Clinical Manifestations of Perinatal Pregnant Women with Pulmonary Embolism

Purpose(cid:0) To analyze the clinical manifestations of perinatal pregnant women with pulmonary embolism(PE) and improve the understanding of maternal PE disease. Methods(cid:0)We retrospectively reviewed maternities diagnosed with PE in a maternity and infant hospital between July 2018 and June 2020. Patients were divided into different groups according to risk strati�cation. Clinical data were collected and statistically analyzed by SPSS. Results: A total of 49 patients, with an average age of (32.31±4.17) years at delivery were clari�ed into low-risk group (28 patients, 57.1%) and medium-risk group (21 patients, 42.9%). The medium-risk group had a signi�cant higher serum level of TnI (0.0052±0.0073 ng/ml) compared with low-risk group (0.0009±0.0013 ng/ml). Although d-dimer level (5.1±3.6 mg/l) of selected patients were higher than normal range at the time of admitting, a signi�cant increasing trend was still observed when diagnosed with PE (p=0.012 in low-risk group, p=0.005 in medium-risk group). The location of thrombosis distributed mainly in right lung (28(57.1%)) and lower �eld of lung (32(65.3%)) according to CTA image, while 5 cases of right ventricular enlargement were limited in medium-risk group. While 87.8% of patients were asymptomatic. The frequencies of PE in Febraury 2020 and March 2020 were higher compared to any other month, which was in accordance with the �rst episode period of COVID-19 in China. Conclusion: Perinatal PE is frequently found in elderly pregnant women, with a more benign clinical presentation compared with reported data. Dynamic monitoring of d-dimer may have more clinical value for early identi�cation of perinatal PE.


Introduction
Pulmonary embolism (PE) is a group of diseases or clinical syndromes caused by various emboli blocking the pulmonary artery or its branches, in which pulmonary thromboembolism (PTE) is the most common type.PTE is a manifestation of venous thromboembolism (VTE), which is a rare but extremely serious disease [1,2].Due to the special physiological conditions, such as blood hypercoagulation, increased cardiac load, blood stasis, and vascular endothelial injury, the maternal have become a high incidence population of VTE.It is reported that their incidence rate is about 4-5 times that of nonpregnant people, and 43%-60% of pregnancy related PE occurs in the puerperium [3][4][5][6].Perinatal PE is still di cult to diagnose because of its hidden clinical symptoms.But it's noteworthy that PE is the leading non-obstetric cause of maternal death [7].The mortality of untreated PE patients with missed diagnosis can reach 25-30%, which has become one of the main causes of maternal sudden death.After early diagnosis and timely anticoagulation treatment, the maternal mortality rate of PE can be reduced to 2-3% [8][9][10].It can be seen that improving the diagnosis rate of PE and carrying out relevant intervention in the early stage is the key to reduce the maternal mortality rate of PE.The venous thromboembolism risk rating scale applied in clinical practice is not applicable to the maternal, and the vast majority of perinatal patients with PE have no speci c risk factors, or only have light to moderate risk scores.Thereby, identifying high-risk population with PE remains a challenge in current clinical practice [11][12][13].The purpose of this study is to improve the understanding of maternal PE disease by analyzing the clinical manifestations of perinatal pregnant women with PE, in order to help identify the population with potential risk of PE in the early clinical stage, and intervene in advance to reduce its mortality.Data collection: These medical data of the selected patients were recorded from the electronic medical record system, including demographic data, medical history, comorbid conditions, risk factors for PE, laboratory examinations, imaging characteristics, symptoms, treatments,and possible adverse drug reactions (ADR).A self-designed form was used for data collection.

Methods
Statistical analysis: Statistical analyses were performed using SPSS 26.0 software (SPSS Inc., Chicago, Ill., USA).The data are expressed as numbers and percentages for categorical variables and mean ± standard deviation for continuous variables.Statistical differences were analyzed using the chi-square test for categorical variables and the t-test for continuous variables.A P value < 0.05 was considered statistically signi cant.

Demographics characteristics
The demographics characteristics of selected patients are summarized in Table1.A total of 49 patients were enrolled, with 28 patients divided into low-risk group and 21 patients in medium-risk group.According to the risk strati cation criteria, no patient was included in the high-risk group in this study.The average age of the patients at delivery was 32.31 ± 4.17 years old; 12 patients (24.9%) were aged > 35 years.The mean body mass index (BMI) was 7.5 ± 3.9 kg/m2.None of these patients had smoking history or history of VTE.No signi cant differences in the age at delivery, age distribution, BMI, SBP, or DBP were noted between low and medium risk groups (Table 1).1).

Laboratory ndings
The medium-risk group had a signi cant higher serum level of TnI (0.0052 ± 0.0073) than low-risk group (0.0009 ± 0.0013), which is consistent with our risk strati cation criteria.Other blood biomarkers for pulmonary embolism including BNP and d-dimer, as well as fundamental parameters like ALT, AST, TBIL, DBIL and TC did not reach signi cant differences (Table 2).However, although the d-dimer level (5.1 ± 3.6) of the selected patients were higher than normal range when admitted to the hospital, a statistically signi cant increase trend was still observed when patients were diagnosed with PE in both group (p = 0.012 in low-risk group, p = 0.005 in medium-risk group), compared with the initial data.Treatment and outcome 25(51.0%)patients in total underwent prophylaxis with LMWH during hospitalization.Among these, the distribution of prophylaxis in low-risk and medium-risk group is 15(51.7%)and 10(47.6%)separately.And all patients were prescribed with LMWH after the diagnosis of PE, the dosage is adjusted based on the weight.4(14.3%)patients in low-risk group and 2(9.5%) patients in medium-risk group transfered to general hospital for further treatment.43(87.8%)patients got improved and discharged from hospital.In the subgroup analysis, patients underwent prophylaxis presented a signi cant lower d-dimer level, while the outcome did not reach the signi cant difference (Table 3).

Imaging characteristics
In study, the of thrombosis distributed mainly in right lung (28(57.1%))and lower eld of lung (32(65.3%))according to CTA image, which is similar to the present understanding of PE.There's no signi cant difference between the two subgroups (Table 4).4).

Clinical manifestations
Patients in this study have a more benign clinical presentation, as compared to the reported data and may follow a good clinical course.Typical presentations of PE (dyspnea, hemoptysis or circulatory collapse) were rather rare in these patients.A percentage of 87.8% were asymptomatic PE patients, with chest pain, chest distress occured only in one case and breathless in 3 cases (Table 5).

Time distribution
Time distribution of the 49 PE cases were presented in Fig. 1.In February 2020, 7 cases of PE were recorded, and when it comes to March 2020, the gure raise to 10.The frequency of PE in these two months were higher compared to any other month (Fig. 1).And the time distribution was in accordance with the rst episode of COVID-19 in China, when people were home-stay spontaneously or nonspontaneously.

Discussion
The risk of VTE exists throughout pregnancy, and the risk of fatal pulmonary embolism (PE) is reported to be higher during the third trimester and postpartum [14][15][16].However, PE has no speci c clinical manifestations.The common symptoms include dyspnea, chest pain, cough, shortness of breath, palpitation, hemoptysis, irritability and panic [17,18].While in this study, we found that most of the maternal patients were asymptomatic and only a few of them had mild symptoms, which may be related with the fact that the maternities are young and in relatively healthy condition.Therefore, it is rather di cult to identify perinatal pregnant women with PE from their clinical manifestations in early stage.
Apart from the signi cant increase of D-dimer during thrombosis, D-dimer may also increase during normal pregnancy course and decrease slowly after delivery [19][20][21][22].Due to the lack of normal reference value range, it is complicated to distinguish thrombosis and physiological elevation during pregnancy and puerperium.In addition, although the negative results of D-dimer have higher clinical or diagnostic value in non pregnant population [23] compared with positive results, studies have shown that low Ddimer level (even < 500ng/ml) is still not su cient to rule out PE [24,25].Therefore a individual D-dimer level is far from convincing in the diagnosis of PE in pregnancy.In this study, regardless of the basic Ddimer level at the time of admission, a statistically signi cant increase trend was always observed when patients were diagnosed with PE in both group (p = 0.012 in low-risk group, p = 0.005 in medium-risk group), which indicates that the dynamic changes of D-dimer may have a certain value for the diagnosis of PE.Thus it is suggested to monitor D-dimer regularly during perinatal period for early detection, regardless of the basic D-dimer level.
Venous thromboembolism (VTE) includes PE and deep vein thrombosis (DVT), and it's generally considered that the majority of PE events derived from an overt or silent DVT of the lower extremities [26,27].In this study, among all 49 patients diagnosed with PE, only 6 patients were diagnosed with VTE, and 6 patients showed slow venous blood ow of lower limbs.In concordance with our study, a previous study using pulmonary angiography and venography of the lower limbs showed that DVT could not be identi ed in 29% of the PE patients [28].And in an autopsy study, 47% of the patients did not have DVT [29].Furthermore, a recent study reported that female sex was the only independent factor associated with the occurrence of isolated PE, which may partly explain the reason of the high proportion of isolated pulmonary embolism in this study [30].Except from lower extremity venous thrombosis, other potential sources of thrombi in PE should also be considered, such as abdominal or jugular vein thrombosis, right-sided cardiac thrombosis associated with heart diseases and in-situ thrombus formation connected with a persistent local in ammatory process of the lung [31][32][33].This reminds the clinic that even if the DVT result is negative, the possibility of PE cannot be ignored.
The age of > 35 years is one of the main risk factors for VTE in pregnancy [34,6].Since the opening of the two-child and three-child policy in China, number of advanced maternal age has increased dramatically who are at greater risk of embolism.In present study, the age distribution of PE patients was most frequent between 30 and 35 years old, which indicated the need for more frequent monitoring and more attention.In this study, PE patients had a high diagnostic rate during the rst episode period of COVID-19 in China, which was considered to be related to the reduction of activities and the nervous mood condition during this period.At that time, people reduced their outside activities spontaneously or unconsciously, and the decrease in activity may cause the blood ow to slow down, which can partly explain the formation of thrombus.This part of the results showed that appropriate age and su cient activities were crucial factors to prevent possible PE.
The study results indicated that the prognosis of most patients was improved, as the CTA was performed after the signi cant elevation of D-dimer was found, and standardized treatment was given immediately after the diagnosis of PE.Because of its lower bleeding risk and stable and predictable pharmacokinetics, Low molecular weight heparin (LMWH) is recommended as the rst choice for treatment or prevention of PE during pregnancy and postpartum [35].Natroparin Calcium, a kind of LMWH commonly used in clinic, is the main therapeutic drug in this study.After the administration of the standard therapeutic dose of Natroparin Calcium, the D-dimer decreased signi cantly, and no drug-related adverse reactions occurred.
Although PE is an important cause of death for pregnant women and parturients, patients can still have a better outcome in condition of early detection and timely intervention.
In this study, 28 patients were divided into low-risk group and 28 patients in medium-risk group.
According to the risk strati cation criteria, no patient was included in the high-risk group in this study.The basic characteristics, majority of laboratory ndings, and treatment were similar in the two groups, but it's noteworthy that the medium-risk group had a signi cant higher serum level of TnI (0.0052 ± 0.0073 ng/ml) compared with low-risk group (0.0009 ± 0.0013 ng/ml), and right ventricular enlargement were limited in medium-risk group.However, these distinctions did not result in the signi cant difference in clinical presentations and outcome of disease.Further studies are required in the future to better understand the clinical value of the two indicators.
Our study has some limitations.First, selection bias was inevitable due to the retrospective nature of our study.Second, several laboratory data were not detected in these patients, and several clinical manifestations may miss as the lack of comprehensiveness and detail in medical history system.Last, although all patients underwent chest CT scans, data on the presence of DVT at relatively infrequent locations, such as upper extremities, iliac vein and inferior vena cava, were not available in some patients.

Conclusion
In conclusion, the present study suggests that perinatal PE is frequently found in elderly pregnant women, with a more benign clinical presentation compared with reported data and may follow a good clinical course.Dynamic monitoring of D-dimer may have more clinical value for early identi cation of patients with PE.
Study design and population: This was a single-center, retrospective cross-sectional study.Maternities admitted in Shanghai First Maternity And Infant Hospital between July 2018 and June 2020, with pulmonary embolism, were enrolled.Inclusion criteria: (1) Computed tomography angiography (CTA) was performed in the hospital and indicated thrombosis.(2) Diagnosis of PE was in line with the PE diagnosis and treatment guidelines of the Chinese Thoracic Society.(3) Clinical data was available in electronic medical record system.Exclusion criteria:(1) Presence of severe renal failure, liver failure or other organ dysfunction.(2) Incomplete data.Risk strati cation: Patients enrolled were divided into low-risk group, medium-risk group and high-risk group based on whether they had a shock, right ventricular dysfunction, or abnormal heart function indicators, which was in accordance with the PE diagnosis and treatment guidelines of the Chinese Thoracic Society.

Figures
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Figure 1 Time
Figure 1

Table 2
Laboratory ndings of selected PE patients

Table 4
Altogether, 35 cases were evaluated by echocardiography.Clinical evidence of pulmonary hypertension were detected in 2(6.9%) patients in lower-risk group and 1(4.8%) patient in medium-risk group.While 5 cases of right ventricular enlargement were limited in medium-risk group, with 0(0%) in low-risk group (Table