Assessment of the tocolytic nifedipine in preclinical primary models of preterm birth.

Spontaneous preterm birth is the leading cause of perinatal morbidity and mortality. Tocolytics are drugs used in cases of imminent preterm birth to inhibit uterine contractions. Nifedipine is a calcium channel blocking agent used to delay threatened spontaneous preterm birth, however, has limited efficacy and lacks preclinical data regarding mechanisms of action. It is unknown if nifedipine affects the pro-inflammatory environment associated with preterm labour pathophysiology and we hypothesise nifedipine only targets myometrial contraction rather than also mitigating inflammation. We assessed anti-inflammatory and anti-contractile effects of nifedipine on human myometrium using in vitro and ex vivo techniques, and a mouse model of preterm birth. We show that nifedipine treatment inhibited contractions in myometrial in vitro contraction assays (P = 0.004 vs. vehicle control) and potently blocked spontaneous and oxytocin-induced contractions in ex vivo myometrial tissue in muscle myography studies (P = 0.01 vs. baseline). Nifedipine treatment did not reduce gene expression or protein secretion of pro-inflammatory cytokines in either cultured myometrial cells or ex vivo tissues. Although nifedipine could delay preterm birth in some mice, this was not consistent in all dams and was overall not statistically significant. Our data suggests nifedipine does not modulate preterm birth via inflammatory pathways in the myometrium, and this may account for its limited clinical efficacy.

The assessment of selected parameters of bioelectric and mechanical activity of the uterus during pharmacologic treatment of threatening preterm delivery.

OBJECTIVES: To analyze and compare the bioelectric and mechanical activity of the uterus in pregnant women with threatening preterm delivery treated with tocolysis. Additionally, auxiliary parameters of the bioelectric signal, as registered by electrohysterography and characteristic only for this method, were measured and analyzed. MATERIAL AND METHODS: Forty-five women with pregnancies from 24 to 36 weeks of gestation with typical clinical symptoms of threatening preterm delivery were given tocolytic therapy. Registration and analysis of bioelectric activity with electrohysterography was performed simultaneously with registration and analysis of mechanical activity with tocography. RESULTS: After administration of tocolytic treatment, the presence of bioelectric activity was accompanied by the lack of or minimal occurrence of mechanical activity. All parameters of contraction recorded by electrohysterography had significantly greater values than those recorded by tocography. CONCLUSIONS: Measurement of bioelectric activity is more sensitive than measurement of mechanical activity of the uterus. Elevated bioelectric activity of the uterine muscle was observed despite the use of tocolysis, a lack of symptoms of threatening preterm delivery, as well as a lack of contraction in tocography. The presence of bioelectric activity may precede the occurrence of mechanical activity of the uterus, but further research is required on larger groups of patients.

Cost effectiveness of nifedipine compared with atosiban in the treatment of threatened preterm birth (APOSTEL III trial).

OBJECTIVE: To assess the cost-effectiveness of treatment with nifedipine compared with atosiban in women with threatened preterm birth. DESIGN: An economic analysis alongside a randomised clinical trial (the APOSTEL III study). SETTING: Obstetric departments of 12 tertiary hospitals and seven secondary hospitals in the Netherlands and Belgium. POPULATION: Women with threatened preterm birth between 25 and 34 weeks of gestation, randomised for tocolysis with either nifedipine or atosiban. METHODS: We performed an economic analysis from a societal perspective. We estimated costs from randomisation until discharge. Analyses for singleton and multiple pregnancies were performed separately. The robustness of our findings was evaluated in sensitivity analyses. MAIN OUTCOME MEASURES: Mean costs and differences were calculated per woman treated with nifedipine or atosiban. Health outcomes were expressed as the prevalence of a composite of adverse perinatal outcomes. RESULTS: Mean costs per patients were significantly lower in the nifedipine group [singleton pregnancies: €34,897 versus €43,376, mean difference (MD) -€8479 [95% confidence interval (CI) -€14,327 to -€2016)]; multiple pregnancies: €90,248 versus €102,292, MD -€12,044 (95% CI -€21,607 to € -1671). There was a non-significantly higher death rate in the nifedipine group. The difference in costs was mainly driven by a lower neonatal intensive care unit admission (NICU) rate in the nifedipine group. CONCLUSION: Treatment with nifedipine in women with threatened preterm birth results in lower costs when compared with treatment with atosiban. However, the safety of nifedipine warrants further investigation. TWEETABLE ABSTRACT: In women with threatened preterm birth, tocolysis using nifedipine results in lower costs when compared with atosiban.

Situational analysis of facilitators and barriers to availability and utilization of magnesium sulfate for eclampsia and severe preeclampsia in the public health system in Brazil.

BACKGROUND: Eclampsia is the main cause of maternal death in Brazil. Magnesium sulfate is the drug of choice for seizure prevention and control in the management of severe preeclampsia and eclampsia. Despite scientific evidence demonstrating its effectiveness and safety, there have been delays in managing hypertensive disorders, including timely access to magnesium sulfate. To conduct a general situational analysis on availability and use of magnesium sulfate for severe preeclampsia and eclampsia in the public health system. METHOD: A situational analysis was conducted with two components: a documental analysis on information available at the official websites on the policy, regulation and availability of the medication, plus a cross sectional study with field analysis and interviews with local managers of public obstetric health services in Campinas, in the southeast of Brazil. We used the fishbone cause and effect diagram to organize study components. Interviews with managers were held during field observations using specific questionnaires. RESULTS: There was no access to magnesium sulfate in primary care facilities, obstetric care was excluded from urgency services and clinical protocols for professional guidance on the adequate use of magnesium sulfate were lacking in the emergency mobile care service. Magnesium sulfate is currently only administered in referral maternity hospitals. CONCLUSION: The lack of processes that promote the integration between urgency/emergency care and specialized obstetric care possibly favors the untimely use of magnesium sulfate and contributes to the high maternal morbidity/mortality rates.

Nifedipine versus placebo in the treatment of preterm prelabor rupture of membranes: a randomized controlled trial: Assessment of perinatal outcome by use of tocolysis in early labor-APOSTEL IV trial.

OBJECTIVE: Preterm birth is the most common cause of neonatal morbidity and mortality. Around one third of preterm deliveries starts with preterm prelabor rupture of membranes (PPROM). The aim of this trial was to study the effect of prolonged tocolysis with nifedipine versus placebo in women with PPROM on perinatal outcome and prolongation of pregnancy. STUDY DESIGN: The Apostel IV was a nationwide multicenter randomized placebo controlled trial. We included women with PPROM without contractions between 24(+0) and 33(+6) weeks of gestation. Participants were randomly allocated to daily 80mg nifedipine or placebo, until the start of labor, with a maximum of 18 days. The primary outcome measure was a composite of poor neonatal outcome, including perinatal death, bronchopulmonary dysplasia, periventricular leukomalacia>grade 1, intraventricular hemorrhage>grade 2, necrotizing enterocolitis>stage 1 and culture proven sepsis. Secondary outcomes were gestational age at delivery and prolongation of pregnancy. Analysis was by intention to treat. To detect a reduction of poor neonatal outcome from 30% to 10%, 120 women needed to be randomized. TRIAL REGISTRY: NTR 3363. RESULTS: Between October 2012 and December 2014 we randomized 25 women to nifedipine and 25 women to placebo. Due to slow recruitment the study was stopped prematurely. The median gestational age at randomization was 29.9 weeks (IQR 27.7-31.3) in the nifedipine group and 27.0 weeks (IQR 24.7-29.9) in the placebo group. Other baseline characteristics were comparable. The adverse perinatal outcome occurred in 9 neonates (33.3%) in the nifedipine group and 9 neonates (32.1%) in the placebo group (RR 1.04, 95% CI 0.49-2.2). Two perinatal deaths occurred, both in the nifedipine group. Bronchopulmonary dysplasia was seen less frequently in the nifedipine group (0% versus 17.9%; p=0.03). Prolongation of pregnancy did not differ between the nifedipine and placebo group (median 11 versus 8 days, HR 1.02; 95% CI 0.58-1.79). CONCLUSION: This randomized trial did not show a beneficial effect of prolonged tocolysis on neonatal outcomes or prolongation of pregnancy in women with PPROM without contractions. However, since results are based on a small sample size, a difference in effectiveness cannot be excluded.

Fetal fibronectin testing for prevention of preterm birth in singleton pregnancies with threatened preterm labor: a systematic review and metaanalysis of randomized controlled trials.

OBJECTIVE DATA: Fetal fibronectin is an extracellular matrix glycoprotein that is produced by amniocytes and cytotrophoblasts and has been shown to predict spontaneous preterm birth. STUDY: The aim of this systematic review and metaanalysis of randomized clinical trials was to evaluate the effect of the use of fetal fibronectin in the prevention of preterm birth in singleton pregnancies with threatened preterm labor. STUDY APPRAISAL AND SYNTHESIS METHODS: The research was conducted with the use of MEDLINE, EMBASE, Web of Sciences, Scopus, ClinicalTrial.gov, OVID, and Cochrane Library as electronic databases from the inception of each database to February 2016. Selection criteria included randomized clinical trials of singleton gestations with threatened preterm labor that were assigned randomly to management based on fetal fibronectin results (ie, intervention group) or not (ie, comparison group). Types of participants included women with singleton gestations at 23 0/7 to 34 6/7 weeks with threatened preterm labor. Studies that included management that was also based on the use of sonographic cervical length were excluded. The primary outcome was preterm birth at <37 weeks of gestation. The summary measures were reported as relative risk or as mean differences with 95% confidence interval. RESULTS: Six trials that included 546 singleton gestations with symptoms of preterm labor were included in the metaanalysis. The overall risk of bias of the included trials was low. Women were eligible for the random assignment in case of symptoms that suggested preterm labor at 23-34 weeks of gestation. During admission, before digital examination, a Dacron swab was rotated in the posterior fornix for 10 seconds to absorb cervicovaginal secretions that were then analyzed for the fetal fibronectin qualitative method, with results reported as either positive or negative. Women who were assigned randomly to the fetal fibronectin group had a similar incidence of preterm birth at <37 weeks of gestation (20.7% vs 29.2%; relative risk, 0.72; 95% confidence interval, 0.52-1.01), at <34 weeks of gestation (8.3% vs 7.9%; relative risk, 1.09; 95% confidence interval, 0.54-2.18), at <32 weeks of gestation (3.3% vs 5.6%; relative risk, 0.64; 95% confidence interval, 0.24-1.74), and at <28 weeks of gestation (1.1% vs 1.7%; relative risk, 0.74; 95% confidence interval, 0.15-3.67) compared with the control group. No differences were found in the number of women who delivered within 7 days (12.8% vs 14.5%; relative risk, 0.76; 95% confidence interval, 0.47-1.21), in the mean of gestational age at delivery (mean difference, 0.20 week; 95% confidence interval, -0.26 to 0.67), in the rate of maternal hospitalization (27.4% vs 26.9%; relative risk, 1.07; 95% confidence interval, 0.80-1.44), in the use of tocolysis (25.3% vs 28.2%; relative risk, 0.97; 95% confidence interval, 0.75-1.24), antenatal steroids (29.2% vs 29.2%; relative risk, 1.05; 95% confidence interval, 0.79-1.39), in the mean time in the triage unit (mean difference, 0.60 hour; 95% confidence interval, -0.03 to 1.23) and in neonatal outcomes that included respiratory distress syndrome (1.3% vs 1.5%; relative risk, 0.91; 95% confidence interval, 0.06-14.06), and admission to the neonatal intensive care unit (19.4% vs 8.1%; relative risk, 2.48; 95% confidence interval, 0.96-6.46). Management based on the fetal fibronectin test required higher hospitalization charges (mean difference, $153; 95% confidence interval, 24.01-281.99). CONCLUSION: Fetal fibronectin testing in singleton gestations with threatened preterm labor is not associated with the prevention of preterm birth or improvement in perinatal outcome but is associated with higher costs.

Availability of treatment for eclampsia in public health institutions in Maharashtra, India.

Severe pre-eclampsia and eclampsia are common causes of maternal deaths worldwide and more so in developing countries. Magnesium sulphate (MgSO4) is now the most-recommended drug of choice to treat these conditions. Despite favourable policies for the use of MgSO4 treatment in India, eclampsia continues to take a high toll. This study examined the availability and use of MgSO4 treatment in the public health system and poor women's recent experiences with eclampsia treatment in Maharashtra state. A mix of qualitative and quantative methods was used. A facility-based survey of all secondary and tertiary healthcare facilities (n = 44) in 3 selected districts and interviews with public and contracted-in private sector obstetricians, health officials, and programme managers were conducted. A list of recently-delivering women from marginalized communities, with up to two livebirths, was drawn through a community-level survey in 272 villages covered by 60 subcentres selected at random. Mothers were selected for interviews, using maximum variation sampling, and interviews were conducted with 17% of the mothers who reported having experienced eclampsia; 61% of facilities had no stock of MgSO4, the stock-out position continuing from a period ranging from 3 months to 3 years while another 20% had some stock, although less than the expected minimum quantity. No treatment for eclampsia was provided in the recent 3 months at 73% facilities. Our survey of recently-delivering mothers recorded a history of eclampsia in 3.2% pregnancies/ deliveries. Interviews with 10 such mothers revealed that treatment for eclampsia has been sought from public as well as private hospitals and from traditional healers. However, facilities where women have received medical treatment are exclusively in the private sector. Almost all public and private care providers were aware of MgSO4 as the gold standard to treat eclampsia; however, it is unclear if they knew of its use to treat severe pre-eclampsia. The private care providers routinely used MgSO4 for eclampsia treatment while the public care providers seemed hesitant to use it fearing risks of complications. We stress the need for improved inventory control practices to ensure sustained availability of supplies and building confidence of care providers in using MgSO4 treatment for severe pre-eclampsia and eclampsia in public facilities, in addition to teaching expectant mothers how to recognize symptoms of these conditions.

Maternal and fetal outcomes after introduction of magnesium sulphate for treatment of preeclampsia and eclampsia in selected secondary facilities: a low-cost intervention.

The aim of this study was to evaluate whether a new low-cost strategy for the introduction of magnesium sulphate (MgSO4) for preeclampsia and eclampsia in low-resource areas will result in improved maternal and perinatal outcomes. Doctors and midwives from ten hospitals in Kano, Nigeria, were trained on the use of MgSO4. The trained health workers later conducted step-down training at their health facilities. MgSO4, treatment protocol, patella hammer, and calcium gluconate were then supplied to the hospitals. Data was collected through structured data forms. The data was analyzed using SPSS software. From February 2008 to January 2009, 1,045 patients with severe preeclampsia and eclampsia were treated. The case fatality rate for severe preeclampsia and eclampsia fell from 20.9 % (95 % CI 18.7-23.2) to 2.3 % (95 % CI 1.5-3.5). The perinatal mortality rate was 12.3 % as compared to 35.3 % in a center using diazepam. Introduction of MgSO4 in low-resource settings led to improved maternal and fetal outcomes in patients presenting with severe pre-eclampsia and eclampsia. Training of health workers on updated evidence-based interventions and providing an enabling environment for their practice are important components to the attainment of the Millennium Development Goals (MDG) in developing countries.

Assessment of fetal inflammatory syndrome by "classical" markers in the management of preterm labor: a possible lesson from metabolomics and system biology.

There exists a huge gap between protocols issued by scientific bodies and evidence derived by system biology studies on the multifactorial origin of threatened preterm delivery and their different associations with neonatal outcome. The objective of this prospective study was the analysis obstetrical and neonatal outcome in a cohort of pregnant patients treated for the risk of preterm delivery according to maternal and fetal assessment determined by amniotic fluid samples. Methods. Threatened preterm delivery and premature rupture of membranes between 24 + 1 and 32 + 6 weeks of gestation were treated by prolonged tocolytic regimens and if necessary by antibiotics for maternal infections when intra-amniotic inflammation (IAI) was excluded on the basis of negative white blood cell count in the amniotic fluid, or opposite, by delivery after a course of betamethasone and 48 hours maintenance tocolysis. Twenty-three cases were compared with 22 historical controls treated by the same teams according to the 48 hours treat and wait criteria. In addition to this, cases with normal and abnormal amniotic fluid white blood cell were compared. Results. Maternal and fetal conditions at admission were not significantly different between the study and control cohort for all maternal and fetal variables. Clinical indices were significantly improved as regard to latency from admission to delivery, number of newborns admitted to neonatal intensive care unit and length of stay in neonatal intensive care unit. Not any perinatal death or sepsis occurred in the study cohort. Overall, improved neonatal outcomes were observed in the study cohort. Composite major neonatal eventful outcomes occurred in 26% of cases vs. 50% in controls. The limited number of cases was not powered enough to reach a statistical significance for these variables. Continued tocolysis on demand and full regimen of mono or combined antibiotic regimen for maternal infection achieved significantly longer delay between admission to delivery with improved in neonatal outcome in cases negative for IAI: only 2 of 14 newborns suffered of major neonatal complications vs. 4 of 9 newborns delivered for IAI. Conclusions. Fetuses without IAI can be treated conservatively and their stay in utero prolonged without harm. However, we confirmed that when IAI is already active in utero a worse neonatal outcome is already partly predetermined. These positive findings must be interpreted with cautions given the limited number of cases considered by this study.

Nifedipine versus fenoterol in the management of preterm labor: a randomized, multicenter clinical study.

PURPOSE: To compare the efficacy of nifedipine and fenoterol in the management of threatened preterm labor (TPL). METHODS: A randomized and multicenter study assessing the tocolytic effect of nifedipine versus fenoterol in patients admitted to the participating maternity units with a diagnosis of TPL and a cost-savings study for economic assessment. For a power of 80% and an α error equal to 0.05, 132 consecutive patients were recruited during the study period; 66 patients were assigned to each group. A χ(2) analysis and a mean differences test were performed according to variable types and survival curves per intention-to-treat. RESULTS: Demographics were similar in both groups. The latency period was similar in both groups (26.7 vs. 25.6; p = 0.3). There were no differences in the results obtained. Nifedipine failed more frequently to obtain tocolysis when used as a first-line agent (80 vs. 90%, p = 0.0001). The group treated with fenoterol showed more drug adverse events (57.8 vs. 19.0%, p = 0.0001). The economic assessment did not evidence a significant difference in terms of cost savings between groups treated with either drug. CONCLUSION: The present study failed to demonstrate either clinical or economic superiority of any of the two drugs used in TPL management. The highest failure percentage of nifedipine when used as a first-line agent should encourage further research.

[Atosiban treatment for preterm labor--financial considerations and savings by implementing clinical guidelines].

INTRODUCTION: Preterm delivery is a significant cause of neonatal morbidity and mortality. Pregnant women, with symptoms and signs consistent with preterm labor, can be treated with various tocolytic drugs. Atosiban is one of many drugs indicated to arrest imminent preterm labor. Various studies show that the efficacy of atosiban is similar to other tocolytic drugs. The main advantage of atosiban is a relativeLy low incidence of adverse maternal reactions. Its considerable shortcoming is the financial cost, compared to other available drugs. AIM: In view of its cost, we have decided to implement a strict protocol to direct the use of atosiban, with the intent to reduce costs, without hampering quality of care. STUDY METHODS: The protocol was implemented from July 2009, and it outlines the medical and procedural terms to use atosiban. We compared similar time periods before and after implementation of the protocol. The outcomes compared included: treatment success, rates of preterm deliveries and financial costs. RESULTS: Within the timeframe that the protocol was implemented, we have been able to demonstrate a 40% reduction in atosiban related costs, compared to a parallel period, when the clinical guidelines were not implemented. This translates into savings of about NIS 40,000 (New Israeli Shekel) (approximately $10,000). This was achieved without an increase in the rate of preterm deliveries. CONCLUSION: Implementing and enforcing a simple protocol of supervision on the use of atosiban enables a considerable reduction of financial costs related to atosiban, without hampering medical care.

Atosiban versus betamimetics in the treatment of preterm labour in Italy: clinical and economic importance of side-effects.

The aim of this study was to determine the cost effectiveness of atosiban compared to betamimetics in the treatment of preterm labour within the Italian setting. A systematic literature review identified randomised controlled trials (RCTs) comparing atosiban with betamimetics. Meta-analysis of nine RCTs determined that atosiban and betamimetics had similar efficacy in delaying preterm birth by at least 48 h (p=0.910). Use of atosiban was associated with significantly fewer adverse events (p<0.008). Results demonstrate that atosiban is cost-saving versus ritodrine or isoxuprine. Atosiban cost savings are €657 per patient from the National Health Service payer's perspective; €299 at 18 h of tocolysis to €189 at 48 h from the hospital's perspective. The respective values versus isoxuprine were €303 and €199. From the combined perspective, using atosiban versus ritodrine saved from €425 to €316; and versus isoxuprine from €429 to €326. Owing to its superior safety profile, atosiban is cost-saving versus betamimetics in the treatment of preterm labour in Italy from the payer's, hospital's and combined perspectives. With the approximate 40,000 annual preterm births in Italy the annual savings could be in excess of €13 million for the payer or €3.8-6.2 million for the hospitals.

The influence of tocolytic drugs on cardiac function, large arteries, and resistance vessels.

PURPOSE: Beta-2 adrenoceptor agonistic drugs like ritodrine have been the reference tocolytic drugs, but are associated with cardiovascular side-effects. Atosiban, a newer drug, is a competitive antagonist of oxytocin and has been claimed to have fewer cardiovascular side effects. Until now, there has mainly been a subjective reporting of adverse reactions and few objective cardiovascular data. Evaluation of the acute effects of therapeutic doses of ritodrine and atosiban compared with placebo on cardiac function, large artery properties, blood pressure, and resistance vessels. METHODS: A double-blind, randomized trial was carried out in 20 non-pregnant female volunteers. Hemodynamic measurements were made under standardized conditions during kinetic steady state. Cardiac output was measured with echocardiography, large artery properties with an echo-tracking device. The effect on the microcirculation was estimated using the total peripheral resistance index (TPRI). RESULTS: Atosiban did not differ from placebo. With ritodrine, cardiac function increased by 79% compared with placebo because of a rise in heart rate (91%). TPRI decreased by 48%. Ritodrine increased the distensibility of the common carotid artery by 62% and the compliance by 83%, independent of blood pressure. Compliance of the common femoral artery increased independently of pressure by 33% and the distensibility by 59%. Aortic pulse wave velocity was not influenced by either medication. CONCLUSIONS: The present study shows potential beneficial vascular effects of ritodrine that are counterbalanced by the cardiac effects. Atosiban has no clinically relevant cardiovascular effects and may be a good alternative for ritodrine in pregnant women at risk of cardiovascular complications.

Identifying barriers to the availability and use of Magnesium Sulphate Injection in resource poor countries: a case study in Zambia.

BACKGROUND: Pre-eclampsia and eclampsia are serious complications of pregnancy and major causes of maternal mortality and morbidity worldwide. According to systematic reviews and WHO guidelines magnesium sulphate injection (MgSO4) should be the first -line treatment for severe pre-eclampsia and eclampsia. Studies have shown that this safe and effective medicine is unavailable and underutilized in many resource poor countries. The objective of this study was to identify barriers to the availability and use of MgSO4 in the Zambian Public Health System. METHODS: A 'fishbone' (Ishikawa) diagram listing probable facilitators to the availability and use of MgSO4 identified from the literature was used to develop an assessment tool. Barriers to availability and use of MgSO4 were assessed at the regulatory/government, supply, procurement, distribution, health facility and health professional levels. The assessment was completed during August 2008 using archival data, and observations at a pragmatic sample of health facilities providing obstetric services in Lusaka District, Zambia. RESULTS: The major barrier to the availability of MgSO4 within the public health system in Zambia was lack of procurement by the Ministry of Health. Other barriers identified included a lack of demand by health professionals at the health centre level and a lack of in-service training in the use of MgSO4. Where there was demand by obstetricians, magnesium sulphate injection was being procured from the private sector by the hospital pharmacy despite not being registered and licensed for use for the treatment of severe pre-eclampsia and eclampsia by the national Pharmaceutical Regulatory Authority. CONCLUSIONS: The case study in Zambia highlights the complexities that underlie making essential medicines available and used appropriately. The fishbone diagram is a useful theoretical framework for illustrating the complexity of translating research findings into clinical practice. A better understanding of the supply system and of the pattern of demand for MgSO4 in Zambia should enable policy makers and stakeholders to develop and implement appropriate interventions to improve the availability and use of MgSO4.

An examination of the clinical benefits and cost-effectiveness of tocolytic replacement following recurrent preterm labor.

We examined pregnancy outcomes in women receiving nifedipine tocolysis having recurrent preterm labor (RPTL). Singleton gestations enrolled for outpatient nursing surveillance and prescribed nifedipine tocolysis were identified (N = 4748). Women hospitalized for RPTL at <35 weeks then resuming outpatient surveillance were included (N = 1366). Pregnancy outcomes of women resuming nifedipine (N = 830) were compared with those having an alteration in treatment to continuous subcutaneous terbutaline (N = 536). Overall, 56.7% (2692/4748) experienced RPTL. Half (50.7%) were stabilized and resumed outpatient surveillance with nifedipine or continuous subcutaneous terbutaline. Infants from women resuming nifedipine versus those with alteration of treatment to terbutaline were more likely to deliver at <35 weeks (28.0% versus 13.8%), weigh <2500 g (32.9% versus 20.3%), and require a stay in the neonatal intensive care unit (34.0% versus 23.1%), all P < 0.001. Alteration of tocolytic treatment following RPTL resulted in a decreased incidence of preterm birth and low birth weight, resulting in less admission to the neonatal intensive care unit and fewer nursery days.

Screening to prevent spontaneous preterm birth: systematic reviews of accuracy and effectiveness literature with economic modelling.

OBJECTIVES: To identify combinations of tests and treatments to predict and prevent spontaneous preterm birth. DATA SOURCES: Searches were run on the following databases up to September 2005 inclusive: MEDLINE, EMBASE, DARE, the Cochrane Library (CENTRAL and Cochrane Pregnancy and Childbirth Group trials register) and MEDION. We also contacted experts including the Cochrane Pregnancy and Childbirth Group and checked reference lists of review articles and papers that were eligible for inclusion. REVIEW METHODS: Two series of systematic reviews were performed: (1) accuracy of tests for the prediction of spontaneous preterm birth in asymptomatic women in early pregnancy and in women symptomatic with threatened preterm labour in later pregnancy; (2) effectiveness of interventions with potential to reduce cases of spontaneous preterm birth in asymptomatic women in early pregnancy and to reduce spontaneous preterm birth or improve neonatal outcome in women with a viable pregnancy symptomatic of threatened preterm labour. For the health economic evaluation, a model-based analysis incorporated the combined effect of tests and treatments and their cost-effectiveness. RESULTS: Of the 22 tests reviewed for accuracy, the quality of studies and accuracy of tests was generally poor. Only a few tests had LR+ > 5. In asymptomatic women these were ultrasonographic cervical length measurement and cervicovaginal prolactin and fetal fibronectin screening for predicting spontaneous preterm birth before 34 weeks. In this group, tests with LR- < 0.2 were detection of uterine contraction by home uterine monitoring and amniotic fluid C-reactive protein (CRP) measurement. In symptomatic women with threatened preterm labour, tests with LR+ > 5 were absence of fetal breathing movements, cervical length and funnelling, amniotic fluid interleukin-6 (IL-6), serum CRP for predicting birth within 2-7 days of testing, and matrix metalloprotease-9, amniotic fluid IL-6, cervicovaginal fetal fibronectin and cervicovaginal human chorionic gonadotrophin (hCG) for predicting birth before 34 or 37 weeks. In this group, tests with LR- < 0.2 included measurement of cervicovaginal IL-8, cervicovaginal hCG, cervical length measurement, absence of fetal breathing movement, amniotic fluid IL-6 and serum CRP, for predicting birth within 2-7 days of testing, and cervicovaginal fetal fibronectin and amniotic fluid IL-6 for predicting birth before 34 or 37 weeks. The overall quality of the trials included in the 40 interventional topics reviewed for effectiveness was also poor. Antibiotic treatment was generally not beneficial but when used to treat bacterial vaginosis in women with intermediate flora it significantly reduced the incidence of spontaneous preterm birth. Smoking cessation programmes, progesterone, periodontal therapy and fish oil appeared promising as preventative interventions in asymptomatic women. Non-steroidal anti-inflammatory agents were the most effective tocolytic agent for reducing spontaneous preterm birth and prolonging pregnancy in symptomatic women. Antenatal corticosteroids had a beneficial effect on the incidence of respiratory distress syndrome and the risk of intraventricular haemorrhage (28-34 weeks), but the effects of repeat courses were unclear. For asymptomatic women, costs ranged from 1.08 pounds for vitamin C to 1219 pounds for cervical cerclage, whereas costs for symptomatic women were more significant and varied little, ranging from 1645 pounds for nitric oxide donors to 2555 pounds for terbutaline; this was because the cost of hospitalisation was included. The best estimate of additional average cost associated with a case of spontaneous preterm birth was approximately 15,688 pounds for up to 34 weeks and 12,104 pounds for up to 37 weeks. Among symptomatic women there was insufficient evidence to draw firm conclusions for preventing birth at 34 weeks. Hydration given to women testing positive for amniotic fluid IL-6 was the most cost-effective test-treatment combination. Indomethacin given to all women without any initial testing was the most cost-effective option for preventing birth before 37 weeks among symptomatic women. For a symptomatic woman, the most cost-effective test-treatment combination for postponing delivery by at least 48 h was the cervical length (15 mm) measurement test with treatment with indomethacin for all those testing positive. This combination was also the most cost-effective option for postponing delivery by at least 7 days. Antibiotic treatment for asymptomatic bacteriuria of all women without any initial testing was the most cost-effective option for preventing birth before 37 weeks among asymptomatic women but this does not take into account the potential side effects of antibiotics or issues such as increased resistance. CONCLUSIONS: For primary prevention, an effective, affordable and safe intervention applied to all mothers without preceding testing is likely to be the most cost-effective approach in asymptomatic women in early pregnancy. For secondary prevention among women at risk of preterm labour in later pregnancy, a management strategy based on the results of testing is likely to be more cost-effective. Implementation of a treat-all strategy with simple interventions, such as fish oils, would be premature for asymptomatic women. Universal provision of high-quality ultrasound machines in labour wards is more strongly indicated for predicting spontaneous preterm birth among symptomatic women than direct management, although staffing issues and the feasibility and acceptability to mothers and health providers of such strategies need to be explored. Further research should include investigations of low-cost and effective tests and treatments to reduce and delay spontaneous preterm birth and reduce the risk of perinatal mortality arising from preterm birth.

Cost-effectiveness of fibronectin testing in a triage in women with threatened preterm labor: alleviation of pregnancy outcome by suspending tocolysis in early labor (APOSTEL-I trial).

BACKGROUND: At present, women with threatened preterm labor before 32 weeks of gestation are, after transfer to a perinatal center, treated with tocolytics and corticosteroids. Many of these women are treated unnecessarily. Fibronectin is an accurate predictor for the occurrence of preterm birth among women with threatened preterm labor. We will assess whether triage of these women with fibronectin testing, cervical length or their combination is cost-effective. METHODS/DESIGN: We will investigate a prospective cohort of women referred to a perinatal centre for spontaneous threatened preterm labor between 24 and 34 weeks with intact membranes. All women will be tested for fibronectin and cervical length. Women with a cervical length <10 mm and women with a cervical length between 10-30 mm in combination with a positive fibronectin test will be treated with tocolytics according to local protocol. Women with a cervical length between 10-30 mm in combination with a negative fibronectin test will be randomised between treatment with nifedipine (intervention) and placebo (control) for 48 hours. Women with a cervical length > 30 mm will be managed according to local protocol. Corticosteroids may be given to all women at the discretion of the attending physician. Primary outcome measure will be delivery within 7 days. Secondary outcome measures will be neonatal morbidity and mortality, complications of tocolytics, costs and health related quality of life. The analysis will be according to the intention to treat principle. We anticipate the probability on preterm birth within 7 days in the group of women with a negative fibronectine test to be 5%. Two groups of 110 women will be needed to assure that in case of non-inferiority the difference in the proportion of preterm deliveries < 7 days will be within a prespecified boundary of 7.5% (one sided test, beta 0.2, alpha 0.05). Data obtained from women with a positive and negative fibronectin tests in both the cohort study and the trial will be integrated in a cost-effectiveness analysis that will assess economic consequences of the use of fibronectin. DISCUSSION: This study will provide evidence for the use of fibronectin testing as safe and cost-effective method in a triage for threatened preterm labor. TRIAL REGISTRATION: Nederlands Trial Register (NTR) number 1857, http://www.trialregister.nl.

Healthcare evaluation of the use of atosiban and fibronectin for the management of pre-term labour.

Our objective was to assess the effectiveness, safety and efficiency of a protocol combining fetal fibronectin diagnostic testing and atosiban tocolysis for the management of pre-term labour, using a combination of narrative review and economic modelling. We compared the proposed protocol to alternatives using nifedipine with or without fetal fibronectin. We have found that the proposed protocol may be safer and more acceptable by women than the alternatives, and its use can result in significant cost-savings.