noopener"> <svg width="40" height="40" viewBox="0 0 40 40" fill="none" xmlns="http://www.w3.org/2000/svg" focusable="false" aria-hidden="true"> <path d="m6.067 8 10.81 13.9L6 33.2h4.2l8.4-9.1 7.068 9.1H34L22.8 18.5 31.9 8h-3.5l-7.7 8.4L14.401 8H6.067Zm3.6 1.734h3.266l16.8 21.732H26.57L9.668 9.734Z"> </path> </svg> <span class="usa-sr-only">NCBI on X (formerly known as Twitter)</span> </a> <a href="https://www.facebook.com/ncbi.nlm" class="ncbi-footer__social-icon ncbi-footer__social-icon--gray" target="_blank" rel="noreferrer noopener"> <svg width="16" height="29" focusable="false" aria-hidden="true" viewBox="0 0 16 29" fill="none" xmlns="http://www.w3.org/2000/svg"> <path d="M3.8809 21.4002C3.8809 19.0932 3.8809 16.7876 3.8809 14.478C3.8809 14.2117 3.80103 14.1452 3.54278 14.1492C2.53372 14.1638 1.52334 14.1492 0.514288 14.1598C0.302626 14.1598 0.248047 14.0972 0.248047 13.8936C0.256034 12.4585 0.256034 11.0239 0.248047 9.58978C0.248047 9.37013 0.302626 9.30224 0.528931 9.3049C1.53798 9.31688 2.54837 9.3049 3.55742 9.31555C3.80103 9.31555 3.8809 9.26097 3.87957 9.00272C3.87158 8.00565 3.85428 7.00592 3.90753 6.00884C3.97142 4.83339 4.31487 3.73115 5.04437 2.78467C5.93095 1.63318 7.15699 1.09005 8.56141 0.967577C10.5582 0.79319 12.555 0.982221 14.5518 0.927641C14.7102 0.927641 14.7462 0.99287 14.7449 1.13664C14.7449 2.581 14.7449 4.02668 14.7449 5.47104C14.7449 5.67604 14.6517 5.68669 14.4946 5.68669C13.4523 5.68669 12.4113 5.68669 11.3703 5.68669C10.3506 5.68669 9.92057 6.10868 9.90593 7.13904C9.89661 7.7647 9.91525 8.39303 9.89794 9.01869C9.88995 9.26364 9.96583 9.31822 10.2015 9.31688C11.7204 9.30623 13.2393 9.31688 14.7595 9.3049C15.0257 9.3049 15.0723 9.3728 15.0444 9.62439C14.89 10.9849 14.7515 12.3467 14.6144 13.7085C14.5691 14.1571 14.5785 14.1585 14.1458 14.1585C12.8386 14.1585 11.5313 14.1665 10.2254 14.1518C9.95119 14.1518 9.89794 14.2317 9.89794 14.4899C9.90593 19.0799 9.89794 23.6752 9.91125 28.2612C9.91125 28.5674 9.8407 28.646 9.53186 28.6433C7.77866 28.6273 6.02414 28.6366 4.27094 28.634C3.82499 28.634 3.87158 28.6992 3.87158 28.22C3.87602 25.9472 3.87913 23.6739 3.8809 21.4002Z"> </path> </svg> <span class="usa-sr-only">NCBI on Facebook</span> </a> <a href="https://www.linkedin.com/company/ncbinlm" class="ncbi-footer__social-icon ncbi-footer__social-icon--gray" target="_blank" rel="noreferrer noopener"> <svg width="25" height="23" viewBox="0 0 26 24" fill="none" xmlns="http://www.w3.org/2000/svg" focusable="false" aria-hidden="true"> <path d="M14.6983 9.98423C15.6302 9.24808 16.5926 8.74754 17.6762 8.51991C19.673 8.09126 21.554 8.30824 23.1262 9.7526C24.2351 10.7723 24.7529 12.1115 25.0165 13.5612C25.1486 14.3363 25.2105 15.1218 25.2015 15.9081C25.2015 18.3043 25.2015 20.6898 25.2082 23.0806C25.2082 23.3468 25.1549 23.444 24.8621 23.4414C23.1297 23.4272 21.3992 23.4272 19.6704 23.4414C19.4041 23.4414 19.3429 23.3588 19.3442 23.1019C19.3535 20.5194 19.3442 17.9368 19.3442 15.3543C19.3442 14.0005 18.3258 12.9448 17.0266 12.9488C15.7273 12.9528 14.6983 14.0071 14.6983 15.361C14.6983 17.9328 14.6917 20.5047 14.6983 23.0753C14.6983 23.3708 14.6198 23.444 14.3296 23.4427C12.6185 23.4294 10.9079 23.4294 9.19779 23.4427C8.93155 23.4427 8.86099 23.3735 8.86232 23.1086C8.8783 19.7619 8.88628 16.4144 8.88628 13.066C8.88628 11.5688 8.87874 10.0708 8.86365 8.57182C8.86365 8.3575 8.90758 8.27896 9.14054 8.28029C10.9048 8.29094 12.6687 8.29094 14.4321 8.28029C14.6464 8.28029 14.6983 8.34818 14.6983 8.54653C14.6903 9.00047 14.6983 9.45441 14.6983 9.98423Z"> </path> <path d="M6.55316 15.8443C6.55316 18.2564 6.55316 20.6699 6.55316 23.082C6.55316 23.3629 6.48127 23.4388 6.19906 23.4374C4.47737 23.4241 2.75568 23.4241 1.03399 23.4374C0.767751 23.4374 0.69986 23.3629 0.701191 23.1006C0.709178 18.2648 0.709178 13.4281 0.701191 8.59053C0.701191 8.34026 0.765089 8.27237 1.01669 8.2737C2.74991 8.28435 4.48048 8.28435 6.20838 8.2737C6.47462 8.2737 6.5465 8.33627 6.54517 8.6065C6.54783 11.0186 6.55316 13.4308 6.55316 15.8443Z"> </path> <path d="M3.65878 0.243898C5.36804 0.243898 6.58743 1.45529 6.58743 3.1406C6.58743 4.75801 5.32145 5.95742 3.60819 5.96807C3.22177 5.97614 2.83768 5.90639 2.47877 5.76299C2.11985 5.61959 1.79344 5.40546 1.51897 5.13334C1.24449 4.86123 1.02755 4.53668 0.881058 4.17902C0.734563 3.82136 0.661505 3.43788 0.666231 3.05141C0.67555 1.42601 1.9362 0.242566 3.65878 0.243898Z"> </path> </svg> <span class="usa-sr-only">NCBI on LinkedIn</span> </a> <a href="https://github.com/ncbi" class="ncbi-footer__social-icon ncbi-footer__social-icon--gray" target="_blank" rel="noreferrer noopener"> <svg width="28" height="27" viewBox="0 0 28 28" fill="none" xmlns="http://www.w3.org/2000/svg" focusable="false" aria-hidden="true"> <path d="M16.7228 20.6334C17.5057 20.5527 18.2786 20.3944 19.0301 20.1608C21.3108 19.4193 22.5822 17.8259 22.963 15.4909C23.1228 14.5112 23.1814 13.5287 22.9883 12.5437C22.8106 11.6423 22.4013 10.8028 21.8007 10.1076C21.7526 10.0605 21.7197 10 21.7064 9.934C21.6931 9.86799 21.7 9.79952 21.7262 9.73748C22.0856 8.6206 21.9711 7.51969 21.601 6.42677C21.582 6.3497 21.5345 6.2827 21.468 6.23923C21.4016 6.19577 21.3211 6.17906 21.2429 6.19248C20.7329 6.21649 20.2313 6.33051 19.7611 6.52928C19.1103 6.7908 18.4899 7.12198 17.9104 7.51703C17.84 7.56996 17.7581 7.60551 17.6713 7.62078C17.5846 7.63605 17.4954 7.6306 17.4112 7.60489C15.2596 7.05882 13.0054 7.06203 10.8554 7.61421C10.7806 7.63586 10.7018 7.63967 10.6253 7.62534C10.5487 7.611 10.4766 7.57892 10.4148 7.53167C9.64788 7.03247 8.85171 6.58918 7.96368 6.33359C7.65781 6.24338 7.34123 6.19458 7.02239 6.18849C6.94879 6.17986 6.87462 6.19893 6.81432 6.242C6.75402 6.28507 6.71191 6.34904 6.69621 6.42145C6.32342 7.51437 6.2209 8.61527 6.56307 9.73348C6.59635 9.84264 6.64694 9.93316 6.54177 10.0516C5.47666 11.2604 5.09988 12.6834 5.19574 14.2676C5.2663 15.4244 5.46201 16.5466 6.01454 17.5769C6.84399 19.1171 8.21664 19.9119 9.85158 20.3352C10.3938 20.4706 10.9444 20.5698 11.4998 20.632C11.5384 20.7492 11.4506 20.7798 11.408 20.8291C11.1734 21.1179 10.9894 21.4441 10.8634 21.7942C10.7622 22.0458 10.8315 22.4039 10.6065 22.5516C10.263 22.7766 9.83827 22.8485 9.42421 22.8871C8.17936 23.0056 7.26471 22.4877 6.6283 21.4348C6.25552 20.8184 5.76956 20.3325 5.08523 20.0663C4.76981 19.9325 4.42139 19.8967 4.08537 19.9638C3.7898 20.029 3.73788 20.1901 3.93891 20.4111C4.03639 20.5234 4.14989 20.6207 4.27575 20.6999C4.9796 21.1318 5.51717 21.7884 5.80152 22.5636C6.37002 23.9973 7.48039 24.5697 8.93825 24.6323C9.43741 24.6575 9.93768 24.615 10.4254 24.5058C10.5892 24.4672 10.6531 24.4872 10.6517 24.6762C10.6451 25.4936 10.6637 26.3123 10.6517 27.131C10.6517 27.6635 10.1684 27.9297 9.58663 27.7393C8.17396 27.2671 6.84977 26.5631 5.66838 25.656C2.59555 23.2891 0.720966 20.1861 0.217704 16.3376C-0.357453 11.9127 0.911353 8.00824 3.98551 4.73881C6.11909 2.42656 8.99932 0.939975 12.1203 0.540191C16.5351 -0.0601815 20.4347 1.14323 23.7232 4.16373C26.2449 6.47869 27.724 9.37672 28.1048 12.7726C28.5828 17.0325 27.3686 20.7945 24.4768 23.9827C22.9762 25.6323 21.0956 26.8908 18.9982 27.6488C18.8783 27.6927 18.7585 27.738 18.636 27.7726C18.0356 27.9404 17.6189 27.6395 17.6189 27.0098C17.6189 25.7452 17.6308 24.4806 17.6295 23.2159C17.6329 22.9506 17.6128 22.6856 17.5696 22.4238C17.4325 21.6664 17.3419 21.484 16.7228 20.6334Z"> </path> </svg> <span class="usa-sr-only">NCBI on GitHub</span> </a> <a href="https://ncbiinsights.ncbi.nlm.nih.gov/" class="ncbi-footer__social-icon ncbi-footer__social-icon--gray" target="_blank" rel="noreferrer noopener"> <svg width="26" height="26" viewBox="0 0 27 27" fill="none" xmlns="http://www.w3.org/2000/svg" focusable="false" aria-hidden="true"> <path d="M23.7778 26.4574C23.1354 26.3913 22.0856 26.8024 21.636 26.3087C21.212 25.8444 21.4359 24.8111 21.324 24.0347C19.9933 14.8323 14.8727 8.80132 6.09057 5.85008C4.37689 5.28406 2.58381 4.99533 0.779072 4.99481C0.202773 4.99481 -0.0229751 4.83146 0.00455514 4.21479C0.0660406 3.08627 0.0660406 1.95525 0.00455514 0.826734C-0.0413285 0.0815827 0.259669 -0.0193618 0.896534 0.00266238C6.96236 0.222904 12.3693 2.24179 16.9889 6.16209C22.9794 11.2478 26.1271 17.7688 26.4372 25.648C26.4629 26.294 26.3179 26.5271 25.6609 26.4684C25.0827 26.417 24.4991 26.4574 23.7778 26.4574Z"> </path> <path d="M14.8265 26.441C14.0924 26.441 13.2371 26.6795 12.6626 26.3786C12.0092 26.0372 12.3781 25.0644 12.246 24.378C11.1154 18.5324 6.6849 14.5497 0.74755 14.1001C0.217135 14.0615 -0.0104482 13.9422 0.0134113 13.3659C0.0519536 12.1454 0.0482829 10.9213 0.0134113 9.69524C-0.00127145 9.14464 0.196946 9.03268 0.703502 9.04736C9.21217 9.27128 16.5994 16.2511 17.2804 24.7231C17.418 26.4446 17.418 26.4446 15.6579 26.4446H14.832L14.8265 26.441Z"> </path> <path d="M3.58928 26.4555C2.64447 26.4618 1.73584 26.0925 1.06329 25.4289C0.39073 24.7653 0.00933763 23.8617 0.0030097 22.9169C-0.00331824 21.9721 0.365937 21.0635 1.02954 20.3909C1.69315 19.7184 2.59675 19.337 3.54156 19.3306C4.48637 19.3243 5.39499 19.6936 6.06755 20.3572C6.7401 21.0208 7.1215 21.9244 7.12782 22.8692C7.13415 23.814 6.7649 24.7226 6.10129 25.3952C5.43768 26.0677 4.53409 26.4491 3.58928 26.4555Z"> </path> </svg> <span class="usa-sr-only">NCBI RSS feed</span> </a> </div> </div> <div data-testid="gridContainer" class="grid-container ncbi-footer__container"> <div class="grid-row ncbi-footer__main-content-container" data-testid="grid"> <div class="ncbi-footer__column"> <p class="ncbi-footer__circled-icons-heading"> Connect with NLM </p> <div class="ncbi-footer__circled-icons-list"> <a href=https://twitter.com/nlm_nih class="ncbi-footer__social-icon ncbi-footer__social-icon--circled" target="_blank" rel="noreferrer noopener"> <svg width="32" height="32" viewBox="0 0 40 40" fill="none" xmlns="http://www.w3.org/2000/svg" focusable="false" aria-hidden="true"> <path d="m6.067 8 10.81 13.9L6 33.2h4.2l8.4-9.1 7.068 9.1H34L22.8 18.5 31.9 8h-3.5l-7.7 8.4L14.401 8H6.067Zm3.6 1.734h3.266l16.8 21.732H26.57L9.668 9.734Z"> </path> </svg> <span class="usa-sr-only">NLM on X (formerly known as Twitter)</span> </a> <a href=https://www.facebook.com/nationallibraryofmedicine class="ncbi-footer__social-icon ncbi-footer__social-icon--circled" target="_blank" rel="noreferrer noopener"> <svg width="13" height="24" viewBox="0 0 13 24" fill="none" xmlns="http://www.w3.org/2000/svg" focusable="false" aria-hidden="true"> <path d="M4.11371 23.1369C4.11371 23.082 4.11371 23.0294 4.11371 22.9745V12.9411H0.817305C0.6709 12.9411 0.670898 12.9411 0.670898 12.8016C0.670898 11.564 0.670898 10.3287 0.670898 9.09341C0.670898 8.97903 0.705213 8.95158 0.815017 8.95158C1.8673 8.95158 2.91959 8.95158 3.97417 8.95158H4.12057V8.83263C4.12057 7.8055 4.12057 6.7738 4.12057 5.74897C4.1264 4.92595 4.31387 4.11437 4.66959 3.37217C5.12916 2.38246 5.94651 1.60353 6.95717 1.1921C7.64827 0.905008 8.3913 0.764035 9.13953 0.778051C10.0019 0.791777 10.8644 0.830666 11.7268 0.860404C11.8869 0.860404 12.047 0.894717 12.2072 0.90158C12.2964 0.90158 12.3261 0.940469 12.3261 1.02968C12.3261 1.5421 12.3261 2.05452 12.3261 2.56465C12.3261 3.16857 12.3261 3.7725 12.3261 4.37642C12.3261 4.48165 12.2964 4.51367 12.1912 4.51138C11.5369 4.51138 10.8804 4.51138 10.2261 4.51138C9.92772 4.51814 9.63058 4.5526 9.33855 4.61433C9.08125 4.6617 8.84537 4.78881 8.66431 4.97766C8.48326 5.16652 8.3662 5.40755 8.32972 5.66661C8.28476 5.89271 8.26027 6.1224 8.25652 6.35289C8.25652 7.19014 8.25652 8.02969 8.25652 8.86923C8.25652 8.89439 8.25652 8.91955 8.25652 8.95615H12.0219C12.1797 8.95615 12.182 8.95616 12.1614 9.10714C12.0768 9.76596 11.9876 10.4248 11.9029 11.0813C11.8312 11.6319 11.7626 12.1824 11.697 12.733C11.6719 12.9434 11.6787 12.9434 11.4683 12.9434H8.26338V22.899C8.26338 22.979 8.26338 23.0591 8.26338 23.1392L4.11371 23.1369Z"> </path> </svg> <span class="usa-sr-only">NLM on Facebook</span> </a> <a href=https://www.youtube.com/user/NLMNIH class="ncbi-footer__social-icon ncbi-footer__social-icon--circled" target="_blank" rel="noreferrer noopener"> <svg width="21" height="15" viewBox="0 0 21 15" fill="none" xmlns="http://www.w3.org/2000/svg" focusable="false" aria-hidden="true"> <path d="M19.2561 1.47914C18.9016 1.15888 18.5699 0.957569 17.2271 0.834039C15.5503 0.678484 13.2787 0.655608 11.563 0.65332H9.43556C7.71987 0.65332 5.4483 0.678484 3.77151 0.834039C2.43098 0.957569 2.097 1.15888 1.74242 1.47914C0.813665 2.32097 0.619221 4.62685 0.598633 6.89384C0.598633 7.31781 0.598633 7.74101 0.598633 8.16345C0.626084 10.4121 0.827391 12.686 1.74242 13.521C2.097 13.8412 2.4287 14.0425 3.77151 14.1661C5.4483 14.3216 7.71987 14.3445 9.43556 14.3468H11.563C13.2787 14.3468 15.5503 14.3216 17.2271 14.1661C18.5676 14.0425 18.9016 13.8412 19.2561 13.521C20.1712 12.6929 20.3725 10.451 20.3999 8.22064C20.3999 7.74025 20.3999 7.25986 20.3999 6.77946C20.3725 4.54907 20.1689 2.30724 19.2561 1.47914ZM8.55942 10.5311V4.65201L13.5601 7.50005L8.55942 10.5311Z" fill="white" /> </svg> <span class="usa-sr-only">NLM on YouTube</span> </a> </div> </div> <address class="ncbi-footer__address ncbi-footer__column"> <p> <a class="usa-link usa-link--external" href="https://www.google.com/maps/place/8600+Rockville+Pike,+Bethesda,+MD+20894/%4038.9959508, -77.101021,17z/data%3D!3m1!4b1!4m5!3m4!1s0x89b7c95e25765ddb%3A0x19156f88b27635b8!8m2!3d38.9959508! 4d-77.0988323" rel="noopener noreferrer" target="_blank">National Library of Medicine <br/> 8600 Rockville Pike<br/> Bethesda, MD 20894</a> </p> </address> <ul class="usa-list usa-list--unstyled ncbi-footer__vertical-list ncbi-footer__column"> <li class="ncbi-footer__vertical-list-item"> <a href="https://www.nlm.nih.gov/web_policies.html" class="usa-link usa-link--alt ncbi-footer__link" > Web Policies </a> </li> <li class="ncbi-footer__vertical-list-item"> <a href="https://www.nih.gov/institutes-nih/nih-office-director/office-communications-public-liaison/freedom-information-act-office" class="usa-link usa-link--alt ncbi-footer__link" > FOIA </a> </li> <li class="ncbi-footer__vertical-list-item"> <a href="https://www.hhs.gov/vulnerability-disclosure-policy/index.html" class="usa-link usa-link--external usa-link--alt ncbi-footer__link" rel="noreferrer noopener" target='_blank' > HHS Vulnerability Disclosure </a> </li> </ul> <ul class="usa-list usa-list--unstyled ncbi-footer__vertical-list ncbi-footer__column"> <li class="ncbi-footer__vertical-list-item"> <a href="https://support.nlm.nih.gov/" class="usa-link usa-link--alt ncbi-footer__link" > Help </a> </li> <li class="ncbi-footer__vertical-list-item"> <a href="https://www.nlm.nih.gov/accessibility.html" class="usa-link usa-link--alt ncbi-footer__link" > Accessibility </a> </li> <li class="ncbi-footer__vertical-list-item"> <a href="https://www.nlm.nih.gov/careers/careers.html" class="usa-link usa-link--alt ncbi-footer__link" > Careers </a> </li> </ul> </div> <div class="grid-row grid-col-12" data-testid="grid"> <ul class="ncbi-footer__bottom-links-list"> <li class="ncbi-footer__bottom-list-item"> <a href="https://www.nlm.nih.gov/" class="usa-link usa-link--alt ncbi-footer__link" > NLM </a> </li> <li class="ncbi-footer__bottom-list-item"> <a href="https://www.nih.gov/" class="usa-link usa-link--alt ncbi-footer__link" > NIH </a> </li> <li class="ncbi-footer__bottom-list-item"> <a href="https://www.hhs.gov/" class="usa-link usa-link--external usa-link--alt ncbi-footer__link" rel="noreferrer noopener" target='_blank' > HHS </a> </li> <li class="ncbi-footer__bottom-list-item"> <a href="https://www.usa.gov/" class="usa-link usa-link--external usa-link--alt ncbi-footer__link" rel="noreferrer noopener" target='_blank' > USA.gov </a> </li> </ul> </div> </div> </footer> <script type="text/javascript" src="https://cdn.ncbi.nlm.nih.gov/core/pinger/pinger.js"> </script> <button class="back-to-top" data-ga-category="pagination" data-ga-action="back_to_top"> <label>Back to Top</label> <svg class="usa-icon order-0" aria-hidden="true" focusable="false" role="img"> <use xlink:href="/static/img/sprite.svg#arrow_upward"></use> </svg> </button> <script type="application/javascript"> window.ncbi = window.ncbi || {}; window.ncbi.pmc = window.ncbi.pmc || {}; window.ncbi.pmc.options = { logLevel: 'INFO', staticEndpoint: '/static/', citeCookieName: 'pmc-cf', }; </script> <script type="module" crossorigin="" src="/static/assets/base-6f05ef93.js"></script> <script type="text/javascript" src="https://cdn.ncbi.nlm.nih.gov/core/jquery/jquery-3.6.0.min.js"> </script> <script type="text/javascript"> jQuery.getScript("https://cdn.ncbi.nlm.nih.gov/core/alerts/alerts.js", function () { galert(['div.nav_and_browser', 'div.header', '#universal_header', '.usa-banner', 'body > *:nth-child(1)']) }); </script> <script type="text/javascript">var exports = {};</script> <script src="/static/CACHE/js/output.13b077bc3ffd.js"></script> <script type="module" crossorigin="" src="/static/assets/article-7a2c2b27.js"></script> </body> </html>

CINXE.COM

Diet during pregnancy and infancy and risk of allergic or autoimmune disease: A systematic review and meta-analysis - PMC