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A 25-year-old woman who is 16 weeks pregnant with her first child is experiencing increased vaginal discharge associated with vaginal itching. A microscopic examination of the discharge confirms your suspicions of vaginal candidiasis. Is oral fluconazole or a topical azole your treatment of choice?
Because of the increased production of sex hormones, vaginal candidiasis is common during pregnancy, affecting up to 10% of pregnant women in the United States.1,2 Treatment options include oral fluconazole and a variety of topical azoles. Although the latter are recommended as firstline therapy, the ease of oral therapy makes it an attractive option.3,4
However, the safety of oral fluconazole during pregnancy has recently come under scrutiny. Case reports have linked high-dose use with congenital malformation.5,6 These case reports led to epidemiologic studies in which no such association was found.7,8
A large cohort study involving 1,079 fluconazole-exposed pregnancies and 170,453 unexposed pregnancies found no increased risk for congenital malformation or stillbirth; rates of spontaneous abortion and miscarriage were not evaluated.9 A prospective cohort study of 226 pregnant women found no association between fluconazole use during the first trimester and miscarriage.10 However, the validity of both studies’ findings was limited by small numbers of participants.
The current study is the largest to date to evaluate whether use of fluconazole in early pregnancy is associated with increased rates of spontaneous abortion and stillbirth, compared to topical azoles.
STUDY SUMMARY
Increased risk for miscarriage, but not stillbirth
This nationwide cohort study, conducted using the Medical Birth Register in Denmark, evaluated more than 1.4 million pregnancies occurring from 1997 to 2013 for exposure to oral fluconazole between 7 and 22 weeks’ gestation. Each oral fluconazole–exposed pregnancy was matched with up to four unexposed pregnancies (based on propensity score, maternal age, calendar year, and gestational age) and to pregnancies exposed to intravaginal formulations of topical azoles. Exposure to fluconazole was documented by filled prescriptions from the National Prescription Register. Primary outcomes were rates of spontaneous abortion (loss before 22 weeks) and stillbirth (loss after 23 weeks).
Rates of spontaneous abortion. Of the total cohort, 3,315 pregnancies were exposed to oral fluconazole between 7 and 22 weeks’ gestation. Spontaneous abortion occurred in 147 of these pregnancies and in 563 of 13,246 unexposed, matched pregnancies (hazard ratio [HR], 1.48).
Rates of stillbirth. Of 5,382 pregnancies exposed to fluconazole from week 7 to birth, 21 resulted in stillbirth; 77 stillbirths occurred in the 21,506 unexposed matched pregnancies (HR, 1.32). In a sensitivity analysis, however, higher doses of fluconazole (350 mg) were four times more likely than lower doses (150 mg) to be associated with stillbirth (HRs, 4.10 and 0.99, respectively).
Oral fluconazole vs topical azole. Use of oral fluconazole in pregnancy was associated with an increased risk for spontaneous abortion, compared to topical azole use (130 of 2,823 pregnancies vs 118 of 2,823 pregnancies; HR, 1.62)—but not an increased risk for stillbirth (20 of 4,301 pregnancies vs 22 of 4,301 pregnancies; HR, 1.18).
WHAT'S NEW
A sizeable study with a treatment comparison
The authors found that exposure in early pregnancy to oral fluconazole, as compared to topical azoles, increases the risk for spontaneous abortion. By comparing treatments in a sensitivity analysis, the researchers were able to eliminate Candida infections causing spontaneous abortion as a confounding factor. In addition, this study challenges the balance between ease of use and safety.
CAVEATS
A skewed population?
This cohort study using a Danish hospital registry may not be generalizable to a larger, non-Scandinavian population. Those not seeking care through a hospital were likely missed; if those seeking care through the hospital had a higher risk for abortion, the results could be biased. However, this would not have affected the results of the comparison between the two active treatments.
In addition, the study focused on women exposed from 7 to 22 weeks’ gestation; the findings may not be generalizable to fluconazole exposure prior to 7 weeks. Likewise, the registry is unlikely to capture very early spontaneous abortions that are not recognized clinically.
In all, given the large sample size and the care taken to match each exposed pregnancy with up to four unexposed pregnancies, these limitations likely had little influence on the overall findings.
CHALLENGES TO IMPLEMENTATION
Balancing ease of use with safety
Given the ease of using oral fluconazole, compared with daily topical azole therapy, many clinicians and patients may still opt for oral treatment.
ACKNOWLEDGEMENT
The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.
Copyright © 2016. The Family Physicians Inquiries Network. All rights reserved.
Reprinted with permission from the Family Physicians Inquiries Network and The Journal of Family Practice. 2016;65(9):624-626.
1. Mølgaard-Nielsen D, Svanström H, Melbye M, et al. Association between use of oral fluconazole during pregnancy and risk of spontaneous abortion and stillbirth. JAMA. 2016;315:58-67.
2. Cotch MF, Hillier SL, Gibbs RS, et al; Vaginal Infections and Prematurity Study Group. Epidemiology and outcomes associated with moderate to heavy Candida colonization during pregnancy. Am J Obstet Gynecol. 1998;178:374-380.
3. Workowski KA, Bolan GA, Centers for Disease Control and Prevention. Sexually transmitted diseases treatment guidelines, 2015. MMWR Recomm Rep. 2015;64:1-137.
4. Tooley PJ. Patient and doctor preferences in the treatment of vaginal candidiasis. Practitioner. 1985;229:655-660.
5. Aleck KA, Bartley DL. Multiple malformation syndrome following fluconazole use in pregnancy: report of an additional patient. Am J Med Genet. 1997;72:253-256.
6. Lee BE, Feinberg M, Abraham JJ, et al. Congenital malformations in an infant born to a woman treated with fluconazole. Pediatr Infect Dis J. 1992;11:1062-1064.
7. Jick SS. Pregnancy outcomes after maternal exposure to fluconazole. Pharmacotherapy. 1999;19:221-222.
8. Mølgaard-Nielsen D, Pasternak B, Hviid A. Use of oral fluconazole during pregnancy and the risk of birth defects. N Engl J Med. 2013;369:830-839.
9. Nørgaard M, Pedersen L, Gislum M, et al. Maternal use of fluconazole and risk of congenital malformations: a Danish population-based cohort study. J Antimicrob Chemother. 2008;62:172-176.
10. Mastroiacovo P, Mazzone T, Botto LD, et al. Prospective assessment of pregnancy outcomes after first-trimester exposure to fluconazole. Am J Obstet Gynecol. 1996;175:1645-1650.
A 25-year-old woman who is 16 weeks pregnant with her first child is experiencing increased vaginal discharge associated with vaginal itching. A microscopic examination of the discharge confirms your suspicions of vaginal candidiasis. Is oral fluconazole or a topical azole your treatment of choice?
Because of the increased production of sex hormones, vaginal candidiasis is common during pregnancy, affecting up to 10% of pregnant women in the United States.1,2 Treatment options include oral fluconazole and a variety of topical azoles. Although the latter are recommended as firstline therapy, the ease of oral therapy makes it an attractive option.3,4
However, the safety of oral fluconazole during pregnancy has recently come under scrutiny. Case reports have linked high-dose use with congenital malformation.5,6 These case reports led to epidemiologic studies in which no such association was found.7,8
A large cohort study involving 1,079 fluconazole-exposed pregnancies and 170,453 unexposed pregnancies found no increased risk for congenital malformation or stillbirth; rates of spontaneous abortion and miscarriage were not evaluated.9 A prospective cohort study of 226 pregnant women found no association between fluconazole use during the first trimester and miscarriage.10 However, the validity of both studies’ findings was limited by small numbers of participants.
The current study is the largest to date to evaluate whether use of fluconazole in early pregnancy is associated with increased rates of spontaneous abortion and stillbirth, compared to topical azoles.
STUDY SUMMARY
Increased risk for miscarriage, but not stillbirth
This nationwide cohort study, conducted using the Medical Birth Register in Denmark, evaluated more than 1.4 million pregnancies occurring from 1997 to 2013 for exposure to oral fluconazole between 7 and 22 weeks’ gestation. Each oral fluconazole–exposed pregnancy was matched with up to four unexposed pregnancies (based on propensity score, maternal age, calendar year, and gestational age) and to pregnancies exposed to intravaginal formulations of topical azoles. Exposure to fluconazole was documented by filled prescriptions from the National Prescription Register. Primary outcomes were rates of spontaneous abortion (loss before 22 weeks) and stillbirth (loss after 23 weeks).
Rates of spontaneous abortion. Of the total cohort, 3,315 pregnancies were exposed to oral fluconazole between 7 and 22 weeks’ gestation. Spontaneous abortion occurred in 147 of these pregnancies and in 563 of 13,246 unexposed, matched pregnancies (hazard ratio [HR], 1.48).
Rates of stillbirth. Of 5,382 pregnancies exposed to fluconazole from week 7 to birth, 21 resulted in stillbirth; 77 stillbirths occurred in the 21,506 unexposed matched pregnancies (HR, 1.32). In a sensitivity analysis, however, higher doses of fluconazole (350 mg) were four times more likely than lower doses (150 mg) to be associated with stillbirth (HRs, 4.10 and 0.99, respectively).
Oral fluconazole vs topical azole. Use of oral fluconazole in pregnancy was associated with an increased risk for spontaneous abortion, compared to topical azole use (130 of 2,823 pregnancies vs 118 of 2,823 pregnancies; HR, 1.62)—but not an increased risk for stillbirth (20 of 4,301 pregnancies vs 22 of 4,301 pregnancies; HR, 1.18).
WHAT'S NEW
A sizeable study with a treatment comparison
The authors found that exposure in early pregnancy to oral fluconazole, as compared to topical azoles, increases the risk for spontaneous abortion. By comparing treatments in a sensitivity analysis, the researchers were able to eliminate Candida infections causing spontaneous abortion as a confounding factor. In addition, this study challenges the balance between ease of use and safety.
CAVEATS
A skewed population?
This cohort study using a Danish hospital registry may not be generalizable to a larger, non-Scandinavian population. Those not seeking care through a hospital were likely missed; if those seeking care through the hospital had a higher risk for abortion, the results could be biased. However, this would not have affected the results of the comparison between the two active treatments.
In addition, the study focused on women exposed from 7 to 22 weeks’ gestation; the findings may not be generalizable to fluconazole exposure prior to 7 weeks. Likewise, the registry is unlikely to capture very early spontaneous abortions that are not recognized clinically.
In all, given the large sample size and the care taken to match each exposed pregnancy with up to four unexposed pregnancies, these limitations likely had little influence on the overall findings.
CHALLENGES TO IMPLEMENTATION
Balancing ease of use with safety
Given the ease of using oral fluconazole, compared with daily topical azole therapy, many clinicians and patients may still opt for oral treatment.
ACKNOWLEDGEMENT
The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.
Copyright © 2016. The Family Physicians Inquiries Network. All rights reserved.
Reprinted with permission from the Family Physicians Inquiries Network and The Journal of Family Practice. 2016;65(9):624-626.
A 25-year-old woman who is 16 weeks pregnant with her first child is experiencing increased vaginal discharge associated with vaginal itching. A microscopic examination of the discharge confirms your suspicions of vaginal candidiasis. Is oral fluconazole or a topical azole your treatment of choice?
Because of the increased production of sex hormones, vaginal candidiasis is common during pregnancy, affecting up to 10% of pregnant women in the United States.1,2 Treatment options include oral fluconazole and a variety of topical azoles. Although the latter are recommended as firstline therapy, the ease of oral therapy makes it an attractive option.3,4
However, the safety of oral fluconazole during pregnancy has recently come under scrutiny. Case reports have linked high-dose use with congenital malformation.5,6 These case reports led to epidemiologic studies in which no such association was found.7,8
A large cohort study involving 1,079 fluconazole-exposed pregnancies and 170,453 unexposed pregnancies found no increased risk for congenital malformation or stillbirth; rates of spontaneous abortion and miscarriage were not evaluated.9 A prospective cohort study of 226 pregnant women found no association between fluconazole use during the first trimester and miscarriage.10 However, the validity of both studies’ findings was limited by small numbers of participants.
The current study is the largest to date to evaluate whether use of fluconazole in early pregnancy is associated with increased rates of spontaneous abortion and stillbirth, compared to topical azoles.
STUDY SUMMARY
Increased risk for miscarriage, but not stillbirth
This nationwide cohort study, conducted using the Medical Birth Register in Denmark, evaluated more than 1.4 million pregnancies occurring from 1997 to 2013 for exposure to oral fluconazole between 7 and 22 weeks’ gestation. Each oral fluconazole–exposed pregnancy was matched with up to four unexposed pregnancies (based on propensity score, maternal age, calendar year, and gestational age) and to pregnancies exposed to intravaginal formulations of topical azoles. Exposure to fluconazole was documented by filled prescriptions from the National Prescription Register. Primary outcomes were rates of spontaneous abortion (loss before 22 weeks) and stillbirth (loss after 23 weeks).
Rates of spontaneous abortion. Of the total cohort, 3,315 pregnancies were exposed to oral fluconazole between 7 and 22 weeks’ gestation. Spontaneous abortion occurred in 147 of these pregnancies and in 563 of 13,246 unexposed, matched pregnancies (hazard ratio [HR], 1.48).
Rates of stillbirth. Of 5,382 pregnancies exposed to fluconazole from week 7 to birth, 21 resulted in stillbirth; 77 stillbirths occurred in the 21,506 unexposed matched pregnancies (HR, 1.32). In a sensitivity analysis, however, higher doses of fluconazole (350 mg) were four times more likely than lower doses (150 mg) to be associated with stillbirth (HRs, 4.10 and 0.99, respectively).
Oral fluconazole vs topical azole. Use of oral fluconazole in pregnancy was associated with an increased risk for spontaneous abortion, compared to topical azole use (130 of 2,823 pregnancies vs 118 of 2,823 pregnancies; HR, 1.62)—but not an increased risk for stillbirth (20 of 4,301 pregnancies vs 22 of 4,301 pregnancies; HR, 1.18).
WHAT'S NEW
A sizeable study with a treatment comparison
The authors found that exposure in early pregnancy to oral fluconazole, as compared to topical azoles, increases the risk for spontaneous abortion. By comparing treatments in a sensitivity analysis, the researchers were able to eliminate Candida infections causing spontaneous abortion as a confounding factor. In addition, this study challenges the balance between ease of use and safety.
CAVEATS
A skewed population?
This cohort study using a Danish hospital registry may not be generalizable to a larger, non-Scandinavian population. Those not seeking care through a hospital were likely missed; if those seeking care through the hospital had a higher risk for abortion, the results could be biased. However, this would not have affected the results of the comparison between the two active treatments.
In addition, the study focused on women exposed from 7 to 22 weeks’ gestation; the findings may not be generalizable to fluconazole exposure prior to 7 weeks. Likewise, the registry is unlikely to capture very early spontaneous abortions that are not recognized clinically.
In all, given the large sample size and the care taken to match each exposed pregnancy with up to four unexposed pregnancies, these limitations likely had little influence on the overall findings.
CHALLENGES TO IMPLEMENTATION
Balancing ease of use with safety
Given the ease of using oral fluconazole, compared with daily topical azole therapy, many clinicians and patients may still opt for oral treatment.
ACKNOWLEDGEMENT
The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.
Copyright © 2016. The Family Physicians Inquiries Network. All rights reserved.
Reprinted with permission from the Family Physicians Inquiries Network and The Journal of Family Practice. 2016;65(9):624-626.
1. Mølgaard-Nielsen D, Svanström H, Melbye M, et al. Association between use of oral fluconazole during pregnancy and risk of spontaneous abortion and stillbirth. JAMA. 2016;315:58-67.
2. Cotch MF, Hillier SL, Gibbs RS, et al; Vaginal Infections and Prematurity Study Group. Epidemiology and outcomes associated with moderate to heavy Candida colonization during pregnancy. Am J Obstet Gynecol. 1998;178:374-380.
3. Workowski KA, Bolan GA, Centers for Disease Control and Prevention. Sexually transmitted diseases treatment guidelines, 2015. MMWR Recomm Rep. 2015;64:1-137.
4. Tooley PJ. Patient and doctor preferences in the treatment of vaginal candidiasis. Practitioner. 1985;229:655-660.
5. Aleck KA, Bartley DL. Multiple malformation syndrome following fluconazole use in pregnancy: report of an additional patient. Am J Med Genet. 1997;72:253-256.
6. Lee BE, Feinberg M, Abraham JJ, et al. Congenital malformations in an infant born to a woman treated with fluconazole. Pediatr Infect Dis J. 1992;11:1062-1064.
7. Jick SS. Pregnancy outcomes after maternal exposure to fluconazole. Pharmacotherapy. 1999;19:221-222.
8. Mølgaard-Nielsen D, Pasternak B, Hviid A. Use of oral fluconazole during pregnancy and the risk of birth defects. N Engl J Med. 2013;369:830-839.
9. Nørgaard M, Pedersen L, Gislum M, et al. Maternal use of fluconazole and risk of congenital malformations: a Danish population-based cohort study. J Antimicrob Chemother. 2008;62:172-176.
10. Mastroiacovo P, Mazzone T, Botto LD, et al. Prospective assessment of pregnancy outcomes after first-trimester exposure to fluconazole. Am J Obstet Gynecol. 1996;175:1645-1650.
1. Mølgaard-Nielsen D, Svanström H, Melbye M, et al. Association between use of oral fluconazole during pregnancy and risk of spontaneous abortion and stillbirth. JAMA. 2016;315:58-67.
2. Cotch MF, Hillier SL, Gibbs RS, et al; Vaginal Infections and Prematurity Study Group. Epidemiology and outcomes associated with moderate to heavy Candida colonization during pregnancy. Am J Obstet Gynecol. 1998;178:374-380.
3. Workowski KA, Bolan GA, Centers for Disease Control and Prevention. Sexually transmitted diseases treatment guidelines, 2015. MMWR Recomm Rep. 2015;64:1-137.
4. Tooley PJ. Patient and doctor preferences in the treatment of vaginal candidiasis. Practitioner. 1985;229:655-660.
5. Aleck KA, Bartley DL. Multiple malformation syndrome following fluconazole use in pregnancy: report of an additional patient. Am J Med Genet. 1997;72:253-256.
6. Lee BE, Feinberg M, Abraham JJ, et al. Congenital malformations in an infant born to a woman treated with fluconazole. Pediatr Infect Dis J. 1992;11:1062-1064.
7. Jick SS. Pregnancy outcomes after maternal exposure to fluconazole. Pharmacotherapy. 1999;19:221-222.
8. Mølgaard-Nielsen D, Pasternak B, Hviid A. Use of oral fluconazole during pregnancy and the risk of birth defects. N Engl J Med. 2013;369:830-839.
9. Nørgaard M, Pedersen L, Gislum M, et al. Maternal use of fluconazole and risk of congenital malformations: a Danish population-based cohort study. J Antimicrob Chemother. 2008;62:172-176.
10. Mastroiacovo P, Mazzone T, Botto LD, et al. Prospective assessment of pregnancy outcomes after first-trimester exposure to fluconazole. Am J Obstet Gynecol. 1996;175:1645-1650.