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The risk of spontaneous preterm birth in asymptomatic women with a short cervix (≤25 mm) at 23−28 weeks’ gestation
Journal Pre-proof The risk of spontaneous preterm birth in asymptomatic women with a short cervix (≤ 25mm) at 23-28 weeks’ gestation Moti Gulersen, MD, MSc, Michael Y. Divon, MD, David Krantz, MA, Frank Chervenak, MD, Eran Bornstein, MD PII:
S2589-9333(19)30092-8
DOI:
https://doi.org/10.1016/j.ajogmf.2019.100059
Reference:
AJOGMF 100059
To appear in:
American Journal of Obstetrics & Gynecology MFM
Received Date: 1 August 2019 Revised Date:
15 October 2019
Accepted Date: 16 October 2019
Please cite this article as: Gulersen M, Divon MY, Krantz D, Chervenak F, Bornstein E, The risk of spontaneous preterm birth in asymptomatic women with a short cervix (≤ 25mm) at 23-28 weeks’ gestation, American Journal of Obstetrics & Gynecology MFM (2019), doi: https://doi.org/10.1016/ j.ajogmf.2019.100059. 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. © 2019 Elsevier Inc. All rights reserved.
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The risk of spontaneous preterm birth in asymptomatic women with a short cervix (≤
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25mm) at 23-28 weeks’ gestation
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Moti GULERSEN1 MD, MSc, Michael Y. DIVON2 MD, David KRANTZ3 MA, Frank
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CHERVENAK1 MD, Eran BORNSTEIN1,2 MD
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1
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NY, 2Division of Maternal-Fetal Medicine, Lenox Hill Hospital – Northwell Health, New York,
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NY, 3Eurofins NTD, Melville, NY
Department of Obstetrics and Gynecology, Lenox Hill Hospital – Northwell Health, New York,
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The authors report no conflict of interest.
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Presented as poster presentations (final abstract numbers 465 and 466) at the 39th annual meeting
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of the Society for Maternal-Fetal Medicine, Las Vegas, NV, February 11th – 16th, 2019.
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Correspondence
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Moti Gulersen MD, MSc
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Department of Obstetrics and Gynecology
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Lenox Hill Hospital – Northwell Health
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100 East 77th Street, New York, NY, 10075
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Email: [email protected]
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Abstract word count: 457
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Main text word count: 2,747
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Condensation
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The risk of spontaneous preterm birth in asymptomatic women with a sonographic short cervix
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(≤ 25mm) at 23-28 weeks’ gestation increases as cervical length decreases.
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Short version of title
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The risk of spontaneous preterm birth with short cervix at 23-28 weeks’ gestation.
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AJOG at a glance
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A. Why was this study conducted?
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•
The relationship between cervical length and the risk of spontaneous preterm birth after
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23 weeks is not well known. Thus, we set out to determine the risk of spontaneous
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preterm birth in asymptomatic women with a short cervix (≤ 25mm) at 23-28 weeks’
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gestation
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B. What are the key findings? •
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The risk for spontaneous preterm birth in asymptomatic women with short cervix (≤ 25mm) increases as cervical length decreases
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Delivery within 1 or 2 weeks from presentation with short cervix (≤ 25mm) was rare in
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our asymptomatic population, regardless of the cervical length (≤ 10mm, 11-15mm, 16-
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20mm, or 21-25mm)
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C. What does this study add to what is already known? •
We add to the limited existing literature regarding the risk of spontaneous preterm birth
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in a population of asymptomatic women with a short cervix (≤ 25mm) between 23-28
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weeks’ gestation
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•
Based on our data indicating rare progression to delivery within 1-2 weeks, we suggest that management decisions such as timing of administration of antenatal corticosteroids
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in asymptomatic patients with CL ≤25mm at 23-28 weeks’ gestation may be delayed
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until additional indications are present
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Abstract
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Background: Asymptomatic short cervical length (CL) is an independent risk factor for
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spontaneous preterm birth (sPTB). However, most studies have focused on the associated risk of
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a short CL when encountered between 16-23 weeks’ gestation. The relationship between CL and
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risk of sPTB after 23 weeks is not well known.
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Objective: To evaluate the risk of a short CL in asymptomatic women at 23-28 weeks’ gestation.
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Study Design: A retrospective cohort study of women with asymptomatic short cervix (CL ≤
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25mm) at extreme prematurity, defined as 23 to 28 weeks’ gestation, was performed at a single
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center from January 2015 to March 2018. Women with symptoms of preterm labor, multiple
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gestations, fetal or uterine anomalies, cervical cerclage or those with incomplete data were
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excluded from the study. Demographic information, as well as data on risk factors for sPTB,
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were collected. Patients were divided into 4 groups based on the CL measurement (≤ 10mm, 11-
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15mm, 16-20mm, and 21-25mm). The primary outcome was time interval from enrollment to
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delivery. Secondary outcomes included delivery within 1 and 2 weeks of enrollment, gestational
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age (GA) at delivery, and delivery prior to 32, 34, and 37 weeks, respectively. Continuous
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variables were compared using Kruskal-Wallis test, while categorical variables were compared
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using Chi-square or Fisher’s exact test as appropriate. The Wilcoxon test for difference in
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survival time was used to compare GA at delivery among the 4 CL groups with data stratified
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based on GA at enrollment.
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Results: Of the 126 pregnancies that met inclusion criteria, 22 (17.4%) had a CL ≤ 10mm, 23
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(18.3%) had a CL of 11-15mm, 37 (29.4%) had a CL of 16-20mm and 44 (34.9%) had a CL of
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21-25mm. Baseline characteristics were similar among all four groups. The shorter CL group
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was associated with a shorter time interval from enrollment of to delivery (CL ≤ 10mm: 10
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weeks, CL 11-15mm: 12.7 weeks, CL 16-20mm 13 weeks, CL 21-25mm: 13.2 weeks; p =
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0.006). Regardless of the CL measurement, delivery within 2 weeks was extremely uncommon
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(1 patient; 0.8%). The prevalence of sPTB < 32 weeks or <34 weeks was higher in women with a
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CL ≤ 10mm compared to those with a longer CL (p < 0.001).
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Conclusions:
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increases as cervical length decreases. The risk is substantially higher in women with a CL
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≤10mm. Women with a CL ≤10mm also had the shortest time interval to delivery. Nevertheless,
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delivery within 1 or 2 weeks is highly unlikely, regardless of the CL at the time of enrollment.
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Therefore, based on our data, we suggest that management decisions such as timing of
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administration of antenatal corticosteroids in asymptomatic patients with CL ≤25mm at 23-28
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weeks’ gestation may be delayed until additional indications are present.
The risk of sPTB in asymptomatic women with a sonographic short cervix
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Key words: cervical length, transvaginal ultrasound, anticipated delivery, prematurity, preterm
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birth, periviability, antenatal corticosteroids
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Introduction
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Preterm birth (PTB) continues to be a leading cause of neonatal morbidity and mortality,1-5 and
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remains the most common indication for antenatal hospitalization.6 Management strategies to
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improve neonatal outcome, such as the administration of antenatal corticosteroids (ACS) and
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hospitalization to provide close proximity to a neonatal intensive care unit (NICU), have been
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implemented in women at risk.6-8
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Screening modalities have also been developed to identify patients at risk of spontaneous PTB
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(sPTB).7 Appropriate screening may be utilized to indicate different intervention strategies aimed
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to reduce the risk of prematurity and its related complications. For example, transvaginal
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ultrasound evaluation of the cervix has been adopted as a mode to identify pregnancies at risk for
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preterm birth.7,9,10 A short cervical length (CL ≤25 mm) has been identified as a risk factor for
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sPTB, with the risk increasing as the CL shortens.9-28
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While the relationship between a sonographic short CL and risk of sPTB is well established,
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most studies have focused on CLs obtained between 16 to 23 weeks’ gestation.11-15,17-21,24,25 The
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clinical significance of a sonographic short CL between 23 to 28 weeks’ gestation is not well
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known. This has substantial clinical implications, as current management concepts, which were
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derived from randomized controlled trials looking at early gestational ages, have been applied to
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patients presenting at a later gestational age as well.29-41
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Moreover, the limited understanding of the risk of sPTB with a short CL between 23 to 28
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weeks’ gestation may contribute to suboptimal timing of ACS administration and
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hospitalization.42-44 Therefore, the aim of our study was to determine the risk of spontaneous
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preterm birth in asymptomatic women with a short CL (≤25 mm) at 23 to 28 weeks of gestation.
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Materials and Methods
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This was a retrospective, cross-sectional, cohort study of all women in which transvaginal
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ultrasound detected a short cervix (CL ≤ 25mm) between 23 and 28 weeks of gestation.. The
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study was conducted at a single center (Center for Maternal-Fetal Medicine, Lenox Hill Hospital,
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New York, NY) between January 2015 and March 2018. Transvaginal cervical length screening
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is performed routinely in all women during the second trimester anatomical survey (performed
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between 18-24 weeks of gestation). Additionally, earlier cervical length screening and
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surveillance are employed in women who are considered to be at high risk for preterm birth due
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to history of prior sPTB, multiple gestations, prior cervical conization via loop electrosurgical
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excision procedure (LEEP) and/or cold knife, or congenital uterine malformation. Cervical
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length assessments are also performed as surveillance in women in which a short cervix had been
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detected incidentally at their anatomical survey. Cervical length surveillance in high-risk patients
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(including those who had a short CL at the time of their anatomical survey) was continued until
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34 weeks. The assessment of the cervix and CL measurements were performed in a uniform
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manner using a transvaginal probe with an empty bladder over a period of approximately 5
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minutes, where the shortest functional CL, out of 3 repeated measurements, were recorded. In
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addition to measuring the CL, the presence of cervical funnelling and intra-amniotic sludge was
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recorded.
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Only women who were asymptomatic at the time of their CL assessment were eligible for
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inclusion to our study. Women were deemed asymptomatic if they had no signs or symptoms of
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preterm labor (i.e. uterine contractions, abdominal or lower back pain, pelvic pressure, vaginal
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bleeding, or leakage of amniotic fluid). If a woman had multiple cervical length assessments, the
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earliest GA (between 23 to 28 weeks’ gestation) in which a CL measurement ≤ 25mm was
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detected was used for the inclusion to the study.
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Women with symptoms of preterm labor upon presentation, multiple gestations, cervical
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cerclage, fetal or uterine anomalies or those with incomplete pregnancy data, were excluded
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from the study. Maternal characteristics such as age, weight, ethnicity and parity were collected.
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Additionally, a detailed medical and obstetric history, including risk factors for sPTB and use of
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any form of progesterone to reduce the likelihood of sPTB, was extracted from the medical
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record. The decision to offer vaginal progesterone suppositories to asymptomatic women with a
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sonographic short CL was left to the discretion of the Obstetrician.
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Cases were stratified into 4 separate groups based on the CL measurement upon enrollment: ≤
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10mm, 11-15mm, 16-20mm and 21-25mm. The primary outcome was the time interval, in
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weeks, from enrollment to delivery. Secondary outcomes included delivery within 1 or 2 weeks
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from enrollment, GA at delivery, and delivery prior to 32, 34, and 37 weeks, respectively. These
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outcomes were compared among the 4 CL groups using the Kruskal-Wallis test for continuous
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variables and Chi-squared of Fisher’s exact test for categorical variables. The Wilcoxon test for
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difference in survival time was used to compare GA at delivery among the 4 CL groups with
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data stratified based on GA at presentation. Statistical significance was defined as a P value <
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0.05. An institutional review board exemption was obtained.
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Results
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Our population included one hundred ninety three (n = 193) women with a short CL between 23
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and 28 weeks of gestation. Of those, 67 cases were excluded as they met one or more of the
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exclusion criteria. Of the remaining 126 patients in our cohort, 115 (91.3%) had been screened at
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the time of their routine anatomical survey. The study cohort included 54 (42.9%) women that
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had a short CL first diagnosed prior to 23 weeks’ gestation (52 at anatomical survey, 2 at
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initiation of screening less than 18 weeks’ gestation due to known risk factor for sPTB) and 72
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(57.1%) women that had a short CL between 23 and 28 weeks of gestation. Furthermore, 22
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(17.4%) had a CL ≤ 10mm, 23 (18.3%) had a CL of 11-15mm, 37 (29.4%) had a CL of 16-
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20mm and 44 (34.9%) had a CL of 21-25mm upon enrollment. A detailed flow chart illustrating
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the exclusion process and the distribution to the different CL groups is presented in Figure 1.
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Baseline demographics, including the presence of risk factors for preterm birth, were similar
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among the four CL groups (Table 1). Among the 52 women diagnosed with a short CL at the
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time of their anatomical survey, 4 (7.7%) had already been receiving treatment with progesterone
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(4 with 17α-hydroxyprogesterone caproate and none with vaginal suppository) and 34 (65.4%)
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subsequently initiated treatment with vaginal progesterone suppository. Among the 72 women
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diagnosed with a short CL between 23 and 28 weeks of gestation, 41 (56.9%) subsequently
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initiated treatment with vaginal progesterone suppository and none received treatment with 17α-
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hydroxyprogesterone caproate. The prevalence of vaginal progesterone suppository use was
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significantly higher as the CL was shorter (p < 0.001). All women in the CL ≤ 10mm group
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received treatment with progesterone (Table 1).
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The median time interval from enrollment with short CL to delivery was directly correlated to
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the CL, with significantly shorter time interval to delivery in shorter CL groups (p = 0.02; Table
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2). The median time interval from diagnosis with short CL to delivery was also directly
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correlated to the CL, with significantly shorter time to delivery in the shorter CL groups (p =
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0.03, Table 2). A survival curve illustrating the probability of delivery as a function of time
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interval from enrollment in each of the different short CL groups is displayed in Figure 2. As
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expected, the risk of sPTB in asymptomatic women with a sonographic short cervix increases as
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CL decreases. The extremely short CL of < 10mm was associated with a significantly higher
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probability (p = 0.006) for sPTB (Figure 2).
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Regardless of the CL measurement at 23 to 28 weeks’ gestation, imminent delivery was
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extremely uncommon. In fact, none of the patients delivered within 7 days of enrollment, and
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delivery within 2 weeks occurred in a single patient from the CL <10mm group (0.8% of all
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patients with CL<25mm; Table 2). This patient had an asymptomatic CL of 7 mm at 23 weeks of
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gestation and subsequently ruptured membranes and delivered eight days after enrollment.
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The risk of sPTB prior to 32 weeks (p < 0.001), 34 weeks (p < 0.001) and 37 weeks (p = 0.002)
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was significantly different among all four groups (Table 2). In particular, the prevalence of sPTB
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< 32 weeks and <34 weeks were disproportionately higher in women with a CL ≤ 10mm. In fact,
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40.9% of women with a CL ≤ 10mm delivered prior to 32 weeks of gestation. In contrast, sPTB
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prior to 32 or 34 weeks of gestation was significantly lower in women with a CL > 10mm,
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occurring in 2.7 to 8.7% (p < 0.001; Table 2). The median GA at delivery decreased as the
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cervical length decreased (p = 0.01; Table 2).
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Comment
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Principal Findings
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The results of the present study illustrate two main findings. First, we demonstrated that the risk
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of sPTB in asymptomatic women with a sonographic short cervix (≤ 25mm) at 23-28 weeks’
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gestation increases as CL decreases. The time interval from enrollment of patients with a short
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CL (≤ 25mm) to delivery was shorter in the more severe short CL group. In fact, women in the
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CL ≤ 10mm group were noted to have an over 10-fold increase in the risk of sPTB prior to 32
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weeks as well as a shorter time interval to delivery compared to those with a longer CL.
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Secondly, regardless of the CL between 23 and 28 weeks’ gestation, delivery within one or two
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weeks was highly unlikely (0% and 0.8% of the total cohort and 0% and 4.6% of the CL ≤ 10mm
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group, delivered within one and two weeks, respectively).
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Clinical implications
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This study highlights the clinical dilemma regarding prediction of sPTB and management of
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asymptomatic women with a short cervix at 23 to 28 weeks of gestation, where interventions
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such as administration of ACS or hospitalization may be utilized. We selected the gestational
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ages of 23 to 28 weeks for several reasons. First, the clinical significance of a short cervix after
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23 weeks’ gestation is not well known, as most studies have evaluated the risk of sPTB based on
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cervical lengths obtained an earlier GA range. Furthermore, early viability represents a critical
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period where neonatal morbidity and mortality is at its highest. Timely administration of ACS
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(within 24 hours to 7 days of delivery) in particular, is an important intervention for optimal
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efficacy in reducing neonatal morbidity and mortality.45,46 Thus, a better understanding and
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assessment of the risk of preterm birth in this select patient population is of major importance.
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However, data on this subject are limited.
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Results
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Our findings indicate an extremely low risk of sPTB within 2 weeks of enrollment with a short
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cervix (0.8% of the total cohort and 4.6% of the CL<10mm group). This is consistent with a
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recent publication by Richards and colleagues47. Their group evaluated the risk of anticipated
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delivery in asymptomatic women with a short cervix. They reported that although 63% of
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patients (230 of the 367 that were included in their cohort) received ACS, only 2 patients (0.5%
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of the cohort) delivered within 7 days of the time a short cervix was identified.47 Their cohort,
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however, included women with mild symptoms such as pelvic pressure, cramping or vaginal
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spotting and was thus, not truly asymptomatic47 Levin et al.48 reported a slightly higher risk of
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sPTB within 7 days as compared to our study. They found that optimal timing of ACS
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administration was unlikely in asymptomatic women at increased risk for sPTB, such as those
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with a short CL detected by ultrasound. In fact, only 11.8% of women in their study cohort
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delivered within 24 hours to 7 days of ACS administration.48 They included women with a
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positive fetal fibronectin test, as well as those with asymptomatic cervical dilation, which may
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have contributed to the higher rate of sPTB within 7 days in their group48, compared to the
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findings reported in our study or those by Richards et al.47
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While delivery within 2 weeks of presentation may be very uncommon in asymptomatic women
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presenting with a short cervix at 23-28 weeks of gestation, these women are still at increased risk
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of sPTB and should be counselled appropriately. We identified that the group of women with an
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extremely short cervix (CL ≤ 10mm) is at a particularly high risk of severe prematurity. Indeed,
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these women had a disproportionately higher risk (over 10-fold higher) for delivery prior to 32
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weeks of gestation compared to those with a longer CL. Similarly, a CL > 10mm and especially
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CL > 15mm can be interpreted as somewhat reassuring given the lower risk for severe
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prematurity in these cases. Berghella and colleagues have also described the increased risk of
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severe prematurity in women with an extremely short cervix.49 Their retrospective analysis
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identified that the probability of delivery prior to 32 weeks of gestation in women with a CL <
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10mm detected between 23 and 28 weeks, was high and ranged between 25.2 and 51%.49 These
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results are very similar to ours, indicating the significant risk of prematurity in the extremely
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short cervix (CL < 10mm) group.
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Strengths and limitations
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There are several strengths to this study. The patient population was carefully selected based on
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strict inclusion and exclusion criteria so that it reflects those with a truly “asymptomatic” short
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cervix in the early viability period. Our inclusion criteria was not limited to only those with risk
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factors for sPTB and included patients with the incidental finding of an asymptomatic short CL
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at the time of their anatomical scan, further supporting the generalizability of our study cohort.
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Furthermore, we utilized a critical gestational age range where neonatal complications are at its
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highest and timely administration of ACS is of importance. Our findings add to the existing
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literature, confirming that transvaginal CL in the second trimester can be used as a screen to
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identify patients at an increased risk of sPTB. we corroborated the prior findings indicating that
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the shorter the CL is associated with a higher the risk for sPTB.9-28
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This study however, has several limitations. The sample size of our cohort and different CL
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groups is relatively small. Nevertheless, the statistical analysis was sufficiently powered,
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indicating a marked difference in both primary and secondary outcomes among women with
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varying degrees of short CL. However, due to the small sample size, it is possible that we were
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unable to detect unmeasured or unknown confounding factors that may explain the significant
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differences found in our study. Additionally, CL results were not blinded and thus, patients were
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subject to interventions at the obstetrician’s discretion that may affect sPTB risk. However, given
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that all providers were from the same center, treatment protocols were homogenous. This was a
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cross-sectional study rather than a longitudinal one and as such, we could not assess the CL
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measurements in a continuous fashion. Nevertheless, a dichotomous division of our study
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population according to different short CL severity groups clearly demonstrated that shorter CL
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groups are associated with a higher risk of sPTB.
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Another limitation exists regarding the use of vaginal progesterone in our study cohort. Vaginal
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progesterone, an intervention shown to reduce the risk of sPTB in asymptomatic women with a
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short cervix28-32,50-52, which is considered “standard of care” was administered to the majority of
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patients in this cohort. However, given the retrospective nature of our analysis, we were not able
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to control for treatment of progesterone and as a result, some patients did not receive it. Most
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patients treated with vaginal progesterone had been diagnosed with a short CL after 23 weeks’
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gestation. Furthermore, there were a few patients who had already been treated with either
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vaginal progesterone or 17α-hydroxyprogesterone caproate prior to their short CL diagnosis.
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While use of progesterone may affect time interval from diagnosis of a short CL to delivery, the
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effect of initiation of progesterone after 23 weeks is less clear and the impact of progesterone on
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time interval to delivery was not the focus of our study.
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Our data indicates that administration of ACS may be delayed in asymptomatic women with
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short cervix given the low risk of imminent delivery. However, this is based on the time interval
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from enrollment to delivery, which is an indirect approach to determine the potential benefit of
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timely steroid administration. We have no data to compare the neonatal outcomes of different
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strategies of ACS administration. In order to provide further evidence to support our conclusions,
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a randomized controlled trial (RCT) comparing the impact of immediate versus delayed
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administration of ACS on neonatal outcomes in asymptomatic patients with a short CL would
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have been optimal. Nevertheless, given the multiple obstacles to perform such a study, as well as
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the accumulating data supporting our findings, we believe that our results have merit.
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Conclusion
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In conclusion, we have demonstrated that asymptomatic women with a short cervix in early
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viability are at an increased risk for sPTB. Moreover, the severity of CL shortening may assist in
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determining the overall risk, as women with a CL ≤ 10mm were at a particularly high risk for
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sPTB. However, management of such pregnancies remain a clinical challenge, as the likelihood
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of anticipated delivery within two weeks of enrollment was extremely low. Our data suggest that
13
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administration of ACS based solely on a short CL measurement may be premature. Therefore,
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we propose that the timing of administration of ACS be individualized in asymptomatic women
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with short cervix at 23-28 weeks’ gestation and determined based on additional findings, such as
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signs and symptoms of preterm labor and preterm prelabor rupture of membranes.
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References
323
1. United Nations Children’s Fund (UNICEF). Committing to child survival: a promise renewed.
324
Progress Report 2014. New York, NY: UNICEF; 2014.
325
2. United Nations Inter-agency Group for Child Mortality Estimation (UN IGME). Levels &
326
trends in child mortality. Report 2014. New York, NY: UNICEF; 2014.
327
3. Savitz DA, Blackmore CA, Thorp JM. Epidemiologic characteristics of preterm delivery:
328
etiologic heterogeneity. Am J Obstet Gynecol 1991;164:467–71.
329
4. Martin JA, Hamilton BE, Sutton PD, Ventura SJ, Mathews TJ, Osterman MJ. Births: final data
330
for 2008. Natl Vital Stat Rep 2010;59:1–72.
331
5. Hamilton BE, Hoyert DL, Martin JA, et al. Annual summary of vital statistics: 2010-2011.
332
Pediatrics 2013;131:548-58.
333
6. American College of Obstetricians and Gynecologists. Management of Preterm Labor. ACOG
334
practice bulletin number 171. Washington, DC: American College of Obstetricians and
335
Gynecologists; 2016.
336
7. American College of Obstetricians and Gynecologists. Prediction and Prevention of Preterm
337
Birth. ACOG practice bulletin number 130. Washington, DC: American College of Obstetricians
338
and Gynecologists; 2012.
339
8. American College of Obstetricians and Gynecologists. Antenatal Corticosteroid Therapy for
340
Fetal Maturation. ACOG committee opinion number 713. Washington, DC: American College of
341
Obstetricians and Gynecologists; 2017.
342
9. Andersen HF, Nugent CE, Wanty SD, et al. Prediction of risk for preterm delivery by
343
ultrasonographic measurement of cervical length. Am J Obstet Gynecol 1990;163(3):859-67.
15
344
10. Iams JD, Goldenberg RL, Meis PJ, et al. The length of the cervix and the risk of spontaneous
345
premature delivery. National Institute of Child Health and Human Development Maternal Fetal
346
Medicine Unit Network. N Engl J Med 1996;334(9):567-72.
347
11. Heath VC, Southall TR, Souka AP, Elisseou A, Nicolaides KH. Cervical length at 23 weeks
348
of gestation: prediction of spontaneous preterm delivery. Ultrasound Obstet Gynecol 1998;12:
349
312–7.
350
12. Owen J, Yost N, Berghella V, Thom E, Swain M, Dildy GA 3rd, Miodovnik M, Langer O,
351
Sibai B, McNellis D; National Institute of Child Health and Human Development, Maternal-
352
Fetal Medicine Units Network. Mid-trimester endovaginal sonography in women at high risk for
353
spontaneous preterm birth. JAMA 2001;286:1340-8.
354
13. To MS, Skentou C, Liao AW, Cacho A, Nicolaides KH. Cervical length and funneling at 23
355
weeks of gestation in the prediction of spontaneous early preterm delivery. Ultrasound Obstet
356
Gynecol 2001;18:200-3.
357
14. Honest H, Bachmann LM, Coomarasamy A, Gupta JK, Kleijnen J, Khan KS. Accuracy of
358
cervical transvaginal sonography in predicting preterm birth: a systematic review. Ultrasound
359
Obstet Gynecol 2003;22:305-22.
360
15. Crane JM, Hutchens D. Transvaginal sonographic measurement of cervical length to predict
361
preterm birth in asymptomatic women at increased risk: a systematic review. Ultrasound Obstet
362
Gynecol 2008;31:579–587.
363
16. Berghella V, Tolosa JE, Kuhlman K, Weiner S, Bolognese RJ, Wapner RJ. Cervical
364
ultrasonography compared with manual examination as a predictor of preterm delivery. Am J
365
Obstet Gynecol. 1997;177:723–30.
366
17. Hassan SS, Romero R, Berry SM, et al. Patients with an ultrasonographic cervical length < or
16
367
=15 mm have nearly a 50% risk of early spontaneous preterm delivery. Am J Obstet Gynecol.
368
2000;182:1458–67.
369
18. Honest H, Bachmann LM, Coomarasamy A, Gupta JK, Kleijnen J, Khan KS. Accuracy of
370
cervical transvaginal sonography in predicting preterm birth: a systematic review. Ultrasound
371
Obstet Gynecol 2003;22(3):305-22.
372
19. Owen J, Yost N, Berghella V, et al. Can shortened midtrimester cervical length predict very
373
early spontaneous preterm birth? Am J Obstet Gynecol. 2004;191:298–303.
374
20. Arabin B, Roos C, Kollen B, Van Eyck J. Comparison of transvaginal sonography in
375
recumbent and standing maternal positions to predict spontaneous preterm birth in singleton and
376
twin pregnancies. Ultrasound Obstet Gynecol. 2006;27:377–86.
377
21. To MS, Skentou CA, Royston P, Yu CK, Nicolaides KH. Prediction of patient-specific risk
378
of early preterm delivery using maternal history and sonographic measurement of cervical
379
length: a population-based prospective study. Ultrasound Obstet Gynecol. 2006;27:362–7.
380
22. Honest H, Forbes CA, Duree KH, et al. Screening to prevent spontaneous preterm birth:
381
systematic reviews of accuracy and effectiveness literature with economic modelling. Health
382
Technol Assess. 2009;13:1–627.
383
23. Domin CM, Smith EJ, Terplan M. Transvaginal ultrasonographic measurement of cervical
384
length as a predictor of preterm birth: a systematic review with meta-analysis. Ultrasound Q.
385
2010;26:241–8.
386
24. Barros-Silva J, Pedrosa AC, Matias A. Sonographic measurement of cervical length as a
387
predictor of preterm delivery: a systematic review. J Perinat Med. 2014;42:281–93.
388
25. Li Q, Reeves M, Owen J, Keith LG. Precocious cervical ripening as a screening target to
389
predict spontaneous preterm delivery among asymptomatic singleton pregnancies: a systematic
17
390
review. Am J Obstet Gynecol 2015;212:145-56.
391
26. Conde-Agudelo A, Romero R. Predictive accuracy of changes in transvaginal sonographic
392
cervical length over time for preterm birth: a systematic review and metaanalysis. Am J Obstet
393
Gynecol 2015;213:789-801.
394
27. Vandermolen BI, Hezelgrave NL, Smout EM, Abbott DS, Seed PT, Shennan AH.
395
Quantitative fetal fibronectin and cervical length to predict preterm birth in asymptomatic
396
women with previous cervical surgery. Am J Obstet Gynecol 2016;215:480.e1-80.e10.
397
28. Romero R, Conde-Agudelo A, Da Fonseca E, et al. Vaginal progesterone for preventing
398
preterm birth and adverse perinatal outcomes in singleton gestations with a short cervix: a meta-
399
analysis of individual patient data. Am J Obstet Gynecol 2018;218(2):161-180.
400
29. Fonseca EB, Celik E, Parra M, Singh M, Nicolaides KH. Progesterone and the risk of
401
preterm birth among women with a short cervix. N Engl J Med. 2007;(5):462-9.
402
30. Hassan SS, Romero R, Vidyadhari D, et al. Vaginal progesterone reduces the rate of preterm
403
birth in women with a sonographic short cervix: a multicenter, randomized, double-blind,
404
placebo- controlled trial. Ultrasound Obstet Gynecol. 2011;38:18-31.
405
31. O’Brien JM, Adair CD, Lewis DF, et al. Progesterone vaginal gel for the reduction of
406
recurrent preterm birth: primary results from a randomized, double-blind, placebo-controlled
407
trial. Ultrasound Obstet Gynecol. 2007;30:687-96.
408
32. Cetingoz E, Cam C, Sakalli M, Karateke A, Celik C, Sancak A. Progesterone effects on
409
preterm birth in high-risk pregnancies: a randomized placebo-controlled trial. Arch Gynecol
410
Obstet. 2011;283(3):423-9.
411
33. Otsuki K, Nakai A, Matsuda Y, et al. Randomized trial of ultrasound-indicated cerclage in
412
singleton women without lower genital tract inflammation. J Obstet Gynaecol Res 2016;42:148-
18
413
157.
414
34. Rust OA, Atlas RO, Reed J, van Gaalen J, Balducci J. Revisiting the short cervix detected by
415
transvaginal ultrasound in the second trimester: Why cerclage therapy
416
Obstet Gynecol 2001;185:1098-1105.
417
35. Althuisius SM, Dekker GA, Hummel P, Bekedam DJ, van Geijn HP. Final results of the
418
cervical incompetence prevention randomized cerclage trial (CIPRACT): Therapeutic cerclage
419
with bed rest versus bed rest alone. Am J Obstet Gynecol 2001;185:1106-1112.
420
36. To MS, Alfirevic Z, Heath VCF, Cacho AM, Williamson PR, Nicolaides KH. Cervical
421
cerclage for prevention of preterm delivery in women with short cervix: randomized controlled
422
trial. Lancet 2004;363:1849-1853.
423
37. Berghella V, Odibo AO, Tolosa JE. Cerclage for prevention of preterm birth in women with
424
a short cervix found on transvaginal ultrasound examination: A randomized trial. Am J Obstet
425
Gynecol 2004;191:1311-7.
426
38. Conde-Agudelo A, Romero R, Da Fonseca E, et al. Vaginal progesterone is as effective as
427
cervical cerclage to prevent preterm birth in women with a singleton gestation, previous
428
spontaneous preterm birth, and a short cervix: updated indirect comparison meta-analysis. Am J
429
Obstet Gyncol 2018;219:10-25.
430
39. Enakpene CA, DiGiovanni L, Jones TN, Marshalla M, Mastrogiannis D, Della Torre M.
431
Cervical cerclage for singleton pregnant patients on vaginal progesterone with progressive
432
cervical shortening. Am J Obstet Gynecol 2018;219(4):397.e1-397.e10.
433
40. Sanchez-Ramos L. Vaginal progesterone is an alternative to cervical cerclage in women with
434
a short cervix and a history of preterm birth. Am J Obstet Gynecol 2018 Jul;219(1):5-9.
may not help. Am J
19
435
41. Romero R, Espinoza J, Erez O, Hassan S. The role of cervical cerclage in obstetric practice:
436
can the patient who could benefit from this procedure be identified? Am J Obstet Gynecol
437
2006;194(1):1-9.
438
42. Sahasrabudhe N, Igel C, Echevarria GC, et al. Universal cervical length screening and
439
antenatal corticosteroid timing. Obstet Gynecol 2017;129(6):1104-1108.
440
43. Makhija NK, Tronnes AA, Dunlap BS, et al. Antenatal corticosteroid timing: accuracy after
441
the introduction of a rescue course protocol. Am J Obstet Gynecol 2016;214:120.e1-6.
442
44. Adams TM, Kinzler WL, Chavez MR, Fazzari MJ, Vintzileos AM. Practice patterns in the
443
timing of antenatal corticosteroids for fetal lung maturity. J Matern Fetal Neonatal Med
444
2015;28(13):1598-1601.
445
45. Liggins GC. Premature delivery of foetal lambs infused with glucocorticoids. J Endocrinol
446
1969;45(4):515-23.
447
46. Roberts D, Dalziel S. Antenatal corticosteroids for accelerating fetal lung maturation for
448
women at risk of preterm birth. Cochrane Database Syst Rev 2006;3:CD004454.
449
47. Richards DS, Wong LF, Esplin MS, Collingridge DS. Anticipatory corticosteroid
450
administration to asymptomatic women with a short cervix. Am J Perinatol 2018;35:394-404.
451
48. Levin HI, Ananth CV, Benjamin-Boamah C, Ziddiq Z, Son M, Friedman AM. Clinical
452
indication and timing of antenatal corticosteroid administration at a single centre. BJOG
453
2016;123:409-414.
454
49. Berghella V, Roman A, Daskalakis C, Ness A, Baxter JK. Gestational age at cervical length
455
measurement and incidence of preterm birth. Obstet Gynecol 2007;110:311-7.
20
456
50. Campbell S. Prevention of spontaneous preterm birth: universal cervical length assessment
457
and vaginal progesterone in women with a short cervix: time for action! Am J Obstet Gynecol
458
2018;218(2):151-158.
459
51. Newnham JP, White SW, Meharry S, et al. Reducing preterm birth by a statewide
460
multifaceted program: an implementation study. Am J Obstet Gynecol 2017;216:434–42.
461
52. Romero R, Yeo L, Miranda J, Hassan SS, Conde-Agudelo A, Chaiworapongsa T. A blueprint
462
for the prevention of preterm birth: vaginal progesterone in women with a short cervix. J Perinat
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Med 2013;41(1):27-44.
464
21
Tables Table 1. Baseline demographic characteristics and risk factors for preterm delivery. Characteristic
CL ≤ 10mm (n = 22) 30.5 (26-36) 32.05 (25-38.4) 24 (23.3-25.1)
CL 11-15mm CL 16-20mm CL 21-25mm P value (n = 23) (n = 37) (n = 44) 30 (29-36) 34 (29-37) 33 (30-35.5) 0.35 28.1 (26.4-36.3) 28.4 (25.9-33.1) 30 (25.25-32.95) 0.76 25.1 (23.4-26.1) 25.1 (24.1-26.3) 25 (23.7-27) 0.11
Maternal age (years) – Median (IQR) BMI (kg/m2) – Median (IQR) GA (weeks) at enrollment – Median (IQR) Race or ethnic group – n (%) African American 8 (36.4) 8 (34.8) 4 (10.8) 8 (18.2) 0.05 Asian 1 (4.5) 1 (4.4) 4 (10.8) 6 (13.6) 0.60 White 3 (13.6) 11 (47.8) 13 (35.1) 17 (38.6) 0.09 Other 10 (45.5) 3 (13) 16 (43.3) 13 (29.6) 0.05 Nulliparous – n (%) 13 (59) 13 (57) 19 (51) 22 (50) 0.89 Prior spontaneous PTB – n (%) 4 (18.2) 3 (13) 3 (8.1) 1 (2.2) 0.10 In vitro fertilization – n (%) 1 (4.6) 1 (4.4) 3 (8.1) 5 (11.4) 0.81 Prior cervical surgery – n (%) 0 (0) 4 (17.4) 7 (18.9) 6 (13.6) 0.14 Prior D&C and/or D&E – n (%) 10 (45.5) 8 (34.8) 9 (24.3) 12 (27.3) 0.33 Vaginal progesterone suppository – n (%) 21 (95.4) 21 (91.3) 18 (48.6) 15 (34.1) <0.001 1 (4.6) 1 (4.4) 2 (5.4) 1 (2.3) 0.91 17α-hydroxyprogesterone caproate – n (%) CL, cervical length; BMI, body mass index; IQR, interquartile range; GA, gestational age; PTB, preterm birth; D&C, dilation & curettage; D&E, dilation & evacuation.
Table 2. Comparison of the primary and secondary outcomes between the different CL groups. Outcome
CL ≤ 10mm (n = 22)
CL 11-15mm (n = 23)
Time interval, enrollment to delivery – 10 (5.4-14.9) 12.7 (10-15) weeks (median, IQR) Time interval, diagnosis of short CL to 11.4 (8.7-16.5) 14.8 (12-18) delivery – weeks (median, IQR) Delivery within 7 days [n, (%)] 0 0 Delivery within 2 weeks [n, (%)] 1 (4.6) 0 Delivery < 32 weeks [n, (%)] 9 (40.9) 1 (4.4) Delivery < 34 weeks [n, (%)] 9 (40.9) 2 (8.7) Delivery < 37 weeks [n, (%)] 10 (45.5) 9 (39.1) GA at delivery – weeks (median, IQR) 37.1 (30.1-39) 38 (36.3-39.4) CL, cervical length; IQR, interquartile range; GA, gestational age.
CL 16-20mm (n = 37)
CL 21-25mm (n = 44)
P value
13 (11.3-14.9)
13.2 (11.5-15.1)
0.02
15.4 (12.8-17.4) 13.3 (11.5-16.0)
0.03
0 0 1 (2.7) 1 (2.7) 5 (13.5) 38.4 (37.4-39.4)
0 0 2 (4.6) 3 (6.8) 5 (11.4) 39 (37.9-39.5)
1 0.17 <0.001 <0.001 0.002 0.01
Figure Legends I. Flow diagram illustrating the exclusion process in the study cohort. CL, cervical length. II. Survival curve illustrating the probability of delivery as a function of time interval from enrollment to delivery in each of the different short CL groups. CL, cervical length.
S2589-9333(19)30092-8
DOI:
https://doi.org/10.1016/j.ajogmf.2019.100059
Reference:
AJOGMF 100059
To appear in:
American Journal of Obstetrics & Gynecology MFM
Received Date: 1 August 2019 Revised Date:
15 October 2019
Accepted Date: 16 October 2019
Please cite this article as: Gulersen M, Divon MY, Krantz D, Chervenak F, Bornstein E, The risk of spontaneous preterm birth in asymptomatic women with a short cervix (≤ 25mm) at 23-28 weeks’ gestation, American Journal of Obstetrics & Gynecology MFM (2019), doi: https://doi.org/10.1016/ j.ajogmf.2019.100059. 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. © 2019 Elsevier Inc. All rights reserved.
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The risk of spontaneous preterm birth in asymptomatic women with a short cervix (≤
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25mm) at 23-28 weeks’ gestation
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Moti GULERSEN1 MD, MSc, Michael Y. DIVON2 MD, David KRANTZ3 MA, Frank
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CHERVENAK1 MD, Eran BORNSTEIN1,2 MD
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1
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NY, 2Division of Maternal-Fetal Medicine, Lenox Hill Hospital – Northwell Health, New York,
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NY, 3Eurofins NTD, Melville, NY
Department of Obstetrics and Gynecology, Lenox Hill Hospital – Northwell Health, New York,
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The authors report no conflict of interest.
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Presented as poster presentations (final abstract numbers 465 and 466) at the 39th annual meeting
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of the Society for Maternal-Fetal Medicine, Las Vegas, NV, February 11th – 16th, 2019.
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Correspondence
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Moti Gulersen MD, MSc
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Department of Obstetrics and Gynecology
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Lenox Hill Hospital – Northwell Health
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100 East 77th Street, New York, NY, 10075
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Email: [email protected]
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Abstract word count: 457
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Main text word count: 2,747
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Condensation
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The risk of spontaneous preterm birth in asymptomatic women with a sonographic short cervix
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(≤ 25mm) at 23-28 weeks’ gestation increases as cervical length decreases.
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Short version of title
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The risk of spontaneous preterm birth with short cervix at 23-28 weeks’ gestation.
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AJOG at a glance
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A. Why was this study conducted?
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•
The relationship between cervical length and the risk of spontaneous preterm birth after
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23 weeks is not well known. Thus, we set out to determine the risk of spontaneous
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preterm birth in asymptomatic women with a short cervix (≤ 25mm) at 23-28 weeks’
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gestation
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B. What are the key findings? •
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The risk for spontaneous preterm birth in asymptomatic women with short cervix (≤ 25mm) increases as cervical length decreases
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Delivery within 1 or 2 weeks from presentation with short cervix (≤ 25mm) was rare in
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our asymptomatic population, regardless of the cervical length (≤ 10mm, 11-15mm, 16-
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20mm, or 21-25mm)
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C. What does this study add to what is already known? •
We add to the limited existing literature regarding the risk of spontaneous preterm birth
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in a population of asymptomatic women with a short cervix (≤ 25mm) between 23-28
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weeks’ gestation
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•
Based on our data indicating rare progression to delivery within 1-2 weeks, we suggest that management decisions such as timing of administration of antenatal corticosteroids
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in asymptomatic patients with CL ≤25mm at 23-28 weeks’ gestation may be delayed
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until additional indications are present
26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46
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Abstract
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Background: Asymptomatic short cervical length (CL) is an independent risk factor for
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spontaneous preterm birth (sPTB). However, most studies have focused on the associated risk of
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a short CL when encountered between 16-23 weeks’ gestation. The relationship between CL and
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risk of sPTB after 23 weeks is not well known.
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Objective: To evaluate the risk of a short CL in asymptomatic women at 23-28 weeks’ gestation.
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Study Design: A retrospective cohort study of women with asymptomatic short cervix (CL ≤
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25mm) at extreme prematurity, defined as 23 to 28 weeks’ gestation, was performed at a single
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center from January 2015 to March 2018. Women with symptoms of preterm labor, multiple
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gestations, fetal or uterine anomalies, cervical cerclage or those with incomplete data were
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excluded from the study. Demographic information, as well as data on risk factors for sPTB,
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were collected. Patients were divided into 4 groups based on the CL measurement (≤ 10mm, 11-
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15mm, 16-20mm, and 21-25mm). The primary outcome was time interval from enrollment to
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delivery. Secondary outcomes included delivery within 1 and 2 weeks of enrollment, gestational
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age (GA) at delivery, and delivery prior to 32, 34, and 37 weeks, respectively. Continuous
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variables were compared using Kruskal-Wallis test, while categorical variables were compared
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using Chi-square or Fisher’s exact test as appropriate. The Wilcoxon test for difference in
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survival time was used to compare GA at delivery among the 4 CL groups with data stratified
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based on GA at enrollment.
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Results: Of the 126 pregnancies that met inclusion criteria, 22 (17.4%) had a CL ≤ 10mm, 23
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(18.3%) had a CL of 11-15mm, 37 (29.4%) had a CL of 16-20mm and 44 (34.9%) had a CL of
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21-25mm. Baseline characteristics were similar among all four groups. The shorter CL group
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was associated with a shorter time interval from enrollment of to delivery (CL ≤ 10mm: 10
3
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weeks, CL 11-15mm: 12.7 weeks, CL 16-20mm 13 weeks, CL 21-25mm: 13.2 weeks; p =
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0.006). Regardless of the CL measurement, delivery within 2 weeks was extremely uncommon
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(1 patient; 0.8%). The prevalence of sPTB < 32 weeks or <34 weeks was higher in women with a
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CL ≤ 10mm compared to those with a longer CL (p < 0.001).
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Conclusions:
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increases as cervical length decreases. The risk is substantially higher in women with a CL
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≤10mm. Women with a CL ≤10mm also had the shortest time interval to delivery. Nevertheless,
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delivery within 1 or 2 weeks is highly unlikely, regardless of the CL at the time of enrollment.
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Therefore, based on our data, we suggest that management decisions such as timing of
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administration of antenatal corticosteroids in asymptomatic patients with CL ≤25mm at 23-28
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weeks’ gestation may be delayed until additional indications are present.
The risk of sPTB in asymptomatic women with a sonographic short cervix
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Key words: cervical length, transvaginal ultrasound, anticipated delivery, prematurity, preterm
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birth, periviability, antenatal corticosteroids
84 85 86 87 88 89 90 91 92
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Introduction
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Preterm birth (PTB) continues to be a leading cause of neonatal morbidity and mortality,1-5 and
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remains the most common indication for antenatal hospitalization.6 Management strategies to
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improve neonatal outcome, such as the administration of antenatal corticosteroids (ACS) and
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hospitalization to provide close proximity to a neonatal intensive care unit (NICU), have been
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implemented in women at risk.6-8
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Screening modalities have also been developed to identify patients at risk of spontaneous PTB
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(sPTB).7 Appropriate screening may be utilized to indicate different intervention strategies aimed
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to reduce the risk of prematurity and its related complications. For example, transvaginal
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ultrasound evaluation of the cervix has been adopted as a mode to identify pregnancies at risk for
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preterm birth.7,9,10 A short cervical length (CL ≤25 mm) has been identified as a risk factor for
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sPTB, with the risk increasing as the CL shortens.9-28
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While the relationship between a sonographic short CL and risk of sPTB is well established,
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most studies have focused on CLs obtained between 16 to 23 weeks’ gestation.11-15,17-21,24,25 The
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clinical significance of a sonographic short CL between 23 to 28 weeks’ gestation is not well
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known. This has substantial clinical implications, as current management concepts, which were
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derived from randomized controlled trials looking at early gestational ages, have been applied to
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patients presenting at a later gestational age as well.29-41
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Moreover, the limited understanding of the risk of sPTB with a short CL between 23 to 28
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weeks’ gestation may contribute to suboptimal timing of ACS administration and
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hospitalization.42-44 Therefore, the aim of our study was to determine the risk of spontaneous
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preterm birth in asymptomatic women with a short CL (≤25 mm) at 23 to 28 weeks of gestation.
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Materials and Methods
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This was a retrospective, cross-sectional, cohort study of all women in which transvaginal
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ultrasound detected a short cervix (CL ≤ 25mm) between 23 and 28 weeks of gestation.. The
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study was conducted at a single center (Center for Maternal-Fetal Medicine, Lenox Hill Hospital,
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New York, NY) between January 2015 and March 2018. Transvaginal cervical length screening
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is performed routinely in all women during the second trimester anatomical survey (performed
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between 18-24 weeks of gestation). Additionally, earlier cervical length screening and
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surveillance are employed in women who are considered to be at high risk for preterm birth due
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to history of prior sPTB, multiple gestations, prior cervical conization via loop electrosurgical
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excision procedure (LEEP) and/or cold knife, or congenital uterine malformation. Cervical
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length assessments are also performed as surveillance in women in which a short cervix had been
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detected incidentally at their anatomical survey. Cervical length surveillance in high-risk patients
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(including those who had a short CL at the time of their anatomical survey) was continued until
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34 weeks. The assessment of the cervix and CL measurements were performed in a uniform
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manner using a transvaginal probe with an empty bladder over a period of approximately 5
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minutes, where the shortest functional CL, out of 3 repeated measurements, were recorded. In
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addition to measuring the CL, the presence of cervical funnelling and intra-amniotic sludge was
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recorded.
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Only women who were asymptomatic at the time of their CL assessment were eligible for
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inclusion to our study. Women were deemed asymptomatic if they had no signs or symptoms of
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preterm labor (i.e. uterine contractions, abdominal or lower back pain, pelvic pressure, vaginal
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bleeding, or leakage of amniotic fluid). If a woman had multiple cervical length assessments, the
6
138
earliest GA (between 23 to 28 weeks’ gestation) in which a CL measurement ≤ 25mm was
139
detected was used for the inclusion to the study.
140
Women with symptoms of preterm labor upon presentation, multiple gestations, cervical
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cerclage, fetal or uterine anomalies or those with incomplete pregnancy data, were excluded
142
from the study. Maternal characteristics such as age, weight, ethnicity and parity were collected.
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Additionally, a detailed medical and obstetric history, including risk factors for sPTB and use of
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any form of progesterone to reduce the likelihood of sPTB, was extracted from the medical
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record. The decision to offer vaginal progesterone suppositories to asymptomatic women with a
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sonographic short CL was left to the discretion of the Obstetrician.
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Cases were stratified into 4 separate groups based on the CL measurement upon enrollment: ≤
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10mm, 11-15mm, 16-20mm and 21-25mm. The primary outcome was the time interval, in
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weeks, from enrollment to delivery. Secondary outcomes included delivery within 1 or 2 weeks
150
from enrollment, GA at delivery, and delivery prior to 32, 34, and 37 weeks, respectively. These
151
outcomes were compared among the 4 CL groups using the Kruskal-Wallis test for continuous
152
variables and Chi-squared of Fisher’s exact test for categorical variables. The Wilcoxon test for
153
difference in survival time was used to compare GA at delivery among the 4 CL groups with
154
data stratified based on GA at presentation. Statistical significance was defined as a P value <
155
0.05. An institutional review board exemption was obtained.
156
Results
157
Our population included one hundred ninety three (n = 193) women with a short CL between 23
158
and 28 weeks of gestation. Of those, 67 cases were excluded as they met one or more of the
159
exclusion criteria. Of the remaining 126 patients in our cohort, 115 (91.3%) had been screened at
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the time of their routine anatomical survey. The study cohort included 54 (42.9%) women that
7
161
had a short CL first diagnosed prior to 23 weeks’ gestation (52 at anatomical survey, 2 at
162
initiation of screening less than 18 weeks’ gestation due to known risk factor for sPTB) and 72
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(57.1%) women that had a short CL between 23 and 28 weeks of gestation. Furthermore, 22
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(17.4%) had a CL ≤ 10mm, 23 (18.3%) had a CL of 11-15mm, 37 (29.4%) had a CL of 16-
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20mm and 44 (34.9%) had a CL of 21-25mm upon enrollment. A detailed flow chart illustrating
166
the exclusion process and the distribution to the different CL groups is presented in Figure 1.
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Baseline demographics, including the presence of risk factors for preterm birth, were similar
168
among the four CL groups (Table 1). Among the 52 women diagnosed with a short CL at the
169
time of their anatomical survey, 4 (7.7%) had already been receiving treatment with progesterone
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(4 with 17α-hydroxyprogesterone caproate and none with vaginal suppository) and 34 (65.4%)
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subsequently initiated treatment with vaginal progesterone suppository. Among the 72 women
172
diagnosed with a short CL between 23 and 28 weeks of gestation, 41 (56.9%) subsequently
173
initiated treatment with vaginal progesterone suppository and none received treatment with 17α-
174
hydroxyprogesterone caproate. The prevalence of vaginal progesterone suppository use was
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significantly higher as the CL was shorter (p < 0.001). All women in the CL ≤ 10mm group
176
received treatment with progesterone (Table 1).
177
The median time interval from enrollment with short CL to delivery was directly correlated to
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the CL, with significantly shorter time interval to delivery in shorter CL groups (p = 0.02; Table
179
2). The median time interval from diagnosis with short CL to delivery was also directly
180
correlated to the CL, with significantly shorter time to delivery in the shorter CL groups (p =
181
0.03, Table 2). A survival curve illustrating the probability of delivery as a function of time
182
interval from enrollment in each of the different short CL groups is displayed in Figure 2. As
183
expected, the risk of sPTB in asymptomatic women with a sonographic short cervix increases as
8
184
CL decreases. The extremely short CL of < 10mm was associated with a significantly higher
185
probability (p = 0.006) for sPTB (Figure 2).
186
Regardless of the CL measurement at 23 to 28 weeks’ gestation, imminent delivery was
187
extremely uncommon. In fact, none of the patients delivered within 7 days of enrollment, and
188
delivery within 2 weeks occurred in a single patient from the CL <10mm group (0.8% of all
189
patients with CL<25mm; Table 2). This patient had an asymptomatic CL of 7 mm at 23 weeks of
190
gestation and subsequently ruptured membranes and delivered eight days after enrollment.
191
The risk of sPTB prior to 32 weeks (p < 0.001), 34 weeks (p < 0.001) and 37 weeks (p = 0.002)
192
was significantly different among all four groups (Table 2). In particular, the prevalence of sPTB
193
< 32 weeks and <34 weeks were disproportionately higher in women with a CL ≤ 10mm. In fact,
194
40.9% of women with a CL ≤ 10mm delivered prior to 32 weeks of gestation. In contrast, sPTB
195
prior to 32 or 34 weeks of gestation was significantly lower in women with a CL > 10mm,
196
occurring in 2.7 to 8.7% (p < 0.001; Table 2). The median GA at delivery decreased as the
197
cervical length decreased (p = 0.01; Table 2).
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Comment
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Principal Findings
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The results of the present study illustrate two main findings. First, we demonstrated that the risk
201
of sPTB in asymptomatic women with a sonographic short cervix (≤ 25mm) at 23-28 weeks’
202
gestation increases as CL decreases. The time interval from enrollment of patients with a short
203
CL (≤ 25mm) to delivery was shorter in the more severe short CL group. In fact, women in the
204
CL ≤ 10mm group were noted to have an over 10-fold increase in the risk of sPTB prior to 32
205
weeks as well as a shorter time interval to delivery compared to those with a longer CL.
206
Secondly, regardless of the CL between 23 and 28 weeks’ gestation, delivery within one or two
9
207
weeks was highly unlikely (0% and 0.8% of the total cohort and 0% and 4.6% of the CL ≤ 10mm
208
group, delivered within one and two weeks, respectively).
209
Clinical implications
210
This study highlights the clinical dilemma regarding prediction of sPTB and management of
211
asymptomatic women with a short cervix at 23 to 28 weeks of gestation, where interventions
212
such as administration of ACS or hospitalization may be utilized. We selected the gestational
213
ages of 23 to 28 weeks for several reasons. First, the clinical significance of a short cervix after
214
23 weeks’ gestation is not well known, as most studies have evaluated the risk of sPTB based on
215
cervical lengths obtained an earlier GA range. Furthermore, early viability represents a critical
216
period where neonatal morbidity and mortality is at its highest. Timely administration of ACS
217
(within 24 hours to 7 days of delivery) in particular, is an important intervention for optimal
218
efficacy in reducing neonatal morbidity and mortality.45,46 Thus, a better understanding and
219
assessment of the risk of preterm birth in this select patient population is of major importance.
220
However, data on this subject are limited.
221
Results
222
Our findings indicate an extremely low risk of sPTB within 2 weeks of enrollment with a short
223
cervix (0.8% of the total cohort and 4.6% of the CL<10mm group). This is consistent with a
224
recent publication by Richards and colleagues47. Their group evaluated the risk of anticipated
225
delivery in asymptomatic women with a short cervix. They reported that although 63% of
226
patients (230 of the 367 that were included in their cohort) received ACS, only 2 patients (0.5%
227
of the cohort) delivered within 7 days of the time a short cervix was identified.47 Their cohort,
228
however, included women with mild symptoms such as pelvic pressure, cramping or vaginal
229
spotting and was thus, not truly asymptomatic47 Levin et al.48 reported a slightly higher risk of
10
230
sPTB within 7 days as compared to our study. They found that optimal timing of ACS
231
administration was unlikely in asymptomatic women at increased risk for sPTB, such as those
232
with a short CL detected by ultrasound. In fact, only 11.8% of women in their study cohort
233
delivered within 24 hours to 7 days of ACS administration.48 They included women with a
234
positive fetal fibronectin test, as well as those with asymptomatic cervical dilation, which may
235
have contributed to the higher rate of sPTB within 7 days in their group48, compared to the
236
findings reported in our study or those by Richards et al.47
237
While delivery within 2 weeks of presentation may be very uncommon in asymptomatic women
238
presenting with a short cervix at 23-28 weeks of gestation, these women are still at increased risk
239
of sPTB and should be counselled appropriately. We identified that the group of women with an
240
extremely short cervix (CL ≤ 10mm) is at a particularly high risk of severe prematurity. Indeed,
241
these women had a disproportionately higher risk (over 10-fold higher) for delivery prior to 32
242
weeks of gestation compared to those with a longer CL. Similarly, a CL > 10mm and especially
243
CL > 15mm can be interpreted as somewhat reassuring given the lower risk for severe
244
prematurity in these cases. Berghella and colleagues have also described the increased risk of
245
severe prematurity in women with an extremely short cervix.49 Their retrospective analysis
246
identified that the probability of delivery prior to 32 weeks of gestation in women with a CL <
247
10mm detected between 23 and 28 weeks, was high and ranged between 25.2 and 51%.49 These
248
results are very similar to ours, indicating the significant risk of prematurity in the extremely
249
short cervix (CL < 10mm) group.
250
Strengths and limitations
251
There are several strengths to this study. The patient population was carefully selected based on
252
strict inclusion and exclusion criteria so that it reflects those with a truly “asymptomatic” short
11
253
cervix in the early viability period. Our inclusion criteria was not limited to only those with risk
254
factors for sPTB and included patients with the incidental finding of an asymptomatic short CL
255
at the time of their anatomical scan, further supporting the generalizability of our study cohort.
256
Furthermore, we utilized a critical gestational age range where neonatal complications are at its
257
highest and timely administration of ACS is of importance. Our findings add to the existing
258
literature, confirming that transvaginal CL in the second trimester can be used as a screen to
259
identify patients at an increased risk of sPTB. we corroborated the prior findings indicating that
260
the shorter the CL is associated with a higher the risk for sPTB.9-28
261
This study however, has several limitations. The sample size of our cohort and different CL
262
groups is relatively small. Nevertheless, the statistical analysis was sufficiently powered,
263
indicating a marked difference in both primary and secondary outcomes among women with
264
varying degrees of short CL. However, due to the small sample size, it is possible that we were
265
unable to detect unmeasured or unknown confounding factors that may explain the significant
266
differences found in our study. Additionally, CL results were not blinded and thus, patients were
267
subject to interventions at the obstetrician’s discretion that may affect sPTB risk. However, given
268
that all providers were from the same center, treatment protocols were homogenous. This was a
269
cross-sectional study rather than a longitudinal one and as such, we could not assess the CL
270
measurements in a continuous fashion. Nevertheless, a dichotomous division of our study
271
population according to different short CL severity groups clearly demonstrated that shorter CL
272
groups are associated with a higher risk of sPTB.
273
Another limitation exists regarding the use of vaginal progesterone in our study cohort. Vaginal
274
progesterone, an intervention shown to reduce the risk of sPTB in asymptomatic women with a
275
short cervix28-32,50-52, which is considered “standard of care” was administered to the majority of
12
276
patients in this cohort. However, given the retrospective nature of our analysis, we were not able
277
to control for treatment of progesterone and as a result, some patients did not receive it. Most
278
patients treated with vaginal progesterone had been diagnosed with a short CL after 23 weeks’
279
gestation. Furthermore, there were a few patients who had already been treated with either
280
vaginal progesterone or 17α-hydroxyprogesterone caproate prior to their short CL diagnosis.
281
While use of progesterone may affect time interval from diagnosis of a short CL to delivery, the
282
effect of initiation of progesterone after 23 weeks is less clear and the impact of progesterone on
283
time interval to delivery was not the focus of our study.
284
Our data indicates that administration of ACS may be delayed in asymptomatic women with
285
short cervix given the low risk of imminent delivery. However, this is based on the time interval
286
from enrollment to delivery, which is an indirect approach to determine the potential benefit of
287
timely steroid administration. We have no data to compare the neonatal outcomes of different
288
strategies of ACS administration. In order to provide further evidence to support our conclusions,
289
a randomized controlled trial (RCT) comparing the impact of immediate versus delayed
290
administration of ACS on neonatal outcomes in asymptomatic patients with a short CL would
291
have been optimal. Nevertheless, given the multiple obstacles to perform such a study, as well as
292
the accumulating data supporting our findings, we believe that our results have merit.
293
Conclusion
294
In conclusion, we have demonstrated that asymptomatic women with a short cervix in early
295
viability are at an increased risk for sPTB. Moreover, the severity of CL shortening may assist in
296
determining the overall risk, as women with a CL ≤ 10mm were at a particularly high risk for
297
sPTB. However, management of such pregnancies remain a clinical challenge, as the likelihood
298
of anticipated delivery within two weeks of enrollment was extremely low. Our data suggest that
13
299
administration of ACS based solely on a short CL measurement may be premature. Therefore,
300
we propose that the timing of administration of ACS be individualized in asymptomatic women
301
with short cervix at 23-28 weeks’ gestation and determined based on additional findings, such as
302
signs and symptoms of preterm labor and preterm prelabor rupture of membranes.
303 304 305 306 307 308 309 310 311 312 313 314 315 316 317 318 319 320 321
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References
323
1. United Nations Children’s Fund (UNICEF). Committing to child survival: a promise renewed.
324
Progress Report 2014. New York, NY: UNICEF; 2014.
325
2. United Nations Inter-agency Group for Child Mortality Estimation (UN IGME). Levels &
326
trends in child mortality. Report 2014. New York, NY: UNICEF; 2014.
327
3. Savitz DA, Blackmore CA, Thorp JM. Epidemiologic characteristics of preterm delivery:
328
etiologic heterogeneity. Am J Obstet Gynecol 1991;164:467–71.
329
4. Martin JA, Hamilton BE, Sutton PD, Ventura SJ, Mathews TJ, Osterman MJ. Births: final data
330
for 2008. Natl Vital Stat Rep 2010;59:1–72.
331
5. Hamilton BE, Hoyert DL, Martin JA, et al. Annual summary of vital statistics: 2010-2011.
332
Pediatrics 2013;131:548-58.
333
6. American College of Obstetricians and Gynecologists. Management of Preterm Labor. ACOG
334
practice bulletin number 171. Washington, DC: American College of Obstetricians and
335
Gynecologists; 2016.
336
7. American College of Obstetricians and Gynecologists. Prediction and Prevention of Preterm
337
Birth. ACOG practice bulletin number 130. Washington, DC: American College of Obstetricians
338
and Gynecologists; 2012.
339
8. American College of Obstetricians and Gynecologists. Antenatal Corticosteroid Therapy for
340
Fetal Maturation. ACOG committee opinion number 713. Washington, DC: American College of
341
Obstetricians and Gynecologists; 2017.
342
9. Andersen HF, Nugent CE, Wanty SD, et al. Prediction of risk for preterm delivery by
343
ultrasonographic measurement of cervical length. Am J Obstet Gynecol 1990;163(3):859-67.
15
344
10. Iams JD, Goldenberg RL, Meis PJ, et al. The length of the cervix and the risk of spontaneous
345
premature delivery. National Institute of Child Health and Human Development Maternal Fetal
346
Medicine Unit Network. N Engl J Med 1996;334(9):567-72.
347
11. Heath VC, Southall TR, Souka AP, Elisseou A, Nicolaides KH. Cervical length at 23 weeks
348
of gestation: prediction of spontaneous preterm delivery. Ultrasound Obstet Gynecol 1998;12:
349
312–7.
350
12. Owen J, Yost N, Berghella V, Thom E, Swain M, Dildy GA 3rd, Miodovnik M, Langer O,
351
Sibai B, McNellis D; National Institute of Child Health and Human Development, Maternal-
352
Fetal Medicine Units Network. Mid-trimester endovaginal sonography in women at high risk for
353
spontaneous preterm birth. JAMA 2001;286:1340-8.
354
13. To MS, Skentou C, Liao AW, Cacho A, Nicolaides KH. Cervical length and funneling at 23
355
weeks of gestation in the prediction of spontaneous early preterm delivery. Ultrasound Obstet
356
Gynecol 2001;18:200-3.
357
14. Honest H, Bachmann LM, Coomarasamy A, Gupta JK, Kleijnen J, Khan KS. Accuracy of
358
cervical transvaginal sonography in predicting preterm birth: a systematic review. Ultrasound
359
Obstet Gynecol 2003;22:305-22.
360
15. Crane JM, Hutchens D. Transvaginal sonographic measurement of cervical length to predict
361
preterm birth in asymptomatic women at increased risk: a systematic review. Ultrasound Obstet
362
Gynecol 2008;31:579–587.
363
16. Berghella V, Tolosa JE, Kuhlman K, Weiner S, Bolognese RJ, Wapner RJ. Cervical
364
ultrasonography compared with manual examination as a predictor of preterm delivery. Am J
365
Obstet Gynecol. 1997;177:723–30.
366
17. Hassan SS, Romero R, Berry SM, et al. Patients with an ultrasonographic cervical length < or
16
367
=15 mm have nearly a 50% risk of early spontaneous preterm delivery. Am J Obstet Gynecol.
368
2000;182:1458–67.
369
18. Honest H, Bachmann LM, Coomarasamy A, Gupta JK, Kleijnen J, Khan KS. Accuracy of
370
cervical transvaginal sonography in predicting preterm birth: a systematic review. Ultrasound
371
Obstet Gynecol 2003;22(3):305-22.
372
19. Owen J, Yost N, Berghella V, et al. Can shortened midtrimester cervical length predict very
373
early spontaneous preterm birth? Am J Obstet Gynecol. 2004;191:298–303.
374
20. Arabin B, Roos C, Kollen B, Van Eyck J. Comparison of transvaginal sonography in
375
recumbent and standing maternal positions to predict spontaneous preterm birth in singleton and
376
twin pregnancies. Ultrasound Obstet Gynecol. 2006;27:377–86.
377
21. To MS, Skentou CA, Royston P, Yu CK, Nicolaides KH. Prediction of patient-specific risk
378
of early preterm delivery using maternal history and sonographic measurement of cervical
379
length: a population-based prospective study. Ultrasound Obstet Gynecol. 2006;27:362–7.
380
22. Honest H, Forbes CA, Duree KH, et al. Screening to prevent spontaneous preterm birth:
381
systematic reviews of accuracy and effectiveness literature with economic modelling. Health
382
Technol Assess. 2009;13:1–627.
383
23. Domin CM, Smith EJ, Terplan M. Transvaginal ultrasonographic measurement of cervical
384
length as a predictor of preterm birth: a systematic review with meta-analysis. Ultrasound Q.
385
2010;26:241–8.
386
24. Barros-Silva J, Pedrosa AC, Matias A. Sonographic measurement of cervical length as a
387
predictor of preterm delivery: a systematic review. J Perinat Med. 2014;42:281–93.
388
25. Li Q, Reeves M, Owen J, Keith LG. Precocious cervical ripening as a screening target to
389
predict spontaneous preterm delivery among asymptomatic singleton pregnancies: a systematic
17
390
review. Am J Obstet Gynecol 2015;212:145-56.
391
26. Conde-Agudelo A, Romero R. Predictive accuracy of changes in transvaginal sonographic
392
cervical length over time for preterm birth: a systematic review and metaanalysis. Am J Obstet
393
Gynecol 2015;213:789-801.
394
27. Vandermolen BI, Hezelgrave NL, Smout EM, Abbott DS, Seed PT, Shennan AH.
395
Quantitative fetal fibronectin and cervical length to predict preterm birth in asymptomatic
396
women with previous cervical surgery. Am J Obstet Gynecol 2016;215:480.e1-80.e10.
397
28. Romero R, Conde-Agudelo A, Da Fonseca E, et al. Vaginal progesterone for preventing
398
preterm birth and adverse perinatal outcomes in singleton gestations with a short cervix: a meta-
399
analysis of individual patient data. Am J Obstet Gynecol 2018;218(2):161-180.
400
29. Fonseca EB, Celik E, Parra M, Singh M, Nicolaides KH. Progesterone and the risk of
401
preterm birth among women with a short cervix. N Engl J Med. 2007;(5):462-9.
402
30. Hassan SS, Romero R, Vidyadhari D, et al. Vaginal progesterone reduces the rate of preterm
403
birth in women with a sonographic short cervix: a multicenter, randomized, double-blind,
404
placebo- controlled trial. Ultrasound Obstet Gynecol. 2011;38:18-31.
405
31. O’Brien JM, Adair CD, Lewis DF, et al. Progesterone vaginal gel for the reduction of
406
recurrent preterm birth: primary results from a randomized, double-blind, placebo-controlled
407
trial. Ultrasound Obstet Gynecol. 2007;30:687-96.
408
32. Cetingoz E, Cam C, Sakalli M, Karateke A, Celik C, Sancak A. Progesterone effects on
409
preterm birth in high-risk pregnancies: a randomized placebo-controlled trial. Arch Gynecol
410
Obstet. 2011;283(3):423-9.
411
33. Otsuki K, Nakai A, Matsuda Y, et al. Randomized trial of ultrasound-indicated cerclage in
412
singleton women without lower genital tract inflammation. J Obstet Gynaecol Res 2016;42:148-
18
413
157.
414
34. Rust OA, Atlas RO, Reed J, van Gaalen J, Balducci J. Revisiting the short cervix detected by
415
transvaginal ultrasound in the second trimester: Why cerclage therapy
416
Obstet Gynecol 2001;185:1098-1105.
417
35. Althuisius SM, Dekker GA, Hummel P, Bekedam DJ, van Geijn HP. Final results of the
418
cervical incompetence prevention randomized cerclage trial (CIPRACT): Therapeutic cerclage
419
with bed rest versus bed rest alone. Am J Obstet Gynecol 2001;185:1106-1112.
420
36. To MS, Alfirevic Z, Heath VCF, Cacho AM, Williamson PR, Nicolaides KH. Cervical
421
cerclage for prevention of preterm delivery in women with short cervix: randomized controlled
422
trial. Lancet 2004;363:1849-1853.
423
37. Berghella V, Odibo AO, Tolosa JE. Cerclage for prevention of preterm birth in women with
424
a short cervix found on transvaginal ultrasound examination: A randomized trial. Am J Obstet
425
Gynecol 2004;191:1311-7.
426
38. Conde-Agudelo A, Romero R, Da Fonseca E, et al. Vaginal progesterone is as effective as
427
cervical cerclage to prevent preterm birth in women with a singleton gestation, previous
428
spontaneous preterm birth, and a short cervix: updated indirect comparison meta-analysis. Am J
429
Obstet Gyncol 2018;219:10-25.
430
39. Enakpene CA, DiGiovanni L, Jones TN, Marshalla M, Mastrogiannis D, Della Torre M.
431
Cervical cerclage for singleton pregnant patients on vaginal progesterone with progressive
432
cervical shortening. Am J Obstet Gynecol 2018;219(4):397.e1-397.e10.
433
40. Sanchez-Ramos L. Vaginal progesterone is an alternative to cervical cerclage in women with
434
a short cervix and a history of preterm birth. Am J Obstet Gynecol 2018 Jul;219(1):5-9.
may not help. Am J
19
435
41. Romero R, Espinoza J, Erez O, Hassan S. The role of cervical cerclage in obstetric practice:
436
can the patient who could benefit from this procedure be identified? Am J Obstet Gynecol
437
2006;194(1):1-9.
438
42. Sahasrabudhe N, Igel C, Echevarria GC, et al. Universal cervical length screening and
439
antenatal corticosteroid timing. Obstet Gynecol 2017;129(6):1104-1108.
440
43. Makhija NK, Tronnes AA, Dunlap BS, et al. Antenatal corticosteroid timing: accuracy after
441
the introduction of a rescue course protocol. Am J Obstet Gynecol 2016;214:120.e1-6.
442
44. Adams TM, Kinzler WL, Chavez MR, Fazzari MJ, Vintzileos AM. Practice patterns in the
443
timing of antenatal corticosteroids for fetal lung maturity. J Matern Fetal Neonatal Med
444
2015;28(13):1598-1601.
445
45. Liggins GC. Premature delivery of foetal lambs infused with glucocorticoids. J Endocrinol
446
1969;45(4):515-23.
447
46. Roberts D, Dalziel S. Antenatal corticosteroids for accelerating fetal lung maturation for
448
women at risk of preterm birth. Cochrane Database Syst Rev 2006;3:CD004454.
449
47. Richards DS, Wong LF, Esplin MS, Collingridge DS. Anticipatory corticosteroid
450
administration to asymptomatic women with a short cervix. Am J Perinatol 2018;35:394-404.
451
48. Levin HI, Ananth CV, Benjamin-Boamah C, Ziddiq Z, Son M, Friedman AM. Clinical
452
indication and timing of antenatal corticosteroid administration at a single centre. BJOG
453
2016;123:409-414.
454
49. Berghella V, Roman A, Daskalakis C, Ness A, Baxter JK. Gestational age at cervical length
455
measurement and incidence of preterm birth. Obstet Gynecol 2007;110:311-7.
20
456
50. Campbell S. Prevention of spontaneous preterm birth: universal cervical length assessment
457
and vaginal progesterone in women with a short cervix: time for action! Am J Obstet Gynecol
458
2018;218(2):151-158.
459
51. Newnham JP, White SW, Meharry S, et al. Reducing preterm birth by a statewide
460
multifaceted program: an implementation study. Am J Obstet Gynecol 2017;216:434–42.
461
52. Romero R, Yeo L, Miranda J, Hassan SS, Conde-Agudelo A, Chaiworapongsa T. A blueprint
462
for the prevention of preterm birth: vaginal progesterone in women with a short cervix. J Perinat
463
Med 2013;41(1):27-44.
464
21
Tables Table 1. Baseline demographic characteristics and risk factors for preterm delivery. Characteristic
CL ≤ 10mm (n = 22) 30.5 (26-36) 32.05 (25-38.4) 24 (23.3-25.1)
CL 11-15mm CL 16-20mm CL 21-25mm P value (n = 23) (n = 37) (n = 44) 30 (29-36) 34 (29-37) 33 (30-35.5) 0.35 28.1 (26.4-36.3) 28.4 (25.9-33.1) 30 (25.25-32.95) 0.76 25.1 (23.4-26.1) 25.1 (24.1-26.3) 25 (23.7-27) 0.11
Maternal age (years) – Median (IQR) BMI (kg/m2) – Median (IQR) GA (weeks) at enrollment – Median (IQR) Race or ethnic group – n (%) African American 8 (36.4) 8 (34.8) 4 (10.8) 8 (18.2) 0.05 Asian 1 (4.5) 1 (4.4) 4 (10.8) 6 (13.6) 0.60 White 3 (13.6) 11 (47.8) 13 (35.1) 17 (38.6) 0.09 Other 10 (45.5) 3 (13) 16 (43.3) 13 (29.6) 0.05 Nulliparous – n (%) 13 (59) 13 (57) 19 (51) 22 (50) 0.89 Prior spontaneous PTB – n (%) 4 (18.2) 3 (13) 3 (8.1) 1 (2.2) 0.10 In vitro fertilization – n (%) 1 (4.6) 1 (4.4) 3 (8.1) 5 (11.4) 0.81 Prior cervical surgery – n (%) 0 (0) 4 (17.4) 7 (18.9) 6 (13.6) 0.14 Prior D&C and/or D&E – n (%) 10 (45.5) 8 (34.8) 9 (24.3) 12 (27.3) 0.33 Vaginal progesterone suppository – n (%) 21 (95.4) 21 (91.3) 18 (48.6) 15 (34.1) <0.001 1 (4.6) 1 (4.4) 2 (5.4) 1 (2.3) 0.91 17α-hydroxyprogesterone caproate – n (%) CL, cervical length; BMI, body mass index; IQR, interquartile range; GA, gestational age; PTB, preterm birth; D&C, dilation & curettage; D&E, dilation & evacuation.
Table 2. Comparison of the primary and secondary outcomes between the different CL groups. Outcome
CL ≤ 10mm (n = 22)
CL 11-15mm (n = 23)
Time interval, enrollment to delivery – 10 (5.4-14.9) 12.7 (10-15) weeks (median, IQR) Time interval, diagnosis of short CL to 11.4 (8.7-16.5) 14.8 (12-18) delivery – weeks (median, IQR) Delivery within 7 days [n, (%)] 0 0 Delivery within 2 weeks [n, (%)] 1 (4.6) 0 Delivery < 32 weeks [n, (%)] 9 (40.9) 1 (4.4) Delivery < 34 weeks [n, (%)] 9 (40.9) 2 (8.7) Delivery < 37 weeks [n, (%)] 10 (45.5) 9 (39.1) GA at delivery – weeks (median, IQR) 37.1 (30.1-39) 38 (36.3-39.4) CL, cervical length; IQR, interquartile range; GA, gestational age.
CL 16-20mm (n = 37)
CL 21-25mm (n = 44)
P value
13 (11.3-14.9)
13.2 (11.5-15.1)
0.02
15.4 (12.8-17.4) 13.3 (11.5-16.0)
0.03
0 0 1 (2.7) 1 (2.7) 5 (13.5) 38.4 (37.4-39.4)
0 0 2 (4.6) 3 (6.8) 5 (11.4) 39 (37.9-39.5)
1 0.17 <0.001 <0.001 0.002 0.01
Figure Legends I. Flow diagram illustrating the exclusion process in the study cohort. CL, cervical length. II. Survival curve illustrating the probability of delivery as a function of time interval from enrollment to delivery in each of the different short CL groups. CL, cervical length.