Preeclampsia is a complication of pregnancy characterised by hypertension and liver and kidney function abnormalities.  Preeclampsia occurs in roughly 5-8% of pregnancies and is a number one explanation for maternal and fetal morbidity and mortality. Risk aspects for preeclampsia include preeclampsia during a previous pregnancy, first pregnancy, multiple gestation, maternal age over 40, obesity, and certain underlying medical conditions including chronic hypertension, diabetes, and kidney disease.

Exactly what causes preeclampsia shouldn’t be fully understood. Because serotonin plays a task in vascular function and the regulation of blood pressure, some have questioned whether using serotonin reuptake inhibitor (SRI) antidepressants may affect a girl’s risk for preeclampsia.  While several studies have indicated an increased risk of preeclampsia in women taking SRIs while pregnant, this finding shouldn’t be consistent, and most of those studies have been small and haven’t been in a position to account for potential confounding aspects.   

A recent meta-analysis including 400,000 SSRI-exposed women did show a small, statistically significant association between prenatal SSRI exposure and risk of preeclampsia.  Nevertheless, the authors noted some necessary limitations of this meta-analysis.  Most significantly, a lot of the studies included within the meta-analysis didn’t account for anxiety/depression severity, SSRI dose, and/or other well-defined preeclampsia risk aspects (e.g., obesity, diabetes, smoking, race).  Probably the most common limitation of the included studies was the failure to account for anxiety/depression severity within the mother, which can independently drive risk for preeclampsia.

Taking a Closer Take a look at SRIs and Preeclampsia

It’s biologically plausible that SRIs may very well decrease risk for preeclampsia.  Each depression and preeclampsia are related to dysregulation of serotonergic neurotransmitter systems; thus, it’s plausible that medications, equivalent to SRI antidepressants, that improve serotonergic regulation might also help to diminish depressive symptoms, in addition to decrease vulnerability to preeclampsia.  

To further explore this possibility,  Vignato and colleagues assessed clinical data from a retrospective study of 9558 SSRI-untreated and 9046 SSRI-treated pregnancies.  Psychiatric diagnoses were identified using a review of medical records, and depressive symptoms were measured using the Patient Health Questionnaire-9 (PHQ-9).  They observed that SSRI use while pregnant was related to decreased risk of preeclampsia after controlling for clinical confounders, including depression severity, history of chronic hypertension, diabetes, body mass index, and age (odds ratio, OR = 0.9 [95% CI 0.7-1.0], p = 0.05).

Going one step further, this study also examined how depression and SSRI treatment may affect risk for preeclampsia by examining copeptin levels.  Copeptin is a peptide co-secreted (at a 1:1 ratio) with arginine vasopressin (AVP) in response to hemodynamic or osmotic stimuli.  In patients with preeclampsia, increased AVP secretion stimulates a rise in blood pressure.  Copeptin is less complicated to measure than AVP, and former studies have demonstrated that copeptin levels are a reliable predictor of preeclampsia risk.  

In a subset of 233 pregnancies, early pregnancy (< 20 weeks) levels of copeptin were measured.  In comparison with women with mild or no depression, women with moderate to severe depressive symptoms produced significantly higher levels of copeptin (240 ± 29 vs. 142 ± 10 ng/mL, p < 0.001).  Treatment with SSRIs significantly reduced first trimester copeptin levels (78 ± 22 in users vs. 240 ± 29 ng/ml in non-users, p < 0.001). 

Looking specifically at women with moderate-to-severe depressive symptoms who were taking SSRIs, copeptin levels were much lower in SSRI-treated women than in women with moderate-to-severe depressive symptoms who were untreated (181?±?64 ng/mL [n?=?10] vs. 657?±?164 [n?=?10], p?=?0.02). 

Clinical Implications

Based on the findings of this study, it is feasible that SSRIs may very well decrease preeclampsia risk, whereas depressive symptoms, especially when more severe, may very well increase risk for preeclampsia.  

While future studies will help to make clear the complex interaction between depression, SSRI treatment and pre-eclampsia, the knowledge now we have up to now is reassuring.  If there may be a risk of preeclampsia related to SSRI treatment, the chance appears to be relatively small.  Nevertheless, there may be considerable data to point that risk of preeclampsia is higher in women with depressive illness (even within the absence of treatment with an SSRI) and will be affected by other co-occurring risk aspects, equivalent to obesity, chronic hypertension, diabetes mellitus, and smoking.

Ruta Nonacs, MD PhD

References

Gumusoglu SB, Schickling BM, Vignato JA, Santillan DA, Santillan MK. Selective serotonin reuptake inhibitors and preeclampsia: A top quality assessment and meta-analysis. Pregnancy Hypertens. 2022 Dec; 30:36-43. 

Vignato JA, Gumusoglu SB, Davis HA, Scroggins SM, Hamilton WS, Brandt DS, Pierce GL, Knosp BA, Santillan DA, Santillan MK. Selective Serotonin Reuptake Inhibitor Use in Pregnancy and Protective Mechanisms in Preeclampsia. Reprod Sci. 2022 Aug 19.