Shitrit Itamar Ben, Idan Daphna, Hassidim Ariel Avraham, Michael Tal, Levy Amalia, Pariente Gali, Lunenfeld Eitan, Daniel Sharon
Joyce and Irving Goldman Medical School, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, 8410501, Israel.
Department of Epidemiology, Biostatistics, and Community Health Sciences, School of Public Health, Faculty of Health Sciences, Ben- Gurion University of the Negev, Beer-Sheva, Israel.
Infection. 2025 Aug 22. doi: 10.1007/s15010-025-02622-9.
Doxycycline is frequently prescribed during pregnancy, yet evidence on fetal safety is inconsistent and often excludes non-live births. We assessed whether exposure during the first or third trimester is associated with major congenital malformations or late-pregnancy adverse outcomes in a population-based cohort that also included stillbirths and terminations.
Using data from Clalit Health Services Southern district, we identified 265,686 pregnancies in women aged 15-45 years (from 1998 to 2017). Pharmacy records classified doxycycline dispensation in the first trimester (≤ 13 weeks) or third trimester (≥ 27 weeks). Crude and adjusted negative-binomial models estimated relative risks (RRs) for total and organ-specific major congenital malformations diagnosed up to age 1 year and for perinatal mortality, preterm birth, low/very-low birthweight, and low Apgar scores. Sensitivity analyses explored dose-response relations and propensity-score-matched cohorts.
Among 2,696 first-trimester exposures, major malformations occurred in 7.7% versus 7.0% of 262,990 unexposed pregnancies (SMD = 0.03, p = 0.17). No association with major malformations was observed in both crude (Crude Relative Risk (RR) = 1.10; 95% CI 0.96-1.27) and adjusted (Adjusted RR = 1.07; 95% CI 0.93-1.23) analyses, nor by organ-specific sub-groups. Third-trimester exposure (n = 112) was linked to a higher risk of very-low birthweight, while other late-pregnancy outcomes were comparable to unexposed pregnancies.
First-trimester doxycycline use was not associated with increased major congenital malformation risk, and most late-pregnancy outcomes were unaffected. These findings support the relative safety of doxycycline when clinically indicated during pregnancy.
多西环素在孕期经常被开具处方，但关于胎儿安全性的证据并不一致，且往往排除了死产情况。我们在一个包含死产和终止妊娠情况的人群队列中评估了孕早期或孕晚期暴露于多西环素是否与严重先天性畸形或孕晚期不良结局相关。
利用克拉利特医疗服务南区的数据，我们确定了15至45岁女性的265,686例妊娠（1998年至2017年）。药房记录将孕早期（≤13周）或孕晚期（≥27周）的多西环素配药情况进行了分类。采用粗率和校正后的负二项式模型估计1岁前诊断出的全部及特定器官严重先天性畸形、围产期死亡率、早产、低/极低出生体重以及低阿氏评分的相对风险（RR）。敏感性分析探讨了剂量反应关系和倾向评分匹配队列。
在2,696例孕早期暴露病例中，严重畸形发生率为7.7%，而262,990例未暴露妊娠的发生率为7.0%（标准化差异=0.03，p=0.17）。在粗率分析（粗相对风险（RR）=1.10；95%置信区间0.96-1.27）和校正分析（校正RR=1.07；95%置信区间0.93-1.23）中，均未观察到与严重畸形的关联，按特定器官亚组分析也未发现关联。孕晚期暴露（n=112）与极低出生体重风险较高相关，而其他孕晚期结局与未暴露妊娠相当。
孕早期使用多西环素与严重先天性畸形风险增加无关，且大多数孕晚期结局未受影响。这些发现支持了孕期临床指征明确时多西环素的相对安全性。
