Vaginal progesterone scores at par with cerclage for preventing preterm births in women with previous mishap and short cervix: a comparison meta-analysis

Vaginal progesterone fares equal with cerclage for preventing preterm births in women who have a short cervix and history of previous mid-trimester miscarriage (MTM) and/or preterm labor (PTL) reports the results of an updated comparison meta-analysis published in July issue of American Journal of Obstetrics and Gynecology.

In a recent update by WHO, every year 15 million babies are born before 37 weeks of gestation and the figures continue to rise. Prematurity is the leading cause of death in children under 5 years of age and is responsible for causing about 1 million deaths worldwide.

In addition, prematurity is a major contributor towards lifelong neurological morbidities such as intellectual disability, cerebral palsy, hearing and visual impairments, and a higher risk of chronic diseases in adulthood.

Women with a previous history of PTL and a short cervix (≤25) face a 3-fold increased risk of recurrent preterm births as compared to women with a cervical length >25 mm in the midtrimester.

The efficacy of vaginal progesterone and cerclage in preventing PTL is a hotly debated topic, but to date, only 2 small RCTs have been conducted to compare these two treatment modalities. However, the sample size was too small to detect any treatment differences.

The 2016 multicenter double-blind randomized placebo-controlled OPPTIMUM trial refuted the claim that progesterone reduces the risk of PTL and helps decrease the associated neonatal morbidity and mortality.

Hence, this adjusted indirect comparison meta-analysis was performed which usually, but not always, provides results similar to head-to-head randomized controlled trials.

An updated literature search of MEDLINE, EMBASE, CINAHL, LILACS, the Cochrane Central Register of Controlled Trials, conference proceedings and research registers of ongoing trials was performed from their inception to March 31, 2018.

All the RCTs comparing vaginal progesterone to placebo/no treatment or cerclage to no cerclage in women with a singleton gestation, previous spontaneous preterm birth, and a sonographic cervical length <25 mm was included in the meta-analysis.

The researchers looked at prevention of preterm birth <35 weeks of gestation and perinatal mortality as the primary outcomes.

Five trials comparing vaginal progesterone vs placebo (265 women), 5 comparing cerclage vs no cerclage (504 women) and the OPPTIMUM study were included in the analysis.

The daily dose of vaginal progesterone used in the trials varied from 90 to 200 mg, and the treatment was administered from 18–25 to 34–36 weeks of gestation. Thirty women in two RCTs underwent a cerclage after randomization.

In direct comparison, the use of vaginal progesterone reduced the risk of preterm birth <35 weeks by 32%, <32 weeks of gestation by 40%, neonatal sepsis by 62%, neonatal morbidity by 71%, and admission to NICU by 54%.

The use of cerclage reduced the risk of preterm birth <35 weeks by 30%, <32 weeks of gestation by 34%, composite neonatal morbidity and mortality by 36%, and birthweight <1500 g by 36%.

Both interventions together were associated with a nonsignificant ∼36% reduction in the rate of perinatal death.

Adjusted indirect comparison meta-analyses didn’t show any differences between vaginal progesterone and cerclage in preventing preterm births and perinatal deaths.

The study has several advantages such as the use of individual patient data, similar patient demographics, and low rates of bias. There were few limitations such as the absence of data on respiratory distress syndrome in the OPPTIMUM study, some women with cerclage received 17-OHPC that could have affected the results and non-reporting of maternal side effects in the individual patient data (IPD) meta-analysis.

In the absence of adequately powered, high-quality, randomized controlled trials comparing vaginal progesterone and cerclage, our indirect comparison treatment meta-analysis provides the best available evidence regarding the comparative efficacy of the 2 interventions.

This meta-analysis results have huge implications in clinical practice. Both progesterone or cerclage show similar efficacy in preventing recurrent preterm births in patients with singleton pregnancy and short cervix. Thus, besides efficacy, the decision to use one intervention over other is based on physician preferences, cost-effectiveness, and maternal side effects.

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A novel ultrasound parameter help predicts mid-trimester cerclage failure-- -- News from SMFM 2017, Las Vegas.

UCA  acute and obtuse Courtesy Researchgate 

Increasingly wide utero cervical angle (UCA) after mid trimester cerclage operation signifies increase risk of preterm delivery.

Dr. Jordan Knight and his colleagues from Indiana University School of Medicine, Indianapolis, IN presented a pilot study, utilizing UCA in predicting the failure of mid-trimester transvaginal cerclage operations. [1]

UCA is defined as the triangular area between the lower uterine segment and cervical canal measured by Transvaginal Ultrasonography (TVUS).

Researchers are exploring the possibilities of using a novel ultrasound parameter, the anterior utero cervical angle (UCA) as a predictor of Spontaneous Preterm Birth along with Cervical length (CL). Previously this angle has been used as one of the parameter for successful induction of labor.

The pathophysiological   principle behind this is based on physics and trigonometry. Pregnant uterus exerts pressure on cervix and depending on the angle of inclination, the cervix is either shut if the angle is acute or opened wide if the angle is obtuse.

The current retrospective study collected data on 142 women who underwent transvaginal cerclage between 2010-2015. UCL was measured thrice in same patient: prior, one week after cerclage placement and prior to delivery by TVUS.

Delivery before 36 weeks was labelled as cerclage failure.

After Univariate regression, it was seen that CL and UCL was strongly associated with gestational age at birth.

UCL angle of 108 degree prior to 34 weeks was a better predictor of preterm delivery than CL = 25 mm. Before28 weeks the UCL angle of 112 degree had 100 sensitivity as compared to 29% that of CL.

Patients with UCA angle> 108 degree had 35 times higher odds of spontaneous preterm birth (PTB) before 34 weeks while the UCL > 112 degree conferred 42 times higher odds of delivering before 28 weeks.

The corresponding odds of delivery if cervical length CL<25mm are 4.7 and OR 6.0 prior to 34 and 28 weeks respectively.

The study cohort had 38% cerclage failure rate and delivered at mean gestational age of 29 +/- 5.2 weeks compared to those who delivered at 37.9 +/- 2.8 weeks (p<0.001).

A study presented at the 36th Annual Pregnancy Meeting concluded that “A wide uterocervical angle ≥95 and ≥105 degrees detected during the second trimester was associated with an increased risk for spontaneous preterm birth <37 and <34 weeks, respectively. Uterocervical angle performed better than cervical length in this cohort.”[2]

The authors concluded that increasing obtuse UCA signify increase chances of cerclage failure and give the obstetrician valuable time to make arrangements for delivery at tertiary center.

UCA performed better than CL as a screening parameter for predicting preterm births (PTB) because of increased sensitivity and NPV.

In fact, a combination of UCA and CL synergistically can be best predictor of PTB in cerclage patients.

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[1] http://www.ajog.org/article/S0002-9378(16)31012-2/fulltext

[2] http://www.ajog.org/article/S0002-9378(16)00525-1/abstract

SMFM recommendations for routine cervical length screening for preventing Preterm Births.

Courtesy: Pixabay 

A summary of Society for Maternal-Fetal Medicine  recommendation for Cervical Length ( CL) screening to prevent Preterm births. 

Preterm birth (PTB) remains a major cause of neonatal death and short and long term disability across the globe. The current global preterm birth rate is 5% to 18% and statistic shows a steady increase recently. CDC data quotes that in the year 2014, every 1 in 10 infants was born preterm in US. 

 Nearly 2/3 of 15 million preterm births are spontaneous with a very high recurrence. A history of previous PTB is the strongest risk factor for preterm delivery in the current pregnancy. Among various other contributing factors prior uterine surgery, especially those performed on cervix (induced termination of pregnancy (I-TOP) or spontaneous abortion (SAB)) has been implicated in its causation.

There are few laboratory tests to predict preterm birth in a pregnancy.

Transvaginal Cervical Length measurement helps in predicting the risk of preterm birth so the obstetrician and his team gets time to intervene, delay or transfer the patient to high risk units.

At present, a single mid-trimester transvaginal CL measurement is the best clinical predictor of a preterm birth. Those with the shortest cervix has the highest risk of prematurity.

The Society for Maternal-Fetal Medicine issued recommendation about the role of routine cervical length screening in selected high-and low-risk women for preterm birth prevention.

• SMFM recommends “routine transvaginal cervical length screening for women with singleton pregnancy and history of prior spontaneous preterm birth (GRADE 1A).”

Transvaginal assessment at 16 and 24 weeks’ gestation by a trained sonologist or obstetrician should be performed. Routine CL screening is not advisable before 16 weeks and after 24 weeks in asymptomatic women.  

In women with prior history of preterm births serial CL measurements are performed every week beginning at 16 weeks to 24 weeks.

• SMFM recommends “Practitioners who decide to implement universal CL screening should follow strict guidelines (GRADE 2B).”
• SMFM recommends “Routine transvaginal CL screening not be performed for women with cervical cerclage, multiple gestation, PPROM, or placenta previa (GRADE 2B).”

Evidence does not support additional screening for women who have undergone cervical conning or LEEP beyond the standard recommendations.

No additional clinical benefit is derived for repeated CL screening in women who have undergone cerclage operation. Although research demonstrates that progressive CL shortening after the stitch increases the risk for PTB, but no options exist to reinforce the short cervix after cerclage.

Routine cervical screening is not recommended by SMFM in multiple gestation as no additional clinical benefit is derived from it.

Transvaginal CL measurement serves as an adjunct to fetal fibronectin (FFN) in predicting PTB in women with CL of 20-29 mm (the grey zone). Cervical length more than 30 mm and less than 20 mm is independently a strong predictor of minimum chances for PTB or high risk for  PTB respectively. 

Not much clinical benefit is derived from cervical length estimate in Preterm premature rupture of membranes (PPROM). Few observational studies have shown that with a transvaginal CL <2 cm, the positive predictive value of delivery within 7 days was 62%.

Routine transvaginal CL measurement is not performed in case of placenta previa as studies do not show any additional benefit is derived for management.

• SMFM recommends “sonographers and/or practitioners receive specific training in the acquisition and interpretation of cervical imaging during pregnancy”.

Steps for proper cervical length measurement as recommended by SMFM.[1]

(1) Ensure patient has emptied her bladder.

(2) Prepare the cleaned probe using a probe cover.

 (3) Gently insert the probe into the patient’s vagina.

 (4) Guide the probe into the anterior fornix.

 (5) Obtain a sagittal, long-axis image of the entire cervix.

(6) Remove the probe until the image blurs and then reinsert gently until the image clears (this ensures you are not using excessive pressure).

(7) Enlarge the image so that the cervix occupies two thirds of the screen.

 (8) Ensure both the internal and external os are seen clearly.

 (9) Measure the cervical length along the endocervical canal between the internal and external os.

(10) Repeat this process twice to obtain 3 sets of images/ measurements.

(11) Use the shortest best measurement.

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[1] SMFM. Role of routine cervical length screening for preterm birth prevention. Am J Obstet Gynecol 2016.

Predicting spontaneous preterm birth in twin pregnancies utilizing cervical length and gestational age: Individual patient data meta-analysis.

Multiple births are steadily climbing all around the world. Developed countries making a significantly higher contribution to this rising rate because of women delaying childbirth, elderly mothers and increased use of ARTs.

US twinning rate rose by 101% from 1980 – 2006. About 68,339 twins were born in 1980 that doubled to 137,085 in 2006. The US current twin birth rate is 33.9 per 1,000 live births.

 According to WHO the rate of singleton preterm birth ranges between 5% to 18% for singleton pregnancy worldwide, the average being 11%, while almost 60% of twins are delivered preterm. About 13% of twins are born before 34 weeks and 7% before 32 weeks.

A multitude of prophylactic therapies have been in use like to gain valuable gestational weeks by supplementing progesterone, vaginal pessaries and strict bed rest without substantially significant results.

The next step was to develop essential biomarkers that can predict the chances of preterm births. Cervical length(CL) has long   been used as a predictive indicator of preterm birth. An earlier review has shown that a CL < or=20 mm at 20-24 weeks' gestation was the most accurate in predicting preterm birth at <32 and <34 weeks respectively. Many other studies have combined fetal fibronectin with CL. 

Studies in singleton pregnancies have also shown that the relationship between CL and spontaneous preterm birth (sPTB) is dependent on the Gestational age (GA) at which the USG is done, a shorter CL early in pregnancy has greater significance than the same measurement at a later GA.

Such studies in twins are few with small sample size and are not comparable. Previous meta-analysis has shown a relationship between CL and sPTB in twins, but did not correlate the GA at screening with prediction of sPTB.

This recent study published in the May, 2016 issue of BJOG is a meta-analysis of independent patient data(IPD), and provides a new estimate in which CL and GA are treated as continuous variables to predict weeks at delivery.

Specific data collected for each patient from the original authors of the study included the exact GA at CL screening, the CL measurement in millimeters and the exact GA at birth in weeks and days.

23 studies met the inclusion criteria, resulting in a total of 6188 transvaginal scans, performed on 4409 twin pregnancies. 

In the first analysis, univariate regression was performed to see what other confounders like maternal age, ethnicity, smoking, BMI, chorionicity, parity and study location affects the GA at birth. 

As second analysis multinomial logistic regression model was derived predicting the probabilities of very early preterm, early preterm, late preterm, and term birth using GA at USG and CL as continuous variables.

Important study results were:

• BMI was the only other variable that correlated significantly with GA at birth in the univariate analysis, but when it was incorporated into multinomial logistic regression model with CL and GA at ultrasound, prediction of GA at birth did not improve.
• A short CL measured at ≤20⁺⁰ weeks by USG indicates a probability of birth significantly earlier than if the same CL was taken at a later GA.
• When screening before 18⁺⁰ weeks, any cervical length <30 mm has a higher risk of sPTB at ≤28⁺⁰ weeks in twins than in singletons.Whereas the best prediction of birth between 28⁺¹ and 36⁺⁰ weeks was provided by screening at ≥24⁺⁰ weeks.
• A 100% probability of preterm birth not occurring before 28 weeks is achieved by CL of 65 mm and 43 mm at ultrasound GA at ≤18⁺⁰ weeks and at 22⁺¹ to 24⁺⁰ weeks, respectively.

In the third analysis, the accuracy of the model to correctly predict term delivery as compared to preterm was assessed. The model has a 68.2% true negative rate, classifying correctly those who were predicted to deliver at ≥36⁺¹ weeks, compared with 26.2, 13.3 and 36.2% correctly predicted to deliver at ≤28⁺⁰, 28⁺¹ to 32⁺⁰ and 32⁺¹ to 36⁺⁰ weeks, respectively (true positive rate).

Although effective intervention for sPTB in twins are limited, the study provides risks of very early, early and late preterm birth, so a personalized cost effective delivery plan, optimal timing of corticosteroids and referring to neonatal unit can be managed. It also justifies serial CL measurements, so that early and late sPTB could be predicted.

To conclude the authors, recommend to start the screening at ≤18⁺⁰ weeks with repeat screening at >22⁺⁰ weeks; this best identifies the patients that may deliver very early at ≤28⁺⁰ weeks as well as the more common later group of sPTB between 28⁺⁰ to 36⁺⁰ weeks. 

References:

http://www.cdc.gov/nchs/fastats/multiple.htm

http://www.who.int/mediacentre/factsheets/fs363/en/

http://www.ncbi.nlm.nih.gov/pubmed/24360590

http://onlinelibrary.wiley.com/doi/10.1111/1471-0528.13575/full

http://onlinelibrary.wiley.com/doi/10.1111/1471-0528.13710/full