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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.

This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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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

(3)

(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.

24

Financial Support: No external financial support was received for this study.

25

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

(4)

Condensation: Physical exam indicated cerclage, indomethacin, and antibiotics in

44

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?

50

• To evaluate if physical exam indicated cerclage will decrease preterm birth 51

in twin pregnancy 52

B. What are the key findings?

53

• 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?

57

• 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

(5)

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

(6)

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

(7)

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

(8)

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

(9)

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

(10)

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

(11)

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

(12)

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

(13)

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

(14)

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

(15)

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

(16)

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

(17)

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

(18)

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

(19)

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

(20)

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

(21)

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

(22)

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

(23)

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

(24)

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

(25)

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(28)

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)

(29)

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

(30)

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

(31)

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

(32)

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

(33)

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

(34)

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

(35)
(36)

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