{"id":1047,"date":"2016-05-11T14:50:07","date_gmt":"2016-05-11T14:50:07","guid":{"rendered":"http:\/\/stg-blogs.bmj.com\/bmjebmspotlight\/?p=1047"},"modified":"2017-08-21T10:54:47","modified_gmt":"2017-08-21T10:54:47","slug":"primary-care-corner-with-geoffrey-modest-md-oral-fluconazole-in-pregnancy-and-spontaneous-abortion-fda-safety-alert","status":"publish","type":"post","link":"https:\/\/stg-blogs.bmj.com\/bmjebmspotlight\/2016\/05\/11\/primary-care-corner-with-geoffrey-modest-md-oral-fluconazole-in-pregnancy-and-spontaneous-abortion-fda-safety-alert\/","title":{"rendered":"Primary Care Corner with Geoffrey Modest MD: Oral Fluconazole in Pregnancy and Spontaneous Abortion: FDA Safety Alert"},"content":{"rendered":"<p><strong>By Dr. Geoffrey Modest<\/strong><\/p>\n<p>The FDA just posted a drug safety alert on the use of fluconazole in pregnancy (see\u00a0<a href=\"http:\/\/www.fda.gov\/downloads\/Drugs\/DrugSafety\/UCM497705.pdf\">http:\/\/www.fda.gov\/downloads\/Drugs\/DrugSafety\/UCM497705.pdf<\/a>\u00a0), based on a recent JAMA article (see Molgaar-Nielsen D. JAMA2016; 315: 58). Details of the JAMA study:<\/p>\n<ul>\n<li>A Danish nationwide registry-based cohort study from 1997-2013, of 1,405,663 pregnancies, looking at the association between\u00a0oral fluconazole use to treat\u00a0vaginal candidiasis during pregnancy and spontaneous abortion, and comparing that to use of topical azole antifungals<\/li>\n<li>Demographics:\u00a026% were\u00a0&lt;age\u00a025, 31% age 25-29, 27% 30-34, 13% 35-39; pretty even distribution of household income by quintiles, and pretty equal level of education<\/li>\n<\/ul>\n<p>Results:<\/p>\n<ul>\n<li>86% had cumulative dose of\u00a0fluconazole\u00a0of 150-300mg, first dose at\u00a0median\u00a069 days of gestation<\/li>\n<li>Of\u00a03315 women exposed to oral fluconazole from 7-23 weeks\u00a0gestation:\n<ul>\n<li>147 had a spontaneous abortion, a 48% increase over pregnancies matched on propensity score (a statistical technique used in analysis of observational\u00a0data\u00a0which attempts to match cases and controls by accounting for likely covariates\/confounders that\u00a0could affect the results, in this case including maternal age, calendar year, gestational age), with HR 1.48 (1.23-1.77)<\/li>\n<\/ul>\n<\/li>\n<li>Of\u00a05382 women exposed to fluconazole from week 7 to birth:\n<ul>\n<li>21 had stillbirth, a nonsignificant HR of 1.32 (0.82-2.14) [but pretty small number of events]<\/li>\n<\/ul>\n<\/li>\n<li>Use of topical azoles vs fluconazole:\n<ul>\n<li>130 of 2823 women given fluconazole vs 118 of 2823 on topical azoles had a spontaneous abortion, a 62% increase associated with fluconazole use, with HR\u00a01.62 (1.26-2.07)<\/li>\n<li>20 of 4301 women given fluconazole vs 22\u00a0of 4301\u00a0on topical azoles had a stillbirth, a nonsignificant HR 1.18 (0.64-2.16)<\/li>\n<\/ul>\n<\/li>\n<li>Further analysis of the spontaneous abortions (all numbers statistically significant):\n<ul>\n<li>32% increase within 2 weeks of taking fluconazole; 65% increase after 2 weeks<\/li>\n<li>32% increase in gestational week 7-10 (the vast\u00a0majority of fluconazole scripts were during this time period), though 90% in gestational weeks 11-22.<\/li>\n<li>No statistical difference between lower cumulative dose of fluconazole (150-300mg) vs higher dose (350-5600mg), though small numbers of women at those higher doses<\/li>\n<\/ul>\n<\/li>\n<\/ul>\n<p>So,<\/p>\n<ul>\n<li>The CDC had previously\u00a0recommended using topical antifungals\u00a0when treating pregnant women, even if needed\u00a0for longer periods of time than usual. However,\u00a0the FDA previously\u00a0suggested that there did not seem to be an increased risk of problems when women were exposed to a single 150mg dose of fluconazole. But given the above Danish study, theyposted a safety alert suggesting\u00a0&#8220;cautious prescribing of oral fluconazole in pregnancy&#8221; while they are completing their review.<\/li>\n<li>Vaginal\u00a0yeast infections are really common in pregnancy: about 10% of pregnant women get them.<\/li>\n<li>Although the 48% increase in spontaneous abortions seems large, I am told by statistician types that this level of increase in a retrospective study, even with attempts at propensity matching, may not be found to be\u00a0significant in a prospective randomized trial. For example, were the women with very severe vaginal candidiasis more likely to get the perhaps\u00a0bigger gun (oral fluconazole), but in fact\u00a0it really was the extensive candidiasis that caused the spontaneous abortion? Or potentially\u00a0T-cell dysfunction which led to the candidiasis and the spontaneous abortion???<\/li>\n<li>BUT, a few issues to support the FDA alert:\n<ul>\n<li>I really doubt there will ever be a formal RCT, since the event rate is small, the number of women needed to be involved would be huge, these are drugs off-patent so drug companies would have little\/no interest in paying the rather large cost of a study, and there are more pressing studies for the NIH to fund<\/li>\n<li>The study did suggest that the associationfound\u00a0with fluconazole is not found with the topical azoles<\/li>\n<li>And, probably in general, and especially in pregnancy, it probably is better to give topical\/local than systemic meds that go right into the blood stream, and then into the fetus<\/li>\n<\/ul>\n<\/li>\n<li>So, I think this probably should be a game-changer: to be safe, we should go with the topical azoles in pregnant women with yeast infections&#8230;<\/li>\n<li>And, as with all of these remarkable huge registry studies done in\u00a0many\u00a0western European\u00a0countries, we in the US stand out again for not having a coherent health care system with systematic registries looking at meds, outcomes, etc. And we do not have universal accessible\u00a0health care which would allow a registry to get reasonable data from the overall population&#8230;.<\/li>\n<\/ul>\n","protected":false},"excerpt":{"rendered":"<p>Primary Care Corner with Geoffrey Modest MD: Oral Fluconazole in Pregnancy and Spontaneous Abortion: FDA Safety Alert [&#8230;]<\/p>\n<p><a class=\"btn btn-secondary understrap-read-more-link\" href=\"https:\/\/stg-blogs.bmj.com\/bmjebmspotlight\/2016\/05\/11\/primary-care-corner-with-geoffrey-modest-md-oral-fluconazole-in-pregnancy-and-spontaneous-abortion-fda-safety-alert\/\">Read More&#8230;<\/a><\/p>\n","protected":false},"author":148,"featured_media":0,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"_jetpack_memberships_contains_paid_content":false,"footnotes":""},"categories":[14283],"tags":[],"class_list":["post-1047","post","type-post","status-publish","format-standard","hentry","category-archive"],"jetpack_featured_media_url":"","jetpack_sharing_enabled":true,"_links":{"self":[{"href":"https:\/\/stg-blogs.bmj.com\/bmjebmspotlight\/wp-json\/wp\/v2\/posts\/1047","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/stg-blogs.bmj.com\/bmjebmspotlight\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/stg-blogs.bmj.com\/bmjebmspotlight\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/stg-blogs.bmj.com\/bmjebmspotlight\/wp-json\/wp\/v2\/users\/148"}],"replies":[{"embeddable":true,"href":"https:\/\/stg-blogs.bmj.com\/bmjebmspotlight\/wp-json\/wp\/v2\/comments?post=1047"}],"version-history":[{"count":0,"href":"https:\/\/stg-blogs.bmj.com\/bmjebmspotlight\/wp-json\/wp\/v2\/posts\/1047\/revisions"}],"wp:attachment":[{"href":"https:\/\/stg-blogs.bmj.com\/bmjebmspotlight\/wp-json\/wp\/v2\/media?parent=1047"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/stg-blogs.bmj.com\/bmjebmspotlight\/wp-json\/wp\/v2\/categories?post=1047"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/stg-blogs.bmj.com\/bmjebmspotlight\/wp-json\/wp\/v2\/tags?post=1047"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}