Abstract
Aim: We prospectively compared the safety of enoxaparin sodium, a low-molecular-weight heparin (LMWH), with unfractionated heparin (UFH), both of which were administered within 24 hours of cesarean section.
Methods: A total of 205 pregnant women at increased risk of venous thromboembolism (VTE) who underwent cesarean section for obstetrical indications between December 2012 and February 2015 were eligible to participate in this trial under written informed consent at Hamamatsu University Hospital. They were randomized into two groups based on the subcutaneous injection of enoxaparin sodium or UFH (Enoxaparin [n=98] and UFH [n=107] groups, respectively) 6, 18, and 30 hours after cesarean section. Incidences of symptomatic VTE, symptomatic bleeding, thrombocytopenia, and other complications were subsequently compared.
Results: One woman in the Enoxaparin group developed symptomatic mild pulmonary embolism (PE). One woman in the UFH group developed a hematoma in the abdominal wound, which required operative evacuation.
Conclusion: The safety of thromboprophylaxis with enoxaparin sodium within 24 hours of cesarean section appeared to be similar to that achieved by UFH. A large-scale cohort study is needed to compare the efficiency of inducing thromboprophylaxis by enoxaparin and UFH, in consideration of its rare onset.
Introduction
Venous thromboembolism (VTE) is an important cause of maternal morbidity and death and the single direct cause of maternal death.1,2) The Japan Association of Obstetricians and Gynecologists (JAOG) examined 83 cases of maternal death in Japan between 2010 and 2012 and reported that eight patients (10%) died primary due to pulmonary embolism (PE), a life-threatening complication of VTE.3) Concerns exist regarding VTE in cesarean section. A Swedish study analyzed data from birth and hospital admission databases and showed that the incidence of VTE after cesarean section was 0.23%, and that cesarean section was associated with a 5-fold higher risk of VTE than vaginal delivery.4) Kobayashi et al. reported similar findings in a Japanese population and found that the incidence of PE was 22-fold higher with cesarean section than with vaginal delivery,5) indicating that cesarean section is a high risk factor for PE.
Clinical guidelines in other counties, such as those set forth by the American Congress of Obstetricians and Gynecologists (ACOG),6) the American College of Chest Physicians (ACCP),7) and the Royal College of Obstetricians and Gynaecologists (RCOG),8) recommend thromboprophylaxis with low-molecular-weight heparin (LMWH) for women at risk of VTE every 12 hours after cesarean section during the peripartum period. The National Institute for Health and Clinical Excellence (NICE) recommends combining VTE prophylaxis with mechanical methods and LMWH for all women undergoing cesarean section, regardless of risk factors.9)
LMWH has replaced unfractionated heparin (UFH) globally as the first-choice medication for thromboprophylaxis in pregnancy.8,10,11) Systematic reviews concluded that LMWH was a safe alternative to UFH as an anticoagulant during pregnancy and the postpartum period,9,12,13) although there were at least two incomplete randomized controlled pilot trails.14) The potential advantages of LMWH include fewer bleeding episodes, a more predictable therapeutic response, a lower risk of heparin-induced thrombocytopenia, a longer half-life, and less bone mineral density loss than UFH.6,12,13,15)
‘The Japanese Guideline for Prevention of Venous Thromboembolism (2004)’ recommended thromboprophylaxis for high-risk women with UFH from six hours after cesarean section16) because LMWH was not available at that time in Japan. The newest Japanese guidelines, ‘The Japanese Guidelines for Obstetrical Practice in Japan (2014)’ recommend the initiation of LMWH (enoxaparin sodium) injections to high-risk women 24 hours after cesarean section due to its official reference sheet in Japan, while UFH can be administered soon after surgery.17) This restriction on the use of LMWH (enoxaparin sodium) to within 24 hours after cesarean section is in contrast with the guidelines of other countries.6,7,8,9) Kobayashi et al. demonstrated that the first postoperative day of cesarean section was the most critical period for PE onset in Japanese women,5) suggesting the potential benefits of initiating thromboprophylaxis with LMWH during the first postoperative day. Therefore, the aim of the present study is to compare the safety and effectiveness of thromboprophylaxis induced with enoxaparin sodium and UFH in Japan, the subcutaneous injections of which were started during the first postoperative day of cesarean section. We conducted a prospective randomized controlled trial at Hamamatsu University Hospital between December 2012 and February 2015. A total of 205 pregnant women at high risk of VTE were enrolled in the trial before undergoing cesarean section for obstetrical indications. They were randomized into two groups (Enoxaparin [n=98] and UFH [n=107] groups); enoxaparin sodium (2,000 IU) or UFH (5,000 U) was subcutaneously injected 6, 18, and 30 hours after cesarean section, followed by the confirmation and comparison of symptomatic thromboembolic events, symptomatic bleeding, thrombocytopenia, and other complications during admission and at the one-month follow-up examination.
Materials and methods
Registration
This prospective cohort study was pre-registered with the University Hospital Medical Information Network (UMIN) on October 10, 2012 (Registration number: R000010613; ID: UMIN000009068).
Enrollment
Subjects were enrolled among pregnant women who underwent cesarean section due to obstetrical indications at Hamamatsu University Hospital between December 2012 and February 2015. In the present study, we modified the high risk criteria of The Japanese Society on Thrombosis and Hemostasis16); pregnant women were enrolled before cesarean section if they were aged ≥35 years and/or if their body mass index (BMI) just before surgery was ≥26 kg/m2. Cesarean section was scheduled at the time of initial recruitment; women were not enrolled if they were complicated by thrombocytopenia (platelet count <104/μl), acute bacterial endocarditis, or renal dysfunction (creatinine clearance <50 ml/min), or if they had a history of previous heparin-induced thrombocytopenia or hypersensitivity to heparin and/or drugs with similar structures to heparin. Women were also not enrolled if they had the highest risk factors, such as thrombophilia or a history of previous VTE16,17) because warfarin treatments were planned during the postpartum period according to the regimen of our institution. Written informed consent was obtained after a full explanation of the study.
Randomization
Subjects were randomized into two groups, i.e. Enoxaparin (n=98) and UFH (n=109) groups, by the sealed envelope method.
Interventions
Enoxaparin (2,000 IU) or UFH (5,000 U) was subcutaneously injected 6, 18, and 30 hours after cesarean section. Epidural tubes, if present, were removed 48 hours or later after cesarean section. Mechanical compression and stocking was performed on both groups. We planned to discontinue the injections in cases of serious bleeding complications, thrombocytopenia (platelet count <104/μl), serious wound complications, osteoporotic symptomatic fracture, or the introduction of other therapeutic anticoagulant therapies for the onset of VTE after cesarean section.
Data collection
Data were collected from clinical records at the time of randomization, at discharge from the hospital after delivery, and at the one-month follow-up examination. At the one-month follow-up examination, we asked participating women about any examinations or admissions to clinics or hospitals since their discharge. If they had been treated, we contacted the relevant clinic or hospital to ascertain whether the treatment was for any of the trial’s outcomes.
Outcomes
The primary clinical outcomes of the present study were symptomatic and confirmed VTE, serious bleeding complications including wound hematomas, thrombocytopenia (platelet count <104/μl), serious wound complications (wound infection or wound breakdown), and osteoporotic symptomatic fracture.
Secondary outcomes were changes in liver enzymes and platelet counts before and after cesarean section, which were obtained from clinical records. The highest levels of liver enzymes, aspartate transaminase (AST) and alanine aminotransferase (ALT), and the lowest number of platelets before and after cesarean section during admission were used in analytical comparisons.
Statistics
Data are expressed as mean±SDs. Differences between two mean values were assessed using the Student’s t-test or Mann-Whitney U test, as appropriate. Fisher’s exact test was used to determine whether there was a significant difference in the data collected. P<0.05 was considered statistically significant.
Approval
The Ethics Committee of the Hamamatsu University School of Medicine approved all procedures of this study (Registration number: 19-048).
Results
Participants
A total of 205 women were enrolled in the present study. At trial entry, basic characteristics were similar between Enoxaparin and UFH groups (Table 1A). The main maternal complications noted were similar between the two groups (Table 1B). Although most participants were Japanese, five Filipinos, two Brazilians, one Chinese, and one Peruvian were also enrolled (Table 2A). Obstetrical indications for cesarean section in the Enoxaparin group were similar to those in the UFH group (Table 2B). Furthermore, the course of cesarean section and anesthesia were similar between the two groups (Table 3A).
Table 1. Subject backgrounds (A) and major maternal obstetrical complications (B)
A
| Enoxaparin group
(98) | UFH group
(107) |
|---|
| Mean maternal age±SD (years old) | 35.9±2.8 | 36.0±4.1 |
| Maternal age (n) | | |
| <35 years old | 24 | 29 |
| ≥35 years old | 74 | 78 |
| Previous history of venous thrombosis | 0 | 0 |
| Parity (n) | | |
| 0 | 48 | 49 |
| 1 | 37 | 42 |
| 2 or 3 | 12 | 16 |
| ≥4 | 1 | 0 |
| BMI<26 kg/m2 (n) | 55 | 56 |
| BMI≥26 kg/m2 (n) | 43 | 51 |
| Mean gestational weeks at the trial±SD (wks) | 37.5±2.7 | 37.3±3.1 |
| Gestational weeks at the trial (n) | | |
| <37 wks | 21 | 26 |
| ≥37 wks | 77 | 81 |
| Twin pregnancy (n) | 3 | 4 |
B
| Enoxaparin group
(98) | UFH group
(107) |
|---|
| Preeclampsia (n) | 17 | 12 |
| Gross varicose veins (n) | 0 | 0 |
| Antiphospholipid antibody syndrome (n) | 0 | 0 |
| Diabetes mellitus (n) | 3 | 2 |
| Gestational diabetes mellitus (n) | 4 | 5 |
UFH, unfractionated heparin; BMI, body mass index; wks, weeks of gestation; SD, standard deviation.
Table 2. Ethnicity of subjects (A) and indications for cesarean section (B)
A
| Enoxaparin group
(98) | UFH group
(107) |
|---|
| Japanese (n) | 92 | 104 |
| Filipino (n) | 2 | 3 |
| Brazilian (n) | 2† | 0 |
| Chinese (n) | 1 | 0 |
| Peruvian (n) | 1 | 0 |
B
| Enoxaparin group
(98) | UFH group
(107) |
|---|
| Previous uterine surgery (n) | 40 | 46 |
| Breech presentation (n) | 17 | 11 |
| Low-lying placenta or placenta previa (n) | 6 | 10 |
| Labor arrest disorder (n) | 5 | 3 |
| Non-reassuring fetal status (n) | 9 | 11 |
| Maternal hypertension (n) | 13 | 11 |
| Intrauterine infection (n) | 2 | 2 |
| Others | 6 | 13 |
UFH, unfractionated heparin. †; Only one Brazilian developed symptomatic VTE (mild PE).
Table 3. Characteristics of cesarean section (A) and thromboprophylaxis treatments other than Enoxaparin or UFH (B)
A
| Enoxaparin group
(98) | UFH group
(107) |
|---|
| Elective cesarean section (n) | 59 | 69 |
| Emergency cesarean section (n) | 39 | 38 |
| General anesthesia (n) | 2 | 5 |
| Spinal anesthesia without epidural anesthesia (n) | 1 | 3 |
| Spinal anesthesia with epidural anesthesia (n) | 95 | 99 |
| Gestational weeks of age | | |
| <40 wks | 83 | 88 |
| ≥40 wks | 15 | 19 |
| Bleeding during cesarean section | | |
| <1,000 ml (n) | 90 | 93 |
| 1,000–2,000 ml (n) | 6 | 12 |
| >2,000 ml (n) | 2 | 2 |
| Blood transfusion during surgery | | |
| Autologous blood transfusion | 2 | 3 |
| Allogeneic blood transfusion | 1 | 4 |
B
| Enoxaparin group
(98) | UFH group
(107) |
|---|
| Received allocated intervention (n) | 98 [100%] | 107 [100%] |
| Other methods of thromboprophylaxis (n) | | |
| Mechanical compression (n) | 98 [100%] | 107 [100%] |
| Stockings (n) | 98 [100%] | 107 [100%] |
UFH, unfractionated heparin.
All women accomplished their allocated full treatment, including the use of mechanical compression and compression stockings (Table 3B), except for three patients. A woman in the Enoxaparin group who was subcutaneously injected with enoxaparin sodium six hours after cesarean section discontinued treatment due to the onset of PE; we instead started a continuous venous injection of high-dose UFH (Table 4A). One woman in the UFH group who was subcutaneously injected with UFH six hours after cesarean section discontinued treatment due to the development of a serious wound hematoma; subsequent emergent operative evacuation was required (Table 4A). One woman in the UFH group who was subcutaneously injected with UFH six hours after cesarean section discontinued treatment because she developed thrombocytopenia due to the acute onset of hemolysis, elevated liver enzyme levels, and low platelet count (HELLP) syndrome (Table 4A, 5).
Table 4. Peripartum thromboprophylaxis outcomes and major complications during admission (A) and in the one-month follow-up examination (B)
A
| Enoxaparin group
(98) | UFH group
(107) | P value |
|---|
| Symptomatic VTE (n) | 1 [mild PE] | 0 | 0.295§ |
| Serious bleeding disorders (n) | 0 | 1 | 0.337§ |
| Thrombocytopenia† (n) | 0 | 1‡ | 0.337§ |
| Serious wound complications (n) | 0 | 0 | |
| Osteoporotic symptomatic fracture (n) | 0 | 0 | |
B
| Enoxaparin group
(98) | UFH group
(107) |
|---|
| Women with outcome information available | 98 (100%) | 107 (100%) |
| Symptomatic VTE (n) | 0 | 0 |
| Serious bleeding disorders (n) | 0 | 0 |
| Serious wound complications (n) | 0 | 0 |
| Osteoporotic symptomatic fracture (n) | 0 | 0 |
UFH, unfractionated heparin; VTE, venous thromboembolism; PE, pulmonary embolism. †; Platelet count less than 104/μl. ‡; This subject developed hemolysis, elevated liver enzyme levels and low platelet count (HELLP) syndrome (different from the subject of serious bleeding disorder). §; Analysis by a Fisher’s exact test.
Table 5. Comparison of liver enzyme levels and platelet counts before (A) and after (B) cesarean section
A
| Enoxaparin group
(98) | UFH group
(107) | P value |
|---|
| Mean ALT levels±SD (IU/l) | 11.7±11.0 | 12.3±18.2 | 0.747 |
| ≥30 IU/l (n) | 2 | 4 | |
| <30 IU/l (n) | 96 | 103 | 0.471§ |
| Mean AST levels±SD (IU/l) | 16.4±5.9 | 17.3±7.6 | 0.321 |
| ≥30 IU/l (n) | 2 | 4 | |
| <30 IU/l (n) | 96 | 103 | 0.471§ |
| Mean platelet count±SD (/μl) | 24.6±5.9 | 24.5±6.2 | 0.861 |
| Thrombocytopenia† (n) | Not enrolled | Not enrolled | |
B
| Enoxaparin group
(98) | UFH group
(107) | P value |
|---|
| Mean ALT levels±SD (IU/l) | 20.7±15.8 | 23.1±16.3 | 0.281 |
| ≥30 IU/l (n) | 14 | 22 | |
| <30 IU/l (n) | 84 | 85 | 0.238§ |
| Mean AST levels±SD (IU/l) | 24.5±14.2 | 27.1±14.8 | 0.210 |
| ≥30 IU/l (n) | 22 | 27 | |
| <30 IU/l (n) | 76 | 80 | 0.641§ |
| Mean platelet count±SD (/μl) | 29.5±6.5 | 28.5±8.3 | 0.301 |
| Thrombocytopenia† (n) | 0 | 1‡ | 0.337§ |
UFH, unfractionated heparin. †; Platelet count less than 104/μl. ‡; This subject developed hemolysis, elevated liver enzyme levels and low platelet count (HELLP) syndrome. §; Analysis by a Fisher’s exact test.
Symptomatic VTE was only observed in one Brazilian woman in the Enoxaparin group during the study (Table 4A). This was a mild PE that occurred on the first postoperative day and was confirmed with contrast-enhanced computed tomography (CT) imaging. She was treated by continuous infusion of high-dose UFH and discharged uneventfully without further complications. A Japanese woman in the UFH group developed a serious bleeding disorder on the first postoperative day (Table 4A). A large hematoma was diagnosed in the abdominal wound approximately six hours after the first subcutaneous injection of UFH. We operatively evacuated the hematoma and carried out autologous and allogeneic blood transfusions. A causative contribution of UFH treatment was speculated with respect to the development of this hematoma. The postoperative course of evacuation was uneventful and she was discharged from the hospital without further complications. Another Japanese woman in the UFH group developed thrombocytopenia on the first postoperative day (Table 4A). We clinically assumed that this was not heparin-induced thrombocytopenia because she simultaneously developed HELLP syndrome and thrombocytopenia did not progress and improved immediately; however, we did not measure anti-platelet antibody levels. No significant differences were observed in the outcomes of the two groups.
At the one-month follow-up examination, symptomatic VTE, serious bleeding disorders, serious wound complications, and osteoporotic symptomatic fracture were not detected in any participants (Table 4B).
Mean levels of ALT and AST before and after cesarean section in the Enoxaparin group were similar to those in the UFH group (Tables 5A and 5B). The rates at which ALT (≥30 IU/l) and AST levels (≥30 IU/l) became elevated after cesarean section were similar in the Enoxaparin and UFH groups (Table 5B).
No significant differences were observed in mean platelet counts after cesarean section between the Enoxaparin and UFH groups (Table 5B). Only one case of thrombocytopenia was observed in the UFH group (Table 5B), but this case was not considered heparin-induced thrombocytopenia, as discussed above.
Discussion
In the present study, VTE, a mild form of PE (1%), was only observed in a Brazilian woman in the Enoxaparin group (n=98), with no cases observed in the UFH group (n=109), as the main outcome of thromboprophylaxis following cesarean section (Table 4A). Fisher’s exact test revealed no significant difference in the incidence of VTE between the two groups. It is important to note that the prevalence of VTE among Asian women, including Japanese women, was previously shown to be 70% lower than that among Caucasians,18) which might have been a factor in this outcome. Gate et al. estimated that the detection of a clinically meaningful decrease in the risk of VTE after cesarean section required a comparison of over 3,000 women.14) Therefore, the small sample size of the present study (205 women) may have been insufficient to conclusively prove the superiority of thromboprophylaxis with enoxaparin over that with UFH after cesarean section.
Regarding major side effects, only one case of a serious bleeding disorder, a large abdominal hematoma that required surgical evacuation, was observed in the UFH group (Table 4A). Fisher’s exact test showed no significant difference in the occurrence of serious bleeding disorders between the two groups (Table 4A). One case of thrombocytopenia was noted in the UFH group (Tables 4A and 4B), but was attributed to HELLP syndrome, rather than heparin-induced thrombocytopenia. Neither serious wound complications nor osteoporotic symptomatic fractures were observed among our subjects. Mean levels of liver enzymes and mean platelet counts during the postoperative period were similar in the Enoxaparin and UFH groups (Table 5). These results cannot conclusively prove the superior safety of enoxaparin over UFH due to the small sample size. Nevertheless, our results suggest that the safety of initiating enoxaparin injections within 24 hours of cesarean section was similar to that of UFH injections during this period.
To the best of our knowledge, this small study is the first to compare the safety and effectiveness of enoxaparin sodium, a LMWH, with UFH administered within 24 hours of cesarean section in Japan. As discussed above, initiating enoxaparin injections within 24 hours of cesarean section showed a similar safety profile to that of UFH injections during this period. We understand that this concept is not novel, since numerous authoritative guidelines in other countries recommend injections of LMWH, not UFH, soon after cesarean section as the first-choice medication for thromboprophylaxis in pregnancy6,7,8,9) due to fewer bleeding episodes, more predictable therapeutic responses, lower risk of heparin-induced thrombocytopenia, longer half-life, and lower bone mineral density loss.6,12,13,14,15) Accordingly, the current official Japanese recommendation to start LMWH (enoxaparin sodium) injections 24 hours after cesarean section17) do not appear to be beneficial for pregnant women at a higher risk of VTE because the first postoperative day of cesarean section was previously reported to be the highest risk period for PE in pregnancy.5) While our findings highlight the safety of enoxaparin injections within 24 hours of cesarean section, the results should be interpreted with caution because we could not carry out a power analysis due to limited number of subjects.
In conclusion, we conducted a prospective randomized controlled trial to compare the safety and effectiveness of enoxaparin sodium, a LMWH, and UFH, both of which were initiated within 24 hours of cesarean section. We could not conclusively prove the superiority of thromboprophylaxis induced by enoxaparin after cesarean section over that by UFH due to the small sample size. However, our results suggest the safety of initiating enoxaparin injections within 24 hours of cesarean section is similar to that of UFH injections during this period. Therefore, enoxaparin sodium injections within 24 hours of cesarean section may be beneficial for Japanese women at a higher risk of VTE, considering its safety and efficiency, and as described by authoritative guidelines in other countries.6,7,8,9)
Acknowledgments
The authors thank Mrs. Naoko Hakamada, Mrs. Yumiko Yamamoto, Mrs. Naoko Kondo, Mrs. Miuta Sawai, and Mrs. Kazuko Sugiyama for their secretarial or technical assistance.
M.M. and Y.K.: data analysis and critical discussion. H.I. and N.K.: concept of the study and preparation of the manuscript. N.F., H.M., N.T.: data analysis and discussion. T.U., K.S., M.S.: statistical analysis and critical discussion.
Conflict of interest
None.
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