The reference protocol is RC17_0247 – Etude Maposure.
The N° ID RCB is: 2017-A02715-48.
The protocol version is n°9 (20/11/2017).
This is a prospective multicenter diagnostic study.
This is a non-interventional study. There was therefore no written consent necessary but a recipe for no opposition.
The two participating centers are the Nantes University Hospital Center (UHC) (Nantes, France) and the Vendée District Hospital Center (La Roche sur Yon, France).
Patients are recruited from among the pregnant women receiving prenatal care in both centers.
Adult woman (at least 18 year old), legally competent.
provides oral consent after information.
affiliated with the French CNAMTS (salaried workers’ health insurance).
gestational age between 24+ 0 and 33+ 6 weeks inclusive.
cervical measurement ≤ 25 mm assessed by transvaginal ultrasound, with or without uterine contractions.
clinically intact membranes.
cervical dilatation < 3 cm assessed by digital examination.
The threshold of 25 mm for cervical measurement would be relevant to rule out the risk of spontaneous premature delivery at 48 h and 7 days . It seems essential to us not to miss a patient who risks giving birth in the hours or days to come, taking into account the consequences of a premature child who has not received corticosteroid therapy. We therefore include more patients than if we took the 15 or 20 mm threshold (ultrasound plays the role of sensitivity) , hence the interest of a specific test.
presence of vaginal bleeding.
history of cervical conization.
history of uterine malformation (bicornuate bicervical uterus, bicornuate unicervical uterus, unicornuate uterus, septate uterus).
presence of polyhydramnios with amniotic fluid index > 25.
obvious premature rupture of the membranes.
clinical or laboratory-confirmed chorioamnionitis.
intercurrent obstetric disease that might induce preterm birth.
patient hospitalized for more than 24 h in another hospital or department for TPD.
We excluded patients who had a conization because the cervix is automatically shorter physiologically . The 25 mm threshold cannot then apply and it remains dependent on the presence or not of uterine contractions . However, these patients, like twin pregnancies, are at greater risk of prematurity, and a specific assessment would be necessary.
To perform the PartoSure® test, a sample of cervicovaginal secretions is taken with the vaginal swab furnished in the test kit. After removing the swab from its packaging, it is held in the middle of the stem, and its extremity is carefully and gently introduced into the vagina for a length of 5–7 cm (a speculum is not necessary to take this sample), when the woman is in a supine position. The swab should be withdrawn from the vagina after 30 s. Once it has been withdrawn, the swab end containing the sample should be immediately placed into the vial of solvent furnished for this purpose, then rinsed by being rotated several times for 30 s. The swab should then be withdrawn from the vial and discarded as biomedical waste. After the dipstick is removed from its packaging, its white portion (indicated by arrows pointed downward) is inserted into the vial of solvent. The dipstick should be removed from the vial once two bands are clearly visible in the test zone, or after 5 min. Then the results are read on a clean, dry, flat surface. Two bands in the test zone indicate a positive result, while a line in the test zone indicates a negative result. It is not recommended that the results be read or interpreted after the dipstick has been immersed in the vial for more than 10 min. It is important to know that the intensity of the bands can vary. The test is considered positive even if the bands are light-colored or appear shadowed. A result is negative when only the control line appears. A test is considered invalid when the control line is absent.
This test can be used after a vaginal examination, and no special equipment or training is necessary.
It can be used between 20+ 0 and 36+ 6 weeks of gestation.
According to the current protocol, when a women presents with TPD and the diagnosis is confirmed by transvaginal ultrasound (with a cervical measurement ≤ 25 mm), a work-up to test for infection is performed, comprising a blood sample with a complete blood count (CBC), C-reactive protein (CRP), a urinary reagent strip, and a vaginal sample to test for genital infection. At the same time, the midwife will perform the PartoSure® test. The test will then be discarded, and the result reported in the CRF. Because this vaginal sample is taken at the same time as that for bacteriological testing, there is no additional gynecologic examination and no psychological risk for the woman. This research is therefore classified as noninterventional.
Cardiotocography is performed to verify fetal status and to show uterine contractions.
In case of uterine contractions, if tocolysis was necessary, the patient received either nifedipine (oral administration) or atosiban (intravenous administration), for a maximum of 48 h. Prenatal corticosteroid treatment aimed at fetal pulmonary maturation was performed with betamethasone 12 mg intramuscularly once a day for 2 days.
The specificity of the PartoSure® test will be estimated with its 95% confidence interval. It will be defined as the number of women with a negative test divided by the number of women who gave birth more than 7 days after their hospitalization for TPD.
- The sensitivity, PPV, and NPV of the Partosure® test for the prediction of delivery within 7 days will be estimated with their 95% confidence intervals.
Sensitivity will be calculated by dividing the number of women who gave birth within 7 days and tested positive (true positives) among all the women who gave birth within 7 days.
The negative predictive value will be calculated by dividing the number of women who did not give birth within 7 days and tested negative (true negatives) by all the women who tested negative. The positive predictive value will be calculated by dividing the number of women who gave birth within 7 days and tested positive (true positives) among all the women who tested positive.
The same estimates will be performed for the diagnostic capacity of the Partosure® test for predicting delivery within 48 h.
If the number of individuals allows, the same analyses will be performed according to subgroups for cervical length and gestational age at inclusion.
The factors associated with false positives will be sought from a univariate logistic regression model. All of the variables significant with a P-value < 0.20 will be introduced into a multivariate model. A backward stepwise procedure will be used to determine the factors associated with a P value < 0.05, which will be retained in the final model.
Costs will be presented as means with their 95% confidence intervals.
A univariate sensitivity analysis will be performed and will consider the variables of interest identified during the study, such as the cost of the PartoSure® test.
From an economic point of view, women hospitalized in the Homogeneous Patient Group 14Z16Z = False labor and threatened preterm delivery are charged a flat fee of €1,082.06 when she is hospitalized for 1 to 4 days, to which is added a daily charge of €359.21 after the 4th day. These charges must make it possible to cover all healthcare utilization (drugs, medical devices, imaging) generated by the woman during her hospitalization but also the time spent by hospital staff and the hospital’s logistics and general management.
A national accounting database estimated that the mean cost of the management described above was €2,020 in 2015. The Nantes UHC estimated this mean cost in 2016 at €2,592.15. For the women hospitalized at the District Hospital Center of La Roche sur Yon, the estimated cost was €654.26 per day of hospitalization.
An isolated analysis of the price of the drugs used in association with TPD shows that:
one ampule of magnesium sulfate costs €0.16.
one ampule of betamethasone costs €0.96.
one ampule of tractocile costs € 43.90 for the loading dose and €14.29 for the maintenance doses.
the nifepidine protocol including 4 tablets costs €0.20.
The cost of the PartoSure® test is €56. It will be fully covered by the Natech® pharmaceutical company in our study.
Based on the standard (reimbursed) price for transport by ambulance, the cost of an in utero transfer between two hospital centers includes a flat fee of €51.30 associated with a price of €2.19 per kilometer traveled. When the transfer takes place in the same city, the flat fee of €57.37 is applied without any charge per kilometer.
There is no data monitoring committee because it is a prospective multicenter diagnostic study and non-interventional study.
This research is classified as noninterventional. It was a verbal consent from the patients. The “Patient Protection Committee (CPP) of Paris VIII” approved this protocol on 07/11/2017 as reference RC17_0247. The study will be conducted in compliance with the current approved version of the protocol.
We wish to assess the specificity of the PartoSure® test to see if it diminishes the number of false positives: the sensitivity of the TPD diagnosis is determined by cervical ultrasound, an examination with mediocre specificity.
Starting with the hypothesis of an anticipated specificity of 89% [16, 17], if we want to estimate this specificity with a confidence interval of ± 5%, we will require 151 women who do not give birth within 7 days. We have estimated the prevalence of the event at 10%, representing approximately 17 women. Accordingly a sample size of 168 women is necessary.
Nonetheless, that means that we will have very few events, since the secondary endpoint assesses the test’s sensitivity. The confidence interval will therefore be very wide, because with an estimated sensitivity of 75%, it will be ± 20%.
In 2016, 220 women were hospitalized for TPD between 24 and 34 weeks at Nantes UHC and 50 at the Vendée CHD (data extracted from the hospitals’ statistics departments).
We therefore decided to include 400 women over a period of two years to have a larger number of events (deliveries within 7 days).
The analysis sub-groups could be:
cervical measurement on transvaginal ultrasound: ≤ 15 mm, 16–20 mm, 21–25 mm.
gestational age between: 24+ 0 and 27+ 6 weeks, 28+ 0 and 31+ 6 weeks, 32+ 0 and 33+ 6 weeks.
Statistical analyses will be performed with SAS v.9.4 software. The primary analysis will be based on the intention-to-treat principle and will be complemented by a per-protocol analysis.
Descriptive analyses will be performed for all of the variables collected and point estimates by 95% confidence intervals for the qualitative and quantitative variables. If the distributions are not normal, medians and interquartile intervals of the corresponding variables will be furnished.
The alpha risk selected is 5%.