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Women’s Health- pregnancy

Primary Care Corner with Geoffrey Modest MD: Oral Fluconazole in Pregnancy and Spontaneous Abortion: FDA Safety Alert

11 May, 16 | by EBM

By Dr. Geoffrey Modest

The FDA just posted a drug safety alert on the use of fluconazole in pregnancy (see http://www.fda.gov/downloads/Drugs/DrugSafety/UCM497705.pdf ), based on a recent JAMA article (see Molgaar-Nielsen D. JAMA2016; 315: 58). Details of the JAMA study:

  • A Danish nationwide registry-based cohort study from 1997-2013, of 1,405,663 pregnancies, looking at the association between oral fluconazole use to treat vaginal candidiasis during pregnancy and spontaneous abortion, and comparing that to use of topical azole antifungals
  • Demographics: 26% were <age 25, 31% age 25-29, 27% 30-34, 13% 35-39; pretty even distribution of household income by quintiles, and pretty equal level of education

Results:

  • 86% had cumulative dose of fluconazole of 150-300mg, first dose at median 69 days of gestation
  • Of 3315 women exposed to oral fluconazole from 7-23 weeks gestation:
    • 147 had a spontaneous abortion, a 48% increase over pregnancies matched on propensity score (a statistical technique used in analysis of observational data which attempts to match cases and controls by accounting for likely covariates/confounders that could affect the results, in this case including maternal age, calendar year, gestational age), with HR 1.48 (1.23-1.77)
  • Of 5382 women exposed to fluconazole from week 7 to birth:
    • 21 had stillbirth, a nonsignificant HR of 1.32 (0.82-2.14) [but pretty small number of events]
  • Use of topical azoles vs fluconazole:
    • 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 1.62 (1.26-2.07)
    • 20 of 4301 women given fluconazole vs 22 of 4301 on topical azoles had a stillbirth, a nonsignificant HR 1.18 (0.64-2.16)
  • Further analysis of the spontaneous abortions (all numbers statistically significant):
    • 32% increase within 2 weeks of taking fluconazole; 65% increase after 2 weeks
    • 32% increase in gestational week 7-10 (the vast majority of fluconazole scripts were during this time period), though 90% in gestational weeks 11-22.
    • 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

So,

  • The CDC had previously recommended using topical antifungals when treating pregnant women, even if needed for longer periods of time than usual. However, the FDA previously suggested 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 “cautious prescribing of oral fluconazole in pregnancy” while they are completing their review.
  • Vaginal yeast infections are really common in pregnancy: about 10% of pregnant women get them.
  • 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 significant in a prospective randomized trial. For example, were the women with very severe vaginal candidiasis more likely to get the perhaps bigger gun (oral fluconazole), but in fact it really was the extensive candidiasis that caused the spontaneous abortion? Or potentially T-cell dysfunction which led to the candidiasis and the spontaneous abortion???
  • BUT, a few issues to support the FDA alert:
    • 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
    • The study did suggest that the associationfound with fluconazole is not found with the topical azoles
    • 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
  • 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…
  • And, as with all of these remarkable huge registry studies done in many western European countries, 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 health care which would allow a registry to get reasonable data from the overall population….

Primary Care Corner with Geoffrey Modest MD: SSRI use in pregnancy and birth defects

29 Jul, 15 | by EBM

By: Dr. Geoffrey Modest

A recent case-control analysis from the National Center on Birth Defects compared women who had children with birth defects to those without, to assess the association of the birth defects with specific SSRIs (selective serotonin reuptake inhibitors) taken from the month before pregnancy and through the third month of pregnancy ​(see BMJ 2015;350:h3190​).

Untitled2

Details:

 –17952 mothers of infants with birth defects from US centers in 10 states were compared with 9857 who did not have infants with birth defects. they looked specifically at the birth defects previously reported to be associated with SSRIs, with data from the US National Birth Defects Prevention Study database. Excluded were mothers at higher risk for having children with birth defects for other reasons (diabetes, teratogenic drugs), or those not on SSRIs for psych conditions including depression, bipolar disorder, obsessive compulsive disorder.

–researchers looked at 5 SSRIs (citalopram, escitalopram, fluoxetine, paroxetine, and sertraline), controlling for maternal race/ethnicity, education, smoking and prepregnancy obesity.

Results:

–3.0% of mothers were on an SSRI (298 women)

–sertraline was the most commonly used SSRI (38.6% of controls), but there was no association with birth defects (assessed for the previously reported problems of anencephaly, septal defects, anal atresia, limb reduction, omphalocele)

–paroxetine (14.1% of controls) was associated with anencephaly [OR 3.2 (1.6-6.2)]; atrial septal defects [OR 1.8(1.1-3.0)]; right ventricular outflow tract obstruction defects [OR 2.4 (1.4-3.9)]; gastroschisis [OR 2.5 (1.2-4.8)]; and omphalocele [OR 3.5 (1.3-8.0)] (also assessed for previously reported hypospadias, cleft palate)

–fluoxetine (24.8% of controls) was associated with right ventricular outflow tract obstruction defects [OR 2.0 (1.4-3.1)] and craniosynostosis [OR 1.9 (1.1-3.0)] (also assessed for ventricular septal defects, esophageal atresia)

–citalopram (9.7% of controls) and escitalopram (8.7% of controls), no association with birth defects, except for marginal association between citalopram and neural tube defects [OR 1.8 (1.0-3.0)]. (citalopram also assessed for ventricular septal defects, cleft lip/palate, hypospadias; escitalopram assessed for septal defects)

So, this was a pretty large database, with presumably pretty thorough data collection, having a few conclusions (though should be confirmed in other large databases)

–Sertraline, which has evolved into being the most prescribed SSRI used in early pregnancy, seems to be pretty safe, not confirming any of the five previously reported birth defects

–Paroxetine should be avoided if possible. that being said, it is important to bear in mind that depression itself may have a significant morbidity an mortality (maternal and fetal), treating depression is very important and often needs meds, and one SSRI may work a lot better than others. so, the perspective here is that the likely very real  higher risk of fetal abnormalities that they found translates to pretty small absolute risks of anencephaly of 2-7/10,000; right ventricular outflow tract obstruction from 10-24/10,000 (assuming the associations are causal).

–The variability of the birth defect risks suggest that it risk is not intrinsic to the serotonin reuptake inhibition itself but to other structure or pharmacokinetic properties of the meds

–In terms of fetal effects of untreated maternal depression, there was a review and set of recommendations from the  American Psychiatric Association and the American College of Obstetricians and Gynecologists (see doi:10.1016/j.genhosppsych.2009.04.003​), with a few more recent studies. Overall,

–miscarriage rate: some suggestion in the literature of an association, but studies were small and methodologically limited. So, no clear-cut association.

–growth effects: some studies found increased risk of low-birth-weight and small-for-gestational-age infants, but again poor quality data. 2 more recent studies have found some evidence of decreased fetal weight gain and fetal growth restriction.  So, no clear-cut association.

–preterm delivery: again, overall not great studies. more recent ones have found modest effect in decreased breast-feeding and more preterm delivery.  So, no clear-cut association.

–neonatal effects: no clear association with congenital abnormalities. but more neonatal irritability, less activity and attentiveness, and fewer facial expressions; and, small studies have found increased blood cortisol levels and decreased dopamine and serotonin levels (as found in the depressed mothers), and greater neonatal right frontal EEG activation and lower vagal tone.

–longer-term effects: no data on mothers with Major Depressive Disorder (formally assessed), but instead in mothers with prenatal depressive symptoms, finding that kids at 18 months had greater developmental delay. other studies were less impressive.

Bottom line to me: good studies have not been done (that I know of) which assess pregnant women with Major Depressive Disorder (which is the group in the general population most responsive to SSRIs) and look at important maternal and fetal/childhood outcomes, including not just the “hard outcomes” of congenital abnormalities, in utero growth, preterm delivery, but also the short-term effects on the pregnant woman (coping skills, function, general sense of well-being) and the longer-term effects on the child (bonding, general assessment of function, happiness, developmental milestones, psychological effects, etc). In the meantime, I think it is important to treat depression in pregnancy, which may well include using medications (as well as support, counseling), and that the BMJ study provides reassurance that there are several antidepressants which are not associated with evident fetal congenital abnormalities, despite some reports to the contrary.

 

Primary Care Corner with Geoffrey Modest MD: New drug labeling for pregnancy and lactation FDA

10 Dec, 14 | by EBM

By: Dr. Geoffrey Modest

The FDA just came out with changes in labeling information regarding pregnancy and lactation on prescription drugs and biological products, replacing the old system of letter categories (A, B, C, D and X)​. These changes will go into effect June 30, 2015 (see FDA release).

In brief:

Untitled–The “pregnancy” subsection will provide information on the use of the drug in pregnant women (eg, dosing and potential risks to the fetus), and whether there is a registry collecting data on how pregnant women are affected by the drug.

–The “lactation” subsection will comment on the amount of drug in breast milk and potential effects on the breastfed child

–The “females and males of  reproductive potential” subsection  will include comments on the drug’s effect on pregnancy testing, contraception, and infertility

–Both the “pregnancy” and “lactation” subsections will include 3 subheadings: “risk summary”, “clinical considerations” and “data”, with information on human and animal data and specific adverse reactions of concern for pregnant of lactating females

 

 

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