Clarithromycin in Early Pregnancy and the Risk of Miscarriage and Malformation: A Register Based Nationwide Cohort Study

Abstract

BackgroundThe antibiotic clarithromycin has been associated with fetal loss in animals and a study has found a doubling in the frequency of miscarriages among women using clarithromycin in pregnancy. The aim of the study was to investigate whether clarithromycin use in early pregnancy was associated with an increased risk for miscarriages and major malformations.MethodsWe conducted a nationwide cohort study including all women in Denmark with a known conception between 1997 and 2007. The Fertility Database was used to identify all women giving birth and the National Hospital Register was used to identify all women with a record of miscarriage or induced abortion. Prescription data was obtained from the National Prescription Register. The primary outcome was the number of miscarriages and offspring with major congenital malformations among users of clarithromycin compared to non-users.ResultsWe identified 931 504 pregnancies (705 837 live births, 77 553 miscarriages, and 148 114 induced abortions). 401 women redeemed a prescription of clarithromycin in the first trimester of which 40 (10.0%) experienced a miscarriage and among the live born nine (3.6%) had offspring with malformations. The hazard ratio (HR) of having a miscarriage after exposure to clarithromycin was 1.56 (CI95% 1.14–2.13). There was no increased hazard of having a miscarriage when being exposed to penicillin or erythromycin. There was no increased prevalence (OR = 1.03 (CI95% 0.52–2.00)) of having offspring with malformations after exposure to clarithromycin.ConclusionsWe found an increased hazard of miscarriage but no increased prevalance of having offspring with malformations among women redeeming a prescription of clarithromycin in early pregnancy. This is supported by previous studies in animals and humans. However, further research is required to explore the possible effect of treatment indication on the associations found.

Use of antibiotics during pregnancy and risk of spontaneous abortion

“…21 The increased risk of spontaneous abortion associated with the use of azithromycin and clarithromycin (65% and twofold increased risk, respectively) was consistent with findings in 2 previous studies (56% and 2-fold increased risk of spontaneous abortion with clarithromycin exposure). 4,5 Conversely, our findings on azithromycin are different from those in a teratology information services study; 3 the difference may be explained by the study's small sample.…”

“…[1][2][3][4] In contrast, a Danish study based on data from a prescription database found an increased risk of spontaneous abortion associated with the use of clarithromycin. 5 Three studies using data from teratology information services failed to show a link between the use of quinolones and the risk of spontaneous abortion, [6][7][8] and an early Medicaid study showed an association with the use of metronidazole. 9 However, the studies were all limited by either small samples, or recall or indication bias.…”

“…9 However, the studies were all limited by either small samples, or recall or indication bias. [1][2][3][4][5][6][7][8][9] Studies of the risk of spontaneous abortion associated with tetracyclines and nitrofurantoin are lacking.…”

Bruk av antibiotika i svangerskapet

“…I en dansk studie med 401 klaritromycineksponerte kvinner ble det påvist signifikant økt risiko for spontanabort etter bruk av midlet i første trimester (OR = 1,56; 95 % KI 1,14 -2,13) sammenlignet med fenoksymetylpenicillin og erytromycin, der det ikke var noen signifikant økt risiko (9). I en annen studie fra Danmark med over 25 000 eksponerte fant man en signifikant økt risiko for pylorusstenose ved bruk av erytromycin tatt i tiden mellom uke 28 og fødselen (OR = 2,24; 95 % KI 1,20 -4,18) (11).…”

“…Risiko for spontanabort etter antibiotikabruk ble undersøkt i syv av studiene (9,14,15,17,21,29). I de tre danske der man fant signifikant økt risiko for spontanabort, var det ikke kontrollert for infeksjon etter bruk av en rekke antibiotika (klaritromycin, pivmecillinam, sulfametizol, trimetoprim).…”