Medical pulse through the guide
This study is the largest study to date exploring the correlation between mirtazapine use and fetal safety during pregnancy, and a nationwide design for matching samples and propensity scores further improves the external validity of the results.
The analysis showed that the risk of exposure to mirtazapine in the critical time window of pregnancy (eg, first trimester) was not higher than that of the control.
In the sensitivity analysis, the exposure window was narrowed to 4-10 weeks' gestation, and the risk of major congenital malformations in the mirtazapine group was still not higher than that of the control, and the risk was the same in all malformation subgroups (heart, digestive system, limbs).
The use of antidepressants during pregnancy is an important and unavoidable clinical topic. In addition to the courage to make decisive decisions, the clinic also needs to clarify as much high-quality evidence as possible about the interference of confounding factors, after all, factors other than drugs may also adversely affect the outcome of mothers and children.
As a commonly used naSSA antidepressant in clinical practice, mirtazapine can not only improve depression, anxiety and insomnia, but also its antiemetic effect may also help treat hyperemesis gravidarum. However, previous studies on mirtazapine pregnancy safety have been inconsistent. It is necessary to clarify this topic by adopting a relatively rigorous study design that minimizes the effect of systematic errors on the results.
Introduction to the study
Using a preference score matching design, Anne Ostenfeld et al. of the University of Copenhagen in Denmark conducted a national population cohort study that assessed the association of mirtazapine use during pregnancy with adverse fetal outcomes, including major congenital malformations, spontaneous miscarriages, stillbirths, and neonatal deaths. The study was published online March 23 in Acta Psychiatr Scand. (Impact Factor 6.392).
The study included all pregnancy data registered in Denmark between 1 January 1997 and 31 December 2016, and matched a 1:4 propensity score for pregnant women's exposure to mirtazapine during pregnancy, forming four separate cohorts.
The risk of teratogenicity is generally thought to be higher in the first trimester, i.e., the first trimester of pregnancy, and this study also used the first trimester as an exposure window to explore teratogenic risk. In addition, the exposure window for spontaneous miscarriage is set to before 22 weeks of pregnancy, while the exposure window for stillbirth and neonatal death is the whole gestational period. Specific statistical analysis methods are detailed in the original literature (open source).
Research results
A total of 1 650 649 pregnancies were included in the study, of which 1 945 were exposed to mirtazapine during pregnancy. The cohort of propensity scores for major congenital malformations, spontaneous miscarriages, stillbirths and neonatal deaths included 4 475 cases, 9 500 cases, 9 725 cases and 4 485 pregnancies, respectively, of which the number of pregnancies exposed to mirtazapine was 895 cases, 1 900 cases, 1 945 cases and 897 cases, respectively.
The main findings for the four reversals are shown in Table 1:
Table 1 Relative risk of exposure to mirtazapine in critical time windows during pregnancy (Ostenfeld A, et al. 2022）
The analysis showed that the risk of exposure to mirtazapine in critical time windows of pregnancy was not increased compared with the control, regardless of major congenital malformations, spontaneous miscarriage, stillbirth, or neonatal death.
Sensitivity analysis based on cumulative dose of mirtazapine showed that the risk of significant congenital malformations and spontaneous miscarriage was no higher in the high cumulative dose group (≥2000 mg) than in the low cumulative dose group (<2000 mg) and unexposed.
In addition, by narrowing the exposure window further to 4-10 weeks' gestation, the risk of major congenital malformations in the mirtazapine group was still no higher than that of the control, and the risk was the same in all malformation subgroups (heart, digestive system, limbs), as shown in Table 2.
Table 2 Relative risk of significant congenital malformations further narrowing of the exposure time window to 4-10 weeks' gestation; included only the subgroup of outcome ≥3 (Ostenfeld A, et al. 2022）
conclusion
This study is the largest study to date to explore the association between mirtazapine exposure and fetal safety during pregnancy, and the nationwide design of sample and propensity score matching further improves the external validity of the results.
Available results show that exposure to mirtazapine in critical time windows of pregnancy (eg, first trimester) does not have a higher risk of major fetal malformations, spontaneous miscarriages, stillbirths, and neonatal death than controls. Researchers believe that the above results can reassure doctors and patients.