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Timing of cerclage removal after preterm premature rupture of membranes: Maternal and neonatal outcomes
Timing of cerclage removal after preterm premature rupture of membranes: Maternal and neonatal outcomes Thomas M. Jenkins, MD,a Vincenzo Berghella, MD,a Philip A. Shlossman, MD,b Catherine J. McIntyre, MD,a Bridget D. Maas, BSN,b Marjorie A. Pollock, MSN,b and Ronald J. Wapner, MDa Philadelphia, Pennsylvania, and Newark, Delaware OBJECTIVE: Our aim was to evaluate immediate versus delayed removal of cerclage for women with preterm premature rupture of membranes with respect to maternal and neonatal outcomes. STUDY DESIGN: We retrospectively analyzed women with preterm premature rupture of membranes at <34 weeks’ gestation with prior cerclage placement. Exclusion criteria included presentation with chorioamnionitis, active labor, or nonreassuring fetal status. Timing of cerclage removal, immediate (<24 hours) or delayed (>24 hours), was compared. RESULTS: There were 25 women in the delayed-removal group and 37 in the immediate-removal group. Average times to removal were 206.8 ± 7.4 and 5.4 ± 0.2 hours, respectively. Use of betamethasone was similar for both groups; however, antenatal antibiotic use (100% vs 80%; P = .03) and short-term tocolytic use (20% vs 3%; P = .04) were higher in the delayed-removal group. Duration of latency was significantly longer with delayed removal (10.1 vs 5.0 days; P < .001). Delivery occurred >48 hours from preterm premature rupture of membranes in 96% (24/25) versus 54% (20/37; P < .001) and >7 days from rupture in 56% (14/25) versus 24% (9/37; P = .02), respectively. Rates of neonatal sepsis (at <10 days) and maternal infection were not statistically different. Neonatal outcomes did not significantly differ regarding mortality, respiratory distress syndrome, birth weight, or duration of stay in the intensive care nursery. CONCLUSION: With the current management scheme for preterm premature rupture of membranes, cerclage retention significantly increases duration of latency without significantly altering maternal or neonatal outcomes. (Am J Obstet Gynecol 2000;183:847-52.)
Key words: Preterm premature rupture of membranes, cervical cerclage, pregnancy outcome
The optimal management of patients with a cervical cerclage and preterm premature ruptured membranes is controversial. The clinician must assess the risks of cerclage removal at the time of admission, balancing the risk of premature delivery versus the risk of sepsis. Prior studies have resulted in the conclusion that latency can be prolonged with cerclage retention but may be associated with higher rates of maternal and neonatal sepsis.1, 2 A fundamental change occurred in the management of preterm premature rupture of membranes subsequent to these studies. The use of antibiotics during the antepartum period has been associated with prolongation of latency, lower rates of maternal infection, and im-
From the Divisions of Maternal-Fetal Medicine, Jefferson Medical College of Thomas Jefferson University,a and Christiana Care Health Services, Christiana Hospital.b Presented at the Twentieth Annual Meeting of the Society for MaternalFetal Medicine, Miami Beach, Florida, January 31–February 5, 2000. Reprint requests: Thomas M. Jenkins, MD, Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine, Jefferson Medical College of Thomas Jefferson University, 834 Chestnut St, Rm 400, Philadelphia, PA 19107-5083. Copyright © 2000 by Mosby, Inc. 0002-9378/2000 $12.00 + 0 6/6/109039 doi:10.1067/mob.2000.109039
proved neonatal morbidity and mortality rates.3 Currently, the antepartum use of antibiotics is the standard of care in the management of preterm premature rupture of membranes,4 but the optimal timing of cerclage removal with concomitant use of antibiotics is not known. No studies to date have been published to help guide management in this situation. We performed this study to assess rates of maternal and neonatal morbidity with either immediate (<24 hours) or delayed (>24 hours) cerclage removal in patients with premature rupture of membranes. Material and methods A retrospective chart review was performed for patients who were seen between March 1990 and October 1999 with preterm premature rupture of membranes between 18 and 34 weeks’ gestation and who had prior cerclage placement at Thomas Jefferson University Hospital, Philadelphia, Pennsylvania, and Christiana Hospital, Newark, Delaware. This 10-year time frame was chosen in an attempt to provide sufficient numbers but also maintain relatively constant practice patterns. The study was approved by the separate institutions’ review boards before review. 847
848 Jenkins et al
The timing of cerclage removal, immediate (<24 hours) or delayed (>24 hours), was based on physician preference. Practice protocols for physician groups were dichotomous, with some routinely performing early cerclage removal and others delayed removal. Patterns of practice regarding cerclage removal were not individualized within each group. These practice approaches limited possible biases for management based on suspicion of infection and provided the opportunity to have 2 distinct groups of patients for comparison. Most of the immediate-removal group was from one institution (35/37) and the delayed-removal group was from the other institution (19/25); however, the intensive care nurseries at both institutions had similar treatment patterns once delivery occurred. If immediate removal was chosen, the cerclage was removed at the time of presentation. If delayed removal was chosen, the cerclage was not removed until the patient had signs of chorioamnionitis, nonreassuring results on fetal testing (nonstress test or biophysical profile), documented fetal lung maturity, or active labor. Exclusion criteria included clinical chorioamnionitis (maternal temperature >100.4°F, uterine tenderness, or fetal tachycardia), active labor, or nonreassuring fetal status at presentation. Patients with preterm premature rupture of membranes at <24 weeks’ gestation who elected termination of pregnancy were also excluded. Patients were managed by the respective maternal-fetal medicine teams at each institution and were evaluated daily for signs of chorioamnionitis, labor, and fetal wellbeing, with delivery ensuing if mandated by their condition. Amniocentesis was not performed routinely, and no patient was managed in an outpatient setting. Outcomes of immediate or delayed cerclage removal were compared with respect to neonatal and maternal outcomes. The primary outcome was the rate of neonatal sepsis (positive blood culture result <10 days after delivery). Secondary outcomes included rates of maternal infection (chorioamnionitis or endometritis), duration of latency, birth weight, either neonatal morbidity or death, or both, delivery >48 hours, and >7 days from presentation. Rates of antibiotic and betamethasone use were also collected. Two primary antibiotic regimens were used in the management of these patients. One used a combination of intravenously administered ampicillin and erythromycin for the first 48 hours, followed by orally administered amoxicillin and erythromycin for an additional 5 days. The other regimen used intravenously administered ampicillin-sulbactam for 48 hours, followed by orally administered amoxicillin-clavulanate for 5 days. Both regimens were described in prior trials and appear to be effective.5, 6 The betamethasone regimen was 12 mg given intramuscularly in 2 doses 12-24 hours apart (dosing frequency was based on assumption of delivery within
October 2000 Am J Obstet Gynecol
the next 12-24 hours). In 1994 the recommendation for betamethasone use with preterm premature rupture of membranes changed to use at <32 weeks’ gestation.7 Previously, corticosteroids were not given to all patients, and care was based on individual practitioner preference. Patients with rupture before 24 weeks’ gestation who did not elect termination of pregnancy were included in the maternal data; however, if they were delivered before 24 weeks, the fetus was considered previable and was not included in the neonatal outcome data. All neonates received prophylactic antibiotics for 48 to 72 hours after delivery. Neonatal sepsis rates (positive blood culture results) were collected for the entire nursery stay but were calculated only if sepsis occurred within the first 10 days of life. Respiratory distress syndrome (RDS) rates were also collected. Criteria for RDS included either clinical or radiographic criteria, or both, including grunting respirations, retractions, nasal flaring, cyanosis, increased oxygen requirement, or x-ray features including air bronchograms.8 The Student t test, χ2 test, and Fisher exact test were performed where appropriate. A P value < .05 was considered significant. Results Seventy-nine women with clinically proven rupture of membranes and a cerclage in place were identified. Seventeen were excluded on presentation with either spontaneous labor (n = 6), chorioamnionitis (n = 1), nonreassuring fetal status (n = 1), or a desire to have labor induced after counseling if rupture of membranes occurred before 24 weeks’ gestation (n = 9). Fig 1 provides a flow diagram of the included and excluded patients. For the excluded women, 6 were admitted in labor; 4 of them were delivered at <24 weeks’ gestation, and the fetus died because of extreme prematurity. One woman was in labor at presentation at 24 weeks and was delivered. Neither the mother nor the infant had signs of sepsis, but the neonate died after 15 days because of prematurity. The other woman was delivered at 30 weeks’ gestation; there was no evidence of maternal or fetal infection, and the neonate survived without complication. One woman initially had triplets and rupture of the membranes occurred at 21 weeks with delivery of fetus A. She was managed expectantly but had chorioamnionitis at 24.0 weeks and was delivered of the other 2 fetuses, both of whom had sepsis but survived after nursery stays of 96 and 189 days. One patient was first seen with preterm premature rupture of membranes at 32 weeks and a nonreassuring fetal heart tracing. Cesarean delivery was performed because of presumed abruptio placentae. Both the mother and neonate did well and did not show signs of sepsis. Nine women, all of whom had ruptured membranes before 24 weeks’ gestation, decided to have labor induced after counseling.
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Fig 1. Patient flow diagram.
Table I. Demographics and risk factors Immediate removal (n = 37) Delayed removal (n = 25) Statistical significance Age (y, mean ± SD) Nulliparous (No.) Race (No.) White African American Asian Private patients (No.) Risk factors for preterm delivery Exposure to diethylstilbestrol Prior cone Preterm delivery at 24-36 wk Müllerian anomaly Preterm delivery at 14-24 wk Gestational age at cerclage placement (wk, mean ± SD) Salvage cerclage (No.) Prophylactic cerclage (No.)
29.7 ± 5.5 16 (43%)
30.8 ± 6.5 09 (36%)
NS NS
16 (43%) 21 (57%) 0 (0%) 25 (68%)
12 (48%) 11 (44%) 2 (8%) 19 (76%)
NS NS NS NS
3 4 14 2 19 16.6 ± 4.2 21 (57%) 17 (43%)
2 2 9 0 8 17.3 ± 3.9 12 (48%) 13 (52%)
NS NS NS NS NS NS NS NS
NS, Not significant.
A total of 62 women were left for the analysis, 37 in the early-removal group and 25 in the delayed-removal group. Table I presents demographic data on the 2 groups. There were no differences in age, parity, ethnicity, or percentage of private patients in either group. Risk factors for preterm delivery did not differ between the 2 groups. The McDonald cerclage was the predominant type of cerclage for either prophylactic or salvage
cerclage; it was used in 58 (94%) of 62 women. The Shirodkar cerclage was placed in the other 4 women. The shortest interval from placement to rupture was 12 days (range, 12 days–22 weeks). Average time from placement to rupture was 11.4 weeks for the immediate-removal group and 10.4 weeks for the delayed-removal group. Table II displays data regarding antepartum management, latency, and mode of delivery. The groups differed
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Table II. Antepartum management, latency, and mode of delivery Immediate removal (n = 37)
Delayed removal (n = 25)
Statistical significance
05.4 ± 0.2 28.0 ± 4.2 30 (81%) 24 (65%) 1 (3%) 119.1 ± 9.7* 20 (54%) 09 (24%) 24 (65%)
206.8 ± 7.40 27.7 ± 3.3 025 (100%) 20 (80%) 05 (20%) 243.5 ± 7.1† 24 (96%) 14 (56%) 15 (60%)
P = .55 P = .03 P = .36 P = .04 P < .001 P < .001 P = .02 P = .81
Time to removal (h, mean ± SD) Gestational age at rupture (wk, mean ± SD) Antibiotic use (No.) Betamethasone use (No.) Tocolytic use (No.) Latency duration (h, mean ± SD) Delivery at >48 h (No.) Delivery at >7 d (No.) Vaginal delivery (No.) *Mean, 5.0 days. †Mean, 10.1 days.
Table III. Characteristics of infection and neonatal outcomes Immediate removal (n = 37) Delayed removal (n = 25) Statistical significance Maternal infection (chorioamnionitis, endometritis) (No.) Neonatal outcomes Sepsis <10 d (No.) Gestational age at delivery (wk, mean ± SD) Mortality rate (No.) Birth weight (g, mean ± SD) RDS (No.) Duration of stay in intensive care nursery (d, mean ± SD)
8 (22%)
11 (44%)
P = .15*
2 (5.4%) 28.8 ± 3.9 04 (10.8%) 1506 ± 662 29 (78%)0 046.2 ± 37.6
04 (16%) 29.1 ± 3.4 1 (4%) 1646 ± 481 21 (84%) 042.8 ± 40.0
P = .29 P = .90 P = .64 P = .82 P = .45 P = .70
*Odds ratio, 2.8 (95% confidence interval, 0.93-8.7).
statistically for antibiotic use; however, the majority of patients in each group received antibiotics. Short-term tocolytic use for betamethasone therapy was also higher in the delayed-removal group but accounted for only 5 of these patients. Duration of latency was statistically different between the 2 groups, with the delayed-removal group gaining >5 additional days on average (Table II). The number of patients who underwent delivery within the first 48 hours also differed, with delivery in 46% (17/37) of the immediate-removal group versus 4% (1/25) in the delayedremoval group. The number of fetuses delivered <7 days after rupture was statistically different, with 76% of the immediate-removal group being delivered versus 44%. Characteristics of infection and neonatal outcome data are presented in Table III. More maternal infections occurred in the delayed-removal group but did not reach a statistical difference. None of the women in either group had serious infectious morbidity. More neonatal infections occurred in the delayed-removal group but did not result in prolonged nursery stays. In fact, an increase in the mortality rate was seen in the immediate-removal group, but this analysis was limited by the small numbers. Neonatal death and sepsis occurred only in patients with rupture before 28 weeks’ gestation; therefore a subanalysis was performed for these women. There were no differences between the 2 groups in any demographic variable, rates of salvage versus prophylactic cerclage, or risk factors for preterm delivery (data not shown).
Table IV presents the data on antepartum management, latency, and mode of delivery for this subgroup. Duration of latency differed statistically between the groups, with the delayed-removal group gaining 11.5 days on average. Thirty-three percent of the infants in the immediateremoval group were delivered before 48 hours, compared with none in the delayed-removal group. Sixty-four percent of the delayed-removal group gained a week or more. Table V displays the characteristics of infection in the subgroup. All neonatal deaths and neonatal sepsis occurred in this early group with preterm premature rupture of membranes. The incidence of infectious morbidity was higher in the delayed-removal group but not statistically significant. This difference was not associated with higher rates of death or prolonged nursery stays in those infants. The birth weights in the delayed-removal group were significantly higher than those in the earlyremoval group. Comment The use of cerclage either to prevent pregnancy loss or to prolong gestation is a fairly common event, and preterm premature rupture of membranes after a cerclage has been placed occurs frequently. Treadwell et al9 reported a 38% rate of preterm premature rupture of membranes in a series of 482 singleton pregnancies with a cerclage. Despite this association, few data exist to guide management.
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Table IV. Antepartum and delivery characteristics at <28 weeks’ gestation at preterm premature rupture of membranes Immediate removal (n = 18)
Delayed removal (n = 14)
Statistical significance
5.3 ± 0.3 24.5 ± 2.00 17 (94%) 11 (61%) 0 (0%) 170.8 ± 14.5* 12 (67%) 04 (22%) 11 (61%)
217.1 ± 8.60 25.1 ± 1.5 14 (100%) 11 (79%)0 2 (14%) 274.9 ± 8.0† 14 (100%) 9 (64%) 7 (50%)
P = .35 P = .99 P = .45 P = .18 P < .001 P = .2 P = .03 P = .72
Time to removal (h, mean ± SD) Gestational age at rupture (wk, mean ± SD) Antibiotic use (No.) Betamethasone use (No.) Tocolytic use (No.) Duration of latency (h, mean ± SD) Delivery at >48 h (No.) Delivery at >7 d (No.) Vaginal delivery (No.) *Mean, 7.1 days. †Mean, 11.5 days.
Table V. Infectious characteristics at preterm premature rupture of membranes <28 weeks’ gestation Immediate removal (n = 18) Delayed removal (n = 14) Statistical significance Maternal infections (chorioamnionitis, endometritis) (No.) Neonatal outcomes Sepsis <10 (d, No.) Gestational age at delivery (wk, mean ± SD) Mortality rate (No.) Birth weight (g, mean ± SD) RDS (No.) Duration of stay in intensive care nursery (d, mean ± SD)
06 (33%)
09 (64%)
P = .15*
02 (11%) 25.7 ± 1.20 04 (22%) 758 ± 212 17 (94%) 71.4 ± 42.6
04 (29%) 26.8 ± 2.20 1 (7%) 942 ± 261 13 (93%) 61.3 ± 43.6
P = .37 P = .09 P = .36 P = .04 P = 1.00 P = .51
*Odds ratio, 3.6 (95% confidence interval, 0.83-15.6).
In 1977, Kuhn and Pepperell1 published an extensive observational series on cerclage use and pregnancy outcome. In their analysis 71 patients with cerclage (29%) had preterm premature rupture of membranes. Labor was induced on arrival in 2 of these patients, so that 69 patients were left for expectant management. Of these 69 patients, 31 had the cerclage left in place. No antepartum antibiotics were used. Pregnancies in which the stitch remained in place had a longer latency (8.4 vs 2.5 days) but also had significantly higher rates of sepsis (38% vs 17% after 28 weeks, and 75% vs 31% before 28 weeks). After the association of retained cerclage with infectious morbidity was reported, 2 studies were performed to analyze women with immediate removal of cerclage and preterm premature rupture of membranes, in comparison with women without cerclage.10, 11 Both of these studies reported that immediate cerclage removal led to rates of infection and neonatal outcomes similar to those observed when preterm premature rupture of membranes occurred without prior cerclage. Ludmir et al2 published the only series on preterm premature rupture of membranes and cerclage that addressed the timing of stitch removal. They assessed 30 women who had a cerclage placed between 12 and 21 weeks’ gestation and had preterm premature rupture of membranes. After counseling, the women were allowed to choose whether the stitch was to be removed. Twenty women elected to have the cerclage removed immediately, and 10 women opted for cerclage retention. The
study of Ludmir et al2 was performed before the use of betamethasone with preterm premature rupture of membranes, and only 1 woman (in the retained-cerclage group) received antibiotics (ampicillin). The authors found a significantly higher percentage of women remaining pregnant after 48 hours with cerclage retention (90% vs 50%). However, the delayed-removal group had much higher rates of neonatal mortality (70% vs 10%), with 71% of the deaths attributed to sepsis. A recommendation for immediate cerclage removal with preterm premature rupture of membranes was made because of the risk of sepsis and associated death with cerclage retention. Since Ludmir et al2 reported their study, the use of antibiotics for women with preterm premature rupture of membranes has been examined in multiple trials. Mercer and Arheart3 recently performed a meta-analysis of 13 randomized, controlled studies using systemic antibiotics in nonlaboring women with preterm premature rupture of membranes. They reported antibiotic use to be associated with a decrease in the number of women delivered within 1 week after preterm premature rupture of membranes, reduced maternal morbidity including chorioamnionitis and postpartum infection, and decreased fetal morbidity including sepsis, pneumonia, and intraventricular hemorrhage. In our study we attempted to assess whether the concomitant use of broad-spectrum antibiotics could diminish infectious morbidity and safely prolong gestation when a cerclage is left in place. Of the
852 Jenkins et al
62 women in our study, 57 received antibiotics as part of their antepartum management. Our study corroborates the findings of Kuhn and Pepperell1 and of Ludmir et al2 regarding prolonged latency with cerclage retention. In fact, many studies have shown that the immediate removal of cerclage with preterm premature rupture of membranes results in delivery in 50% to 65% of patients within the first 48 hours.2, 9-11 Whether this occurrence is caused by a physical disruption of the cervix that leads to bacterial invasion or results from prostaglandin release after suture removal is not specifically known. However, in the other studies the prolonged latency period did not result in improved neonatal outcomes. Our data show that the concomitant use of broad-spectrum antibiotics with cerclage retention did significantly prolong latency whereas it did not significantly alter neonatal morbidity and mortality rates. We also noted a significant increase in neonatal weights with delayed removal of the stitch in the group with rupture at <28 weeks’ gestation. One alteration that we did not see was an improvement in the condition of infants with RDS after a prolonged latency period. Because of the small number of patients and the criteria used to diagnose RDS, this lack of improvement is not surprising. Of our entire sample, 83% of neonates weighed <2000 g at delivery; the occurrence of RDS is high in infants in this weight category.8 Conclusive statements regarding overall safety to mother or fetus are impossible to make with the numbers of our study. Our study is underpowered, and the results could represent a type II error; however, the large incidence of infectious morbidity seen in prior studies1, 2 was not seen in our series. Our study has limitations such as the relatively small numbers and the retrospective evaluation. The use of 2 groups with different management paradigms allowed us to make our comparison; however, bias can still be introduced. A randomized prospective study is needed and would ideally include long-term follow-up of the neonates. We estimate that this study would require 318 patients (159 per group) to obtain 80% power with α = .05. In the interim we believe that delaying cerclage removal at least 48 hours in an attempt to lengthen the latency period appears to be a safe practice if antibiotic
October 2000 Am J Obstet Gynecol
prophylaxis is used. Patients should be free of signs of infection and labor and have reassuring fetal test results. The decision regarding retention of the cerclage after 48 hours should be individualized, with the infectious risk being weighed against the chances of gaining a week or more of latency. For earlier gestations, in which prolonged latency could result in improved neonatal outcomes, there may be a benefit of retaining the cerclage and modifying the latency period. For gestations after 32 weeks, in which long-term neonatal morbidity is a rare event and corticosteroid therapy is not fully recommended,7 the trend toward higher rates of infection may outweigh the benefit of prolonged latency. Clinical judgment and suspicion of infection will affect these management decisions. REFERENCES
1. Kuhn RJP, Pepperell RJ. Cervical ligation: a review of 242 pregnancies. Aust N Z J Obstet Gynaecol 1977;17:79-83. 2. Ludmir J, Bader T, Chen L, Lindenbaum C, Wong G. Poor perinatal outcome associated with retained cerclage in patients with premature rupture of membranes. Obstet Gynecol 1994;84:823-6. 3. Mercer BM, Arheart K. Antimicrobial therapy in expectant management of preterm premature ruture of the membranes. Lancet 1995;346:1271-9. 4. American College of Obstetricians and Gynecologists. Premature rupture of membranes. Washington: The College; 1998 Jun. ACOG Practice Bulletin No.: 1. 5. Mercer BM, Miodovnik M, Thurnau GR, Goldenberg RL, Das AF, Ramsey RD, et al. Antibiotic therapy for reduction of infant morbidity after preterm premature rupture of the membranes: a randomized controlled trial. JAMA 1997;278:989-95. 6. Lovett SM, Weiss JD, Diogo MJ, Williams PT, Garite TJ. A prospective double-blind, randomized, controlled clinical trial of ampicillin-sulbactam for preterm premature rupture of membranes in women receiving antenatal corticosteroid therapy. Am J Obstet Gynecol 1997;176:1030-8. 7. Effect of corticosteroids for fetal maturation on perinatal outcomes, February 28–March 2, 1994. National Institutes of Health Consensus Development Conference Statement. Am J Obstet Gynecol 1995;173:246-52. 8. Martin RJ, Fanaroff AA. The respiratory distress syndrome and its management. In: Fanaroff AA, Martin RJ, editors. Volume 2: neonatal-perinatal medicine: diseases of the fetus and infant. 6th ed. St Louis: Mosby; 1997. p. 1018-28. 9. Treadwell MC, Bronsteen RA, Bottoms SF. Prognostic factors and complication rates for cervical cerclage: a review of 482 cases. Am J Obstet Gynecol 1991;165:555-8. 10. Yeast JD, Garite TR. The role of cervical cerclage in the management of preterm premature rupture of the membranes. Am J Obstet Gynecol 1988;158:106-10. 11. Blickstein I, Katz Z, Lancet M, Molgilner BM. The outcome of pregnancies complicated by preterm rupture of the membranes with and without cerclage. Int J Gynecol Obstet 1989;28:237-42.
Key words: Preterm premature rupture of membranes, cervical cerclage, pregnancy outcome
The optimal management of patients with a cervical cerclage and preterm premature ruptured membranes is controversial. The clinician must assess the risks of cerclage removal at the time of admission, balancing the risk of premature delivery versus the risk of sepsis. Prior studies have resulted in the conclusion that latency can be prolonged with cerclage retention but may be associated with higher rates of maternal and neonatal sepsis.1, 2 A fundamental change occurred in the management of preterm premature rupture of membranes subsequent to these studies. The use of antibiotics during the antepartum period has been associated with prolongation of latency, lower rates of maternal infection, and im-
From the Divisions of Maternal-Fetal Medicine, Jefferson Medical College of Thomas Jefferson University,a and Christiana Care Health Services, Christiana Hospital.b Presented at the Twentieth Annual Meeting of the Society for MaternalFetal Medicine, Miami Beach, Florida, January 31–February 5, 2000. Reprint requests: Thomas M. Jenkins, MD, Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine, Jefferson Medical College of Thomas Jefferson University, 834 Chestnut St, Rm 400, Philadelphia, PA 19107-5083. Copyright © 2000 by Mosby, Inc. 0002-9378/2000 $12.00 + 0 6/6/109039 doi:10.1067/mob.2000.109039
proved neonatal morbidity and mortality rates.3 Currently, the antepartum use of antibiotics is the standard of care in the management of preterm premature rupture of membranes,4 but the optimal timing of cerclage removal with concomitant use of antibiotics is not known. No studies to date have been published to help guide management in this situation. We performed this study to assess rates of maternal and neonatal morbidity with either immediate (<24 hours) or delayed (>24 hours) cerclage removal in patients with premature rupture of membranes. Material and methods A retrospective chart review was performed for patients who were seen between March 1990 and October 1999 with preterm premature rupture of membranes between 18 and 34 weeks’ gestation and who had prior cerclage placement at Thomas Jefferson University Hospital, Philadelphia, Pennsylvania, and Christiana Hospital, Newark, Delaware. This 10-year time frame was chosen in an attempt to provide sufficient numbers but also maintain relatively constant practice patterns. The study was approved by the separate institutions’ review boards before review. 847
848 Jenkins et al
The timing of cerclage removal, immediate (<24 hours) or delayed (>24 hours), was based on physician preference. Practice protocols for physician groups were dichotomous, with some routinely performing early cerclage removal and others delayed removal. Patterns of practice regarding cerclage removal were not individualized within each group. These practice approaches limited possible biases for management based on suspicion of infection and provided the opportunity to have 2 distinct groups of patients for comparison. Most of the immediate-removal group was from one institution (35/37) and the delayed-removal group was from the other institution (19/25); however, the intensive care nurseries at both institutions had similar treatment patterns once delivery occurred. If immediate removal was chosen, the cerclage was removed at the time of presentation. If delayed removal was chosen, the cerclage was not removed until the patient had signs of chorioamnionitis, nonreassuring results on fetal testing (nonstress test or biophysical profile), documented fetal lung maturity, or active labor. Exclusion criteria included clinical chorioamnionitis (maternal temperature >100.4°F, uterine tenderness, or fetal tachycardia), active labor, or nonreassuring fetal status at presentation. Patients with preterm premature rupture of membranes at <24 weeks’ gestation who elected termination of pregnancy were also excluded. Patients were managed by the respective maternal-fetal medicine teams at each institution and were evaluated daily for signs of chorioamnionitis, labor, and fetal wellbeing, with delivery ensuing if mandated by their condition. Amniocentesis was not performed routinely, and no patient was managed in an outpatient setting. Outcomes of immediate or delayed cerclage removal were compared with respect to neonatal and maternal outcomes. The primary outcome was the rate of neonatal sepsis (positive blood culture result <10 days after delivery). Secondary outcomes included rates of maternal infection (chorioamnionitis or endometritis), duration of latency, birth weight, either neonatal morbidity or death, or both, delivery >48 hours, and >7 days from presentation. Rates of antibiotic and betamethasone use were also collected. Two primary antibiotic regimens were used in the management of these patients. One used a combination of intravenously administered ampicillin and erythromycin for the first 48 hours, followed by orally administered amoxicillin and erythromycin for an additional 5 days. The other regimen used intravenously administered ampicillin-sulbactam for 48 hours, followed by orally administered amoxicillin-clavulanate for 5 days. Both regimens were described in prior trials and appear to be effective.5, 6 The betamethasone regimen was 12 mg given intramuscularly in 2 doses 12-24 hours apart (dosing frequency was based on assumption of delivery within
October 2000 Am J Obstet Gynecol
the next 12-24 hours). In 1994 the recommendation for betamethasone use with preterm premature rupture of membranes changed to use at <32 weeks’ gestation.7 Previously, corticosteroids were not given to all patients, and care was based on individual practitioner preference. Patients with rupture before 24 weeks’ gestation who did not elect termination of pregnancy were included in the maternal data; however, if they were delivered before 24 weeks, the fetus was considered previable and was not included in the neonatal outcome data. All neonates received prophylactic antibiotics for 48 to 72 hours after delivery. Neonatal sepsis rates (positive blood culture results) were collected for the entire nursery stay but were calculated only if sepsis occurred within the first 10 days of life. Respiratory distress syndrome (RDS) rates were also collected. Criteria for RDS included either clinical or radiographic criteria, or both, including grunting respirations, retractions, nasal flaring, cyanosis, increased oxygen requirement, or x-ray features including air bronchograms.8 The Student t test, χ2 test, and Fisher exact test were performed where appropriate. A P value < .05 was considered significant. Results Seventy-nine women with clinically proven rupture of membranes and a cerclage in place were identified. Seventeen were excluded on presentation with either spontaneous labor (n = 6), chorioamnionitis (n = 1), nonreassuring fetal status (n = 1), or a desire to have labor induced after counseling if rupture of membranes occurred before 24 weeks’ gestation (n = 9). Fig 1 provides a flow diagram of the included and excluded patients. For the excluded women, 6 were admitted in labor; 4 of them were delivered at <24 weeks’ gestation, and the fetus died because of extreme prematurity. One woman was in labor at presentation at 24 weeks and was delivered. Neither the mother nor the infant had signs of sepsis, but the neonate died after 15 days because of prematurity. The other woman was delivered at 30 weeks’ gestation; there was no evidence of maternal or fetal infection, and the neonate survived without complication. One woman initially had triplets and rupture of the membranes occurred at 21 weeks with delivery of fetus A. She was managed expectantly but had chorioamnionitis at 24.0 weeks and was delivered of the other 2 fetuses, both of whom had sepsis but survived after nursery stays of 96 and 189 days. One patient was first seen with preterm premature rupture of membranes at 32 weeks and a nonreassuring fetal heart tracing. Cesarean delivery was performed because of presumed abruptio placentae. Both the mother and neonate did well and did not show signs of sepsis. Nine women, all of whom had ruptured membranes before 24 weeks’ gestation, decided to have labor induced after counseling.
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Fig 1. Patient flow diagram.
Table I. Demographics and risk factors Immediate removal (n = 37) Delayed removal (n = 25) Statistical significance Age (y, mean ± SD) Nulliparous (No.) Race (No.) White African American Asian Private patients (No.) Risk factors for preterm delivery Exposure to diethylstilbestrol Prior cone Preterm delivery at 24-36 wk Müllerian anomaly Preterm delivery at 14-24 wk Gestational age at cerclage placement (wk, mean ± SD) Salvage cerclage (No.) Prophylactic cerclage (No.)
29.7 ± 5.5 16 (43%)
30.8 ± 6.5 09 (36%)
NS NS
16 (43%) 21 (57%) 0 (0%) 25 (68%)
12 (48%) 11 (44%) 2 (8%) 19 (76%)
NS NS NS NS
3 4 14 2 19 16.6 ± 4.2 21 (57%) 17 (43%)
2 2 9 0 8 17.3 ± 3.9 12 (48%) 13 (52%)
NS NS NS NS NS NS NS NS
NS, Not significant.
A total of 62 women were left for the analysis, 37 in the early-removal group and 25 in the delayed-removal group. Table I presents demographic data on the 2 groups. There were no differences in age, parity, ethnicity, or percentage of private patients in either group. Risk factors for preterm delivery did not differ between the 2 groups. The McDonald cerclage was the predominant type of cerclage for either prophylactic or salvage
cerclage; it was used in 58 (94%) of 62 women. The Shirodkar cerclage was placed in the other 4 women. The shortest interval from placement to rupture was 12 days (range, 12 days–22 weeks). Average time from placement to rupture was 11.4 weeks for the immediate-removal group and 10.4 weeks for the delayed-removal group. Table II displays data regarding antepartum management, latency, and mode of delivery. The groups differed
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Table II. Antepartum management, latency, and mode of delivery Immediate removal (n = 37)
Delayed removal (n = 25)
Statistical significance
05.4 ± 0.2 28.0 ± 4.2 30 (81%) 24 (65%) 1 (3%) 119.1 ± 9.7* 20 (54%) 09 (24%) 24 (65%)
206.8 ± 7.40 27.7 ± 3.3 025 (100%) 20 (80%) 05 (20%) 243.5 ± 7.1† 24 (96%) 14 (56%) 15 (60%)
P = .55 P = .03 P = .36 P = .04 P < .001 P < .001 P = .02 P = .81
Time to removal (h, mean ± SD) Gestational age at rupture (wk, mean ± SD) Antibiotic use (No.) Betamethasone use (No.) Tocolytic use (No.) Latency duration (h, mean ± SD) Delivery at >48 h (No.) Delivery at >7 d (No.) Vaginal delivery (No.) *Mean, 5.0 days. †Mean, 10.1 days.
Table III. Characteristics of infection and neonatal outcomes Immediate removal (n = 37) Delayed removal (n = 25) Statistical significance Maternal infection (chorioamnionitis, endometritis) (No.) Neonatal outcomes Sepsis <10 d (No.) Gestational age at delivery (wk, mean ± SD) Mortality rate (No.) Birth weight (g, mean ± SD) RDS (No.) Duration of stay in intensive care nursery (d, mean ± SD)
8 (22%)
11 (44%)
P = .15*
2 (5.4%) 28.8 ± 3.9 04 (10.8%) 1506 ± 662 29 (78%)0 046.2 ± 37.6
04 (16%) 29.1 ± 3.4 1 (4%) 1646 ± 481 21 (84%) 042.8 ± 40.0
P = .29 P = .90 P = .64 P = .82 P = .45 P = .70
*Odds ratio, 2.8 (95% confidence interval, 0.93-8.7).
statistically for antibiotic use; however, the majority of patients in each group received antibiotics. Short-term tocolytic use for betamethasone therapy was also higher in the delayed-removal group but accounted for only 5 of these patients. Duration of latency was statistically different between the 2 groups, with the delayed-removal group gaining >5 additional days on average (Table II). The number of patients who underwent delivery within the first 48 hours also differed, with delivery in 46% (17/37) of the immediate-removal group versus 4% (1/25) in the delayedremoval group. The number of fetuses delivered <7 days after rupture was statistically different, with 76% of the immediate-removal group being delivered versus 44%. Characteristics of infection and neonatal outcome data are presented in Table III. More maternal infections occurred in the delayed-removal group but did not reach a statistical difference. None of the women in either group had serious infectious morbidity. More neonatal infections occurred in the delayed-removal group but did not result in prolonged nursery stays. In fact, an increase in the mortality rate was seen in the immediate-removal group, but this analysis was limited by the small numbers. Neonatal death and sepsis occurred only in patients with rupture before 28 weeks’ gestation; therefore a subanalysis was performed for these women. There were no differences between the 2 groups in any demographic variable, rates of salvage versus prophylactic cerclage, or risk factors for preterm delivery (data not shown).
Table IV presents the data on antepartum management, latency, and mode of delivery for this subgroup. Duration of latency differed statistically between the groups, with the delayed-removal group gaining 11.5 days on average. Thirty-three percent of the infants in the immediateremoval group were delivered before 48 hours, compared with none in the delayed-removal group. Sixty-four percent of the delayed-removal group gained a week or more. Table V displays the characteristics of infection in the subgroup. All neonatal deaths and neonatal sepsis occurred in this early group with preterm premature rupture of membranes. The incidence of infectious morbidity was higher in the delayed-removal group but not statistically significant. This difference was not associated with higher rates of death or prolonged nursery stays in those infants. The birth weights in the delayed-removal group were significantly higher than those in the earlyremoval group. Comment The use of cerclage either to prevent pregnancy loss or to prolong gestation is a fairly common event, and preterm premature rupture of membranes after a cerclage has been placed occurs frequently. Treadwell et al9 reported a 38% rate of preterm premature rupture of membranes in a series of 482 singleton pregnancies with a cerclage. Despite this association, few data exist to guide management.
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Table IV. Antepartum and delivery characteristics at <28 weeks’ gestation at preterm premature rupture of membranes Immediate removal (n = 18)
Delayed removal (n = 14)
Statistical significance
5.3 ± 0.3 24.5 ± 2.00 17 (94%) 11 (61%) 0 (0%) 170.8 ± 14.5* 12 (67%) 04 (22%) 11 (61%)
217.1 ± 8.60 25.1 ± 1.5 14 (100%) 11 (79%)0 2 (14%) 274.9 ± 8.0† 14 (100%) 9 (64%) 7 (50%)
P = .35 P = .99 P = .45 P = .18 P < .001 P = .2 P = .03 P = .72
Time to removal (h, mean ± SD) Gestational age at rupture (wk, mean ± SD) Antibiotic use (No.) Betamethasone use (No.) Tocolytic use (No.) Duration of latency (h, mean ± SD) Delivery at >48 h (No.) Delivery at >7 d (No.) Vaginal delivery (No.) *Mean, 7.1 days. †Mean, 11.5 days.
Table V. Infectious characteristics at preterm premature rupture of membranes <28 weeks’ gestation Immediate removal (n = 18) Delayed removal (n = 14) Statistical significance Maternal infections (chorioamnionitis, endometritis) (No.) Neonatal outcomes Sepsis <10 (d, No.) Gestational age at delivery (wk, mean ± SD) Mortality rate (No.) Birth weight (g, mean ± SD) RDS (No.) Duration of stay in intensive care nursery (d, mean ± SD)
06 (33%)
09 (64%)
P = .15*
02 (11%) 25.7 ± 1.20 04 (22%) 758 ± 212 17 (94%) 71.4 ± 42.6
04 (29%) 26.8 ± 2.20 1 (7%) 942 ± 261 13 (93%) 61.3 ± 43.6
P = .37 P = .09 P = .36 P = .04 P = 1.00 P = .51
*Odds ratio, 3.6 (95% confidence interval, 0.83-15.6).
In 1977, Kuhn and Pepperell1 published an extensive observational series on cerclage use and pregnancy outcome. In their analysis 71 patients with cerclage (29%) had preterm premature rupture of membranes. Labor was induced on arrival in 2 of these patients, so that 69 patients were left for expectant management. Of these 69 patients, 31 had the cerclage left in place. No antepartum antibiotics were used. Pregnancies in which the stitch remained in place had a longer latency (8.4 vs 2.5 days) but also had significantly higher rates of sepsis (38% vs 17% after 28 weeks, and 75% vs 31% before 28 weeks). After the association of retained cerclage with infectious morbidity was reported, 2 studies were performed to analyze women with immediate removal of cerclage and preterm premature rupture of membranes, in comparison with women without cerclage.10, 11 Both of these studies reported that immediate cerclage removal led to rates of infection and neonatal outcomes similar to those observed when preterm premature rupture of membranes occurred without prior cerclage. Ludmir et al2 published the only series on preterm premature rupture of membranes and cerclage that addressed the timing of stitch removal. They assessed 30 women who had a cerclage placed between 12 and 21 weeks’ gestation and had preterm premature rupture of membranes. After counseling, the women were allowed to choose whether the stitch was to be removed. Twenty women elected to have the cerclage removed immediately, and 10 women opted for cerclage retention. The
study of Ludmir et al2 was performed before the use of betamethasone with preterm premature rupture of membranes, and only 1 woman (in the retained-cerclage group) received antibiotics (ampicillin). The authors found a significantly higher percentage of women remaining pregnant after 48 hours with cerclage retention (90% vs 50%). However, the delayed-removal group had much higher rates of neonatal mortality (70% vs 10%), with 71% of the deaths attributed to sepsis. A recommendation for immediate cerclage removal with preterm premature rupture of membranes was made because of the risk of sepsis and associated death with cerclage retention. Since Ludmir et al2 reported their study, the use of antibiotics for women with preterm premature rupture of membranes has been examined in multiple trials. Mercer and Arheart3 recently performed a meta-analysis of 13 randomized, controlled studies using systemic antibiotics in nonlaboring women with preterm premature rupture of membranes. They reported antibiotic use to be associated with a decrease in the number of women delivered within 1 week after preterm premature rupture of membranes, reduced maternal morbidity including chorioamnionitis and postpartum infection, and decreased fetal morbidity including sepsis, pneumonia, and intraventricular hemorrhage. In our study we attempted to assess whether the concomitant use of broad-spectrum antibiotics could diminish infectious morbidity and safely prolong gestation when a cerclage is left in place. Of the
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62 women in our study, 57 received antibiotics as part of their antepartum management. Our study corroborates the findings of Kuhn and Pepperell1 and of Ludmir et al2 regarding prolonged latency with cerclage retention. In fact, many studies have shown that the immediate removal of cerclage with preterm premature rupture of membranes results in delivery in 50% to 65% of patients within the first 48 hours.2, 9-11 Whether this occurrence is caused by a physical disruption of the cervix that leads to bacterial invasion or results from prostaglandin release after suture removal is not specifically known. However, in the other studies the prolonged latency period did not result in improved neonatal outcomes. Our data show that the concomitant use of broad-spectrum antibiotics with cerclage retention did significantly prolong latency whereas it did not significantly alter neonatal morbidity and mortality rates. We also noted a significant increase in neonatal weights with delayed removal of the stitch in the group with rupture at <28 weeks’ gestation. One alteration that we did not see was an improvement in the condition of infants with RDS after a prolonged latency period. Because of the small number of patients and the criteria used to diagnose RDS, this lack of improvement is not surprising. Of our entire sample, 83% of neonates weighed <2000 g at delivery; the occurrence of RDS is high in infants in this weight category.8 Conclusive statements regarding overall safety to mother or fetus are impossible to make with the numbers of our study. Our study is underpowered, and the results could represent a type II error; however, the large incidence of infectious morbidity seen in prior studies1, 2 was not seen in our series. Our study has limitations such as the relatively small numbers and the retrospective evaluation. The use of 2 groups with different management paradigms allowed us to make our comparison; however, bias can still be introduced. A randomized prospective study is needed and would ideally include long-term follow-up of the neonates. We estimate that this study would require 318 patients (159 per group) to obtain 80% power with α = .05. In the interim we believe that delaying cerclage removal at least 48 hours in an attempt to lengthen the latency period appears to be a safe practice if antibiotic
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prophylaxis is used. Patients should be free of signs of infection and labor and have reassuring fetal test results. The decision regarding retention of the cerclage after 48 hours should be individualized, with the infectious risk being weighed against the chances of gaining a week or more of latency. For earlier gestations, in which prolonged latency could result in improved neonatal outcomes, there may be a benefit of retaining the cerclage and modifying the latency period. For gestations after 32 weeks, in which long-term neonatal morbidity is a rare event and corticosteroid therapy is not fully recommended,7 the trend toward higher rates of infection may outweigh the benefit of prolonged latency. Clinical judgment and suspicion of infection will affect these management decisions. REFERENCES
1. Kuhn RJP, Pepperell RJ. Cervical ligation: a review of 242 pregnancies. Aust N Z J Obstet Gynaecol 1977;17:79-83. 2. Ludmir J, Bader T, Chen L, Lindenbaum C, Wong G. Poor perinatal outcome associated with retained cerclage in patients with premature rupture of membranes. Obstet Gynecol 1994;84:823-6. 3. Mercer BM, Arheart K. Antimicrobial therapy in expectant management of preterm premature ruture of the membranes. Lancet 1995;346:1271-9. 4. American College of Obstetricians and Gynecologists. Premature rupture of membranes. Washington: The College; 1998 Jun. ACOG Practice Bulletin No.: 1. 5. Mercer BM, Miodovnik M, Thurnau GR, Goldenberg RL, Das AF, Ramsey RD, et al. Antibiotic therapy for reduction of infant morbidity after preterm premature rupture of the membranes: a randomized controlled trial. JAMA 1997;278:989-95. 6. Lovett SM, Weiss JD, Diogo MJ, Williams PT, Garite TJ. A prospective double-blind, randomized, controlled clinical trial of ampicillin-sulbactam for preterm premature rupture of membranes in women receiving antenatal corticosteroid therapy. Am J Obstet Gynecol 1997;176:1030-8. 7. Effect of corticosteroids for fetal maturation on perinatal outcomes, February 28–March 2, 1994. National Institutes of Health Consensus Development Conference Statement. Am J Obstet Gynecol 1995;173:246-52. 8. Martin RJ, Fanaroff AA. The respiratory distress syndrome and its management. In: Fanaroff AA, Martin RJ, editors. Volume 2: neonatal-perinatal medicine: diseases of the fetus and infant. 6th ed. St Louis: Mosby; 1997. p. 1018-28. 9. Treadwell MC, Bronsteen RA, Bottoms SF. Prognostic factors and complication rates for cervical cerclage: a review of 482 cases. Am J Obstet Gynecol 1991;165:555-8. 10. Yeast JD, Garite TR. The role of cervical cerclage in the management of preterm premature rupture of the membranes. Am J Obstet Gynecol 1988;158:106-10. 11. Blickstein I, Katz Z, Lancet M, Molgilner BM. The outcome of pregnancies complicated by preterm rupture of the membranes with and without cerclage. Int J Gynecol Obstet 1989;28:237-42.