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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

  • J. Lee
    Correspondence
    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.
    Affiliations
    Department of Anaesthesia and Perioperative Services, The Royal Brisbane and Women’s Hospital, Brisbane, QLD, Australia

    The University of Queensland, QLD, Australia
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  • K.H. Wyssusek
    Affiliations
    Department of Anaesthesia and Perioperative Services, The Royal Brisbane and Women’s Hospital, Brisbane, QLD, Australia

    The University of Queensland, QLD, Australia
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  • R.M.N. Kimble
    Affiliations
    The University of Queensland, QLD, Australia

    Department of Obstetrics and Gynaecology, The Royal Brisbane and Women’s Hospital, Brisbane, QLD, Australia
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  • M. Way
    Affiliations
    QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
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  • A.A. van Zundert
    Affiliations
    Department of Anaesthesia and Perioperative Services, The Royal Brisbane and Women’s Hospital, Brisbane, QLD, Australia

    The University of Queensland, QLD, Australia

    Queensland University of Technology, Brisbane, QLD, Australia
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  • J. Cohen
    Affiliations
    The University of Queensland, QLD, Australia

    Department of Intensive Care Medicine, The Royal Brisbane and Women’s Hospital, Brisbane, QLD, Australia
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  • J. Rowell
    Affiliations
    The University of Queensland, QLD, Australia

    Department of Haematology, The Royal Brisbane and Women’s Hospital, Brisbane, QLD, Australia
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  • V.A. Eley
    Affiliations
    Department of Anaesthesia and Perioperative Services, The Royal Brisbane and Women’s Hospital, Brisbane, QLD, Australia

    The University of Queensland, QLD, Australia
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Published:November 18, 2019DOI:https://doi.org/10.1016/j.ijoa.2019.10.003

      Highlights

      • Thromboelastometry compared for labouring vs non-labouring women.
      • Measures of clot firmness were higher in labouring women than non-labouring women.
      • Time to clotting onset was shorter in labouring women than non-labouring women.
      • ROTEM® reference ranges in labouring women and non-labouring women were different.
      • 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.

      Keywords

      Introduction

      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.
      • King K.
      • Setty S.
      • Thompson K.
      • McGlennan A.
      • Wright A.
      Rotational thromboleastometry (ROTEM) – the future of point of care testing in obstetrics?.
      • Wegner J.
      • Popovsky M.A.
      Clinical utility of thromboelastography: one size does not fit all.
      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.
      • Shreeve N.E.
      • Barry J.A.
      • Deutsch L.R.
      • Gomez K.
      • Kadir R.A.
      Changes in thromboelastography parameters in pregnancy, labor, and the immediate postpartum period.
      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.
      • Shreeve N.E.
      • Barry J.A.
      • Deutsch L.R.
      • Gomez K.
      • Kadir R.A.
      Changes in thromboelastography parameters in pregnancy, labor, and the immediate postpartum period.
      • Yoshimura T.
      • Ito M.
      • Nakamura T.
      • Okamura H.
      The influence of labor on thrombotic and fibrinolytic systems.
      • Bremer H.A.
      • Brommer E.J.P.
      • Wallenburg H.C.S.
      Effects of labor and delivery on fibrinolysis.
      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.
      • Koh S.C.L.
      • Arulkumaran S.
      • Biswas A.
      • Ratnam S.S.
      The influence of labor and placental separation on hemostasis in term pregnancy.
      Activation of the fibrinolytic system begins during labour, prior to placental separation, as compensation for the hypercoagulable state of pregnancy.
      • Yoshimura T.
      • Ito M.
      • Nakamura T.
      • Okamura H.
      The influence of labor on thrombotic and fibrinolytic systems.
      • Bremer H.A.
      • Brommer E.J.P.
      • Wallenburg H.C.S.
      Effects of labor and delivery on fibrinolysis.
      • Koh S.C.L.
      • Arulkumaran S.
      • Biswas A.
      • Ratnam S.S.
      The influence of labor and placental separation on hemostasis in term pregnancy.
      • Bellart J.
      • Gilabert R.
      • Fontcuberta J.
      • Borrell M.
      • Miralles R.M.
      • Cabero L.
      Fibrinolysis changes in normal pregnancy.
      • Bellart J.
      • Gilabert R.
      • Miralles R.M.
      • Monasterio J.
      • Cabero L.
      Endothelial cell markers and fibrinopeptide A to D-dimer ratio as a measure of coagulation and fibrinolysis balance in normal pregnancy.
      At the end of the first stage of labour there is a rise in tissue-type plasminogen-activator (t-PA) which can enhance endogenous fibrinolysis.
      • Yoshimura T.
      • Ito M.
      • Nakamura T.
      • Okamura H.
      The influence of labor on thrombotic and fibrinolytic systems.
      • Bremer H.A.
      • Brommer E.J.P.
      • Wallenburg H.C.S.
      Effects of labor and delivery on fibrinolysis.
      Tissue plasminogen activator and D-dimer also reach maximal levels during delivery.
      • Bellart J.
      • Gilabert R.
      • Fontcuberta J.
      • Borrell M.
      • Miralles R.M.
      • Cabero L.
      Fibrinolysis changes in normal pregnancy.
      This activation of the clotting mechanism at delivery results in decreased levels of factors XI and XII, and increased levels of fibrinopeptide A.
      • Hellgren M.
      • Blombäck M.
      Studies on blood coagulation and fibrinolysis in pregnancy, during delivery and in the puerperium.
      • Bonnar J.
      • Douglas A.S.
      • McNicol G.P.
      Coagulation and fibrinolytic mechanisms during and after normal childbirth.
      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.
      • Lee J.
      • Eley V.
      • Wyssusek K.
      • et al.
      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.
      • Bowden F.
      • Bhalla A.
      • Kelly S.
      • et al.
      Changes in rotational thromboelastometry (ROTEM) parameters during the first, second and third trimesters of pregnancy.
      • Duraj L.
      • Stasko J.
      • Hasko M.
      • et al.
      Monitoring of hemostasis by rotational thromboelastometry during normal pregnancy and postpartum.
      • Huissoud C.
      • Carrabin N.
      • Benchaib M.
      • et al.
      Coagulation assessment by rotation thrombelastometry in normal pregnancy.
      • De Lange N.M.
      • Van Rheenen-Flach L.E.
      • Lance M.D.
      • et al.
      Peri-partum reference ranges for ROTEM thromboelastometry.
      • Armstrong S.
      • Fernando R.
      • Ashpole K.
      • Simons R.
      • Columb M.
      Assessment of coagulation in the obstetric population using ROTEM® thromboelastometry.
      These studies demonstrated hypercoagulability, represented by a faster time to clot formation and increased clot firmness in pregnancy.
      • Bowden F.
      • Bhalla A.
      • Kelly S.
      • et al.
      Changes in rotational thromboelastometry (ROTEM) parameters during the first, second and third trimesters of pregnancy.
      • Duraj L.
      • Stasko J.
      • Hasko M.
      • et al.
      Monitoring of hemostasis by rotational thromboelastometry during normal pregnancy and postpartum.
      • Huissoud C.
      • Carrabin N.
      • Benchaib M.
      • et al.
      Coagulation assessment by rotation thrombelastometry in normal pregnancy.
      • De Lange N.M.
      • Van Rheenen-Flach L.E.
      • Lance M.D.
      • et al.
      Peri-partum reference ranges for ROTEM thromboelastometry.
      • Armstrong S.
      • Fernando R.
      • Ashpole K.
      • Simons R.
      • Columb M.
      Assessment of coagulation in the obstetric population using ROTEM® thromboelastometry.
      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.
      • Shreeve N.E.
      • Barry J.A.
      • Deutsch L.R.
      • Gomez K.
      • Kadir R.A.
      Changes in thromboelastography parameters in pregnancy, labor, and the immediate postpartum period.
      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
      • Lowe S.A.
      • Bowyer L.
      • Lust K.
      • et al.
      The SOMANZ guideline for the management of hypertensive disorders of pregnancy. 2014.
      ; and anaemia defined according to the World Health Organization definition.

      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.
      • Lee J.
      • Eley V.
      • Wyssusek K.
      • et al.
      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.
      • Lee J.
      • Eley V.
      • Wyssusek K.
      • et al.
      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.
      • Lee J.
      • Eley V.
      • Wyssusek K.
      • et al.
      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.
      Figure thumbnail gr1
      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.
      • Lee J.
      • Eley V.
      • Wyssusek K.
      • et al.
      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
      CharacteristicsLabouring women

      n=121

      n (%)
      Non-labouring women
      • Lee J.
      • Eley V.
      • Wyssusek K.
      • et al.
      Baseline parameters for rotational thromboelastometry (ROTEM®) in healthy women undergoing elective caesarean delivery: a prospective observational study in Australia.


      n=132

      n (%)
      P-value
      Maternal age (y), mean (SD)29.6 (5.4)32.7 (5.0)<0.001
      Nulliparous (n)75 (62.0)26 (19.7)<0.001
      Gestation (weeks), median (IQR)39.4 (37.4–40.4)39.0 (38.6–39.3)0.10
      Body mass index (kg/m2), median (IQR)22.9 (21.2–27.2)23.8 (21.5–26.4)0.29
      Mode of birth (n)
       Spontaneous vaginal delivery46 (38.0)N/A
       Emergency caesarean section50 (41.3)N/A
       Induction of labour and assisted delivery25 (20.7)N/A
      Cervical dilatation during labour (cm), mean (SD)4.76 (2.58)N/A
      Ethnicities (%)
       Caucasian57.0%75.8%
       South East Asian7.4%9.1%
       Indian5.7%6.8%
       Other28.9%7.6%
       Indigenous Australian0.8%0.8%
      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.
      • Lee J.
      • Eley V.
      • Wyssusek K.
      • et al.
      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.
      • Lee J.
      • Eley V.
      • Wyssusek K.
      • et al.
      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 womenNon-labouring women
      n=121n=132P-value
      FIBTEMCT51.7 (6.21)53.4 (7.85)0.065
      CFT
      A521.05 (4.10)19.7 (3.90)0.008
      A1023.3 (4.54)21.7 (4.18)0.004
      A1524.4 (4.76)22.8 (4.34)0.005
      A2025.1 (4.93)23.4 (4.60)0.004
      A3025.8 (4.93)24.1 (4.60)0.008
      MCF25.8 (4.86)24.1 (4.68)0.007
      CFR76.9 (2.84)76.3 (3.45)0.09
      α-angle76.2 (2.93)75.5 (3.81)0.076
      AUC2551.9 (485.71)2390.9 (460.26)0.007
      MaxV18.1 (4.01)17.4 (5.00)0.25
      EXTEMCT52.2 (5.91)53.7 (6.26)0.049
      CFT62.6 (13.08)65.7 (15.20)0.08
      A554.8 (5.35)53.2 (6.02)0.025
      A1064.6 (4.42)63.2 (5.32)0.02
      A1568.4 (3.94)67.0 (4.85)0.014
      A2070.1 (3.66)68.8 (4.57)0.017
      A3071.0 (3.32)70.0 (4.13)0.044
      MCF71.1 (3.36)70.2 (4.01)0.042
      CFR78.5 (2.40)78.5 (2.31)0.08
      α-angle77.6 (2.64)77.4 (2.65)0.6
      AUC7060.8 (328.9)6964.5 (390.7)0.036
      MaxV20.6 (4.23)20.3 (4.09)0.64
      INTEMCT162.5 (26.19)167.7 (32.06)0.16
      CFT60.47 (12.6)64.2 (15.30)0.035
      A553.06 (5.11)51.3 (5.76)0.012
      A1063.0 (4.29)61.4 (5.14)0.007
      A1566.9 (3.9)65.4 (4.79)0.009
      A2068.7 (3.72)67.3 (4.53)0.008
      A3069.6 (3.79)68.4 (4.55)0.028
      MCF69.6 (3.77)68.3 (4.43)0.009
      CFR78.8 (2.30)78.2 (2.53)0.054
      α-angle77.7 (2.47)77.1 (2.73)0.11
      AUC6925.0 (367.04)6791.6 (429.60)0.009
      MaxV21.0 (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
      ROTEM® ParameternReference range for labouring womennReference range for non-labouring women
      • Lee J.
      • Eley V.
      • Wyssusek K.
      • et al.
      Baseline parameters for rotational thromboelastometry (ROTEM®) in healthy women undergoing elective caesarean delivery: a prospective observational study in Australia.
      FIBTEM Parameters
      CT (s)12141–6613240–74
      CFR (°)12170–82131*67–82
      Alpha angle (°)12169–81131*67–81
      MCF (mm)12116–4013216–34
      A5 (mm)12114–3313213–28
      A10 (mm)12115–3713214–30
      A15 (mm)12116–39130*15–32
      A20 (mm)120*16–40127*16–33
      A30 (mm)116*16–40124*16–34
      AUC (mm x 100)1211589–39171321634–3366
      MaxV (mm min−1)12111–271329–27
      EXTEM Parameters
      CT (s)12140–6513243–69
      CFT (s)12141–9313243–108
      CFR (°)12173–8313271–82
      Alpha angle (°)12171–8213269–82
      MCF (mm)12163–7713260–78
      A5 (mm)12144–6713239–66
      A10 (mm)12156–7413250–73
      A15 (mm)120*60–77129*55–76
      A20 (mm)120*62–77127*57–77
      A30 (mm)115*63–77123*60–78
      AUC (mm x 100)1216562–76671325960–7645
      MaxV (mm min−1)12112–3013212–30
      INTEM Parameters
      CT (s)121118–222132115–245
      CFT (s)12136–8913242–103
      CFR (°)12173–8313271–83
      Alpha angle (°)12172–8213270–82
      MCF (mm)12161–7813259–76
      A5 (mm)12143–6513238–63
      A10 (mm)12154–7313249–70
      A15 (mm)120*59–80127*54–74
      A20 (mm)120*60–76127*57–75
      A30 (mm)115*61–78122*59–76
      AUC (mm x 100)1216072–76861325886–7524
      MaxV (mm min−1)12113–3313212–31
      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.
      • Lee J.
      • Eley V.
      • Wyssusek K.
      • et al.
      Baseline parameters for rotational thromboelastometry (ROTEM®) in healthy women undergoing elective caesarean delivery: a prospective observational study in Australia.

      Discussion

      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,
      • Lee J.
      • Eley V.
      • Wyssusek K.
      • et al.
      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.
      • Shreeve N.E.
      • Barry J.A.
      • Deutsch L.R.
      • Gomez K.
      • Kadir R.A.
      Changes in thromboelastography parameters in pregnancy, labor, and the immediate postpartum period.
      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.
      • Shreeve N.E.
      • Barry J.A.
      • Deutsch L.R.
      • Gomez K.
      • Kadir R.A.
      Changes in thromboelastography parameters in pregnancy, labor, and the immediate postpartum period.
      • Yoshimura T.
      • Ito M.
      • Nakamura T.
      • Okamura H.
      The influence of labor on thrombotic and fibrinolytic systems.
      • Bremer H.A.
      • Brommer E.J.P.
      • Wallenburg H.C.S.
      Effects of labor and delivery on fibrinolysis.
      Activation of the fibrinolytic system also begins during labour, along with platelet activation and elevated plasminogen activator inhibitor-1 and -2
      • Bremer H.A.
      • Brommer E.J.P.
      • Wallenburg H.C.S.
      Effects of labor and delivery on fibrinolysis.
      and factor VII, prior to placental separation, likely in order to compensate for the hypercoagulable state of pregnancy.
      • Yoshimura T.
      • Ito M.
      • Nakamura T.
      • Okamura H.
      The influence of labor on thrombotic and fibrinolytic systems.
      • Bremer H.A.
      • Brommer E.J.P.
      • Wallenburg H.C.S.
      Effects of labor and delivery on fibrinolysis.
      • Koh S.C.L.
      • Arulkumaran S.
      • Biswas A.
      • Ratnam S.S.
      The influence of labor and placental separation on hemostasis in term pregnancy.
      • Bellart J.
      • Gilabert R.
      • Fontcuberta J.
      • Borrell M.
      • Miralles R.M.
      • Cabero L.
      Fibrinolysis changes in normal pregnancy.
      • Bellart J.
      • Gilabert R.
      • Miralles R.M.
      • Monasterio J.
      • Cabero L.
      Endothelial cell markers and fibrinopeptide A to D-dimer ratio as a measure of coagulation and fibrinolysis balance in normal pregnancy.
      Overall, labour is a dynamic process with consumption of platelets, and coagulation factors including fibrinogen and inhibitors, at delivery.
      • Hellgren M.
      • Blombäck M.
      Studies on blood coagulation and fibrinolysis in pregnancy, during delivery and in the puerperium.
      • Bonnar J.
      • Douglas A.S.
      • McNicol G.P.
      Coagulation and fibrinolytic mechanisms during and after normal childbirth.
      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).
      • Huissoud C.
      • Carrabin N.
      • Audibert F.
      • et al.
      Bedside assessment of fibrinogen level in postpartum haemorrhage by thrombelastometry.
      Given that FIBTEM parameters have been shown to correlate well with fibrinogen levels,
      • Huissoud C.
      • Carrabin N.
      • Audibert F.
      • et al.
      Bedside assessment of fibrinogen level in postpartum haemorrhage by thrombelastometry.
      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

        • King K.
        • Setty S.
        • Thompson K.
        • McGlennan A.
        • Wright A.
        Rotational thromboleastometry (ROTEM) – the future of point of care testing in obstetrics?.
        Arch Dis Child Fetal Neonatal Ed. 2011; 96: 120-121
        • Wegner J.
        • Popovsky M.A.
        Clinical utility of thromboelastography: one size does not fit all.
        Semin Thromb Hemost. 2010; 36: 699-706
        • Shreeve N.E.
        • Barry J.A.
        • Deutsch L.R.
        • Gomez K.
        • Kadir R.A.
        Changes in thromboelastography parameters in pregnancy, labor, and the immediate postpartum period.
        Int J Gynaecol Obstet. 2016; 134: 290-293
        • Yoshimura T.
        • Ito M.
        • Nakamura T.
        • Okamura H.
        The influence of labor on thrombotic and fibrinolytic systems.
        Eur J Obstet Gynecol Reprod Biol. 1992; 44: 195-199
        • Bremer H.A.
        • Brommer E.J.P.
        • Wallenburg H.C.S.
        Effects of labor and delivery on fibrinolysis.
        Eur J Obstet Gynecol Reprod Biol. 1994; 55: 163-168
        • Koh S.C.L.
        • Arulkumaran S.
        • Biswas A.
        • Ratnam S.S.
        The influence of labor and placental separation on hemostasis in term pregnancy.
        Clin Appl Thromb Hemost. 1998; 4: 262-267
        • Bellart J.
        • Gilabert R.
        • Fontcuberta J.
        • Borrell M.
        • Miralles R.M.
        • Cabero L.
        Fibrinolysis changes in normal pregnancy.
        J Perinat Med. 1997; 25: 368-372
        • Bellart J.
        • Gilabert R.
        • Miralles R.M.
        • Monasterio J.
        • Cabero L.
        Endothelial cell markers and fibrinopeptide A to D-dimer ratio as a measure of coagulation and fibrinolysis balance in normal pregnancy.
        Gynecol Obstet Invest. 1998; 46: 17-21
        • Hellgren M.
        • Blombäck M.
        Studies on blood coagulation and fibrinolysis in pregnancy, during delivery and in the puerperium.
        Gynecol Obstet Invest. 1981; 12: 141-154
        • Bonnar J.
        • Douglas A.S.
        • McNicol G.P.
        Coagulation and fibrinolytic mechanisms during and after normal childbirth.
        Br Med J. 1970; 2: 200-203
        • Lee J.
        • Eley V.
        • Wyssusek K.
        • et al.
        Baseline parameters for rotational thromboelastometry (ROTEM®) in healthy women undergoing elective caesarean delivery: a prospective observational study in Australia.
        Int J Obstet Anesth. 2019; 38: 10-18
        • Bowden F.
        • Bhalla A.
        • Kelly S.
        • et al.
        Changes in rotational thromboelastometry (ROTEM) parameters during the first, second and third trimesters of pregnancy.
        Int J Obstet Anesth. 2016; 25: S11
        • Duraj L.
        • Stasko J.
        • Hasko M.
        • et al.
        Monitoring of hemostasis by rotational thromboelastometry during normal pregnancy and postpartum.
        Acta Medica Martiniana. 2015; 15: 5-12
        • Huissoud C.
        • Carrabin N.
        • Benchaib M.
        • et al.
        Coagulation assessment by rotation thrombelastometry in normal pregnancy.
        Thromb Haemost. 2009; 101: 755-761
        • De Lange N.M.
        • Van Rheenen-Flach L.E.
        • Lance M.D.
        • et al.
        Peri-partum reference ranges for ROTEM thromboelastometry.
        Br J Anaesth. 2014; 112: 852-859
        • Armstrong S.
        • Fernando R.
        • Ashpole K.
        • Simons R.
        • Columb M.
        Assessment of coagulation in the obstetric population using ROTEM® thromboelastometry.
        Int J Obstet Anesth. 2011; 20: 293-298
        • Lowe S.A.
        • Bowyer L.
        • Lust K.
        • et al.
        The SOMANZ guideline for the management of hypertensive disorders of pregnancy. 2014.
        Aust N Z J Obstet Gynaecol. 2015; 55: 11-16
      1. 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.

        • Huissoud C.
        • Carrabin N.
        • Audibert F.
        • et al.
        Bedside assessment of fibrinogen level in postpartum haemorrhage by thrombelastometry.
        Br J Obstet Gynaecol. 2009; 116: 1097-1102