HEALTHx2: patient-centered approaches for studying the effectiveness and reproductive safety of antidepressant medication in perinatal women

Psychiatric disorders are not uncommon among pregnant women and postpartum mothers. A significant number of women may require antidepressant treatment during pregnancy. To protect both the mother and the child, it is necessary to weigh the benefits of antidepressant treatment for the mother against the risks associated with the illness, while also preventing harmful medication effects on the child. User involvement is central to this research project. By combining women's perspectives with various population-based data sources and genetic data, this project will generate new knowledge crucial for important clinical decisions: whether perinatal psychiatric disorders should be treated with antidepressants or not. Using health registry data from Norway and Denmark, we found that the timing of women discontinuing antidepressant treatment during pregnancy significantly impacted women's mental health after childbirth. Women who were treated for a short period with antidepressants and discontinued treatment before or early in pregnancy, had a lower likelihood of hospitalization due to depression/anxiety after childbirth compared to women who were treated with antidepressants throughout pregnancy. This may suggest that depressive symptoms in these women were well controlled and stable enough to discontinue antidepressant treatment safely. Conversely, women who used higher doses of antidepressants before pregnancy and discontinued treatment towards the end of pregnancy had a higher likelihood of starting additional treatment with other psychotropic drugs after childbirth. Monitoring the mental health of these women is crucial, and it is essential to weigh the potential risks of antidepressant treatment in late pregnancy for the child against the benefits for the mother. Findings from the analysis of health registry data in Italy showed no difference in the risk of hospitalization due to depression/anxiety among pregnant women who continued antidepressant treatment during pregnancy compared to women who discontinued the medication at the beginning of pregnancy. Among women with eating disorders and obsessive-compulsive disorders, the use of antidepressants during pregnancy did not appear to prevent mental health challenges after childbirth. However, we observed a reduction in the likelihood of seeking psychiatric help after childbirth among women who continued treatment throughout pregnancy and the first three months after childbirth. Using data from the Mother-Father-and-Child study in Norway, we also found that women with eating disorders who continued to use antidepressants during pregnancy experienced a lower severity of anxiety symptoms throughout the remainder of pregnancy compared to those who discontinued treatment. Regarding the long-term metabolic and psychiatric health in children following exposure to antidepressants during pregnancy, findings from the Mother-Father-and-Child study, combined with data from MobaGenetics, show no increased risk of overweight, obesity, or growth problems in children by the age of 8 years. However, we observed that children who had been exposed to antidepressant treatment during pregnancy had a slower growth rate up to 18 months of age compared to children who had not been exposed. Our findings further indicate that exposure to antidepressant medications during fetal development does not have significant negative consequences for depression, anxiety, or eating disorders in the child up to 18 years of age. In Norway, we recruited 500 women who were offered antidepressant treatment during, before, or after pregnancy, and we conducted four focus group interviews. The most recent data show that one out of every two pregnant women experiences significant challenges in decision-making regarding the use of antidepressants during pregnancy. Several barriers in the decision-making process were highlighted during the focus group interviews, including a lack of evidence-based information about the risks of antidepressant medications during pregnancy, suboptimal communication with doctors and other healthcare professionals, and limited access to non-pharmacological treatment, such as psychotherapy.

The results of the HEALTHx2 project have produced important outcomes that inform clinical treatment strategies of women with a perinatal psychiatric illness. The project has filled important knowledge gaps about the clinical benefit of antidepressant treatment in pregnant and postpartum women, which has been under prioritized research for decades. The project has shown that timing of discontinuation of pharmacological treatment with antidepressants is key in relation to postpartum mental health outcomes in women with pre-existing depression and/or anxiety. In the context of treatment of eating and obsessive-compulsive-disorders, treatment continuation with antidepressants in pregnancy does not confer a definite benefit on severe outcomes such as psychiatric admission, but clinically relevant benefit is observed in terms of depressive and anxiety symptom severity in the women. When it comes to the reproductive safety of antidepressants in pregnancy, the project shows that prenatal use of antidepressant is not posing substantial health risk in the offspring in relation to metabo-psychiatric outcomes, but the possible link with decelerated growth in the first years of life must be further elucidated. Taken together, the outcomes include new knowledge about the clinical benefit of antidepressant treatment in perinatal women for the broader spectrum of mental illnesses, as well as for safety outcomes in the child that remained unclear. This new evidence-based knowledge has direct implication of clinical treatment guidelines and for risk communication about psychotropic drug exposure during pregnancy to women and their partners. User perspectives and results from focus group interviews underscore the need for increased provision of clear, evidence-based information by healthcare professionals, to facilitate shared decision-making and create personalized treatments for perinatal women considering antidepressant use during pregnancy.

HEALTHx2 is an international consortium using patient-oriented approaches for studying the effectiveness and reproductive safety of antidepressant treatment in perinatal women with depression, anxiety, obsessive-compulsive, or eating disorders. The initiative aims to i) actively engage female patients in all phases of research; ii) explore health outcomes that matter most to women in the context of psychotropic drug use in the perinatal period; iii) quantify the clinical benefits of antidepressants in pregnancy and postpartum on maternal mental illness and quality of life, across the specific psychiatric disorders; iv) estimate time-dependent effects of antidepressant exposure in pregnancy on child weigh-for-height trajectories and risks of disordered eating up to adolescence, independently of genetic heritability. The project uses biological markers of maternal stress and mental illness, genetic variants encoding drug response, and observational pregnancy and postpartum data in the Norwegian Mother and Child Cohort Study. HEALTHx2 also explores the same hypotheses in two additional population-based data sources to corroborate any observed drug effects, and to explore health outcomes from both dimensional and diagnosis perspectives. The initiative employs cutting-edge methods for causal inference to undertake a quasi-randomized, ethically feasible drug trial in women with serious perinatal psychiatric illness. The HEALTHx2 methodological approaches are novel in this setting, and thus highly challenging. Yet, they may constitutes a new framework for future drug safety and efficacy studies, which is of high relevance for perinatal research, and thereby of substantial benefit to society. The project will provide the evidence base for important clinical decisions: whether to treat a perinatal psychiatric disorder or no. It will also facilitate women empowerment in developing an evidence-based understanding of the benefits and risks of perinatal use of antidepressants.