Cervical pessary versus vaginal progesterone in women with a singleton pregnancy, a short cervix, and no history of spontaneous preterm birth at less than 34 weeks' gestation: open label, multicentre, randomised, controlled trial.

OBJECTIVE: To compare the effectiveness of cervical pessary and vaginal progesterone in the prevention of adverse perinatal outcomes and preterm birth in pregnant women of singletons with no prior spontaneous preterm birth at less than 34 weeks' gestation and who have a short cervix of 35 mm or less. DESIGN: Open label, multicentre, randomised, controlled trial. SETTING: 20 hospitals and five obstetric ultrasound practices in the Netherlands. PARTICIPANTS: Women with a healthy singleton pregnancy and an asymptomatic short cervix of 35 mm or less between 18 and 22 weeks' gestation were eligible. Exclusion criteria were prior spontaneous preterm birth at less than 34 weeks, a cerclage in situ, maternal age of younger than 18 years, major congenital abnormalities, prior participation in this trial, vaginal blood loss, contractions, cervical length of less than 2 mm or cervical dilatation of 3 cm or more. Sample size was set at 628 participants. INTERVENTIONS: 1:1 randomisation to an Arabin cervical pessary or vaginal progesterone 200 mg daily up to 36 weeks' of gestation or earlier in case of ruptured membranes, signs of infection, or preterm labour besides routine obstetric care. MAIN OUTCOME MEASURES: Primary outcome was a composite adverse perinatal outcome. Secondary outcomes were rates of (spontaneous) preterm birth at less than 28, 32, 34, and 37 weeks. A predefined subgroup analysis was planned for cervical length of 25 mm or less. RESULTS: From 1 July 2014 to 31 March 2022, 635 participants were randomly assigned to pessary (n=315) or to progesterone (n=320). 612 were included in the intention to treat analysis. The composite adverse perinatal outcome occurred in 19 (6%) of 303 participants with a pessary versus 17 (6%) of 309 in the progesterone group (crude relative risk 1.1 (95% confidence interval (CI) 0.60 to 2.2)). The rates of spontaneous preterm birth were not significantly different between groups. In the subgroup of cervical length of 25 mm or less, spontaneous preterm birth at less than 28 weeks occurred more often after pessary than after progesterone (10/62 (16%) v 3/69 (4%), relative risk 3.7 (95% CI 1.1 to 12.9)) and adverse perinatal outcomes seemed more frequent in the pessary group (15/62 (24%) v 8/69 (12%), relative risk 2.1 (0.95 to 4.6)). CONCLUSIONS: In women with a singleton pregnancy with no prior spontaneous preterm birth at less than 34 weeks' gestation and with a midtrimester short cervix of 35 mm or less, pessary is not better than vaginal progesterone. In the subgroup of a cervical length of 25 mm or less, a pessary seemed less effective in preventing adverse outcomes. Overall, for women with single baby pregnancies, a short cervix, and no prior spontaneous preterm birth less than 34 weeks' gestation, superiority of a cervical pessary compared with vaginal progesterone to prevent preterm birth and consecutive adverse outcomes could not be proven. TRIAL REGISTRATION: International Clinical Trial Registry Platform (ICTRP, EUCTR2013-002884-24-NL).

Uniform International Method to Measure Cervical Length: Are We There Yet?

INTRODUCTION: Cervical length is an important predictor of spontaneous preterm birth. So far, the best way to measure cervical length has not been established. We aimed to compare the incidence of short cervical length between three methods of cervical length measurement with and without the inclusion of cervico-isthmic complex (CIC) (six methods in total) and to determine the positive predictive value for spontaneous preterm birth. MATERIAL AND METHODS: We performed a prospective single-center cohort study in women with a singleton pregnancy between August 2014 and December 2018. During the routine fetal anomaly scan (18-22 weeks), women were offered transvaginal ultrasound for cervical length measurement to screen for the risk of spontaneous preterm birth. Each cervix was measured in six different ways: single-line, two-line, and tracing method between the internal and external os of the cervix with and without CIC. We evaluated the predictive value of the different measurements for spontaneous delivery before 37 weeks using positive predictive values. RESULTS: Our final study population comprised 1,691 women. The overall rate of preterm birth <37 weeks was 8.0% (4.6% spontaneous, 3.4% iatrogenic preterm birth). The mean gestational age at cervical length measurement was 19+6 weeks. The different measuring techniques resulted in significant different cervical lengths, showing a maximum difference of >8 mm between the techniques (41.04 mm [SD 7.1] with one-line without CIC and 49.18 [SD 9.05] mm with trace with CIC) with an incidence of short cervical length below <25 mm ranging from 0.4% to 1.1% (p = 0.18). The positive predictive values for spontaneous preterm birth <37 weeks ranged from 42.9% to 20.0%. CONCLUSION: Different measurement methods for cervical length resulted in statistically significant differences in measured cervical length. Depending on the chosen cut-off this translates to different incidences of short cervical length and influences the number of women designated as high risk for preterm birth and receiving treatment. For interpretation and comparability between (inter-) national studies, it is important to adequately report on the employed technique. Future research should focus on determining the optimal measuring technique and a universal method of measurement.

The association between parity and spontaneous preterm birth: a population based study.

BACKGROUND: Preterm birth is the leading cause of perinatal mortality and neonatal morbidity worldwide. Many factors have been associated with preterm birth, including parity. The aim of the present study was to investigate associations between parity and risk of spontaneous preterm birth. METHODS: We conducted a retrospective study including live singleton births (≥22 weeks) of women with a first, second, third, fourth or fifth pregnancy in The Netherlands from 2010 through 2014. Our primary outcome was risk of spontaneous preterm birth < 37 weeks. Secondary outcomes were spontaneous preterm birth < 32 and < 28 weeks. RESULTS: We studied 802,119 pregnancies, including 30,237 pregnancies that ended spontaneously < 37 weeks. We identified an increased risk for spontaneous preterm birth < 37 weeks in nulliparous women (OR 1.95, 95% CI 1.89-2.00) and women in their fifth pregnancy (OR 1.26, 95% CI 1.13-1.41) compared to women in their second pregnancy. Similar results were seen for spontaneous preterm birth < 32 and < 28 weeks. CONCLUSION: Our data show an independent association between nulliparity and spontaneous preterm birth < 37, < 32 and < 28 weeks. Furthermore, we observed an increased risk for spontaneous preterm birth in women in their fifth pregnancy, with highest risk for preterm birth at early gestational age.

Trends in preterm birth in singleton and multiple gestations in the Netherlands 2008-2015: A population-based study.

OBJECTIVE: Preterm birth is the most important cause of perinatal morbidity and mortality. Over the past years several preventive measures have been studied and implemented. Preterm birth percentage in 2015 in the Netherlands was 6.9 %, according to data from the European Peristat project, reporting on perinatal health in Europe. Various preventive measures might have influenced the incidence and outcome of preterm birth. Our aim was to give an overview of the trends in preterm births for both singleton and multiple gestations in the Netherlands in order to guide future research. STUDY DESIGN: We studied a nationwide cohort including both singleton and multiple gestations without congenital anomalies between 2008 and 2015. Outcomes were total preterm birth (defined as birth before 37 weeks of gestation), spontaneous and iatrogenic preterm birth < 37 weeks, spontaneous and iatrogenic preterm birth percentages between 34-36 weeks, 32-34 weeks, 28-31 weeks and ≤ 27 weeks using a moving average technique. Trend analysis was performed using the Cochran Armitage test. Singleton and multiple gestations were analyzed separately. RESULTS: Our final study population comprised 1,303.786 women with a singleton and 44,951 women with a multiple pregnancy. Preterm birth < 37 weeks in singletons decreased from 5.6 % in 2008 to 5.3 % in 2015 (P < 0.0001), in both spontaneous and iatrogenic preterm birth. Preterm birth ≤ 27 weeks increased from 0.40 % to 0.45 % (P for trend <0.0001). The number of multiple gestations decreased over the years, as well as the percentage of multiples conceived through IVF/ICSI. There was an increase in total and iatrogenic preterm birth < 37 weeks from 36.7-38.2% (P < 0.0001) in multiples. The number of multiples <32 decreased, in both the spontaneous and iatrogenic group. CONCLUSION: In the Netherlands preterm birth risk in singletons decreased between 2008 and 2015 but an increase was noted in preterm birth ≤ 27 weeks. In multiples the total preterm birth risk increased, due to an increase in indicated preterm birth.

Cervical Augmentation with an Injectable Silk-Based Gel: Biocompatibility in a Rat Model of Pregnancy.

The aim of this study was to study the biocompatibility of an injectable silk gel in the cervix in a rat model of pregnancy. The rationale is to study an injectable gel as an alternate treatment for cervical insufficiency. We further aimed to perform cervical injections via a vaginal route to mimic the clinical procedure of a cervical cerclage. We performed an in vivo study in pregnant female Sprague Dawley rats. Cervical procedures were performed using a customized speculum under general anesthesia. Injections were performed on gestational day 16. The responses to silk gel injections were compared to polyethylene terephthalate suture and saline controls on gestational day 19 and postpartum. The inflammatory response was evaluated by histology, PCR for inflammatory gene expression, and ELISA for protein levels of proinflammatory mediators. Silk gel injections were performed on 13 animals. All animals tolerated the procedure. Silk gel occupied 5% of the stroma after injection. Injected silk gel caused neither preterm birth nor prolonged pregnancy and had no effect on the kits. When comparing inflammatory responses, expression of inflammatory genes and proinflammatory proteins in the silk gel group was intermediate between saline (lowest) and cerclage suture (highest). Injectable silk gel was more inflammatory compared to saline injections but less inflammatory compared to the suture material used for cervical cerclage. This study is an important step toward development of an alternative treatment for cervical insufficiency.

The predictive capacity of uterine artery Doppler for preterm birth-A cohort study.

INTRODUCTION: Mid-trimester uterine artery resistance measured with Doppler sonography is predictive for iatrogenic preterm birth. In view of the emerging association between hypertensive disease in pregnancy and spontaneous preterm birth, we hypothesized that uterine artery resistance could also predict spontaneous preterm birth. MATERIAL AND METHODS: We performed a cohort study of women with singleton pregnancies. Uterine artery resistance was routinely measured at the 18-22 weeks anomaly scan. Pregnancies complicated by congenital anomalies or intrauterine fetal death were excluded. We analyzed if the waveform of the uterine artery (no notch, unilateral notch or bilateral notch) was predictive for spontaneous and iatrogenic preterm birth, defined as delivery before 37 weeks of gestation. Furthermore, we assessed whether the uterine artery pulsatility index was associated with the risk of preterm birth. RESULTS: Between January 2009 and December 2016 we collected uterine Doppler indices and relevant outcome data in 4521 women. Mean gestational age at measurement was 19+6  weeks. There were 137 (3.0%) women with a bilateral and 213 (4.7%) with a unilateral notch. Mean gestational age at birth was 38+6  weeks. Spontaneous and iatrogenic preterm birth rates were 5.7% and 4.9%, respectively. Mean uterine artery resistance was 1.12 in the spontaneous preterm birth group compared with 1.04 in the term group (P = 0.004) The risk of preterm birth was increased with high uterine artery resistance (OR 2.9 per unit; 95% CI 2.4-3.9). Prevalence of spontaneous preterm birth increased from 5.5% in women without a notch in the uterine arteries to 8.0% in women with a unilateral notch and 8.0% in women with a bilateral notch. For iatrogenic preterm birth, these rates were 3.9%, 13.6% and 23.4%, respectively. Likelihood ratios for the prediction of spontaneous preterm birth were 1.6 (95% CI 1.0-2.6) and 1.9 (95% CI 1.0-3.5) for unilateral and bilateral notches, respectively, and for iatrogenic preterm birth they were 3.6 (95% CI 2.5-5.2) and 6.8 (95% CI 4.7-9.9) for unilateral and bilateral notches, respectively. Of all women with bilateral notching, 31.4% delivered preterm. CONCLUSIONS: Mid-trimester uterine artery resistance measured at 18-22 weeks of gestation is a weak predictor of spontaneous preterm birth.

Spontaneous and iatrogenic preterm birth rates among unselected women in three consecutive pregnancies.

OBJECTIVE: To assess the risk of sPTB and iPTB in women with three consecutive singleton pregnancies and the impact of the outcome of the 1st and 2nd pregnancy on the (recurrent) PTB risk in the 3rd pregnancy. STUDY DESIGN: A nationwide retrospective cohort study using the population based longitudinal linked dataset of the Netherlands. We included all nulliparous women with three consecutive singleton pregnancies ending between 22 and 44 weeks of gestation between 1999 and 2009. We excluded congenital abnormalities and stillbirths. We compared the incidence of sPTB and iPTB in the three pregnancies (<37, <34 and <30 weeks). Logistic regression analysis was performed to predict PTB in the 3rd pregnancy, adjusting for maternal age, fetal gender, socio-economic status, hypertension, interpregnancy interval, artificial reproductive technology, and small for gestational age. Analyses were also performed stratified by prior PTB subtype, gestational age and combined outcome of the 1st and 2nd pregnancy. RESULTS: We studied 52,978 women. PTB occurred in 7.0%, 3.7% and 3.4% in the 1st, 2nd and 3rd pregnancy, respectively. The outcome of the 2nd pregnancy is more predictive for PTB in the 3rd pregnancy then the outcome of the 1st pregnancy (sPTB aOR7.3 (95%CI 6.3-8.4) and iPTB (aOR 5.9 (95% CI 4.5-7.9) in 2nd pregnancy vs. sPTB aOR 3.0 (95% CI 2.6-3.4) and iPTB aOR 2.7 (95% CI 2.1-3.4) in the 1st pregnancy). In the prediction of sPTB in the 3rd pregnancy, sPTB in the 2nd pregnancy is most predictive (aOR8.2 (95% CI 7.1-9.6) and for prediction iPTB in the 3rd pregnancy, iPTB in the 2nd pregnancy is most predictive (aOR12.1 (95% CI 8.5-17.2). CONCLUSION: We studied a population with three subsequent singleton deliveries within 10 year. The incidence of PTB decreased with 50% from the 1st to the 2nd pregnancy, to then stay relative stable in the 3rd pregnancy. Compared to PTB in the 1st pregnancy, PTB in the 2nd pregnancy is more predictive for the occurrence of PTB in the 3rd pregnancy.

Prevention of preterm birth: Novel interventions for the cervix.

Preterm birth is the leading cause of neonatal mortality and morbidity worldwide. Spontaneous preterm birth is a complex, multifactorial condition in which cervical dysfunction plays an important role in some women. Current treatment options for cervical dysfunction include cerclage and supplemental progesterone. In addition, cervical pessary is being studied in research protocols. However, cerclage, supplemental progesterone and cervical pessary have well known limitations and there is a strong need for alternate treatment options. In this review, we discuss two novel interventions to treat cervical dysfunction: (1) injectable, silk protein-based biomaterials for cervical tissue augmentation (injectable cerclage) and (2) a patient-specific pessary. Three-dimensional computer simulation of the cervix is performed to provide a biomechanical rationale for the interventions. Further development of these novel interventions could lead to new treatment options for women with cervical dysfunction.

Repeated cervical length measurements for the verification of short cervical length.

OBJECTIVE: To determine if the verification of short cervical length with a repeated measurement improved the identification of patients with short cervical length at increased risk of preterm delivery. METHODS: The present secondary analysis analyzed prospective cohort study data from patients with singleton pregnancies without a history of preterm delivery who presented for obstetric care in the Netherlands and delivered between November 18, 2009, and January 1, 2013. Cervical length was measured during standard anomaly scan and a second measurement was performed if the cervical length was 30 mm of shorter. Logistic regression and Cox proportional hazards modeling were used to evaluate associations between cervical length measurements and spontaneous preterm delivery before 37 weeks of pregnancy. RESULTS: Cervical length measurements from 12 358 patients were included; 221 (1.8%) had an initial cervical length measurement of 30 mm or shorter. A second cervical length measurement was performed for 167 (75.6%) patients; no differences were identified in the odds of spontaneous preterm delivery when evaluated using the first, second, or a mean of both measurements, regardless of whether cervical length was analyzed as a continuous or dichotomous variable. CONCLUSION: Among patients with singleton pregnancies, verification of short cervical length did not improve the identification of short cervical length.

Pessary or Progesterone to Prevent Preterm delivery in women with short cervical length: the Quadruple P randomised controlled trial.

BACKGROUND: Preterm birth is in quantity and in severity the most important topic in obstetric care in the developed world. Progestogens and cervical pessaries have been studied as potential preventive treatments with conflicting results. So far, no study has compared both treatments. METHODS/DESIGN: The Quadruple P study aims to compare the efficacy of vaginal progesterone and cervical pessary in the prevention of adverse perinatal outcome associated with preterm birth in asymptomatic women with a short cervix, in singleton and multiple pregnancies separately. It is a nationwide open-label multicentre randomized clinical trial (RCT) with a superiority design and will be accompanied by an economic analysis. Pregnant women undergoing the routine anomaly scan will be offered cervical length measurement between 18 and 22 weeks in a singleton and at 16-22 weeks in a multiple pregnancy. Women with a short cervix, defined as less than, or equal to 35 mm in a singleton and less than 38 mm in a multiple pregnancy, will be invited to participate in the study. Eligible women will be randomly allocated to receive either progesterone or a cervical pessary. Following randomization, the silicone cervical pessary will be placed during vaginal examination or 200 mg progesterone capsules will be daily self-administered vaginally. Both interventions will be continued until 36 weeks gestation or until delivery, whichever comes first. Primary outcome will be composite adverse perinatal outcome of perinatal mortality and perinatal morbidity including bronchopulmonary dysplasia, intraventricular haemorrhage grade III and IV, periventricular leukomalacia higher than grade I, necrotizing enterocolitis higher than stage I, Retinopathy of prematurity (ROP) or culture proven sepsis. These outcomes will be measured up until 10 weeks after the expected due date. Secondary outcomes will be, among others, time to delivery, preterm birth rate before 28, 32, 34 and 37 weeks, admission to neonatal intensive care unit, maternal morbidity, maternal admission days for threatened preterm labour and costs. DISCUSSION: This trial will provide evidence on whether vaginal progesterone or a cervical pessary is more effective in decreasing adverse perinatal outcome in both singletons and multiples. TRIAL REGISTRATION: Trial registration number: NTR 4414 . Date of registration January 29th 2014.

The Effect of Interpregnancy Interval on the Recurrence Rate of Spontaneous Preterm Birth: A Retrospective Cohort Study.

Objective We assessed, in women with a previous spontaneous preterm birth, the effect of interpregnancy interval on the subsequent preterm birth rate. Design Retrospective cohort study. Setting A nationwide longitudinal dataset of the the Netherlands Perinatal Registry. Population Women with three sequential singleton pregnancies between 1999 and 2009 and a spontaneous preterm birth <37 weeks in the first pregnancy. Methods We evaluated the impact of interpregnancy interval on the course of the next pregnancies. Antenatal death and/or congenital abnormalities were excluded. Conventional and conditional logistic regression analysis were applied. We adjusted for maternal age, ethnicity, socioeconomic status, artificial reproductive techniques, and year of birth. Main Outcome Measures Outcomes studied were preterm birth <37 weeks, <32 weeks, low birth weight <2500 g, and small for gestational age <10th percentile. Results Among 2,361 women with preterm birth in the first pregnancy, logistic regression analysis indicated a significant effect of a short interpregnancy interval (0-5 mo) on recurrent preterm birth <37 weeks (odds ratio [OR], 2.22; 95% confidence interval [CI], 1.62-3.05), <32 weeks (OR, 2.90; 95% CI, 1.43-5.87), and low birth weight (OR, 2.69; 95% CI, 1.79-4.03). In addition, a long interval (≥60 mo) had a significant effect on preterm birth <37 weeks (OR, 2.19; 95% CI, 1.29-3.74). Conditional logistic regression analysis confirmed the effect of a short interval on the recurrence of preterm birth rate <37 weeks and low birth weight. Conclusion In women with a previous spontaneous preterm birth, a short interpregnancy interval has a strong impact on the risk of preterm birth before 37 weeks and low birth weight in the next pregnancy, irrespective of the type of analysis performed.

Prevention of preterm delivery: current challenges and future prospects.

Preterm birth (PTB), defined as delivery at <37 weeks of gestation, is the most important cause of neonatal morbidity and mortality. Therefore, preventing PTB is one of the main goals in obstetric care. In this review, we provide an overview of the current available literature on screening for risk factors for PTB and a summary of preventive strategies in both low-risk and high-risk women with singleton or multiple gestations. Furthermore, current challenges and future prospects on PTB are discussed. For an optimal prevention of PTB, risk stratification should be based on a combination of (maternal) risk factors, obstetric history, and screening tools. Cervical length measurements can help identify women at risk. Thereafter, preventive strategies such as progesterone, pessaries, and cerclage may help prevent PTB. Effective screening and prevention of PTB vary between the different pregnancy populations. In singleton or multiple pregnancies with a short cervix, without previous PTB, a pessary or progesterone might prevent PTB. In women with a (recurrent) PTB in the past, progesterone and a cerclage may prevent recurrence. The effect of a pessary in these high-risk women is currently being studied. A strong collaboration between doctors, patients' organizations, pharmaceutical companies, and (international) governments is needed to reduce the morbidity and mortality as a result of spontaneous PTB.

Fetal Gender of the First Born and the Recurrent Risk of Spontaneous Preterm Birth.

OBJECTIVE: To study, in women with a spontaneous preterm birth (sPTB) in the first pregnancy, the effect of fetal sex in that first pregnancy on the recurrent sPTB risk. STUDY DESIGN: A nationwide retrospective cohort study (data from National Perinatal Registry) on all women with two sequential singleton pregnancies (1999-2009) with the first delivery ending in sPTB <37 weeks. We used logistic regression analysis to study the association between fetal gender in the first pregnancy and the risk of recurrent sPTB. We repeated the analysis for sPTB < 32 weeks. RESULTS: The overall incidence of sPTB <37 weeks in the first pregnancy was 4.5% (15,351/343,853). Among those 15,351 women, the risk of recurrent sPTB <37 weeks was increased when the first fetus was female compared when that fetus was male (15.8 vs. 15.2%; adjusted odds ratio [aOR] 1.2; 95% confidence interval [CI] 1.05-1.3). A similar effect was seen for sPTB <32weeks (8.2 vs. 5.9%; aOR 4.5; 95% CI 1.5-13). CONCLUSION: Women who suffer sPTB of a female fetus have an increased risk of recurrent sPTB compared with women who suffer sPTB of a male fetus. This information provides proof for the hypothesis that sPTB is due to an independent maternal and fetal factor.