Background
Cesarean section (CS) is the most frequently performed surgical procedure in the world. An increasing rate of CS has increased the rate of a uterine scar after surgery [
1,
2]. Pregnant women who already underwent CS are usually recommended two delivery options: trial of labor after a previous cesarean delivery (TOLAC) or elective repeat CS. However, repeated CS is associated with an increased risk of morbidity and mortality. On the other hand, TOLAC has fewer complications, and faster recovery compared with CS [
3,
4] and provides an option for women who are willing to undergo vaginal birth after a cesarean section (VBAC) [
5]. Yet, TOLAC has also been associated with certain maternal and neonatal complications as well as the more stringent criteria [
3,
6].
Symptomatic uterine rupture is the most serious complication of TOLAC [
7] and an uncommon obstetric emergency. Its reported incidence is approximately 1%, with a range of 0.3–1.7% during the trial of labor [
8‐
10]. In 1995, the American College of Obstetricians and Gynecologists (ACOG) concluded that oxytocin use for induction or augmentation of labor in TOLAC had no contraindications [
11]. Flamm et al provided evidence in support of this conclusion [
12]. However, some studies reported that the increased risk of uterine rupture might be associated with oxytocin induction or augmentation after controlling for potential confounders [
13,
14]. Moreover, other studies have reported an increased rate of uterine rupture associated with either high-dose oxytocin or the use of oxytocin in the latent phase [
15,
16]. Also, the administration of oxytocin during the process of labor was found to be related to an increased rate of uterine rupture [
17,
18].
This meta-analysis aimed to evaluate the safety of oxytocin in TOLAC and compared the risk of uterine rupture between women using oxytocin and those not using oxytocin during TOLAC, and the risk of uterine rupture between oxytocin augmentation among women with spontaneous labor and those who had a successful induction of labor.
Discussion
The primary purpose of the current meta-analysis was to systematically identify the effect of oxytocin on the risk of uterine rupture in TOLAC. In addition, we also explored differences in the usage rate of oxytocin, rate of VBAC between spontaneous delivery and induction of labor. In this study, we identified 14 studies, which included 48,457 women undergoing TOLAC. The results showed that women with spontaneous delivery had a higher rate of VBAC and lower risk of uterine rupture than those with the induced labor. The risk of uterine rupture increased in women using oxytocin in TOLAC compared to those not using oxytocin in TOLAC. Moreover, we compared the risk of uterine rupture in augmentation among women with spontaneous labor and women who had a successful induction of labor whilst controlling for potential factors, which revealed no significant statistical differences. These data revealed that the process labor induction or cervix condition might influence the effect of oxytocin on the uterine.
In our study, the VBAC rates in women with spontaneous delivery and labor induction were 74.3 and 60.7%, respectively. These results were consistent with a previous report, which suggested that the average success rate of a TOLAC resulting in a VBAC ranges between 60 and 80% [
36‐
40]. We also found that the VBAC rate was significantly different between women with spontaneous and induction labor. Some mechanisms, such as inflammatory cytokines, regulation of endocrine hormone, and mechanical stimulus, may contribute to these differences [
41]. Besides, we found that the rates of oxytocin usage in women with spontaneous and induction labor were 39.8 and 60.6%, respectively, though there was no significant difference between groups. Other prognostic variables, including maternal age < 40 years, ethnicity, body mass index (BMI) < 30, gestational age < 40 weeks, infant birth weight < 4 kg, and higher admission bishop score might also influence the results [
42,
43]. However, we were unable to obtain enough information to separately analyze these variables.
Our results demonstrated a low rate of uterine rupture in women attempting TOLAC with spontaneous versus induced labor (0.7% versus 2.2%,
p = 0.0003). A previous study found that the rate of uterine rupture was from 0.15 to 5.5% in women with spontaneous labor and from 0.3 to 10.7% in women with induced labor [
44]. Thus, we concluded that the rate of uterine rupture tends to vary from study to study, which may be partly due to the way uterine rupture is defined in researches. Generally speaking, uterine rupture includes complete uterine rupture and incomplete rupture (uterine scar dehiscence). This study took a definition of complete uterine rupture. However, incomplete uterine rupture is defined as a disruption of the uterine muscle with intact uterine serosa, which is mostly asymptomatic. Different conditions may lead to different outcomes. Complete uterine rupture is associated with severe maternal (risk of hemorrhage with a need for transfusion, hysterectomy) and perinatal (risks of anoxoischemic encephalopathy, and even fetal death) morbidity and mortality. In addition, it remains one of the most catastrophic obstetrical emergencies [
45]. However, uterine dehiscence has little to no consequence on immediate maternal or neonatal morbidity and is only detected in cases of emergency cesarean section [
46]. To avoid the effect of ambiguous definition on heterogeneity, we have calculated the pooled effect by excluding the studies that did not have a clear explanation of uterine rupture. The results showed that heterogeneity obviously increased, which proved that heterogeneity did not come from the ambiguous definition. Moreover, an unavoidable source of heterogeneity may come from the medical level in different areas. In a general way, senior or specialized hospitals may have more experience and the ability to prevent and treat a uterine rupture. In contrast, junior or comprehensive hospitals may have a higher rate of uterine rupture. It may cause the main heterogeneity of these results, but we need more detailed information to deal with this issue.
The most exciting aspect of our study was the safety of oxytocin using in TOLAC. Consequently, we compared the rate of uterine rupture in women using oxytocin and not using oxytocin in TOLAC (1.4% versus 0.5%). We found that oxytocin may increase the risk of uterine rupture in TOLAC. According to the previous researches, the association between oxytocin and uterine rupture remains unknown. In Goetzl’s study, no difference in oxytocin duration or oxytocin dose was found between cases of uterine rupture and controls [
47]. Contrary, Landon et al reported that augmentation and induction with oxytocin were associated with an increased risk of uterine rupture [
6]. In the studies of Cahill et al, there was a dose-response relationship between maximum oxytocin dose and risk of uterine rupture. They argued that higher maximum dose of oxytocin should be cautiously used in a trial of labor after cesarean and that an upper limit of oxytocin in TOLAC should be 20 mU/min [
48,
49], which suggested that long-time exposure to oxytocin in TOLAC is positively correlated with higher risk of uterine rupture. This provided an explanation for why women who had more labors induced with oxytocin were at greater risk of uterine rupture than those with spontaneous labor.
To further investigate how oxytocin increases the risk of uterine rupture, we compared the risk of uterine rupture in labor augmentation among women with spontaneous labor and women with successfully induced labor. We found no statistical significance between groups, which supported the premise that the process of induction labor or individual cervix condition may change the effect of oxytocin and increase the risk of uterine rupture. Previous researches reported that other potential factors, such as induction of labor with prostaglandin or Foley catheters, could also increase the risk of uterine rupture compared to spontaneous delivery [
50,
51]. The process of induction may make scarred uteruses more sensitive and brittle. Our study also showed that neither oxytocin nor other way of induction could indirectly increase postpartum complications; however, this needs to be further investigated by future studies. Another possible cause of increased risk may be the individual cervix condition. Unfavorable cervix could enhance the difficulty of parturition, which in turn could increase the chances of exposure to risk factors. The Bishop score is commonly used in most clinical evaluations for the ripeness of the cervix. A previous study reported that women who underwent induction with a favorable cervical score had a lower rate of uterine rupture [
52]. While this assessment tool is not perfect in its repeatability and objectivity, currently it is the best option [
53]. More suitable evaluation tools need to be developed to help clinical observation.
Limitations
The present meta-analysis has some limitations. First, we could only make the conclusion on the risk association between oxytocin and uterine rupture. However, different protocols of oxytocin use in TOLAC may lead to different outcomes. Thus, more studies are needed in the future. Second, the high heterogeneity among the included studies could not be ignored. Though we have excluded the influence of the diagnosis, other potential factors, such as maternal age, ethnicity, BMI, gestational age, infant birth weight, higher admission bishop score, medical level, and so on could also be relevant. However, it was not possible to obtain more detailed information from the included studies. Though it is common for meta-analyses of observational studies to present high heterogeneity, more studies in the future are necessary. In addition, we have made the Newcastle-Ottawa Scale to evaluate and ensure the quality of the included studies so as to reduce bias as much as possible.
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