The objectives of the study was to determine whether salivary progesterone (P) or estriol (E3) concentration at 16–20 weeks’ gestation predicts preterm birth or the response to 17α-hydroxyprogesterone caproate (17OHPC) and whether 17OHPC treatment affected the trajectory of salivary P and E3 as pregnancy progressed.
This was a secondary analysis of a clinical trial of 17OHPC to prevent preterm birth. Baseline saliva was assayed for P and E3. Weekly salivary samples were obtained from 40 women who received 17OHPC and 40 who received placebo in a multicenter ran-domized trial of 17OHPC to prevent recurrent preterm delivery.
Both low and high baseline saliva P and E3 were associated with a slightly increased risk of preterm birth. However, 17OHPC prevented preterm birth comparably, regardless of baseline salivary hormone concentrations. 17OHPC did not alter the trajectory of salivary P over pregnancy, but it significantly blunted the rise in salivary E3 as well as the rise in the E3/P ratio.
17OHPC flattened the trajectory of E3 in the second half of pregnancy, suggesting that the drug influences the fetoplacental unit.
17-alpha-hydroxyprogesterone caproate; longitudinal studies; preterm birth; salivary estriol; salivary progesterone
To compare the rates of gestational diabetes (GDM) among women who received serial doses of 17 alpha hydroxyprogesterone caproate (17-OHPC) versus placebo.
Secondary analysis of two double-blind randomized placebo-controlled trials of 17-OHPC given to women at risk for preterm delivery. The incidence of GDM was compared between women who received 17-OHPC or placebo.
We included 1094 women; 441 had singleton and 653 had twin gestations. Combining the two studies, 616 received 17-OHPC and 478 received placebo. Among singleton and twin pregnancies, rates of GDM were similar in women receiving 17-OHPC versus placebo (5.8% vs. 4.7%, p= 0.64 and 7.4% vs 7.6%, p =0.94, respectively). In the multivariable model, progesterone was not associated with GDM (adjusted odds ratio (adj OR) 1.04, 95% confidence interval (CI) 0.62 to 1.73).
Weekly administration of 17-OHPC is not associated with higher rates of gestational diabetes in either singleton or twin pregnancies.
17-α hydroxy progesterone caproate; gestational diabetes; singletons; twins
To evaluate the role of 17 α hydroxyprogesterone caproate (17OHPC) in the prevention of preterm labor in high risk asymptomatic patients with a history of preterm delivery.
The study included 96 patients with a singleton pregnancy and having a prior preterm birth. They were divided in 2 groups, group I (treatment group) included 46 asymptomatic patients who were given 17OHPC injections starting from 16–20 weeks till 36 weeks and group II (control group) included 50 patients who did not receive any treatment.
The incidence of preterm delivery was found to be 6.9 %. The median gestational age at delivery was 36 weeks in group I and 33 W5D in controls. 50 % cases in group I and 80 % of controls delivered prematurely in the group with a prior preterm birth between 20–28 weeks.
In patients who had a prior history of a preterm delivery the recurrence of a preterm birth was less in the treated group as compared to controls. The median gestational age at delivery was significantly higher in 17OHPC treated patients with history of earliest prior preterm delivery at 20–28 weeks.
17 alpha-hydroxyprogesterone caproate (17-OHPC) reduces recurrent preterm birth (PTB). We hypothesized that single nucleotide polymorphisms (SNPs) in the human progesterone receptor (PGR) will affect response to 17-OHPC in the prevention of recurrent PTB.
Secondary analysis of a study of 17-OHPC vs. placebo for recurrent PTB prevention. 20 PGR gene SNPs were studied. Multivariable logistic regression was used to assess for an interaction between PGR genotype and treatment status in modulating the risk of recurrent PTB.
380 women were included; 253 (66.6%) received 17-OHPC and 127 (33.4%) received placebo. The majority (61.1%) of women were African-American. Multivariable logistic regression analysis demonstrated significant treatment-genotype interactions for African-Americans delivering <37 weeks' for rs471767 and rs578029, and for Hispanics/Caucasians delivering <37 weeks' for rs500760 and <32 weeks' for rs578029, rs503362, and rs666553.
The clinical efficacy of 17-OHPC for prevention of recurrent PTB may be altered by PGR gene polymorphisms.
17-alpha hydroxyprogesterone caproate; genetic polymorphisms; progesterone receptor; recurrent preterm birth
Progestational agents may reduce the risk of preterm birth in women with various risk factors. We sought to test the hypothesis that a weekly dose of 17-hydroxyprogesterone caproate (17P) given to women with preterm rupture of the membranes (PROM) will prolong pregnancy and thereby reduce neonatal morbidity.
Double-blind, placebo-controlled randomized clinical trial. Women with PROM at 23.0 to 31.9 weeks of gestation were randomly assigned to receive a weekly intramuscular injection of 17P (250 mg in 1 mL castor oil) or placebo (1 mL castor oil). The primary outcome was the rate of continuing the pregnancy until 34.0 weeks of gestation or until documentation of fetal lung maturity at 32.0 to 33.9 weeks of gestation. Planned secondary outcomes were duration of latency period and rate of composite neonatal morbidity. Enrollment of 111 participants per group, 222 total, was planned to yield 80% power to detect an increase in the primary outcome from 30% with placebo to 50% with 17P.
Twelve women were enrolled of whom 4 were randomly assigned to receive 17P and 8 to receive placebo. The trial was terminated prematurely because of two separate issues related to the supply of 17P. No adverse events attributable to 17P were identified.
Because of premature termination, the trial does not have adequate statistical power to evaluate efficacy or safety of 17P in women with PROM. Nonetheless, ethical principles dictate that we report the results, which may contribute to possible future metaanalyses and systematic reviews.
Supported by a research grant from the Center for Research, Education, and Quality, Pediatrix Medical Group, Sunrise, FL
To examine whether women treated with 17 alpha hydroxyprogesterone caproate (17OHPC) to prevent recurrent preterm birth (PTB) experienced a change in cervical shortening over time as compared to women who were not treated.
A retrospective exposure cohort study of women, enrolled in a prematurity prevention clinic from 1999–2008, with a singleton pregnancy, ≥ one prior spontaneous PTB (<37 weeks) who underwent at ≥ 2 cervical length (CL) measurements by endovaginal ultrasound were included.
Of 200 women, 105 received and 95 did not receive treatment with 17OHPC. Women treated with 17OHPC were more likely to have experienced an earlier prior PTB (26.0 vs 27.8 wks, p=0.01) than those not treated with 17OHPC. There was no difference in the average weekly change in cervical length among women treated with 17OHPC compared with those who did not receive treatment after adjustment for covariates [0.79 mm/week, 95% CI: (−1.18, 2.76)].
There was no difference in the average weekly change in cervical length measurements over time in women receiving 17OHPC treatment compared with those who were not treated.
cervical length; preterm birth; 17 OHPC; progesterone
To compare rates of preterm birth before 35 weeks based on cervical length measurement at 16-20 weeks in women with twin gestations who received 17 alpha hydroxyprogesterone caproate (17OHPC) or placebo.
This is a secondary analysis of a randomized, double-blind, placebo-controlled trial of twin gestations exposed to 17OHPC or placebo. Baseline transvaginal ultrasound evaluation of cervical length was performed prior to treatment assignment at 16-20 weeks. Cervical length measurements were categorized according to the 10th, 25th, 50th and 75th percentiles in the women studied. The effect of 17OHPC administration in women with a short (25th percentile) and long (75th percentile) cervix was evaluated.
Of 661 twin gestations studied, 221 (33.4%) women enrolled at 11 centers underwent cervical length measurement. The 10th, 25th, 50th, 75th percentiles for cervical length at 16-20 weeks were 32, 36, 40 and 44 mm, respectively. The risk of preterm birth < 35 weeks was increased in women with a cervical length < 25th percentile (55.8 vs. 36.9%, p=0.02). However, a cervical length >75th percentile at this gestational age interval was not protective for preterm birth (36.5 vs. 42.9%, p=0.42). Administration of 17OHPC did not reduce preterm birth before 35 weeks among those with either a short or a long cervix (64.3 vs. 45.8%, p=0.18 and 38.1 vs. 35.5%, p= 0.85, respectively).
Women with twin gestations and a cervical length below the 25th percentile at 16-20 weeks had higher rates of preterm birth. In this subgroup of women, 17 OHPC did not prevent preterm birth before 35 weeks gestation. A cervical length above the 75th percentile at 16-20 weeks did not significantly reduce the risk of preterm birth in this high risk population.
To evaluate in women with twin gestation the relationship between 17-hydroxyprogesterone caproate (17-OHPC) concentration and gestational age at delivery and select biomarkers of potential pathways of drug action.
Blood was obtained between 24–28 weeks (epoch 1) and 32–35 weeks (epoch 2) in 217 women with twin gestation receiving 17-OHPC or placebo. Gestational age at delivery and concentrations of 17-OHPC, 17-hydroxyprogesterone, progesterone, C-reactive protein (CRP) and corticotrophin releasing hormone were assessed.
Women with higher concentrations of 17-OHPC delivered at earlier gestational ages than women with lower concentrations (p<0.001). Women receiving 17-OHPC demonstrated significantly higher (p=0.005) concentrations of CRP in epoch 1 than women receiving placebo but CRP values were similar in epoch 2 in both groups. A highly significant (p<0.0001) positive relationship was observed between 17-OHPC concentration and progesterone and 17-hydroxyprogesterone concentrations at both epochs. CRH concentrations did not differ by treatment group.
17-OHPC may adversely impact gestational age at delivery in women with twin gestation.
17-hydroxyprogesterone caproate (17-OHPC); pharmacodynamics; twin gestation
Preterm birth is the leading cause of neonatal mortality and morbidity and long-term disability of non-anomalous infants. Previous studies have identified a prior early spontaneous preterm birth as the risk factor with the highest predictive value for recurrence. Two recent double blind randomized placebo controlled trials reported lower preterm birth rate with the use of either intramuscular 17 alpha-hydroxyprogesterone caproate (IM 17OHP-C) or intravaginal micronized progesterone suppositories in women at risk for preterm delivery. However, it is still unclear which high-risk women would truly benefit from this treatment in a general clinical setting and whether socio-cultural, racial and genetic differences play a role in patient’s response to supplemental progesterone. In addition the patient’s acceptance of such recommendation is also in question. More research is still required on identification of at risk group, the optimal gestational age at initiation, mode of administration, dose of progesterone and long-term safety.
preterm birth prevention; 17-alpha-hydroxyprogesterone caproate
To assess whether 17 alpha-hydroxyprogesterone caproate reduces the rate of preterm birth in women carrying triplets.
We performed this randomized, double blinded, placebo controlled trial in 14 centers. Healthy women with triplets were randomized to weekly intramuscular injections of either 250 mg of 17 alpha-hydroxyprogesterone caproate or matching placebo, starting at 16-20 weeks and ending at delivery or 35 weeks of gestation. The primary study outcome was delivery or fetal loss prior to 35 weeks.
One hundred thirty-four women were randomized, 71 to 17 alpha-hydroxyprogesterone caproate and 63 to placebo; none were lost to followup. Baseline demographic data were similar in the two groups. The proportion of women experiencing the primary outcome (a composite of delivery or fetal loss prior to 35 0/7 weeks) was similar in the two treatment groups : 83% of pregnancies in the 17 alpha-hydroxyprogesterone caproate group and 84% in the placebo group, relative risk (RR) 1.0, 95% confidence interval (CI) 0.9 to1.1. The lack of benefit of 17 alpha-hydroxyprogesterone caproate was evident regardless of the conception method or whether a gestational age cut off for delivery was set at 32 or 28 weeks.
Treatment with 17 alpha-hydroxyprogesterone caproate did not reduce the rate of preterm birth in women with triplet gestation.
Multiple pregnancies are at high risk for preterm birth, and therefore an important cause of infant mortality and morbidity. A pessary is a simple and potentially effective measure for the prevention of preterm birth. Small studies have indicated its effectiveness, but large studies with sufficient power on the subject are lacking. Despite this lack of evidence, the treatment is at present applied by some gynaecologists in The Netherlands.
We aim to investigate the hypothesis that prophylactic use of a cervical pessary will be effective in the prevention of preterm delivery and the neonatal mortality and morbidity resulting from preterm delivery in multiple pregnancy. We will evaluate the costs and effects of this intervention. At study entry, cervical length will be measured. Eligible women will be randomly allocated to receive either a cervical pessary or no intervention. The cervical pessary will be placed in situ at 16 to 20 weeks, and will stay in situ up to 36 weeks gestation or until delivery, whatever comes first.
The primary outcome is composite bad neonatal condition (perinatal death or severe morbidity). Secondary outcome measures are time to delivery, preterm birth rate before 32 and 37 weeks, days of admission in neonatal intensive care unit, maternal morbidity, maternal admission days for preterm labour and costs. We need to include 660 women to indicate a reduction in bad neonatal outcome from 7.2% without to 3.9% with a cervical pessary, using a two-sided test with an alpha of 0.05 and a power of 0.80.
This trial will provide evidence on whether a cervical pessary will decrease the incidence of early preterm birth and its concomitant bad neonatal outcome in multiple pregnancies.
Current Controlled Trials: NTR 1858
Women with a sonographic short cervix in the mid-trimester are at increased risk for preterm delivery. This study was undertaken to determine the ef cacy and safety of using micronized vaginal progesterone gel to reduce the risk of preterm birth and associated neonatal complications in women with a sonographic short cervix.
This was a multicenter, randomized, double-blind, placebo-controlled trial that enrolled asymptomatic women with a singleton pregnancy and a sonographic short cervix (10–20 mm) at 19 + 0to23 + 6 weeks of gestation. Women were allocated randomly to receive vaginal progesterone gel or placebo daily starting from 20 to 23 + 6 weeks until 36 + 6 weeks, rupture of membranes or delivery, whichever occurred rst. Randomization sequence was strati ed by center and history of a previous preterm birth. The primary endpoint was preterm birth before 33 weeks of gestation. Analysis was by intention to treat.
Of 465 women randomized, seven were lost to follow-up and 458 (vaginal progesterone gel, n = 235; placebo, n = 223) were included in the analysis. Women allocated to receive vaginal progesterone had a lower rate of preterm birth before 33 weeks than did those allocated to placebo (8.9% (n = 21) vs 16.1% (n = 36); relative risk (RR), 0.55; 95% CI, 0.33–0.92; P = 0.02). The effect remained signi cant after adjustment for covariables (adjusted RR, 0.52; 95% CI, 0.31–0.91; P = 0.02). Vaginal progesterone was also associated with a signi cant reduction in the rate of preterm birth before 28 weeks(5.1%vs10.3%; RR, 0.50;95%CI, 0.25–0.97; P = 0.04) and 35 weeks (14.5% vs 23.3%; RR, 0.62; 95% CI, 0.42–0.92; P = 0.02), respiratory distress syndrome (3.0% vs 7.6%; RR, 0.39; 95% CI, 0.17–0.92; P = 0.03), any neonatal morbidity or mortality event (7.7% vs 13.5%; RR, 0.57; 95% CI, 0.33–0.99; P = 0.04) and birth weight < 1500 g (6.4% (15/234) vs 13.6% (30/220); RR, 0.47; 95% CI, 0.26–0.85; P = 0.01). There were no differences in the incidence of treatment-related adverse events between the groups.
The administration of vaginal progesterone gel to women with a sonographic short cervix in the mid-trimester is associated with a 45% reduction in the rate of preterm birth before 33 weeks of gestation and with improved neonatal outcome.
pregnancy; preterm delivery; preterm labor; progestins; progestogens; respiratory distress syndrome; transvaginal ultrasound; uterine cervix; vaginal administration
The purpose of this study was to estimate pharmacokinetic parameters and to evaluate placental transport of 17-hydroxyprogesterone caproate (17-OHPC) in singleton gestation.
Sixty-one women who received weekly injections of 17-OHPC underwent 2 pharmacokinetic studies at 20 + 0 to 24 + 6 weeks’ gestation (study 1) and 31 + 0 to 34 + 6 weeks’ gestation (study 2); daily blood samples were obtained between injections. In 18 women, blood samples were obtained over a 28-day period beyond the last injection (extended study). Maternal and/or cord blood were obtained at delivery.
The half-life (median ± SD) of 17-OHPC was 16.2 ± 6 days. Concentrations of 17-OHPC were higher during study 2 than during study 1. Body mass index affected maternal 17-OHPC concentrations. Cord:maternal 17-OHPC concentration ratios averaged 0.2; 17-OHPC was detectible in cord plasma 44 days after the last maternal injection.
The apparent half-life of 17-OHPC is long, and pharmacokinetic parameters vary widely between subjects and are affected by maternal body mass index. The drug crosses the placental barrier.
cord blood; pharmacokinetics; placenta; preterm birth
The truncated mitochondrial progesterone receptor (PR-M) is homologous to nuclear PRs with the exception of an amino terminus hydrophobic membrane localization sequence, which localizes PR-M to mitochondria. Given the matrilineal inheritance of both spontaneous preterm birth (SPTB) and the mitochondrial genome, we hypothesized that (a) PR-M is polymorphic and (b) PR-M localization sequence polymorphisms could result in variable progesterone mitochondrial effects and variable responsiveness to progesterone prophylaxis.
Secondary analysis of DNA from women enrolled in a multicenter, prospective, study of 17 alpha-hydroxyprogesterone caproate (17OHPC) versus placebo for the prevention of recurrent SPTB. DNA was extracted from stored saliva.
The PR-M localization sequence was sequenced on 344 patients. Sequences were compared with the previously published 48 base-pair sequence, and all were identical.
We did not detect genetic variation in the mitochondrial localization sequence of the truncated PR-M in a group of women at high risk for SPTB.
mitochondria; prematurity; progesterone
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). Although an improvement in short term neonatal outcomes has been shown in some trials these have not consistently been confirmed in meta-analyses. Additionally data on longer term outcomes is limited to a single trial where no difference in outcomes was demonstrated at four years of age of the child, despite those in the “progesterone” group having a lower incidence of preterm birth.
The OPPTIMUM study is a double blind randomized placebo controlled trial to determine whether progesterone prophylaxis to prevent preterm birth has long term neonatal or infant benefit. Specifically it will study whether, in women with singleton pregnancy and at high risk of preterm labour, prophylactic vaginal natural progesterone, 200 mg daily from 22 – 34 weeks gestation, compared to placebo, improves obstetric outcome by lengthening pregnancy thus reducing the incidence of preterm delivery (before 34 weeks), improves neonatal outcome by reducing a composite of death and major morbidity, and leads to improved childhood cognitive and neurosensory outcomes at two years of age. Recruitment began in 2009 and is scheduled to close in Spring 2013. As of May 2012, over 800 women had been randomized in 60 sites.
OPPTIMUM will provide further evidence on the effectiveness of vaginal progesterone for prevention of preterm birth and improvement of neonatal outcomes in selected groups of women with singleton pregnancy at high risk of preterm birth. Additionally it will determine whether any reduction in the incidence of preterm birth is accompanied by improved childhood outcome.
Preterm birth is the principal factor contributing to adverse outcomes in multiple pregnancies. Randomized controlled trials of progestogens to prevent preterm birth in twin pregnancies have shown no clear benefits. However, individual studies have not had sufficient power to evaluate potential benefits in women at particular high risk of early delivery (for example, women with a previous preterm birth or short cervix) or to determine adverse effects for rare outcomes such as intrauterine death.
We propose an individual participant data meta-analysis of high quality randomized, double-blind, placebo-controlled trials of progestogen treatment in women with a twin pregnancy. The primary outcome will be adverse perinatal outcome (a composite measure of perinatal mortality and significant neonatal morbidity). Missing data will be imputed within each original study, before data of the individual studies are pooled. The effects of 17-hydroxyprogesterone caproate or vaginal progesterone treatment in women with twin pregnancies will be estimated by means of a random effects log-binomial model. Analyses will be adjusted for variables used in stratified randomization as appropriate. Pre-specified subgroup analysis will be performed to explore the effect of progestogen treatment in high-risk groups.
Combining individual patient data from different randomized trials has potential to provide valuable, clinically useful information regarding the benefits and potential harms of progestogens in women with twin pregnancy overall and in relevant subgroups.
To evaluate whether 17-alpha hydroxyprogesterone caproate (17-OHP) reduces preterm birth (PTB) in nulliparous women with a midtrimester cervical length (CL) less than 30 mm.
In this multicenter randomized controlled trial, nulliparous women with a singleton gestation between 16 and 22 3/7 weeks with an endovaginal CL < 30 mm (<10th percentile in this population) were randomized to weekly intramuscular 17-OHP (250 mg) or placebo through 36 weeks. The primary outcome was PTB < 37 weeks.
The frequency of PTB did not differ between the 17-OHP (N = 327) and placebo (N = 330) groups (25.1% vs. 24.2%; relative risk (RR) 1.03, 95% confidence interval (CI), 0.79 – 1.35). There also was no difference in the composite adverse neonatal outcome (7.0% vs. 9.1%: RR 0.77, 95% CI 0.46 – 1.30).
Weekly 17-OHP does not reduce the frequency of PTB in nulliparous women with a midtrimester CL < 30 mm. (ClinicalTrials.gov number, NCT00439374).
progestogen; progesterone; short cervix; nulliparous
Preterm delivery (PTD), defined as birth before 37 completed weeks of gestation, is the leading cause of perinatal morbidity and mortality. Evaluation of the cervical morphology and biometry with transvaginal ultrasonography at 16–24 weeks of gestation is a useful tool to predict the risk of preterm birth in low- and high-risk singleton pregnancies. For instance, a sonographic cervical length (CL) > 30 mm and present cervical gland area have a 96-97% negative predictive value for preterm delivery at <37 weeks. Available evidence supports the use of progesterone to women with cervical length ≤25 mm, irrespective of other risk factors. In women with prior spontaneous PTD with asymptomatic cervical shortening (CL ≤ 25 mm), prophylactic cerclage procedure must be performed and weekly to every two weeks follow-up is essential. This article reviews the evidence in support of the clinical introduction of transvaginal sonography for both the prediction and management of spontaneous preterm labour.
Both dexamethasone and betamethasone, given to women at risk of preterm birth, substantially improve short-term neonatal health, increase the chance of the baby being discharged home alive, and reduce childhood neurosensory disability, remaining safe into adulthood. However, it is unclear which corticosteroid is of greater benefit to mother and child.
This study aims to determine whether giving dexamethasone to women at risk of preterm birth at less than 34 weeks’ gestation increases the chance of their children surviving free of neurosensory disability at two years’ corrected age, compared with betamethasone.
Design randomised, multicentre, placebo controlled trial.
Inclusion criteria women at risk of preterm birth at less than 34 weeks’ gestation with a singleton or twin pregnancy and no contraindications to the use of antenatal corticosteroids and who give informed consent.
Trial entry & randomisation at telephone randomisation eligible women will be randomly allocated to either the dexamethasone group or the betamethasone group, allocated a study number and corresponding treatment pack.
Study groups women in the dexamethasone group will be administered two syringes of 12 mg dexamethasone (dexamethasone sodium phosphate) and women in the betamethasone group will be administered two syringes of 11.4 mg betamethasone (Celestone Chronodose). Both study groups consist of intramuscular treatments 24 hours apart.
Primary study outcome death or any neurosensory disability measured in children at two years’ corrected age.
Sample size a sample size of 1449 children is required to detect either a decrease in death or any neurosensory disability from 27.0% to 20.1% with dexamethasone compared with betamethasone, or an increase from 27.0% to 34.5% (two-sided alpha 0.05, 80% power, 5% loss to follow up, design effect 1.2).
This study will provide high-level evidence of direct relevance for clinical practice. If one drug clearly results in significantly fewer deaths and fewer disabled children then it should be used consistently in women at risk of preterm birth and would be of great importance to women at risk of preterm birth, their children, health services and communities.
Trial registration number:
Antenatal corticosteroids; Dexamethasone; Betamethasone; Preterm birth; Randomised controlled trial; Neurosensory disability
Women with a short cervical length in mid-trimester pregnancy have a higher risk of preterm birth and therefore a higher rate of neonatal mortality and morbidity. Progesterone can potentially decrease the number of preterm births and lower neonatal mortality and morbidity. Previous studies showed good results of progesterone in women with either a history of preterm birth or a short cervix. However, it is unknown whether screening for a short cervix and subsequent treatment in mid trimester pregnancy is effective in low risk women.
We plan a combined screen and treat study among women with a singleton pregnancy without a previous preterm birth. In these women, we will measure cervical length at the standard anomaly scan performed between 18 and 22 weeks. Women with cervical length ≤ 30 mm at two independent measurements will be randomly allocated to receive either vaginal progesterone tablets or placebo between 22 and 34 weeks. The primary outcome of this trial is adverse neonatal condition, defined as a composite outcome of neonatal mortality and severe morbidity. Secondary outcomes are time to delivery, preterm birth rate before 32, 34 and 37 weeks, days of admission in neonatal intensive care unit, maternal morbidity, maternal admission days for preterm labour and costs. We will assess growth, physical condition and neurodevelopmental outcome of the children at two years of age.
This study will provide evidence for the usefulness and cost-effectiveness of screening for short cervical length at the 18-22 weeks and subsequent progesterone treatment among low risk women.
Netherlands Trial Register (NTR): NTR207
A detailed retrospective analysis was made of the records of 486 preterm infants, who accounted for 5-1% of all births during 1973 and 1974. Whereas preterm delivery did not contribute to perinatal mortality in terms of stillbirth, it outweighed all other causes in terms of early neonatal deaths. Preterm birth was responsible for 85% of the early neonatal deaths not due to lethal congenital deformities. Early neonatal mortality rates were closely linked both to gestational age and birth weight and to the reason for preterm birth. Early neonatal mortality was high (97 per 1000) when preterm labour was spontaneous, whether or not associated with material or fetal disease or with multiple pregnancy, but low (27 per 1000) when preterm delivery was elective. Preventing spontaneous preterm labour would considerably reduce neonatal mortality in our community.
No randomized controlled trial has directly compared vaginal progesterone and cervical cerclage for the prevention of preterm birth in women with a sonographic short cervix in the midtrimester, singleton gestation, and previous spontaneous preterm birth. We performed an indirect comparison of vaginal progesterone versus cerclage, using placebo/no cerclage as the common comparator.
Adjusted indirect meta-analysis of randomized controlled trials.
Four studies evaluating vaginal progesterone versus placebo (158 patients) and five evaluating cerclage versus no cerclage (504 patients) were included. Both interventions were associated with a statistically significant reduction in the risk of preterm birth <32 weeks of gestation and composite perinatal morbidity and mortality compared with placebo/no cerclage. Adjusted indirect meta-analyses did not show statistically significant differences between vaginal progesterone and cerclage in reducing preterm birth or adverse perinatal outcomes.
Based on state-of-the-art methodology for indirect comparisons, either vaginal progesterone or cerclage are equally efficacious in the prevention of preterm birth in women with a sonographic short cervix in the midtrimester, singleton gestation, and previous preterm birth. The selection of the optimal treatment may depend upon adverse events, cost and patient/clinician preferences.
prematurity; uterine cervix; transvaginal ultrasound; perinatal mortality; admission to neonatal intensive care unit; birth weight <1500 g; progestin
Magnesium sulphate is currently recommended for neuroprotection of preterm infants for women at risk of preterm birth at less than 30 weeks’ gestation, based on high quality evidence of benefit. However there remains uncertainty as to whether these benefits apply at higher gestational ages.
The aim of this randomised controlled trial is to assess whether giving magnesium sulphate compared with placebo to women immediately prior to preterm birth between 30 and 34 weeks’ gestation reduces the risk of death or cerebral palsy in their children at two years’ corrected age.
Design: Randomised, multicentre, placebo controlled trial.
Inclusion criteria: Women, giving informed consent, at risk of preterm birth between 30 to 34 weeks’ gestation, where birth is planned or definitely expected within 24 hours, with a singleton or twin pregnancy and no contraindications to the use of magnesium sulphate.
Trial entry & randomisation: Eligible women will be randomly allocated to receive either magnesium sulphate or placebo.
Treatment groups: Women in the magnesium sulphate group will be administered 50 ml of a 100 ml infusion bag containing 8 g magnesium sulphate heptahydrate [16 mmol magnesium ions]. Women in the placebo group will be administered 50 ml of a 100 ml infusion bag containing isotonic sodium chloride solution (0.9%). Both treatments will be administered through a dedicated IV infusion line over 30 minutes.
Primary study outcome: Death or cerebral palsy measured in children at two years’ corrected age.
Sample size: 1676 children are required to detect a decrease in the combined outcome of death or cerebral palsy, from 9.6% with placebo to 5.4% with magnesium sulphate (two-sided alpha 0.05, 80% power, 5% loss to follow up, design effect 1.2).
Given the magnitude of the protective effect in the systematic review, the ongoing uncertainty about benefits at later gestational ages, the serious health and cost consequences of cerebral palsy for the child, family and society, a trial of magnesium sulphate for women at risk of preterm birth between 30 to 34 weeks’ gestation is both important and relevant for clinical practice globally.
Australian New Zealand Clinical Trials Registry - ACTRN12611000491965
Magnesium sulphate; Neuroprotection; Preterm birth; Randomised controlled trial; Cerebral palsy
The aim of this study was to determine the incidence of singleton preterm breech babies born in a teaching hospital, and to study the influence of the mode of delivery on perinatal outcome in preterm births with breech presentation.
A retrospective analysis from the medical records of patients who had preterm singleton breech delivery (24 – 36 weeks gestation) was undertaken in a tertiary care hospital in the Eastern province of Saudi Arabia between January 1992 and December 2001. All the patients with intrauterine fetal death, multiple pregnancies and lethal congenital fetal malformations were excluded from the study. Intrapartum and neonatal morbidity and mortality in vaginal versus cesarean delivery groups were the main outcomes measured.
Of 24,708 deliveries that occurred in the hospital during the period of study, there were 195 preterm singleton breech deliveries, giving an incidence of 0.08%. One hundred and forty-eight (75.9%) patients delivered vaginally and did not have any medical or obstetric complications. Forty-seven (24.1%) patients underwent caesarean section. While the neonatal morbidity was similar in the two groups, the neonatal mortality was significantly higher for vaginal delivery than cesarean section (p<0.00069).
In view of the significantly higher neonatal mortality found in vaginal delivery, the present study favors abdominal delivery for a singleton preterm breech fetus.
Breech presentation; premature breech delivery; caesarean section for preterm breech; neonatal mortality
Prevention of preterm birth remains one of the most important challenges in maternity care. We propose a randomised trial with: a simple Candida testing protocol that can be easily incorporated into usual antenatal care; a simple, well accepted, treatment intervention; and assessment of outcomes from validated, routinely-collected, computerised databases.
Using a prospective, randomised, open-label, blinded-endpoint (PROBE) study design, we aim to evaluate whether treating women with asymptomatic vaginal candidiasis early in pregnancy is effective in preventing spontaneous preterm birth. Pregnant women presenting for antenatal care <20 weeks gestation with singleton pregnancies are eligible for inclusion. The intervention is a 6-day course of clotrimazole vaginal pessaries (100 mg) and the primary outcome is spontaneous preterm birth <37 weeks gestation.
The study protocol draws on the usual antenatal care schedule, has been pilot-tested and the intervention involves only a minor modification of current practice. Women who agree to participate will self-collect a vaginal swab and those who are culture positive for Candida will be randomised (central, telephone) to open-label treatment or usual care (screening result is not revealed, no treatment, routine antenatal care). Outcomes will be obtained from population databases.
A sample size of 3,208 women with Candida colonisation (1,604 per arm) is required to detect a 40% reduction in the spontaneous preterm birth rate among women with asymptomatic candidiasis from 5.0% in the control group to 3.0% in women treated with clotrimazole (significance 0.05, power 0.8). Analyses will be by intention to treat.
For our hypothesis, a placebo-controlled trial had major disadvantages: a placebo arm would not represent current clinical practice; knowledge of vaginal colonisation with Candida may change participants' behaviour; and a placebo with an alcohol preservative may have an independent affect on vaginal flora. These disadvantages can be overcome by the PROBE study design.
This trial will provide definitive evidence on whether screening for and treating asymptomatic candidiasis in pregnancy significantly reduces the rate of spontaneous preterm birth. If it can be demonstrated that treating asymptomatic candidiasis reduces preterm births this will change current practice and would directly impact the management of every pregnant woman.
Australian New Zealand Clinical Trials Registry ACTRN12610000607077