Use of Oral Fluconazole during Pregnancy and the Risk of Birth Defects

Preseptor
dr. Fonda octarianingsih, Sp.OG

YULIANA
11310414

LATAR BELAKANG
Ibu hamil :
candidiasis vaginalis / infeksi
jamur lainnya

Anti jamur
topikal

hewan : antijamur
gol azole risiko
cacat lahir

Anti jamur oral

Ibu 5 anak :
Flukonazole 400-800
mg risiko cacat lahir

FDA 2011 : terapi

jangka panjang
flukonazole dosis
tinggi : kategori C
menjadi D

METODE
Diidentifikasi bayi yang lahir :
1 januari 1996 31 maret 2011
di Denmark dari data kelahiran medis.
Umur kehamilan ibu: USG , HPHT
Antifungal oral : Data resep nasional
Cacat lahir : 15 tipe cacat lahir

ANALISIS STATISTIK
Analisis Utama
Flukonazole oral dengan dosis tertentu ---- cacat lahir

Analisis Tambahan
Penggunaan flukonazole pada waktu tertentu dan
Kriteria eksklusi dimasukkan dalam penelitian

HASIL
Total 976.300 bayi lahir hidup yang
dimasukkan dalam penelitian

995.742 bayi lahir hidup di Denmark

19,442 dikeluarkan
6322 data umur kehamilan hilang
672 kehamilan yang berakhir (<22 minggu atau
>45 minggu)
2284 mempunyai aberasi kromosom
1893 mempunyai sindrom genetik
1157 cacat lahir yang diketahui penyebabnya
253 infeksi virus kongenital
34 infeksi jamur yang didiagnosis ketika di RS 4 minggu
sebelum hamil
6827 konsumsi flukonazole oal 4 minggu sebelum hamil

976.300 dimasukkan dalam penelitian. 8064

mengonsumsi antijamur pada trimester 1

712 di eksklusikan
(konsumsi
ketokonazole/itrakonazol

975,588 dimasukkan pada

penelitian :
Hubungan flukonazole
dan cacat lahir

7377 di eksklusikan
(konsumsi
ketokonazole/fluconazole

968,923 dimasukkan pada

penelitian : hubungan
itrakonazole dan cacat
lahir

7992 di eksklusikan
(konsumsi
flukonazole/itrakonazole

968,308 dimasukkan pada

penelitian : hubungan
ketokonazole dan cacat
lahir

Table 1. Characteristics of the 975,588 Women in the Study Cohort According to Whether They Were Exposed to Oral
Fluconazole in the First Trimester of Pregnancy.*

Characteristic
968,236)
Cumulative dose of fluconazole no. (%)
150 mg
300 mg
3506000 mg

Exposed
(N = 7352)

4082 (56)

Unexposed
(N =

2252 (31)

1018 (14)

Previous births no. (%)

0
1

3465 (47)

438,327 (45)

3887 (53)

529,909 (55)

Age at pregnancy onset yr

294.9

304.8

Married or living with a partner no. (%)

5966 (81)

839,194 (87)

Bachelors degree or higher educational level no. (%)

Household income in third quintile for overall study cohort no. (%)
Smoking during pregnancy no. (%)
One or more previous births with congenital malformations no. (%)

2044 (28)
1417 (19)
1481 (20)

312,089 (32)
193,764 (20)
177,619 (18)

395 (5)

49,072 (5)

128 (2)

8,811 (1)

Coexisting conditions and other medications taken no. (%)

Infectious disease in first trimester
Immunodeficiency at any time before pregnancy through first trimester
Diabetes mellitus at any time before pregnancy through first trimester
Oral antibiotics in first trimester
Immunosuppressive agent during period from 3 months before pregnancy through first
trimester
Oral contraceptives or drugs for in vitro fertilization in first trimester

7 (0.1)

445 (0.05)

156 (2)

13,893 (1)

1937 (26)

118,331 (12)

49 (0.7)
455 (6)

13,031 (1)
62,260 (6)

Birth Defect

Exposed

Unexposed

Crude Prevalence Odds Ratio (95% CI)

Adjusted Prevalence Odds Ratio (95% CI)

n o. (%)
Birth defects overall

Any dose (N=7352)

210 (2.86)

25,159 (2.60)

1.10 (0.961.27)

1.06 (0.921.21)

150 mg (N=4082)

107 (2.62)

25,159 (2.60)

1.01 (0.831.22)

0.99 (0.821.20)

300 mg (N=2252)

71 (3.15)

25,159 (2.60)

1.22 (0.961.55)

1.15 (0.911.46)

3506000 mg (N=1018)

32 (3.14)

25,159 (2.60)

1.22 (0.861.73)

1.12 (0.791.59)

Craniosynostosis

6 (0.08)

716 (0.07)

Cleft palate alone

5 (0.07)

10 (0.14)

Cleft lip, cleft palate, or both

Other craniofacial defects

Middle-ear defects

Limb defects

1.10 (0.492.47)

1.07 (0.482.39)

497 (0.05)

1.33 (0.553.20)

1.24 (0.513.00)

1,264 (0.13)

1.04 (0.561.94)

1.02 (0.551.91)

14 (<0.01)

NE

NE (P=0.65)

NE

NE

27 (0.37)

4,143 (0.43)

0.86 (0.591.25)

0.84 (0.571.23)

Limb-reduction defects

3 (0.04)

553 (0.06)

0.71 (0.232.22)

0.71 (0.232.21)

Polydactyly

5 (0.07)

592 (0.06)

1.11 (0.462.68)

1.06 (0.442.56)

Syndactyly

2 (0.03)

679 (0.07)

0.39 (0.101.55)

0.38 (0.101.54)

Diaphragmatic hernia

2 (0.03)

202 (0.02)

1.30 (0.325.25)

1.36 (0.345.49)

Any heart defects

76 (1.03)

7,835 (0.81)

1.28 (1.021.61)

1.20 (0.951.50)

Tetralogy of Fallot

7 (0.10)

287 (0.03)

3.21 (1.526.81)

3.16 (1.496.71)

Pulmonary-artery hypoplasia

Ventricular septal defects

31 (0.42)

2 (<0.01)

3,172 (0.33)

NE (P=0.86)

1.29 (0.901.84)

NE

1.24 (0.871.77)

Table 2. Sensitivity Analyses of the Association between Oral Fluconazole

Exposure (Any Dose) and Birth Defects Overall.

Analysis

Birth Defects
Overall*
no./total no. (%)
45/1716 (2.62)

Odds Ratio (95% CI)

0.95 (0.711.28)

Exposure in 5th to 10th wk of

gestation
Exposure only in second or
third trimester

75/2477 (3.03)

1.11 (0.881.40)

Exclusion of multiple births

198/7139 (2.77)

1.06 (0.921.22)

Exclusion of women with

missing data

192/6946 (2.76)

1.03 (0.901.19)

Table 3. Sensitivity Analyses of the Association between Oral Fluconazole Exposure and Tetralogy of
Fallot.*
Analysis
Exposure in 5th to 10th week of gestation
Exposure only in second or third trimester

Tetralogy
of Fallot
3/1716 (0.17)

Adjusted Prevalence
Odds Ratio (95%
CI)
5.86 (1.8718.35)

1/2477 (0.04)

1.39 (0.209.93)

150 mg

4/4082 (0.10)

3.18 (1.188.55)

300 mg

2/2252 (0.09)

3.03 (0.7512.21)

3506000 mg

1/1018 (0.10)

3.37 (0.4724.06)

Exclusion of multiple births

7/7139 (0.10)

3.42 (1.617.26)

Exclusion of women with missing data

7/6946 (0.10)

Additional adjustment for drugs in FDA pregnancy categories D and

X
Additional adjustment for prepregnancy BMI in a subcohort from
2004 through March 2011

7/7352 (0.10)

3.14 (1.486.68)

5/3855 (0.13)

4.55 (1.8511.19)

Cumulative fluconazole dose in first trimester

3.48 (1.647.39)

DISKUSI
Ketokonazole
Itrakonazole

Flukonazole
150,300,350
6000 mg

Trimester 1
kehamilan

Trimester
1,2,3
kehamilan
Risiko
cacat lahir

Tetralogi
fallot
3x

Anti fungi
topikal

Potensi
teratogenik

Penelitian sebelumnya
1079 Ibu
hamil :
flukonazole

Cacat
kraniofasial,
jantung

Case control
Ibu hamil :
flukonazole

Hernia
diafragma

Hipoplasia
jantung kir
2x

Ibu hamil :
ketokonazole
trimester 1

Kelainan
jantung
3x

KESIMPULAN
Penggunaan flukonazole trimester 1 kehamilan tidak
berhubungan dengan risiko cacat lahir
Walaupun flukonazole meningkatkan risiko terjadinya
tetralogi fallot (risiko ) tetapi perlu dikonfirmasi lagi.