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Baseline parameters for rotational thromboelastometry (ROTEM®) in healthy pregnant Australian women: a comparison of labouring and non-labouring women at term
Correspondence to: J. Lee, Department of Anaesthesia and Perioperative Medicine, Level 4 Ned Hanlon Building Q5, The Royal Brisbane and Women’s Hospital, Butterfield St, Herston, QLD 4029, Australia.
Department of Anaesthesia and Perioperative Services, The Royal Brisbane and Women’s Hospital, Brisbane, QLD, AustraliaThe University of Queensland, QLD, Australia
Department of Anaesthesia and Perioperative Services, The Royal Brisbane and Women’s Hospital, Brisbane, QLD, AustraliaThe University of Queensland, QLD, Australia
The University of Queensland, QLD, AustraliaDepartment of Obstetrics and Gynaecology, The Royal Brisbane and Women’s Hospital, Brisbane, QLD, Australia
Department of Anaesthesia and Perioperative Services, The Royal Brisbane and Women’s Hospital, Brisbane, QLD, AustraliaThe University of Queensland, QLD, AustraliaQueensland University of Technology, Brisbane, QLD, Australia
Department of Anaesthesia and Perioperative Services, The Royal Brisbane and Women’s Hospital, Brisbane, QLD, AustraliaThe University of Queensland, QLD, Australia
Thromboelastometry compared for labouring vs non-labouring women.
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Measures of clot firmness were higher in labouring women than non-labouring women.
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Time to clotting onset was shorter in labouring women than non-labouring women.
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ROTEM® reference ranges in labouring women and non-labouring women were different.
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Greater hypercoagulability is seen in labouring compared to non-labouring women.
Abstract
Background
Rotational thromboelastometry (ROTEM®) is a point-of-care coagulation test. Reference ranges in non-labouring women have recently been established from a cohort of women presenting for elective caesarean delivery using the recommended minimum sample size of 120. This study aimed to present baseline parameters for labouring and non-labouring women and to compare the mean values of these ROTEM® parameters.
Methods
Ethical approval was granted for an opt-out recruitment approach for labouring women and written consent was obtained from non-labouring women (data published previously). ROTEM® testing was performed in these two cohorts at term gestation. Women with any condition affecting coagulation were excluded. ROTEM® Delta reference ranges were derived by calculating the 2.5 and 97.5 percentiles for INTEM/EXTEM/FIBTEM amplitude at 5 min (A5), coagulation time (CT), maximum clot firmness (MCF) and clot formation time (CFT).
Results
One hundred and twenty-one labouring and 132 non-labouring women met inclusion criteria. The mean values for selected ROTEM® parameters for labouring and non-labouring women respectively were: FIBTEM A5, 21.05 and 19.7 mm (P=0.008); EXTEM A5, 54.8 and 53.2 mm (P=0.025); and EXTEM CT, 52.2 and 53.7 s (P=0.049). Significant differences between the groups were observed in measures of clotting onset and clot firmness.
Conclusions
We demonstrated a significant decrease in the mean time-to-clotting onset in labouring women compared with non-labouring women. Mean values for measures of clot firmness were greater in labouring women. In comparison to previously established ROTEM® baseline parameters for non-labouring women, this study provides evidence that there is greater hyper-coagulability in labouring women.
Rotational thromboelastometry (ROTEM®; Instrumentation Laboratory™, Munich, Germany) is a point-of-care visco-elastic test of coagulation that is well established in hepatic and cardiac surgery, obstetrics and trauma.
Women become more hypercoagulable as pregnancy progresses through the three trimesters and this has been measured by both thromboelastography and rotational thromboelastometry in uncomplicated pregnancies.
To date there has been a paucity of substantial, well-researched reference ranges for ROTEM® in pregnant labouring and non-labouring women. The increasing utilisation of point-of-care coagulation testing for obstetric patients warrants proper validation of hypercoagulable changes demonstrated by ROTEM®.
Changes consistent with clotting activation occur during normal vaginal delivery.
During labour, a hypercoagulable state is accompanied by enhanced fibrinolysis and platelet activation, along with elevated fibrinogen, plasminogen activator inhibitor-1 and -2 levels, and decreased total protein S and antithrombin III activity.
We have recently published ROTEM® reference ranges in non-labouring women, presenting for elective caesarean delivery at term gestation, using the recommended minimum sample size of 120.
Baseline parameters for rotational thromboelastometry (ROTEM®) in healthy women undergoing elective caesarean delivery: a prospective observational study in Australia.
Prior reports of ROTEM® reference ranges in pregnancy included fewer than the 120 patients recommended by the International Federation of Clinical Chemistry (IFCC) for establishing reference ranges.
From the time of active labour to the postpartum period, comparison of visco-elastic testing demonstrated a dynamic shift from maximum clot formation to increased clot lysis.
The current study aimed to compare mean values of ROTEM® baseline parameters for labouring women to those established for non-labouring women who had presented for elective caesarean delivery at term gestation.
Methods
The study was performed in a tertiary hospital with approximately 4500 deliveries annually and a caesarean delivery rate of 35%. Ethical approval was obtained from The Royal Brisbane and Women’s Hospital (RBWH) Human Research Ethics Committee (HREC/14/QRBW/497). This manuscript adheres to the STROBE (Strengthening the Reporting of Observational Studies in Epidemiology) Statement.
An opt-out approach to the recruitment of labouring women was approved. Eligible women were aged 18–45 years, with a body mass index (BMI) of 18.5–30 kg/m2, and in active labour at term gestation (>37 weeks). Labour was defined as regular uterine contractions with a cervical dilatation of at least three centimetres.
Labouring women were excluded if they had pre-existing comorbidities, pregnancy-related conditions or were taking medications affecting coagulation. Excluded pregnancy-related conditions included the following: gestational hypertension, pre-eclampsia and HELLP syndrome (haemolysis, elevated liver enzymes and low platelet count) defined according to guidelines of the Society of Obstetric Medicine of Australia and New Zealand
World Health Organization (2011). Haemoglobin concentrations for the diagnosis of anaemia and assessment of severity. Vitamin and Mineral Nutrition Information System. Available at: https://www.who.int/vmnis/indicators/haemoglobin/en/. Accessed 1 October, 2019.
Women with the following conditions were also excluded: gestational thrombocytopaenia, cholestasis of pregnancy, antepartum haemorrhage, Factor V Leiden deficiency, antiphospholipid syndrome, haemochromatosis and thalassaemia and human immunodeficiency virus. Women medicated with anticoagulants or aspirin were excluded.
Baseline parameters for rotational thromboelastometry (ROTEM®) in healthy women undergoing elective caesarean delivery: a prospective observational study in Australia.
The recruitment and study methodology for the non-labouring women who were presenting for elective caesarean delivery at term has been described previously.
Baseline parameters for rotational thromboelastometry (ROTEM®) in healthy women undergoing elective caesarean delivery: a prospective observational study in Australia.
For labouring women, ROTEM® sampling occurred at the time of insertion of an intravenous cannula or venepuncture for non-research related blood tests. This occurred at varying times after the onset of labour in the labouring women cohort. Samples were collected in 3.5 mL Vacutainer™ collection tubes (Becton-Dickinson, North Ryde, Australia) containing 3.2% sodium citrate. ROTEM® analysis occurred within two hours of specimen collection. ROTEM® results were reviewed retrospectively and were not used to alter clinical management.
All ROTEM® tests, performed by certified personnel on citrated whole blood, used a ROTEM® Delta analyser. INTEM, EXTEM and FIBTEM tests were performed on three parallel channels simultaneously using pipette programmes set by the manufacturer.
A minimum sample size of 120 was targeted for establishing reference values, as per IFCC recommendations for both the labouring and the non-labouring women (presenting for elective caesarean delivery at term). ROTEM® reference ranges were derived by calculating the 2.5 and 97.5 percentiles for INTEM/EXTEM/FIBTEM parameters, including the A5, A15, CT, MCF and CFT. Statistical analysis was performed using SPSS Statistics Software Version 23, IBM®, NY, USA. Categorical variables were summarised by frequencies and percentages; continuous variables by means and standard deviations (SD); and by median and interquartile ranges (IQR) for non-normally distributed variables. The means (SD) of ROTEM® parameters for the labouring and non-labouring groups were compared using an independent Student t-test and P-values less than 0.05 were considered statistically significant.
Results
One hundred and twenty-one women met inclusion criteria for the labouring women reference range calculations and these women were compared to values of the 132 non-labouring women presenting for elective caesarean delivery.
Baseline parameters for rotational thromboelastometry (ROTEM®) in healthy women undergoing elective caesarean delivery: a prospective observational study in Australia.
Fig. 1 details the application of inclusion and exclusion criteria. Recruitment occurred between January and December 2016. Demographic characteristics are summarised in Table 1. Median BMI and gestation were similar between the two groups, while there was a significant difference in the mean maternal age and parity.
Fig. 1Recruitment flowchart detailing participant exclusions. BMI: body mass index, HELLP: haemolysis, elevated liver enzymes and low platelets. Data for non-labouring women presenting for elective caesarean delivery at term has been previously described.
Baseline parameters for rotational thromboelastometry (ROTEM®) in healthy women undergoing elective caesarean delivery: a prospective observational study in Australia.
. aPre-eclampsia and gestational hypertension as described in the SOMANZ Guidelines. Sourced from The SOMANZ Guidelines for the Management of Hypertensive Disorders of Pregnancy. https://www.somanz.org/documents/HTPregnancyGuidelineJuly2014.pdf (Accessed August 1, 2018). bGestational diabetes mellitus as described in the guidelines from the Queensland Clinical Guidelines. Sourced from The Maternity and Neonatal Clinical Guideline: Gestational diabetes mellitus, published by Queensland Health, Australia. 2015. URL:// https://www.health.qld.gov.au/__data/assets/pdf_file/0023/140099/g-gdm.pdf Accessed August 1, 2018
Table 1Patient demographics and delivery details for labouring and non-labouring women presenting to The Royal Brisbane and Women’s Hospital for delivery at term gestation
Baseline parameters for rotational thromboelastometry (ROTEM®) in healthy women undergoing elective caesarean delivery: a prospective observational study in Australia.
Data are presented as n (%), except where labelled mean (SD) or median (IQR). Data for non-labouring women presenting for elective caesarean delivery at term has been previously described.
Baseline parameters for rotational thromboelastometry (ROTEM®) in healthy women undergoing elective caesarean delivery: a prospective observational study in Australia.
Table 2 shows a comparison between the mean (SD) of each ROTEM® parameter for the labouring and non-labouring groups. There were significant differences between the two groups for most ROTEM® parameters, including the FIBTEM amplitudes at various times and the EXTEM CT. Reference ranges for selected ROTEM® parameters are shown in Table 3, with the FIBTEM, EXTEM and INTEM panels compared with previously established values from non-labouring women.
Baseline parameters for rotational thromboelastometry (ROTEM®) in healthy women undergoing elective caesarean delivery: a prospective observational study in Australia.
Table 2Comparison of mean values of ROTEM® parameters for labouring and non-labouring women presenting to The Royal Brisbane and Women’s Hospital for delivery at term gestation
Labouring women
Non-labouring women
n=121
n=132
P-value
FIBTEM
CT
51.7 (6.21)
53.4 (7.85)
0.065
CFT
–
–
–
A5
21.05 (4.10)
19.7 (3.90)
0.008
A10
23.3 (4.54)
21.7 (4.18)
0.004
A15
24.4 (4.76)
22.8 (4.34)
0.005
A20
25.1 (4.93)
23.4 (4.60)
0.004
A30
25.8 (4.93)
24.1 (4.60)
0.008
MCF
25.8 (4.86)
24.1 (4.68)
0.007
CFR
76.9 (2.84)
76.3 (3.45)
0.09
α-angle
76.2 (2.93)
75.5 (3.81)
0.076
AUC
2551.9 (485.71)
2390.9 (460.26)
0.007
MaxV
18.1 (4.01)
17.4 (5.00)
0.25
EXTEM
CT
52.2 (5.91)
53.7 (6.26)
0.049
CFT
62.6 (13.08)
65.7 (15.20)
0.08
A5
54.8 (5.35)
53.2 (6.02)
0.025
A10
64.6 (4.42)
63.2 (5.32)
0.02
A15
68.4 (3.94)
67.0 (4.85)
0.014
A20
70.1 (3.66)
68.8 (4.57)
0.017
A30
71.0 (3.32)
70.0 (4.13)
0.044
MCF
71.1 (3.36)
70.2 (4.01)
0.042
CFR
78.5 (2.40)
78.5 (2.31)
0.08
α-angle
77.6 (2.64)
77.4 (2.65)
0.6
AUC
7060.8 (328.9)
6964.5 (390.7)
0.036
MaxV
20.6 (4.23)
20.3 (4.09)
0.64
INTEM
CT
162.5 (26.19)
167.7 (32.06)
0.16
CFT
60.47 (12.6)
64.2 (15.30)
0.035
A5
53.06 (5.11)
51.3 (5.76)
0.012
A10
63.0 (4.29)
61.4 (5.14)
0.007
A15
66.9 (3.9)
65.4 (4.79)
0.009
A20
68.7 (3.72)
67.3 (4.53)
0.008
A30
69.6 (3.79)
68.4 (4.55)
0.028
MCF
69.6 (3.77)
68.3 (4.43)
0.009
CFR
78.8 (2.30)
78.2 (2.53)
0.054
α-angle
77.7 (2.47)
77.1 (2.73)
0.11
AUC
6925.0 (367.04)
6791.6 (429.60)
0.009
MaxV
21.0 (4.49)
20.2 (4.48)
0.14
Data are presented as mean (SD). CT: clotting time. CFR: clot formation rate. MCF: maximum clot firmness. A5, A10, A15, A20, A30: amplitude (firmness) at x minutes. α-angle: alpha angle. AUC: area under curve. MaxV: maximum velocity.
Table 3Reference ranges for ROTEM® parameters in labouring and non-labouring women presenting to The Royal Brisbane and Women’s Hospital for delivery at term gestation
Baseline parameters for rotational thromboelastometry (ROTEM®) in healthy women undergoing elective caesarean delivery: a prospective observational study in Australia.
ROTEM® reference ranges were derived by calculating the 2.5 and 97.5 percentiles. CT: clotting time. CFR: clot formation rate. MCF: maximum clot firmness. A5, A10, A15, A20, A30: amplitude (firmness) at x minutes. AUC: area under curve. MaxV: maximum velocity. *Fewer samples were analysed for these parameters due to laboratory prioritisation of clinical samples over research samples. Data for non-labouring women presenting for elective caesarean delivery at term has been previously described.
Baseline parameters for rotational thromboelastometry (ROTEM®) in healthy women undergoing elective caesarean delivery: a prospective observational study in Australia.
For most ROTEM® parameters, there was a significant difference between the labouring and non-labouring groups. In comparison to non-labouring women presenting for elective caesarean delivery at term gestation,
Baseline parameters for rotational thromboelastometry (ROTEM®) in healthy women undergoing elective caesarean delivery: a prospective observational study in Australia.
measures of clot firmness at various times were greater for labouring women. In addition, the onset of clot formation was significantly faster in labouring women. These differences were statistically significant for all except the alpha-angle, MaxV, EXTEM CFT and INTEM CT values. Mean values for FIBTEM/EXTEM/INTEM alpha-angle, MCF, AUC and MaxV did not significantly differ. This is consistent with the findings of Shreeve et al.
who demonstrated that women in established labour had a further progression toward a hypercoagulable state.
In both cohorts, measured ROTEM® parameters were obtained from three different assays (FIBTEM, EXTEM and INTEM). In keeping with other studies recruiting smaller numbers of patients, we observed changes consistent with clotting activation occurring during normal vaginal delivery.
The FIBTEM/EXTEM/INTEM amplitudes were higher in labouring women. The amplitudes at various times reflect the degree of clot firmness at those times following clot initiation. The MCF is the maximum amplitude over time and represents overall clot firmness based on the contribution of fibrinogen and platelets. The higher amplitudes found in the labouring population reflect increased hypercoagulability. The clotting time is the time from the addition of the clotting activator until the time when the clot amplitude reaches two millimetres. Narrower ranges were demonstrated for FIBTEM/EXTEM/INTEM CT, EXTEM/INTEM CFT and FIBTEM/EXTEM/INTEM alpha-angle in the labouring group.
Obstetric haemorrhage can be catastrophic if not managed effectively and immediately. When using ROTEM®-directed resuscitation, management may be less effective if test results are not interpreted for the specific reference population of labouring women at term gestation. Women with lower fibrinogen levels detected in early labour have been identified as being at risk of postpartum haemorrhage (PPH).
detection of low fibrinogen by FIBTEM assay may identify labouring women at risk of PPH. ROTEM®-guided transfusion is based on specific thresholds as triggers. Those women showing a lower degree of hypercoagulability in labour may have a reduced physiologic buffer against PPH at the time of delivery; so further studies to evaluate this possibility, and of appropriate therapeutic interventions, are needed. Further research will also involve evaluating ROTEM® at specific time points in labour, particularly during prolonged labour and in comparison with postpartum values.
The study has limitations. Our study population was restricted to pregnant women at term, either admitted in labour, anticipating vaginal delivery or admitted for elective caesarean delivery. Therefore, our results are not generalisable to pregnant women at earlier gestational ages or to non-obstetric populations. Also, the exclusion criteria were different for the two groups in that women with gestational diabetes mellitus (GDM) were excluded from the non-labouring group whilst six women with GDM were included in the labouring group. Currently, there are few data available on the impact of GDM on coagulation as measured by ROTEM®. Standard coagulation tests (PT, aPTT, fibrinogen, and platelet count) were not performed for correlation with ROTEM® values in either study cohort. In a subset of assays (FIBTEM CFT; FIBTEM/EXTEM/INTEM A30) among labouring women, fewer than 120 patient samples were analysed due to laboratory prioritisation of clinical samples over research samples. Therefore, not all of the reference ranges comply with the IFCC criteria for establishing reference ranges. Timing of our coagulation testing in relation to onset of labour or proximity to delivery was not standardised and theoretically this may have introduced some variation in the results.
In conclusion, in our study comparing ROTEM® results from a group of labouring women with those from a group of non-labouring women (at term and scheduled for elective caesarean delivery), we demonstrated greater hypercoagulability in labouring women. The onset of clot formation (EXTEM CT and INTEM CT, CFT) was significantly faster in labouring women and measures of clot firmness (FIBTEM/EXTEM/INTEM A5, A10, A15, A20, A30, MCF) were significantly higher. Our results contribute to the current understanding of changes in coagulation during pregnancy, specifically during labour. Future research should assess ROTEM® values at specific time points throughout labour in order to define dynamic coagulation changes during this process and to examine the potential for the use of pre-labour ROTEM® values to predict bleeding risk.
Funding
This study was conducted at The Royal Brisbane and Women’s Hospital (RBWH), Brisbane, QLD, Australia.
Pathology Queensland (SERC) provided funding for ROTEM® testing and consumables; National Blood Authority Australia, Australian Society of Anaesthetists, and The RBWH and RBWH Foundation provided funding for research nursing support and time to conduct the research. None of these organisations had any involvement in the study design, data collection, analyses, interpretation of data or the writing of this report.
Conflict of interest
The authors report no conflicts of interest
Acknowledgements
We wish to acknowledge help from The National Blood Authority, The RBWH and RBWH Foundation, Pathology Queensland (SERC) and The Australian Society of Anaesthetists (ASA). The following persons made significant contributions: Sue Williams, Sue Freney and the RBWH Blood Bank Team for the processing of blood samples, collating of results and project planning; Dr Ellen Coonan (anaesthetic registrar) for help with data collection; the RBWH obstetric anaesthesia staff, anaesthetic technicians, obstetric staff, midwifery staff and research nurse team for blood sampling and patient recruitment.
References
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Rotational thromboleastometry (ROTEM) – the future of point of care testing in obstetrics?.
Baseline parameters for rotational thromboelastometry (ROTEM®) in healthy women undergoing elective caesarean delivery: a prospective observational study in Australia.
World Health Organization (2011). Haemoglobin concentrations for the diagnosis of anaemia and assessment of severity. Vitamin and Mineral Nutrition Information System. Available at: https://www.who.int/vmnis/indicators/haemoglobin/en/. Accessed 1 October, 2019.
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