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

OPPTIMUM Trial: vaginal progesterone does not help in preterm birth prevention !

Preterm birth is a global problem, with a prevalence of 8 to 12% depending on location.

Several large trials and systematic reviews have shown progestogens to be effective in preventing or delaying preterm birth in selected high risk women with a singleton pregnancy (including those with a short cervix or previous preterm birth).

However, the OPPTIMUM study results presented recently at the Society for Maternal and Fetal Medicine (SMFM) 36^th Annual pregnancy meeting at Atlanta Georgia in February, 2016 have shown that vaginal progesterone confers no obstetrical or neonatal benefit, and no long-term benefit with respect to cognitive and neurosensory outcomes in children when used to prevent preterm birth.


The findings from OPPTIMUM – the largest trial to date looking at progesterone for the prevention of preterm birth – have important implications for current practice. Vaginal progesterone is not currently approved for the prevention of preterm birth in the United States, but is commonly used off label for this purpose.

The OPPTIMUM study is a randomized double blind placebo controlled trial recruited over 1,228 women around  UK to test whether giving natural progesterone daily from 22 to 34 weeks of gestation is a cost-effective way to reduce the likelihood of preterm birth.  It also aims to look whether compared to placebo, vaginal progesterone:

• improve obstetric outcome by lengthening pregnancy and thus reducing the incidence of preterm delivery (before 34 weeks gestation)?
• improve neonatal outcome by reducing a composite of death and major morbidity?
• lead to improved childhood cognitive and neurosensory outcomes at two years?
• represent cost effective management for women at high risk of preterm delivery?

Dr. Jane Norman, MD, from the University of Edinburgh in the United Kingdom said “We saw no significant effect of vaginal progesterone on obstetrical, neonatal, or childhood outcomes, this was true even for women with a cervix of 25 mm or less, and "we found no evidence of benefit in any identifiable subgroups."

A Cochrane meta-analysis  in 2013 assessed the role of both the vaginal and intramuscular form of progesterone in preventing PTB (Cochrane Database Syst Rev. 2013;7:CD004947). Progesterone was shown to prevent preterm births, reduce perinatal mortality, reduce the incidence of birthweight below 2500 g, and reduce neonatal deaths. In women with a short cervix, progesterone was shown to reduce preterm births, but did not affect the other parameters. 

But there has been little information about the long-term risk this may have on children Dr Norman explained. "We felt we needed to look at the long-term effects. We cannot assume that things with short-term benefit will not have long-term harm," she added.

The study recruited 1228 women with singleton pregnancies at risk for preterm birth because of a positive fetal fibronectin test, a history of spontaneous preterm birth at 34 weeks of gestation or earlier, or a cervical length 25 mm or less.

About 618 women were randomized to receive 200 mg of natural vaginal progesterone starting at 22-24 weeks and continuing to 34 weeks, compared with 600 women who received placebo.

The primary obstetric outcome was delivery <34 weeks of gestation, the primary neonatal outcome is a composite of death or two markers of neonatal morbidity (brain injury or bronchopulmonary dysplasia); and the primary childhood outcome is developmental status at two years. A formal economic evaluation was also a key part of the study.

It was seen that progesterone had no significant effect on either the obstetric or childhood outcomes. It also had no significant effect on any components of the primary outcome, including fetal death or live-born delivery before 34 weeks.

“A secondary analysis looking at the individual components of the composite neonatal outcomes showed that progesterone reduced the risk of brain injury and neonatal death, but not bronchopulmonary dysplasia.” Dr. Norman said.

“We were really surprised that we didn’t show that progesterone prevented preterm birth, and we became concerned that perhaps our cutoff of 34 weeks was just the wrong time to choose a cutoff,” Dr. Norman said, noting that a post hoc survival curve analysis was performed to look at the trajectory to delivery, and a “very marginal benefit” was seen with progesterone, but the difference was not statistically significant.

On subgroup analysis it was seen that in women with a short cervix, no evidence was seen that progesterone was more or less effective than in women with a longer cervix. Other subgroups studied included fibronectin-positive and fibronectin-negative women and women with a history of preterm birth. Progesterone was no more or less effective in any of these subgroups. 

“OPPTIMUM is the largest trial of progesterone to prevent preterm birth, and after adjusting for multiple comparisons as we planned, we did not disprove the null hypothesis that progesterone doesn’t prevent preterm birth, it doesn’t reduce adverse neonatal outcomes, and it doesn’t have a beneficial effect on childhood outcomes,” Dr. Norman said, concluding that “there is a remaining unmet need for a safe and effective agent to prevent preterm birth.”

Further it was commented at the  Society for Maternal and Fetal Medicine (SMFM) conference by Mary D'Alton, MD, the William C. Rappleye Professor of Obstetrics and Gynecology at the Columbia University Medical Center in New York Citythat that the results should not be extrapolated to 17-hydroxyprogesterone, which was not part of this analysis.

This certainly gives pause around vaginal progesterone," said Mary D'Alton, MD, the William C. Rappleye Professor of Obstetrics and Gynecology at the Columbia University Medical Center in New York City. But she said she would not advise a change in practice before seeing the final published results.

The US Food and Drug Administration has not approved vaginal progesterone for the prevention of preterm birth in women with a short cervix.