Weight-Based Compared With Fixed-Dose Enoxaparin Prophylaxis After Cesarean Delivery: A Randomized Controlled Trial : Obstetrics & Gynecology

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Contents: Original Research

Weight-Based Compared With Fixed-Dose Enoxaparin Prophylaxis After Cesarean Delivery

A Randomized Controlled Trial

Bruno, Ann M. MD; Allshouse, Amanda A. MS; Campbell, Heather M. MD; Branch, D. Ware MD; Lim, Ming Y. MBBCh, MS; Silver, Robert M. MD; Metz, Torri D. MD, MS

Author Information
Obstetrics & Gynecology 140(4):p 575-583, October 2022. | DOI: 10.1097/AOG.0000000000004937

Venous thromboembolism (VTE) is a major contributor to maternal morbidity and mortality.1–4 Thrombotic risk peaks in the first 3 weeks postpartum with risk accentuated by additional factors including obesity and cesarean delivery.3,5–7 Low-molecular-weight heparin is efficacious in preventing VTE after nonobstetric surgey.8,9 Although efficacy of prophylaxis after cesarean delivery has not been established, some guidelines recommend prophylaxis based on patient risk status.4,10–12

Enoxaparin is the most widely used low-molecular-weight heparin in obstetrics in the United States due to its availability, bioavailability, and favorable safety profile.4,8,9 The American College of Obstetricians and Gynecologists recommends a fixed dose of low-molecular-weight heparin (enoxaparin 40 mg daily) as prophylaxis.4 The dosing suggestion is based on expert opinion and extrapolation from data in nonpregnant individuals. Prior studies in postpartum patients with obesity found weight-based dosing superior to fixed dosing of enoxaparin in achieving prophylaxis, as defined by inhibition of factor Xa.13,14 Whether weight-based enoxaparin dosing should be used across all body mass index (BMI, calculated as weight in kilograms divided by height in meters squared) categories is less well understood. Pregnancy results in significant physiologic changes affecting drug metabolism and clearance, and adjustments in medication dose and frequency are often required irrelevant of obesity.15,16

The objective of this study was to evaluate the effectiveness of fixed compared with weight-based enoxaparin dosing in achieving prophylactic anti-Xa levels after cesarean delivery.

METHODS

This was a single-center, parallel group, randomized controlled trial of weight-based compared with fixed-dose enoxaparin for postpartum thromboprophylaxis. Individuals aged 18 years or older delivering at University of Utah Health from June 19, 2020, to November 18, 2021, were screened for eligibility. We included individuals undergoing cesarean delivery and meeting institutional criteria for postpartum enoxaparin thromboprophylaxis (Box 1). Exclusion criteria included contraindication to anticoagulation, plan for postpartum therapeutic anticoagulation, or known renal impairment (defined as creatinine clearance less than 30 mL/minute). Eligible individuals were approached before delivery or within 6 hours postpartum, in advance of their anticipated first dose of enoxaparin prophylaxis. Informed written consent was obtained from all participants.

Box 1.

Institutional Risk-Stratification Protocol for Low-Molecular-Weight Heparin Thromboprophylaxis in Postpartum Patients

Major risk factors*

  • History of VTE
  • BMI 40 or higher
  • High-risk thrombophilia
    •   Antiphospholipid syndrome
    •   Antithrombin deficiency
    •   Factor V Leiden homozygote
    •   Prothrombin gene mutation homozygote
    •   Compound heterozygote for Factor V Leiden and Prothrombin gene mutation
  • Medical comorbidities
    •   Heart disease
    •   Cancer
    •   Systemic lupus erythematosus
    •   Inflammatory bowel disease or inflammatory polyarthropathy
    •   Sickle cell disease
    •   Intravenous drug use
  • Nephrotic-range proteinuria
  • Cesarean hysterectomy
  • Cesarean delivery in labor

Moderate risk factors

  • BMI 30 or higher
  • Multifetal gestation
  • PPH (more than 1 L blood loss or intrapartum blood transfusion)
  • Tobacco use
  • Elective or scheduled cesarean delivery
  • Preeclampsia
  • Infection
  • Preterm delivery (less than 37 wk gestation)
  • Age older than 35 y
  • Family history of VTE
  • Varicose veins
  • Stillbirth
  • Prolonged labor (more than 24 h)
  • Low-risk thrombophilia
    •   Factor V Leiden heterozygote
    •   Prothrombin gene mutation heterozygote
    •   Protein C deficiency
    •   Protein S deficiency

VTE, venous thromboembolism; BMI, body mass index; PPH, postpartum hemorrhage.

*Chemical prophylaxis is recommended at our institution for postpartum individuals with one major or two or more moderate risk factors for VTE.

Individuals who consented to participate in the study were randomized to receive weight-based or fixed-dose enoxaparin thromboprophylaxis. Individuals were randomly assigned in a 1:1 ratio by research staff using an electronic block randomization schema with random block sizes. Randomization was stratified by BMI to ensure balanced randomization within BMI category (normal weight: 18.5–24.9; overweight: 25.0–29.9; class I obesity: 30.0–34.9; class II obesity: 35.0–39.9; class III obesity: 40 or higher). The randomization schema was generated in SAS and uploaded and maintained through REDCap (Research Electronic Data Capture).

Fixed enoxaparin dosing was defined as 40 mg daily for those with BMIs lower than 40 or 40 mg every 12 hours for those with BMIs 40 or higher.4Weight-based enoxaparin dosing was calculated as 0.5 mg/kg (rounded to the nearest 10 mg) every 12 hours. Admission weight was used for dosing. Patients, medical care teams (physicians, nurses, pharmacists), and research staff were unmasked to study group allocation.

All patients received mechanical prophylaxis with sequential compression devices intraoperatively and postpartum until ambulatory. The first dose of enoxaparin prophylaxis was scheduled 6–12 hours postcesarean delivery, and at least 12 hours postneuraxial anesthesia placement, consistent with institutional protocol. For patient satisfaction, an optional single rotation in enoxaparin dosing by 1–4 hours at the second or third dose was used to move medication administration to “waking” hours. All patients received education on the indications for enoxaparin use and VTE risk factors per institutional practice. Enoxaparin thromboprophylaxis was continued throughout the inpatient hospitalization and after discharge for 14 days. Earlier discontinuation of enoxaparin was at the discretion of the clinical care team.

The primary outcome was prophylactic peak anti-Xa level 4–6 hours after at least the third enoxaparin dose. Enoxaparin steady state is reached between the second and third doses; collection after at least the third dose of enoxaparin was selected to ensure drug steady state was achieved before outcome ascertainment.4,8,16 Blood was collected 4–6 hours after receiving an enoxaparin dose to reflect the peak level. Participants underwent blood collection for anti-Xa levels at enrollment (baseline) and peak. The peak prophylactic anti-Xa range was defined as 0.2–0.6 international units/mL.8,16,17 All enoxaparin anti-Xa assays were performed using the standard chromogenic assay for clinical measurement of anti-Xa levels at ARUP Laboratories, which is affiliated with University of Utah.

Secondary outcomes included subprophylactic and supraprophylactic peak anti-Xa levels, peak anti-Xa level at postpartum visit, and VTE and wound complication within 6 weeks postpartum. Subprophylactic peak was defined as anti-Xa level less than 0.2 international units/mL, and supraprophylactic as anti-Xa greater than 0.6 international units/mL.8,9,16 The postpartum peak anti-Xa level was collected at outpatient visit between postoperative day 10 and 18. Self-reported compliance with enoxaparin therapy at postoperative visit was assessed. Venous thromboembolism was defined as pulmonary embolism, diagnosed by ventilation/perfusion scan or computed tomography angiography, and deep vein thrombosis, diagnosed by lower extremity Doppler. Wound complications included wound hematoma, surgical site infection or other wound disruption. The diagnosis of wound complications was at the discretion of the clinical care team.

Trained research staff abstracted data from medical records including demographics, medical and obstetric history, delivery outcomes, and postpartum course. If a patient reported complications for which they were evaluated outside our health care system, patient self-report was recorded and records obtained, if possible. Final medical record review extended through 6 weeks postpartum to ascertain secondary outcome events.

Two prior studies evaluated fixed (or BMI) based enoxaparin in comparison with weight-based enoxaparin dosing in patients with class II and III obesity. These studies were used to inform the baseline expected rate of prophylactic anti-Xa level in the fixed-dose group (26%) and the effect size (60%) for individuals with obesity.13,14 A more conservative but still clinically meaningful effect size was used for the overall sample size calculation considering planned inclusion of individuals across all BMIs, and to allow additional power for robust subgroup comparisons by BMI and weight categories. We estimated that to have 80% power to detect an 18% difference in the proportion of individuals with prophylactic anti-Xa levels with weight-based compared with fixed enoxaparin dosing with a two-sided type I error rate of 5%, 121 individuals per group were required for the study. Allowing for 10% loss to follow-up, we planned to recruit 266 individuals.

Analyses were performed following the intention-to-treat principle. Baseline characteristics were compared between participants with and without missing primary outcome. To address missing outcomes, worst-case imputation was used in a primary modified intention-to-treat analysis. Frequencies and percentages were calculated for categorical data with study groups compared using χ2 or Fisher exact tests, as appropriate. Means and SDs were calculated for continuous data with study groups compared using t tests. Results are presented as relative risk (RR) with 95% CIs. A secondary complete case analysis was performed, consisting of the subset of participants with complete outcome ascertainment and not using imputation.

A Data and Safety Monitoring Board monitored trial progress and any adverse events. Adverse events included delayed (more than 24 hours postdelivery) hemorrhage, wound hematoma or disruption, hospital re-admission, re-operation, unexpected bleeding complication or participant death. An independent Data Safety Monitoring Committee composed of two maternal–fetal medicine subspecialists external to the trial institution reviewed trial progress, protocol violations, adverse events, and interim analysis results.

One interim analysis was completed. Using the Pocock18 boundary for a single interim analysis maintaining a type 1 error rate of 5%, P=.029 was considered to be statistically significant. Interim analysis stopping criteria were defined as a statistically significant difference between study groups (P<.029) by a two-sided χ2 test for the primary outcome. If stopping criteria were met, the trial was planned to stop enrollment; if stopping criteria were not met, the trial was planned to continue enrollment through full sample size. The adjusted P-value was used at the time of interim analysis, and if trial enrollment continued was planned for the final analysis. At time of interim analysis with 50% enrollment, stopping criteria were met and enrollment was concluded per the recommendation of the independent Data Safety Monitoring Committee.

This study was approved by the IRB of the University of Utah (#00130494). The trial was registered at ClinicalTrials.gov in advance of initiation of study enrollment (NCT04305756). Study data were collected and managed using REDCap (Research Electronic Data Capture) hosted at University of Utah.19 All analyses were performed using SAS 9.4. The study was reported following the CONSORT (Consolidated Standards of Reporting Trials) guidelines.20

RESULTS

Of 1,832 individuals assessed for eligibility, 146 met inclusion criteria and consented to participate, with 74 assigned to weight-based enoxaparin and 72 assigned to fixed enoxaparin dosing (Fig. 1). Fifteen patients withdrew from the study: nine in the weight-based group and six in the fixed-dose group. Reasons for participant withdrawal included aversion to venipuncture (five), declined enoxaparin injections (eight), or therapy discontinued at the discretion of the clinical team (two). Eleven patients did not undergo venipuncture for primary outcome ascertainment. Baseline characteristics were similar between groups (Table 1).

F1
Fig. 1.:
CONSORT (Consolidated Standards of Reporting Trials) flow diagram. Enrollment, randomization, and follow-up. *Worst-case imputation was used in the primary modified intention-to-treat analysis for missing outcomes.
T1
Table 1.:
Baseline Characteristics of the Study Participants

The primary outcome was not ascertained for 29 of 146 participants (20%). Comparisons of characteristics between people missing the primary outcome and complete cases did not yield substantially significant differences (Appendix 1, available online at https://links.lww.com/AOG/C853). Thus, data were considered to be missing completely at random. All participants received therapy consistent with randomization group; therefore, per-protocol analysis was not completed.

The baseline anti-Xa level was less than 0.1 international units/mL in all participants. In primary intention-to-treat analysis, the primary outcome of prophylactic peak anti-Xa level occurred in 66% (49/74) in the weight-based group and 44% (32/72) in the fixed-dose group (RR 1.49, 95% CI 1.10–2.02, P=.008; Table 2). Subprophylactic peak anti-Xa levels occurred less frequently in the weight-based group (n=24) compared with the fixed-dose group (n=40; 32% vs 56%, RR 0.58, 95% CI 0.40–0.86, P=.005). Supraprophylactic peak anti-Xa levels (n=15 fixed-dose group and n=15 weight-based group) did not significantly differ between groups (20% vs 20%, RR 0.97, 95% CI 0.51–1.84).

T2
Table 2.:
Primary and Secondary Outcomes by Intention-to-Treat Analysis

At outpatient postoperative visit, prophylactic peak anti-Xa level was found in 20% (15/74) in the weight-based group compared with 7% (5/72) in the fixed-dose group (RR 2.92, 95% CI 1.12–7.61, P=.019). Overall, 28 participants in the weight-based group and 26 in the fixed-dose group were queried regarding compliance with enoxaparin by self-report at postoperative visit. The proportion who reported using enoxaparin did not differ between groups (79% vs 88%, P=.599).

There were no VTE events in either group. Postpartum wound complications occurred in 4% (6/146) of participants and did not significantly differ by group (Table 2). The five wound complications in the weight-based group included three hematomas, managed conservatively without additional surgical interventions, and two cases of cellulitis managed with oral antibiotics. There was one wound complication in the fixed-dose group, a suprafascial subcutaneous tissue dehiscence requiring wet-to-dry dressing changes and wound follow-up.

In complete case analysis, 82% (49/60) in the weight-based group compared with 56% (32/57) in the fixed-dose group achieved prophylactic peak anti-Xa level (RR 1.45, 95% CI 1.12–1.88, P=.003; Table 3). Subprophylactic peak anti-Xa levels were significantly less frequent with weight-based dosing (10/60, 17%) compared with fixed dosing (25/57, 44%; RR 0.38, 95% CI 0.20–0.72). Supraprophylactic peak anti-Xa level did not significantly differ by group (1/60 in the weight-based group vs 0/57 in the fixed-dose group, P=.328). At outpatient follow up, prophylactic peak anti-Xa level was achieved in 52% (15/29) in the weight-based group compared with 15% (5/33) in the fixed-dose group (RR 3.41, 95% CI 1.42–8.24, P=.002). Wound complications did not differ significantly between dosing groups (8% in the weight-based group vs 2% in the fixed-dose group; RR 4.75, 95% CI 0.57–39.42, P=.107) in complete case analysis.

T3
Table 3.:
Primary and Secondary Outcomes by Complete Case Analysis

There were 21 adverse events. These included superficial wound separation or bruising (three), emergency department evaluation (six), readmission for postpartum preeclampsia (three), Clostridium difficile infection (one), endometritis (one), lupus cerebritis (one), and wound complications (six), as previously described in the secondary outcomes (Appendix 2, available online at https://links.lww.com/AOG/C853). None of the adverse events were considered directly related to research, although some may be associated with enoxaparin use.

DISCUSSION

In this single-center, randomized controlled trial, weight-based enoxaparin dosing was more effective than fixed enoxaparin dosing at achieving prophylactic peak anti-Xa levels after cesarean delivery. Weight-based enoxaparin remained more effective than fixed dosing at achieving prophylactic peak anti-Xa level at outpatient follow-up. There were no postpartum VTEs identified in either group. Wound complications did not significantly differ by dosing regimen, although there were five in the weight-based group and one in the fixed-dose group.

Prior evaluation of enoxaparin dosing in postpartum individuals has been largely limited to those with obesity. In a single-center, prospective sequential cohort study of 85 individuals after cesarean delivery with class III obesity (BMI 40 or higher), weight-based enoxaparin dosing (0.5 mg/kg every 12 hours) was more likely to achieve postpartum prophylactic peak anti-Xa levels (0.2–0.6 international units/mL) than fixed BMI-based dosing (40 mg every 12 hours for BMI 40–59.9; 60 mg every 12 hours for BMI 60 or higher) (86% vs 26%, P<.001).14 Similarly, in a single-center, randomized controlled trial of 88 individuals after cesarean delivery with class II obesity or greater (BMI 35 or higher), Stephenson et al13 found weight-based enoxaparin dosing (0.5 mg/kg every 12 hours) more effectively achieved prophylactic peak anti-Xa levels (0.2–0.6 international units/mL) than fixed dosing (40 mg daily) (88% vs 14%; odds ratio 44.4, 95% CI 12.44–158.48). These findings are consistent with those in nonobstetric literature demonstrating weight-based enoxaparin dosing is more effective in individuals with obesity.21,22

Despite evidence supporting a weight-based approach to enoxaparin dosing in postpartum patients with obesity, current national guidelines only reflect the potential need for such adjustments. The American College of Obstetricians and Gynecologists’ thromboprophylaxis guidelines state that dose modifications may be necessary at extremes of body weight; the Society for Maternal-Fetal Medicine guidelines recommend a fixed increase in enoxaparin dose (40 mg every 12 hours) for individuals with class III obesity.4,12 Our study considered the dosing approach in individuals after cesarean delivery inclusive of individuals with normal weight, overweight, and obesity. We found weight-based dosing to be superior to fixed dosing in achieving prophylactic anti-Xa levels. These results are consistent with findings from a prospective cohort in which weight-based dosing achieved prophylactic anti-Xa levels in the majority of patients (71%).23

In a retrospective before-and-after study, Lu et al24 found increased odds of wound hematomas after fixed-dose chemical thromboprophylaxis guideline implementation at a single academic institution (0.4% preguidance vs 0.7% postguideline; adjusted odds ratio 2.34, 95% CI 1.54–3.57). We found wound complications in 4% of participants, which did not significantly differ by enoxaparin dosing regimen; however, we did not have a no prophylaxis comparison. Although not statistically significant, differences between groups may be clinically significant. Notably, supraprophylactic peak anti-Xa levels were rare.

Guidelines differ on suggested length of postpartum thromboprophylaxis to inpatient only compared with post–hospital discharge.4,10,11 Our institution uses an extended therapy protocol with enoxaparin continued outpatient. Weight-based dosing remained more effective than fixed dosing in achieving prophylactic peak anti-Xa levels at the postoperative visit.

Although enoxaparin prophylaxis is effective at preventing postoperative VTE in nonobstetric surgical populations, no prospective data have demonstrated efficacy of enoxaparin prophylaxis to prevent postcesarean VTE.25–27 Critical discourse on the best approach to postpartum thromboprophylaxis is ongoing and use varies widely across the United States.25,26,28,29 If we consider adequate prophylaxis as a prerequisite to evaluating efficacy, weight-based enoxaparin for thromboprophylaxis should be the intervention evaluated in future prospective studies addressing this question.

Our study has several strengths. This trial is randomized and larger than previous studies evaluating weight-based enoxaparin in individuals after cesarean delivery. Individuals with and without obesity were included, increasing generalizability. We measured the peak anti-Xa at steady state and at outpatient follow-up visits.

Our study also has limitations. We had multiple missed primary outcome collections and slower than anticipated accrual largely reflecting recruitment during the coronavirus disease 2019 (COVID-19) pandemic.30 Patients were discharged earlier from the hospital than anticipated during the pandemic and were not willing to have home visits from the research staff for ascertainment of the primary outcome after discharge for fear of contracting severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). To address missingness, we completed worst case imputation in the primary analysis and completed a secondary complete case analysis. Findings were similar in both analyses. Additional individuals were lost to follow-up for outpatient peak anti-Xa level ascertainment, yielding high rates of imputation and potential for bias in this measure. Prior studies have not reported on outpatient peak anti-Xa levels; we report these findings, despite their limitations, as they add to the literature. Participant compliance to therapy after hospital discharge is uncertain. There remains a possibility that patients were seen outside of our health care system and outcomes were not ascertained. The trial was unmasked, which may have introduced bias. However, this would not have affected the primary outcome, which was an objectively measured anti-Xa level.

Trials stopped early for benefit are at risk to overestimate treatment effects secondary to greater variability with a smaller sample size. However, the Pocock boundary selected for this trial requires less extreme differences at the time of interim analysis than other spending functions, resulting on average, in a lower risk for overstated differences.31 Although statistical power was retained for the primary outcome, differences in secondary outcomes should be considered exploratory. Further, subanalyses by weight and BMI category were not completed secondary to the smaller final sample size than originally anticipated after stopping of the trial for efficacy.

In conclusion, among individuals after cesarean delivery, weight-based enoxaparin dosing was more effective than fixed enoxaparin dosing in achieving prophylactic peak anti-Xa levels. A question not answered by this study is whether chemical thromboprophylaxis is effective or safe, who are appropriate candidates, and on what scale it should be used after cesarean delivery.

Authors' Data Sharing Statement

  • Will individual participant data be available (including data dictionaries)? Yes, upon reasonable request within 1 year of publication.
  • What data in particular will be shared? Not applicable.
  • What other documents will be available? Not applicable.
  • When will data be available (start and end dates)? Not applicable.
  • By what access criteria will data be shared (including with whom, for what types of analyses, and by what mechanism)? Not applicable.

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