The association between history of retained placenta and success rate of misoprostol treatment for early pregnancy failure

Early pregnancy failure (EPF) is estimated to occur in 10–20% of all clinical pregnancies and is one of the most common complications of early pregnancy [1]. While traditionally surgical intervention, i.e. dilatation and curettage (D&C) was considered to be the preferred treatment option, over the past two decades, medical treatment has become increasingly popular showcasing high efficacy and safety with few adverse events [2‐6]. Moreover, medical treatment does not appear to impair future fertility potential [7, 8]. Several studies have compared medical treatment to surgical intervention for treatment of EPF showing favorable results [9‐11]. This has led to a shift in paradigm and nowadays medical treatment is considered the primary approach for treatment of EPF.

The common medical treatment for EPF is misoprostol (PGE1) which can be administered orally, buccally or vaginally. Side effects are for the most part mild with few reports of major adverse events [10]. Advantages of vaginal administration compared to the oral route include decreased side effects such as nausea, diarrhea, vomiting and abdominal pain [12].

Success rate of treatment with misoprostol for EPF has been reported to range from 50 to 84% [13‐15]. Previous studies have attempted to discover variables which may affect treatment efficacy. Dosage, route of administration, gestational age, gestational sac size and fetal size have all been suggested as factors which may influence treatment success [16‐19].

Retained placenta affects 0.5-3% of all vaginal deliveries [20]. This clinical scenario is associated with substantial morbidity for women following vaginal delivery mostly due to post-partum hemorrhage. Several mechanisms have been proposed to explain retained placenta such as failed myometrial contraction and partial placenta accreta preventing placental detachment [20, 21]. Notably, treatment with misoprostol has not previously been shown to increase risk of placental complications [22]. Instead, it is plausible that there may be similar mechanisms, such as abnormal implantation or impaired uterine contractility, that may be associated with both failure of medical treatment of EPF and retained placenta after vaginal delivery. However, to date, the association between retained placenta and treatment success rate of misoprostol for EPF has yet to be evaluated.

The aim of this study was to test the hypothesis that patients with a history of complete or partial retained placenta were more likely to have failed medical management of EPF compared to women without a history of retained placenta. We further investigated the connection between medical, clinical and sonographic parameters and treatment success.

We conducted a retrospective cohort study at a tertiary university medical center from 2006 to 2021. Institutional ethical review board approval was received (0627-22-HMO).

The cohort included women up to 13 weeks gestation diagnosed with EPF who underwent medical management. Women with a case of manual placental extraction or uterine cavity inspection at time of delivery or retained placenta with need for medical intervention post-partum in a previous pregnancy comprised the study group. The control group included cases collected for a previous study we conducted, comprised of women who underwent treatment with misoprostol for EPF without history of retained placenta between January 2011 and June 2012. Excluded from both groups were non-singleton pregnancies, cases of scar pregnancy, patients with allergy to prostaglandins and women who did not complete the full protocol of medical treatment.

Early pregnancy failure was defined as missed abortion or blighted ovum up to 13 weeks gestation. Diagnosis of missed abortion was made according to the criteria established by Doubilet et al. [23]. Crown rump length (CRL) of 7 mm and mean sac diameter of 25 mm with the absence of cardiac activity on trans-vaginal ultrasound (TVUS) were considered indicative of missed abortion. Further criteria included absence of a visible heartbeat over 2 weeks after a scan showing a gestational sac without a yolk sac or over 11 days after a scan showing a gestational sac with a yolk sac [23].

Confirmation of EPF was established by TVUS scan performed in our medical center reviewed by a specialist in obstetrics and gynecology. According to our routine clinical pathway, following diagnosis each woman was offered one of three options: expectant management, surgical treatment (dilatation and curettage) or medical treatment with vaginal misoprostol. Women were counselled regarding benefits and risks of each option. Those who opted for medical treatment with vaginal misoprostol were eligible for inclusion in the study.

Our department’s protocol for administration of misoprostol has been described previously [24]. In short, following examination by a gynecologist and receipt of informed consent, 800 mcg of misoprostol (4 tablets of Cytotec 200 mcg each) are placed in the posterior vaginal fornix. All patients are asked to present again to the hospital 48–72 h after treatment for an ultrasound scan. If this ultrasound shows a gestational sac or endometrial thickness of above 20 mm, an additional dose of 800 mcg of misoprostol is administered in the same fashion described above. Patients are then instructed to undergo another ultrasound after two weeks or after the next period and if there is still evidence of retained products of conception, they are referred for surgical management. According to our department’s protocol, when the gestational sac is present, women are referred to undergo D&C as opposed to cases of increased endometrial thickness for which operative hysteroscopy is the treatment of choice.

Women in the study group had at least one case of retained placenta following delivery during a previous pregnancy. Retention of placental products included the need for manual placental removal, partial placental evacuation requiring manual inspection of the uterine cavity or retained products of conception diagnosed during the post-partum period. Patients with any one of these clinical scenarios were eligible for inclusion in our study group. Diagnosis of placental retention was made by the most senior physician in the labor and delivery ward at the time. Diagnosis of post-partum retained products of conception was confirmed with pelvic ultrasound.

Data were retrieved from the electronic medical record and included demographic, clinical and sonographic characteristics such as age, gravidity, parity, previous miscarriage, previous treatment with misoprostol, size of gestational sac, fetal crown-rump length (CRL), presence of fetal heart rate on ultrasound prior to diagnosis of EPF, uterine position and treatment success.

The primary outcome was successful medical treatment compared between women who had an event of retained placenta and women who did not. Successful treatment was defined as endometrial thickness of less than 20 mm with no evidence of retained products of conception after one or two doses of misoprostol.