Background
Preterm birth is the leading cause of neonatal death and handicap in survivors. Although twins are found in 1.5% of pregnancies they account for about 25% of preterm births. Randomized controlled trials in singleton pregnancies reported that the prophylactic use of progestogens, cervical cerclage and cervical pessary reduce significantly the rate of early preterm birth. In twin pregnancies, progestogens and cervical cerclage have been shown to be ineffective in reducing preterm birth.
Objective
The objective of this study was to test the hypothesis that the insertion of a cervical pessary in twin pregnancies would reduce the rate of spontaneous early preterm birth.
Study Design
This was a multicenter, randomized controlled trial in unselected twin pregnancies of cervical pessary placement from 20 +0 –24 +6 weeks’ gestation until elective removal or delivery vs. expectant management. Primary outcome was spontaneous birth <34 weeks. Secondary outcomes included perinatal death and a composite of adverse neonatal outcomes (intraventricular haemorrhage, respiratory distress syndrome, retinopathy of prematurity or necrotizing enterocolitis) or need for neonatal therapy (ventilation, phototherapy, treatment for proven or suspected sepsis, or blood transfusion). Analysis was by intention to treat. This trial is registered in the ISRCTN registry, number 01096902.
Results
A total of 1,180 (56.0%) of the 2,107 eligible women agreed to take part in the trial; 590 received cervical pessary and 590 had expectant management. Two of the former and one of the latter were lost to follow up. There were no significant differences between the pessary and control groups in rates of spontaneous birth <34 weeks (13.6% vs. 12.9%; relative risk 1.054, 95% confidence interval [CI] 0.787-1.413; p=0.722), perinatal death (2.5% vs. 2.7%; relative risk 0.908, 95% CI 0.553-1.491; p=0.702), adverse neonatal outcome (10.0 vs. 9.2%; relative risk 1.094, 95% CI 0.851-1.407; p=0.524) or neonatal therapy (17.9% vs. 17.2%; relative risk 1.040, 95% CI 0.871-1.242; p=0.701). A post hoc subgroup analysis of 214 women with short cervix (≤25 mm) showed no benefit from the insertion of a cervical pessary.
Conclusion
In women with twin pregnancy, routine treatment with cervical pessary does not reduce the rate of spontaneous early preterm birth.
Preterm birth is responsible for >70% of all neonatal and infant deaths. Additionally, children born preterm, compared to those born at term, have a 10-fold increase in risk of cerebral palsy. Twins, with a prevalence of 1.5% of pregnancies, account for about 25% of preterm births. Mortality and morbidity are inversely related to gestational age at delivery and are therefore more common in cases with early preterm birth. Randomized controlled trials (RCT) in singleton pregnancies with short cervical length reported that the prophylactic use of progesterone reduces significantly the rate of preterm birth and neonatal morbidity. Cervical cerclage in singleton pregnancies with short cervix is beneficial only in the subgroup with history of preterm birth. In twin pregnancies, progestogens and cervical cerclage have been shown to be ineffective in reducing preterm birth.
An alternative approach for prevention of preterm birth is transvaginal placement of a silicone pessary around the cervix; this is thought to support the cervix and change its direction toward the sacrum, thereby reducing the direct pressure from the uterine contents on the cervical cana. Two RCTs, published after the start of this study, in singleton pregnancies with short cervix provided contradictory results on the effect of cervical pessary on the rate of spontaneous birth at <34 weeks; in 1 study, the pessary reduced the rate from 27–6%, but in the second study of 108 pregnancies there was no significant effect (5.5% vs 9.4%). A RCT in 813 unselected multiple pregnancies, published after the start of this study, reported that cervical pessary did not reduce significantly the rate of birth at <32 weeks (12% vs 10%), but in an unplanned subgroup analysis of 133 patients with cervical length <38 mm the rate was reduced (29% vs 14%).
The objective of this multicenter RCT was to test the hypothesis that the insertion of a cervical pessary in twin pregnancies, compared to expectant management, would reduce the rate of spontaneous birth at <34 weeks’ gestation.
Materials and Methods
Study design and participants
This was an open-label randomized study of cervical pessary vs expectant management in twin pregnancies in 23 maternity hospitals in the United Kingdom, Spain, Germany, Austria, Slovenia, Portugal, Italy, Belgium, Albania, China, Brazil, and Chile.
All patients with twin pregnancies undergoing routine ultrasound examination at 20 +0 –24 +6 weeks’ gestation for assessment of fetal anatomy and measurement of cervical length were eligible for the study. Exclusion criteria were maternal age <16 years, fetal death, major fetal defect, severe twin-to-twin transfusion syndrome or selective fetal growth restriction, cervical cerclage in situ, painful regular uterine contractions, and history of ruptured membranes diagnosed before randomization.
Women agreeing to participate in the study gave written informed consent. The study was approved by the National Research Ethics Committee in the United Kingdom, as well as the local ethics committees of the participating hospitals outside of the United Kingdom. The trial was registered in the International Standard Randomized Controlled Trials registry, number N01096902.
Randomization
Eligible patients were randomized in a 1:1 ratio to either cervical pessary or expectant management, using a World Wide Web–based application with a computer-generated random-number list. In the random-sequence generation there were no restrictions, such as block size or stratification by site. At each center the patients agreeing to participate in the study were registered with a central computer that then instructed the operator as to whether the patient should receive a cervical pessary or be managed expectantly. Consequently, there was no way for study personnel to know or guess the group assignment prior to allocation.
Procedures
Gestational age was determined from the menstrual history and confirmed from the measurement of the crown-rump length of the bigger fetus at 11–13 weeks’ gestation. At the same scan chorionicity was determine from examination of the junction between the intertwin membrane and the placenta.
Cervical length was measured by transvaginal ultrasound examination at 20–24 weeks with patients, who had emptied the bladder, placed in the dorsal lithotomy position as previously described, by operators with certification of competence in the technique (Fetal Medicine Foundation Certificate of Competence in Cervical Assessment).
Cervical pessaries (Conformite Europeene marking 0482), which consist of flexible silicone, were purchased from the manufacturer (Dr Arabin GmbH & Co, Witten, Germany). Speculum examination was carried out to inspect the cervix for any pathology and obtain a high vaginal swab for bacteriological examination. If there was offensive vaginal discharge antibiotic therapy was given and insertion of the pessary was delayed until the discharge subsided. The pessary was inserted through the vagina with the woman in the recumbent position and placed upward around the cervix. The research team members introducing the cervical pessaries received instruction on selecting the appropriate size and introducing the device.
Women in the control group received the same obstetrical care as those in the pessary group. Follow-up visits for ultrasound assessment of fetal growth and cervical length were carried out every 4 weeks until 34 weeks’ gestation. If after 26 weeks the cervical length was <10 mm, steroids were administered for fetal lung maturation. At the time of randomization, the participants were informed that a symptom related to the insertion of the pessary could include increased vaginal discharge. At each follow-up visit we asked the participants in both arms of the study and recorded their answer as to whether they had noted an increase in severity or frequency of this symptom and whether they had developed any new symptoms since the beginning of treatment. Women reporting increased vaginal discharge were examined by a doctor for evidence of infection; bacterial swabs were taken and antibiotic therapy was given without removal of the pessary.
The cervical pessary was removed by a simple vaginal examination at 37 weeks’ gestation in asymptomatic patients. Earlier removal of the pessary was undertaken if: firstly, there was medically indicated induction of labor or elective cesarean delivery; secondly, there was preterm labor not responding to tocolytic therapy or preterm prelabor rupture of the membranes or active vaginal bleeding; and thirdly, at patient request because of discomfort.
Quality control of screening, handling of data, and verification of adherence to protocols at the different centers were performed on a regular basis by the trial coordinators. Data on pregnancy outcomes were obtained from hospital maternity records or the patients’ general medical practitioners. The records of all patients delivering at <34 weeks were examined to determine whether the birth was medically indicated or spontaneous. Spontaneous births included those with spontaneous onset of labor and those with rupture of membranes before labor.
Outcome measures
The primary outcome was spontaneous birth from randomization to <34 weeks (237 days) of gestation. The secondary outcome measures were: birthweight (mean <2.5 kg and <1.5 kg), perinatal death, composite of major adverse events for the neonate before discharge from the hospital (intraventricular hemorrhage, respiratory distress syndrome, retinopathy of prematurity, or necrotizing enterocolitis), composite of neonatal therapy (ventilation, phototherapy, treatment for proven or suspected sepsis, or blood transfusion), and major maternal complication attributable to the pessary.
Statistical analysis
The sample size calculation was based on detecting a treatment effect that produces a one-third reduction in the incidence of spontaneous delivery between randomization and 33 +6 weeks from an anticipated 13% in the expectant management group. In the computer simulations it was assumed that the distribution of cervical lengths and risks in the expectant group were the same as previously reported in our population. Using logistic regression analysis, with adjustment for cervical length, a total sample of 1180 patients has 85% power of detecting this difference at a (2-tailed) significance level of 5%.
Statistical analyses were by intention to treat and no interim analyses were performed. Baseline data for the cervical pessary and expectant groups were summarized by the median and the interquartile range. Comparisons between groups were performed with the use of the Mann-Whitney U test. Univariate comparisons of dichotomous data were performed with the use of Fisher exact test. The P values for all hypothesis tests were 2-sided and P < .05 was considered to indicate statistical significance. The risk of spontaneous preterm birth <34 weeks was quantified by the relative risk and 95% confidence interval (CI). The risk of spontaneous birth from randomization until 34 weeks was assessed using Kaplan-Meier analysis, where gestational age was the time scale, spontaneous birth was the event, and elective deliveries were treated as censored. For the purposes of this analysis, all pregnancies were considered to be no longer at risk for the event at the start of the 34th week. Hazard ratios were estimated with the use of the Cox proportional hazards model, with a formal test of the proportional hazards assumption. Odds ratios were converted to relative risk with the use of the method of Zhang and Yu. Results on perinatal and neonatal outcome were examined both at the pregnancy and fetal/neonatal level because of the potential of nonindependence of outcomes from the 2 twins arising from the same pregnancy.
Post hoc analysis
We conducted a post hoc analysis to examine the effect of cervical pessary in patients with short cervix (≤25 mm). The reason for undertaking this analysis is that a recent RCT in multiple pregnancies reported that although the pessary was not beneficial in the total population, in an unplanned subgroup analysis of those with cervical length <38 mm the rate of early preterm birth was halved. The cut-off of 38 mm was selected because only 1% of the patients had cervical length <25 mm, which was the cut-off selected for a preplanned subgroup analysis. However, in our study the cervical length was <25 mm in 18% of cases.
Role of the funding source
Funding for the study was provided by the Fetal Medicine Foundation (United Kingdom charity no. 1037116), which had no role in study design, data collection, data analysis, data interpretation, or the writing of the report. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication.
Results
Study population
A total of 1180 of the 2107 eligible pregnant patients agreed to take part in the trial ( Figure 1 ). The participants were recruited from August 2008 through May 2011. There were 600 patients from England, 391 from Spain, 145 from other European countries, and 44 from non-European countries. There were no important differences in baseline characteristics between the pessary and the expectant groups ( Table 1 ). Two pregnancies in the pessary group and 1 in the controls were lost to follow-up. Two of the patients in the control group were treated with vaginal progesterone from 26 and 28 weeks’ gestation, respectively, because of cervical shortening; in both cases delivery was >34 weeks.
| Characteristics | Pessary group, n = 590 | Control group, n = 590 |
|---|---|---|
| Age, median (IQR), y | 33.1 (29.5–36.7) | 33.2 (29.1–36.6) |
| Weight, median (IQR), kg | 67.0 (60.0–76.3) | 68.0 (60.0–79.0) |
| Height, median (IQR), cm | 165 (160–170) | 164 (160–169) |
| Racial origin, n (%) | ||
| Caucasian | 497 (84.2) | 483 (81.9) |
| Afro-Caribbean | 43 (7.3) | 54 (9.2) |
| South Asian | 19 (3.2) | 20 (3.4) |
| East Asian | 19 (3.2) | 22 (3.7) |
| Mixed | 12 (2.0) | 11 (1.9) |
| Obstetric history, n (%) | ||
| Nulliparous | 363 (61.5) | 360 (61.0) |
| Parous | 227 (38.5) | 230 (39.0) |
| Delivery at 24–33 wk | 9 (4.0) | 15 (6.5) |
| Delivery at 34–36 wk | 11 (4.8) | 18 (7.8) |
| Delivery at ≥37 wk | 207 (91.2) | 197 (85.7) |
| Conception, n (%) | ||
| Spontaneous | 373 (63.2) | 366 (62.0) |
| Ovulation drugs | 21 (3.6) | 20 (3.4) |
| In vitro fertilization | 196 (33.2) | 204 (34.6) |
| Cigarette smoking during pregnancy, n (%) | 45 (7.6) | 53 (9.0) |
| Previous cervical surgery, n (%) | ||
| Loop excision of transformation of zone | 14 (2.4) | 17 (2.9) |
| Cone biopsy | 5 (0.8) | 4 (0.7) |
| Chorionicity, n (%) | ||
| Dichorionic | 479 (81.2) | 479 (81.2) |
| Monochorionic | 111 (18.8) | 111 (18.8) |
| GA at randomization, median (IQR), wk | 22.6 (21.4–23.9) | 22.7 (21.4–23.9) |
| GA at pessary insertion, median (IQR), wk | 22.7 (21.7–23.9) | – |
| Cervical length at randomization | ||
| Median (IQR), mm | 32.0 (27.0–36.0) | 32.0 (27.0–37.0) |
| ≤25 mm, n (%) | 107 (18.1) | 108 (18.3) |
Outcomes
There was no significant difference between the cervical pessary and control groups in rates of spontaneous birth at <34 weeks, perinatal death, adverse neonatal event, or neonatal therapy ( Table 2 ). Logistic regression analysis, with adjustment for cervical length, demonstrated no significant effect of the cervical pessary in the rate of spontaneous birth at <34 weeks (odds ratio, 1.058; 95% CI, 0.740–1.511; P = .7584). The cumulative percentage of patients who did not give birth spontaneously at <34 weeks was not significantly different between the 2 groups (hazard ratio, 1.061; 95% CI, 0.776–1.453; P = .709) ( Figure 2 ).
| Outcome | Pregnancy level | Fetal/neonatal level | ||||
|---|---|---|---|---|---|---|
| Pessary group | Control group | RR (95% CI) | Pessary group | Control group | RR (95% CI) | |
| Primary outcome | ||||||
| Spontaneous birth at <34 weeks | 80/588 (13.6%) | 76/589 (12.9%) | 1.054 (0.787-1.413) | – | – | – |
| Other outcome measures | ||||||
| Spontaneous birth at <34 weeks | – | – | – | |||
| Dichorionic twins | 62/477 (13.0%) | 62/478 (13.0%) | 1.002 (0.722-1.392) | – | – | – |
| Monochorionic twins | 18/111 (16.2%) | 14/111 (12.6%) | 1.286 (0.673-2.455) | – | – | – |
| Gestational age at birth, median (IQR) | 36.6 (34.9-37.9) | 36.7 (35.0-37.9) | – | – | – | – |
| Any birth at <34 weeks | 98/588 (16.7%) | 92/589 (15.6%) | 1.067 (0.822-1.385) | – | – | – |
| Any birth at <32 weeks | 52/588 (8.8%) | 53/589 (9.0%) | 0.983 (0.682-1.416) | – | – | – |
| Any birth at <30 weeks | 32/588 (5.4%) | 26/589 (4.4%) | 1.233 (0.744-2.042) | – | – | – |
| Any birth at <28 weeks | 19/588 (3.2%) | 15/589 (2.5%) | 1.269 (0.651-2.473) | – | – | – |
| Secondary outcomes | ||||||
| Birth weight | ||||||
| Mean in g, (IQR) | – | – | – | 2,331 (2,020-2,740) | 2,353 (2,050-2,732) | |
| <2500 g | 395/588 (67.2%) | 407/589 (69.1%) | 0.972 (0.899-1.051) | 664/1176 (56.5%) | 670/1178 (56.9%) | 0.993 (0.925-1.065) |
| <1500 g | 60/588 (10.2%) | 65/589 (11.0%) | 0.925 (0.664-1.288) | 100/1176 (8.5%) | 96/1178 (8.1%) | 1.043 (0.798-1.364) |
| Perinatal death | 20/588 (3.4%) | 22/589 (3.7%) | 0.911 (0.502-1.651) | 29/1176 (2.5%) | 32/1178 (2.7%) | 0.908 (0.553-1.491) |
| Fetal death | 7/588 (1.2%) | 14/589 (2.4%) | 0.501 (0.204-1.232) | 12/1176 (1.0%) | 18/1178 (1.5%) | 0.668 (0.323-1.380) |
| Neonatal death | 13/588 (2.2%) | 9/589 (1.5%) | 1.447 (0.623-3.359) | 17/1176 (1.4%) | 14/1178 (1.2%) | 1.216 (0.602-2.456) |
| Secondary outcomes in survivors | ||||||
| Adverse neonatal event | 88/579 (15.2%) | 69/579 (11.9%) | 1.275 (0.951-1.710) | 115/1147 (10.0%) | 105/1146 (9.2%) | 1.094 (0.851-1.407) |
| Intraventricular hemorrhage | 16/579 (2.8%) | 12/579 (2.1%) | 1.333 (0.636-2.793) | 18/1147 (1.6%) | 15/1146 (1.3%) | 1.199 (0.607-2.367) |
| Respiratory distress syndrome | 84/579 (14.5%) | 67/579 (11.6%) | 1.254 (0.929-1.692) | 109/1147 (9.5%) | 100/1146 (8.7%) | 1.089 (0.841-1.411) |
| Retinopathy of prematurity | 8/579 (1.4%) | 3/579 (0.5%) | 2.667 (0.711-10.001) | 12/1147 (1.0%) | 3/1146 (0.3%) | 3.997 (1.131-14.125) |
| Necrotizing enterocolitis | 6/579 (1.0%) | 6/579 (1.0%) | 1.000 (0.324-3.082) | 8/1147 (0.7%) | 6/1146 (0.5%) | 1.332 (0.464-3.827) |
| Neonatal therapy | 137/579 (23.7%) | 127/579 (21.9%) | 1.079 (0.873-1.334) | 205/1147 (17.9%) | 197/1146 (17.2%) | 1.040 (0.871-1.242) |
| Ventilation | 80/579 (13.8%) | 64/579 (11.1%) | 1.250 (0.919-1.701) | 114/1147 (9.9%) | 97/1146 (8.5%) | 1.174 (0.907-1.520) |
| Phototherapy | 86/579 (14.9%) | 80/579 (13.8%) | 1.075 (0.811-1.425) | 111/1147 (9.7%) | 116/1146 (10.1%) | 0.956 (0.747-1.224) |
| Treatment for sepsis, n (%) | 41/579 (7.1%) | 45/579 (7.8%) | 0.911 (0.606-1.369) | 66/1147 (5.8%) | 66/1146 (5.8%) | 0.999 (0.717-1.392) |
| Blood transfusion, n (%) | 26/579 (4.5%) | 25/579 (4.3%) | 1.040 (0.608-1.779) | 36/1147 (3.1%) | 36/1146 (3.1%) | 0.999 (0.634-1.574) |
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