Abstract
Since July 2022, obstetrical disseminated intravascular coagulation (DIC) in Japan has been diagnosed based on the new criteria (tentative version), which assesses the main underlying disease, fibrinogen level, and fibrin/fibrinogen degradation products or D-dimer level. In June 2024, the tentative version underwent minor revision and the final version was released. The previous Japanese criteria assessed underlying disease, clinical symptoms, and various laboratory findings. This study aimed to prove the effectiveness, reliability, and validity of the new criteria (final version). We analyzed 212 women with singleton pregnancies who delivered after 22 gestational weeks and experienced blood loss ≥ 1000 mL during vaginal delivery or ≥ 2000 mL during cesarean section. Those with missing laboratory findings before receiving blood transfusion at delivery were excluded. In the obstetrical DIC group, the frequency of fibrinogen levels < 150 mg/dL was significantly higher than in the control group (90% vs. 5%, p < 0.0001), as was the frequency of scores ≥ 8 according to the previous Japanese criteria (100% vs. 10%, p < 0.0001). Cronbach alpha was 0.757 and Spearman’s rank-order correlation was 0.558 between the new and previous criteria. In conclusion, we proved the effectiveness, reliability, and validity of the Japanese new criteria (final version) to diagnose obstetrical DIC.
Keywords: Criteria, Obstetrical disseminated intravascular coagulation, Tentative version, Reliability, Validity
Subject terms: Physical examination, Diagnostic markers
Introduction
The new Japanese diagnostic criteria for obstetrical disseminated intravascular coagulation (DIC) (tentative version) was released by the Japan Society of Obstetrics and Gynecology (JSOG) and the Japan Society of Obstetrical, Gynecological and Neonatal Hematology (JSOGNH) in June 20221 (see Supplementary Table S1 online). This tentative version was a revision of the 1985 Japanese criteria for obstetrical DIC score2,3, which assessed three factors: underlying disease, clinical symptoms, and laboratory findings (see Supplementary Table S2 online). However, some women with underlying disease/pathology and a severe coagulability finding but not with fibrinolysis were diagnosed with obstetrical DIC according to the new Japanese diagnostic criteria (tentative version). Thus, to address this issue, the scoring system in the tentative version was revised and the final version was released in June 2024 (Table 1).
Table 1.
Diagnostic criteria for obstetrical DIC (final version)1.
| I. Underlying disease/pathology (select only one) | Points | II. Coagulability finding | Points | III. Fibrinolysis finding (select either a or b) | Points |
|---|---|---|---|---|---|
| a. Placental abruption | 4 | Fibrinogen (mg/dL) | a. FDP (µg/mL) | ||
| b. Amniotic fluid embolism | 4 | ≥ 300 | 0 | < 30 | 0 |
| c. Postpartum hemorrhage with coagulopathy * | 4 | ≥ 200 to < 300 | 1 | ≥ 30 to < 60 | 1 |
| ≥ 150 to < 200 | 2 | ≥ 60 | 2 | ||
| < 150 | 3 | b. D-dimer (µg/mL) | |||
| < 15 | 0 | ||||
| ≥ 15 to < 25 | 1 | ||||
| ≥ 25 | 2 | ||||
| Obstetrical DIC is diagnosed if the total of the three factors is ≥ 8 points | |||||
*Postpartum hemorrhage with coagulopathy was defined as massive postpartum hemorrhage without blood clots.
DIC disseminated intravascular coagulation, FDP fibrin-fibrinogen degradation product.
The JSOGNH conducted a national surveillance questionnaire and retrospective cohort study to investigate the capability of different types of medical institutions in Japan to manage obstetrical DIC in 20184. The number of medical institutions that always used the previous Japanese obstetrical DIC score was significantly lower for primary maternal facilities than for perinatal medical centers (39.4% vs. 79.4%, p < 0.0001). Thus, the role of the previous Japanese criteria in predicting the necessity for an immediate transfer of women with postpartum hemorrhage (PPH) from primary maternal facilities to perinatal medical centers and for initiating treatment for obstetrical DIC was minimal. Thus, the JSOGNH decided to revise the obstetrical DIC score to make it easier to use at any type of healthcare facility regardless of its capacity.
The JSOGNH also conducted a multicenter retrospective cohort study including seven perinatal medical centers to investigate the main underlying disease in obstetrical DIC and determine the role of hypofibrinogenemia levels as a predictor of obstetrical DIC5. The multivariate analysis results showed that in women with PPH where the previous Japanese criteria were used, underlying diseases of abruptio placenta and amniotic fluid embolism, clinical symptoms of acute renal failure and hemorrhage diathesis, and laboratory findings of fibrinogen levels < 189 mg/dL and platelet counts < 143 × 109/L had a significantly positive relationship with higher obstetrical DIC scores, excluding the points allocated to laboratory findings. Instead of hemorrhage diathesis as an underlying disease, PPH non-clottable was included in the new Japanese criteria. Subsequently, blood viscoelasticity testing was performed as an additional investigation, and the higher obstetrical DIC score showed a significantly positive relationship with lower fibrinogen levels (< 150 mg/dL) and higher FDP levels (≥ 50 μg/mL) but not with lower platelet counts (data were not shown, to be submitted). In addition, FDP levels showed a significantly positive relationship with D-dimer levels, and the ratio of FDP levels to D-dimer levels was approximately 2:1 (data were not shown, to be submitted). The abovementioned findings led to the determination of the three factors of the Japanese new criteria. The new Japanese diagnostic criteria (tentative version) was released in June 2023. After undergoing a minor revision (Table 1), the final version was released in June 2024.
JSOG and JSOGNH used these findings to revise the DIC score parameters and develop the Japanese new criteria, which assesses three factors: main underlying disease, plasma fibrinogen level, and level of plasma fibrin/fibrinogen degradation products (FDP) or D-dimer. The main underlying diseases include placental abruption, amniotic fluid embolism, and PPH non-clottable. A total score ≥ 8 points indicates a diagnosis of obstetrical DIC1. (Table 1).
The new Japanese criteria (tentative version) have been used to diagnose obstetrical DIC since July 2022 in Japan. However, their validity and reliability were never evaluated. The aim of this study was to prove the effectiveness, reliability, and validity of the criteria (final version) revised from tentative version in June 2024 so that they could be accepted as the final version.
Results
Participants
Figure 1 shows the flow chart of study participants. Of 7744 women with singleton pregnancies women who delivered after 22 gestational weeks, 677 experienced massive PPH, with 532 losing ≥ 1000 mL of blood during vaginal delivery and 145 losing ≥ 2000 mL of blood loss during cesarean section. Of them, 465 were missing laboratory test results before receiving blood transfusion at delivery and were excluded. The final study cohort comprised 212 women, including 121 with blood loss during vaginal delivery ≥ 1,000 mL and 91 with blood loss during cesarean section ≥ 2000 mL. These 212 women were divided into an obstetrical DIC group (n = 10) and a control group (n = 202) according to the new Japanese criteria (final version).
Figure 1.
Flow chart of study participants. DIC, disseminated intravascular coagulation.
Characteristics, treatments, and maternal/neonatal outcomes
Table 2 presents the characteristics of the obstetrical DIC and control groups. The median maternal age, frequency of primiparity, median gestational weeks at delivery, and frequency of women who had undergone cesarean section were similar for both groups. The median blood loss at cesarean section was similar for both groups, but the median blood loss at vaginal delivery in the obstetrical DIC group was significantly higher (p < 0.0001) than in the control group.
Table 2.
Characteristics of participants.
| Overall (n = 212) | Obstetrical DIC (n = 10) | Control (n = 202) | P-value | |
|---|---|---|---|---|
| Age (years) | 36 [19–46] | 37 [27–45] | 36 [19–46] | 0.9937 |
| Primiparous (%) | 123 (58.0%) | 3 (30.0%) | 120 (59.4%) | 0.0987 |
| Gestational weeks at delivery (weeks) | 39.4 [26.9–41.6] | 39.0 [26.9–40.7] | 39.4 [28.7–41.6] | 0.4398 |
| Cesarean section (%) | 49 (23.1%) | 4 (40.0%) | 45 (22.3%) | 0.2446 |
| Blood loss at delivery (mL) | 1824 [1001–7748] | 4223 [2019–7748] | 1756 [1001–6742] | < 0.0001 |
| ≥ 3000 mL (%) | 36 (17.0%) | 7 (70.0%) | 29 (14.4%) | < 0.0001 |
| ≥ 5000 mL (%) | 9 (4.2%) | 5 (50.0%) | 4 (2.0%) | < 0.0001 |
| Cesarean section | 2452 [2000–6742] | 4223 [2019–5780] | 2384 [2000–6742] | 0.2047 |
| Vaginal delivery | 1537 [1001–7748] | 4246 [2702–7748] | 1531 [1001–6716] | 0.0003 |
| Maternal outcomes | ||||
| Intrauterine balloon packing (%) | 56 (27.6%) | 6 (60.0%) | 50 (25.9%) | 0.0284 |
| Interventional radiology (%) | 8 (4.0%) | 2 (20.0%) | 6 (3.1%) | 0.0528 |
| Hysterectomy (%) | 4 (1.9%) | 2 (20.0%) | 2 (1.0%) | 0.0126 |
| Maternal death (%) | 1 (0.47%) | 1 (10.0%) | 0 (0.0%) | 0.0472 |
| Neonatal outcomes | ||||
| Birthweight (g) | 3195 [1004–4182] | 2894 [1004–3912] | 3195 [1238–4182] | 0.0431 |
| Stillbirth (%) | 3 (1.4%) | 2 (20.0%) | 1 (0.5%) | 0.0059 |
| Early neonatal death (%) | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) | - |
DIC disseminated intravascular coagulation.
Regarding PPH treatments, the frequencies of intrauterine balloon packing and/or hysterectomy in the obstetrical DIC group were significantly higher (p = 0.0284 and p = 0.0126, respectively) than in the control group. The frequency of maternal death and stillbirth in the obstetrical DIC group was significantly higher (p = 0.0059) than in the control group. One maternal death was because of obstetrical DIC induced by postpartum hemorrhage non-clottable after uterine rupture and massive bleeding (7748 mL). Her fibrinogen level was < 25 mg/dL, FDP was ≥ 400 μg/mL, D-dimer was 135 μg/mL, and the Japanese obstetrical DIC score according to the new and previous criteria was 9 and 33 points, respectively.
Underlying disease/pathology and laboratory findings
Tables 3 and 4 shows the underlying disease/pathology and the laboratory findings of the study cohort.
Table 3.
Underlying disease/pathology and laboratory findings of participants.
| Overall (n = 212) | Obstetrical DIC (n = 10) | Control (n = 202) | P-value | |
|---|---|---|---|---|
| New Japanese obstetrical DIC scores (points) | 1 [0–9] | 9 [8–9] | 1 [0–7] | < 0.0001 |
| I. Underlying disease/pathology (points) | 0 [0–4] | 4 [4–4] | 0 [0–4] | < 0.0001 |
| One or more (4 points) | 25 (11.8%) | 10 (100%) | 15 (7.4%) | < 0.0001 |
| Placental abruption | 6 (2.8%) | 2 (20.0%) | 4 (2.0%) | 0.0272 |
| Amniotic fluid embolism | 2 (0.94%) | 2 (20.0%) | 0 (0.0%) | 0.0020 |
| Postpartum hemorrhage non-clottable* | 19 (9.0%) | 8 (80.0%) | 11 (5.5%) | < 0.0001 |
| II. Coagulability finding (points) | 0 [0–3] | 3 [2–3] | 0 [0–3] | < 0.0001 |
| Fibrinogen < 150 mg/dL (3 points) | 19 (9.0%) | 9 (90.0%) | 10 (5.0%) | < 0.0001 |
| Fibrinogen ≥ 150– < 200 mg/dL (2 points) | 13 (6.1%) | 1 (10.0%) | 12 (5.9%) | 0.4765 |
| Fibrinogen ≥ 200 to < 300 mg/dL (1 point) | 55 (25.9%) | 0 (0.0%) | 55 (27.2%) | 0.0668 |
| III. Fibrinolysis finding (points) | 0 [0–2] | 2 [0–2] | 0 [0–2] | < 0.0001 |
| FDP ≥ 60 μg/mL or D-dimer ≥ 25 μg/mL (2 points) | 34 (16.0%) | 10 (100%) | 24 (11.9%) | < 0.0001 |
| FDP ≥ 30 μg/mL or D-dimer ≥ 15 μg/mL (1 point) | 27 (12.7%) | 0 (0.0%) | 27 (13.4%) | 0.3681 |
| Previous Japanese obstetrical DIC score (points) | 2 [0–33] | 12 [8–33] | 2 [0–16] | < 0.0001 |
| ≥ 8 points | 30 (14.2%) | 10 (100%) | 20 (9.9%) | < 0.0001 |
| Pregnancy-specific modified ISTH DIC score (points) | 12 [0–52] | 51 [26–52] | 11 [0–52] | < 0.0001 |
| ≥ 26 points | 82 (38.7%) | 10 (100%) | 72 (35.6%) | < 0.0001 |
*Postpartum hemorrhage (PPH) non-clottable was defined as massive PPH without blood clots.
DIC disseminated intravascular coagulation, FDP fibrin-fibrinogen degradation product, ISTH the International Society on Thrombosis and Hemostasis.
Table 4.
Laboratory findings of participants.
| Overall (n = 212) | Obstetrical DIC (n = 10) | Control (n = 202) | Univariate analysis P-value | Multivariate analysis P-value | |
|---|---|---|---|---|---|
| Fibrinogen (mg/dL) | 321 [24–634] | 73 [24–194] | 332 [53–634] | < 0.0001 | 0.0372 |
| FDP* (μg/mL) | 22.2 [2.7–960] | 500 [68.6–960] | 20.3 [2.7–850] | < 0.0001 | |
| D-dimer* (μg/mL) | 7.4 [1.2–400] | 261 [34.6–400] | 7.0 [1.2–300] | < 0.0001 | < 0.0001 |
| Platelet count (× 109/L) | 179 [19–385] | 119 [19–150] | 184 [43–385] | 0.0002 | |
| Antithrombin activity (%) | 68.0 [22.9–104.0] | 52.4 [25.0–82.0] | 68.6 [22.9–104.0] | 0.0395 | |
| PT (sec) | 11.3 [7.6 – 34.6] | 17.5 [13.6 – 34.6] | 11.2 [7.6 – 28.8] | < 0.0001 |
*Data on D-dimer and FDP were missing for 21 and 110 women, respectively; however, all 212 women had data for one or both of these parameters.
DIC disseminated intravascular coagulation, FDP fibrin-fibrinogen degradation product, PT prothrombin time.
All women in the obstetrical DIC group had an obstetrical DIC score (previous criteria) ≥ 8 points. The overall obstetrical DIC score (previous criteria) and the frequency of overall obstetrical DIC scores (previous criteria) ≥ 8 points in the obstetrical DIC group were significantly higher (p < 0.0001 and p < 0.0001, respectively) than in the control group (Table 3). Notably, the frequency of women with fibrinogen levels < 150 mg/dL in the obstetrical DIC group was significantly higher (p < 0.0001) than in the control group. The pregnancy-specific modified International Society on Thrombosis and Haemostasis (ISTH) DIC score and the frequency of women with scores ≥ 26 points in the obstetrical DIC group according to the new Japanese criteria were significantly higher than those in the control group (p < 0.0001 and p < 0.0001, respectively). All women classified as obstetrical DIC according to the new Japanese criteria scored ≥ 26 points, whereas only 12.2% of women classified as obstetrical DIC according to the pregnancy-specific modified ISTH scored ≥ 26 points according to new Japanese criteria.
According to the laboratory findings in Table 4, in the obstetrical DIC group, the rate of underlying disease/pathology and levels of FDP/D-dimer and prothrombin time (PT) were significantly higher (p < 0.0001 and p < 0.0001, respectively) and the fibrinogen level was significantly lower (p < 0.0001) than those in the control group. Furthermore, the median platelet count and antithrombin activity were significantly lower (p = 0.0002 and p = 0.0395, respectively) in the obstetrical DIC group than in the control group. Finally, lower fibrinogen levels and higher D-dimer levels showed a positive relationship with the onset of obstetrical DIC by multivariate analysis (p = 0.0372 and p < 0.0001, respectively), but the onset of obstetrical DIC was not related to the platelet count or antithrombin activity.
The obstetrical DIC score was significantly correlated with blood loss at delivery and with the levels of fibrinogen, FDP, and D-dimer (all p < 0.0001; Fig. 2).
Figure 2.
Relationship between obstetrical DIC score and blood loss at delivery/laboratory findings in the new Japanese diagnostic criteria (final version). The women shown in the gray areas were diagnosed with obstetrical DIC according to the new Japanese diagnostic criteria (final version in 2024). Relationship between obstetrical DIC score and blood loss at delivery (a), obstetrical DIC score and fibrinogen level (b), obstetrical DIC score and FDP level (c), and obstetrical DIC score and D-dimer level (d). DIC, disseminated intravascular coagulation; FDP, fibrinogen/fibrin degradation products.
Blood transfusion and/or blood product therapies
The frequencies of transfusions of fresh frozen plasma and red blood cell, platelet, and fibrinogen concentrate in the obstetrical DIC group were significantly higher (p < 0.0001) than those in the control group (Table 5).
Table 5.
Blood transfusion and/or blood product therapies.
| Overall (n = 212) | Obstetrical DIC (n = 10) | Control (n = 202) | P-value | |
|---|---|---|---|---|
| FFP* | 56 (26.4%) | 10 (100%) | 46 (22.8%) | < 0.0001 |
| Dosage (units) | 0 [0–50] | 9 [4–50] | 0 [0–32] | < 0.0001 |
| Fibrinogen concentrates | 20 (9.4%) | 8 (80.0%) | 12 (5.9%) | < 0.0001 |
| Dosage (g) | 0 [0–12] | 3 [0–12] | 0 [0–6] | < 0.0001 |
| RBCs | 86 (40.6%) | 10 (100%) | 76 (37.6%) | < 0.0001 |
| Dosage (units) | 0 [0–54] | 14 [4–54] | 0 [0–42] | < 0.0001 |
| PCs | 11 (5.2%) | 5 (50.0%) | 6 (3.0%) | < 0.0001 |
| Dosage (units) | 0 [0–40] | 5 [0–40] | 0 [0–40] | < 0.0001 |
| Autologous blood | 16 (7.5%) | 0 (0.0%) | 16 (7.9%) | 0.9999 |
| Dosage (units) | 0 [0–8] | 0 [0–0] | 0 [0–8] | 0.3562 |
| Antithrombin products | 11 (5.2%) | 1 (10.0%) | 10 (5.0%) | 0.4200 |
| Dosage (units) | 0 [0–3000] | 0 [0–3000] | 0 [0–3000] | 0.4497 |
*Both groups had one woman who received cryoprecipitate.
DIC disseminated intravascular coagulation, FFP fresh frozen plasma, RBC red cell concentrates, PC platelet concentrates.
Comparison of reliability and validity of new criteria (final version in 2024) with previous criteria (in 1985) and with the pregnancy-specific modified the ISTH score
There was a significantly positive relationship between the overall obstetrical DIC scores using the new criteria (final version) and the overall obstetrical DIC scores using the previous criteria (Fig. 3a) and the overall obstetrical DIC scores using the pregnancy-specific modified ISTH score (Fig. 3c). The frequency of women with fibrinogen levels < 150 mg/dL diagnosed with obstetrical DIC according to the new criteria was significantly higher than in women diagnosed with obstetrical DIC according to the previous Japanese criteria (p = 0.0235; Fig. 3b) and the overall obstetrical DIC scores using the pregnancy-specific modified the ISTH score (p < 0.0001; Fig. 3d).
Figure 3.
Relationship between new and previous diagnostic criteria, and the pregnancy-specific modified ISTH DIC score for obstetrical DIC. (a) Relationship between the obstetrical DIC score using the previous criteria (in 1985) and the obstetrical DIC score using the new criteria (final version in 2024). The women shown in the gray areas were diagnosed with obstetrical DIC according to the new Japanese diagnostic criteria for obstetrical DIC. (b) Frequency of women with fibrinogen < 150 mg/dL in women with/without an obstetrical DIC score ≥ 8 points. (c) Relationship between the pregnancy-specific modified ISTH DIC and obstetrical DIC scores using the new criteria. The women shown in the gray areas were diagnosed with obstetrical DIC according to the new Japanese diagnostic criteria for obstetrical DIC. (d) Frequency of women with fibrinogen < 150 mg/dL in women with/without an obstetrical DIC score ≥ 8 points. DIC, disseminated intravascular coagulation; ISTH, the International Society on Thrombosis and Hemostasis.
Cronbach alpha was 0.757 and Spearman’s rank-order correlation was 0.558 between the new Japanese criteria (final version) and previous Japanese criteria, respectively. These findings verified the reliability and validity of the new criteria in comparison with the previous criteria.
Table 6 shows the difference between the women diagnosed with obstetrical DIC by the new and previous Japanese criteria (n = 10) and the women diagnosed with obstetrical DIC by the previous Japanese criteria alone (n = 20). A comparison between the two groups showed that the women diagnosed with obstetrical DIC by the new and previous criteria had significantly lower levels of fibrinogen and higher levels of fibrinogen, FDP, and D-dimer by univariate analysis (p = 0.0010, p = 0.0027, and p = 0.0013, respectively), and multivariate analysis also revealed a tendency toward higher FDP levels (p = 0.0809).
Table 6.
Differences between women diagnosed with obstetrical DIC according to the new and previous Japanese criteria and women diagnosed with obstetrical DIC according to the Japanese previous criteria alone.
| Obstetrical DIC by new and previous criteria (n = 10) | Obstetrical DIC by previous criteria alone (n = 20) | Univariate analysis P-value | Multivariate analysis P-value | |
|---|---|---|---|---|
| Laboratory findings | ||||
| Fibrinogen (mg/dL) | 73 [24–194] | 161 [53–342] | 0.0010 | |
| FDP* (μg/mL) | 500 [68.6–960] | 70.7 [6.0–850] | 0.0027 | 0.0809 |
| D-dimer* (μg/mL) | 261 [34.6–400] | 11.0 [1.6–300] | 0.0013 | |
| Platelet count (× 109/L) | 119 [19–150] | 127 [61–282] | 0.2679 | |
| Antithrombin activity (%) | 52.4 [25.0–82.0] | 47.0 [25.0–99.1] | 0.7751 | |
| PT (sec) | 17.5 [13.6–34.6] | 15.4 [8.5–28.8] | 0.0810 | |
| Treatments | ||||
| FFP† | 10 (100%) | 14 (70.0%) | 0.0741 | |
| Fibrinogen concentrates | 8 (80.0%) | 8 (40.0%) | 0.0577 | |
| RBCs | 10 (100%) | 18 (90.0%) | 0.5402 | |
| PCs | 5 (50.0%) | 4 (20.0%) | 0.1155 | |
| Autologous blood | 0 (0.0%) | 3 (15.0%) | 0.5320 | |
| Antithrombin products | 1 (10.0%) | 0 (0.0%) | 0.3333 | |
DIC disseminated intravascular coagulation, FDP fibrin/fibrinogen degradation products, PT prothrombin time, FFP fresh frozen plasma, RBC red blood cell concentrate, PC platelet concentrate.
*Data on D-dimer and FDP were missing for 4 and 8 women, respectively; however, all 20 women had data for one or both of these parameters.
†Both groups had one woman who received cryoprecipitate.
Discussion
Our study results revealed three key points. First, the new Japanese diagnostic criteria for obstetrical DIC (final version revised in 2024) was effective for the diagnosis of obstetrical DIC in women with PPH. Second, almost all women with obstetrical DIC had hypofibrinogenemia. Conversely, almost all women without obstetrical DIC did not have hypofibrinogenemia. Third, a comparison of the new criteria with the obstetrical DIC score (previous criteria released in 1985) proved the reliability and validity of the new criteria.
The scoring system of the previous criteria was complicated. There were three significant differences between the previous criteria and the new criteria1. First, both criteria had placental abruption and amniotic fluid embolism as underlying diseases. The previous criteria also had DIC type-PPH, eclampsia, and others as underlying diseases, but the new criteria only had PPH non-clottable. Second, compared with the previous criteria, the new criteria excluded clinical symptoms. Third, the new criteria did not include all the laboratory findings from the previous criteria (notably platelet count and PT).
Regarding underlying diseases, the previous criteria did not define DIC type-PPH. In the new criteria, PPH non-clottable was defined as massive PPH without blood clots1,3. Thus, it should be checked that the hemorrhage collected in the basin does not form a blood clot. The previous criteria had five categories of clinical symptoms (acute renal failure, acute respiratory failure excluding amniotic fluid embolism, organ failure, hemorrhage diathesis, and shock symptoms), which included a total of 13 factors3, and the clinical symptoms were sufficiently specific to effectively diagnose critical obstetrical hemorrhage. In contrast, the new criteria are specific to the diagnosis of obstetrical DIC. The platelet count was excluded as a laboratory finding in the new criteria because platelets are involved in primary hemostasis, and fibrinogen was included because it is involved in secondary hemostasis6. In fact, blood viscoelasticity testing was performed as an additional investigation, and the higher obstetrical DIC score showed a significantly positive relationship with lower fibrinogen levels and higher FDP levels but not with lower platelet counts (data were not shown, to be submitted). In the obstetrical DIC, there is a malfunction of not only the primary hemostasis system but also the secondary hemostasis system. If the secondary hemostasis system is compromised, this leads to certain death; thus hypofibrinogenemia and hypercoagulation (high levels of FDP and/or D-dimer) are critical laboratory findings. Therefore, the new criteria consider fibrinogen and FDP/D-dimer levels more important than platelet counts. In Japan, DIC is classified as either DIC with suppressed fibrinolysis or DIC with enhanced fibrinolysis. For example, obstetrical DIC induced by abruptio placenta is classified as DIC with in enhanced fibrinolysis7. According to the algorithm for applying DIC diagnostic criteria in the Japanese Society on Thrombosis and Hemostasis criteria to diagnose DIC (2017 version), the criteria are not aimed at obstetrical DIC (and neonatal DIC), and DIC with hematopoietic disorders (i.e., DIC with enhanced fibrinolysis) should not be diagnosed using platelet count data8. Generally, most cases of obstetrical DIC are considered to be of the enhanced fibrinolytic type. Hematopoietic disorders, including systemic inflammatory response syndrome (SIRS) or sepsis, may be an underlying disease/pathology in women with obstetrical DIC. However, the new Japanese criteria to diagnose obstetrical DIC excluded hematopoietic disorders (e.g., severe invasive streptococcal infection/streptococcal toxic shock syndrome) as an underlying disease/pathology. Thus, in June 2024, JSOGNH recommended that obstetrical DIC induced by a hematopoietic disorder should be diagnosed according to the DIC scoring system for critical illness of the Japanese Association for Acute Medicine9 instead of the new Japanese obstetrical DIC criteria (final version). According to this scoring system, DIC is diagnosed using the total scores of four diagnostic criteria: SIRS, platelet count, PT ratio, and FDP (including the value converted from D-dimer levels).
The primary aim of the previous Japanese DIC criteria was to identify women who needed treatment for DIC so that it could be started as soon as possible. In answer to clinical question CQ418-2 (How should one intervene for women with critical obstetrical hemorrhage?) of the Japanese guidelines for obstetrical practice, it was recommended that if the transition to critical obstetrical hemorrhage became a concern, the patient should be transferred to a facility with a higher level of care (recommendation level B) and that critical obstetrical hemorrhage should be declared when bleeding persists; when vital signs are abnormal, such as shock index ≥ 1.5, oliguria, peripheral coldness, or low SpO2; or the obstetrical DIC score is ≥ 810. A score ≥ 8 for the new Japanese criteria was positively related to a score ≥ 8 for the previous Japanese criteria in this study. Thus, a score ≥ 8 points in new Japanese criteria was used as one of the predictors of women who needed DIC treatment and indicated that the treatment should start as soon as possible. In many primary institutions in Japan, fibrinogen levels are quickly measured using point-of-care testing, but there are no point-of-care tests for FDP or D-dimer; therefore, these tests need to be performed in a laboratory. Thus, in women with the presence of underlying disease/pathology and coagulation abnormalities (i.e., abnormal fibrinogen levels) who do not have laboratory test results on the status of fibrinolysis (i.e., FDP and D-dimer levels), the use of the new Japanese criteria in primary institutions would more likely result in immediate transfer before the FDP and D-dimer test results are received. However, herein, only a few women were transferred from primary institutions. While, in Japan, many obstetricians in primary institutions would determine when to transfer women with “critical obstetric hemorrhage” from their institutions according to the presence of abnormal vital signs, such as a shock index ≥ 1.5, rather than an obstetrical DIC score ≥ 810, because the number of primary maternal institutions that always used the previous Japanese obstetrical DIC score was significantly low4. Thus, the new Japanese DIC criteria (final version) will be used to make a definitive diagnosis of DIC and to start treatment rather than to determine whether women with “critical obstetric hemorrhage” should be transferred from primary institutions when obstetrical DIC is suspected regardless of a definitive diagnosis. Therefore, in Japan, the unnecessary administration of therapy for DIC to women without obstetrical DIC but who have PPH may decrease. We plan to analyze whether the new criteria can predict the necessity for an immediate transfer from primary institutions in a future multicenter prospective study.
Generally, DIC is defined as a severe condition in which the underlying disease causes sustained and significant activation of systemic coagulation, resulting in the formation of multiple microvascular microthrombi, with activation of coagulation and fibrinolysis7. Thus, women with obstetrical DIC should have abnormal coagulation findings and findings of fibrinolysis. According to new the Japanese criteria, almost women in our study with obstetrical DIC had fibrinogen levels < 150 mg/dL and all women had fibrinogen levels < 200 mg/dL. However, not all women with hypofibrinogenemia (i.e., abnormal coagulability finding) caused by PPH had obstetrical DIC. Thus, although hypofibrinogenemia occurs in obstetrical DIC, obstetrical DIC is not the same as hypofibrinogenemia.
Decreases in maternal coagulability findings in women with PPH and/or obstetrical DIC have been reported to cause maternal death. In a study in France, on 38 women who died from PPH from 2000–2003 revealed that 30 of the women had laboratory findings before starting treatment, and the fibrinogen levels were 50 (0–284) mg/dL11. In another study in France on 730 women severe PPH from 2012 to 2013, the fibrinogen levels before treatment and proportion of patients who received fibrinogen concentrate were compared between women without near-miss or death (n = 588) and those who died (n = 142), revealing that the women with near-miss or who had died had a significantly higher incidence of obstetrical DIC (34.7% vs. 58.5%, p < 0.001) and a significantly higher frequency of fibrinogen levels < 100 mg/dL (6.1% vs. 18.6%, p < 0.001)12. A study in Japan from 2010 to 2013 on 46 women with maternal death related to amniotic fluid embolism reported that 14 women (30.4%) had undetectable fibrinogen levels (< 50 mg/dL) and 1 (2.2%) woman had a fibrinogen level of 65 mg/dL13. Thus, hypofibrinogenemia of women with PPH and/or obstetrical DIC should be treated using FFP and/or fibrinogen concentrate products as soon as possible to prevent the maternal death.
Our study has proved the effectiveness, reliability, and validity of the new Japanese diagnostic criteria for obstetrical DIC (final version) in comparison with the previous Japanese criteria. The median FDP levels of the women diagnosed with obstetrical DIC by the previous Japanese criteria alone were not high, but high FDP levels (i.e., a finding of abnormal fibrinolysis) are necessary to diagnose obstetrical DIC. Thus, according to the previous Japanese criteria, some women without obstetrical DIC would have been incorrectly diagnosed.
Overt DIC is diagnosed worldwide according to the criteria of the ISTH published in 200114. Erez et. al. published the pregnancy-specific modified ISTH DIC score in 201415, which excluded underlying disease and clinical symptoms as factors to diagnose obstetrical DIC (see Supplementary Table S3 online). The inclusion of underlying diseases as one of the factors in both the previous and new Japanese criteria is a clear departure from the worldwide criteria1–3. Regarding the laboratory findings, the overt DIC diagnostic criteria included platelet count, FDP/D-dimer/soluble fibrin, fibrinogen, and PT, while the pregnancy-specific modified ISTH DIC score included PT difference, platelet count, and fibrinogen level. The new Japanese criteria do not include platelet count as one of the factors, which is a clear deviation from the worldwide criteria1. Thus, the new Japanese criteria are globally unique.
A retrospective single-center case-control study demonstrated that the new Japanese criteria (tentative version) detected more severe cases of obstetrical DIC that needed treatment with a higher number of transfusions of fresh frozen plasma and/or cryoprecipitate, red blood cell concentrate, and platelet concentrate compared with the pregnancy-specific modified ISTH DIC score16. In our study, the new Japanese criteria (final version) detected more severe cases of obstetrical DIC compared with the previous obstetrical DIC score and the pregnancy-specific modified ISTH DIC score, respectively. Thus, the frequency of pregnant women diagnosed with obstetrical DIC may decrease in Japan with the use of the new criteria (final version).
This study had two limitations: (1) the sample size was small and the study design was retrospective, not prospective, and (2) the numbers of laboratory findings of fibrinolysis and coagulation (Fibrinogen, D-dimer/FDP, platelet counts, antithrombin activity and PT) were small. Thus, a multicenter prospective study with the other laboratory findings of fibrinolysis and coagulation is necessary to confirm our findings.
Conclusion
We proved the effectiveness, reliability, and validity of the new Japanese diagnostic criteria for obstetrical DIC (final version in 2024). Thus, they can be accepted as the final version.
Methods
Study design and Setting
This retrospective multicenter cohort study was conducted at eight institutions (Aiiku Hospital, Juntendo University Juntendo Hospital, Juntendo University Urayasu Hospital, Kansai Medical University Hospital, Hamamatsu Medical Center, Mie University School of Medicine, Okayama University Hospital, and Saitama Medical University Saitama Medical Center) supported by JSOGNH.
Data collection
Data were collected from the medical records of pregnant women with massive PPH (blood loss ≥ 1000 mL during vaginal delivery or ≥ 2000 mL during cesarean section), including maternal and neonatal characteristics, underlying diseases. The laboratory test results (fibrinogen, FDP or D-dimer, platelet counts, and antithrombin activity) were collected before the treatment for obstetrical DIC (transfusion of blood or blood products).
Inclusion and exclusion criteria
Between July 2022 and June 2023, 7,744 women with a singleton pregnancy delivered after 22 gestational weeks at the eight predetermined institutions. Those with massive PPH were included in the study cohort. Women who had received a transfusion of blood or blood products at a primary facility prior to being transferred to one of the eight institutions were excluded, as were those with one or more missing laboratory results before receiving blood transfusion at delivery.
Diagnosis and treatment of obstetrical DIC
Obstetrical DIC was diagnosed at all institutions according to the new Japanese criteria (in 2024) for obstetrical DIC (Table 1). All women with obstetrical DIC were treated as per JSOG10 and JSOGNH recommendations17.
According to the previously used Japanese obstetrical DIC score, a total score ≥ 8 indicates DIC suspicion and a total score ≥ 13 (including ≥ 2 points for laboratory findings) confirms DIC (see Supplementary Table S1online) 2,3. In the present study, we considered an obstetrical DIC score ≥ 8 as confirmation of DIC.
Sample size calculation
According to the hypothesis of a study population with the primary outcome as the presence of hypofibrinogenemia (fibrinogen < 150 mg/dL), we calculated that the study cohort required four women with obstetrical DIC and 80 women without obstetrical DIC. Thus, the ideal minimum sample size was 49 if the rates of hypofibrinogenemia were 80% among women with obstetrical DIC and 20% among women without obstetrical DIC and the ratio of women with obstetrical DIC to those without obstetrical DIC was 1:20 (rate of obstetrical DIC in women with massive PPH was 5%) with an error level of 0.05 and power of 0.8.
Statistical analysis
Data were presented as medians (minimum–maximum) or numbers (%). Statistical analyses were performed using JMP Pro v17.0 (SAS Institute Inc., Cary, NC, USA). We used Tukey–Kramer honestly significant difference test, Wilcoxon signed rank test, or Mann–Whitney U test to compare medians (minimum–maximum) and Fisher exact test to compare categorical variables. P-values < 0.05 were considered to indicate statistical significance for all analyses. Furthermore, we used Cronbach’s alpha and Spearman rank correlation coefficient to clarify the reliability and validity, respectively, of comparisons between the new and previous criteria.
Ethics approval
This study was conducted in accordance with the principles of the Declaration of Helsinki and approved en bloc for all institutions by the Kansai Medical University Hospital Institutional Review Board (approval no. 2022042; accepted April 24, 2023). All study participants provided a written informed consent.
Supplementary Information
Acknowledgements
The authors thank the Working Group for Revision of Obstetric DIC Score in the Japan Society of Obstetrical, Gynecological and Neonatal Hematology. The authors thank the Working Group for Revision of Obstetric DIC Score in the Japan Society of Obstetrical, Gynecological and Neonatal Hematology. In particular, the authors thank Dr. Takao Kobayashi (Hamamatsu Medical Center) and Dr. Tomoko Adachi (Aiiku Hospital) for their advice. Furthermore, the authors thank Dr. Norikazu Ueki (Juntendo University, Urayasu Hospital) and Dr. Sachi Kijima and Dr. Shina Sakaguchi (Saitama Medical University, Saitama Medical Center) for their support with data collection. The authors thank Enago (www.enago.jp) for the English language review.
Author contributions
M.M. collected data, wrote the manuscript, conducted the research, formal analysis, and contributed to the discussion. Y.T., S.M., S.M., E.E., M.S., M.N., J.T. collected data, contributed to the discussion and reviewed/edited the manuscript. H.M. and A.I. supervised, contributed to the discussion and reviewed/edited the manuscript. All authors have read and approved the manuscript.
Funding
The first author (Mamoru Morikawa) received funding for this work from Japan Blood Products Organization (Tokyo, Japan. URL: https://www.jbpo.or.jp/english/).
Data availability
The datasets generated during and/or analyzed during the current study are available from the corresponding author upon reasonable request.
Competing interests
The authors declare no competing interests.
Footnotes
Publisher's note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary Information
The online version contains supplementary material available at 10.1038/s41598-024-68298-7.
References
- 1.Itakura, A. et al. Disseminated intravascular coagulation (DIC) in obstetrics field: Diagnostic criteria for obstetrical DIC (Tentative version). Jpn. J. Obstet. Gynecol. Neonatal. Hematol.32, 43–49 (2023). [Google Scholar]
- 2.Maki, M., Terao, T. & Ikenoue, K. Obstetrical DIC score. Obstet. Gynecol. Ther.50, 119–124 (1985). [Google Scholar]
- 3.Kobayashi, T. Obstetrical disseminated intravascular coagulation score. J. Obstet. Gynaecol. Res.40, 1500–1506 (2014). 10.1111/jog.12426 [DOI] [PubMed] [Google Scholar]
- 4.Morikawa, M. et al. Capacity of Japanese institutions to manage obstetrical disseminated intravascular coagulation in 2018: A national surveillance questionnaire and retrospective cohort study. J. Obstet. Gynaecol. Res.47, 3159–3170 (2021). 10.1111/jog.14875 [DOI] [PubMed] [Google Scholar]
- 5.Morikawa, M. et al. Effect of hypofibrinogenemia on obstetrical disseminated intravascular coagulation in Japan in 2018: A multicenter retrospective cohort study. Int. J. Hematol.114, 18–34 (2021). 10.1007/s12185-021-03119-5 [DOI] [PubMed] [Google Scholar]
- 6.Winter, W. E., Flax, S. D. & Harris, N. S. Coagulation testing in the core laboratory. Lab Med.48, 295–313 (2017). 10.1093/labmed/lmx050 [DOI] [PubMed] [Google Scholar]
- 7.Asakura, H. et al. Proposal for new diagnostic criteria for DIC from the Japanese Society on thrombosis and hemostasis. Thromb. J.14, 42 (2016). 10.1186/s12959-016-0117-x [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Asakura, H. et al. The Japanese Society on Thrombosis and Hemostasis - the criteria to diagnose DIC, 2017 version. Jpn. J. Thromb. Hemost.28, 369–391 (2017). 10.2491/jjsth.28.369 [DOI] [Google Scholar]
- 9.Gando, S. et al. Disseminated intravascular coagulation scoring system for critical illness: Multicenter prospective study. J. Jpn. Assoc. Acute. Med.16, 188–202 (2005). [Google Scholar]
- 10.Itakura, A. et al. Guidelines for obstetrical practice in Japan: Japan Society of Obstetrics and Gynecology and Japan Association of Obstetricians and Gynecologists 2020 edition. J. Obstet. Gynaecol. Res.49, 5–53 (2023). 10.1111/jog.15438 [DOI] [PubMed] [Google Scholar]
- 11.Bonnet, M. P., Deneux-Tharaux, C. & Bouvier-Colle, M. H. Critical care and transfusion management in maternal deaths from postpartum haemorrhage. Eur. J. Obstet. Gynecol. Reprod. Biol.158, 183–188 (2011). 10.1016/j.ejogrb.2011.04.042 [DOI] [PubMed] [Google Scholar]
- 12.Deleu, F. et al. Fibrinogen concentrate and maternal outcomes in severe postpartum hemorrhage: A population-based cohort study with a propensity score-matched analysis. J. Clin. Anesth.81, 110874 (2022). 10.1016/j.jclinane.2022.110874 [DOI] [PubMed] [Google Scholar]
- 13.Tanaka, H. et al. Value of fibrinogen in cases of maternal death related to amniotic fluid embolism. J. Matern. Fetal. Neonatal. Med.30, 2940–2943 (2017). 10.1080/14767058.2016.1269166 [DOI] [PubMed] [Google Scholar]
- 14.Taylor, F. B. Jr., Toh, C. H., Hoots, W. K., Wada, H. & Levi, M. Scientific subcommittee on disseminated intravascular coagulation (DIC) of the International Society on Thrombosis and Hemostasis (ISTH). Towards definition, clinical and laboratory criteria, and a scoring system for disseminated intravascular coagulation. Thromb. Haemost.86, 1327–1330 (2001). 10.1055/s-0037-1616068 [DOI] [PubMed] [Google Scholar]
- 15.Erez, O. et al. DIC score in pregnant women–a population based modification of the International Society on thrombosis and hemostasis score. PLoS One.9, e93240 (2014). 10.1371/journal.pone.0093240 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Morikawa, M., Kamiya, A., Yoshida, A., Nishibata, S. & Okada, H. Differences between Japanese new criteria and pregnancy-specific modified ISTH DIC scores for obstetrical DIC diagnosis. Int. J. Hematol.119, 265–274 (2024). 10.1007/s12185-023-03702-y [DOI] [PubMed] [Google Scholar]
- 17.Kobayashi, T., Terao, T., Maki, M. & Ikenoue, T. Diagnosis and management of acute obstetrical DIC. Semin. Thromb. Hemost.27, 161–167 (2001). 10.1055/s-2001-14076 [DOI] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
The datasets generated during and/or analyzed during the current study are available from the corresponding author upon reasonable request.