Abstract
Objective:
To determine whether vaginal progesterone treatment for women with a short cervix, diagnosed after 24 weeks of gestation, reduces preterm birth rates.
Methods:
A retrospective cohort study that included women with a singleton pregnancy, threatened preterm labor, and a short cervix measured between 24+0 and 33+6 weeks. Women who received vaginal progesterone were compared to women who did not receive progesterone. The primary outcome was spontaneous preterm birth prior to 37 weeks of gestation.
Results:
Patients who received vaginal progesterone had a lower rate of preterm delivery at less than 37 weeks of gestation (18.2% [22/121] vs. 28.9% [73/253]; aHR 0.50; 95%CI 0.28 to 0.73, p = 0.001). The diagnosis-to-delivery interval was significantly greater in patients who received progesterone than in those who did not (median time-to-delivery in weeks [IQR]: 8.2 [6.2–9.8] vs. 6.6 [4.8–8.8], (p < 0.001)). The frequency of NICU admissions was significantly lower in patients who received progesterone than in those who did not (8.3% [10/121] vs. 16.2% [41/253], p=0.04).
Conclusions:
The administration of vaginal progesterone to patients with an episode of threatened premature labor and a short cervix presenting after 24 weeks of gestation was associated with lower rates of premature births.
Keywords: singleton pregnancy, preterm delivery, preterm labor, prematurity, progesterone, progestogen, short cervix, transvaginal ultrasound
Introduction
Preterm birth is the leading cause of perinatal mortality and morbidity worldwide1,2, and the leading cause of death before the age of 5 years3,4. Moreover, preterm birth is a major cause of long-term morbidity in adult life. Therefore, predicting and preventing preterm birth is a major healthcare priority1,5,6. Irregular contractions, lower backache, vaginal discharge, or bleeding are indicators of threatened preterm labor that may or may not lead to preterm birth. In addition, threatened preterm labor may appear with or without cervical changes, and a sonographic short cervix is the most powerful method for predicting preterm birth7.
Vaginal progesterone reduces the rate of preterm birth in women with a short cervix, and the treatment is effective regardless of history of preterm birth8,9. Cervical cerclage is also effective in the subgroup of patients with a short cervix and a history of preterm birth10. Cervical pessary has also been proposed as a viable intervention, and its effectiveness is the subject of ongoing studies11.
Most randomized clinical trials that have examined the efficacy of interventions to reduce the rate of preterm birth have focused on patients diagnosed with a short cervix prior to 24 weeks of gestation. Only a few studies have examined the issue of a short cervical length diagnosed after 24 weeks of gestation12,13. This study was conducted to determine whether administering vaginal progesterone to women with threatened labor and a short cervix diagnosed after 24 weeks of gestation is associated with reduced preterm birth rates and lower rates of neonatal intensive care unit (NICU) admissions.
Materials and Methods
Study design
This retrospective cohort study included women with a singleton pregnancy, diagnosed with threatened labor and a cervical length of 25 mm or less between 24+0 and 33+6 weeks of gestation at Hadassah Medical Center between March 2010 and January 2017. Maternal and neonatal clinical and demographic parameters were compared between women who had received progesterone treatment (the progesterone treatment group) and women who had not (the non-treatment group). The study was approved by the Institutional Review Board (0446-20-HMO) on June 22, 2020. As a retrospective study based on existing data and containing no identifying details, no informed consent was required.
Data was collected from the electronic medical records of women who had a cervical length assessment between 24+0 and 33+6 weeks of gestation and who had presented to the ultrasound unit of two tertiary referral centers. Gestational age was confirmed by menstrual history or fetal biometry in the first trimester. Cervical length measurements were performed according to the Cervical Length Education and Review (CLEAR) program14,15.
Cervical length was measured by one of six experienced sonographers in patients with an empty bladder presenting in the dorsal lithotomy position. A vaginal probe was placed in the anterior fornix. After visualization of the internal os, external os, and the entire length of the cervical canal, calipers were placed between both ora, and the shortest, best measurement was recorded. The ultrasound equipment used for cervical length measurement included the Voluson 730 Expert, E6, E8, E10 (GE Healthcare, Zipf, Austria) and the Samsung Accuvix A30 (Samsung Co, Ltd, Seoul, Korea).
Patients were excluded from the study for any of the following: multiple gestation, major fetal or uterine anomalies, a history of conization, a short cervix diagnosed earlier in the index pregnancy, or previous interventional treatment for preterm birth prevention (progestogen, cerclage, or pessary) in the current pregnancy. Patients were excluded if they had a medically indicated preterm birth, as the medical indications for medically induced preterm birth, such as preterm premature rupture of membranes, preeclampsia, and placental insufficiency, are not affected by the proposed treatment. Further exclusion criteria included incomplete outcome data, and delivery within one day from diagnosis (as this interval is too short for the proposed treatment to achieve medical benefit).
The decision to prescribe vaginal progesterone had been made by the attending physician. Its administration began at diagnosis, and the treatment continued until 36+6 weeks or until delivery if preterm birth occurred. No formal recommendation exists for progesterone treatment in women with a short cervix diagnosed after 24 weeks. However, based on the beneficial effect of progesterone in women with a short cervix diagnosed in mid-trimester, some physicians choose to use progesterone to treat this population as well. The women receiving treatment were instructed to use a vaginal suppository of micronized progesterone (Utrogestan, 200 mg capsules, CTS Ltd.) nightly before bedtime. The drug, dose, and method of administration in the progesterone treatment group were similar, and patients with a different dosage or method of administration were excluded.
Outcomes
The primary outcome measure was spontaneous delivery prior to 37 completed weeks of gestation. The secondary maternal outcome measures were spontaneous delivery before 34, 32, and 28 weeks of pregnancy, diagnosis-to-delivery interval, gestational age at delivery, tocolytic therapy, antepartum corticosteroid administration, mode of delivery, and length of hospitalization. The secondary neonatal outcomes measured included neonatal birthweight, Apgar score at 5 minutes, NICU admissions, and severe prematurity and morbidity, including respiratory distress syndrome, bronchopulmonary dysplasia, intraventricular hemorrhage, periventricular leukomalacia, necrotizing enterocolitis, neonatal sepsis, and perinatal mortality.
Statistical Analysis
Differences in continuous variables between the groups were analyzed by the independent samples t-test or a non-parametric Mann–Whitney test. Differences in categorical variables were analyzed via the χ2 or Fisher’s exact test. A two-sided P < 0.05 was considered statistically significant. Diagnosis-to-delivery interval was assessed by using a Kaplan–Meier plot, for which the number of days from diagnosis until delivery was the time scale, and spontaneous delivery was the event. The Cox proportional-hazards model was used with a formal test of the proportional-hazards assumption to adjust the risk factors and calculations of the hazard ratios (HR). Cox proportional-hazards regression analysis was used to test the associations between vaginal progesterone treatment and the diagnosis-to-delivery interval, following adjustments for maternal age, history of preterm birth, cervical length, and gestational age at diagnosis.
Results
Study population
During the study period, 3,871 women presented to our institution and underwent cervical assessments between 24+0 and 33+6 weeks of gestation. Among them, 643 women (16.6%) had a cervical length measuring 25 mm or less. Two hundred and sixty-nine women were excluded from the study according to the previously determined exclusion criteria. Furthermore, 374 women were diagnosed with threatened labor and a cervical length of 25 mm or less and included in the final analysis of this study. Among them, 121 (32.4%) received progesterone treatment (progesterone treatment group), whereas 253 (67.6%) did not receive progesterone (non-treatment group), as shown in Figure 1.
Figure 1.
Study Design
*Seven women received a combination of cervical cerclage and vaginal micronized progesterone treatment.
Baseline characteristics of the study population are presented in Table 1. The mean gestational age at diagnosis was 29.8 ± 2.6 weeks in the progesterone treatment group and 31.1 ± 2.2 weeks in the non-treatment group (p < 0.001). Distribution of gestational age at diagnosis for both study groups is presented in Figure 2 (p < 0.001).
Table 1.
Baseline Characteristics of the Study Population
| Characteristic | Progesterone Group (n = 121) | Non-Treatment Group (n = 253) | p-value |
|---|---|---|---|
|
| |||
| Maternal Age (years, mean ± SD) | 29.3 ± 5.8 | 28.3 ± 5.6 | 0.119 |
|
| |||
| Nulliparity (n, (%)) | 55 (45.4) | 114 (45.0) | 0.910 |
|
| |||
| Gravidity (n, mean ± SD) | 2.74 ± 1.91 | 2.69 ± 2.06 | 0.815 |
|
| |||
| Prior Caesarian Delivery (n, (%)) | 8 (6.6) | 22 (8.6) | 0.676 |
|
| |||
| Prior Preterm Births (n, (%)) | 29 (24.4) | 43 (17.1) | 0.097 |
|
| |||
| GA* at Diagnosis (weeks, mean ± SD) | 29.82 ± 2.59 | 31.18 ± 2.23 | < 0.001 |
|
| |||
| GA at Diagnosis, Categorized (n, (%)) | < 0.001 | ||
| - Prior to 30 weeks | 59 (48.7) | 60 (23.7) | |
| - At 30 weeks or later | 62 (51.3) | 193 (76.3) | |
|
| |||
| Cervical Length at Diagnosis (mm, mean ± SD, median [range], [IQR]) | 19.5 ± 4.4 | 20.5 ± 4.2 | 0.062 |
| 20 [3–25] | 22 [3–25] | ||
| [17–23] | [18–24] | ||
|
| |||
| Severe Short Cervix** (n, (%)) | 21 (17.5) | 33 (13.0) | 0.071 |
|
| |||
| Cervical Length – Categorized | 0.044 | ||
| - 0–9 mm | 3 (2.5) | 4 (1.6) | |
| - 10–19 mm | 50 (41.3) | 75 (29.6) | |
| - 20–25 mm | 68 (56.2) | 174 (68.8) | |
GA = gestational age.
Severe short cervix defined as cervical length of 15 mm or less.
Figure 2.
Gestational age at diagnosis
A statistically significant difference in baseline cervical length was observed between the two groups. The incidence of a cervical length between 0-9 mm and 10-19 mm was higher in the progesterone treatment group than in the non-treatment group (2.5% vs. 1.6%, and 41.3% vs. 29.6%, respectively). Additionally, the incidence of extremely short cervixes (less than or equal to 15 mm) was 17.5% (21/121) in the progesterone treatment group, compared to 13.0% (33/253) in the non-treatment group.
Progesterone treatment was associated with a lower rate of preterm delivery prior to 37 weeks (18.2% [22/121] in the progesterone treatment group and 28.9% [73/253] in the non-treatment group) and prior to 34 weeks (5.0% [6/121] in the progesterone treatment group and 10.3% [26/253] in the non-treatment group). Additionally, the incidence of preterm birth prior to 32 and 28 weeks was lower in the progesterone treatment group (Figure 3).
Figure 3.
Preterm birth rate
Spontaneous preterm birth rate before 37, 34, 32, and 28 weeks of pregnancy for women in the progesterone treatment group (red) and the no treatment group (blue).
The diagnosis-to-delivery intervals in the study groups were assessed using a Kaplan–Meier survival plot (Figure 4). The cumulative percentage of women who did not deliver spontaneously prior to 37 weeks was significantly higher in the progesterone treatment group than in the non-treatment group. Progesterone treatment was associated with a reduced risk of spontaneous delivery prior to prior to 37 weeks (HR 0.52, CI 95% 0.32 to 0.84, p=0.008), while the reduction of spontaneous preterm delivery prior to 34 weeks did not reach statistical significance (HR 0.43, CI 95% 0.18 to 1.05, p=0.06).
Figure 4.
Kaplan-Meier plot
Survival analysis shows the probability of patients continuing pregnancy without spontaneous delivery by days from the cervical length measurement to delivery for the progesterone treatment group (red line) and the no-treatment group (blue line). Progesterone reduces the risk of spontaneous delivery before 37 weeks of pregnancy with an adjusted hazard ratio of 0.50 (95% confidence interval 0.28–0.73; P = 0.001). An adjustment was performed to maternal age, cervical length, gestational age at the diagnosis, and preterm birth history.
Multivariable analysis showed that the interval-to-delivery was longer among women treated with progesterone than in patients who were not, after adjustments for maternal age, history of preterm birth, cervical length, and gestational age at diagnosis (Table 2). Progesterone was associated with a reduced risk of spontaneous delivery prior to 37 weeks (aHR of 0.50 [95% CI 0.28–0.73] p = 0.001).
Table 2.
Cox Proportional Hazard Regression Analysis of Spontaneous Preterm Birth Prior to 37 Weeks
| Parameter | Adjusted Hazard Ratio | 95% Confidence Interval | p-value |
|---|---|---|---|
| Progesterone Treatment (yes) | 0.501 | 0.283–0.729 | 0.001 |
| Cervical Length (mm) | 0.552 | 0.332–0.924 | 0.023 |
| Prior Preterm Births (yes) | 1.782 | 1.155–2.786 | 0.011 |
| Gestational Age at Diagnosis (week) | 0.989 | 0.973–0.994 | 0.024 |
| Maternal Age (year) | 1.051 | 1.012–1.086 | 0.008 |
The unadjusted hazard ratio for spontaneous preterm birth prior to 37 weeks after progesterone treatment was 0.52; CI 95% 0.32–0.84; p=0.008. B=0.650, SE(β)=0.244, Wald=7.099. In this model, adjustments were performed for maternal age, history of preterm births, cervical length, and gestational age at diagnosis.
Maternal and neonatal outcomes are presented in Table 3. The NICU admission rate was significantly lower among patients who received progesterone treatment than among those who did not (8.3% [10/121] vs. 16.2 [41/253], p = 0.04). Furthermore, the length of neonatal hospitalization was shorter in the progesterone treatment group than in the non-treatment group; however, this difference was not significant (5.7 vs. 7.7 days, p = 0.06).
Table 3.
Maternal and Neonatal Outcomes
| Progesterone Group (n = 121) | No Treatment Group (n = 253) | p-value | |
|---|---|---|---|
|
| |||
| Maternal | |||
|
| |||
| GA at Birth (weeks, mean ± SD, median [range], [IQR]) | 38.1 ± 2.3 | 37.8 ± 2.7 | 0.319 |
| 38.4 [27.7–42.7] | 38.4 [26.2–42.8] | ||
| [37.6–39.4] | [36.6–39.6] | ||
|
| |||
| Diagnosis to Delivery Interval (weeks, mean ± SD, median [range], [IQR]) | 8.2 ± 2.9 | 6.6 ± 3.2 | < 0.001 |
| 8.2 [0.8–16.2] | 6.6 [0.1–16.8] | ||
| [6.2–9.8] | [4.8–8.8] | ||
|
| |||
| Tocolytic Therapy for Threatened Preterm Birth (n (%)) | 82 (67.8) | 164 (64.8) | 0.574 |
|
| |||
| Antepartum Corticosteroid Administration (n (%)) | 116 (95.9) | 208 (82.5) | < 0.001 |
|
| |||
| Mode of Delivery (n (%)) | 0.572 | ||
| - Spontaneous vaginal | 87 (71.9) | 185 (73.1) | |
| - Operative vaginal | 10 (8.3) | 27 (10.7) | |
| - Caesarean | 24 (19.8) | 41 (16.2) | |
|
| |||
|
| |||
| Neonatal | |||
|
| |||
| Apgar Score <7 at 5 min (n (%)) | 4 (3.3) | 0 (0) | 0.017 |
|
| |||
| Birth Weight (grams, mean ± SD, median, [range], [IQR]) | 2878 ± 510 | 2907 ± 579 | 0.620 |
| 2945 [1120–4145] | 2930 [1020–4480] | ||
| [2610–3180] | [2594–3312] | ||
|
| |||
| Fetal Sex (n (%)) | 0.439 | ||
| - Female | 57 (47.01) | 130 (51.4) | |
| - Male | 64 (52.9) | 123 (48.6) | |
|
| |||
| NICU Admissions (n (%)) | 10 (8.3) | 41 (16.2) | 0.036 |
|
| |||
| Days of Hospitalization (days, mean ± SD, median [range], [IQR]) | 5.7 ± 6.9 | 7.7 ± 13.5 | 0.060 |
| 4.0 [1–44] | 4 [1–160] | ||
| [3–5] | [3–6] | ||
|
| |||
|
| |||
| Adverse Prematurity Outcome (n (%)) | |||
| - Respiratory distress syndrome (RDS) | 3 (2.5) | 8 (3.2) | 0.713 |
| - Intraventricular hemorrhage (IVH) | 2 (1.6) | 1 (0.4) | 0.551 |
| - Necrotizing enterocolitis (NEC) | 0 (0) | 1 (0.4) | 0.782 |
| - Retinopathy of prematurity (ROP) | 1 (0.8) | 2 (0.8) | 0.551 |
| - Broncho-Pulmonary Dysplasia (BPD) | 0 (0) | 0 (0) | 0.751 |
|
| |||
| Any adverse prematurity outcome* (n (%)) | 4 (3.3) | 9 (3.6) | 0.490 |
Any adverse prematurity outcome is defined as one or more of the following complications: RDS, IVH, NEC, ROP, or BPD.
Discussion
Main findings
Administration of vaginal progesterone to patients with an episode of preterm labor and a sonographic cervical length of less than 25 mm presenting after 24 weeks of gestation, was associated with a lower rate of preterm delivery and less NICU admissions compared to those who received no treatment.
Interpretation
Cervical assessment prior to 24 weeks of gestation has gained increasing acceptance in clinical practice because of its availability and its positive effects in reducing preterm delivery. The clinical application of cervical assessment has proven to be both successful and cost-effective. Nonetheless, an important remaining question is the optimal management of patients diagnosed with a short cervix after 24 weeks of gestation16. Currently, no randomized clinical trial using vaginal progesterone has been conducted among such patients.
This study presents the outcomes of examining this intervention in the “real world.” There is no evidence to indicate that vaginal progesterone would be effective only prior to 24 weeks of gestation. Optimally, the data available from retrospective studies within that gestational period should be tested in randomized clinical trials. Nonetheless, real-life situations are rarely optimal. Patients may have a short cervix diagnosed after 24 weeks of gestation, and physicians in clinical practice may or may not use vaginal progesterone, even without definitive clinical evidence.
In this study, we found that vaginal progesterone reduced the rate of preterm deliveries prior to 37 weeks of gestation, increased the diagnosis-to-delivery intervals, and reduced the frequency of NICU admission. These findings are consistent with previous studies, which evaluated the administration of vaginal progesterone prior to 24 weeks of gestation. The magnitude of the reduction in the rate of preterm births was lower than that reported in randomized clinical trials evaluating similar treatment prior to 24 weeks of gestation, such as the PREGNANT trial9. In cases of late administration of vaginal progesterone for a short cervix, the efficacy is likely reduced.
The patients treated with progesterone were more likely to have a history of preterm birth, shorter cervical length, and to present earlier in pregnancy. Despite the higher risk of preterm birth in the progesterone treatment group (as a result of the aforementioned risk factors), the prevalence of preterm birth in this group was lower prior to 28, 32, 34, and 37 weeks of gestation. The Cox proportional-hazards analysis, which considered the gestational age at presentation, and adjusted for maternal age, cervical length, gestational age at diagnosis, and a history of preterm birth, showed a reduced preterm birth rate prior to 37 weeks in the progesterone treatment group, (aHR of 0.50 [95% CI 0.28–0.73] p = 0.001). The fact that the study group showed improved outcomes with progesterone, despite having more risk factors, further highlights the potential efficacy of the treatment.
Regarding neonatal outcome, the study group showed a statistically significant reduction in NICU admissions. These improved outcomes could be attributed primarily to the reduction in the preterm birth rate. Another factor that might have affected the neonatal outcomes is the increased rate of antenatal steroid administration in this group.
Progesterone therapy for a short cervical length diagnosed between 18 and 24 weeks of gestation is an effective intervention that significantly reduces the preterm delivery rate in both low-risk and high-risk singleton pregnancies9,17. Current practice guidelines advocate cervical length screening during this period of pregnancy for high-risk patients7,18,19 and the initiation of progesterone therapy if the cervix is considered short. However, to the best of our knowledge, no study has evaluated the utility of vaginal progesterone as a preventative intervention for women with a short cervical length diagnosed after 24 weeks12, 20–22.
Cervical length normally decreases with advancing gestation23,24. Nevertheless, we chose a uniform cut-off of 25 mm for all gestational ages to simplify the analysis. This cut-off represents approximately the 5th percentile at 24 weeks to slightly over the 10th percentile at 33 weeks25. We are aware that a fixed cut-off of 25 mm may lose its clinical significance over gestational duration. However, despite decreasing significance, the predictive accuracy for spontaneous preterm birth increases slightly with advancing gestational age25.
Preterm birth is a syndrome with multiple etiologies. This process can potentially start at any stage during pregnancy and can progress at any rate. For some patients, it is reasonable to expect that the process of preterm cervical shortening would be slower-than-usual or become clinically relevant only later than usual. If that is the case, a portion of patients will “escape,” as discovery of their risk for preterm birth would usually occur during screening, limited only to the 18–24 week interval. Nevertheless, progesterone treatment could still halt or slow the process and its effects.
Strengths and limitations
The current study has several strengths. It includes a relatively large patient cohort. Strict inclusion and exclusion criteria were applied to refine the study population. The study was designed to include only those who could potentially benefit from progesterone therapy and exclude those receiving other treatments to prevent preterm birth.
This study also has several limitations. The retrospective nature of the study makes both groups prone to selection bias. There were no clear criteria for the initiation of progesterone treatment in the study population. Thus, the decision to treat was left to the discretion of the attending obstetrician. The retrospective nature of the present study means that the authors cannot determine what influenced the attending obstetrician’s decision to initiate progesterone treatment, and the choice of progesterone administration remains individual; presenting another possible source of bias, given the higher prevalence of previous preterm birth, earlier gestational age at diagnosis, and a shorter cervical length in the progesterone treatment group. Despite this, the preterm birth rate was lower in the progesterone treatment group, which strengthens the study’s conclusions.
The patients who received progesterone were those with a shorter cervix, a history of preterm birth, and an earlier gestational age at diagnosis. One would expect that the outcomes for these patients would be worse, yet the outcomes were better than those in the non-treatment group.
Furthermore, as this is a retrospective study based on the electronic medical records of tertiary referral centers, the present study does not include information regarding ambulatory follow up or further treatment by primary physicians, and therefore there is no statistical analysis on this matter or how it affected the measured outcomes.
Moreover, 67.8% of the women in the progesterone treatment group and 64.8% of the women in the no progesterone treatment group received tocolytic therapy. Because of the retrospective nature of the present study, the authors cannot determine what influenced the attending physician’s decision to initiate tocolytic treatment. According to clinical treatment protocols, tocolytic therapy was only administered when the attending physician diagnosed the patient with preterm uterine contractions and estimated high probability of preterm labor within 48 hours of admission to hospital if not treated. As not all women presenting for treatment with short cervix and symptoms of threatened preterm labor fall under these terms, not all of them received this treatment. However, this variable was found to be insignificant when comparing the progesterone treatment and the non-treatment groups (67.8% versus 64.8%, P = 0.574).
The study population was considered high risk, with over 25% experiencing preterm birth in the studied pregnancies and 19.4% with a history of previous preterm birth. Hence, the generalizability of the conclusions to low-risk populations remains uncertain. Based on these findings, the authors believe that mass cervical length screening after 24 weeks for a low-risk population is not justified.
Conclusions
The findings of the current study suggest that progesterone treatment between 24 and 34 weeks is effective and safe in preventing preterm birth in women with a short cervix and an episode of preterm labor. Cervical length screening in singleton pregnancies with an episode of preterm labor occurs after 24 weeks of gestation may be useful to identify those who would benefit from vaginal progesterone therapy.
We suggest further randomized controlled multicenter trials to confirm the conclusions and to test their validity in other populations and settings. The question of the potential benefit of population screening is beyond the scope of this study. However, if our findings can be reproduced, this question should be addressed.
Synopsis.
Administration of vaginal progesterone to women with threatened labor and a short cervix after 24 weeks of gestation is associated with reduced rates of preterm birth and NICU admissions.
Key Message.
Administration of vaginal progesterone to women with threatened labor and a short cervix after 24 weeks of gestation is associated with reduced rates of preterm birth and NICU admissions.
Acknowledgements
This study was conducted as part of the author Dror Raif Nesher’s requirements for receiving the title of Medical Doctor from the Faculty of Medicine of The Hebrew University of Jerusalem.
Funding
This research was supported, in part, by the Perinatology Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, U.S. Department of Health and Human Services (NICHD/NIH/DHHS); and, in part, with Federal funds from NICHD/NIH/DHHS under Contract No. HHSN275201300006C. Dr. Romero has contributed to this work as part of his official duties as an employee of the United States Federal Government. Dr. Romero has contributed to this work as part of his official duties as an employee of the United States Federal Government. Hadassah Hebrew University has a Federal Wide Assurance with the Office for Human Research Protections (OHRP) of the Department of Health and Human Services (DHHS) of the United States The funder had no role in the design or conduct of the study; collection, management, analysis or interpretation of the data; preparation, review or approval of the manuscript or the decision to submit the manuscript for publication.
List of abbreviations
- NICU
neonatal intensive care unit
- PPROM
preterm premature rupture of the membranes
Footnotes
Disclosure of interests
The authors declare no conflicts of interest.
Data Availability Statement
Data available on request from the authors.
REFERENCES
- 1.WHO Recommendations on Interventions to Improve Preterm Birth Outcomes. Published online 2015:19(1):234–243. [PubMed] [Google Scholar]
- 2.Liu L, Oza S, Hogan D, et al. Global, regional, and national causes of under-5 mortality in 2000–15: an updated systematic analysis with implications for the Sustainable Development Goals. Lancet. 2016;388(10063):3027–3035. doi: 10.1016/S0140-6736(16)31593-8 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Ward RM, Beachy JC. Neonatal complications following preterm birth. In: BJOG: An International Journal of Obstetrics and Gynaecology. Vol 110. Elsevier BV; 2003:8–16. doi: 10.1016/S1470-0328(03)00012-0 [DOI] [PubMed] [Google Scholar]
- 4.Saigal S, Doyle LW. An overview of mortality and sequelae of preterm birth from infancy to adulthood. Lancet. 2008;371(9608):261–269. doi: 10.1016/S0140-6736(08)60136-1 [DOI] [PubMed] [Google Scholar]
- 5.Jacobsson B, Simpson JL. Preterm birth: A clinical enigma and a worldwide public health concern. Int J Gynecol Obstet. 2020;150(1):1–2. doi: 10.1002/ijgo.13194 [DOI] [PubMed] [Google Scholar]
- 6.Walani SR. Global burden of preterm birth. Int J Gynecol Obstet. 2020;150(1):31–33. doi: 10.1002/ijgo.13195 [DOI] [PubMed] [Google Scholar]
- 7.McIntosh J, Feltovich H, Berghella V, Manuck T. The role of routine cervical length screening in selected high- and low-risk women for preterm birth prevention. Am J Obstet Gynecol. 2016;215(3):B2–B7. doi: 10.1016/j.ajog.2016.04.027 [DOI] [PubMed] [Google Scholar]
- 8.Romero R, Nicolaides KH, Conde-Agudelo A, et al. Vaginal progesterone decreases preterm birth ≤ 34 weeks of gestation in women with a singleton pregnancy and a short cervix: an updated meta-analysis including data from the OPPTIMUM study. Ultrasound Obstet Gynecol. 2016;48(3):308–317. doi: 10.1002/uog.15953 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Hassan SS, Romero R, Vidyadhari D, et al. Vaginal progesterone reduces the rate of preterm birth in women with a sonographic short cervix: A multicenter, randomized, double-blind, placebo-controlled trial. Ultrasound Obstet Gynecol. 2011;38(1):18–31. doi: 10.1002/uog.9017 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Alfirevic Z, Stampalija T, Medley N. Cervical stitch (cerclage) for preventing preterm birth in singleton pregnancy. Cochrane database Syst Rev. 2017;6(6):CD008991. doi: 10.1002/14651858.CD008991.pub3 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Conde-Agudelo A, Romero R, Nicolaides KH. Cervical pessary to prevent preterm birth in asymptomatic high-risk women: a systematic review and meta-analysis. Am J Obstet Gynecol. 2020;223(1):42–65.e2. doi: 10.1016/j.ajog.2019.12.266 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Melamed N, Hiersch L, Domniz N, Maresky A, Bardin R, Yogev Y. Predictive value of cervical length in women with threatened preterm labor. Obstet Gynecol. 2013;122(6):1279–1287. doi: 10.1097/AOG.0000000000000022 [DOI] [PubMed] [Google Scholar]
- 13.Souka AP, Papastefanou I, Papadopoulos G, Chrelias C, Kassanos D. Cervical length in late second and third trimesters: A mixture model for predicting delivery. Ultrasound Obstet Gynecol. 2015;45(3):308–312. doi: 10.1002/uog.13407 [DOI] [PubMed] [Google Scholar]
- 14.Perinatal Quality Foundation. CLEAR: Cervical Length Education and Review. Https://Clear.Perinatalquality.Org/. doi: 10.1016/0920-9964(88)90043-6 [DOI]
- 15.Iams JD, Goldenberg RL, Meis PJ, et al. The length of the cervix and the risk of spontaneous premature delivery. N Engl J Med. 1996;334(9):567–572. doi: 10.1056/NEJM199602293340904 [DOI] [PubMed] [Google Scholar]
- 16.Berghella V, Lesser T, Boelig RC, Roman A. Cervical length screening after 24 weeks for prediction and prevention of preterm birth: not evidence based yet…. Am J Obstet Gynecol MFM. 2020;2(2):100097. doi: 10.1016/j.ajogmf.2020.100097 [DOI] [PubMed] [Google Scholar]
- 17.Romero R, Conde-Agudelo A, Da Fonseca E, et al. Vaginal progesterone for preventing preterm birth and adverse perinatal outcomes in singleton gestations with a short cervix: a meta-analysis of individual patient data. Am J Obstet Gynecol. 2018;218(2):161–180. doi: 10.1016/j.ajog.2017.11.576 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.Salomon LJ, Alfirevic Z, Berghella V, et al. Practice guidelines for performance of the routine mid-trimester fetal ultrasound scan. Ultrasound Obstet Gynecol. 2011;37(1):116–126. doi: 10.1002/uog.8831 [DOI] [PubMed] [Google Scholar]
- 19.RANZCOG guideline. Measurement of cervical length for prediction of preterm birth. https://ranzcog.edu.au/RANZCOG_SITE/media/RANZCOG-MEDIA/Women%27sHealth/Statementandguidelines/Clinical-Obstetrics/Measurement-of-cervical-length-for-prediction-of-preterm-birth(C-Obs-27)-Review-July-2017.pdf?ext=.pdf
- 20.Goldenberg RL, Iams JD, Das A, et al. The Preterm Prediction Study: Sequential cervical length and fetal fibronectin testing for the prediction of spontaneous preterm birth. Am J Obstet Gynecol. 2000;182(3):636–643. doi: 10.1067/mob.2000.104212 [DOI] [PubMed] [Google Scholar]
- 21.Hiersch L, Yogev Y, Domniz N, Meizner I, Bardin R, Melamed N. The role of cervical length in women with threatened preterm labor: Is it a valid predictor at any gestational age? Am J Obstet Gynecol. 2014;211(5):532.e1–532.e9. doi: 10.1016/j.ajog.2014.06.002 [DOI] [PubMed] [Google Scholar]
- 22.Kokanali MK, Çelik H, Kokanali D, Taşçi Y. Predictive role of transvaginal ultrasonographic measurement of cervical length at 34 weeks for late pre-term and late-term deliveries in nulliparous women. J Matern Neonatal Med. 2016;29(11):1789–1794. doi: 10.3109/14767058.2015.1063609 [DOI] [PubMed] [Google Scholar]
- 23.Gramellini D, Fieni S, Molina E, Berretta R, Vadora E. Transvaginal sonographic cervical length changes during normal pregnancy. J Ultrasound Med. 2002;21(3):227–232. doi: 10.7863/jum.2002.21.3.227 [DOI] [PubMed] [Google Scholar]
- 24.Silva SVL, Damião R, Fonseca EB, Garcia S, Lippi UG. Reference ranges for cervical length by transvaginal scan in singleton pregnancies. J Matern Neonatal Med. 2010;23(5):379–382. doi: 10.3109/14767050903177169 [DOI] [PubMed] [Google Scholar]
- 25.Gudicha DW, Romero R, Kabiri D, et al. Personalized assessment of cervical length improves prediction of spontaneous preterm birth: a standard and a percentile calculator. Am J Obstet Gynecol. Published online September 2020. doi: 10.1016/j.ajog.2020.09.002 [DOI] [PMC free article] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
Data available on request from the authors.