妊娠中の抗生物質使用と早産：不滅時間バイアスを解消するための新たな使用者コホートデザインの普及

Observational studies of the association between antibiotics and preterm delivery report conflicting findings. We assessed the effects of third trimester antibiotic use on preterm delivery and low birthweight, using a study design that accounts for immortal time bias.

We used the UK's Clinical Practice Research Datalink to identify pregnant females aged 12-50, over the period 2002 to 2016, reaching 27 weeks of gestation without antibiotic use until that point. We applied the prevalent new-user design, matching each third trimester antibiotic initiator with a reference non-user at the same gestational day, using time-conditional propensity scores. The two matched groups were compared on the incidence of preterm delivery and low birthweight. The full cohort was also analyzed with antibiotic use considered as time-fixed and time-varying exposures.

The cohort included 207,027 pregnancies, with 16,865 initiating antibiotics matched to 16,865 non-users. The hazard ratio (HR) of preterm delivery with third trimester antibiotic use was 1.14 (95% CI: 1.04-1.24), compared with non-use. With time-fixed exposure, subject to immortal time bias, the HR was 0.78 (95% CI: 0.73-0.83), while with time-varying exposure, the HR was 1.23 (95% CI: 1.16-1.32). The HR of low birthweight with antibiotic initiation was 1.07 (95% CI: 0.93-1.25) compared with 0.91 (95% CI: 0.83-1.00) under the time-fixed approach.

Using the prevalent new-user design, which emulates a randomized trial, antibiotic use late in pregnancy was associated with a modest increased incidence of preterm delivery. Previous inconclusive studies may have resulted from observational methods that introduced, or insufficiently addressed, immortal time bias.