Is Elevated First Trimester Mean Arterial Blood Pressure Associated With Increased Risk of Placenta Accreta?

Purpose: The present study investigated whether rst trimester mean arterial blood pressure (MAP) differed among pregnancies with placenta accreta and healthy pregnancies. Methods: We recruited 176 pregnant females totally from 1 January 2016 to 30 September 2018 in this study, as follows: 65 cases of placenta accreta and 111 cases of BMI and age matched, healthy pregnant controls. First trimester mean arterial blood pressure (MAP) were acquired from laboratory data les. Multiple logistic regression analysis were used to study analyzed the probable risk predictor of placenta accreta. Results: The performance of MAP was lower in healthy pregnancies. The MAP of the placenta accreta group was signicantly higher than that of the cont rol group (p=0.001<0.05). Our results also showed that MAP was signicantly positively associated with placenta accreta after adjusting for age, BMI, fertilization type, gestational week at time of blood pressure measurement, and previous cesarean section history (odds ratio [β]: 1.11; 95% condence interval [CI]: 1.04–1.69; p=0.0013<0.05). In addition, smoking during pregnancy (β: 7.57; 95% CI: 1.41–40.72; p=0.018<0.05) and previous cesarean section history (β: 2.57; 95% CI: 1.19–5.54; p=0.016<0.05) were signicantly positively associated with placenta accreta. Conclusions: Increased rst trimester MAP was signicantly positively associated with placenta accreta, suggesting the potential role of MAP in identifying high-risk pregnancies for placenta accreta. Smoking during pregnancy and previous cesarean section history may be risk factors for placenta accreta. by numbers and percentage ( 𝑛 , %).Results were analyzed by One-way ANOVA (Brown-Forsythe). p*-value: between groups, p # -value: with in groups, p < 0.05 statistically signicant. Statistically signicant p values are marked as bold text.


Background
In the eld of obstetrics, placenta accreta is a life-threating complication that can lead to serious bleeding, secondary infection, uterine perforation, shock, and even death [1]. Placenta accreta affects approximately 3 out of 1000 pregnancies [2,3]. In addition, the incidence of this condition is rising [4].
The prevalence of placenta accreta continues to rise internationally, placing a signi cant impact on health resources. Placenta accreta occurs by 10 weeks, and accreta cases have been diagnosed as early as the rst trimester [5]. Accurate antenatal diagnosis and prediction of placenta accreta are pivotal and important considering the gradually rising incidence and severe adverse outcomes of placenta accreta.
Evidence shows that accurate antenatal diagnosis of placenta accreta may reduce maternal peripartum hemorrhage and morbidity [6]. Ultrasound techniques such as ultrasound and magnetic resonance imaging (MRI) are mainly used in the current prenatal diagnosis of placenta accreta. However, the accuracy of MRI and ultrasound diagnosis of placenta accreta is controversial. In addition, many patients may not have access to a high-risk prenatal diagnosis center for antenatal examination [7][8][9]. The early accurate risk assessment of placenta accreta would identify high-risk women for targeted early prevention. In addition, the early accurate antenatal diagnosis of the risk of placenta accreta may allow for the improvement of the outcome by increasing patient surveillance or by initiating therapeutic interventions. Thus, developing an effective and convenient prediction strategy of placenta accreta at the rst trimester is important to avoid adverse outcomes.
Extravillous trophoblast cells invade into the maternal decidua and play a critical role in the maintenance of a successful pregnancy [10]. Pre-eclampsia and gestational diabetes mellitus are pregnancyassociated diseases related to the invasion ability of trophoblasts [11][12][13]. By contrast, excessive trophoblast invasion, abnormal vascular remodeling, and decidual de ciency are the main pathophysiological mechanisms of placenta accreta [14]. These pregnancy-associated diseases are related to abnormal early trophoblastic invasion. First trimester mean arterial blood pressure (MAP) is closely related to some adverse pregnancy outcomes such as hypertensive disorders, pre-eclampsia, small for gestational age, and gestational diabetes mellitus [15][16][17][18]. In addition, rst trimester MAP is typically used for assessing the risk of pre-eclampsia, small for gestational age, intrauterine growth restriction, and gestational diabetes mellitus during the trimesters of pregnancy [16][17][18][19][20][21]. The relationship between rst trimester MAP and placenta accreta is still unclear. Thus, the present study aimed to determine the relationship between rst trimester MAP and placenta accreta. First trimester MAP may help to improve the prenatal diagnosis of placenta accreta. In addition, knowing the risks of placenta accreta early may contribute to the accuracy of interpretation of MRI or sonogram ndings and the customization of personalized diagnosis and treatment schemes.

Study settings and population
We conducted a retrospective study in the Department of Obstetrics of the A liated Hospital of Jining Medical University between 1 January 2016 and 30 January 2020. A total of 215 pregnancies were involved in our retrospective study prior to being screened according to the exclusion criteria. The inclusion criteria were as follows: (1) placenta accreta group: pregnant women were diagnosed as placenta accreta later histologically; (2) control group: age-and BMI-matched pregnant controls (Fig. 1).
The exclusion criteria were as follows: (1) pregnant women whose delivery or clinical data were missing; (2) twin or multiple pregnancies and miscarriage or stillbirths; (3) pregnant women with trophoblast tumor, gestational diabetes, acute and chronic infectious diseases, and other pregnancy complications.
Finally, a total of 176 cases were eligible in this study (111 for the control group and 65 for the placenta accreta group). Gestational age was compiled from last menstrual period (LMP) and con rmed by rst trimester ultrasound where LMP was not known. The MAPs of all pregnant women in the study were measured and calculated during the rst trimester according to the requirements of their attending doctors. Before systolic and diastolic blood pressure measurement, all pregnant women were required to rest for 15 min. All pregnant women were in the sitting position with their arms supported at the level of the heart, and a small (22 cm), normal (22-32 cm), or large (33-42 cm) adult cuff was used, depending on the mid-arm circumference. Two recordings of blood pressure were made in both arms simultaneously. We calculated the nal MAP as the average of all four measurements.
[16] Additionally, maternal demographic characteristics, obstetrical and medical history, and other maternal information were collected from the maternity records of the A liated Hospital of Jining Medical University or the general medical practitioners of the women. To protect patient privacy, our report did not include participants' identi able data. The study was approved by the Human Ethics Committee of the A liated Hospital of Jining Medical University (Shandong, China).

Statistical analysis
Based on whether the continuous variables are normally distributed, we presented continuous variables in this study as medium (min-max, skewed distribution) or mean ± standard deviation (normal distribution).
Categorical variables were expressed in frequency or percentage. We used χ2 (categorical variables), oneway ANOVA (normal distribution), or Kruskal-Wallis H test (skewed distribution). All analyses were performed with SPSS 22.0 (IBM SPSS Statistics for Windows, Version 22.0. IBM Corp. Armonk, NY, USA). Categorical data are shown with n (number) and percentage (%). Binary logistic regression with single and multi-categorical predictor was used to determine the possible risk factors for placenta accreta. The data were examined at the 95% con dence level, and a p-value of < 0.05 was considered signi cant.

Baseline characteristics and first trimester MAP of the two groups
We recruited 215 gestational women, among which 176 were eligible. Two groups were included as follows: 111 age-and BMI-matched healthy controls and 65 placenta accreta patients. Table 1 lists the demographic characteristics, laboratory features, clinical history, and rst trimester MAP of all groups. No statistical difference was observed in terms of age, BMI, height, gestational week at time of blood pressure measurement, cesarean hysterectomy incidence at the time of delivery, and mean birth weight in both groups. The incidence of smoking during pregnancy and previous cesarean section history in the placenta accreta group were signi cantly higher than those in the control group (p = 0.018 < 0.05, p = 0.016 < 0.05) ( Table 1). Delivery pregnancy week in the placenta accreta group was signi cantly lower than that in the control group (p < 0.05, Table 1). Blood transfusion incidence and vaginal bleeding incidence in the placenta accreta group were signi cantly higher than those in the control group (p < 0.05, p < 0.05, Table 1). Delivery pregnancy week and neonatal weight in the placenta accreta group were signi cantly decreased than those in the control group (p < 0.05, p < 0.05, Table 1). The normally distributed rst trimester MAP is expressed as the median (min-max) in Table 1. The median rst trimester MAP of placenta accreta cases was 89.74, which was signi cantly higher than that in the control group (84.79, p = 0.001 < 0.05).   Discussion MAP, a feasible tool and part of antenatal surveillance, has remained the target of scienti c research in the prediction of pregnancy-related diseases [17,22]. The association between rst trimester MAP and placenta accreta is still unclear. In our retrospective case-control study, we investigated the association between rst trimester MAP and placenta accreta. Our results showed that elevated rst trimester MAP remained signi cantly positively associated with placenta accreta. Furthermore, rst trimester MAP, smoking during pregnancy, and previous cesarean section history were signi cantly positively associated with placenta accreta, indicating that they may be probable risk predictors of placenta accreta.
Placenta accreta refers to abnormal placental invasion to the uterine wall, which is characterized by invasion of trophoblasts into the myometrium, but not beyond [23,24]. Placenta accreta is a lifethreatening obstetrical disease and has a high maternal morbidity and mortality rate, presenting speci c intrapartum challenges [25,26]. Placenta accreta affects about 2% of singleton deliveries, and its incidence is gradually increasing [27]. Considering the rising incidence and associated severe adverse outcomes of placenta accreta, methods that can accurately diagnose placenta accreta in the prenatal period before patients develop symptoms need to be developed so that plans for the prevention of bleeding and related complications and individualized treatment can be made. Currently, ultrasound and MRI are the methods used to diagnose placenta accreta. The diagnostic factors include the presence of placental lacunae, loss of the hypoechoic retroplacental interface, and hypervascularity of the interface between the placenta and the bladder or uterine wall. However, the effectiveness and accuracy of the above mentioned methods are controversial. Recently, an increasing number of studies showed that rst trimester MAP is associated with adverse pregnancy outcomes [28,29].
In the present study, we observed that elevated rst trimester MAP remained signi cantly positively associated with placenta accreta. Previous studies showed that rst trimester MAP values may change in pregnant women who have already developed or are destined to develop placenta accreta. First trimester MAP may be helpful to improve the antenatal diagnosis of placenta accreta. Furthermore, knowing the risks early may contribute to explain the MRI or sonogram ndings more accurately.
MAP, the mean value of arterial pressure in one cardiac cycle, is a part of antenatal surveillance. In addition, higher levels of MAP are related to the increased risk of developing hypertension during pregnancy, pre-eclampsia, and gestational diabetes [15,16,19]. All these pregnant outcomes and placenta accreta belong to the disorders of placental development. Placenta accreta starts to develop in the rst trimester [10].
In women with pre-eclampsia, the values of uterine artery pulsatility index and mean arterial pressure are increased. Interestingly, our ndings showed that rst trimester MAP is signi cantly increased in the placenta accreta group compared with that in the healthy control group. However, all the values are within normal range. Uteroplacental vasculature circulation undergoes signi cant structural and functional modi cations to ensure an adequate blood supply to the developing placenta and the fetus in the rst trimester [30]. In early stages of pregnancy, trophoblasts invade the uterine spiral arteries, replacing muscular and endothelial cells of the arterial wall and transforming them in low resistance vessels with an increased blood ow [31]. As mentioned above, placenta accreta starts to develop in the rst trimester [10]. Thus, the probable mechanisms underlying this phenomenon may be that increased MAP within normal limits may provide more blood supply to the placental circulation and other organs of placenta accreta patients [32].
Considering the excessive trophoblast invasion and abnormal vascular remodeling of placenta accreta patients, these patients need more blood supply. Hence, factoring rst trimester MAP into the risk assessment could better identify patients who are at risk of developing placenta accreta, and placenta accreta patients would be subjected to closer and re ned monitoring and treatment.
In addition, we found that the incidence of smoking during pregnancy was signi cantly positively associated with placenta accreta in our study, suggesting that smoking during pregnancy may be related to the occurrence and development of placenta accreta. A potential mechanism is that cigarette smoke increases placental adrenomedullin expression and aggravates trophoblast invasion via the adrenomedullin pathway [26]. Excessive invasion of trophoblast cells leads to the occurrence and development of placenta accreta eventually.
The incidence of placenta accreta is increasing every year [33]. There are parallels between the increasing number of caesarean section cases and the increasing incidence of placenta accreta [34,35]. Evidence shows that women with a history of caesarean delivery have the highest risk of developing placenta accreta [36][37][38]. In the present study, we found a signi cant positive association between previous cesarean section history and the incidence of placenta accreta. Our results also echo those of previous studies, suggesting that previous cesarean section history may be an important factor of placenta accreta [33,39,40]. The probable mechanisms underlying this phenomenon may include abnormal angiogenesis, abnormal trophoblast differentiation, and oxygen tension in the uterine scar [41,42].
Despite our ndings, our study has several limitations. One limitation is the small number of cases, which possibly introduces selection bias. Another limitation is that all pregnant women were from China, which fully minimized the confounding effects of ethnic background. Whether our results can be extended to other ethnic groups remains to be con rmed.

Conclusion
Taken together, increased values of rst trimester MAP were signi cantly positively related to placenta accreta, suggesting the potential role of rst trimester MAP in identifying high-risk pregnancies for placenta accreta. Smoking during pregnancy and previous cesarean section history may increase the risk of placenta accreta. Future large-scale studies investigating the association between placenta accreta and rst trimester MAP need to be conducted. Competing interests: The authors declare that they have no competing interests.
Ethics approval and consent to participate: The study was approved by the Human Ethics Committee of the A liated Hospital of Jining Medical University (Shandong, China)(2019-zr-016).

Consent for publication:
Not applicable Availability of data and materials: The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.