Prostaglandin E2 (PGE2), also known by the name dinoprostone, is a naturally occurring compound that is involved in promoting labor, though it is also present in the inflammatory pathway.[1] Prostaglandin E2 is FDA approved for cervical ripening for the induction of labor in patients for which there is a medical indication for induction. When used as a vaginal suppository, it is indicated as an abortifacient from gestational week 12 to 20 or for the evacuation of uterine contents for the management of missed abortion and intrauterine fetal death up to 28 weeks. Prostaglandin E2 is also useful for the management of gestational trophoblastic disease. Importantly, it is not a feticidal agent. Given its oxytocic properties, the administration of dinoprostone should only be at the proper dosages by experienced clinicians.[2]

While the exact mechanism of action is unknown, prostaglandin E2 causes contractions in the myometrium via direct stimulation.  It binds to G protein-coupled receptors (GPCRs) EP1-4 that lead to a variety of downstream events depending on the EP subtype and cell-type-specific expression patterns.[3] For example, EP receptors in the myometrium act via cell membrane calcium channels and intracellular cyclic 3’5’-adenosine monophosphate (cAMP). As some of the known receptors for prostaglandin E2 antagonize each other, researchers have hypothesized that the expression of these receptors determines the specific effects. The efficacy of prostaglandin E2 during pregnancy may link to the expression of these receptors. Prostaglandin E2 also promotes cervical dilation, effacement, and softening similar to the natural progression of pregnancy, possibly due to increased collagenase secretion.[4]

The role of prostaglandin E2 in inflammation is complex; it has demonstrated pro-inflammatory activity in specific settings and plays an anti-inflammatory role in others.[5] These diverse functions appear to depend on the cell type and expression patterns of various receptors. It can promote the activation of inflammatory Th17 cells but suppress IL-2 and IL-12 production in other T cell subsets. Importantly, though in vitro experiments have demonstrated that prostaglandin E2 can inhibit T-cell production, in vivo studies have not yet shown similar results.[6]

PGE2 is administered vaginally as a suppository, gel, or insert.

The vaginal suppository is for the evacuation of uterine contents. One 20 mg suppository is inserted into the posterior fornix of the vagina every three hours until abortion occurs. If the abortion does not take place within twenty-four hours, or if there are severe side effects, the clinician should stop the drug.[7]

The endocervical gel and vaginal inserts are agents for cervical ripening induction. The cervical gel has a more rapid release than the vaginal insert, but might be less convenient, as the procedure requires more vaginal examinations.[4] PGE2 is inserted into the posterior fornix and replaced every six hours until labor induction, as determined by regular, painful contractions.[8] However, drug administration should cease if there are no contractions within twenty-four hours, or if there are severe adverse effects, including membrane rupture or uterine hyperstimulation.[9]

The most common side effects of prostaglandin E2 concern its impact on gastrointestinal smooth muscle. The suppository correlates with the most severe side effects, with two-thirds experiencing vomiting, two-fifths experiencing diarrhea, and one third experiencing nausea. Other adverse effects include temperature elevation in half of the patients, headache in one-tenth, and shivering and chills in one-tenth. Anti-emetics and anti-diarrheal medications may be necessary before and during the administration of the drug to counteract these side effects.[9]

The insert and gel have a less than one percent incidence of gastrointestinal symptoms. However, studies have shown that they have links to a higher chance of uterine hyperstimulation with and without fetal distress (greater than 2%) versus placebo (under1%). Additionally, they also have an increased chance of fetal distress without uterine hyperstimulation (over 2%) versus placebo (1%). There were also associated fetal heart rate changes, with and without distress. In all of these cases, removal of the product resulted in a return to normal, though one case did require treatment with tocolytics.[10]

Prostaglandin E2 is contraindicated in patients with a known hypersensitivity to prostaglandins. As an oxytocic agent, prostaglandin E2 should be avoided in scenarios in which vaginal delivery or the induction of labor is contraindicated and should be stopped before the administration of oxytocin. 

Suppository

Clinicians should avoid the suppository should in patients with acute inflammatory pelvic disease, as well as patients with active cardiac, renal, pulmonary, or hepatic disease. Additionally, it requires caution in patients with a history of these diseases as well as with a history of cervical malignancy, asthma, hypo- or hypertension, anemia, jaundice, pulmonary disease, or epilepsy. The prostaglandin E2 suppository is not indicated for uterine evacuation for fetuses at the stage of viability.[11]

Gel/Insert

The gel or insert versions used for cervical ripening are contraindicated in patients with fetal distress where delivery is not imminent, or who have vaginal bleeding during pregnancy, marked cephalopelvic disproportion, and/or multipara with six or more previous term pregnancies. Prostaglandin E2 should also be avoided when prolonged uterine contraction may pose a risk to uterine integrity or fetal safety, such as with prior cesarean section or major uterine surgery. Prostaglandin E2 for the induction of labor should also be avoided in patients with a history of asthma, glaucoma, or heart disease.[12]