Pregnancy Complications and Risk of Uterine Rupture: a Study Based on More Than 9 Million Singleton Pregnant Women

To investigate whether pregnancy complications are associated with increased risk of UR and how that risk changes with gestational age. We obtained all data from China’s National Maternal Near Miss Surveillance System (NMNMSS) between 2012 and 2018. Poisson regression analysis was used to assess the risk of UR with pregnancy complications (preeclampsia, gestational diabetes mellitus, placental abruption, placenta previa and placenta accreta) among 9,502,250 pregnant women. Furthermore, we analyzed the risks of UR with pregnancy complications in different gestational age groups. Compared to women without pregnancy complications, those with different complications (except for preeclampsia) had a 1- to 3-fold greater risk of UR. These associations also persisted in women without previous cesarean delivery. Women with placental abruption or placenta accreta had an increased risk of UR in all gestational age groups, while the increased risk of UR among women with placenta previa was only observed at term. Moreover, an increased risk of UR among women with gestational diabetes mellitus was only observed at 32 to 36 weeks gestation and increased with the offspring’s birth weight. Better quality antenatal care and early intervention for women with these pregnancy complications are needed to minimize the incidence of UR. infections), thrombophlebitis, renal disease, lung disease, and connective tissue disorders. the effects of preeclampsia/eclampsia and gestational diabetes mellitus on UR risk. A population-based Negev study of 138 pregnant women with UR found that hypertension disorders (including preeclampsia/eclampsia) were associated with a twofold increased risk of UR (OR: 2.05, 95% CI: 1.20-3.50), but diabetes mellitus (prepregnancy and gestation) was not related to the risk of UR (OR: 0.87, 95% CI: 0.41-1.86) . However, this study was limited the diagnoses of hypertension disorder and diabetes mellitus did not distinguish between the different subtypes. In contrast, we found that gestational diabetes increased the risk of UR (aOR:1.22, 95 % CI: 1.05-1.42), but preeclampsia did not increase the risk of UR (aOR:0.83, 95 % CI: 0.64-1.08). Our nding was similar to results from two previous studies, where gestational diabetes increased the risk of UR (aOR:5.78, 95% CI: 1.12-20.00) 29 , and eclampsia was not related to the risk of UR (aOR: 0.08, 95% CI: 0.01-0.71) 18


Introduction
Uterine rupture (UR) is a tear in the uterine wall that occurs before or during labor. It poses considerable risks for adverse maternal and perinatal outcomes, including serious health risks for both mothers (e.g., maternal death) and fetuses (e.g., stillbirth, neonatal death) 1,2 . Mounting evidence supports that a history of cesarean section is a major risk factor for UR in subsequent pregnancy 1,3 . The incidence rate of UR varies across countries, ranging from 0.18 to 9 cases per 1,000 pregnant women 1,4,5 . Many countries have created policies to decrease cesarean rates 6,7 , but the UR rate has increased over the years 8,9 . It is unknown whether the increasing rate of UR is due to the effects of potential risk factors related to a history of cesarean section.
Evidence suggests that women who have a history of cesarean section may be at increased risk of pregnancy complications, such as placental abruption, placenta previa, placenta accreta, gestational diabetes mellitus and preeclampsia [10][11][12] . These pregnancy complications may be partly considered as manifestations of dysfunctional placental functions 13,14 . To date, placenta accreta has been reported to be associated with an increased risk of UR 15,16 . However, there are limited data on the association of other pregnancy complications with UR. Few studies with small sample sizes have analyzed the impacts of diabetes and hypertension on the risk of UR 5,17,18 , but these studies yielded different conclusions. In addition, current guidelines only discussed the impact of vaginal trial delivery after cesarean section on the occurrence of UR 19,20 , but the effects of pregnancy complications related to previous cesarean deliveries were not reported. If a link between pregnancy complications and UR is con rmed, it may provide additional preventive measures.
We hypothesize that pregnancy complications (preeclampsia, gestational diabetes mellitus, placental abruption, placenta previa, placenta accreta) may be associated with an increased risk of UR. Therefore, our study analyzed more than 9 million singleton pregnant women from China's National Maternal Near Miss Surveillance System (NMNMSS) to evaluate whether these pregnancy complications were associated with the risk of UR. By analyzing the impact of each pregnancy complication in different gestational age groups, we provided insights into the early interventions that would contribute to reducing the incidence of UR in pregnant women.

Design and setting
We obtained data from China's National Maternal Near Miss Surveillance System (NMNMSS) between 2012 and 2018. The system covers 438 hospitals in 326 districts or counties throughout 30 provinces, each of which manages more than 1,000 deliveries annually 9 . Data collected included sociodemographic characteristics, obstetric history, pregnancy complications, and pregnancy outcomes of all pregnant or postpartum women in a hospital. Doctors in each hospital were trained to collect data prospectively from admission to discharge. Quality assurance was ensured by staff from county-level, municipal-level and provincial-level maternal and child health hospitals1-2 times a year. At the same time, the National O ce for Maternal and Child Health Surveillance veri ed the quality of the records by selecting 6-8 hospitals randomly in each province once a year 21  Data used in our study is not publicly available, and all methods were performed in accordance with the relevant guidelines and regulations.

Study population
We restricted the analysis to pregnant women with singleton births who delivered at a gestational age of 14 weeks or more. Women with multiple pregnancies were not included because they were prone to the occurrence of pregnancy complications 22 and UR 23 . Women without information on delivery method, history of cesarean section, or gravidity were excluded. We also excluded women with an unlikely combination of gravidity and parity. This left a total of 9,502,250 women for the study.
Variable de nition UR was de ned as uterine or lower uterine dehiscence during late pregnancy or delivery, including complete and incomplete UR 9 . We identi ed ve pregnancy complications related to previous cesarean delivery for analysis: preeclampsia, gestational diabetes mellitus, placental abruption, placenta previa and placenta accreta 11,12 . Preeclampsia includes pregnancies with preeclampsia, eclampsia or HELLP (hemolysis, elevated liver enzymes and low platelets) syndrome, as well as chronic hypertension with superimposed preeclampsia. Gestational diabetes is diagnosed by an oral glucose tolerance test (OGTT) during pregnancy.
We selected variables that may be related to the occurrence of UR, including region, hospital level, gestational age, the number of antenatal visits (none, 1-3, 4-6, 7-9, ≥10), education level (none, primary school, middle school, high school, college or higher), maternal age at delivery (20, 20-24, 25-29, 30-34, 35-39 and ≥40 years old) , fetal presentation (cephalic and other abnormal lies), birthweight (<2500, 2500-4000 and >4,000 grams), and mode of delivery (vaginal delivery and cesarean section). We divided China's regions into three categories (eastern, central and western) and classi ed hospitals into three levels (the rst level represents the smallest hospital) according to standard de nitions 21 . Gestational age was de ned based on ultrasound measurement results or estimated from the date of the last menstrual period and classi ed as 14-31 weeks, 32-36 weeks, or ≥ 37 weeks. Other factors thought to be associated with UR included gestational hypertension, chronic hypertension, heart disease, hepatic disease, severe anemia (hemoglobin concentration lower than 70 g/L), infections (excluding abortionrelated infections, puerperal infections and abdominal incision infections), thrombophlebitis, renal disease, lung disease, and connective tissue disorders.

Primary analysis
We expressed the UR rate as the number of pregnant women with UR per 1,000 pregnant women. Since some women giving birth in township hospitals were not included in the NMNMSS, we weighted the UR rate for the sampling distribution of the population according to the 2010 census of China, as detailed elsewhere 21 .
Pregnancy complications were classi ed into 5 separate categories: preeclampsia, gestational diabetes mellitus, placental abruption, placenta previa, and placenta accreta. We used Poisson regression with a robust variance estimator to assess the association of UR with pregnancy complications, reporting the results from two models. The reference for each model was women without any of the ve pregnancy complications. Model 1 describes the crude odds ratio (cOR) and 95% con dence Interval (CI), taking into account the sampling distribution of the population and birth clustering within hospitals. Model 2 further adjusts for medical institutionsand pregnant women's sociodemographic and clinical factors that might contribute to the observed associations. We did not adjust for gestational age or nal mode of delivery because they included consequences of UR (i.e., laparotomy due to UR). To identify the most robust and stable model, we investigated both multicollinearity and model goodness-of-t.
Due to a history of cesarean section related to both pregnancy complications 1,3 and UR 10-12 , pregnancy complications may be only an intermediate factor in the causal chain between a history of cesarean section and the risk of UR. To examine whether the association of UR with pregnancy complications still existed in women without previous cesarean delivery, we divided women into two subgroups (with and without previous cesarean delivery) and repeated the association analysis of pregnancy complications with UR.

Secondary analysis
Restricting to a group of women To investigate the association between pregnancy complications and UR without potential maternal confounding factors(advanced maternal age 1 and multiple gravidities 24 ), we performed sensitivity analyses excluding women with advanced maternal age (≥35 years) and/or multiple gravidities (≥4). Given the possible impacts of abnormal fetal presentation and macrosomia on the occurrence of UR 25 , we restricted the association analysis to women with offspring having cephalic lies and birth weight of less than or equal to 4000 g.
Co-occurrence of pregnancy complications and UR risk Pregnancy complications may co-occur in a given pregnancy. We therefore repeated models 1 and 2 testing for the associations between having any two or more pregnancy complications and the risk of UR. Because the numbers were too small to assess unique combinations of pregnancy complications, we therefore modeled the variables no pregnancy complications, any one pregnancy complication, and any two or more pregnancy complications in a single model.

Risk of UR in different gestational age groups
To understand the distribution of women with UR by pregnancy complications and gestational age, we examined the proportion of women with UR in each pregnancy complication and gestational age group. We tested for an interaction between pregnancy complications and gestational age, comparing the UR rates in women for each pregnancy complication and gestational age against those in women without pregnancy complications at 14-31 weeks of gestational age.

Role of birthweight
To address a possible contribution of fetal weight among women with gestational diabetes mellitus, we analyzed the risk of UR strati ed by gestational age (32-36 weeks, ≥37 weeks) in three birthweight groups (<2500 g, 2500-3000 g, >3000 g).

Trends over time in UR rates
To assess whether the possible impact of changes in clinical practice over time were similar among women with different pregnancy complications, we reported UR rates and changes among these women during 2012-2018. Statistical analysis was performed using Stata (version 14.2, Stata Corp LP., College Station, United States of America). P<0.05 (2-sided) was considered statistically signi cant.

Patient involvement
Informed consent from the patient was waived from the Ethics Committee, as the data used in our study were obtained from a national routine surveillance system established by the government. Data use was authorized by the National Health Commission, and data provided to us were de-identi ed.

Results
Of the 9,502,250 pregnant women enrolled in this study, 892,069 (9.39%) women had pregnancy complications. Compared to women without pregnancy complications, women with pregnancy complications tended to be older, to have multiple gravidities and were more likely to have had a history of cesarean section (Table 1). At the time of birth, women with pregnancy complications had a higher percentage of preterm delivery, abnormal fetal presentation and macrosomia (Table 1).  Figure 1). For single events, gestational diabetes mellitus was the most common pregnancy complication, followed by preeclampsia, placenta previa, placenta accreta and placental abruption.

Trends over time in UR rates
There were 17,133 pregnant women with UR, giving a weighted UR rate of 1.6 cases per thousand pregnant women. Figure 2A shows that the rate of UR in women with pregnancy complications increased with the growing number of pregnancy complications during 2012 and 2018.
Notably, the rate of UR was markedly higher in women with pregnancy complications than in women without pregnancy complications, irrespective of medical institutions or pregnant women's sociodemographic and clinical factors. Moreover, the rate of UR increased substantially over time in women with preeclampsia, gestational diabetes mellitus, and placenta previa ( Figure 2B). The rate of UR in women with preeclampsia increased steadily from 1.

Risk of UR strati ed by history of cesarean section
The incidence rate of UR varied in women with different single-complications (Table 2), with the highest rate in women with placenta accreta (14.6‰). Except for preeclampsia, the other four pregnancy complications were associated with a signi cantly increased risk of UR before adjustment for risk factors (Table 2). These associations were slightly attenuated after adjusting for known sociodemographic characteristics and clinical risk factors, which remained unchanged.  The results were also similar after restricting the dataset to those women without advanced maternal age and multiple gravidities (Supplementary Table 2). When women with offspring having abnormal fetal presentation and birth weight of more than 4000 g were excluded, the risks of UR with pregnancy complications were largely unchanged (Supplementary Table 3

Role of birthweight
The rate of UR among women with gestational diabetes was highest at 32-36 weeks when the birth weight of their offspring was greater than 3000 g (Figure 3). Meanwhile, the risk of UR among women with gestational diabetes signi cantly increased with birth weight at preterm (Table  4). However, a trend toward increasing birth weight was not found at term.

Discussion
Main ndings Using data from more than 9 million singleton pregnant women in China, approximately one-tenth of all women had pregnancy complications, and most of these complications occurred as single events. The incidence rate of UR varied in women with different single-complications, and the highest rate was observed in women with placenta accreta (14.6‰). Gestational diabetes mellitus, placental abruption, placenta previa and placenta accreta were associated with a substantially increased risk of UR. The risks for UR were 1-to 3-fold higher among women with these pregnancy complications. The associations persisted in women without previous cesarean delivery. Moreover, women with placental abruption or placenta accreta had a signi cantly increased risk of UR in all gestational age groups.

Results in context
In our data, the largest increased risk of UR was seen for placenta accreta (aOR: 2.82, 95 % CI: 1.86-4.27). Among women without previous cesarean delivery, the risk of UR was approximately 11 times higher in women with placenta accreta than in those without pregnancy complications (aOR: 11.37, 95 % CI: 7.02-18.02). A large retrospective cohort study from Negev found that pregnant women with placenta accreta had a signi cantly increased risk of UR (OR: 6.42, 95% CI: 2.0-20.4) 15 . Moreover, previous research found that UR occurs in women without a history of cesarean section 3,26,27 , and identi ed spontaneous UR due to placenta percreta occurs in a primigravida woman without prior uterine operation 28 . Thus, our ndings were consistent with previous studies, suggesting that placenta accreta (especially placenta accreta without previous cesarean delivery) may increase the risk of UR. Furthermore, we found that approximately six percent of women had two or more pregnancy complications. A previous study identi ed that placenta previa has often been combined with placenta accreta, leading to a higher incidence of bleeding complications 30 . Moreover, placental abruption concurrently presentes with preeclampsia in the same pregnancy, and these two complications have a similar pathogenesis, such as placental ischemia 13 . The cooccurrence of preeclampsia and placental abruption was associated with worse maternal, fetal and neonatal outcomes (e.g., stillbirth/neonatal deaths) 31 . However, the combined effect of pregnancy complications on the risk of UR has been less closely studied. Our results indicated that having two or more pregnancy complications may increase the risk of UR (aOR: 1.43, 95% CI: 1.16-1.78), but we failed to assess the effects of unique combinations due to small samples.
The pathophysiological mechanism underlying the relationship between pregnancy complications and the occurrence of UR remains unclear.
As we all know, the occurrence of UR may be directly or indirectly caused by weak myometrium and excessive expansion of the uterine cavity. We speculate that the increased risk of UR may be due to pregnancy complications itself through a certain mechanism. For example, UR from placenta accreta occurs because the placental villi invades the myometrium at the site of placental implantation (particularly at a previous scar site), resulting in UR 16 . Stratifying our analysis by history of cesarean section revealed that placenta accreta was still associated with an increased risk of UR among women without previous cesarean delivery. The possible reason for this might be the thinning of the uterus after multiple induced abortions, resulting in placental accreta leading to UR. In addition, we hypothesize that pregnancy complications may indirectly increase the occurrence of UR by increasing the occurrence of certain obstetric complications. Our results support the hypothesis that macrosomia, which is related to gestational diabetes 32 , may increase the risk of UR 25 . In our study, we found that the increased risk of UR for women with gestational diabetes was observed only at 32 to 36 weeks gestation (aOR: 1.51, 95% CI: 1.05-2.18), and the risk of UR signi cantly increased with birth weight. Our ndings raise the possibility that UR may occur during the third trimester of pregnancy among diabetic women, when excess fetal growth leads to excessive expansion of the uterine cavity. Future research is required to investigate the mechanism of pregnancy complications on the occurrence of UR.
UR often occurs before or during labor without warning. The risk of UR would increase in the presence of predisposing factors, such as a history of cesarean section and its related pregnancy complications. Clinicians may tend to focus on women with a history of cesarean delivery, ignoring those without a history of cesarean delivery but with complications during pregnancy. Current guidelines developed by the American College of Obstetricians and Gynecologists (ACOG) and Royal College of Obstetricians and Gynecologists (RCOG) place a strong emphasis on the impact of vaginal trial delivery after cesarean section on UR 19,20 . Unfortunately, there is currently a lack of guidelines for pregnant women with pregnancy complications to prevent the occurrence of UR. For example, we found that a large-for-gestational-age fetus increased risk of UR in the third trimester among women with gestational diabetes mellitus. Our ndings suggest that controlling weight throughout pregnancy in women with gestational diabetes mellitus plays an important role in preventing the occurrence of UR. However, current guidelines developed by the ACOG only recommend that women with gestational diabetes mellitus should be counseled regarding the risks and bene ts of a scheduled cesarean delivery when the estimated fetal weight is 4,500 g or more 33 . In our study, we found that women with pregnancy complications tended to have more risk factors for UR, including advanced maternal age, multiple gravidities, abnormal fetal presentation, macrosomia and a history of cesarean section. Evidence has shown that accurate prenatal diagnosis and the standardized multidisciplinary team approach improve the pregnancy outcomes of women with placenta accreta 34 . Thus, standardized protocols for prenatal diagnosis and management of pregnancy complications should be established throughout pregnancy to reduce the occurrence of UR. Moreover, we found that UR usually occurred at term for women with pregnancy complications. Our nding supports the recommendation that women with uncomplicated placenta previa should have a planned delivery at 36-37 weeks of gestation to avoid hemorrhage 35 .

Strengths and limitations
Our study has a number of strengths. First, we used common protocols to collect data by uniformly trained clinicians, so the data quality was high. Second, the large sample size allowed us to analyze the risk of UR with different pregnancy complications for women with and without previous cesarean delivery. Third, this study included pregnant women with a wider gestational week; thus, we assessed the risks of UR for women with different types of pregnancy complications in different gestational age groups.
We acknowledge some limitations within this study. First, there was a lack of information on the duration and severity of pregnancy complications in our study. Therefore, there may be deviations in evaluating the impact of pregnancy complications on the risk of UR. Second, we did not distinguish between complete and partial UR 25 , so we cannot analyze the in uence of pregnancy complications on the different types of UR. Third, we were unable to obtain several variables that may be related to the occurrence of UR, including information on the intended mode of delivery 36 , the interval between this pregnancy and the last cesarean section 25 , and the history of other uterine operations (e.g., myomectomy) 29 . Therefore, the estimation of UR risk may be biased.
In conclusion, our study identi ed that gestational diabetes mellitus, placental abruption, placenta previa and placenta accreta increased the risk of UR and found a particularly high risk in women with placenta accreta but without previous cesarean delivery. Furthermore, we found that the risk of UR varied with gestational age in women with different pregnancy complications. Thus, physicians should provide early, better antenatal care and intervention for women with these high-risk pregnancy complications.  Uterine rupture rate for women with gestational diabetes mellitus at 32-36 weeks by birthweight category of fetus Note: The UR rate was weighted for the sampling distribution of the population covered by the Chinese National Maternal Near Miss Surveillance System.

Supplementary Files
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