Assessment of D-dimer levels in pregnant women diagnosed with COVID-19: A case-control study

Abstract Objective We aimed to evaluate D-dimer levels in pregnant women diagnosed with COVID-19. Methods This single-center study was carried out in a tertiary center hospital serving as a pandemic hospital. 151 pregnant women with COVID-19 diagnosis were included as the study group, and 70 healthy pregnant women as the control group. The data were analyzed separately in 3 different trimesters of pregnancy. Results Of the 221 pregnant women included in the study, 151 had a diagnosis of COVID-19. 70 healthy pregnant women were taken as the control group. It was observed that D-dimer values in pregnancy increased as the trimesters progressed. No significant difference was observed when this was compared with pregnant women with COVID-19 (p = .428, .75, .927 according to the 1st, 2nd and 3rd trimesters, respectively). Conclusion The diagnosis of pulmonary embolism is difficult due to the lack of reliable alternative D-dimer thresholds for pregnant patients. On the other hand, D-dimer elevation continues to be a sign of poor prognosis in patients with COVID-19. The situation remains uncertain in patients who are pregnant and have COVID-19. Maybe D-dimer value should be removed from being a poor prognosis criterion in pregnant women.


Introduction
Normal pregnancy is a state of hypercoagulation caused by increased procoagulant concentration, decreased anticoagulant levels and decreased fibrinolytic activity, which is regulated by the balance between plasminogen activators and inhibitors.With the general effect of hypercoagulation and hypofibrinolysis caused by pregnancy, an increase occurs in fibrin degradation products including D-dimer and intravascular thrombosis [1].This condition is designed to protect women against miscarriage or bleeding during childbirth.
D-dimer is formed by the destruction of fibrin by plasmin [2].D-dimer was first isolated in the 1970s [3].D-dimer measurements act as a global indicator of coagulation and activation of fibrinolytic systems.As the activity of plasmin increases in the blood, an increase in D-dimer levels is observed.In cases of venous thrombosis or pulmonary embolism, their value can be very high [4].
There are many studies evaluating thresholds adjusted for normal D-dimer levels between trimesters of pregnancy.Many studies from the 1990s have shown that D-dimer levels increase steadily throughout pregnancy [5].The specificity of the D-dimer test is significantly reduced during pregnancy [6].In particular, most of the suspicions of pulmonary embolism occur in the third trimester, where the specificity of the D-dimer test approaches 0%.
The disease due to coronavirus infection appeared in Wuhan, China in December 2019, spread rapidly worldwide and created a major public health problem [7].Some hemostatic abnormalities have been reported with Covid-19 survivors with significantly higher D-dimer levels [8].However, an optimal cutoff value for D-dimer and its effect on prognosis have not yet been assessed to predict mortality in admission.
Therefore, studies comparing D-dimer values of COVID-19 patients and healthy pregnant women are needed.Our study gives the opportunity to make this comparison.

Material and Methods
This single-center, case-control study was conducted at a tertiary center, in Turkey, between May to July 2020.The annual birth number in our department is approximately 11000.During the pandemic period, many hospitals in our country were declared as "pandemic hospitals."The hospital to which our clinic belongs to is one of them.Therefore, approximately 50 to 100 COVID-19 positive pregnant women apply to our clinic per month.The study protocol was approved by The Local Ethics Committee and registered to ClinicalTrials.gov(NCT04389554) Our study criteria included 18-45 years old pregnant women with a history of COVID-19 positive reverse-transcription polymerase chain reaction (RT-PCR).We excluded that potential source of elevated D-dimer such as morbid obesity (BMI > 40 kg/m2), advanced maternal age (>45 years); family or personal history of VTE and antiphospholipid syndrome, multiple gestations, the clinical story of neoplasia, burns, trauma, comorbid disease (pregestational diabetes mellitus, gestational hypertension, preeclampsia, HELLP syndrome, chronic kidney and liver disease, autoimmune diseases, etc.), coagulopathies, have been admitted to our hospital or surgery in the previous four weeks.
The study was planned in two groups.The patients were divided into 3 different subgroups according to their gestational periods: thirty-seven as 1st trimester, sixty-nine as 2nd trimester and one hundred twelve as 3rd trimester.The control group was formed from healthy pregnant women with similar demographic data, with a ratio of approximately 2:1.
There are over thirty D-dimer measurements.Among them there are three general types: immunofluorescent assays, latex agglutination assays and enzyme-linked immunosorbent assays (ELISA) [9].In the study, we used a particle-reinforced immunoturbidimetric test method for the quantitative determination of cross-linked fibrin degradation products (INNOVANCEV R D-Dimer, BCSV R XP System, Siemens).Samples were taken into citrated tubes.After centrifugation at 3500 rpm at room temperature for 10 min in the lab, it was worked within 4 h at the latest.In our hospital, the cutoff point of D-dimer is 0,55 mg/L as the exclusion criteria of the venous thromboembolism.Data analysis will be done using SPSS (version 22.0; SPSS Inc., Chicago, IL, USA).All data will be prepared as mean ± standard deviation and mean (min-max).Student's t-test will be used to compare continuous parametric variables, and Mann-Whitney U test will be used to compare non-parametric data between the two groups.In all calculations, p-value less than .05will be considered statistically significant.

Results
Two hundred and twenty one pregnant women were contained in the study.One hundred and fifty one of these pregnant women were diagnosed with COVID-19 and were considered as the study group.The other 70 are healthy pregnant women with similar demographic data and trimesters.Only age was compared as demographic data (Table 1).Comparison of D-dimer values of all pregnant women with COVID-19 and Ddimer values of healthy pregnant women is given in Table 2.We divided all pregnant women into trimesters and compared them in terms of D-dimer values.This assessment is given in Table 3.

Discussion
Both pregnancy and COVID-19 disease have a coagulation-enhancing effect in the body [10].High D-dimer values may be associated with poor prognosis in COVID-19 disease [11].However, this issue has not been studied much in pregnant women.As the trimester progresses, physiologically, D-dimer values increase in pregnancy [12].Our study showed that Ddimer values increased as the trimester progresses in pregnancy.However, no significant difference was found in the elevation of D-dimer in pregnant patients with and without COVID-19.
Although many studies have examined the change of D-dimer during pregnancy and puerperium, it has not been possible to compare D-dimer concentrations because different results are obtained depending on the instrument being measured.As the D-dimer does not have a uniform simple structure, assays may vary [13].In our study, we analyzed a good sample size of both healthy pregnant women and pregnant women with COVID-19 using the same measurement method.We know that the D-dimer value increases as the trimesters progress in both pregnancy and COVID-19.Diagnosis of pulmonary embolism during pregnancy is still difficult due to the absence of D-dimer thresholds and the lack of adequate prospective studies on clinical probability assessment [14].In addition to an increased risk of pulmonary embolism, especially in the third trimester, most of the common venous thromboembolism symptoms, such as leg swelling, shortness of breath, tachypnea, and tachycardia, are also associated with normal pregnancy [15].Different D-dimer thresholds have been proposed, but there is no approved cutoff value for D-dimer to safely exclude PE during pregnancy.For now, imaging tests continue to be cornerstones in the diagnosis of PE suspected in pregnancy due to the lack of reliable alternative Ddimer thresholds for pregnant patients [16].
Thromboembolic prophylaxis is recommended for people diagnosed with COVID-19 because of the coagulapathy caused by the disease [17].The same is true for pregnant women.In fact, prophylaxis is even more important as pregnancy itself can cause a coagulation.It should be considered together with the patient [18].According to American Society of Hematology guidelines, anticoagulant therapy should be offered to patients with COVID-19 with high D-dimer values [19].However, there are some gaps about the treatment effect in pregnant women with COVID-19.In the panel where the guide was created, the priority of working on this subject was targeted.
According to the current literature, D-dimer elevation is one of the indicators of poor prognosis in COVID-19 disease [20].According to the current literature, D-dimer elevation is one of the indicators of poor prognosis in the disease.There are several studies suggesting that this value is also high in pregnant women with COVID-19, but it is difficult to distinguish as pregnancy itself also raises D-dimer [21,22].In a case-control study by Hazari et al. they said that the D-dimer value increased in pregnant patients with COVID-19, but it was compared with patients with non-pregnant COVID-19 [23].In our study, pregnant women without any symptoms and pregnant women with COVID-19 were compared and it was seen that D-Dimer values increased in both groups and there was no significant difference.Perhaps this value should not be used as a poor prognosis criterion in pregnant women.
There are some limitations in our study.We did not stratify patients by COVID-19 disease symptoms and extent of illness and have limited demographic data.We are of the opinion that this issue will be further clarified with new studies to be conducted with larger series and classification according to the degree of the disease..753rd trimester (n ¼ 112) 2.67 ± 2.17(n ¼ 84) 2.64 ± 1.4(n ¼ 28) .927

Table 1 .
Comparison of demographic data.

Table 2 .
Comparison of D-dimer values.