Periodic Reporting for period 1 - PregnancyAD (Antidepressant discontinuation during pregnancy and relapse risk in the perinatal period) Reporting period: 2021-05-01 to 2022-04-30 Summary of the context and overall objectives of the project Why is it important for society?Antidepressants are the mainstay of pharmacological treatment for affective disorders. Pregnant women are among those who receive antidepressant treatment. Concerns have been raised about offspring sequelae of in-utero antidepressant exposure. As a result, more than 50% of women discontinue antidepressants during pregnancy. Untreated or incompletely treated depression or anxiety during pregnancy is associated with poor maternal health and adverse health outcomes in offspring, or at worst, suicide or infanticide in the perinatal period, and thus should be avoided. Consequently, expectant mothers face significant dilemmas regarding psychiatric medication use around conception, balancing their health and the unborn child.What is the problem/issue being addressed?Although the efficacy of psychiatric medications has been proven in the general population, human research on the efficacy of antidepressant treatment during pregnancy is limited. No personalized recommendations exist to support or suggest who can safely taper their antidepressants during pregnancy without relapse concerns. From a clinical perspective, it is, therefore, critical to providing evidence to guide treatment decisions in a personalized manner to mitigate unnecessary exposure while sustaining remission.What are the overall objectives?The overall objective is to provide an overview of relapse risk during the perinatal period following antidepressant discontinuation during pregnancy and thus pave the way toward personalized recommendations on antidepressant treatment during pregnancy. Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far Study 1. Is there a minimum time on antidepressant treatment that will reduce relapse risk? Most countries in Europe recommend continued antidepressant treatment for at least six months after achieving remission, while 6–9 months are suggested in Canada and 4–9 months in the USA. In a population-based cohort study of 89,442 adults, we found that relapse risk within one year was 37%, 35%, 35%, and 33% for individuals on antidepressant treatment <4, 4–6, 7–9, and 10–12 months, respectively. The risk of restarting antidepressants was high, especially among individuals treated for <4 months, which was 1.21 times higher than those on antidepressants for 10–12 months. The relapse risk was 1.11 times higher for antidepressant treatment 4–6 months and 1.09 higher for 7–9 months. Based on our findings, a minimum of 10–12 months of treatment appears to be preferable if there is concern about relapse after discontinuation. Study 2. Antidepressant discontinuation before or during pregnancy and risk of psychiatric emergency in Denmark: Limited evidence is available on the efficacy of continuing versus discontinuing antidepressant treatment during pregnancy. In a propensity score-matched cohort study, we found antidepressant discontinuation during pregnancy was associated with an increased risk of psychiatric emergency (5.0% for discontinuation versus 3.7% for continuation). This indicates that for every 76 pregnant women who discontinue antidepressants, there is one additional psychiatric emergency. While causality cannot be determined from this study, if the association we observed indicates a causal relationship, continuing antidepressant treatment across pregnancy may effectively reduce psychiatric emergency risk. Study 3. Association of genetic, demographic, and clinical factors with antidepressant treatment trajectories during pregnancy and the postpartum period: Study 2 suggested that an increased psychiatric emergency risk was associated with the timing of antidepressant discontinuation during pregnancy, necessitating a better understanding of antidepressant treatment trajectories around pregnancy. We conducted a population-based cohort study among 2,316 pregnant women with affective disorders in the iPSYCH2015 cohort. We identified four antidepressant treatment trajectories: early discontinuers (23%), late discontinuers (24%), interrupters (15%), and continuing users (38%). Primiparous women were less likely to discontinue antidepressants around conception. Women on antidepressant treatment for two or more years and women who received a higher antidepressant dosage before pregnancy were more likely to continue their treatment, whereas genetic liability to mental illnesses, measured as polygenic risk scores, does not affect antidepressant fill trajectories. A draft for this study is under preparation. Study 4. Antidepressant fill trajectories during pregnancy and psychiatric outcomes in the postpartum: Previous studies have not addressed the effect of complex patterns of antidepressant use throughout pregnancy on the relapse risk. We conducted a cohort study using data from nationwide registers in Denmark and Norway. Compared to continuers, women who discontinued antidepressants late in pregnancy had an elevated moderate risk of postpartum psycholeptics initiation but not psychiatric emergencies or self-harm. The risk was more pronounced among women with previous affective disorders (relative risk=1.28 95% CI: 1.12–1.47). Early discontinuers and discontinuers after recent initiation with a lower risk of psychiatric emergencies and psycholeptics initiation. The findings of Study 4 further verify the findings from Study 2. A draft for this study is under preparation.Study 5–7. Antidepressant use during pregnancy and risk of adverse health outcomes in the offspring. To provide a balanced overview of efficacy and the safety of antidepressant treatment, we also investigated broad health outcomes in offspring following in-utero antidepressant exposure. We found an increased risk for moderate-to-late preterm birth, moderately low birth weight, postnatal adaptation syndrome, neonatal admission, and neonatal persistent pulmonary hypertension (PPHN) among children prenatally exposed to antidepressants. However, the relative risks are moderate, and the absolute risks are low. Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far) The project so far provided evidence on the efficacy of continuing antidepressant treatment during pregnancy to reduce relapse risk, which was not previously available. Moreover, we provided a comprehensive risk estimation of adverse health outcomes in the children exposed to antidepressants in utero. We will identify subgroups of pregnant mothers with low relapse risk after discontinuing their antidepressants. At the end of the project, our findings will add to the limited evidence on the efficacy and safety of continued antidepressant treatment during pregnancy. The project's findings will impact public health by informing national guidelines on antidepressant use during pregnancy and guiding decision-making for pregnant women and their physicians. The provision of evidence-based risk-benefit information through counseling can help women attain more nuanced risk perceptions.