The present results suggest that women with abnormal labor patterns are at a risk of PPH, regardless of uterotonics use. We assumed that innate poor uterine contractility lead to the reported abnormal labor patterns: hypotonic uterine dysfunction, prolonged labor, and arrest of labor.
Previous studies have reported that longer duration of labor, particularly during the second stage of labor, induction or augmentation of labor, or instrumental delivery, were independent risk factors for PPH [4, 7, 16, 19, 20]. Another study reported that women with PPH secondary to uterine atony were exposed to oxytocin for a longer duration of time and required higher maximal oxytocin dosing for delivery [18]. Additionally, one study reported that repeated dinoprostone vaginal insets increase the risk of PPH [21]. These previous reports were, in part, consistent with our findings. However no previous studies have focused on the innate uterine contractility and its role in PPH.
Our study is novel in that we examined the risk factor for PPH by separated according to the use of uterotonics and the diagnosis of abnormal labor patterns. In previous studies, it is unclear if the provided risk factors include both medical indications and medical interventions. For example, women with a longer duration of labor will be augmented by uterotonics. If the uterine contractility is still insufficient after the administration of uterotonics, more uterotonics may be required. It might be difficult to judge which one causes PPH. Therefore, medical indications and medical interventions should be considered separately.
The present results showed that women who were diagnosed with abnormal labor patterns in the first or second stage of labor had an increased risk of PPH, regardless of uterotonics use. This suggests that the administration of uterotonics alone might not be responsible for PPH. We hypothesized that an innate uterine dysfunction was underlying the abnormal labor patterns that were associated with PPH.
Uterine contraction in the third stage for postpartum hemostasis depends on two kinds of hormones, oxytocin and prostaglandins, as in the first and second stage. At the time of labor, oxytocin and prostaglandins bind to cell-surface receptors, causing depolarization of the uterine myocyte, which in turn promotes the opening of ligand-regulated calcium channels. Increased intracellular calcium activates myosin-light chain kinase, which activates myosin. Consequently, myocyte contractility is activated [23]. After delivery, myometrial fibers surrounding the maternal spiral artery of the placental bed contract owing to the oxytocin and prostaglandin stimulations, and then myometrial contraction compresses the spiral arteries and veins. As a result of myometrial contraction, the uterine walls strongly oppose one another. It is thought that these mechanisms regulate hemostasis in the third stage of labor [24]. During labor, oxytocin is released in pulses, increasing in both the frequency and duration of pulse as labor progresses [25]. Additionally, myometrial oxytocin receptor (OXTR) density increases throughout pregnancy [26]. Prostaglandins are potent stimulators of myometrial contractility, and among many prostaglandin classes, PGE2 and PGF2ɑ are involved in uterine contractions. Large amounts of prostaglandins are released in the third stage of labor, and plasma levels of PGF2ɑ reach their maximum and start to decline within 10 minutes after placental separation [27]. These studies suggested that prostaglandins play an important role in securing hemostasis by way of myometrial contraction in the third stage of labor. In women with clinically abnormal labor patterns, we assumed that there is some dysfunction in the above described mechanisms. Namely, uterine contractility might be poor in the first two stages of labor (sometimes uterotonics may be required). Subsequently, in the third stage of labor, the myometrium intrinsically may not be able to contract, fails to respond to hemostatic regulation, which may result in PPH. Some pathogenic dysfunction may also play a role, including such as the synthesis dysfunction of oxytocin and prostaglandins or decreased sensitivity or expression of OXTRs, FP receptors, EP1 receptors, or EP3 receptors. Reinl et al. [28] have suggested that some OXTR gene variants are associated with increased oxytocin responsiveness during labor. Grotegut et al. [29] reported that the genetic variation in OXTR and gene encoding G protein-coupled receptor kinase-6, which regulates desensitization of the OXTR, is associated with the amount of oxytocin required as well as the duration of labor.
Uterine fatigue and lactate accumulation in myometrium might also contribute to uterine dysfunction. Under muscle contraction, lactic acid is produced by glycolysis in all human cells. Under myometrium contraction during labor, lactate is produced, which leads to intracellular acidification. Intracellular acidification inhibits the calcium channels in myometrial cells and decreased intracellular calcium will lead to a weakening of the myometrial contraction [30, 31]. Thus, women diagnosed with abnormal labor patterns might include cases of lactate-induced uterine dysfunction.
Our findings suggested that women used uterotonics even in the absence of diagnosis of abnormal labor patterns had increased the risk of PPH. Aside from abnormal labor patterns, indications for use of uterotonics include HDP, FGR, PROM, post-term pregnancy, or prevention of macrosomia. Unfortunately, there are no indications for use of uterotonics in this database. In the obstetric clinical situation, oxytocic agents are routinely used in the first two stages. Previous studies have reported that prolonged or large amounts of oxytocin exposure, which may lead to the downregulation of OXTRs and failed uterine involution, results in PPH [6]. OXTR desensitization has been demonstrated in in vitro studies [32–34]. There is no consensus on whether prostaglandin use is a risk factor for PPH, however some studies have demonstrated an association between prostaglandin use and an increase risk for PPH [17, 35, 36]. One possible reason for increased PPH risk in women who used uterotonics without abnormal labor patterns may be due to the above-mentioned mechanisms.
In this study, we could use true low-risk subjects extracted from a large-scale clinical database certified by JSOG, defined as primiparous women who had live birth to singleton fetus via vaginal delivery in cephalic presentation at 37 weeks’ gestation. For caesarean delivery, the amount of bleeding has been reported to be almost twice that of vaginal delivery [12, 14]. Some reasons for this result include: the effects of anesthesia, bleeding from a myometrial incision, active bleeding persisting after suture of the incision, or the effects of surgical procedures. Additionally, the amount of bleeding might include the amniotic fluid volume. Therefore, PPH after vaginal delivery and PPH after caesarean delivery should be assessed separately. Furthermore, we excluded women who had well-established risk factors for PPH, including coagulopathy, uterine leiomyoma, placental abruption, placenta accreta, low-lying placenta, polyhydramnios and HDP, which could be determined within the antenatal period [6, 9, 14, 17].
HDP is an independent risk factors for PPH, as previous studies have demonstrated [37, 38]. Particularly in preeclampsia, patients are usually hypovolemic, so they are more likely to receive blood transfusions than in those with a normal pregnancy [39]. In addition, angiogenic factors, which are strongly associated with an increased risk of preeclampsia, also play an important role in the clotting system through the activation of coagulation and vascular thrombosis [40]. Positive association between angiogenic factors and postpartum bleeding has been reported [37]. This is because women with HDP were excluded from this study.
Additionally, we excluded women who were administered epidural analgesia during labor. A meta-analysis of randomized trials comparing epidural with non-epidural analgesia in women in labor reported that epidural analgesia prolongs the second stage of labor and increases the likelihood of requiring an instrumental vaginal delivery [41]. The use of epidural analgesia may change the course of labor from the course of a woman's natural uterine contractility. On the other hand, the prolonged labor itself is also an indication for epidural analgesia. It is difficult to judge which of the above factors individually caused PPH. In Japan, only a few obstetric hospitals perform epidural analgesia, thus the rate of women who receive epidural analgesia during labor in Japan was only 6.1% [42]. Therefore, for generalizability in obstetric hospitals, women received epidural analgesia were excluded from this study.
In this study, we were able to use a sufficient sample size even after strict extraction and adjustment for several other risk factors for the analysis because of a large-scale database. There are no studies in Japan that have investigated the risk factors for PPH using such a large sample size. Furthermore, contrary to previous studies [18, 43], detailed information about the type of uterotonics allowed us to investigate their effects on PPH according to the type and number of uterotonics required during delivery.
However, this study had some limitations. First, this database is not a national registry, so, between 2013 and 2016, it covered only 22.1% of the total live births and stillbirths. Among the facilities registered in this database, the tertiary perinatal medical centers included 85 facilities in 2013, 87 facilities in 2014, 91 facilities in 2015, and 103 facilities in 2016, indicating that > 70% of the facilities in this database are referral hospitals; hence the sample is not representative of all delivery cases. Second, there is no detailed information of the indication, timing, and dosage of uterotonics administration, including oxytocin and prostaglandins. Third, according to the ACOG reVITALize program [44], PPH was defined as cumulative blood loss ≥ 1,000 mL or blood loss accompanied by signs or symptoms of hypovolemia within 24 hours after the birth progress regardless of route of delivery. In this database, however, the amount of bleeding within only 2 hours after delivery was registered and signs or symptoms of hypovolemia was not registered. Therefore, women with blood loss of ≥ 1,000 mL or women who received blood transfusion were defined as PPH cases to compensate for the above missing information.