Background
The rising cesarean birth rate has drawn attention to risks associated with repeat cesarean birth. Prevention of adhesions with adhesion barriers has been promoted as a way to decrease operative difficulty. However, robust data demonstrating effectiveness of such interventions are lacking.
Objective
We report data from a multicenter trial designed to evaluate the short-term safety and effectiveness of a modified sodium hyaluronic acid (HA)-carboxymethylcellulose (CMC) absorbable adhesion barrier for reduction of adhesions following cesarean delivery.
Study Design
Patients who underwent primary or repeat cesarean delivery were included in this multicenter, single-blinded (patient), randomized controlled trial. Patients were randomized into either HA-CMC (N = 380) or no treatment (N = 373). No other modifications to their treatment were part of the protocol. Short-term safety data were collected following randomization. The location and density of adhesions (primary outcome) were assessed at their subsequent delivery using a validated tool, which can also be used to derive an adhesion score that ranges from 0-12.
Results
No differences in baseline characteristics, postoperative course, or incidence of complications between the groups following randomization were noted. Eighty patients from the HA-CMC group and 92 controls returned for subsequent deliveries. Adhesions in any location were reported in 75.6% of the HA-CMC group and 75.9% of the controls ( P = .99). There was no significant difference in the median adhesion score; 2 (range 0-10) for the HA-CMC group vs 2 (range 0-8) for the control group ( P = .65). One third of the HA-CMC patients met the definition for severe adhesions (adhesion score >4) compared to 15.5% in the control group ( P = .052). There were no significant differences in the time from incision to delivery ( P = .56). Uterine dehiscence in the next pregnancy was reported in 2 patients in HA-CMC group vs 1 in the control group ( P = .60).
Conclusion
Although we did not identify any short-term safety concerns, HA-CMC adhesion barrier applied at cesarean delivery did not reduce adhesion formation at the subsequent cesarean delivery.
Introduction
Cesarean delivery occurs in approximately one third of all births and has become the most common surgical procedure in the United States. While guidelines have encouraged a reduction in cesarean births, little progress has been made in significantly impacting the rate. According to preliminary data from the Centers for Disease Control and Prevention, the cesarean delivery rate declined slightly in 2013, to 32.7% of all births (down from 32.8% in 2012). The cesarean delivery rate had increased approximately 60% from 1996 through 2009, reaching a peak 32.9%, where it remained unchanged for several years. Coincidentally, there has been a decline in the vaginal birth after cesarean delivery rate, with >90% of women who undergo a primary cesarean delivery delivering a subsequent pregnancy by repeat cesarean delivery. These statistics have prompted investigation into the short- and long-term impact of cesarean delivery on fetal and maternal outcomes. Postoperative complication rates for both primary and repeat cesarean delivery vary widely and are reported as anywhere from 5-35%. The most common causes of maternal perioperative morbidity associated with cesarean delivery include surgical-site infection and wound complications, hemorrhage, bowel/bladder injury and obstruction, and thromboembolic complications. The incidence of many of these complications increases in the presence of adhesion formation.
Adhesion prevalence following cesarean delivery has been reported to be 46% after a first cesarean delivery, 75% after a second, and 83% after a third. There are several adhesion prevention barriers approved by the US Food and Drug Administration (FDA) for the prevention of postoperative adhesions. One such barrier, which is composed of modified sodium hyaluronic acid (HA) and carboxymethylcellulose (CMC) (Seprafilm; Sanofi Biosurgery, Cambridge, MA), has been studied in the setting of a variety of procedures. This barrier is FDA approved to reduce adhesion formation following laparotomy for abdominal or pelvic surgery. Initial studies on the use of this barrier at the time of cesarean delivery suggest reduction in the amount and severity of adhesion formation. However, the previously reported studies designed to specifically address this indication for use are limited, their sample sizes are small, and their methodologies were not well described. Additionally, they were not designed or powered to reasonably evaluate safety.
We performed a multicenter, single-blinded, randomized controlled trial to determine the short-term safety and effectiveness of HA-CMC to reduce adhesion formation when used at the time of cesarean delivery.
Materials and Methods
We performed a multicenter, single (patient)-blinded, randomized controlled trial conducted in 3 sites: Winthrop University Hospital, Mineola, NY; Stony Brook University Medical Center, Stony Brook, NY; and Lehigh Valley Health Network, Allentown, PA from November 2007 through June 2010 ( ClinicalTrials.gov identifier NCT00565643 ). Following institution-specific review board approvals, and with the approval of the managing physician, pregnant women presenting to labor and delivery were screened for enrollment. Some patients presented in the perioperative period specifically for a scheduled cesarean delivery, while others presented for a trial of labor (ie, planned vaginal delivery).
Patients were considered eligible for the study if they were age ≥18 years, planning or had the potential to undergo cesarean delivery, and able to consent to participate. Patients were excluded if there was a planned tubal ligation, infertility resulting in ≥2 years of treatment to achieve (current) pregnancy, medical or other serious conditions that could interfere with either compliance or ability to complete study protocol, or known allergy to modified HA or CMC. Once a patient met eligibility criteria, she was offered enrollment in the study. Upon providing consent, she was considered a candidate for randomization. If and when the patient subsequently underwent a cesarean delivery, she was randomized to either placement of HA-CMC adhesion barrier prior to abdominal closure or to routine closure without placement of an adhesion barrier.
The chance of being assigned to either group was equal (ie, 1:1 randomization). Randomization was done in permuted blocks of varying sizes (6-14) with the randomization code generated using software (SAS, Version 9.1; SAS Institute, Cary, NC). Enrollment was stratified by primary and repeat cesarean deliveries using separate randomization sequences. A statistician not involved in enrollment, data collection, or analysis performed the randomization allocation. The randomization code was not accessible to those enrolling patients. Assignments were kept in sequentially numbered, sealed, opaque envelopes readily accessible to the operating room. Most patients undergoing cesarean delivery were under regional anesthesia. Thus, communication regarding randomization was performed nonverbally in an effort to keep the patient blinded. The randomization card was shown to the operating physician. If the adhesion barrier was to be placed, the circulating nurse placed the product onto the sterile field and recorded the number of sheets used.
The goal of the adhesion barrier placement was to cover the hysterotomy site, bladder flap (if created), and the midline anterior surface of the uterus. This was usually accomplished with 1 sheet of HA-CMC product, which was cut into smaller pieces to facilitate placement. However, if the surgeon believed that additional sheets were indicated, this was permitted under the protocol. Prior to the study beginning at each institution, department-wide presentations were made about the study protocol and the placement of the HA-CMC barrier. Physician training on HA-CMC placement was provided prior to the beginning of the study and at any time during the study period at their request.
The primary outcome was the prevalence of adhesions at the time of the subsequent cesarean delivery. Secondary outcomes (assessed at the time of subsequent delivery) included incision to delivery time, total operative time, estimated blood loss, and the rate of complications (bowel or bladder injury, hysterectomy, blood transfusion, and uterine rupture or dehiscence). We also sought to examine the short-term safety of HA-CMC at the time of placement (immediately following randomization) as measured by postoperative complications (fever, ileus, abscess formation, wound complication), postoperative white blood cell count, narcotic pain medication use, length of stay, readmission, and the frequency of postpartum office visits).
Sample size calculation for the primary endpoint of the study (adhesion formation) was performed with the following assumptions: type 1 error (alpha) of 0.05, a background risk of adhesion of 50% in the no treatment group, and a 25% risk of adhesion in the treated group (ie, a 50% reduction in adhesion formation). A sample size of 65 (patients who returned for a subsequent cesarean delivery) in each arm would be required to detect the above difference with 80% power. Using existing hospital data on rates of subsequent pregnancy after cesarean, we anticipated the need to randomize approximately 900 patients to obtain our final sample size to be able to assess our primary outcome (adhesion formation seen at the following cesarean), assuming 12-24 months of enrollment and a desire to be able to report the primary outcome within 3 years of completing enrollment.
Data collection involved the antepartum course, intraoperative events, and postoperative course of the patients. There were no additional tests or procedures ordered or performed during the hospital stay as part of this study, either at the time of enrollment or at the subsequent delivery. The operative and postoperative care of the patients were managed by the patient’s physician and with hospital-specific standard policies and procedures. After delivery, all inpatient and outpatient electronic records, and hospital admission records were reviewed. We performed a telephone follow-up (2 attempts) at 6-8 weeks following delivery to capture the postoperative course and complications. The definitions used for postoperative complications are shown in Table 1 .
| Event | Definition |
|---|---|
| Ileus/bowel obstruction | Nausea/vomiting that necessitates reduction in diet (eg, regular to clear liquids or NPO status), inability to advance diet, insertion of nasal-gastric tube, administration of intravenous fluids, or reoperation; radiologic evidence of obstruction or ileus would be supportive, but not necessary |
| Fever | Temperature ≥100.4°F (≥38°C) occurring >24 h postoperatively, regardless of suspected cause |
| Abscess | Evidence of abdominal-pelvic fluid collection with signs of inflammation/infection requiring intervention including, but not limited to, antibiotic administration or drainage |
| Wound cellulitis | Evidence of superficial infection (eg, redness, warmth, fever) necessitating intervention (eg, antibiotic administration, wound exploration) |
| Wound separation | Separation of superficial layers of surgical site requiring any intervention (including debridement, packing, primary closure, healing by secondary intention, or additional patient visits) |
| Wound dehiscence | Separation of deep layers of surgical site including fascia |
| Deep venous thrombosis | Radiologic evidence of new-onset deep venous thrombosis |
| Pulmonary embolism | New-onset radiologic evidence (eg, computed tomography, angiography, V-Q scan) of pulmonary embolism in appropriate clinical setting (oxygen desaturation, chest pain, tachycardia) |
| Antibiotic administration | Need for initiation of therapeutic antibiotic administration for any reason (eg, endometritis, urinary tract infection, pneumonia) during hospital stay or upon discharge; does not include continuation of prehospital antibiotics |
| Readmission | Hospital admission within 6 wk following delivery for any reason |
Both primary and repeat cesarean deliveries, as well as patients with previous abdominal surgery were eligible for enrollment. Therefore, adhesions were assessed at the time of randomization utilizing a previously validated adhesion assessment tool by Lyell et al. This tool was modified to include assessment of adhesions in the area of the bladder, as this site was previously reported by Lyell et al to be commonly included in the “other location” area in their experience. Documentation of the adhesion score was completed immediately following conclusion of the procedure. To calculate the score, we assigned a value of “1” to each location where filmy adhesions were noted and “2” to each location where dense adhesions were noted. Therefore, the score could range from 0-12 based on the location and severity of adhesion formation. In addition, each participating institution agreed to modify the labor and delivery medical record to begin assessing adhesions on every patient delivering at the respective institution. With this modification, adhesion data would be collected on enrolled patients who returned for subsequent deliveries and could then be abstracted from the medical record. Other measures included in this analysis (eg, incision-to-delivery time, total operative time, blood loss) were routinely collected for all patients. The database of enrolled patients was periodically compared to the electronic medical record from each institution to screen for patients who had returned for a subsequent delivery. Once identified, study data were abstracted from their medical record.
All data were analyzed in an intent-to-treat fashion. Differences in continuous variables were assessed by the unpaired t test or 2-sample median test. Differences in proportions were evaluated by Fisher exact probability test. All analyses were performed using software (SAS, Version 9.2 for Windows). Risk ratios and 95% confidence intervals are reported as appropriate. No interim analyses were planned or performed.
With regard to the financial support for this project, the funding organizations (including the product manufacturer) had no role in study design, data collection, analysis, or interpretation, or in the decision to publish results. The authors designed the project and funding was then sought to support its execution through investigator-sponsored grants and other available sources (including the product manufacturer).
Materials and Methods
We performed a multicenter, single (patient)-blinded, randomized controlled trial conducted in 3 sites: Winthrop University Hospital, Mineola, NY; Stony Brook University Medical Center, Stony Brook, NY; and Lehigh Valley Health Network, Allentown, PA from November 2007 through June 2010 ( ClinicalTrials.gov identifier NCT00565643 ). Following institution-specific review board approvals, and with the approval of the managing physician, pregnant women presenting to labor and delivery were screened for enrollment. Some patients presented in the perioperative period specifically for a scheduled cesarean delivery, while others presented for a trial of labor (ie, planned vaginal delivery).
Patients were considered eligible for the study if they were age ≥18 years, planning or had the potential to undergo cesarean delivery, and able to consent to participate. Patients were excluded if there was a planned tubal ligation, infertility resulting in ≥2 years of treatment to achieve (current) pregnancy, medical or other serious conditions that could interfere with either compliance or ability to complete study protocol, or known allergy to modified HA or CMC. Once a patient met eligibility criteria, she was offered enrollment in the study. Upon providing consent, she was considered a candidate for randomization. If and when the patient subsequently underwent a cesarean delivery, she was randomized to either placement of HA-CMC adhesion barrier prior to abdominal closure or to routine closure without placement of an adhesion barrier.
The chance of being assigned to either group was equal (ie, 1:1 randomization). Randomization was done in permuted blocks of varying sizes (6-14) with the randomization code generated using software (SAS, Version 9.1; SAS Institute, Cary, NC). Enrollment was stratified by primary and repeat cesarean deliveries using separate randomization sequences. A statistician not involved in enrollment, data collection, or analysis performed the randomization allocation. The randomization code was not accessible to those enrolling patients. Assignments were kept in sequentially numbered, sealed, opaque envelopes readily accessible to the operating room. Most patients undergoing cesarean delivery were under regional anesthesia. Thus, communication regarding randomization was performed nonverbally in an effort to keep the patient blinded. The randomization card was shown to the operating physician. If the adhesion barrier was to be placed, the circulating nurse placed the product onto the sterile field and recorded the number of sheets used.
The goal of the adhesion barrier placement was to cover the hysterotomy site, bladder flap (if created), and the midline anterior surface of the uterus. This was usually accomplished with 1 sheet of HA-CMC product, which was cut into smaller pieces to facilitate placement. However, if the surgeon believed that additional sheets were indicated, this was permitted under the protocol. Prior to the study beginning at each institution, department-wide presentations were made about the study protocol and the placement of the HA-CMC barrier. Physician training on HA-CMC placement was provided prior to the beginning of the study and at any time during the study period at their request.
The primary outcome was the prevalence of adhesions at the time of the subsequent cesarean delivery. Secondary outcomes (assessed at the time of subsequent delivery) included incision to delivery time, total operative time, estimated blood loss, and the rate of complications (bowel or bladder injury, hysterectomy, blood transfusion, and uterine rupture or dehiscence). We also sought to examine the short-term safety of HA-CMC at the time of placement (immediately following randomization) as measured by postoperative complications (fever, ileus, abscess formation, wound complication), postoperative white blood cell count, narcotic pain medication use, length of stay, readmission, and the frequency of postpartum office visits).
Sample size calculation for the primary endpoint of the study (adhesion formation) was performed with the following assumptions: type 1 error (alpha) of 0.05, a background risk of adhesion of 50% in the no treatment group, and a 25% risk of adhesion in the treated group (ie, a 50% reduction in adhesion formation). A sample size of 65 (patients who returned for a subsequent cesarean delivery) in each arm would be required to detect the above difference with 80% power. Using existing hospital data on rates of subsequent pregnancy after cesarean, we anticipated the need to randomize approximately 900 patients to obtain our final sample size to be able to assess our primary outcome (adhesion formation seen at the following cesarean), assuming 12-24 months of enrollment and a desire to be able to report the primary outcome within 3 years of completing enrollment.
Data collection involved the antepartum course, intraoperative events, and postoperative course of the patients. There were no additional tests or procedures ordered or performed during the hospital stay as part of this study, either at the time of enrollment or at the subsequent delivery. The operative and postoperative care of the patients were managed by the patient’s physician and with hospital-specific standard policies and procedures. After delivery, all inpatient and outpatient electronic records, and hospital admission records were reviewed. We performed a telephone follow-up (2 attempts) at 6-8 weeks following delivery to capture the postoperative course and complications. The definitions used for postoperative complications are shown in Table 1 .
| Event | Definition |
|---|---|
| Ileus/bowel obstruction | Nausea/vomiting that necessitates reduction in diet (eg, regular to clear liquids or NPO status), inability to advance diet, insertion of nasal-gastric tube, administration of intravenous fluids, or reoperation; radiologic evidence of obstruction or ileus would be supportive, but not necessary |
| Fever | Temperature ≥100.4°F (≥38°C) occurring >24 h postoperatively, regardless of suspected cause |
| Abscess | Evidence of abdominal-pelvic fluid collection with signs of inflammation/infection requiring intervention including, but not limited to, antibiotic administration or drainage |
| Wound cellulitis | Evidence of superficial infection (eg, redness, warmth, fever) necessitating intervention (eg, antibiotic administration, wound exploration) |
| Wound separation | Separation of superficial layers of surgical site requiring any intervention (including debridement, packing, primary closure, healing by secondary intention, or additional patient visits) |
| Wound dehiscence | Separation of deep layers of surgical site including fascia |
| Deep venous thrombosis | Radiologic evidence of new-onset deep venous thrombosis |
| Pulmonary embolism | New-onset radiologic evidence (eg, computed tomography, angiography, V-Q scan) of pulmonary embolism in appropriate clinical setting (oxygen desaturation, chest pain, tachycardia) |
| Antibiotic administration | Need for initiation of therapeutic antibiotic administration for any reason (eg, endometritis, urinary tract infection, pneumonia) during hospital stay or upon discharge; does not include continuation of prehospital antibiotics |
| Readmission | Hospital admission within 6 wk following delivery for any reason |
Both primary and repeat cesarean deliveries, as well as patients with previous abdominal surgery were eligible for enrollment. Therefore, adhesions were assessed at the time of randomization utilizing a previously validated adhesion assessment tool by Lyell et al. This tool was modified to include assessment of adhesions in the area of the bladder, as this site was previously reported by Lyell et al to be commonly included in the “other location” area in their experience. Documentation of the adhesion score was completed immediately following conclusion of the procedure. To calculate the score, we assigned a value of “1” to each location where filmy adhesions were noted and “2” to each location where dense adhesions were noted. Therefore, the score could range from 0-12 based on the location and severity of adhesion formation. In addition, each participating institution agreed to modify the labor and delivery medical record to begin assessing adhesions on every patient delivering at the respective institution. With this modification, adhesion data would be collected on enrolled patients who returned for subsequent deliveries and could then be abstracted from the medical record. Other measures included in this analysis (eg, incision-to-delivery time, total operative time, blood loss) were routinely collected for all patients. The database of enrolled patients was periodically compared to the electronic medical record from each institution to screen for patients who had returned for a subsequent delivery. Once identified, study data were abstracted from their medical record.
All data were analyzed in an intent-to-treat fashion. Differences in continuous variables were assessed by the unpaired t test or 2-sample median test. Differences in proportions were evaluated by Fisher exact probability test. All analyses were performed using software (SAS, Version 9.2 for Windows). Risk ratios and 95% confidence intervals are reported as appropriate. No interim analyses were planned or performed.
With regard to the financial support for this project, the funding organizations (including the product manufacturer) had no role in study design, data collection, analysis, or interpretation, or in the decision to publish results. The authors designed the project and funding was then sought to support its execution through investigator-sponsored grants and other available sources (including the product manufacturer).
Results
A total of 1670 patients were assessed for eligibility. Of the 1226 eligible patients, 808 (65.9%) consented for participation and 753 patients were randomized. There were 55 nonrandomized individuals (50 underwent a vaginal delivery, 3 revoked consent, and 2 underwent a hysterectomy). There were 380 randomized to the HA-CMC adhesion barrier treatment group and 373 to the no-treatment group. Enrollment was discontinued before the target sample of 900 was reached due to lack of additional funding. However, the target of 130 subsequent cesarean deliveries was exceeded (N = 172), which satisfied the intent of the original sample size calculation. The recruitment flow diagram is shown in Figure 1 . There were no deviations between randomization and actual intervention received. There were no differences in patient demographics or preoperative characteristics at the time of randomization ( Table 2 ).
| Patient characteristics | HA-CMC, N = 380 | No treatment, N = 373 |
|---|---|---|
| Maternal age, y a | 30.4 ± 5.1 | 30.9 ± 5.3 |
| Gravidity b | 2 (1–20) | 2 (1–11) |
| Parity b | 1 (0–4) | 1 (0–4) |
| Race/ethnicity, % (n) | ||
| Caucasian | 68.2 (259) | 70.6 (264) |
| African American | 10.3 (39) | 10.2 (38) |
| Asian | 3.7 (14) | 4.8 (18) |
| Latino | 15.2 (59) | 11.5 (43) |
| Other race/ethnicity | 2.4 (9) | 2.7 (10) |
| Gestational age, wk a | 38.7 ± 1.9 | 38.7 ± 3.9 |
| Body mass index, kg/m 2 a | 33.3 ± 6.6 | 33.2 ± 7.8 |
| No. of previous cesareans b | 1 (0–3) | 1 (0–3) |
| Indication for cesarean, % (n) | ||
| Planned repeat cesarean | 70.0 (266) | 67.0 (250) |
| Nonreassuring fetal heart rate | 2.6 (10) | 3.0 (11) |
| Arrest of labor | 5.5 (21) | 3.2 (12) |
| Failed induction | 1.8 (7) | 3.2 (12) |
| Previous uterine surgery | 1.8 (7) | 2.4 (9) |
| Malpresentation | 14.2 (54) | 13.9 (52) |
| Abnormal placentation | 1.3 (5) | 2.7 (10) |
| Multiple gestation | 4.5 (17) | 6.7 (25) |
| Maternal infection | 0.8 (3) | 1.3 (5) |
| Diabetes [any], % of arm (n) | 9.8 (37) | 11.8 (44) |
| Type I | 0.8 (3) | 0.5 (2) |
| Type II | 1.0 (4) | 0.5 (2) |
| Gestational diabetes, A1 | 4.5 (17) | 4.8 (18) |
| Gestational diabetes, A2 | 3.4 (13) | 5.6 (21) |
| Preoperative hematocrit a | 34.8 ± 4.3 | 34.4 ± 5.0 |
| Preoperative WBC count a | 10.3 ± 3.4 | 10.7 ± 4.6 |
| Preoperative T max , °F a | 97.8 ± 1.0 | 97.9 ± 0.9 |
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