Maternal and pregnancy characteristics affect plasma fibrin monomer complexes and D-dimer reference ranges for venous thromboembolism in pregnancy




Background


D-dimers have a high negative predictive value for excluding venous thromboembolism outside of pregnancy but the use in pregnancy remains controversial. A higher cut-off value has been proposed in pregnancy due to a continuous increase across gestation. Fibrin monomer complexes have been considered as an alternative diagnostic tool for exclusion of venous thromboembolism in pregnancy due to their different behavior.


Objective


We sought to establish normal values of fibrin monomer complexes and D-dimer as a diagnostic tool for the exclusion of venous thromboembolism in pregnancy and examine the effect of maternal and obstetric factors on these markers.


Study Design


Plasma D-dimer and fibrin monomer complexes were measured by quantitative immunoturbidimetry in 2870 women with singleton pregnancies attending their routine first-trimester hospital visit in a prospective screening study for adverse obstetric outcome. Multiple regression analysis was used to determine maternal characteristics and obstetric factors affecting the plasma concentrations and converting these into multiple of the median values after adjusting for significant maternal and obstetric characteristics.


Results


Plasma fibrin monomer complexes increased with maternal weight and were lower in women with a history of cocaine abuse and chronic hypertension. D-dimers increased with gestational age and maternal weight and were higher in sickle cell carriers and in women of African and South Asian racial origin compared to Caucasians.


Conclusion


Fibrin monomer complexes and D-dimers are affected by maternal and obstetric characteristics rather than only gestational age. The utility of these fibrin-linked markers as a tool for exclusion of venous thromboembolism in pregnancy might be improved by adjusting for patient-specific characteristics.


Introduction


Pregnancy is a hypercoagulable state exemplifying Virchow triad of altered coagulation, stasis, and vascular damage. Venous thromboembolism (VTE) is one of the leading causes of maternal death in developed countries with about 1–2 deaths per 100,000 maternities or 9% of all maternal deaths in the United States. The incidence of VTE in pregnancy is 1–2 per 1000, 5-fold higher than in nonpregnant women. The antenatal risk for VTE is highest in the first and third trimester and in the United Kingdom the majority of antenatal deaths occurred in the first trimester.


Outside of pregnancy, diagnostic pathways for deep vein thrombosis (DVT) and pulmonary embolism are based on a combination of clinical scoring systems, blood tests, and imaging using compression ultrasound, ventilation-perfusion scans, or computed tomography pulmonary angiography. Both ventilation-perfusion scans and computed tomography pulmonary angiography are considered safe but concerns remain about fetal radiation and breast radiation exposure, respectively, with these modalities.


In pregnancy there are no clinically validated scoring systems and the clinical presentation can be confused with features of a healthy pregnancy.


D-dimer (DD) is integral to diagnostic pathways outside of pregnancy and in individuals with low clinical probability has a high negative predictive value for VTE. Another marker of thrombin activation is the fibrin monomer (FM), an intermediate in cross-linked fibrin formation. FM are produced through thrombin induced proteolysis of fibrinogen into fibrinopeptides A and B and FM. In prothrombotic conditions such as disseminated intravascular coagulation syndrome soluble complexes may be formed when FM join with fibrinogen and fibrin degradation products.


DD are produced by lysis of cross-linked fibrin and are therefore downstream from FM in this pathway. However DD levels normally rise in pregnancy and higher cut-off value have been proposed. There is evidence that DD and FM might behave differently in clinical scenarios, possibly reflecting the different stages of thrombin activation and fibrinolysis. For instance, there are small studies showing that changes in FM concentrations in uncomplicated pregnancy seem to be minimal compared to other hemostatic markers and FM are therefore considered an alternative tool for exclusion of VTE in pregnancy.


It would be desirable to be able to utilize fibrin-linked markers within pregnancy to help exclude the likelihood of VTE and reduce the requirement for imaging as shown for the use of FM outside pregnancy. Further, it is likely that characteristics of the mother as well as the pregnancy might also affect hemostatic markers. The objectives of this screening study at 11–13 weeks’ gestation are to establish a reference range for plasma FM and DD and examine the maternal and pregnancy characteristics that affect the measurements.




Materials and Methods


Study population


The data for the study were derived from prospective screening for adverse obstetric outcomes in women attending their routine hospital visit in the first-trimester of pregnancy at King’s College Hospital, London, from October 2011 through May 2012. This visit, which was held at 11 +0 –13 +6 weeks’ gestation, included recording of maternal characteristics and medical history, ultrasound examination for measurement of fetal crown-rump length, diagnosis of fetal abnormalities, and measurement of fetal nuchal translucency thickness as part of combined screening for fetal trisomies. Venous blood (4 mL) was obtained from the antecubital vein and collected into tubes containing liquid 0.109 mol/L trisodium citrate (BD Medical Systems, Franklin Lakes, NJ).


Written informed consent was obtained from the women agreeing to participate in the study, which was approved by the ethics committee of the hospital. The pregnancies included in the study were those resulting in live birth or stillbirth of phenotypically normal babies at ≥24 weeks’ gestation. Women on current anticoagulation were excluded.


Patient characteristics


Patient characteristics recorded included maternal age; racial origin (Caucasian, Afro-Caribbean, South Asian, East Asian, and mixed); method of conception (spontaneous or assisted conception requiring the use of ovulation drugs); cigarette smoking during pregnancy; medical history of chronic hypertension, diabetes mellitus, sickle cell trait, and autoimmune disease, including systemic lupus erythematosus or rheumatoid arthritis; family history of thromboembolic events; and obstetric history including parity (parous or nulliparous if no previous pregnancies at ≥24 weeks’ gestation). The maternal weight and height were measured.


Sample analysis


The blood samples were processed within 1 hour after collection. After centrifugation at 2200 g for 15 minutes at 20°C the undiluted plasma was analyzed immediately in the STA-Compact coagulation analyzer (Diagnostica Stago, Asnières-sur-Seine, France) by quantitative immunoturbidimetry following the manufacturer’s instructions. We used STA-Liatest FM (Diagnostica Stago) and STA-Liatest DD (Diagnostica Stago) assays with respective working ranges of 5-150 μg/mL and 0.22-4.0 μg /mL, and an expected normal threshold in the adult nonpregnant population of <6 μg/mL for FM and <0.5 μg/mL (expressed in fibrinogen equivalent units) for DD. The intraassay and interassay coefficients of variation were 5.55% and 5.7% for FM and 8.4% and 10.3% for DD, respectively.


Pregnancy outcome


Data on pregnancy outcome were collected from the hospital maternity records or the general medical practitioners of the women. The birthweight percentile for gestational age at delivery was derived from a reference range for our population. The definition of preeclampsia was that of the International Society for the Study of Hypertension in Pregnancy. Diagnosis of gestational diabetes mellitus was based on a 75-g oral glucose tolerance test performed at 24–28 weeks’ gestation.


Statistical analysis


Data for continuous variables are presented as median (interquartile range) and data for categorical variables are presented as n (%). The observed values of serum DD and FM concentrations were log 10 transformed to make their distributions gaussian. Normality was assessed using histograms and probability plots. Univariable regression analysis was used to examine the individual variables contributing significantly to prediction of log 10 -transformed values of DD and FM. Multivariable regression analysis with backward stepwise regression analysis was used to determine the significance of contribution from maternal and pregnancy characteristics. The measured concentration of DD and FM were converted into multiple of the median (MoM) values after adjusting for maternal characteristics that significantly affected log 10 -transformed values in the multiple regression analysis. A statistical software package (SPSS 21; IBM Corp, Armonk, NY) was used for data analyses.




Materials and Methods


Study population


The data for the study were derived from prospective screening for adverse obstetric outcomes in women attending their routine hospital visit in the first-trimester of pregnancy at King’s College Hospital, London, from October 2011 through May 2012. This visit, which was held at 11 +0 –13 +6 weeks’ gestation, included recording of maternal characteristics and medical history, ultrasound examination for measurement of fetal crown-rump length, diagnosis of fetal abnormalities, and measurement of fetal nuchal translucency thickness as part of combined screening for fetal trisomies. Venous blood (4 mL) was obtained from the antecubital vein and collected into tubes containing liquid 0.109 mol/L trisodium citrate (BD Medical Systems, Franklin Lakes, NJ).


Written informed consent was obtained from the women agreeing to participate in the study, which was approved by the ethics committee of the hospital. The pregnancies included in the study were those resulting in live birth or stillbirth of phenotypically normal babies at ≥24 weeks’ gestation. Women on current anticoagulation were excluded.


Patient characteristics


Patient characteristics recorded included maternal age; racial origin (Caucasian, Afro-Caribbean, South Asian, East Asian, and mixed); method of conception (spontaneous or assisted conception requiring the use of ovulation drugs); cigarette smoking during pregnancy; medical history of chronic hypertension, diabetes mellitus, sickle cell trait, and autoimmune disease, including systemic lupus erythematosus or rheumatoid arthritis; family history of thromboembolic events; and obstetric history including parity (parous or nulliparous if no previous pregnancies at ≥24 weeks’ gestation). The maternal weight and height were measured.


Sample analysis


The blood samples were processed within 1 hour after collection. After centrifugation at 2200 g for 15 minutes at 20°C the undiluted plasma was analyzed immediately in the STA-Compact coagulation analyzer (Diagnostica Stago, Asnières-sur-Seine, France) by quantitative immunoturbidimetry following the manufacturer’s instructions. We used STA-Liatest FM (Diagnostica Stago) and STA-Liatest DD (Diagnostica Stago) assays with respective working ranges of 5-150 μg/mL and 0.22-4.0 μg /mL, and an expected normal threshold in the adult nonpregnant population of <6 μg/mL for FM and <0.5 μg/mL (expressed in fibrinogen equivalent units) for DD. The intraassay and interassay coefficients of variation were 5.55% and 5.7% for FM and 8.4% and 10.3% for DD, respectively.


Pregnancy outcome


Data on pregnancy outcome were collected from the hospital maternity records or the general medical practitioners of the women. The birthweight percentile for gestational age at delivery was derived from a reference range for our population. The definition of preeclampsia was that of the International Society for the Study of Hypertension in Pregnancy. Diagnosis of gestational diabetes mellitus was based on a 75-g oral glucose tolerance test performed at 24–28 weeks’ gestation.


Statistical analysis


Data for continuous variables are presented as median (interquartile range) and data for categorical variables are presented as n (%). The observed values of serum DD and FM concentrations were log 10 transformed to make their distributions gaussian. Normality was assessed using histograms and probability plots. Univariable regression analysis was used to examine the individual variables contributing significantly to prediction of log 10 -transformed values of DD and FM. Multivariable regression analysis with backward stepwise regression analysis was used to determine the significance of contribution from maternal and pregnancy characteristics. The measured concentration of DD and FM were converted into multiple of the median (MoM) values after adjusting for maternal characteristics that significantly affected log 10 -transformed values in the multiple regression analysis. A statistical software package (SPSS 21; IBM Corp, Armonk, NY) was used for data analyses.




Results


Study population


During the study period we examined 2870 singleton pregnancies with a live fetus at 11–13 weeks, but 256 were excluded: miscarriage or termination for fetal abnormalities and those with major fetal defects (n = 107), anticoagulation therapy (n = 28), or no pregnancy follow-up (n = 121). The characteristics of the study population of 2614 pregnancies are shown in Table 1 . In keeping with the South East London population, 61.7% women were Caucasian, 27.9% Afro-Caribbean, and 10.4% of other ethnic origins. DD was measured in all cases but FM was measured in only 1286 of the cases due to reagent availability.



Table 1

Maternal and pregnancy characteristics in study population






















































































































Maternal and pregnancy characteristics Study population, n = 2614
Maternal characteristics
Maternal age, y, median (IQR) 32.0 (28.1–35.5)
Maternal weight, kg, median (IQR) 66.5 (59.3–77.0)
Maternal height, m, median (IQR) 1.65 (1.60–1.69)
Gestational age, wk, median (IQR) 12.7 (12.3–13.0)
Cigarette smoker, n (%) 197 (7.5)
Cocaine use, n (%) 15 (0.6)
Racial origin, n (%)
Caucasian 1612 (61.7)
Afro-Caribbean 728 (27.9)
South Asian 121 (4.5)
East Asian 72 (2.8)
Mixed 81 (3.1)
Conception, n (%)
Spontaneous 2518 (96.3)
Assisted 96 (3.7)
Medical disorder, n (%)
Sickle cell trait 90 (3.4)
Thyroid disorders 47 (1.8)
Chronic hypertension 54 (2.1)
Autoimmune disease 4 (0.2)
Diabetes mellitus 25 (1.0)
Family history, n (%)
History of preeclampsia in mother 94 (3.6)
Diabetes mellitus 371 (14.2)
Obstetric history, n (%)
Nulliparous 1223 (46.8)
Parous–previous preeclampsia 102 (3.9)
Parous–previous gestational diabetes 21 (0.8)
Current pregnancy complication, n (%)
Preeclampsia 62 (2.4)
Gestational diabetes 82 (3.1)
Fetal growth restriction 281 (10.7)
Pregnancy outcome, median (IQR)
Gestation at delivery, wk 40.0 (39.0–40.9)
Birthweight, g 3390 (3080–3696)
Birthweight percentile 40.0 (39.0–40.9)

IQR , interquartile range.

Grossman et al. Characterizing plasma fibrin monomer complexes and D-dimer in pregnancy. Am J Obstet Gynecol 2016 .


FM complex


The median and 5th and 95th percentiles of the measured FM concentration were 4.3, 2.16, and 8.84 mg/L, respectively. In 282 (21.9%) of the 1286 pregnancies the values were >6 mg/L.


Univariable regression analysis demonstrated that significant contributions to log 10 FM were provided by several maternal and pregnancy characteristics ( Table 2 ). Multivariable regression analysis demonstrated that significant contributions to log 10 FM were provided by maternal weight, cocaine use, and medical history of chronic hypertension ( Figure 1 ).



Table 2

Univariable and multivariable regression analysis to examine factors from maternal and pregnancy characteristics affecting concentration of log 10 -transformed fibrin monomer complex



















































































































































































































Variable Univariable analysis Multivariable analysis
Estimate (95% CI) P value Estimate (95% CI) P value
Maternal characteristics
Maternal age, y, 32 –0.001 (–0.003 to 0.001) .339
Maternal weight, kg, 69 0.001 (7.8e –05 to 0.002) .031 0.001 (2.3e–04 to 0.002) .012
Maternal height, m, 1.64 0.099 (–0.076 to 0.274) .266
Gestational age, wk, 11 0.007 (–0.013 to 0.027) .468
Cigarette smoker –0.023 (–0.066 to 0.020) .296
Cocaine use –0.145 (–0.279 to –0.011) .034 –0.147 (–0.280 to –0.014) .030
Racial origin
Caucasian (reference) 1.000
Afro-Caribbean 0.019 (–0.007 to 0.044) .149
South Asian 0.011 (–0.042 to 0.064) .680
East Asian –0.010 (–0.081 to 0.061) .780
Mixed 0.054 (–0.015 to 0.124) .124
Conception
Spontaneous (reference) 1.000
Assisted conception –0.030 (–0.086 to 0.026) .295
Medical disorders
Sickle cell trait –0.026 (–0.088 to 0.035) .405
Thyroid disorders –0.036 (–0.127 to 0.054) .432
Chronic hypertension –0.136 (–0.224 to –0.048) .002 –0.150 (–0.238 to –0.062) .001
Autoimmune disease –0.312 (–0.712 to 0.089) .127
Diabetes mellitus –0.136 (–0.288 to 0.016) .079
Family history
History of preeclampsia in mother 0.010 (–0.050 to 0.070) .740
Diabetes mellitus –0.005 (–0.036 to 0.027) .776
Obstetric history
Nulliparous 1.000
Parous–previous preeclampsia 0.017 (–0.037 to 0.071) .540
Parous–previous gestational diabetes 0.032 (–0.066 to 0.130) .519
Current pregnancy complication
Preeclampsia –0.018 (–0.089 to 0.053) .616
Gestational diabetes 0.022 (–0.043 to 0.087) .503
Fetal growth restriction –0.014 (–0.049 to 0.022) .447

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May 2, 2017 | Posted by in GYNECOLOGY | Comments Off on Maternal and pregnancy characteristics affect plasma fibrin monomer complexes and D-dimer reference ranges for venous thromboembolism in pregnancy
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