Discussion
If the placenta does not separate from the uterus after delivery, the NICE and the WHO guidelines recommend that the placenta should be removed manually within 30 minutes to 1 hours after delivery with a set-up to deal with heavy bleeding. If bleeding does not stop, UAE or hysterectomy is required4). In Europe and the United States, deliveries are centralized in regional general hospitals. This allows obstetrical providers to perform MROP under anaesthesia, which is performed by anaesthesiologists. In Japan, on the other hand, private clinics handle half of all deliveries, and high-risk cases are transported to advanced medical facilities. As a result, many cases with RPOC have been referred to our hospital. In this study, 41 cases of RPOC delivered after 34 weeks of gestation were successfully treated without hysterectomy or death. The strengths of this retrospective study are as follows: (i) The research period was relatively short (10 years), and the participants were treated consistently. (ii) The clinical characteristics of the participants were homogeneous and were limited to cases delivered after 34 weeks of gestation. (iii) The detailed clinical course of surgical removal and spontaneous disappearance of RPOC was clarified in all cases.
In this study, 15 of 19 cases with MROP within 24 hours of delivery experienced heavy bleeding during the procedure or the following day. A Japanese multicentre retrospective study demonstrated that the incidence of bleeding of 1000 ml or more at delivery was significantly higher in 41.1% of the women who underwent MROP than in 4.1% of those who did not17). The cause of heavy bleeding during or after MROP is considered to be that uterine contraction cannot prevent damage to large blood vessel, which occurs after MROP when decidua formation is insufficient or absent18). In one study, seven of 37 MROP cases were reported to have undergone hysterectomy due to massive bleeding, and those cases were pathologically diagnosed with placenta accreta and no decidua formation19). Interestingly, in the current study, when MROP was performed on patients with no bleeding or other emergencies, heavy bleeding and partially retained placenta were frequently observed both intraoperatively and postoperatively (Figure 1A). This result suggests that MROP immediately after delivery should be avoided in cases of retained placenta without bleeding because of extensive decidual defect and placental adhesion.
Of the 22 RPOC cases managed conservatively, six cases experienced spontaneous heavy bleeding. Previous studies reported that the RPOC diameters ≧ 4 - 4.4 cm6,8) or blood flow in RPOC7,21) had been associated with heavy bleeding during conservative management of RPOC. However, these studies differ from the present study in several respects. First, these studies included cases before 20 weeks’ gestation6-8, 21). Although the size of RPOC is smaller, trophoblast cell viability is higher in early and mid-pregnancy than in late pregnancy20). Furthermore, these studies included cases in which the placenta was manually removed within 24 hours after delivery6,8). Therefore, the results of previous studies were based on a heterogenous population and may have had various biases. In the present study, there was no correlation between heavy bleeding and RPOC size or blood flow (Table S1). Further research is needed to determine the relationship between RPOC size, blood flow, and heavy bleeding.
The median time for conservatively treated RPOC to develop massive bleeding is reported to be 22-42 days, with a maximum of 38-43 days6,8). In this study, no events such as heavy bleeding, blood transfusion, UAE, or infection, were observed after 60 days during conservative management (Figure 2). This result may help patients understand when the risk of bleeding decreases during conservative management. There were six cases in which placental removal was attempted despite the absence of heavy bleeding (Figure 1B). None of the cases resulted in the removal of the placenta, and afterwards, the placenta spontaneously disappeared. Therefore, if conservative management does not cause bleeding or infection, placental removal should be avoided and spontaneous resolution can be expected. In this study, the rate of RPOC disappearance during conservative management was approximately 50% at 100 days and 80% at 1 year (Figure 3). In previous studies, the time to spontaneous disappearance of RPOC ranged from 48 to 84 days6,7,22,23), which was shorter than that in the present study, likely due to the small size of RPOC in early to mid-pregnancy. This study is the first to demonstrate the time until spontaneous resolution of RPOC in late pregnancy. More research is needed to determine whether these data can be validated under the same conditions.
The half-life of serum hCG after intramuscular injection of hCG is 30-32 hours in the absence of hCG-producing tissues in the body24). The longer half-life indicates that hCG-producing trophoblast cells do exist, but gradually undergo apoptosis. In RPOC cases delivered at before 22 weeks of gestation, serum hCG has been reported to be below the measurable threshold at 67 (6-183) days postpartum, and no cases experienced heavy bleeding afterwards22). The present study also showed that heavy bleeding did not occur when serum hCG levels fell below the measurable threshold. Therefore, it is important to measure serum hCG levels over time to assess the risk of heavy bleeding. We previously reported an average serum hCG half-life of 5.2 days in five cases of RPOC25), similar to the average of 4.7 days in this study (Figure 4A). Interestingly, in three cases, serum hCG levels decreased rapidly after UAE (Figure 4B), suggesting that acute interception of uteroplacental blood flow causes sudden death of trophoblast cells. There were cases of RPOC after 20 weeks’ gestation in which the half-life of hCG exceeded 10 days (Figure 4D), but there were no such cases after 34 weeks. The molecular mechanisms of apoptosis in post-partum trophoblast cells may differ between early and mid-term and late pregnancy. Methotrexate is effective in treating ectopic pregnancy and RPOC during early pregnancy26,27). Methotrexate has also been used for RPOC in late pregnancy9), but its effectiveness has yet to be proven. The effect of methotrexate on RPOC in late pregnancy should be confirmed by measuring serum hCG half-life and comparing it with the data obtained in this study.