Physical Exam Indicated Cerclage in Twin pregnancy: a Randomized Controlled Trial Amanda Roman, MD, Noelia Zork, MD, Sina Haeri, MD, MHSA, Corina N. Schoen, MD, Gabriele Saccone, MD, Sarah Colihan, MD, Craig Zelig, MD, Alexis C.
Gimovsky, MD, Neil S. Seligman, MD, Fulvio Zullo, MD, Vincenzo Berghella, MD
PII: S0002-9378(20)30672-4
DOI: https://doi.org/10.1016/j.ajog.2020.06.047 Reference: YMOB 13338
To appear in: American Journal of Obstetrics and Gynecology Received Date: 1 January 2020
Revised Date: 19 May 2020 Accepted Date: 22 June 2020
Please cite this article as: Roman A, Zork N, Haeri S, Schoen CN, Saccone G, Colihan S, Zelig C, Gimovsky AC, Seligman NS, Zullo F, Berghella V, Physical Exam Indicated Cerclage in Twin pregnancy: a Randomized Controlled Trial, American Journal of Obstetrics and Gynecology (2020), doi: https:// doi.org/10.1016/j.ajog.2020.06.047.
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Title: Physical Exam Indicated Cerclage in Twin pregnancy: a Randomized
1
Controlled Trial
2
Authors: Amanda ROMAN, MD (1), Noelia ZORK, MD (2), Sina HAERI, MD, MHSA
3
(3), Corina N. SCHOEN, MD (4) Gabriele SACCONE, MD (5), Sarah COLIHAN, MD (6), 4
Craig ZELIG, MD (6), Alexis C. GIMOVSKY, MD (7); Neil S. SELIGMAN, MD (8), Fulvio 5
ZULLO, MD, (5), Vincenzo BERGHELLA, MD (1) 6
(1) Maternal Fetal Medicine Division, Obstetrics and Gynecology Department, Sidney 7
Kimmel Medical College at Thomas Jefferson University, Philadelphia, PA, United 8
States. 9
(2) Maternal Fetal Medicine Division, Obstetrics and Gynecology Department, Columbia 10
University, New York, NY 11
(3) St David’s Women’s Center of Texas, Austin Maternal-Fetal Medicine, Austin, TX 12
(4) Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine, 13
University of Massachusetts-Baystate, Springfield, MA 14
(5) Department of Neuroscience, Reproductive Sciences and Dentistry, School of 15
Medicine, University of Naples Federico II, Naples, Italy 16
(6) Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine, 17
Albany Medical Center, Albany, NY 18
(7) Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine, The 19
George Washington University School of Medicine and Health Sciences, Washington, 20
DC 21
(8) Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine, 22
University of Rochester Medical Center, Rochester, NY 23
Disclosure: The authors report no conflicts of interest.
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Financial Support: No external financial support was received for this study.
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Data from this manuscript was presented at the 40th SMFM Meeting, February 3–8, 26 2020 at Grapevine, Texas, 27 28 Corresponding author 29 Amanda Roman, MD 30
Department of Obstetrics and Gynecology 31
Division of Maternal-Fetal Medicine 32
Thomas Jefferson University 33
833 Chestnut Street, First floor, Philadelphia, PA, 19107 USA 34 Email: amanda.roman@jefferson.edu 35 Phone: 215-955-9200 36 Fax: 215-955-5041 37 38 Word count 39 Abstract: 447 40 Main manuscript: 4013 41 42 43
Condensation: Physical exam indicated cerclage, indomethacin, and antibiotics in
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asymptomatic twin pregnancies <24 weeks significantly decreases preterm birth at all 45
evaluated gestational ages and perinatal mortality. 46
Short Title: Physical exam indicated cerclage in twin pregnancy decreases preterm
47
birth 48
AJOG at a Glance:
49
A. Why was the study conducted?
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• To evaluate if physical exam indicated cerclage will decrease preterm birth 51
in twin pregnancy 52
B. What are the key findings?
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• Physical exam indicated cerclage in twins significantly decreases preterm 54
birth at all gestational age cutoff studied and decreases perinatal morbidity 55
and mortality 56
C. What does this study add to what is already known?
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• This study is the first randomized controlled trial evaluating physical exam 58
indicated cerclage in twins. 59
60
Clinical trials registration number: NCT02490384 61
First registered: July 3, 2015 62
First patient enrolled: July 25, 2015 63
https://clinicaltrials.gov/ct2/show/NCT02490384?cond=twin+cerclage&draw=2&rank=5 64
ABSTRACT
66
Background: Twin pregnancies with dilated cervix in the second trimester are at
67
increased risk of pregnancy loss and early preterm birth; currently there is no proven 68
therapy to prevent preterm birth in this group of women. 69
Objective: To determine if physical exam indicated cerclage reduces the incidence of
70
preterm birth in asymptomatic women with twin gestations and cervical dilation 71
diagnosed before 24 weeks of pregnancy. 72
Study design: Multicenter, parallel-group, open-label, randomized controlled trial of
73
women with twin pregnancy, and asymptomatic cervical dilation from 1-5 cm between 74
16 0/7 to 23 6/7 weeks were enrolled from 7/2015 to 7/2019 in 8 centers. Eligible 75
women were randomized in a 1:1 ratio to either cerclage or no cerclage. We excluded 76
women with: monochorionic-monoamniotic pregnancy, selective fetal growth restriction, 77
twin-twin transfusion syndrome, major fetal malformation, known genetic anomaly, 78
placenta previa, signs of labor, or clinical chorioamnionitis. The primary outcome was 79
the incidence of preterm birth <34 weeks. Secondary outcomes were preterm birth <32, 80
<28 and <24 weeks, interval from diagnosis to delivery, and perinatal mortality. Data 81
were analyzed as intention to treat. 82
Results: After an interim analysis was performed, the Data Safety Monitoring Board
83
recommended stopping the trial due to significant decrease of perinatal mortality in the 84
cerclage group. We randomized 34 women, four were excluded due to expired informed 85
consent. Seventeen women were randomized to physical exam indicated cerclage and 86
13 women to no cerclage. Four women randomized to cerclage did not receive the 87
surgical procedure, while no women in the no cerclage group received cerclage. 88
Maternal demographics were not significantly different. All women in the cerclage group 89
also received indomethacin and antibiotics. When comparing cerclage vs no cerclage 90
group, the incidence of preterm birth <34 weeks was significantly decreased: 12/17 91
(70%) vs 13/13 (100%) (RR: 0.71 95% CI 0.52-0.96), as well as preterm birth <32 92
weeks 11/17 (64.7%) vs 13/13 (100%) (RR: 0.65 95% CI 0.46-0.92), preterm birth <28 93
weeks 7/17 (41%) vs 11/13 (84%) (RR: 0.49 95% CI 0.26-0.89) and preterm birth <24 94
weeks 5/17 (30%) vs 11/13 (84%) (RR: 0.35 95% CI 0.16-0.75). The mean gestational 95
age at delivery was later: 29.05±1.7 vs. 22.5±3.9 weeks (p<0.01); the mean interval 96
from diagnosis of cervical dilation to delivery was longer: 8.3±5.8 vs. 2.9±3.0 weeks 97
(p=0.02). Perinatal mortality was also significantly reduced in the cerclage group 6/34 98
(17.6%) vs 20/26 (77%), (RR: 0.22 95% CI 0.1-0.5). 99
Conclusion: A combination of physical exam indicated cerclage, indomethacin, and
100
antibiotics in asymptomatic twin pregnancies before 24 weeks significantly decreases 101
preterm birth at all evaluated gestational ages. Most importantly, cerclage in this 102
population is associated with a 50% decrease in very early preterm birth <28 weeks and 103
with a 78% decrease in perinatal mortality. 104
Keywords: Physical exam indicated cerclage, twins, cerclage, cervical dilation, preterm
105
birth, perinatal mortality. 106
107
108
INTRODUCTION
110
Twins pregnancies represent a small proportion of annual births in the United States but 111
account for 20% of preterm births. The 2017 twin birth rate in the United States was 112
33.3 twins per 1,000 births but 59.4% of twin pregnancies delivered before 37 weeks, 113
and 9.45% before 32 weeks, compared with singleton pregnancies, of whom 8.13% 114
delivered before 37 weeks and 2.12% before 32 weeks1. Twins are also at increased 115
risk for low birth-weight (LBW), have five times higher risk of early neonatal and infant 116
death and complications related to prematurity and LBW.1, 2 117
Singleton pregnancies with cervical dilation of 1 cm or more in the second trimester are 118
associated with a poor prognosis. Greater than 90% will result in pretem birth (PTB), 119
regardless of history of PTB, cervical length, obstetric history, or other PTB risk 120
factors.3-7 Physical exam indicated cerclage, previously called at times rescue, 121
emergency, or urgent cerclage, is defined as a cerclage placed in the presence of 1 cm 122
or more cervical dilation detected on physical examination (speculum or digital exam).8, 123
9
Placement of cerclage in patients with singleton gestations who have cervical dilation 124
in the second trimester has been shown to decrease incidences of PTB and perinatal 125
mortality.3-7, 9-11 126
In twins, the data on the efficacy of physical exam indicated cerclage is limited. The only 127
published randomized controlled trial (RCT) evaluating cerclage for cervical dilation 128
compared 13 women who received cerclage, indomethacin and bed rest, and 10 129
women who received bed rest-only; all women received antibiotics. This RCT included 7 130
twin pregnancies, 3 in the cerclage and 4 in the bed rest group. This RCT showed 131
overall a significant decrease in PTB < 34 weeks of gestation and longer latency interval 132
from diagnosis to delivery (by 30 days). However, outcomes of twin pregnancies were 133
not reported separately.3 134
Multiple case series and cohorts studies on physical exam indicated cerclage in twins or 135
twins compared with singleton pregnancies have been published.12 The three 136
retrospective case-control studies in twins, where physical exam indicated cerclage was 137
compared with no cerclage,12-14 showed a significant decrease in spontaneous PTB 138
<34, and <32 weeks, two of the studies also had significant spontaneous PTB < 28 139
weeks12, 13 and one of them showed a decrease in the incidence of perinatal mortality.12 140
Our aim was to evaluate if physical exam indicated cerclage would reduce the rate of 141
spontaneous PTB before 34 weeks’ gestation and adverse perinatal outcomes in 142
women with twin pregnancy, and asymptomatic cervical dilation from 1-5 cm before 24 143
weeks when compared to no cerclage in a randomized controlled trial. 144
145
MATHERIALS AND METHODS
146
Study design and participants 147
This multicenter, parallel group, open-label, randomized controlled trial was performed 148
by a consortium of 8 clinical centers between July 2015 and July 2019. The Institutional 149
Review Board (IRB) approved this study at each center, and all participants were 150
provided with and signed written informed consent. This trial was registered as a 151
randomized clinical trial (NCT02490384; clinicaltrials.gov). This trial had no external 152
funding. Eligible participants were women between 18 - 50 years of age carrying a 153
diamniotic twin gestation with asymptomatic cervical dilation from 1 to 5 cm and/or 154
visible membranes by pelvic exam or speculum exam between 16 0/7 to 23 6/7 weeks. 155
Women were identified either by transvaginal ultrasound cervical length (TVUCL) at the 156
time of the anatomy scan or by pelvic examination during prenatal visits. We excluded 157
women with monochorionic-monoamniotic pregnancy, selective fetal growth restriction, 158
twin-twin transfusion syndrome, major fetal malformation or known genetic anomaly, 159
placenta previa, regular painful contractions with cervical changes over 12 hours of 160
observation, active bleeding or clinical chorioamnionitis at the time of diagnosis, cervical 161
dilation 6 cm or more, amniotic membranes prolapsed beyond external os into the 162
vagina, unable to visualize cervical tissue, fetal reduction after 14 weeks from higher-163
order multiples, ruptured membranes prior to randomization, and cerclage already in 164
place. 165
All pregnancies were dated by crown-rump length during the first trimester, and 166
chorionicity was determined. Before randomization, they underwent anatomy scan for 167
both twins by a certified sonographer or Maternal-Fetal Medicine specialist. Cervical 168
dilation was determined by pelvic exam and/or speculum exam between 16 0/7 and 23 169
6/7 weeks and confirmed to have a dilated cervix from 1-5 cm by the primary 170
investigator at each site. Premature preterm rupture of the membranes (PPROM) 171
defined as rupture of membranes that occurred prior of labor and delivery but not 172
intrapartum. PPROM was diagnosed by visualization of amniotic fluid on sterile 173
speculum exam, a positive Nitrazine test and/or a ferning pattern on microscopy. Active 174
labor was defined as the presence of regular uterine contractions 3 or more in 10 175
minutes with cervical change. Subclinical chorioamnionitis was identified by 176
amniocentesis of the presenting twin with: 1) presence of any bacteria on amniotic fluid 177
Gram stain, 2) amniotic fluid leukocyte count ≥ 6 leukocytes per high-power field or >30 178
cells/mm3, 3) amniotic fluid glucose concentration ≤15 mg/dL; or by positive amniotic 179
fluid culture. Clinical chorioamnionitis was defined as: maternal fever ≥38°C (≥100.4° F) 180
plus 1 of the following: maternal tachycardia (>100 beats/min), fetal tachycardia, (>160 181
beats/min), marked leukocytosis (>15,000 cells/mm3), uterine tenderness, or foul odor 182
of the amniotic fluid.15 Amniocentesis was offered to all patients before randomization; 183
however, it was not a prerequisite for enrollment. Patients who declined amniocentesis 184
were observed for approximately 12 hours for signs of labor, bleeding, or infection, and 185
those who remained stable were offered randomization. At the time of pelvic exam, 186
specimens for gonorrhea, chlamydia, group B streptococcus (GBS), bacterial vaginosis 187
and trichomonas’s were collected. Gonorrhea and chlamydia were identified by 188
polymerase chain reaction (PCR). The diagnosis of bacterial vaginosis was done by 189
Amsel criteria,16 (at least three criteria must be present): 1) homogeneous, thin, grayish-190
white discharge that smoothly coats the vaginal walls, 2) vaginal pH >4.5, 3) positive 191
whiff-amine test, defined as the presence of a fishy odor when a drop of 10% potassium 192
hydroxide (KOH) is added to a sample of vaginal discharge and 4) clue cells on saline 193
wet mount (vaginal epithelial cells studded with adherent coccobacilli at the edge of the 194
cell in at least 20% of the epithelial cells on wet mount). Trichomonas were identified on 195
wet mount. Urinary tract infections (UTI) were diagnosed by positive urine culture. All 196
detected infections were treated. Initiation of indomethacin during the observation 197
period was acceptable. After delivery, the placentas were sent to pathology. Histologic 198
chorioamnionitis was defined by the presence of neutrophils that marginated into the 199
placental chorionic plate; funisitis was defined by the presence of neutrophils in the 200
umbilical cord vessel wall.17 201
Randomization and masking 202
Eligible participants were randomly allocated in a 1:1 ratio by blocks of 4 to either 203
cerclage or no cerclage using a computer-based platform programmed in REDCap 204
(Research Electronic Data Capture) hosted at Thomas Jefferson University.18, 19 The 205
sequence of randomization was set by a third party. Principal investigators at each site 206
were masked to the allocation of patients; institutions were only able to see their own 207
patients. Due to small sample size of the study, enrollment was not stratified by 208
institution or any of the maternal characteristics. 209
Interventions 210
Physical exam indicated cerclage was to be placed by a trained physician in the 211
operating room under anesthesia (regional or general at the discretion of the 212
anesthesiologist). Amnioreduction at the time of the amniocentesis, use of 213
indomethacin, antibiotics before and/or after the cerclage, surgical technique, selection 214
of sutures, additional tocolysis, vaginal progesterone, admission to the hospital for 215
observation, or maternal physical activity after randomization were at the discretion of 216
the physician performing the cerclage. 217
Parcipants follow-up 218
Women on both arms cerclage and no cerclage were observed in the hospital until they 219
were stable for discharge, and preterm labor precautions were given. Readmission to 220
the hospital per physician discretion. Antenatal steroids were offered to all women ≥ 23 221
weeks, and a second course of steroids was offered if delivery was considered 222
imminent ≥ 2 weeks after the first course. Prenatal care continued according to the 223
local guidelines, there were no other study-specific recommendations for pregnancy 224
care. 225
Women were contacted monthly either by phone or in person at the time of their 226
prenatal visit. Consents for release of medical information were signed at the time of 227
randomization to gather information pertinent to the study in case of admissions to other 228
institutions. Fetal growth evaluations were done every 3 to 4 weeks; estimated fetal 229
weight calculations were based on the Hadlock, et al. growth curve.20 Patients 230
diagnosed with intrauterine growth restriction (IUGR) in one or both twins were followed 231
by biweekly non-stress test, weekly umbilical artery Doppler and maximal vertical 232
pocket on each side of the membrane. The primary care provider removed the cerclage 233
during the 36th week of gestation or sooner in the presence of active vaginal bleeding, 234
labor, PPROM, or membranes prolapsed through the suture. Delivery time and mode of 235
delivery were per obstetrical indications. After delivery, all neonates were followed until 236
they were discharged home. 237
Primary and secondary outcomes 238
The primary outcome was the incidence of spontaneous PTB <34 weeks of gestation. 239
Secondary maternal outcomes included: incidence of spontaneous PTB <32, <28, and 240
<24 weeks gestation, PPROM at <34 weeks gestation, GA at delivery, interval between 241
diagnosis and delivery, and birth weight. Secondary neonatal outcomes include: Apgar 242
score at 5 minutes, admission to neonatal intensive care unit (NICU), neonatal death, 243
length of stay (LOS) in the NICU until discharge home, and composite neonatal adverse 244
outcome, defined as at least 1 of the following: respiratory distress syndrome (RDS) 245
(ventilator support, intubation, continuous positive airway pressure [CPAP], or use of 246
surfactant), intraventricular hemorrhage (IVH) grade 3 and 4 as determined by cranial 247
ultrasound or computed tomography (CT) according to the Papile classification,21 248
necrotizing enterocolitis (NEC) grade 3 and 4 requiring surgery,22 proven sepsis 249
(clinically ill infant with suspected infection plus positive blood, cerebrospinal fluid [CSF], 250
or catheterized/ suprapubic urine culture or cardiovascular collapse or unequivocal x-ray 251
finding), or retinopathy of prematurity (ROP) requiring laser treatment.23 Significant 252
adverse maternal effects included: intraoperative rupture of membranes, clinical 253
chorioamnionitis, postpartum hemorrhage, cervical laceration or tear, and uterine 254
rupture. 255
Sample Size Calculation 256
Calculation of sample size was based on a reduction in the incidence of PTB < 34 257
weeks from 80% in the no cerclage group to 40% in the cerclage group, with a power of 258
80%.12 To detect this difference at a significance level of 5%, we calculated 46 subjects 259
with 23 subjects in each arm, plus 10% for loss of follow up. A total sample size of 52 260
subjects was needed. 261
It was planned that the Data and Safety Monitoring Board (DSMB) would review data 262
relevant to safety (not efficacy) after approximately 50% of the subjects had delivered 263
and the DSMB would provide a recommendation as to whether the study should 264
continue without modification of the protocol or informed consent. Pre-specified 265
stopping rules were: significantly different maternal sepsis with admission to the 266
intensive care unit, maternal death, maternal bleeding requiring blood transfusion, or 267
fetal or neonatal mortality associated with the cerclage placement when compared with 268
no cerclage. Adverse events were reported to the Human Research Protection Office 269
and the Institutional Review Board (IRB) as they occurred. 270
Statistical analysis 271
Statistical analysis was conducted using Statistical Package for Social Sciences (SPSS) 272
version. 22 (IBM Inc., Armonk, NY, USA). Data are shown as mean ± standard 273
deviation (SD) or number (percentage). Univariate comparisons of dichotomous data 274
were performed with the use of the chi-square test with continuity correction. 275
Comparisons between groups were performed with the use of the T-test to test group 276
means by assuming equal within-group variances for parametric data, and with the use 277
of Wilcoxon and Mann-Whitney tests for nonparametric data. The primary analysis was 278
an intention to treat comparison of the treatment assigned at randomization. The 279
incidence of primary and secondary outcomes were quantified by the crude relative ratio 280
(RR) or mean difference with 95% of confidence interval (CI). In addition to standard 281
logistic regression analysis, in which each fetus was treated as an independent unit, we 282
used a generalized model-model approach in which each twin pair was a cluster unit for 283
outcomes of neonates born alive. For these outcomes, intracluster correlation 284
coefficient was also estimated. ICC was calculated using the two-way mixed model with 285
95% CI. Risk of PTB was assessed with the use of Kaplan-Meier analysis, in which 286
gestational age (GA) was time scale, and delivery the event. Log-Rank Hazard Ratio 287
was estimated. For outcomes in which cerclage had a statistically significant beneficial 288
or harmful effect number needed to treat (NNT) was calculated. P value <0.05 was 289
considered statistically significant. This trial was reported following the CONSORT 290 guidelines.24 291 292 RESULTS 293 Trial participants 294
A total of 70 women were assessed for eligibility between July 2015 and July 2019 295
(Figure 1). Of these, 14 women had an exclusion criteria and 22 declined participation, 296
34 women provided informed consent and were randomized to either cerclage (n=18) or 297
from analysis when their consent form was identified to be expired, and a new consent 298
was not available due to lapse in the IRB documents renewal at two enrolling sites (1 299
woman in the cerclage group and 3 women in the no cerclage group). Therefore a total 300
of 30 women were included in the final analysis (17 cerclage and 13 no cerclage). Four 301
women assigned to cerclage did not receive the surgical procedure: 2 of them due to 302
contraindications to the procedure, which occurred soon after randomization (rupture of 303
amniotic membranes, and vaginal bleeding), one due to friable cervix and the cerclage 304
placement was suspended, while one declined cerclage after being randomized. All four 305
patients were included in the intention to treat analysis. At the interim analysis 306
performed with 30 enrolled women (58% of the sample size), the DSMB recommended 307
stopping the trial due to significant decrease of perinatal mortality in the cerclage group. 308
Participant demographic characteristics were similar for each group (Table 1). 309
Gestational age at diagnosis and randomization was the same. Most twin gestations 310
were diamniotic-dichorionic 28 (93.3%); assisted reproductive technology was used by 311
11 (36.6%); 6 women (20%) had a history of singleton PTB; 24 (80%) women had one 312
or more TVUCL done as part of the screening for preterm birth; of them, 20 (66.6%) had 313
TVUCL ≤ 25 mm and 7 (23.3%) had TVUCL ≤15mm, while 19 (63.3%) received vaginal 314
progesterone due to the finding of short cervix. All 24 women subsequently were 315
identified as having a dilated cervix. The other 10 women were identified with dilated 316
cervix during a pelvic examination indicated by other symptoms (pain, pressure, or 317
vaginal discharge) but considered not in active labor. Four women (13%) agreed and 318
had an amniocentesis before randomization, and all were negative for intra-amniotic 319
infection. UTI was identified in 4 (13.3%) women; cervico-vaginal evaluation identified 320
bacterial vaginosis in 3 (10%) and chlamydia in 1 (3%), all patients received appropriate 321
treatment. Cerclage placement was successful in 13 of 14 women. McDonald cerclage 322
with one suture was done on all patients. Manipulation of the amniotic membrane was 323
required on 9/14 (64%) with either Foley balloon or sponge. Mersilene™ tape was used 324
on 8 women, Mersilene™ suture in 2, Ethibond™ in 3 and Prolene™ in 1 woman. All 325
women who underwent cerclage, received antibiotics (12 cephalosporin, 1 clindamycin-326
gentamycin and 1 azithromycin) and indomethacin (50-100mg loading dose followed by 327
25-50 mg every 6 hours for 48 hours). Intraoperative complications was present in only 328
one case when physical exam indicated cerclage was attempted but the cervix was 329
more effaced and friable than expected, therefore the procedure was stopped and 330
placement was considered unsuccessful. No serious adverse events were identified. 331
Primary and secondary outcomes 332
The primary outcome of spontaneous PTB <34 weeks of gestation was observed in 333
12/17 (70%) of women in the cerclage group vs 13/13 (100%) in the no cerclage group 334
(RR, 0.7, 95% CI, 0.46–0.96; p=0.05). Secondary outcomes of spontaneous PTB <32, 335
<28, and <24 weeks of gestation were also significantly decreased in the cerclage 336
group (Table 2). There were no cases of medically indicated PTB. The latency period 337
from diagnosis to delivery was significantly prolonged in the cerclage group by mean 338
difference of 5.6 (2.0-9.3) weeks (p=0.02). The cumulative percentage of participants 339
who did not give birth preterm was significantly higher in the cerclage group than in the 340
no cerclage group (Log-Rank Hazard Ratio 0.33 [95%CI 0.13-0.80], p<0.001), (Figure 341
2). While more women in the cerclage delivered between 23 0/7 to 27 6/7 weeks: 5/17 342
(29.4%) vs. 1/13 (7.7%), this difference was not significantly different, p=0.2. Overall 343
perinatal mortality was observed in 6/34 (17.6%) of cerclage group versus 20/26 (77%) 344
in the no cerclage group RR 0.23 (0.11-0.49), p< 0.0001. There were no cases of fetal 345
demise. All perinatal mortality cases were associated with delivery < 24 weeks, (Table 346
2). Delivery prior to 23 weeks was seen in 2/17 (11.7%) women in the cerclage group 347
and 10/13 (76.9%) in the no cerclage group, all neonates died secondary to extreme 348
prematurity and received palliative care. Two women (11.7%) in the cerclage group 349
delivered between 23 0/7 and 23 6/7 weeks, they were born alive but one twin of each 350
women died in the first 48 hours (one secondary to sepsis and the other due to 351
respiratory failure). There were no significant differences in other neonatal outcomes, 352
but the trial was not powered for these outcomes (Table 3). 353
COMMENT
355
Principal Findings 356
In women with twin pregnancies and asymptomatic cervical dilation from 1 to 4 cm 357
before 24 weeks, a combination of physical exam indicated cerclage, indomethacin, and 358
antibiotics significantly decreases the incidence of spontaneous PTB at all evaluated 359
GA providing a longer latency period from diagnosis to delivery by 5.6 weeks. Most 360
importantly, cerclage in these population was associated with a 50% decrease in very 361
early PTB <28 weeks, and a 78% decrease in perinatal mortality. 362
Results 363
Twin pregnancy with asymptomatic cervical dilation before 24 weeks offers a formidable 364
challenge for obstetricians. Physical exam indicated cerclage in twins with dilated cervix 365
before 24 weeks has been evaluated in only three retrospective studies in twins with no 366
cerclage as a control group, all of them favored cerclage placement. Our results are 367
similar to these studies. Roman et al, published in 201612 was the first case control 368
study of twins with cervical dilation ≥ 1 cm before 24 weeks from 6 different institutions 369
in the United States and one in Italy. The study showed that the combination of physical 370
exam indicated cerclage, indomethacin, and antibiotics were associated with a 371
significant prolongation of latency from diagnosis to delivery by 6.7 weeks, decreased 372
incidence of spontaneous PTB at any given GA by 80-90%, decreased perinatal 373
mortality by 76% and improved perinatal outcome when compared with no cerclage. 374
Abbasi et al.13 published a retrospective cohort study conducted at a single institution in 375
Toronto. This study included women with twin pregnancies, dilated cervix, and intact 376
membranes <25 weeks of gestation, 27 women had cerclage compared to 9 women 377
managed expectantly. Compared with the subjects enrolled in this study, their cohort 378
had more advanced GA and cervical dilation at diagnosis as 16 (44%) of them were ≥ 3 379
cm at diagnosis. Additionally, antibiotics, indomethacin or progesterone were not given 380
in either group. Women in the cerclage group experienced longer latency from 381
presentation to delivery (7.3±5.5 versus 0.5±0.3 weeks, p<.001) and a lower incidence 382
of PTB before 34, 32 and 28 weeks, while all women in the no cerclage group delivered 383
<28 weeks. The overall neonatal survival at discharge was 38/54 (70.4%) in the 384
cerclage group versus 10/18 (55.6%) in the no cerclage group (p=0.2). Han et al.14 385
published a cohort study from two hospitals in California that included twins with cervical 386
dilation > 1cm; the study included 54 women who received physical exam indicated 387
cerclage, and 17 women no cerclage. Maternal demographics were not presented 388
separately limiting comparison of the groups. Nonetheless, the use of cerclage was 389
associated with a significant decrease in the odds of PTB <32, <34, and <36 weeks. 390
Physical exam indicated cerclage in our study had no intraoperative complications; in 391
one case, the surgeon was unable to place the cerclage due to effaced and friable 392
cervix. Larger cohorts in singleton pregnancies have informed a 10-20% risk of 393
intraoperative rupture of the membranes, cervical laceration, and bleeding during the 394
procedure.25 395
Strengths and Limitations 396
The strengths of our study: this is the first randomized study enrolling only twin 397
pregnancies with dilated cervix to cerclage or no cerclage. Expectant management with 398
no cerclage is the current standard of care for these women. There are no prior 399
dedicated RCTs in this population. Despite small sample size, we were able to show a 400
significant benefit to physical exam indicated cerclage. In our RCT, physical exam 401
indicated cerclage was associated with decreased perinatal mortality and overall 402
decreased in preterm birth at all gestational ages, however with the potential of more 403
early preterm deliveries. Some of the limitations include: small sample size as the 404
enrollment did not reach the intended 52 cases. The DSMB considered that it was 405
unethical to continue the study due to the considerable perinatal mortality in one of the 406
arms: 76.9% versus 17.6% (p<0.0001) and requested to unmask the arms of the study. 407
The primary and secondary outcomes were also significantly different, favoring the 408
cerclage group. Due to early termination of the study, we were unable to perform 409
additional sub analysis based on the degree of cervical dilation, GA before and after 20 410
weeks, use of progesterone or surgical techniques. The incidence of this challenging 411
obstetrical problem is very low. Only 3% of all deliveries are twins, of which about 5% 412
will have TVUCL ≤15mm,26 and even fewer will be identified with asymptomatic cervical 413
dilation ≥ 1cm before 24 weeks. The challenge of studying this clinical question is 414
highlighted by the fact that enrollment and randomization of 34 women was over a 415
period of 4 years at 8 academic centers in 8 different cities. The demographic 416
characteristics were not significant different but some imbalance in the participant 417
characteristics were noticed suggesting bias in the intervention allocation as the 418
enrollment was not stratified by institution or any of the maternal characteristics (like 419
history of preterm birth, gestational age or cervical dilation). In addition, we 420
acknowledge that four women were excluded from the study due to expired consent. 421
We did not renew IRB documentation on time to have a new consent. There is also a 422
discrepancy between groups in withdrawals from the study (1 of 18 in the cerclage 423
group [5.6%] vs 3 of 16 in the no cerclage group [18.8%]). The outcomes of these four 424
cases could have biased the outcome of the study. 425
The history of PTB in prior pregnancy was present in only 6 (20%) of our study group 426
while TVUCL ≤ 25mm preceded cervical dilation in 20/24 (83.3%) evaluated women. It 427
has been established that cervical length <25 mm is the best predictor of PTB in twin 428
pregnancy,27 and the shorter the TVUCL and the earlier GA at presentation, the higher 429
the risk of PTB.28 Cervical changes are dynamic, in singleton pregnancy TVUCL may 430
present with further shortening as pregnancy progresses; this is the bases of the 431
recommendation of serial TVUCL in women with history of preterm birth.29 In women 432
without risk for preterm birth, 30% of women with TVUCL <11mm had cervical dilation > 433
1cm at pelvic exam.30 Serial cervical evaluation have shown cervical shortening in twins 434
as well,31 however there are no studies assessing how many of them will have cervical 435
dilation. We did not performed serial TVUCL evaluation in twins and we are not able to 436
provide the incidence of cervical dilation. While TVUCL is currently the best tool 437
available to screen for PTB in twin pregnancy, independent of other risk factors, 438
ACOG32 and SMFM still recommends against TVCL in twins as there are no current 439
proven therapies to offer and TVUCL should be reserved for randomized controlled. 440
Retrospective studies in singleton pregnancy recommend amniocentesis to rule out 441
subclinical intrauterine infection; amniocentesis is expected to select a better candidate 442
prior to physical exam indicated cerclage.33, 34 In our trial amniocentesis was not 443
mandatory as IRB found it coercive, only 4/30 (13.3%) participants agreed with the 444
procedure. Assessment of amniotic fluid gram stain or amount of glucose in patients 445
prior to physical exam indicated cerclage have shown a positive predictive value of 446
47%, and a negative predictive value of 98% for intrauterine infection.35 Amniotic fluid 447
culture is considered the “gold standard” for diagnosis of infection, but cultures take 448
several days for final result and therefore limit the utility in clinical decision-making. 449
Multiple studies have reported an association between preterm labor/delivery and 450
various urogenital tract infections/colonization.36 The presence of cervico-vaginal 451
infections correlates with intra-amniotic infections and histologic chorioamnionitis, 452
considering the ascending infection and colonization the most probable pathway.37 In 453
our study only 4/30 (13.3%) had positive vaginal bacterial studies and 4/30 (13.3%) 454
were diagnosed with UTI. Our study had limited financial resources for additional 455
vaginal microbial studies or evaluation of cytokines in amniotic fluid or vagina, as we did 456
not have external funding; those studies included in our study were considered standard 457
of care per each institution. 458
While it was not prespecified in our RCT, all women who received physical exam 459
indicated cerclage also received indomethacin and antibiotics. This management is 460
similar to previous studies. The RCT by Althuisius et al. in 2003,3 used a combination of 461
indomethacin and antibiotics in all cases randomized to cerclage. In Roman et al.,12 462
retrospective case-control study of physical exam indicated cerclage in twins, the 463
majority of women received indomethacin 29 (76%) and prophylactic antibiotics 36 464
(94%) at the time of the cerclage placement. In a study by Miller et al.,38 a large 465
retrospective cohort of physical exam indicated cerclage in twins, 59 (57.3%) subjects 466
received indomethacin and 56 (54.3%) received antibiotics. Miller et al39 randomized 467
women with singleton pregnancies undergoing physical exam indicated cerclage to 468
indometacin and antibiotics (n=26) or no additional treatment (n=24). The median 469
latency from cerclage placement to delivery, GA at delivery, and neonatal outcomes 470
were no different between groups, but post hoc analysis revealed a greater proportion 471
of pregnancies were prolonged by at least 28 days among women who received 472
indomethacin and perioperative antibiotics (24 [92.3%] vs 15 [62.5%], p=0.01). In our 473
trial, the combination of cerclage, indomethacin, and antibiotics significantly decreased 474
the PTB at different GA cut-offs, increased median latency from cerclage placement to 475
delivery, and decreased perinatal mortality. Finally, the numerous secondary endpoints 476
with no adjustment for multiple comparisons could have led to type 1 error. 477
Clinical implications 478
A prospective registry of twin pregnancies receiving physical exam indicated cerclage 479
would allow us to examine how differences in gestational age, cervical dilation, prolapse 480
of amniotic membranes, surgical technique, and association with other therapies like 481
progesterone supplementation may affect the prognosis and outcome. Prospective 482
studies on the incidence of twin diamniotic pregnancies with TVUCL < 25 mm before 24 483
weeks that presented posteriorly with dilated cervix and lastly prospective studies 484
evaluating therapies in diamniotic twins with short cervix. Our group is enrolling for an 485
RCT in twins with TVUCL <15mm comparing cerclage vs. no cerclage and vaginal 486
progesterone on both arms, NCT03340688. 487
Conclusion 488
A combination of physical exam indicated cerclage, indomethacin, and antibiotics in 489
asymptomatic twin pregnancies before 24 weeks significantly decreases preterm birth 490
and perinatal mortality. 491
492
ACKNOWLEDGMENT
493
We thank the participant centers that screened for women with twin pregnancy at risk of 494
preterm birth but were unable to enroll patients: David McKenna, MD at Wright State 495
University, (Dayton, Ohio), Montse Palacio, MD at Hospital Clinic of Barcelona (Spain), 496
Federico Prefumo, MD at University of Brescia (Italy), Giuliana Simonazzi, MD at 497
University of Bologna (Italy), Patrycja Jarmużek, MD at University of Warsaw, (Poland), 498
Kate Pettit, MD at University of Virginia, Lone Hvidman, MD at Aarthus 499
Universitethospital, (Denmark) and Begona Martinez de Tejada, MD at University 500
Hospital of Geneva, (Switzerland). 501 502 503 504 505 506 507 508 509
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TABLES
632
Table 1. Maternal Demographics 633
VARIABLE Physical exam
Indicated Cerclage n=17 No Cerclage n=13
Maternal Age (years) 31.6±4.4 28.2±5.1
Race Caucasian African-American Hispanic Asian/Indian 7 (41.2) 6 (35.3) 2 (11.8) 2 (11.8) 6 (46.2) 4 (30.8) 2 (15.4) 1 (7.7) Nuliparity 11 (64.7) 9 (69.2) Diamniotic-Dichorionic 16 (94.1) 12 (92.3) Level of education Incomplete high school Completed high school College/some college 2 (11.8) 6 (35.3) 9 (52.9) 2 (15.4) 2 (15.4) 9 (69.2)
Assisted Reproductive Technology 7 (41.2) 4 (30.8)
Prior PTB (16-36 weeks) 4 (23.5) 2 (15.4)
Prior cervical surgery (LEEP/CKC) 1 (5.9) 1 (7.7)
Smoking 1 (5.9) 0 (0) BMI 27.8±4.4 30.0±8.6 BMI ≥ 30 4 (23.5) 6 (46.2) CHTN 0 (0) 2 (15.4) History of Preeclampsia 2 (11.8) 0 (0) TVUCL done 14 (82.4) 10 (76.9) TVUCL (<25 mm) 10/14 (71.4) 10/10 (100) GA at randomization (weeks) 20.7±1.7 19.4±1.5 GA < 20 weeks 5 (29.4) 8 (61.5)
Cervical dilation at diagnosis (cm) 1.8±0.8 2.1±0.7 1 cm 2 cm 3 cm 4 cm 6 (35.3) 9 (52.9) 1 (5.9) 1 (5.9) 2 (15.4) 7 (53.8) 3 (23.1) 1 (7.7) Amniotic membrane prolapse
50% Into cervical canal At external os 8 (47.1) 9 (52.9) 6 (46.1) 7 (53.8) Amniocentesis 2 (11.8) 2 (15.4) Vaginal progesterone 9 (52.9) 10 (76.9) Indomethacin administration 14 (82.4) 4 (30.8) Antibiotics at cerclage 14 (82.4) 0 (0) Urinary infection 1 (5.9) 4 (30.8) Bacterial vaginosis 2 (11.8) 1 (7.7) Chlamydia 1 (5.9) 0 (0) Gonorrhea 0 (0) 0 (0) 634
Variables described as mean ± standard deviation or frequencies (percentage). 635
GA: Gestational age 636
PTB: Preterm birth 637
CHTN: Chronic hypertension 638
BMI: Body mass index 639
TVUCL: Transvaginal ultrasound cervical length 640
LEEP: Loop electrosurgical excision procedure 641
CKC: Cold knife cone 642 643 644 645 646 647 648
Table 2. Antepartum and delivery outcomes of twin pregnancies with dilated cervix 649 VARIABLE Physical exam Indicated Cerclage n=17 No Cerclage n=13 RR (Cl, 95%) or MD (Cl, 95%) p-value NNT SPTB < 34 weeks 12 (70.6) 13 (100) 0.71 (0.52-0.96) 0.05 3.4 SPTB < 32 weeks 11 (64.7) 13 (100) 0.65 (0.46-0.92) 0.02 2.8 SPTB < 28 weeks 7 (41.2) 11(84.6) 0.49 (0.26-0.89) 0.02 2.3 SPTB < 24 weeks 5 (29.4) 11 (84.6) 0.35 (0.16-0.75) 0.004 1.8 Antepartum admission ǂ 9 (52.9) 1 (7.7) 6.88 (1.43-40) 0.02 PPROM <34 weeks 11 (64.7) 5 (38.5) 1.68 (0.83-3.86) 0.26 Antenatal steroids 13 (76.5) 4 (30.8) 2.51 (1.12-5.84) 0.02 Tocolysis 6 (35.3) 3 (23.1) 1.50 (0.47-4.94) 0.7 GA at PPROM (weeks) 28.4±5.6 19.3±0.5 9.0 (3.4-14.6) † 0.02 GA at delivery (weeks) 29.1±1.7 22.5±3.9 6.9 (2.9-10.9) † <0.01 Diagnosis to delivery interval (weeks) 8.3±5.8 2.9±3.0 5.6 (2.0-9.3) † 0.02 Mode of delivery • Vaginal delivery both • CS both 4 (23.5) 13 (76.5) 10 (76.9) 3 (23.1) 0.30 (0.12-0.76) 3.30 (1.19-9.3) 0.008 Clinical chorioamnionitis 2 (11.8) 3 (23.1) 0.51 (0.1-2.6) 0.62 Histological chorioamnionitis 4 (23.5) 8 (61.5) 0.38 (0.14-1.0) 0.06 Abruption 3 (17.6) 1 (7.7) 2.29 (0.26-19.6) 0.6
Birth weight Twin A 1331±850 529±479 801 (1306 to 297) † 0.003 Birth weight Twin B 1349±950 502±432 847 (1384 to 309) † 0.003 Birth weight (g)* 1349±874 544±434 823 (446 to 1200) † <0.0001 Birth weight <1500g* 21/34 (61.7) 24/26
(92.3) 0.67 (0.50-0.89) 0.007
3.3
A Apgar < 7 at 5 min Twin B 5/17 11/13 0.34 (0.16-0.75) 0.004 Apgar < 7 at 5 min* 9/34 (26.5) 22/26 (84.6) 0.26 (0.16-0.50) <0.0001 1.7
Both twins died 2/17 (11.7) 10/13
(76.9) 0.15 (0.04-0.58) 0.005
One twin died 2/17 (11.7) 0/13 (0) NA 0.49
Both twins alive 13/17 (76.4) 3/17 (17.6) 3.31 (1.18-9.25) 0.009 At least 1 newborn
home 15/17 (88.2) 3/13 (0.23) 3.8 (1.4-10.4) 0.0005
Perinatal mortality Twin
A 3/17 (17.6) 10/13 (76.9 0.22 (0.1-0.67) 0.002
Perinatal mortality Twin B 3/17 (17.6) 10/13 (76.9) 0.22 (0.1-0.67) 0.002 Overall perinatal mortality* 6/34 (17.6) 20/26 (76.9) 0.23 (0.1-0.49) <0.0001 1.7 650
Variables described as mean ± standard deviation or frequencies (percentage). 651
GA: Gestational age 652
PTB: Preterm birth 653
PPROM: Preterm premature rupture of membranes 654 CS: Cesarean section 655 MD: mean difference 656 RR: relative risk 657
CI: Confidence interval 658
NNT: number needed to treat 659
* Data including both twins A and B 660
† Data correspond to mean difference 661
ǂ Antenatal admission refers to admission for expectant management but not admission 662
for imminent delivery 663
664 665 666 667
Table 3 Outcome of neonates born alive 668
VARIABLE Physical exam Indicated Cerclage n=30 No Cerclage n=6 RR (Cl, 95%) or MD (Cl, 95%) p-value Admission to NICU 22 (73.3) 6 (100) 0.73 (0.6-1.0) 0.3 GA admitted to NICU (weeks) 27.9±3.6 28.1±3.4 0.15 (-5.1 to 5.4) † 0.9 Neonatal mortality 2 (6.6) 0 -1.3 (0.1 to -21.01) 1.0 Composite neonatal outcome 14 (46.6) 3 (50) 0.93 (0.4-2.2) 1.0
NICU LOS (days) 68.2±65.3 92.3±53.4 29.8 (-14.6 to -74.2) † 0.3 RDS (intubation or CPAP) 14 (46.6) 2 (33.3) 1.41 (0.42-4.6) 0.67 IVH stage 3,4 4 (13.3) 1 (16.6) 0.80 (0.1-5.9) 1.0 NEC stage 3,4 0 0 NA -- Sepsis 2 (6.6) 1 (16.6) 0.40 (0.04-3.74) 0.43 ROP/Laser 5 (16.6) 1 (16.6) 1.0 (0.14-7.1) 1.0 669
Variables described as mean ± standard deviation or frequencies (percentage). 670
RR: relative ratio 671
MD: Mean difference 672
CI: Confidence interval 673
GA: Gestational age 674
LOS: Length of stay in the hospital 675
NICU: Neonatal intensive care unit 676
RDS: respiratory distress syndrome 677
CPAP: continuous positive airway pressure 678
IVH: Intraventricular hemorrhage 679
NEC: Necrotizing enterocolitis 680
ROP: Retinopathy of prematurity 681
NA: not applicable 682
† Data correspond to mean difference 683
Table 4. Neonatal outcomes treating twin pair as cluster unit
684 685
686 VARIABLE OR (CI 95%)* p-value * ICC (95% CI) Admission to NICU** 0.37 (0.02 to 8.58) 0.53 1 Perinatal mortality 0.09 (0.02 to 0.51) 0.006 0.86 (0.73 to 0.93) Neonatal mortality** 1.30 (0.05 to 33.63) 0.88 -0.34 (-0.38 to 0.32) 687
Variables described as mean ± standard deviation or frequencies (percentage). 688
Boldface data, statistically significant 689
OR: odds ratio 690
CI: Confidence interval 691
NICU: Neonatal intensive care unit 692
ICC: intracluster correlation coefficient 693
*Generalized mixed-model analysis, treating twin pair as cluster unit 694
**Outcomes of only neonates born alive 695 696 697 698 699 700 701 702 703 704 705 706 707 FIGURE LEGENDS 708
Figure 1. Randomization and follow up of participants 709
710 711
Figure 2. Survival curves of twin pregnancies that remained undelivered across 712
gestation 713
714
Kaplan-Meier survival curves indicating the proportions of women with twin pregnancy 715
in the physical exam indicated cerclage and control groups. The log-rank test showed 716
significant difference Hazard Ratio 0.33 (95%CI 0.13-0.8) p=0.0006 717
718
