Use of anti-infective drugs during pregnancy : prevalence, predictors of use
and the risk of preterm birth and small-for-gestational-age newborns

Abstract: Anti-infective drugs are among the most used medications during pregnancy. Gestational infections are related to some adverse pregnancy outcomes, such as preterm birth and infants born small for their gestational age (SGA), which increases the risk of mortality and long-term morbidity. Given its health impacts, prompt management and treatment of these infections are warranted. However, there is some controversy on the use of anti-infective drugs to prevent adverse pregnancy outcomes, such as preterm birth. Furthermore, there is growing concern regarding its independent effects on these outcomes, when treatment of maternal infections is instituted. Therefore, we conducted 4 large population-based studies aimed to investigate the gestational use of anti-infective drugs during pregnancy and the risk of preterm birth and SGA. In addition, we systematically reviewed the available evidence on the use of metronidazole during gestation. We used data from the Quebec Pregnancy Registry, a longitudinal population-based cohort established with the linkage of three administrative databases from the province of Quebec (RAMQ, Med-Echo and ISQ). Data are available on prescriptions, pharmaceutical and healthcare services, acute care hospitalization and patient demographics. For study 1 and 2, we conducted a drug utilisation review within a cohort of 97 680 pregnant women. Study 3 and 4 were two independent case-control studies. Cases of preterm birth were defined as those with a delivery occurring before the 37th week of gestation (study 3). Cases of SGA were defined as a pregnancy resulting in a baby’s weigh adjusted for gestational age and gender <10th percentile, according to the Canadian gender-specific reference curves (Study 4). Oral use of anti-infective drugs during the last two trimesters of pregnancy was the exposure definition for both studies. Independent analyses were done to assess the risk for different classes of anti-infectives and individual agents. Our results indicate that the use of anti-infective drugs during pregnancy is prevalent (25%). Use of well-known agents increased once pregnancy was diagnosed, and the most frequent indications for use were respiratory and urinary infections. Predictors associated with use were having more that 2 different prescribers (adj. OR= 3.83,  95% CI: 3.3-4.3), having a diagnosis of urinary tract infections (adj. OR= 1.50, 95% CI: 1.3-1.8) and respiratory tract infection (adj. OR= 1.40, 95% CI: 1.2-1.6). The use of macrolides was associated with a decreased risk of preterm birth (adj. OR=0.65, 95% CI: 0.50-0.85), whereas metronidazole increased the risk (adj. OR=1.81, 95% CI: 1.30-2.54). Azithromycin had a protective effect in women with premature rupture of membranes (adj. OR=0.31, 95% CI: 0.10-0.93). Use of sulfamethoxazole/trimethoprim was associated with an increased risk of SGA (adj. OR= 1.61, 95%CI: 1.16-2.23), whereas the use of urinary anti-infectives decreased the risk (adj. OR= 0.80, 95%CI: 0.65-0.97).The results of this thesis suggest that the use of macrolides and penicillins decrease the risk of preterm birth and SGA. Health care professionals should consider other therapeutic alternatives to metronidazole and sulfonamides, such as azithromycin.

Keyphrases: anti-infective drugs, pregnancy, preterm birth, small for gestational age, Quebec Pregnancy Registry, case-control study