Hemodynamic assessment of indomethacin-induced fetal heart failure in high-output state.

Hemodynamic study was performed on a 32-year-old woman presenting at 27 weeks' gestation. Ultrasound revealed a single normal fetus with mild cardiomegaly, polyhydramnios, and placental chorioangioma. Doppler study showed increased middle cerebral artery peak systolic velocity, normal Tei index, and forward flow of "a" wave with normal preload in the ductus venosus. Twelve hours after initiation of indomethacin for tocolysis, frank hydrops fetalis developed rapidly. The right ventricle showed poor contractility and performance. Markedly increased preload in ductus venosus with reversed "a" wave and pulsations in the umbilical vein were demonstrated. This study suggests that indomepacin treatment in fetal high-cardiac output state should be used with extreme caution.

[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.

Atosiban versus betamimetics in the treatment of preterm labour in Germany: an economic evaluation.

BACKGROUND: The use of tocolytics is central in delaying birth; however, therapeutic options vary in effectiveness and adverse events profiles, which in turn could have consequences for medical resource use and cost of treatment. Betamimetics are commonly used tocolytic agents, but their mechanism of action affects multiple organ systems leading to numerous adverse events. The availability of an oxytocin receptor antagonist, specific for prevention of preterm labour, offers a treatment option that merits further evaluation. We aimed to compare economic implications of tocolysis using atosiban and betamimetics, considering treatment efficacy and safety, as well as cost consequences of treatment of associated adverse events. METHODS: A systematic literature review identified six randomised clinical trials, three of them double-blinded, comparing atosiban with betamimetics, in which tocolysis was initiated within 48 hours of admission. Cost of drug treatment was calculated based on trial protocols and German hospital drug purchase costs. G-DRG Grouper was used to obtain cost per case. The drug regimen was concordant with the German guidelines for the management of preterm labour, with two alternative modalities of fenoterol analysed: continuous or bolus administrations. RESULTS: According to the results of the meta-analysis of the three double-blinded, placebo-controlled clinical trials, atosiban and betamimetics have similar efficacy (RR = 0.99, 95%CI:0.94-1.04, p = 0.772). Compared to betamimetics, use of atosiban was associated with a significantly lower frequency of adverse events for tachycardia, palpitation, vomiting, headache, hyperglycaemia, tremor, dyspnoea, chest pain, hypocalemia and foetal tachycardia. In our economic analysis, cost savings from using atosiban versus continuous, or bolus, fenoterol was 423euro per patient from the payer's perspective. From the hospital's perspective, savings from using atosiban versus continuous fenoterol ranged from 259euro for 18 hours of tocolysis to 105euro for 48 hours; the respective values for bolus fenoterol were 244euro and 55euro. In the probabilistic sensitivity analysis atosiban was cost saving versus both continuous and bolus fenoterol in 87%-100% of scenarios. CONCLUSION: In a German setting, atosiban is cost saving versus betamimetics in the treatment of preterm labour from the payer, hospital and combined perspectives. Cost savings stem from the superior safety profile of atosiban.

Developments in the pharmacotherapeutic management of spontaneous preterm labor.

BACKGROUND: Preterm birth is the major cause of perinatal mortality and morbidity in the developed world. OBJECTIVE: The aim of this study was to establish the importance of preterm birth and the huge healthcare costs involved and review the pathophysiology of preterm labor and the use of antepartum glucocorticoids, which are the main reason why tocolytics are used to prevent or delay preterm birth. The study also reviewed the range of tocolytics available, their mode of action and the evidence for their efficacy and fetomaternal safety. METHODS: An extensive review of the literature using well-recognized and accepted scientific search engines was employed. RESULTS/CONCLUSIONS: The perfect tocolytic does not exist. The evidence to support the use of magnesium sulfate as a tocolytic is poor. The use of beta-agonists is decreasing worldwide as clinicians move to nifedipine or atosiban, which are as effective but much safer. Although nifedipine is cheaper than atosiban and can be administered orally, the evidence to support atosiban is much superior to that of nifedipine and there have been recent safety concerns over nifedipine.

A cost decision analysis of 4 tocolytic drugs.

OBJECTIVE: The purpose of this study was to determine the optimal tocolytic agent, based on a cost decision analysis. STUDY DESIGN: A PubMed search of commonly used tocolytics was performed to determine the probability of adverse events. Cost for an agent was determined by acquisition cost and the probability and cost of adverse events. A decision tree was constructed to determine which tocolytic had the lowest total costs, with subsequent sensitivity analysis. RESULTS: A total of 19 clinical trials combined for a cohort of 1073 patients (indomethacin, 176 patients; magnesium sulfate, 451 patients; nifedipine, 176 patients; and terbutaline, 270 patients). The probability of adverse events was 57.9% for terbutaline, 22.0% for magnesium sulfate, 27.2% for nifedipine, and 11.4% for indomethacin. Nifedipine ($16.75) and indomethacin ($15.40) were the least expensive treatment options, compared with magnesium sulfate ($197.90) and terbutaline ($399.02) because of the cost of monitoring and treating adverse events. CONCLUSION: If one elects a tocolytic, both nifedipine and indomethacin should be the agents of choice, based on a cost decision analysis.

[Comparison of the cost of treatment of premature labor with atosiban or beta-sympathomimetics from the perspective of the health care payer--a pharmacoeconomic model]. / Srovnání nákladu na lécbu predcasného porodu atosibanem nebo beta-sympatomimetiky z perspektivy plátce zdravotní péce--farmakoekonomický model.

OBJECTIVE: To evaluate the cost of treating premature delivery with atosiban or beta-sympatomimetic drugs (fenoterol and hexoprenalin) from the perspective of health care payer--the medical insurance company. DESIGN: A pharmaco-economic model based on the results of randomized, controlled clinical study. SETTING: Hospital Pharmacy at Vitkovice Hospital of Blessed Mary Antonia, Ostrava. METHODS: The study is based on the application of clinical decision-making analysis, which includes results of a randomized controlled clinical study as well as data on the cost of clinical interventions and cost of drug therapy. The pharmaco-economic model was created from the perspective of the payer of health care--the insurance company. This model presumes the administration of atosiban or beta-sympatomimetic drugs (fenoterol and hexoprenalin) for the period of 18 and 48 h and the therapy of possible untoward effects for the next 72 h after the administration of the drugs. The analysis of sensitivity of pharmacokinetic model also employs so called low and high estimate of supplementary cost for the treatment of untoward effects. RESULTS: After the administration of the drugs for the period of 18 h the total cost of the payer of medical care was in the range of 21,914.5-21,974.4 CKr in atosiban, 19,878.7-22,661.4 CKr in fenoterol and 19,942.9-21,974.4 CKr in hexoprenalin. In the administration of the drugs for 48 h, the overall cost of the payer of medical care was in the range of 43,082.5-43,142.4 CKr in atosiban, 19,960.3-23,150.7 CKr in fenoterol and 20,131.3-23,574.0 in hexoprenalin. CONCLUSIONS: This study compared overall cost associated with hospitalization of a premature delivery from the perspective of the medical care payer, i.e. the health insurance company. The authors applied a pharmaco-economic model evaluating hospitalization for the period of 48 h and subsequent therapy of possible untoward effects for the period of up to 72 h. In case of a shorter administration of atosiban (up to 18 h) the overall cost of hospitalization for premature delivery for the period of 48 h from the point of view of medical insurance company is basically comparable with the administration of beta-sympatomimetic drugs. If atosiban is administered for more than 18 h, the overall cost of hospitalization is higher than with beta-sympatomimetic drugs, and the cost increases in relation to the duration of atosiban administration.

Review of clinical experience with atosiban and the Tractocile Efficacy Assessment Survey in Europe (TREASURE) study protocol.

A phase IV multinational, multicentre study has been designed--the Tractocile Efficacy Assessment Survey in Europe (TREASURE). The aim is to assess atosiban in the clinical setting, which is associated with fewer restrictions than in phase III trials. Atosiban is to be compared with 'usual care' in women eligible for treatment, and will also be evaluated as deferred or immediate treatment in women who have not yet fulfilled the diagnostic criteria for pre-term labour. Exploring the use of atosiban beyond the normal indications may allow the identification of additional subpopulations of women who will benefit from early treatment. TREASURE will offer data on new diagnostic tools, investigate respiratory distress syndrome according to severity and record the use of antenatal steroids. It is hoped that additional information concerning the subtle differences in clinical practice will broaden our understanding of how to manage pre-term labour and offer the chance to revise treatment guidelines.

A retrospective assessment of Canadian preterm birth prevention efforts: 1979-1999.

OBJECTIVES: To assess the achievements and effectiveness of efforts to reduce preterm deliveries through the collaborative efforts of funding agencies, scientists, obstetricians, pediatricians, and health care providers in Canada. METHODS: Chronological review of studies carried out in Canada within the past two decades using several methodological approaches, including randomized clinical trials, surveys of women and physicians, and prospective cohort studies. RESULTS: Tertiary prevention by treatment of spontaneous preterm labor with beta-agonists was effective in delaying delivery by 48 hr compared with placebo. Ongoing studies tested the comparative efficacy of oxytocin antagonists to beta-adrenergic agents. Recently, nitric oxide donors have been tested. Secondary prevention using various approaches showed that high-risk factors could not be modified by these interventions. Before applying primary prevention approaches, surveys disclosed the lack of knowledge among both physicians and pregnant women. CONCLUSION: A recent Canadian consensus meeting emphasized the potential for success by using multidiscplinary, community-based health promotion approaches to prevent preterm labor; enhancing basic research in predictive markers such as cervical change, infection/inflammation, and psychosocial stress; and increasing political involvement of health decision makers.

The effect of oral terbutaline on maternal glucose metabolism and energy expenditure in pregnancy.

OBJECTIVE: Terbutaline, a selective beta2-agonist, is a frequently used tocolytic known to affect maternal metabolism. The purpose of this study was to evaluate the effect of oral terbutaline on maternal glucose metabolism and energy expenditure. STUDY DESIGN: Six healthy pregnant women with normal glucose tolerance were evaluated between 30 and 34 weeks' gestation. Oral terbutaline was administered to determine the effects on hepatic glucose production with [6-6(2)H2] glucose tracer, insulin sensitivity (hyperinsulinemic-euglycemic clamp), and energy expenditure (indirect calorimetry). Terbutaline, insulin, and glucagon levels were also obtained. Subjects were randomly assigned to either oral terbutaline 5 mg every 6 hours for 24 hours or no medication. Repeat studies were conducted 1 week apart, each subject serving as her own control. RESULTS: In the basal state terbutaline was associated with a trend toward increased basal glucose levels (81.6 +/- 6.6 vs 93.7 +/- 12.0 mg/dl, p = 0.06) but no significant increase in hepatic glucose production (3.2 +/- 0.3 vs 3.6 +/- 0.4 mg/kg fat-free mass/min, p = 0.23). However, there was a significant increase in basal insulin concentration (17.6 +/- 9.2 vs 25.6 +/- 10.4 microU/ml, p = 0.02). There was a 28% decrease in insulin sensitivity as measured by the glucose infusion rate during the euglycemic clamp plus residual hepatic glucose turnover (5.78 +/- 1.91 vs 4.16 +/- 1.49 mg/kg fat-free mass/min, p = 0.005). Glucagon concentration was significantly decreased both in the basal state (163 +/- 26 vs 144 +/- 27 pg/ml, p = 0.0007) and during the clamp (144 +/- 27 vs 133 +/- 27 pg/ml, p = 0.003). Basal oxygen consumption increased 9% (270 +/- 49 vs 294 +/- 50 ml oxygen/min, p = 0.007) and caloric expenditure 14% (1.32 +/- 0.23 vs 1.50 +/- 0.31 kcal/min, p = 0.025) or 260 kcal/day with terbutaline. CONCLUSION: Decreased peripheral insulin sensitivity, and to a lesser degree increased endogenous glucose production, may represent the pathophysiology of abnormal glucose tolerance observed in many women treated with oral terbutaline. Common side effects such as tremors and tachycardia experienced by many women on a regimen of terbutaline are consistent with our finding of a significant increase in basal energy expenditure.

Optimising maternal-fetal outcomes in preterm labour: a decision analysis.

OBJECTIVE: To compare, using decision analytic techniques, maternal and fetal risk and benefits of three strategies for the management of preterm labour after 32 weeks. These strategies are empiric tocolysis, no tocolysis, or amniocentesis for fetal maturity testing. DATA SOURCES: Published medical literature provided the probabilities, including those for tocolysis efficacy, maternal and neonatal outcomes, and steroid efficacy. DATA: Synthesis Separate decision trees were created for hypothetical cohorts of patients presenting with preterm labour at 32, 34, and 36 weeks of gestation to compare strategies. The primary outcome was the total number of expected adverse maternal and neonatal events for each strategy at each gestational age. RESULTS: At 32 weeks tocolysis yielded the lowest total number of adverse maternal and neonatal events. At 34 weeks, both tocolysis and no tocolysis yielded similar overall outcomes. At 36 weeks most clinical outcomes were good regardless of strategy. CONCLUSIONS: This analysis supports the empiric use of tocolytics at 32 weeks. At 34 weeks, either tocolysis or no tocolysis appear to be reasonable alternatives. At 36 weeks no tocolysis is probably preferred. This analysis also suggests that amniocentesis should not be employed in the management of preterm labour at these gestational ages.

Premature rupture of the membranes--aggressive versus conservative approach: effect of tocolytic and antibiotic therapy.

The purpose of this randomized, prospective study was to evaluate the efficacy of tocolytic and antibiotic therapy in the prolongation of pregnancy and neonatal outcome in the treatment of premature rupture of the membranes without clinical labor. Delivery was delayed for 48 h, 7 days and beyond 35 weeks of gestation in 87, 39 and 18%, respectively, of patients in the treated group (n = 39) compared with 50, 12 and 17% of patients in the nontreated group (n = 42). The incidence of a low Apgar score (< 7 at 5 min), requiring artificial ventilation, and infectious morbidity was more common in the treated group than in the nontreated group (18 vs. 0, 41 vs. 17 and 39 vs. 17%, respectively). There was no significant cost difference in survivors between the treated and nontreated groups, although the mothers in the treated group were significantly more expensive. From these observations, it appears that tocolysis and antibiotics are not effective in PROM cases.

Risk-benefit assessment of tocolytic drugs.

beta 2-Mimetics are the principal agents used for myometrial relaxation. As all the available drugs also have beta 1-stimulant effects, the various side effects (cardiovascular, pulmonary and metabolic) require a critical consideration of the clinical indications, thorough supervision and combined therapeutic concepts. With regard to clinical indications, 'prophylactic tocolysis' frequently turns out to be unnecessary, as does the treatment of physiological uterine contractions during pregnacy which have no effect on the cervix. The benefit of tocolysis must be seen not so much in a reduction of preterm labour but in enabling the obstetrician and neonatologist to optimise the handling of the premature baby, e.g. by allowing lung maturation or by enabling the patient to reach a centre for perinatal medicine before the birth. Labour-dependent fetal distress situations during birth at term can also be managed successfully. Supervision involves thorough control of both mother (especially of cardiovascular and metabolic parameters, electrolyte and water balance) and fetus (cardiotocography, fetometry) in order to decide individually when possible benefits are outweighed by maternal or fetal risks. Combination of beta 2-mimetic treatment with magnesium therapy reduces the beta-mimetic dosage required, has a cardioprotective action, and reduces the development of drug tolerance and the risk of lung oedema. This combination, therefore, should become routine in tocolytic therapy. If further protection against cardiovascular and risk of lung oedema is required, administration of beta 1-blockers is advisable.