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<meta name="description" content="There is evidence to suggest that hydroxyurea is effective in decreasing the frequency of pain episodes and other acute complications in adults and children with sickle cell anaemia of HbSS or HbSβºthal genotypes and in preventing life-threatening neurological events in those with sickle cell anaemi …"><meta name="keywords" content="pmid:28426137, PMC6478259, doi:10.1002/14651858.CD002202.pub2, Meta-Analysis, Review, Systematic Review, Sarah J Nevitt, Ashley P Jones, Jo Howard, Adult, Anemia, Sickle Cell / blood, Anemia, Sickle Cell / drug therapy*, Anemia, Sickle Cell / mortality, Antisickling Agents / adverse effects, Antisickling Agents / therapeutic use*, Chelation Therapy, Child, Erythrocyte Transfusion, Genotype, Hemoglobin SC Disease / blood, Hemoglobin SC Disease / drug therapy, Humans, Hydroxyurea / adverse effects, Hydroxyurea / therapeutic use*, Phlebotomy / adverse effects, Randomized Controlled Trials as Topic, Watchful Waiting, PubMed Abstract, NIH, NLM, NCBI, National Institutes of Health, National Center for Biotechnology Information, National Library of Medicine, MEDLINE"><meta name="robots" content="index,nofollow,noarchive"><meta property="og:title" content="Hydroxyurea (hydroxycarbamide) for sickle cell disease - PubMed"><meta property="og:url" content="https://pubmed.ncbi.nlm.nih.gov/28426137/"><meta property="og:description" content="There is evidence to suggest that hydroxyurea is effective in decreasing the frequency of pain episodes and other acute complications in adults and children with sickle cell anaemia of HbSS or HbSβºthal genotypes and in preventing life-threatening neurological events in those with sickle cell anaemi …"><meta property="og:image" content="https://cdn.ncbi.nlm.nih.gov/pubmed/persistent/pubmed-meta-image-v2.jpg"><meta property="og:image:secure_url" content="https://cdn.ncbi.nlm.nih.gov/pubmed/persistent/pubmed-meta-image-v2.jpg"><meta property="og:type" content="website"><meta property="og:site_name" content="PubMed"><meta name="twitter:domain" content="pubmed.ncbi.nlm.nih.gov"><meta name="twitter:card" content="summary_large_image"><meta name="twitter:title" content="Hydroxyurea (hydroxycarbamide) for sickle cell disease - PubMed"><meta name="twitter:url" content="https://pubmed.ncbi.nlm.nih.gov/28426137/"><meta name="twitter:description" content="There is evidence to suggest that hydroxyurea is effective in decreasing the frequency of pain episodes and other acute complications in adults and children with sickle cell anaemia of HbSS or HbSβºthal genotypes and in preventing life-threatening neurological events in those with sickle cell anaemi …"><meta name="twitter:image" content="https://cdn.ncbi.nlm.nih.gov/pubmed/persistent/pubmed-meta-image-v2.jpg">
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<label for="email-citation-format" class="action-panel-label">
Format:
</label>
<select id="email-citation-format" name="citation-format" class="action-panel-selector email-citation-format">
<option selected="selected" value="summary">Summary</option>
<option value="summary-text">Summary (text)</option>
<option value="abstract">Abstract</option>
<option value="abstract-text">Abstract (text)</option>
</select>
</div>
<div class="include-supplemental-container">
<input type="checkbox" aria-label="Include MeSH and other data" name="include-supplemental" id="email-include-supplemental" class="email-include-supplemental">
<label for="email-include-supplemental" class="email-include-supplemental-label">MeSH and other data</label>
</div>
<div class="form-field recaptcha ">
<div class="g-recaptcha" id="id-recaptcha" data-sitekey="6LfsWHMdAAAAAClKbtOpjQ2pMjgsGxvv7NdZW9uI"></div>
</div>
<div id="captcha-error-message" class="usa-input-error-message captcha-validation-message" role="alert"></div>
<div class="action-panel-actions">
<button class="action-panel-submit"
type="submit"
data-loading-label="Sending..."
data-ga-category="save_share"
data-ga-action="email"
data-ga-label="send">
Send email
</button>
<button class="action-panel-cancel"
aria-label="Close 'Email citations' panel"
ref="linksrc=close_email_panel"
aria-controls="email-action-panel"
aria-expanded="false"
data-ga-category="save_share"
data-ga-action="email"
data-ga-label="cancel">
Cancel
</button>
</div>
<input type="hidden" name="email-search-details" value="" />
<input type="hidden" name="email-search-details-hash" value="0e42663a6c3bd85498fcb88798998fed7bfdc45d457db35281e41afe13cc0524" />
</form>
</div>
</div>
<div id="collections-action-panel"
class="collections-action-panel action-panel in-progress-dots-panel"
aria-hidden="true"
data-collections-open-panel-enabled="false"
data-collections-open-panel-url-hash="#open-collections-panel">
<div class="inner-wrap">
<h3 class="action-panel-heading">
Add to Collections
</h3>
<form id="collections-action-panel-form"
class="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-get-article-ids-by-search-url="/get-article-ids-by-search/"
data-myncbi-max-collection-name-length="100"
data-add-to-collection-max-amount="1000"
data-collections-root-url="https://www.ncbi.nlm.nih.gov/myncbi/collections/">
<input type="hidden" name="csrfmiddlewaretoken" value="ndON4S6rNMdmw8X0NqkJYuUG02mpBUJAE0ySHIzNnn0Qqz3QqJXLsCqky64BuvhU">
<div class="choice-group" role="radiogroup">
<ul class="radio-group-items">
<li>
<input type="radio"
id="collections-action-panel-new"
class="collections-new"
name="collections"
value="new"
data-ga-category="save_share"
data-ga-action="collections"
data-ga-label="collections_radio_new">
<label for="collections-action-panel-new">Create a new collection</label>
</li>
<li>
<input type="radio"
id="collections-action-panel-existing"
class="collections-existing"
name="collections"
value="existing"
checked="true"
data-ga-category="save_share"
data-ga-action="collections"
data-ga-label="collections_radio_existing">
<label for="collections-action-panel-existing">Add to an existing collection</label>
</li>
</ul>
</div>
<div class="controls-wrapper">
<div class="action-panel-control-wrap new-collections-controls">
<label for="collections-action-panel-add-to-new" class="action-panel-label required-field-asterisk">
Name your collection:
</label>
<input
type="text"
name="add-to-new-collection"
id="collections-action-panel-add-to-new"
class="collections-action-add-to-new"
pattern="[^&quot;&amp;=&lt;&gt;\/]*" title="The following characters are not allowed in the Name field: &quot;&amp;=&lt;&gt;/"
maxlength="100"
data-ga-category="save_share"
data-ga-action="create_collection"
data-ga-label="non_favorties_collection">
<div class="collections-new-name-too-long usa-input-error-message selection-validation-message">
Name must be less than 100 characters
</div>
</div>
<div class="action-panel-control-wrap existing-collections-controls">
<label for="collections-action-panel-add-to-existing" class="action-panel-label">
Choose a collection:
</label>
<select id="collections-action-panel-add-to-existing"
class="action-panel-selector collections-action-add-to-existing"
data-ga-category="save_share"
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>
</div>
<div class="action-panel-actions">
<button class="action-panel-submit"
type="submit"
data-loading-label="Adding..."
data-pinger-ignore
data-ga-category="save_share"
data-ga-action="collections"
data-ga-label="add">
Add
</button>
<button class="action-panel-cancel"
aria-label="Close 'Add to Collections' panel"
ref="linksrc=close_collections_panel"
aria-controls="collections-action-panel"
aria-expanded="false"
data-ga-category="save_share"
data-ga-action="collections"
data-ga-label="cancel">
Cancel
</button>
</div>
</form>
</div>
</div>
<div id="bibliography-action-panel"
class="bibliography-action-panel action-panel in-progress-dots-panel"
aria-hidden="true"
data-bibliography-open-panel-enabled="false"
data-bibliography-open-panel-url-hash="#open-bibliography-panel">
<div class="inner-wrap">
<h3 class="action-panel-heading">
Add to My Bibliography
</h3>
<form id="bibliography-action-panel-form"
class="bibliography-action-panel-form action-panel-content action-form action-panel-smaller-selectors"
data-add-to-bibliography-max-amount="100"
data-add-to-bibliography-batch-size="10"
data-bibliography-delegates-url="/list-bibliography-delegates/"
data-add-to-bibliography-url="/add-to-bibliography/"
data-get-article-ids-by-search-url="/get-article-ids-by-search/"
data-mybib-root-url="https://www.ncbi.nlm.nih.gov/myncbi/collections/mybibliography/">
<input type="hidden" name="csrfmiddlewaretoken" value="ndON4S6rNMdmw8X0NqkJYuUG02mpBUJAE0ySHIzNnn0Qqz3QqJXLsCqky64BuvhU">
<div class="action-panel-control-wrap bibliographies-controls">
<div class="choice-group">
<ul class="bibliographies-action-add radio-group-items">
<li>
<input name="bibliography" id="my-bibliography" class="my-bibliography" type="radio" checked/>
<label for="my-bibliography">My Bibliography</label>
</li>
</ul>
</div>
</div>
<div class="bibliographies-retry-load-on-error usa-input-error-message selection-validation-message">
Unable to load your delegates due to an error<br>
<a href="#">Please try again</a>
</div>
<div class="action-panel-actions">
<button class="action-panel-submit"
type="submit"
data-loading-label="Adding..."
data-pinger-ignore>
Add
</button>
<button class="action-panel-cancel"
aria-label="Close 'Add to bibliography' panel"
ref="linksrc=close_bibliography_panel"
aria-controls="bibliography-action-panel"
aria-expanded="false"
data-ga-category="save_share"
data-ga-action="mybib"
data-ga-label="cancel">
Cancel
</button>
</div>
</form>
</div>
</div>
<div id="saved-search-action-panel" class="saved-search-action-panel action-panel " aria-hidden="true"
data-saved-search-open-panel-enabled="false"
data-saved-search-open-panel-url-hash="#open-saved-search-panel">
<div class="inner-wrap">
<h2 class="action-panel-heading">
Your saved search
</h2>
<form id="saved-search-action-panel-form"
class="saved-search-action-panel-form action-panel-content action-form"
data-create-saved-search-url="/create-saved-search/"
data-try-search-terms-url="/try-search-term/"
data-saved-search-root-url="https://www.ncbi.nlm.nih.gov/myncbi/searches/">
<input type="hidden" name="csrfmiddlewaretoken" value="ndON4S6rNMdmw8X0NqkJYuUG02mpBUJAE0ySHIzNnn0Qqz3QqJXLsCqky64BuvhU">
<div class="action-panel-control-wrap">
<label for="saved-search-name" class="action-panel-label saved-search-name-label required-field-asterisk">
Name of saved search:
</label>
<input maxlength="200"
type="text"
name="saved-search-name"
id="saved-search-name"
class="saved-search-name"
value=""
required
pattern="[^&quot;&amp;=&lt;&gt;\/]*" title="The following characters are not allowed in the Name field: &quot;&amp;=&lt;&gt;/">
</div>
<div class="action-panel-control-wrap">
<label for="saved-search-term" class="action-panel-label required-field-asterisk">
Search terms:
</label>
<textarea name="saved-search-term" id="saved-search-term" class="saved-search-term" required></textarea>
</div>
<div class="test-search-term-wrap">
<a href="#" class="try-search-term">Test search terms</a>
</div>
<div class="choice-group action-panel-extra-margin-top">
<span class="action-panel-label" id="fieldset-label">
Would you like email updates of new search results?
</span>
<fieldset id="saved-search-alert" aria-describedby="fieldset-label">
<legend class="usa-sr-only">Saved Search Alert Radio Buttons</legend>
<ul class="radio-group-items">
<li>
<input type="radio" id="saved-search-alert-yes" class="saved-search-alert-yes" name="saved-search-alert" value="yes" checked>
<label for="saved-search-alert-yes" class="action-panel-label">Yes</label>
</li>
<li>
<input aria-label="No radio input" type="radio" id="saved-search-alert-no" class="saved-search-alert-no" name="saved-search-alert" value="no">
<label for="saved-search-alert-no" class="action-panel-label">No</label>
</li>
</ul>
</fieldset>
</div>
<div class="alert-schedule-wrap">
<div class="action-panel-control-wrap">
<label class="action-panel-label">
Email:
</label>
<span aria-label="Email address" id="saved-search-email" class="action-panel-label"><span class="action-panel-label-bold"></span> (<a class="myncbi-account-settings" href="https://www.ncbi.nlm.nih.gov/account/settings/">change</a>)</span>
</div>
<div class="action-panel-control-wrap action-panel-extra-margin-top">
<label for="saved-search-frequency" class="action-panel-label">
Frequency:
</label>
<select id="saved-search-frequency" class="no-border-panel-selector saved-search-frequency">
<option value="monthly">Monthly</option>
<option value="weekly">Weekly</option>
<option value="daily">Daily</option>
</select>
</div>
<div class="action-panel-control-wrap saved-search-monthly-additional">
<label for="saved-search-monthly-on-day" class="action-panel-label">
Which day?
</label>
<select id="saved-search-monthly-on-day" class="no-border-panel-selector">
<option value="Sunday">The first Sunday</option>
<option value="Monday">The first Monday</option>
<option value="Tuesday">The first Tuesday</option>
<option value="Wednesday">The first Wednesday</option>
<option value="Thursday">The first Thursday</option>
<option value="Friday">The first Friday</option>
<option value="Saturday">The first Saturday</option>
<option value="day">The first day</option>
<option value="weekday">The first weekday</option>
</select>
</div>
<div class="action-panel-control-wrap saved-search-weekly-additional">
<label for="saved-search-weekly-on-day" class="action-panel-label">
Which day?
</label>
<select id="saved-search-weekly-on-day" class="no-border-panel-selector saved-search-weekly-on-day">
<option value="Sunday">Sunday</option>
<option value="Monday">Monday</option>
<option value="Tuesday">Tuesday</option>
<option value="Wednesday">Wednesday</option>
<option value="Thursday">Thursday</option>
<option value="Friday">Friday</option>
<option value="Saturday">Saturday</option>
</select>
</div>
<div class="action-panel-control-wrap">
<label for="saved-search-report" class="action-panel-label">
Report format:
</label>
<select id="saved-search-report" class="no-border-panel-selector saved-search-report">
<option value="DocSum">Summary</option>
<option value="DocSumText">Summary (text)</option>
<option value="Abstract">Abstract</option>
<option value="AbstractText">Abstract (text)</option>
<option value="MEDLINE">PubMed</option>
</select>
</div>
<div class="action-panel-control-wrap">
<label for="saved-search-amount" class="action-panel-label">
Send at most:
</label>
<select id="saved-search-amount" class="no-border-panel-selector saved-search-amount">
<option value="1">1 item</option>
<option value="5" selected>5 items</option>
<option value="10">10 items</option>
<option value="20">20 items</option>
<option value="50">50 items</option>
<option value="100">100 items</option>
<option value="200">200 items</option>
</select>
</div>
<div>
<input type="checkbox" id="saved-search-send-if-no-result" class="saved-search-send-if-no-result" name="saved-search-send-if-no-result">
<label for="saved-search-send-if-no-result" class="action-panel-label smaller-checkbox">
Send even when there aren't any new results
</label>
</div>
<div class="action-panel-control-wrap option-text-in-email-wrap">
<label for="saved-search-email-text" class="action-panel-label">
Optional text in email:
</label>
<textarea name="saved-search-email-text"
id="saved-search-email-text"
class="saved-search-email-text"></textarea>
</div>
</div>
<div class="action-panel-actions">
<button class="action-panel-submit"
type="submit"
data-loading-label="Saving..."
data-ga-category="save_share"
data-ga-action="alert"
data-ga-label="save">
Save
</button>
<button class="action-panel-cancel"
aria-label="Close 'Your saved search' panel"
ref="linksrc=close_saved_search_panel"
aria-controls="saved-search-action-panel"
aria-expanded="false"
data-ga-category="save_share"
data-ga-action="alert"
data-ga-label="cancel">
Cancel
</button>
</div>
</form>
</div>
</div>
<div id="citation-manager-action-panel" class="citation-manager-action-panel action-panel" aria-hidden="true">
<div class="inner-wrap">
<h2 class="action-panel-heading">
Create a file for external citation management software
</h2>
<form id="citation-manager-action-panel-form"
class="action-panel-content action-form"
action="/results-export-ids/"
data-by-search-action="/results-export-search-data/"
data-by-ids-action="/results-export-ids/"
method="post"
data-by-search-method="post"
data-by-ids-method="post">
<input type="hidden" name="csrfmiddlewaretoken" value="ndON4S6rNMdmw8X0NqkJYuUG02mpBUJAE0ySHIzNnn0Qqz3QqJXLsCqky64BuvhU">
<input name="results-format" type="hidden" value="pubmed"/>
<div class="action-panel-actions">
<button class="action-panel-submit"
type="submit"
data-loading-label="Sending..."
data-ga-category="save_share"
data-ga-action="citation_manager"
data-ga-label="save">
Create file
</button>
<button class="action-panel-cancel"
aria-label="Close 'Send citations to citation manager' panel"
ref="linksrc=close_citation_manager_panel"
aria-controls="citation-manager-action-panel"
aria-expanded="false"
data-ga-category="save_share"
data-ga-action="citation_manager"
data-ga-label="cancel">
Cancel
</button>
</div>
</form>
</div>
</div>
<div id="rss-action-panel" class="rss-action-panel action-panel " aria-hidden="true">
<div class="inner-wrap">
<h2 class="action-panel-heading">
Your RSS Feed
</h2>
<form id="rss-action-panel-form"
class="rss-action-panel-form action-panel-content action-form"
data-create-rss-feed-url="/create-rss-feed-url/"
data-search-form-term-value="">
<input type="hidden" name="csrfmiddlewaretoken" value="ndON4S6rNMdmw8X0NqkJYuUG02mpBUJAE0ySHIzNnn0Qqz3QqJXLsCqky64BuvhU">
<div class="action-panel-control-wrap">
<label for="rss-name" class="action-panel-label required-field-asterisk">
Name of RSS Feed:
</label>
<input maxlength="200"
placeholder="Name"
type="text"
name="rss-name"
id="rss-name"
class="rss-name"
value=''
required
pattern="[^&quot;&amp;=&lt;&gt;\/]*" title="The following characters are not allowed in the Name field: &quot;&amp;=&lt;&gt;/">
</div>
<div class="rss-limit-wrap">
<div class="action-panel-control-wrap action-panel-extra-margin-top">
<label for="rss-limit" class="action-panel-label">
Number of items displayed:
</label>
<select id="rss-limit" class="no-border-panel-selector rss-limit">
<option value="5">5</option>
<option value="10">10</option>
<option value="15" selected="selected">15</option>
<option value="20">20</option>
<option value="50">50</option>
<option value="100">100</option>
</select>
</div>
</div>
<div class="action-panel-actions">
<button class="action-panel-submit"
type="submit"
data-loading-label="Creating..."
data-ga-category="save_share"
data-ga-action="alert"
data-ga-label="save">
Create RSS
</button>
<button class="action-panel-cancel"
aria-label="Close 'Your RSS' panel"
ref="linksrc=close_rss_panel"
aria-controls="rss-action-panel"
aria-expanded="false"
data-ga-category="save_share"
data-ga-action="alert"
data-ga-label="cancel">
Cancel
</button>
</div>
<div class="action-panel-control-wrap rss-link-copy-wrap">
<label for="rss-link" class="usa-sr-only">RSS Link</label>
<input placeholder="Your RSS Feed Link" type="text" name="rss-link" id="rss-link" class="rss-link" title="RSS Link">
<button
type="button"
disabled
class="rss-link-copy-button disabled"
data-ga-category="save_share"
data-ga-action="rss"
data-ga-label="copy">
Copy
</button>
</div>
</form>
</div>
</div>
</div>
</div>
<div class="article-page" id="article-page" data-article-pmid="28426137">
<aside class="page-sidebar">
<div class="inner-wrap">
<div class="full-text-links">
<div class="full-view">
<h3 class="title">
Full text links
</h3>
<div class="full-text-links-list">
<a class="link-item
dialog-focus"
href="https://doi.org/10.1002/14651858.CD002202.pub2"
target="_blank"
rel="noopener"
ref="linksrc=fulltextorjournal_fulltext&amp;is_pmc=False&amp;PrId=3058&amp;itool=Abstract-def&amp;log$=linkouticon&amp;uid=28426137&amp;db=pubmed&amp;nlmid=100909747"
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Wiley
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pmc
"
href="https://pmc.ncbi.nlm.nih.gov/articles/pmid/28426137/"
target="_blank"
rel="noopener"
ref="linksrc=fulltextorjournal_fulltext&amp;is_pmc=True&amp;PrId=3494&amp;itool=Abstract-def&amp;log$=linkouticon&amp;uid=28426137&amp;db=pubmed&amp;nlmid=100909747"
title="Free full text at PubMed Central"
data-ga-category="full_text"
data-ga-action="PMC"
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Free PMC article
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</div>
<div class="short-view">
<a href="#" class="full-text-links-button full-text-links-dialog-trigger">
Full text links
</a>
</div>
</div>
<div class="actions-buttons sidebar"><h3 class="title">Actions</h3><div class="inner-wrap"><button class="citation-button citation-dialog-trigger"
aria-label="Open dialog with citation text in different styles"
data-ga-category="save_share"
data-ga-action="cite"
data-ga-label="open"
data-all-citations-url="/28426137/citations/"
data-citation-style="nlm"
data-pubmed-format-link="/28426137/export/"><span class="button-label">Cite</span></button><link type="text/css" href="ncbi-overlay-block/src/overlay-block.css"><div class="collections-button-container" data-article-id="28426137" data-article-db="pubmed"><button class="collections-button collections-dialog-trigger"
aria-label="Save article in MyNCBI collections."
data-ga-category="collections_button"
data-ga-action="click"
data-ga-label="collections_button"
data-collections-open-dialog-enabled="false"
data-collections-open-dialog-url="https://account.ncbi.nlm.nih.gov/?back_url=https%3A%2F%2Fpubmed.ncbi.nlm.nih.gov%2F28426137%2F%23open-collections-dialog"
data-in-collections="false"><span class="button-label">Collections</span></button><div class="overlay" role="dialog"><div id="collections-action-dialog"
class="dialog collections-dialog"
aria-hidden="true"><div class="title">Add to Collections</div><div class="collections-action-panel action-panel"><form id="collections-action-dialog-form"
class="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="ndON4S6rNMdmw8X0NqkJYuUG02mpBUJAE0ySHIzNnn0Qqz3QqJXLsCqky64BuvhU"><div class="choice-group" role="radiogroup"><ul class="radio-group-items"><li><input type="radio"
id="collections-action-dialog-new"
class="collections-new"
name="collections"
value="new"
data-ga-category="collections_button"
data-ga-action="click"
data-ga-label="collections_radio_new"><label for="collections-action-dialog-new">Create a new collection</label></li><li><input type="radio"
id="collections-action-dialog-existing"
class="collections-existing"
name="collections"
value="existing"
checked="true"
data-ga-category="collections_button"
data-ga-action="click"
data-ga-label="collections_radio_existing"><label for="collections-action-dialog-existing">Add to an existing collection</label></li></ul></div><div class="controls-wrapper"><div class="action-panel-control-wrap new-collections-controls"><label for="collections-action-dialog-add-to-new" class="action-panel-label required-field-asterisk">
Name your collection:
</label><input
type="text"
name="add-to-new-collection"
id="collections-action-dialog-add-to-new"
class="collections-action-add-to-new"
pattern="[^&quot;&amp;=&lt;&gt;\/]*" title="The following characters are not allowed in the Name field: &quot;&amp;=&lt;&gt;/"
maxlength="100"
data-ga-category="collections_button"
data-ga-action="create_collection"
data-ga-label="non_favorties_collection"><div class="collections-new-name-too-long usa-input-error-message selection-validation-message">
Name must be less than 100 characters
</div></div><div class="action-panel-control-wrap existing-collections-controls"><label for="collections-action-dialog-add-to-existing" class="action-panel-label">
Choose a collection:
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Hydroxyurea (hydroxycarbamide) for sickle cell disease.
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<span class="docsum-authors full-authors">Rankine-Mullings AE, Nevitt SJ.</span>
<span class="docsum-authors short-authors">Rankine-Mullings AE, et al.</span>
<span class="docsum-journal-citation full-journal-citation">Cochrane Database Syst Rev. 2022 Sep 1;9(9):CD002202. doi: 10.1002/14651858.CD002202.pub3.</span>
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Abstract
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<p>
<strong class="sub-title">
Background:
</strong>
Sickle cell disease (SCD) is one of the most common inherited diseases worldwide. It is associated with lifelong morbidity and a reduced life expectancy. Hydroxyurea (hydroxycarbamide), an oral chemotherapeutic drug, ameliorates some of the clinical problems of SCD, in particular that of pain, by raising fetal haemoglobin. This is an update of a previously published Cochrane Review.
</p>
<p>
<strong class="sub-title">
Objectives:
</strong>
To assess the effects of hydroxyurea therapy in people with SCD (all genotypes), of any age, regardless of setting.
</p>
<p>
<strong class="sub-title">
Search methods:
</strong>
We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Haemoglobinopathies Register, comprising of references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings. We also searched online trial registries.Date of the most recent search: 16 January 2017.
</p>
<p>
<strong class="sub-title">
Selection criteria:
</strong>
Randomised and quasi-randomised controlled trials, of one month or longer, comparing hydroxyurea with placebo, standard therapy or other interventions for people with SCD.
</p>
<p>
<strong class="sub-title">
Data collection and analysis:
</strong>
Authors independently assessed studies for inclusion, carried out data extraction and assessed the risk of bias.
</p>
<p>
<strong class="sub-title">
Main results:
</strong>
Seventeen studies were identified in the searches; eight randomised controlled trials were included, recruiting 899 adults and children with SCD (haemoglobin SS (HbSS), haemoglobin SC (HbSC) or haemoglobin Sβºthalassaemia (HbSβºthal) genotypes). Studies lasted from six to 30 months.Four studies (577 adults and children with HbSS or HbSβºthal) compared hydroxyurea to placebo; three recruited individuals with only severe disease and one recruited individuals with all disease severities. There were statistically significant improvements in terms of pain alteration (using measures such as pain crisis frequency, duration, intensity, hospital admissions and opoid use), measures of fetal haemoglobin and neutrophil counts and fewer occurrences of acute chest syndrome and blood transfusions in the hydroxyurea groups. There were no consistent statistically significant differences in terms of quality of life and adverse events (including serious or life-threatening events). Seven deaths occurred during the studies, but the rates by treatment group were not statistically significantly different.Two studies (254 children with HbSS or HbSβºthal also with risk of primary or secondary stroke) compared hydroxyurea and phlebotomy to transfusion and chelation; there were statistically significant improvements in terms of measures of fetal haemoglobin and neutrophil counts, but more occurrences of acute chest syndrome and infections in the hydroxyurea and phlebotomy group. There were no consistent statistically significant differences in terms of pain alteration and adverse events (including serious or life-threatening events). Two deaths occurred during the studies (one in a the hydroxyurea treatment arm and one in the control arm), but the rates by treatment group were not statistically significantly different. In the primary prevention study, no strokes occurred in either treatment group but in the secondary prevention study, seven strokes occurred in the hydroxyurea and phlebotomy group (none in the transfusion and chelation group) and the study was terminated early.The quality of the evidence for the above two comparisons was judged as moderate to low as the studies contributing to these comparisons were mostly large and well designed (and at low risk of bias); however evidence was limited and imprecise for some outcomes such as quality of life, deaths during the studies and adverse events and results are applicable only to individuals with HbSS and HbSβºthal genotypes.Of the remaining two studies, one (22 children with HbSS or HbSβºthal also at risk of stoke) compared hydroxyurea to observation; there were statistically significant improvements in terms of measures of fetal haemoglobin and neutrophil counts but no statistically significant differences in terms of adverse events (including serious or life-threatening events).The final study (44 adults and children with HbSC) compared treatment regimens with and without hydroxyurea - there was statistically significant improvement in terms of measures of fetal haemoglobin, but no statistically significant differences in terms of adverse events (including serious or life-threatening events). No participants died in either of these studies and other outcomes relevant to the review were not reported.The quality of the evidence for the above two comparisons was judged to be very low due to the limited number of participants, the lack of statistical power (as both studies were terminated early with approximately only 20% of their target sample size recruited) and the lack of applicability to all age groups and genotypes.
</p>
<p>
<strong class="sub-title">
Authors&#x27; conclusions:
</strong>
There is evidence to suggest that hydroxyurea is effective in decreasing the frequency of pain episodes and other acute complications in adults and children with sickle cell anaemia of HbSS or HbSβºthal genotypes and in preventing life-threatening neurological events in those with sickle cell anaemia at risk of primary stroke by maintaining transcranial doppler velocities. However, there is still insufficient evidence on the long-term benefits of hydroxyurea, particularly in preventing chronic complications of SCD, recommending a standard dose or dose escalation to maximum tolerated dose. There is also insufficient evidence about the long-term risks of hydroxyurea, including its effects on fertility and reproduction. Evidence is also limited on the effects of hydroxyurea on individuals with HbSC genotype. Future studies should be designed to address such uncertainties.
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Conflict of interest statement
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<p xmlns:xlink="http://www.w3.org/1999/xlink" xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:p1="http://pubmed.gov/pub-one">Sarah Nevitt: none known. Ashley Jones: none known. Jo Howard: no declarations in relation to the use of hydroxyurea. In general, has undertaken consultancy for Bluebird Bio; AesRx; and Global Blood Therapeutics. Her institution has the following grants: NIHR grant for the POMS trial (prevention of morbidity in SCD); and an NIH grant for natural history in stroke in SCD (pending).</p>
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<span class="docsum-authors full-authors">Davies S, Olujohungbe A.</span>
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References
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<h4 class="refs-list-title">References to studies included in this review</h4>
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<h5 class="refs-list-title">BABY HUG 2011 {published data only}</h5>
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Adams RJ, Barredo J, Bonds DR, Brown C, Casella J, Daner L, et al. TCD in infants: A report from the BABY HUG trial. Blood 2005;106(11). [Abstract no: 952]
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Adams RJ, Luden J, Miller S, Wang W, Rees R, Li D, et al. TCD in infants: a report from the Baby Hug study. 28th Annual Meeting of the National Sickle Cell Disease Program; 2005 Apr 9‐13; Cincinnati, Ohio. 2005:105.
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Alvarez O, Miller ST, Wang WC, Luo Z, McCarville MB, Schwartz GJ, et al. Effect of hydroxyurea treatment on renal function parameters: results from the multi‐center placebo‐controlled BABY HUG clinical trial for infants with sickle cell anemia. Pediatric Blood &amp; Cancer 2012;59(4):668‐74. [CENTRAL: 848700; CRS: 5500125000000525; PUBMED: 22294512]
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Armstrong FD, Elkin TD, Brown RC, Glass P, Rana S, Casella JF, et al. Developmental function in toddlers with sickle cell anemia. Pediatrics 2013;131(2):e406‐14. [CENTRAL: 853612; CRS: 5500125000000530; PUBMED: 23296434]
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Armstrong FD, Elkin TD, Brown RC, Glass P, Rees RC, Wang WC, et al. Neurodevelopment in infants with sickle cell anemia: baseline data from the Baby HUG trial. Blood 2008;112(11):713.
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<h5 class="refs-list-title">Belgian Study 1996 {published data only}</h5>
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Ferster A, Vermylen C, Cornu G, Buyse M, Corazza F, Devalck C, et al. Hydroxyurea for treatment of severe sickle cell anemia: a pediatric clinical trial. Blood 1996;88(6):1960‐4.
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<h5 class="refs-list-title">CHAMPS 2011 {published data only}</h5>
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Wang W, Brugnara C, Snyder C, Wynn L, Rogers Z, Kalinyak K, et al. The effects of hydroxycarbamide and magnesium on haemoglobin SC disease: results of the multi‐centre CHAMPS trial. British Journal of Haematology 2011;152(6):771‐6. [CENTRAL: 801819; CRS: 5500125000000521; PUBMED: 21275961]
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Wang WC, Snyder C, Brugnara C, Telen MJ, Steinberg MH, Wynn LW, et al. Effects of hydroxyurea (HU) and magnesium pidolate (Mg) in hemoglobin SC disease (HbSC): the "CHAMPS" trial. Blood 2009; Vol. 22. [Abstract no: 819]
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<h5 class="refs-list-title">Jain 2012 {published data only}</h5>
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Jain D. Low dose hydroxyurea in children severely affected with sickle cell disease: hospital based randomized controlled study. 4th Annual Sickle Cell Disease Research and Educational Symposium &amp; Grant Writing Institute AND Annual Sickle Cell Disease Scientific Meeting; 2010 Feb 14‐19; Hollywood, Florida. 2010. [Abstract no: 076]
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Jain DL, Sarathi V, Desai S, Bhatnagar M, Lodha A. Low fixed‐dose hydroxyurea in severely affected Indian children with sickle cell disease. Hemoglobin 2012;36(4):323‐32. [CENTRAL: 879848; CRS: 5500125000000522; PUBMED: 22734586]
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<h5 class="refs-list-title">MSH 1995 {published data only}</h5>
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Armstrong FD, Steinberg MH, Ballas SK, Ataga KI, Waclawiw MA, Kutlar A, et al. Development outcomes of offspring of adults treated with hydroxyurea in the multicenter study of hydroxyurea. Blood 2009, issue 22. [Abstract no: 1543]
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value="1">
Ballas SK, Barton F, Castro O, Bellevue R, Investigators of the multicenter study of hydroxyurea in sickle cell anemia. Narcotic analgesia use among adult patients with sickle cell anemia. Blood 1995;86(10 Suppl 1):642a.
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Ballas SK, Barton F, Castro O, Koshy M, Bellevue R. Pattern of narcotic analgesic consumption among adult patients with sickle cell anemia. National Sickle Cell Disease Program 21st Annual Meeting; 1996 Mar. 1996:63.
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Ballas SK, Barton FB, Waclawiw MA, Swerdlow P, Eckman JR, Pegelow CH, et al. Hydroxyurea and sickle cell anemia: effect on quality of life. Health and Quality of Life Outcomes 2006;4:59.
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Ballas SK, Bauserman RL, McCarthy WF, Castro OL, Smith WR, Waclawiw MA. Utilization of analgesics in the multicenter study of hydroxyurea in sickle cell anemia: Effect of sex,age, and geographical location. American Journal of Hematology 2010;85(8):613‐6.
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<h5 class="refs-list-title">SCATE 2015 {published data only}</h5>
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Hankins JS, McCarville MB, Rankine‐Mullings A, Reid ME, Lobo CL, Moura PG, et al. Prevention of conversion to abnormal transcranial Doppler with hydroxyurea in sickle cell anemia: a phase III international randomized clinical trial. American Journal of Hematology 2015;90(12):1099‐105. [DOI: ]
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NCT01531387. Sparing Conversion to Abnormal TCD (Transcranial Doppler) Elevation (SCATE). <a class="external-link-urlize" href="http://clinicaltrials.gov/show/NCT01531387" rel="nofollow noopener" target="_blank">http://clinicaltrials.gov/show/NCT01531387</a>.
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<h5 class="refs-list-title">SWiTCH 2012 {published data only}</h5>
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Alvarez O, Yovetich NA, Scott JP, Owen W, Miller ST, Schultz W, et al. Pain and other non‐neurological adverse events in children with sickle cell anemia and previous stroke who received hydroxyurea and phlebotomy or chronic transfusions and chelation: results from the SWiTCH clinical trial. American Journal of Hematology 2013;88(11):932‐8. [CENTRAL: 963136; CRS: 5500125000000520; PUBMED: 23861242]
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Aygun B, Mortier NA, Kesler K, Lockhart A, Schultz WH, Cohen AR, et al. Therapeutic phlebotomy is safe in children with sickle cell anaemia and can be effective treatment for transfusional iron overload. British Journal of Haematology 2015;169(2):262‐6. [CRS: 5500135000001418; PUBMED: 25612463]
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Aygun B, Mortier NA, Kesler K, Schultz WH, Alvarez OA, Rogers ZR, et al. Therapeutice phlebotomy in children with sickle cell anemia, stroke, and iron overload: the SWiTCH experience. 53rd ASH Annual Meeting and Exposition; 2011 Dec 10‐13; San Diego, California. 2011. [Abstract no: 1044]
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Kwiatkowski JL, Cohen AR, Garro J, Alvarez O, Nagasubramanian R, Sarnaik S, et al. Transfusional iron overload in children with sickle cell anemia on chronic transfusion therapy for secondary stroke prevention. American Journal of Hematology 2012;87(2):221‐3. [CENTRAL: 864015; CRS: 5500100000011226; PUBMED: 22120913]
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NCT00122980. Stroke with transfusions changing to hydroxyurea. <a class="external-link-urlize" href="http://clinicaltrials.gov/show/NCT00122980" rel="nofollow noopener" target="_blank">clinicaltrials.gov/show/NCT00122980</a> Date first received: 20 July 2005.
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<h5 class="refs-list-title">TWiTCH 2016 {published data only}</h5>
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Aygun B, Wruck LM, Schultz WH, Mueller BU, Brown C, Luchtman‐Jones L, et al. Chronic transfusion practices for prevention of primary stroke in children with sickle cell anemia and abnormal TCD velocities. American Journal of Hematology 2012;87(4):428‐30.
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Helton KJ, Roberts D, Schultz WH, Davis BR, Kalfa TA, Pressel SL, et al. Effects of chronic transfusion therapy on MRI and MRA in children with sickle cell anemia. Blood 2014;124(21):4052. [CENTRAL: 1261883; CRS: 5500135000001683]
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Imran H, Aygun B, Davis BR, Pressel SL, Herbert Schultz W, Jackson SM, et al. Effects of chronic transfusion therapy on transcranial doppler ultrasonography velocities in children with sickle cell anemia at risk for primary stroke: baseline findings from the Twitch trial. Blood 2014;124(21):87. [CENTRAL: 1261882; CRS: 5500135000001682]
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Ware RE, Davis BR, Schultz WH, Brown RC, Aygun B, Sarnaik S, et al. Hydroxycarbamide versus chronic transfusion for maintenance of transcranial doppler flow velocities in children with sickle cell anaemia—TCD With Transfusions Changing to Hydroxyurea (TWiTCH): a multicentre, open‐label, phase 3, non‐inferiority trial. Lancet 2016;387:661‐70.
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Wood JC, Cohen A, Aygun B, Imran H, Luchtman‐Jones L, Thompson. Extrahepatic iron deposition in chronically transfused children with sickle cell anemia‐ baseline findings from the Twitch trial. Blood 2013;122(21):2238. [CENTRAL: 1261881; CRS: 5500135000001681]
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<h5 class="refs-list-title">Al‐Nood 2011 {published data only}</h5>
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Al‐Nood HA, Al‐Khawlani MM, Al‐Akwa A. Fetal hemoglobin response to hydroxyurea in Yemeni sickle cell disease patients. Hemoglobin 2011, issue 1:13‐21.
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<h5 class="refs-list-title">De Montalembert 2006 {published data only}</h5>
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<li
class="skip-numbering"
value="1">
Montalembert M, Bachir D, Hulin A, Gimeno L, Mogenet A, Bresson JL, et al. A phase 1 pharmacokinetics (PK) study of hydroxyurea (HU) 1,000 mg coated breakable tablets and 500mg capsules in pediatric and adult patients with sickle cell disease. Blood 2005;106(11):Abst 3194. [Abstract no: 3194]
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<a
class="reference-link"
href="/0/"
ref="linksrc=references_link&amp;ordinalpos=1"
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PubMed
</a>
</li>
</ol>
</li>
<li>
<ol class="references-and-notes-list">
<li
class="skip-numbering"
value="1">
Montalembert M, Bachir D, Hulin A, Gimeno L, Mogenet A, Bresson JL, et al. Pharmacokinetics of hydroxyurea 1,000 mg coated breakable tablets and 500 mg capsules in pediatric and adult patients with sickle cell disease. Haematologica 2006;91(12):1685‐8.
-
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class="reference-link"
href="/17145606/"
ref="linksrc=references_link&amp;ordinalpos=1"
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PubMed
</a>
</li>
</ol>
</li>
</ol>
</div>
<div class="refs-list">
<h5 class="refs-list-title">George 2013 {published data only}</h5>
<ol id="top-references-list-13" class="references-list">
<li>
<ol class="references-and-notes-list">
<li
class="skip-numbering"
value="1">
George A, Aygun B, Mortier N, Sparreboom A, Ware R. A randomized controlled trial of a dose‐prediction equation to determine maximum tolerated dose of hydroxyurea in children with sickle cell anemia. Pediatric Blood &amp; Cancer 2013;60 Suppl. [Abstract no: 588; CENTRAL: 1007869; CRS: 5500050000000224; EMBASE: 71047876]
</li>
</ol>
</li>
</ol>
</div>
<div class="refs-list">
<h5 class="refs-list-title">NCT00004492 {published data only}</h5>
<ol id="top-references-list-14" class="references-list">
<li>
<ol class="references-and-notes-list">
<li
class="skip-numbering"
value="1">
NCT00004492. Phase I/II Randomized Study of Hydroxyurea With or Without Clotrimazole in Patients With Sickle Cell Anemia. <a class="external-link-urlize" href="https://clinicaltrials.gov/show/NCT00004492" rel="nofollow noopener" target="_blank">https://clinicaltrials.gov/show/NCT00004492</a>.
</li>
</ol>
</li>
</ol>
</div>
<div class="refs-list">
<h5 class="refs-list-title">NCT01848925 {published data only}</h5>
<ol id="top-references-list-15" class="references-list">
<li>
<ol class="references-and-notes-list">
<li
class="skip-numbering"
value="1">
NCT01848925. A Phase I Open‐label, Randomized, Safety and Efficacy Study of SANGUINATE™ at Two Doses Levels Versus Hydroxyurea in Sickle Cell Disease (SCD) Patients. <a class="external-link-urlize" href="http://clinicaltrials.gov/show/NCT01848925" rel="nofollow noopener" target="_blank">clinicaltrials.gov/show/NCT01848925</a> (date first received 23 April 2013).
</li>
</ol>
</li>
</ol>
</div>
<div class="refs-list">
<h5 class="refs-list-title">NCT01960413 {published data only}</h5>
<ol id="top-references-list-16" class="references-list">
<li>
<ol class="references-and-notes-list">
<li
class="skip-numbering"
value="1">
NCT01960413. Phase 2 Study of Montelukast for the Treatment of Sickle Cell Anemia. <a class="external-link-urlize" href="https://clinicaltrials.gov/show/NCT01960413" rel="nofollow noopener" target="_blank">https://clinicaltrials.gov/show/NCT01960413</a>.
</li>
</ol>
</li>
</ol>
</div>
<div class="refs-list">
<h5 class="refs-list-title">NCT02149537 {published data only}</h5>
<ol id="top-references-list-17" class="references-list">
<li>
<ol class="references-and-notes-list">
<li
class="skip-numbering"
value="1">
NCT02149537. Risk Stratification for Clinical Severity of Sickle Cell Disease in Nigeria and Assessment of Efficacy and Safety During Treatment With Hydroxyurea. <a class="external-link-urlize" href="https://clinicaltrials.gov/show/NCT02149537" rel="nofollow noopener" target="_blank">https://clinicaltrials.gov/show/NCT02149537</a>.
</li>
</ol>
</li>
</ol>
</div>
<div class="refs-list">
<h5 class="refs-list-title">Pushi 2000 {published data only}</h5>
<ol id="top-references-list-18" class="references-list">
<li>
<ol class="references-and-notes-list">
<li
class="skip-numbering"
value="1">
Pushi A. Hydroxyurea ameliorates importantly the clinical course of sickle cell disease reducing the frequency of painful crises. Hematology Journal 2000;1(Suppl. 1):34, Abstract no: 130.
</li>
</ol>
</li>
</ol>
</div>
<div class="refs-list">
<h5 class="refs-list-title">Silva‐Pinto 2007 {published data only}</h5>
<ol id="top-references-list-19" class="references-list">
<li>
<ol class="references-and-notes-list">
<li
class="skip-numbering"
value="1">
Silva‐Pinto AC, Carrara RC, Oliveira VC, Palma PV, Campos AD, Zago MA, et al. Hydroxyurea treatment of sickle cell diseases causes megaloblastic transformation of the bone marrow that is responsible for the increase of the mean corpuscular volume. Haematologica 2007;Suppl 1:298.
</li>
</ol>
</li>
</ol>
</div>
<div class="refs-list">
<h5 class="refs-list-title">Silva‐Pinto 2014 {published data only}</h5>
<ol id="top-references-list-20" class="references-list">
<li>
<ol class="references-and-notes-list">
<li
class="skip-numbering"
value="1">
Silva‐Pinto AC, Dias‐Carlos C, Saldanha‐Araujo F, Ferreira FI, Palma PV, Araujo AG, et al. Hydroxycarbamide modulates components involved in the regulation of adenosine levels in blood cells from sickle‐cell anemia patients. Annals of Hematology 2014;93(9):1457‐65. [CENTRAL: 1000846; CRS: 5500131000000084; JID:: 9107334; PUBMED: 24696091]
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<a
class="reference-link"
href="/24696091/"
ref="linksrc=references_link&amp;ordinalpos=1"
data-ga-category="reference"
data-ga-action="24696091"
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PubMed
</a>
</li>
</ol>
</li>
</ol>
</div>
<div class="refs-list">
<h5 class="refs-list-title">Vichinsky 2013 {published data only}</h5>
<ol id="top-references-list-21" class="references-list">
<li>
<ol class="references-and-notes-list">
<li
class="skip-numbering"
value="1">
Vichinsky E, Torres M, Glass J, Minniti CP, Barrette S, Habr D, et al. A randomized phase II study evaluating the efficacy and safety of deferasirox versus deferoxamine in patients with sickle cell disease (SCD0: 2‐year results including pharmacokinetics (PK) and safety of deferasirox with concomitant hydroxyurea therapy. Blood 2011;118(21). [Abstract no: 1082]
</li>
</ol>
</li>
<li>
<ol class="references-and-notes-list">
<li
class="skip-numbering"
value="1">
Vichinsky E, Torres M, Minniti CP, Barrette S, Habr D, Zhang Y, et al. Efficacy and safety of deferasirox compared with deferoxamine in sickle cell disease: two‐year results including pharmacokinetics and concomitant hydroxyurea. American Journal of Hematology 2013;88(12):1068‐73. [CRS: 5500125000000523; PUBMED: 23946212]
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<a
class="reference-link"
href="/23946212/"
ref="linksrc=references_link&amp;ordinalpos=1"
data-ga-category="reference"
data-ga-action="23946212"
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PubMed
</a>
</li>
</ol>
</li>
</ol>
</div>
<div class="refs-list">
<h5 class="refs-list-title">Voskaridou 2005 {published data only}</h5>
<ol id="top-references-list-22" class="references-list">
<li>
<ol class="references-and-notes-list">
<li
class="skip-numbering"
value="1">
Voskaridou E, Terpos E, Margeli A, Hantzi E, Meletis J, Papassotiriou I, et al. Renal dysfunction and osteodystrophy in patients with sickle cell thalassaemia under long‐term treatment with hydroxyurea. 10th Congress of the European Hematology Association; 2005 June 2‐5; Stockholm International Fairs, Sweden. 2005. [Abstract no: 0174]
</li>
</ol>
</li>
</ol>
</div>
</div>
<div class="refs-list">
<h4 class="refs-list-title">References to studies awaiting assessment</h4>
<div class="refs-list">
<h5 class="refs-list-title">Anyanwu 2016 {published data only}</h5>
<ol id="top-references-list-24" class="references-list">
<li>
<ol class="references-and-notes-list">
<li
class="skip-numbering"
value="1">
Anyanwu JN, Williams O, Sautter CL, Kasirye P, Hume H, Opoka RO, Latham T, Ndugwa C, Ware RE, John CC. Novel Use of Hydroxyurea in an African Region With Malaria: Protocol for a Randomized Controlled Clinical Trial. JMIR research protocols 2016;5(2):e110.
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<a
class="reference-link"
href="https://pmc.ncbi.nlm.nih.gov/articles/PMC4937184/"
ref="linksrc=references_link&amp;ordinalpos=1"
data-ga-category="reference"
data-ga-action="PMC4937184"
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PMC
</a>
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<a
class="reference-link"
href="/27339303/"
ref="linksrc=references_link&amp;ordinalpos=2"
data-ga-category="reference"
data-ga-action="27339303"
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PubMed
</a>
</li>
</ol>
</li>
</ol>
</div>
<div class="refs-list">
<h5 class="refs-list-title">NCT02560935 {published data only}</h5>
<ol id="top-references-list-25" class="references-list">
<li>
<ol class="references-and-notes-list">
<li
class="skip-numbering"
value="1">
NCT02560935. Primary Prevention of Stroke in Children With SCD in Sub‐Saharan Africa II (SPRING). <a class="external-link-urlize" href="http://clinicaltrials.gov/show/NCT02560935" rel="nofollow noopener" target="_blank">clinicaltrials.gov/show/NCT02560935</a> (first received 02 September 2015).
</li>
</ol>
</li>
</ol>
</div>
<div class="refs-list">
<h5 class="refs-list-title">NCT02675790 {published data only}</h5>
<ol id="top-references-list-26" class="references-list">
<li>
<ol class="references-and-notes-list">
<li
class="skip-numbering"
value="1">
NCT02675790. Low Dose Hydroxyurea for Secondary Stroke Prevention in Children With Sickle Cell Disease in Sub‐Saharan Africa (SPRINT). <a class="external-link-urlize" href="http://clinicaltrials.gov/ct2/show/NCT02675790" rel="nofollow noopener" target="_blank">clinicaltrials.gov/ct2/show/NCT02675790</a> (first received 08 January 2016).
</li>
</ol>
</li>
</ol>
</div>
</div>
<div class="refs-list">
<h4 class="refs-list-title">References to ongoing studies</h4>
<div class="refs-list">
<h5 class="refs-list-title">NCT01389024 {published data only}</h5>
<ol id="top-references-list-28" class="references-list">
<li>
<ol class="references-and-notes-list">
<li
class="skip-numbering"
value="1">
NCT01389024. Hydroxyurea to Prevent Brain Injury in Sickle Cell Disease (HUPrevent). <a class="external-link-urlize" href="http://clinicaltrials.gov/ct2/show/NCT01389024" rel="nofollow noopener" target="_blank">clinicaltrials.gov/ct2/show/NCT01389024</a> (first received 30 June 2011).
</li>
</ol>
</li>
</ol>
</div>
</div>
<div class="refs-list">
<h4 class="refs-list-title">Additional references</h4>
<div class="refs-list">
<h5 class="refs-list-title">Aumont 2015</h5>
<ol id="top-references-list-30" class="references-list">
<li>
<ol class="references-and-notes-list">
<li
class="skip-numbering"
value="1">
Aumont C, Driss F, Lazure T, Picard V, Creidy R, Botton S, et al. Myelodysplastic syndrome with clonal cytogenetic abnormalities followed by fatal erythroid leukemia after 14 years of exposure to hydroxyurea for sickle cell anemia. American Journal of Hematology 2015;90(7):E131‐2.
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href="/25801602/"
ref="linksrc=references_link&amp;ordinalpos=1"
data-ga-category="reference"
data-ga-action="25801602"
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PubMed
</a>
</li>
</ol>
</li>
</ol>
</div>
<div class="refs-list">
<h5 class="refs-list-title">Ballas 1996</h5>
<ol id="top-references-list-31" class="references-list">
<li>
<ol class="references-and-notes-list">
<li
class="skip-numbering"
value="1">
Ballas SK, Barton F, Castro O, Koshy M, Bellevue R. Pattern of narcotic analgesic consumption among adult patients with sickle cell anemia. National Sickle Cell Disease Program 21st Annual Meeting; 1996 Mar. 1996:63.
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<div class="refs-list">
<h5 class="refs-list-title">Ballas 2006</h5>
<ol id="top-references-list-32" class="references-list">
<li>
<ol class="references-and-notes-list">
<li
class="skip-numbering"
value="1">
Ballas SK, Barton FB, Waclawiw MA, Swerdlow P, Eckman JR, Pegelow CH, et al. Hydroxyurea and sickle cell anemia: effect on quality of life. Health and Quality of Life Outcomes 2006;4:59.
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ref="linksrc=references_link&amp;ordinalpos=1"
data-ga-category="reference"
data-ga-action="PMC1569824"
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PMC
</a>
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<a
class="reference-link"
href="/16942629/"
ref="linksrc=references_link&amp;ordinalpos=2"
data-ga-category="reference"
data-ga-action="16942629"
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PubMed
</a>
</li>
</ol>
</li>
</ol>
</div>
<div class="refs-list">
<h5 class="refs-list-title">Ballas 2009</h5>
<ol id="top-references-list-33" class="references-list">
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<ol class="references-and-notes-list">
<li
class="skip-numbering"
value="1">
Ballas SK, Guo N, DeCastro L, Bellevue R. Exposure to hydroxyurea and pregnancy outcomes in patients with sickle cell anemia. JAMA 2009;101(10):1046.
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PubMed
</a>
</li>
</ol>
</li>
</ol>
</div>
<div class="refs-list">
<h5 class="refs-list-title">Barton 1996</h5>
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<li
class="skip-numbering"
value="1">
Barton F, Terrin M, Moore R, McMahon RP, Charache S. Ascertainment of the primary end point in the Multicenter Study of Hydroxyrea in Sickle Cell Anemia (MSH). The MSH Investigators. Controlled Clinical Trials 1996;17:67S.
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data-ga-action="8925656"
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PubMed
</a>
</li>
</ol>
</li>
</ol>
</div>
<div class="refs-list">
<h5 class="refs-list-title">Baz 2012</h5>
<ol id="top-references-list-35" class="references-list">
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<li
class="skip-numbering"
value="1">
Baz W, Najfeld V, Yotsuya M, Talwar J, Terjanian T, Forte F. Development of myelodysplastic syndrome and acute myeloid leukemia 15 years after hydroxyurea use in a patient with sickle cell anemia. Clinical Medicine Insights. Oncology 2012;6:149‐52.
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PMC
</a>
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PubMed
</a>
</li>
</ol>
</li>
</ol>
</div>
<div class="refs-list">
<h5 class="refs-list-title">Berk 1995</h5>
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value="1">
Berk PD, Wasserman LR, Fruchtman SM, Goldberg JD. Treatment of polycythemia vera: a summary of clinical trials conducted by the Polycythemia Vera Study Group. In: Wasserman LR BP, Berlin NI editor(s). Polycythemia Vera and the Myeloproliferation Disorders. Philadelphia: W B Saunders, 1995:166‐94.
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<h5 class="refs-list-title">Bernaudin 2016</h5>
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class="skip-numbering"
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Bernaudin F, Verlhac S, Arnaud C, Kamdem A, Hau I, Leveillé E, et al. Long‐term treatment follow‐up of children with sickle cell disease monitored with abnormal transcranial Doppler velocities. Blood 2016;127(15):1814‐22. [10.1182/blood‐2015‐10‐675231. Epub 2016 Feb 5.]
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<h5 class="refs-list-title">Berthaut 2008</h5>
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class="skip-numbering"
value="1">
Berthaut I, Guignedoux G, Kirsch‐Noir F, Larouziere V, Ravel C, Bachir D, et al. Influence of sickle cell disease and treatment with hydroxyurea on sperm parameters and fertility of human males. Haematologica 2008;93(7):988‐93.
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<h5 class="refs-list-title">Brousseau 2010</h5>
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Brousseau DC, A Panepinto J, Nimmer M, Hoffmann RG. The number of people with sickle‐cell disease in the United States: national and state estimates. American journal of hematology 2010 Jan 1;85(1):77‐8.
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PubMed
</a>
</li>
</ol>
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</ol>
</div>
<div class="refs-list">
<h5 class="refs-list-title">Brozovic 1987</h5>
<ol id="top-references-list-40" class="references-list">
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<li
class="skip-numbering"
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Brozovic M, Davies SC. Management of sickle cell disease. Postgraduate Medical Journal 1987;63:605‐9.
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PMC
</a>
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PubMed
</a>
</li>
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</li>
</ol>
</div>
<div class="refs-list">
<h5 class="refs-list-title">Chakravorty 2015</h5>
<ol id="top-references-list-41" class="references-list">
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<ol class="references-and-notes-list">
<li
class="skip-numbering"
value="1">
Chakravorty S, Williams TN. Sickle cell disease: a neglected chronic disease of increasing global health importance. Archives of Disease in Childhood 2015;100(1):48‐53.
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PMC
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PubMed
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</li>
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</div>
<div class="refs-list">
<h5 class="refs-list-title">Charache 1995</h5>
<ol id="top-references-list-42" class="references-list">
<li>
<ol class="references-and-notes-list">
<li
class="skip-numbering"
value="1">
Charache S, Terrin TL, Moore RD, Dover GJ, Barton FB, Eckert SV, et al. Effect of hydroxyurea on the frequency of painful crises in sickle cell anaemia. New England Journal of Medicine 1995;332:1317‐22.
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PubMed
</a>
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</ol>
</li>
</ol>
</div>
<div class="refs-list">
<h5 class="refs-list-title">Davies 1997a</h5>
<ol id="top-references-list-43" class="references-list">
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<li
class="skip-numbering"
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Davies SC, Roberts‐Harewood M. Blood transfusion in sickle cell disease. Blood Reviews 1997;11:57‐71.
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<div class="refs-list">
<h5 class="refs-list-title">Davies 1997b</h5>
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Davies SC, Oni L. The management of patients with sickle cell disease. British Medical Journal 1997;315:656‐60.
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PMC
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PubMed
</a>
</li>
</ol>
</li>
</ol>
</div>
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