Methods
This is a prospective multicenter cohort study involving singleton
pregnant women screened during a multicenter randomized controlled trial
entitled “Pessary plus Progesterone for Preventing Preterm Birth” (P5
trial; Registration no. RBR-3t8prz, approved by the Brazilian National
Review Board/CONEP - number 1.055.555) 11. The P5
trial was conducted by the University of Campinas (UNICAMP) and involved
17 centers in nine states of Brazil from July 2015 to March 2019. Women
between 18 and 22(+6/7) gestational weeks were invited to participate in
the P5 screening phase. A consent form was signed and TVU was performed
to measure the CL.
The standard technique followed the P5 study protocol and the Fetal
Medicine Foundation orientation for CL measurement. Briefly, with the
woman in dorsal lithotomy position and empty bladder, a TVU probe was
introduced inside the vagina until the anterior fornix avoiding
pressure. A sagittal view of the cervix, including the edge, identified
the internal and external ostium. Calipers were used to measure the
linear distance (in mm) between the external and internal ostium.
Funneling and Sludge were described. All data from the screening phase
were included in the online database Gsdoctor. Every participating
center stored their ultrasound images with the CL measurements to
confirm that all centers were correctly applying the TVU technique.
All women with a CL ≤30mm who did not have exclusion criteria and who
accepted to participate in the trial were randomized into two groups:
200 mg/day vaginal progesterone or 200 mg/day vaginal progesterone +
cervical pessary. Randomized women have delivery information in the P5
database. Women with CL >30 mm had their childbirth and
postnatal information collected from hospital medical registers and
added to the P5 database.
The sample for this analysis considered all women with CL ≤30mm
receiving only progesterone and a random selection of women with CL
>30mm, keeping the populational distribution of cervical
length. Women using cervical pessary were excluded since we did not have
clear information of how it could influence the gestational age at birth
and this treatment is not routine for preventing PTB. Considering that
progesterone is an established evidence-based treatment for preventing
PTB and women are encouraged to use it if they have a short CL
identified in the mid-trimester, we included the P5 trial progesterone
group in our cohort sample. The P5 trial total sample screened 13.7%
women with CL≤30mm and 86.3% of CL>30mm. To maintain the
same CL distribution, we projected the progesterone group to correspond
to 13.7% of CL ≤30mm for our analysis. To complete our final sample and
reach the complementary 86.3% of CL >30mm, we selected
singleton women with CL >30 mm using a random model. We
excluded women who had received a cervical pessary, multiple gestations
and those with incomplete gestational outcome data. We kept very similar
baseline characteristics percentages found in the total of singleton
pregnant that participated in the P5 trial screening, maintaining
homogeneity and avoiding any possible selection bias (Table S1). The
primary outcome was PTB at <37 weeks’ gestation and secondary
outcomes were sPTB at <37, <34, <32 and
<28 weeks’ gestation.
Descriptive statistical analysis was performed for demographic
characteristics, expressed as means and percentages. Logistic regression
was used to estimate odds ratios for baseline characteristics,
gestational age and CL at measurement. A multivariate logistic
regression analysis was performed to estimate adjusted odds ratio for
different gestational ages.
For our primary outcome, receiver operating characteristic (ROC) curve
analysis was performed to identify the most effective cutoff point to
predict a PTB (<37 weeks). Our secondary outcomes were ROC
curve analysis to identify the most effective cutoff points to predict
sPTB at different gestational ages (<37, <34,
<32 and <28 weeks). Kaplan-Meyer survival curves
were used to analyze time to delivery, considering CL intervals (≤10mm,
10-15mm, 15-20mm, 20-25mm, 25-30mm, 30-35mm, 35-40mm and
>40mm). We calculated the number needed to screen (NNS) to
detect one true positive sPTB<34 in women with CL ≤25mm.
Considering a recent IPD-metanalysis that included RCTs involving women
with CL ≤25mm treated with vaginal progesterone, the number needed to
treat (NNT) with vaginal progesterone to prevent one sPTB <34
weeks is 1812. Therefore, we estimated the number of
TVU necessary to identify 18 women with CL ≤25mm. P<0.05 was considered as statistically significant. All
statistical analyses were performed using R version 3.6.2 software.
This study was funded by Bill & Melinda Gates Foundation
[OPP1107597], the Brazilian Ministry of Health, and the Brazilian
National Council for Scientific and Technological Development (CNPq)
[401615/20138]. The funders had no role in the design, development
of the study, analysis, interpretation of data, writing the manuscript
and in the decision to submit the article for publication.