Preeclampsia is a severe hypertensive complication of pregnancy associated with multiple health risks within and beyond pregnancy.[1], [2], [3] The incidence of preeclampsia is high and continues to grow (now 3-10% worldwide), making it a significant public health concern.[4] Despite a robust literature on the immune, neurological, and cardiovascular mechanisms underlying preeclampsia,[5], [6], [7], [8] there is no cure for this often-devastating gestational disorder.[9] Recent work has found that preeclampsia is associated with dysregulation of serotonergic systems, which are also involved in neuropsychiatric function.[10], [11], [12] Studies of mood disorders further point to a link between preeclampsia and serotonin dysfunction. There is a significant bidirectional interaction between risk for preeclampsia and mood disorders, particularly in the peripartum period. Perinatal or postpartum mood and anxiety disorders (PMAD) are a significant and growing public health concern.[13], [14] Mood disorders (e.g., depression, dysthymia) are associated with an approximately three-fold increase in risk for preeclampsia,[15], [16] and preeclampsia is a significant risk factor for PMAD and is associated with increased depression severity.[2], [17] Women who are diagnosed with preeclampsia are at 2.4 times higher odds of developing PMAD,[18] and gestational hypertensive disease is significantly more common in women with psychiatric illness.[19] For example, women with depression have significantly increased rates of preeclampsia and gestational hypertension (1.28 and 1.23 odds, respectively).[20] Furthermore, ongoing debates in the field biological psychiatry about the role of serotonin in major depression underscore the need to understand non-nervous system mechanisms of SSRI action. Inflammatory and vascular mechanisms, for example, which are implicated in depression and gestational hypertension, are explored here as potential substrates for SSRI efficacy.

The objective of this meta-analysis and quality assessment was to review the existing literature, including its limitations, linking gestational SSRI use to preeclampsia or gestational hypertension risk. The research question considered was whether gestational SSRI use altered the risk for hypertensive disorders of pregnancy. Additionally, we examined potential sources of bias and confounds in the existent literature. Because SSRIs are used in mood disorder patients, who are themselves at increased risk for preeclampsia/gestational hypertension, this and psychiatric symptom severity are significant potential sources of confounding bias. We propose future directions to improve the application of serotonin therapeutics to hypertensive disorders of pregnancy and the use of serotonin biomarkers for preeclampsia treatment and detection. This work has important implications for current psychiatric and obstetrics care, as well as for future development of targeted, mechanistic therapeutics.