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
Introduction. Reduction of preterm birth is a major goal in obstetric care. We performed a systematic review of randomized controlled trials and cohort studies on the effectiveness of the cervical pessary to prevent preterm birth. Methods. We searched the electronic databases of MEDLINE and Embase from inception until April 2012 to identify studies investigating treatment with a cervical pessary to prevent preterm birth. We constructed two-by-two tables for delivery before 28, 34, and 37 weeks of gestation and calculated relative risks (RRs) with 95% confidence intervals. Results. The search revealed 103 potentially eligible abstracts of which six cohort studies and four randomized controlled trials (RCTs) investigated the effectiveness of the pessary. One RCT (n = 380) demonstrated a lower delivery rate prior to 34 weeks (RR 0.24; 95% CI 0.13–0.43) in the pessary group, while another RCT (n = 108) showed no positive effect of pessary for delivery before 34 weeks (RR 1.73; 95% CI 0.43–6.88). Two older quasi randomized studies and cohort studies indicated potential effect of the pessary. Conclusions. Available randomized and nonrandomized studies indicate potential effectiveness of a cervical pessary in the prevention of preterm birth. More randomized clinical trials are needed before this device can be used in clinical practice.
Preterm delivery (PD) is the most important cause of neonatal mortality, particularly before the 32nd week of pregnancy. A short cervix is the most important quantitative marker for predicting PD. However, there are other qualitative markers such as cervical gland area, cervical funneling, and sludge. We present the case of a pregnant woman who was diagnosed with a short cervix at 14-weeks and demonstrate the use of triple therapy, which helped to achieve a good perinatal result. A 37-year-old pregnant woman (G3P0) was referred to our service at 14-weeks of pregnancy presenting with a short cervix (20 mm) and a positive sludge sign. She was hospitalized; a pessary was inserted, and started on antibiotic therapy (clindamycin and cefalotin for 10 days). At 20 weeks, she was again admitted to the hospital, and this time presented with a further shortened cervix (9 mm), cervical funneling, and a positive sludge sign, with the pessary in position. The following procedures were performed: Amniocentesis on the sludge (negative bacterioscopy), another cycle of antibiotics, administration of oral progesterone, and imaging to determine retention of pessary position. The patient was placed in the Trendelenburg position and remained hospitalized for 82 days. At 32 + 1 weeks, the fetus presented distress (tachycardia). C-section was performed, producing a live female newborn weighing 2,180 g and presenting Apgar indexes of 8/8. This case report demonstrates the importance of magnetic resonance imaging to assess the position of pessary in a pregnant woman with short cervix.
Magnetic resonance imaging; pessary; preterm delivery; progesterone; short cervix syndrome; ultrasound
Luteal support with progesterone is necessary for successful implantation of the embryo following egg collection and embryo transfer in an in-vitro fertilization (IVF) cycle. Progesterone has been used for as little as 2 weeks and for as long as 12 weeks of gestation. The optimal length of treatment is unresolved at present and it remains unclear how long to treat women receiving luteal supplementation.
The trial is a prospective, randomized, double-blind, placebo-controlled trial to investigate the effect of the duration of luteal support with progesterone in IVF cycles. Following 2 weeks standard treatment and a positive biochemical pregnancy test, this randomized control trial will allocate women to a supplementary 8 weeks treatment with vaginal progesterone or 8 weeks placebo. Further studies would be required to investigate whether additional supplementation with progesterone is beneficial in early pregnancy.
Currently at the Hewitt Centre, approximately 32.5% of women have a positive biochemical pregnancy test 2 weeks after embryo transfer. It is this population that is eligible for trial entry and randomization. Once the patient has confirmed a positive urinary pregnancy test they will be invited to join the trial. Once the consent form has been completed by the patient a trial prescription sheet will be sent to pharmacy with a stated collection time. The patient can then be randomized and the drugs dispensed according to pharmacy protocol. A blood sample will then be drawn for measurement of baseline hormone levels (progesterone, estradiol, free beta-human chorionic gonadotrophin, pregnancy-associated plasma protein-A, Activin A, Inhibin A and Inhibin B). The primary outcome measure is the proportion of all randomized women that continue successfully to a viable pregnancy (at least one fetus with fetal heart rate >100 beats/minute) on transabdominal/transvaginal ultrasound at 10 weeks post embryo transfer/12 weeks gestation (that is at the end of 8 weeks supplementary trial treatment).
IVF; Luteal phase; Progesterone; Support
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.
15% of multiple pregnancies ends in a preterm delivery, which can lead to mortality and severe long term neonatal morbidity. At present, no generally accepted strategy for the prevention of preterm birth in multiple pregnancies exists. Prophylactic administration of 17-alpha hydroxyprogesterone caproate (17OHPC) has proven to be effective in the prevention of preterm birth in women with singleton pregnancies with a previous preterm delivery. At present, there are no data on the effectiveness of progesterone in the prevention of preterm birth in multiple pregnancies.
We aim to investigate the hypothesis that 17OHPC will reduce the incidence of the composite neonatal morbidity of neonates by reducing the early preterm birth rate in multiple pregnancies. Women with a multiple pregnancy at a gestational age between 15 and 20 weeks of gestation will be entered in a placebo-controlled, double blinded randomised study comparing weekly 250 mg 17OHPC intramuscular injections from 16–20 weeks up to 36 weeks of gestation versus placebo. At study entry, cervical length will be measured. 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 15% to 8%. Analysis will be by intention to treat. We will also analyse whether the treatment effect is dependent on cervical length.
This trial will provide evidence as to whether or not 17OHPC-treatment is an effective means of preventing bad neonatal outcome due to preterm birth in multiple pregnancies.
Current Controlled Trials ISRCTN40512715
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
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
We compared neonatal outcomes in twin pregnancies following moderately preterm birth (MPTB), late preterm birth (LPTB) and term birth. A secondary analysis of a multi-center, randomized controlled trial of multiple gestations was conducted. MPTB was defined as delivery between 320/7 and 336/7 weeks and LPTB between 340/7 and 366/7 weeks. Primary outcome was a neonatal outcome composite consisting of one or more of the following: neonatal death, respiratory distress syndrome, early onset culture-proven sepsis, stage 2 or 3 necrotizing enterocolitis, bronchopulmonray dysplasia, grade 3 or 4 intraventricular hemorrhage, periventricular leukomalacia, pneumonia, or severe retinopathy of prematurity. Among 552 twin pregnancies, the MPTB rate was 14.5%, LPTB 49.8% and term birth rate 35.7%. The rate of the primary outcome was different between groups: 30.0% for MPTB, 12.8% for LPTB, 0.5% for term (p< 0.001). Compared with term neonates, the primary neonatal outcome composite was increased following MPTB (relative risk [RR] 58.5; 95% confidence interval [CI] 11.3 to 1693.0) and LPTB (RR 24.9; 95% CI 4.8 to 732.2). Twin pregnancies born moderately and late preterm encounter higher rates of neonatal morbidities compared to twins born at term.
twin pregnancy; late preterm birth; neonatal morbidities
To evaluate the feasibility of continuous telemetric trans-abdominal fetal electrocardiogram (a-fECG) in women undergoing labour induction at home.
Low risk women with singleton term pregnancy undergoing labour induction with retrievable, slow-release dinoprostone pessaries (n = 70) were allowed home for up to 24 hours, while a-fECG and uterine activity were monitored in hospital via wireless technology. Semi-structured diaries were analysed using a combined descriptive and interpretive approach.
62/70 women (89%) had successful home monitoring; 8 women (11%) were recalled because of signal loss. Home monitoring lasted between 2–22 hours (median 10 hours). Good quality signal was achieved most of the time (86%, SD 10%). 3 women were recalled back to hospital for suspicious a-fECG. In 2 cases suspicious a-fECG persisted, requiring Caesarean section after recall to hospital. 48/51 women who returned the diary coped well (94%); 46/51 were satisfied with home monitoring (90%).
Continuous telemetric trans-abdominal fetal ECG monitoring of ambulatory women undergoing labour induction is feasible and acceptable to women.
A 35-year-old gravida 7, para 1, and abortus 5 female with hypogastric pain and inability to void urine after 14 + 3 weeks of amenorrhea was examined in the emergency department. One year before, a uterine prolapse had been diagnosed in another hospital. Examination showed a uterine prolapse grade 2 with palpable bladder. The patient was unable to void urine. After a manual reduction of the uterine prolapse, the patient underwent an emergency catheterization for bladder drainage. A Hodge pessary (size 70) was placed, which led to spontaneous micturitions. Due to the persistence of the symptoms the following day, Hodge pessary was replaced by an Arabin cerclage pessary. Although the pessary could be removed from the beginning of the second trimester, due to the uterine prolapse as a predisposing factor in the patient and the uncomplicated progression of pregnancy, it was decided to maintain it in our patient. Therefore, Arabin cerclage pessary allowed a successful pregnancy outcome and was not associated with threatened preterm delivery or vaginal infection.
Objective. We evaluated the use of a one-week ambulatory pessary trial in predicting patients' postoperative outcomes for occult stress incontinence.
Methods. Patients with anterior vaginal wall prolapse were offered a pessary trial to predict response to reconstruction. We performed a retrospective review of 4 years of cases. All patients underwent a detailed evaluation including videourodynamics with and without pessary reduction.
Results. Twenty-six patients completed the 1-week pessary trial. Ten (38%) women showing no evidence of stress urinary incontinence (SUI) underwent surgical repair of prolapse without anti-incontinence procedure. None of these patients had SUI postoperatively. Sixteen women (61%) had occult stress urinary incontinence on evaluation and underwent concurrent sling procedure. Three (19%) of these patients were identified by the pessary trial alone. Twenty-five of the 26 patients were without clinical stress incontinence at a mean follow up of 12 months (range 4–37 months). The pessary trial correctly predicted persistent urgency in six patients and persistent frequency in five. No patients with SUI or persistent voiding difficult were missed in a pessary trial.
Conclusion. An ambulatory pessary trial is an effective, easy, and inexpensive method to approximate anatomic results achieved by surgery under real-life conditions. In our series, 20% of patients with occult SUI were identified by pessary trial alone.
There is a well recognized risk of complications for both women and infants of a twin pregnancy, increasing beyond 37 weeks gestation. Preterm birth prior to 37 weeks gestation is a recognized complication of a twin pregnancy, however, up to 50% of twins will be born after this time.
The aims of this randomised trial are to assess whether elective birth at 37 weeks gestation compared with standard care in women with a twin pregnancy affects the risk of perinatal death, and serious infant complications.
Design: Multicentred randomised trial.
Inclusion Criteria: women with a twin pregnancy at 366 weeks or more without contraindication to continuation of pregnancy.
Trial Entry & Randomisation: Following written informed consent, eligible women will be randomised from 36+6 weeks gestation. The randomisation schedule uses balanced variable blocks, with stratification for centre of birth and planned mode of birth. Women will be randomised to either elective birth or standard care.
Treatment Schedules: Women allocated to the elective birth group will be planned for elective birth from 37 weeks gestation. Where the plan is for vaginal birth, this will involve induction of labour. Where the plan is for caesarean birth, this will involve elective caesarean section. For women allocated to standard care, birth will be planned for 38 weeks gestation or later. Where the plan is for vaginal birth, this will involve either awaiting the spontaneous onset of labour, or induction of labour if required. Where the plan is for caesarean birth, this will involve elective caesarean section (after 38 and as close to 39 weeks as possible).
Primary Study Outcome: A composite of perinatal mortality or serious neonatal morbidity.
Sample Size: 460 women with a twin pregnancy to show a reduction in the composite outcome from 16.3% to 6.7% with adjustment for the clustering of twin infants within mothers (p = 0.05, 80% power).
This is a protocol for a randomised trial, the findings of which will contribute information about the optimal time of birth for women with an uncomplicated multiple pregnancy at and beyond 37 weeks gestation.
Clinical Trial Registration
Current Controlled Trials ISRCTN15761056
To compare the effectiveness of a continence pessary to evidence-based behavioral therapy for stress incontinence and to assess whether combined pessary and behavioral therapy is superior to single-modality therapy.
Multi-site, randomized clinical trial (“Ambulatory Treatments for Leakage Associated with Stress Incontinence” (ATLAS)) randomized 446 women with stress incontinence to pessary, behavioral therapy, or combined treatment. Primary outcome measures, at 3months, were Patient Global Impression of Improvement (PGI-I) and the stress incontinence subscale of the Pelvic Floor Distress Inventory (PFDI). A priori, to be considered clinically superior, combination therapy had to be better than both single-modality therapies. Outcomes measures were repeated at 6 and 12 months. Primary analyses used intention-to-treat approach.
At 3 months, 40% of the pessary group and 49% of the behavioral group were “much better” or “very much better” on PGI-I (p=0.09). Compared to the pessary group, more women in the behavioral group reported having no bothersome incontinence symptoms (49% vs. 33%, p=0.006) and treatment satisfaction (75% vs. 63%, p=0.02). Combination therapy was significantly better than pessary on PGI-I (53%, p=0.02) and PFDI (44%, p=0.05), but not better than behavioral therapy; it was therefore not superior to single-modality therapy. Group differences were not sustained to12 months on any measure, and patient satisfaction remained above 50% for all treatment groups.
Behavioral therapy resulted in greater patient satisfaction and fewer bothersome incontinence symptoms than pessary at 3 months, but differences did not persist to 12 months. Combination therapy was not superior to single-modality therapy.
Pessaries have been used to treat women with pelvic organ prolapse (POP) since the beginning of recorded history. This review aims to assess the effect of pessary treatment on the disease-specific, health-related quality of life in women with pelvic organ prolapse. After a Medline search using the Mesh term ‘pessary’ and critical appraisal, 41 articles were selected and used in this review. Pessaries are widely used to treat pelvic organ prolapse. It is minimally invasive and appears to be safe. Although there is evidence that the use of pessaries in the treatment of pelvic organ prolapse is effective in alleviating symptoms and that patient satisfaction is high, the follow-up in many published papers is short, and the use of validated urogynaecological questionnaires is limited. Comparison with surgical treatment of pelvic organ prolapse is rare and not assessed in a randomised controlled trial.
Pelvic organ prolapse; Pessaries; Pessary; Quality of life; Surgery; Urogenital
To determine if differences exist in pelvic symptom distress and impact in women randomized to pessary versus behavioral therapy for treatment of stress urinary incontinence (SUI).
Change in symptom and condition-specific health related quality of life (HRQOL) measures were compared between pessary and behavioral groups 3-months after randomization in the Ambulatory Treatments for Leakage Associated with Stress Incontinence [ATLAS]) trial. 446 women with symptoms of SUI were randomized to continence pessary, behavioral therapy (pelvic floor muscle training and continence strategies) or combination therapy. Validated measures utilized included urinary (UDI), prolapse (POPDI) and colorectal (CRADI) scales of the Pelvic Floor Distress Inventory; urinary (UIQ), prolapse (POPIQ) and colorectal (CRAIQ) scales of the Pelvic Floor Impact Questionnaire; and stress and urge scale of the Questionnaire for Urinary Incontinence Diagnosis (QUID). Student t- test and ANOVA was used to compare scores within and between groups.
Mean age of participants was 49.8±11.9 years; 84% were Caucasian and 10% African American. 149 were randomized to pessary and 146 to behavioral therapy. Baseline symptoms and HRQOL scores were significantly reduced within treatment arms at three months post randomization, but there was no statistically significant difference between groups.
There was no difference in pelvic floor symptom bother and HRQOL between the pessary and behavioral therapy arms in women undergoing conservative treatment for SUI. Individualized preference issues should be considered in the approach to the non-surgical treatment of SUI.
Pessary; Behavioral Therapy; Stress Urinary Incontinence
Many aspects of postnatal development are influenced by events before birth, including cognitive and language development. An adverse intrauterine environment, for example secondary to poor maternal nutritional status, multiple pregnancy, or late preterm birth, is associated with increased risks of delayed or impaired childhood development and altered physiology in adulthood that may predispose to increased risk of adult disease. Maternal periconceptional undernutrition and twin conception can both result in late preterm birth, but it is less clear whether cases of late preterm birth not following a recognized early pregnancy event may still have their origin in the periconceptional period. Thus, the very earliest periods of pregnancy, and perhaps even the pre-pregnancy period, may be an important period determining the developmental trajectory of the fetus, and thus both pregnancy and later health outcomes. Profound epigenetic modifications to the genome occur in the early embryo as a normal part of development. Recent evidence suggests that environmental signals acting during early development may also result in epigenetic changes which may play a role in mediating the association between early life exposures and later phenotype.
Maternal nutrition; Twin conception; Late preterm birth; Developmental origins of health and disease; Epigenetics
A fertilisation cohort of 244 pregnancies resulting from in vitro fertilisation was reported to a national register by eight units specialising in in vitro fertilisation. Early pregnancy losses were high, with 5% tubal ectopic pregnancies, 18% biochemical pregnancies, and an incidence of spontaneous abortion of 27%. Among pregnancies of at least 20 weeks' gestation 22% were multiple, with 26 pairs of twins and four sets of triplets. The incidence of preterm births was more than three times higher than in the general population. Low birthweight rates were also higher, owing both to preterm births and to multiple pregnancies. The sex ratio and the incidence of major congenital malformations were similar to those in naturally conceived pregnancies. In this series the high fetal losses at all stages of pregnancy suggested maternal reproductive causes and should not be interpreted as being due to factors peculiar to in vitro fertilisation. Further analysis will be necessary when larger numbers are available.
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.
To investigate the accuracy of cervicovaginal fetal fibronectin in predicting preterm birth in women carrying multiple pregnancies.
Systematic review and meta-analysis of predictive test accuracy. Cohort or cross-sectional studies were identified through searches in databases, reference lists, proceedings, and reviews. Study selection, quality assessment, and data extraction were performed. We constructed summary receiver operating characteristic curves and calculated pooled sensitivities and specificities using a bivariate, random-effects meta-regression model. We also calculated summary likelihood ratios and post-test probabilities of preterm birth.
Fifteen studies (11 in asymptomatic women and 4 in women with symptoms of preterm labor) involving 1221 women with multiple pregnancies were included. Among asymptomatic women with multiple or twin pregnancies, the pooled sensitivities, specificities, and positive and negative likelihood ratios for predicting preterm birth before 32, 34, and 37 weeks’ gestation ranged from 33% to 45%, 80% to 94%, 2.0 to 5.5, and 0.68 to 0.76, respectively. Among women with twin pregnancies and threatened preterm labor, the test was most accurate in predicting spontaneous preterm birth within 7 days of testing (pooled sensitivity, specificity, and positive and negative likelihood ratios of 85%, 78%, 3.9, and 0.20, respectively).
Cervicovaginal fetal fibronectin provides moderate to minimal prediction of preterm birth in women with multiple pregnancies. The test is most accurate in predicting spontaneous preterm birth within 7 days of testing in women with twin pregnancies and threatened preterm labor.
multiple pregnancy; twin pregnancy; preterm labor; prematurity; twins
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.
To examine whether blood pressure in early pregnancy and its rise in second half of gestation are associated with spontaneous preterm birth in healthy, normotensive, nulliparous women.
We included 5,167 women with singleton gestation who participated in the World Health Organization Calcium Supplementation for the Prevention of Preeclampsia Trial. Systolic, diastolic, mean arterial blood pressure and pulse pressure at baseline (12 – 19 weeks of gestation) and mid 3rd trimester (30 – 34 weeks) were calculated. Rise in blood pressure was the difference between the mid 3rd trimester and baseline. Preterm birth was defined as early preterm (< 34 completed weeks) and late preterm birth (34 – 36 weeks).
Women experiencing early or late preterm birth had over 10 mmHg and 3 mmHg higher rise, respectively, in systolic, diastolic and mean arterial blood pressure than women delivering at term. A rise in systolic pressure over 30 mmHg or diastolic pressure over 15 mmHg was associated with a statistically significant 2 – 3-fold increase in risk of spontaneous preterm birth.
An excessive rise in either systolic or diastolic blood pressures from early pregnancy to mid 3rd trimester is associated with spontaneous preterm birth in a dose-response pattern.
blood pressure; preeclampsia; preterm birth
The analysis of genetic and environmental contributions to preterm birth is not straightforward in family studies, as etiology could involve both maternal and fetal genes. Markov Chain Monte Carlo (MCMC) methods are presented as a flexible approach for defining user-specified covariance structures to handle multiple random effects and hierarchical dependencies inherent in children of twin (COT) studies of pregnancy outcomes. The proposed method is easily modified to allow for the study of gestational age as a continuous trait and as a binary outcome reflecting the presence or absence of preterm birth. Estimation of fetal and maternal genetic factors and the effect of the environment are demonstrated using MCMC methods implemented in WinBUGS and maximum likelihood methods in a Virginia COT sample comprising 7,061 births. In summary, although the contribution of maternal and fetal genetic factors was supported using both outcomes, additional births and/or extended relationships are required to precisely estimate both genetic effects simultaneously. We anticipate the flexibility of MCMC methods to handle increasingly complex models to be of particular relevance for the study of birth outcomes.
preterm birth; fetal; maternal; genetic; environment; MCMC; ML
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
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