~8% of pregnant women will suffer a major depressive episode; 14-23% of pregnant women will experience some type of depressive disorder; and ~7-13% of pregnant women will receive antidepressants. The literature consistently links antidepressant use in pregnancy with an increased risk of preterm birth, even after carefully controlling for confounding factors. In particular, serotonin reuptake inhibitor (SRI) antidepressant use in pregnancy is associated with preterm premature rupture of membranes (PPROM), a major cause of spontaneous preterm birth. Despite antidepressants being the most commonly used class of drugs during pregnancy, and widespread concerns about their use in pregnancy, no studies have attempted to understand the impact SRIs have on pregnancy, biologically or mechanistically. Given that PPROM is common in the setting of an infection, it is thought that inflammation serves as the downstream pathway. However, a significant proportion of PPROM/preterm deliveries have no evidence of infection. Rather inflammatory intermediaries may cause tissue injury that promotes membrane weakening and rupture. Recent studies found that PPROM is associated with cellular senescence and a unique sterile inflammatory signature, known as a senescence-associated secretory phenotype (SASP). Thus, in the absence of infection, fetal membrane (FM) senescence and sterile inflammation may be an underlying mechanism of PPROM; and similar processes may underlie PPROM in women exposed to SRIs. In preliminary studies we found that commonly used SRIs induce human FM activation of the senescence-mediator, p38 MAPK; and induces a specific inflammatory SASP. We also have in vivo evidence of elevated FM p38 MAPK activation in women exposed to SRIs during pregnancy. Since there is no way to prevent PPROM and preterm birth in the general population, there is a need to investigate novel therapeutic strategies. Moreover, women receiving SRIs during pregnancy represent a unique high-risk population where information is needed to make their pregnancies safer. A recent study reported that statins reduce FM senescence and associated SASPs. Thus, the detection of FM senescence and associated SASPs may be a marker that identifies patients for whom statins might be useful at preventing PPROM and and thus, subsequent preterm birth. Our central hypothesis is that SRI antidepressants induce FM senescence and sterile inflammation, leading to PPROM and subsequent preterm birth; and that statins can prevent this. To test this, our specific aims are to:
Aim 1. Characterize the effect of SRIs on human FM senescence and associated sterile inflammation.
Aim 2. Determine the impact SRI exposure during pregnancy has on FM senescence and associated sterile inflammation.
Aim 3. Determine whether statins can prevent the effects of SRIs on FM senescence and associated sterile inflammation.
The major objective of this proposal is to explore the mechanisms underlying the association between serotonin reuptake inhibitor (SRI) antidepressant use in pregnancy and premature rupture of membranes (PPROM), a major cause of spontaneous preterm birth; and to examine ways to prevent PPROM and preterm birth in women exposed to antidepressants during pregnancy.
