Alternativas terapéuticas para la tocólisis en el manejo de la amenaza de parto pretérmino / Therapeutic alternatives for the tocolysis in the management of the threatened preterm labour

La amenaza de parto pretérmino (APP) es una urgencia obstétrica que, en ausencia de intervención, desemboca en un parto prematuro. Detener la APP y prolongar la gestación todo lo posible permite trasladar a la gestante a un centro apropiado, administrar los cuidados necesarios y conceder un mayor periodo de maduración al feto, esencial para reducir la morbimortalidad asociada al parto prematuro. El empleo de tocolíticos al inicio de este proceso es esencial. En este artículo se revisa el escenario clínico y la información sobre los tocolíticos actualmente autorizados en España, dos de ellos por vía intravenosa (ritodrina y atosibán) y otro por vía oral (nifedipino solución oral) (AU)

Threatened preterm labour is an urgent obstetric condition leading to a preterm birth in the absence of medical intervention. Intervention must focus on stopping birth progression in order for the patient and the fetus be administered an adequate medical care, providing a temporal window for fetus´ maturation. This medical management is aimed to reduce the morbimortality associated to preterm birth. This manuscript consists of a review of the toclytics of more extended use in our context. Currently, three drugs are authorised as tocolytics in Spain: ritodrine and atosiban (intravenous) and nifedipine (oral solution) (AU)

Magnesium maintenance therapy for preventing preterm birth after threatened preterm labour.

BACKGROUND: Magnesium maintenance therapy is one of the types of tocolytic therapy used after an episode of threatened preterm labour (usually treated with an initial dose of tocolytic therapy) in an attempt to prevent the onset of further preterm contractions. OBJECTIVES: To assess whether magnesium maintenance therapy is effective in preventing preterm birth after the initial threatened preterm labour is arrested. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (31 January 2013). SELECTION CRITERIA: Randomised controlled trials of magnesium therapy given to women after threatened preterm labour. DATA COLLECTION AND ANALYSIS: The review authors independently assessed the studies for inclusion, assessed risk of bias and carried out data extraction. We checked data entry. MAIN RESULTS: We included four trials involving 422 women. Three trials had high risk of bias and none included any long-term follow-up of infants. No differences in the incidence of preterm birth or perinatal mortality were seen when magnesium maintenance therapy was compared with placebo or no treatment; or alternative therapies (ritodrine or terbutaline). The risk ratio (RR) for preterm birth (less than 37 weeks) for magnesium compared with placebo or no treatment was 1.05, 95% confidence interval (CI) 0.80 to 1.40 (two trials, 99 women); and 0.99, 95% CI 0.57 to 1.72 (two trials, 100 women) for magnesium compared with alternative therapies. The RR for perinatal mortality for magnesium compared with placebo or no treatment was 5.00, 95% CI 0.25 to 99.16 (one trial, 50 infants); and 5.00, 95% CI 0.25 to 99.16 (one trial, 50 infants) for magnesium compared with alternative treatments.Women taking magnesium preparations were less likely to report side effects (RR 0.67, 95% CI 0.47 to 0.96, three trials, 237 women), including palpitations or tachycardia (RR 0.26, 95% CI 0.13 to 0.52, three trials, 237 women) than women receiving alternative therapies. Women receiving magnesium were however, more likely to experience diarrhoea (RR 6.79, 95% CI 1.26 to 36.72, three trials, 237 women). AUTHORS' CONCLUSIONS: There is not enough evidence to show any difference between magnesium maintenance therapy compared with either placebo or no treatment, or alternative therapies (ritodrine or terbutaline) in preventing preterm birth after an episode of threatened preterm labour.

Magnesium sulfate as a second-line tocolytic agent for preterm labor: a randomized controlled trial in Kyushu Island.

OBJECTIVES: We evaluated the efficacy of magnesium sulfate as a second-line tocolysis for 48 hours. MATERIALS AND METHODS: A multi-institutional, simple 2-arm randomized controlled trial was performed. Forty-five women at 22 to 34 weeks of gestation were eligible, whose ritodrine did not sufficiently inhibit uterine contractions. After excluding 12 women, 33 were randomly assigned to either magnesium alone or combination (ritodrine and magnesium). The treatment was determined as effective if the frequency of uterine contraction was reduced by 30% at 48 hours of the treatment. RESULTS: After magnesium sulfate infusion, 90% prolonged their pregnancy for >48 hours. Combination therapy was effective in 95% (18/19), which was significantly higher than 50% (7/14) for magnesium alone. CONCLUSION: This randomized trial revealed that combination therapy significantly reduced uterine contractions, suggesting that adjuvant magnesium with ritodrine is recommended, rather than changing into magnesium alone, when uterine contractions are intractable with ritodrine infusion.

Magnesium maintenance therapy for preventing preterm birth after threatened preterm labour.

BACKGROUND: Magnesium maintenance therapy is one of the types of tocolytic therapy used after an episode of threatened preterm labour (usually treated with an initial dose of tocolytic therapy) in an attempt to prevent the onset of further preterm contractions. OBJECTIVES: To assess whether magnesium maintenance therapy is effective in preventing preterm birth after the initial threatened preterm labour is arrested. SEARCH STRATEGY: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (May 2010). SELECTION CRITERIA: Randomised controlled trials of magnesium therapy given to women after threatened preterm labour. DATA COLLECTION AND ANALYSIS: The review authors independently assessed the studies for inclusion, assessed risk of bias and carried out data extraction. We checked data entry. MAIN RESULTS: We included four trials, which recruited 422 women. Three trials had high risk of bias and none included any long-term follow up of infants. No differences in the incidence of preterm birth or perinatal mortality were seen when magnesium maintenance therapy was compared with placebo or no treatment; or alternative therapies (ritodrine or terbutaline). The risk ratio (RR) for preterm birth (less than 37 weeks) for magnesium compared with placebo or no treatment was 1.05, 95% confidence interval (CI) 0.80 to 1.40 (two trials, 99 women); and 0.99, 95% CI 0.57 to 1.72 (2 trials, 100 women) for magnesium compared with alternative therapies. The RR for perinatal mortality for magnesium compared with placebo or no treatment was 5.00, 95% CI 0.25 to 99.16 (one trial, 50 infants) and also compared with alternative treatments, was 5.00, 95% CI 0.25 to 99.16 (one trial, 50 infants). Women taking magnesium preparations were less likely to report palpitations or tachycardia than women receiving alternative therapies (RR 0.26, 95% CI 0.13 to 0.52, three trials, 237 women) but were much more likely to experience diarrhoea (RR 7.66, 95% CI 2.18 to 26.98, three trials, 237 women). AUTHORS' CONCLUSIONS: There is not enough evidence to show any difference between magnesium maintenance therapy compared with either placebo or no treatment, or alternative therapies (ritodrine or terbutaline) in preventing preterm birth after an episode of threatened preterm labour.

[Effects of abdominal breathing on state anxiety, stress, and tocolytic dosage for pregnant women in preterm labor].

PURPOSE: The purpose of this study was to identify the effects of abdominal breathing on state anxiety, stress and tocolytic dosage for pregnant women in preterm labor. METHODS: The participants were 60 pregnant women in preterm labor who were hospitalized from April to July, 2009. Thirty participants were assigned to the experimental group and 30 to the control group. None of them had any other complications except preterm labor. The modified Mason's breathing technique was used with the experimental group 3 times a day for 3 days. Data were collected using a self-report questionnaire and chart review, and analyzed with the SPSS 13.0 WIN program. RESULTS: "State anxiety of the experimental group will be lower than that of the control group" was supported. "Stress of the experimental group will be lower than that of the control group" was supported. "The Ritodrine dosage for the experimental group will be lower than that of the control group" was supported. "The Atosiban dosage for the experimental group will be lower than that of the control group" was supported. CONCLUSION: These results indicate that abdominal breathing is an effective nursing intervention for pregnant women in preterm labor.

Effects of Abdominal Breathing on State Anxiety, Stress, and Tocolytic Dosage for Pregnant Women in Preterm Labor

PURPOSE: The purpose of this study was to identify the effects of abdominal breathing on state anxiety, stress and tocolytic dosage for pregnant women in preterm labor. METHODS: The participants were 60 pregnant women in preterm labor who were hospitalized from April to July, 2009. Thirty participants were assigned to the experimental group and 30 to the control group. None of them had any other complications except preterm labor. The modified Mason's breathing technique was used with the experimental group 3 times a day for 3 days. Data were collected using a self-report questionnaire and chart review, and analyzed with the SPSS 13.0 WIN program. RESULTS: "State anxiety of the experimental group will be lower than that of the control group" was supported. "Stress of the experimental group will be lower than that of the control group" was supported. "The Ritodrine dosage for the experimental group will be lower than that of the control group" was supported. "The Atosiban dosage for the experimental group will be lower than that of the control group" was supported. CONCLUSION: These results indicate that abdominal breathing is an effective nursing intervention for pregnant women in preterm labor.

Employing nifedipine as a tocolytic agent prior to external cephalic version.

BACKGROUND: External cephalic version (ECV) is accepted as a means of reducing the rate of breech presentation at term. Routine use of tocolysis prior to an ECV has been described to increase its success rate. The study's objective was to evaluate the efficacy of oral nifedipine as a tocolytic agent prior to ECV, and to compare it with intravenous ritodrine (IR). METHODS: Women with breech presentation at term considered suitable for ECV were given nifedipine prior to the procedure. The success rate was compared to a cohort of women who underwent an ECV attempt at our department during the years 1999-2002 using IR prior to the procedure. Power analysis indicated that 70 women were needed in each group to detect a difference of 25% from our baseline success rate of 50%. RESULTS: Seventy-six women receiving nifedipine before their ECV attempt were compared to 90 women who received IR. Age, parity, gestational age at ECV, type of breech, placental location, fetal weight, and gestational age at delivery were not different between the groups. The overall success rate was 54% and 50% in the nifedipine and ritodrine groups respectively (p=0.6). The success rate among primiparous women was 35% and 29% respectively (p=0.8). The success rate among multiparous women was 64% and 63% respectively (p=1.0). The success rate was statistically different between primiparous and multiparous women in each group (p<0.05). CONCLUSION: Oral nifedipine may be as effective as IR when administered before ECV.

Cost-effectiveness of ritodrine and fenoterol for treatment of preterm labor in a low-middle-income country: a case study.

OBJECTIVES: In countries with high income, tocolytic therapy with beta-mimetic agents is a cost-effective strategy compared to placebo. In our study, the cost-effectiveness of two beta-mimetic agents, ritodrine and fenoterol, used in the management of preterm labor was compared in the setting of a low-middle-income transitional country, Serbia & Montenegro. METHODS: This case study was conducted at the Gynecology-Obstetrics Clinic, Clinical Center "Kragujevac," in Kragujevac, Serbia & Montenegro, between October 2004 and January 2006. In total, 235 pregnant patients with threatened preterm labor were enrolled, but 35 were lost to follow-up. Of the remaining 200 patients, 85 were given ritodrine, and 115 fenoterol. The perspective of Republic Institute for Health Insurance in Serbia was taken into account. Only direct costs were calculated; primary outcomes of the study were length of pregnancy (in weeks), time passed from the onset of uterine contractions to delivery (in weeks), and score on modified Flanagan's quality-of-life scale for chronic diseases, measured after discharge from hospital. RESULTS: Prolongation of pregnancy was significantly longer in the fenoterol group (12.7 +/- 8.4 weeks) than in the ritodrine group (11.6 +/- 7.1 weeks). The mean duration of hospitalization was shorter in the fenoterol group (11.9 +/- 8.8 days) than in the ritodrine group (14.9 +/- 11.3 days). The treatment with fenoterol was less costly and more cost-effective than the treatment with ritodrine, but the difference in cost-effectiveness was not statistically significant. The cost of treatment per gained week of pregnancy prolongation was 3345.51 +/- 7668.04 CSD in the fenoterol group, and 4181.96 +/- 12,069.83 CSD in the ritodrine group. CONCLUSIONS: The observed differences in treatment costs and duration of hospitalization per patient did not translate into significant differences in cost-effectiveness ratios, because of low costs of hospitalization and human labor in Serbian health system. Nevertheless, fenoterol treatment still has a tendency to be more cost-effective, and its lower acquisition cost is an advantage to this treatment option.

Tocolytic effectiveness of nifedipine versus ritodrine and follow-up of newborns: a randomised controlled trial.

BACKGROUND: Several studies have demonstrated the superior tocolytic effectiveness of nifedipine over ritodrine. Only 1 trial conducted a long-term follow-up of newborns and found no difference in psychosocial and motor functioning. In a randomised, multicentre trial, we compared the tocolytic effectiveness of nifedipine and ritodrine and included a long-term follow-up of the newborns after 2 years of age. METHODS: Patients with imminent preterm labour were randomised and received either nifedipine or ritodrine. Side-effects, tocolytic effectiveness and neonatal outcome were studied. Development of the children was studied after the age of 2 years by a parental questionnaire. RESULTS: Ninety-three patients were included. Birth was postponed for an average of 4.3 weeks in the ritodrine group and 5.0 weeks in the nifedipine group (p=0.4). Patients who received ritodrine experienced significantly more side-effects compared to patients who received nifedipine (29 versus 4%, p<0.05). No significant differences were found in either group for average birth weight, Apgar scores after 1 min, neonatal intensive care unit (NICU) admission and neonatal complications. Parental questionnaires after 2 years had a response rate of 70%. Two-thirds of the children had developed normally in both groups. In both groups, only a few children were severely retarded (n=4). No significant differences in development were found between the 2 groups. CONCLUSIONS: Both nifedipine and ritodrine proved effective tocolytic drugs, however ritodrine caused significantly more maternal side-effects. Neonatal outcome and long-term development after 2 years of age were not significantly different. We favour nifedipine over ritodrine as a tocolytic drug.

Edema agudo de pulmón y tratamiento secuencial con nifedipino y ritodrina en la amenaza de parto pretérmino / Acute pulmonary edema and sequential treatment with nifedipine and ritodrine in threatened premature labor

Se presenta el caso de un edema agudo de pulmón en una gestante que se diagnosticó de amenaza de parto pretérmino; se instauró tratamiento secuencialmente con nifedipino y con ritodrina al no tener una respuesta adecuada a la primera medicación. Probablemente, la hidratación, la corticoterapia y el uso secuencial de ambos medicamentos contribuyeron a la etiología del edema agudo del pulmón, que tuvo una evolución favorable, tanto en la madre como en el feto (AU)

We report the case of a pregnant woman with threatened premature labor who developed acute pulmonary edema after treatment with nifedipine with inadequate response and subsequent treatment with ritodrine. The intravenous fluids, corticosteroid treatment and the sequential use of both drugs may have contributed to the development of the pulmonary edema. Maternal and fetal outcomes were satisfactory (AU)

Nifedipine versus ritodrine for suppression of preterm labor. Comparison of their efficacy and secondary effects.

OBJECTIVES: To compare the efficacy of nifedipine and ritodrine in prolonging pregnancy beyond 48 h, 1 week and 36.0 weeks and to evaluate maternal side effects and adverse perinatal outcome. STUDY DESIGN: Non-blinded, randomized controlled trial. Eighty patients with singleton pregnancies admitted for preterm labor with intact membranes between 22 and 35 weeks of gestation were included in the study. Preterm labor was defined as the persistence of at least two symptomatic uterine contractions within a 10 min period during 60 min after admission and despite bed rest. RESULTS: Forty women received oral nifedipine and forty intravenous ritodrine. Two patients, one from each group, were excluded because of loss to follow-up after discharge. Therefore, 39 women in the nifedipine and the ritodrine groups, respectively, were evaluable for the final analysis. Baseline characteristics were comparable in both groups. The percentage of initial response, the speed of onset of action and the rate of successful treatment within 48 h were significantly better in the ritodrine group. However, prolongation of pregnancy beyond 7 days and 36 weeks of pregnancy was similar with a significantly lower rate of side effects in the nifedipine group. CONCLUSIONS: In this small trial, ritodrine provided more effective tocolysis within the first 48 h than nifedipine at the doses used in this study, although with a significantly higher rate of side effects.

Severe hyperinsulinaemic hypoglycaemia in a baby born to a mother taking oral ritodrine therapy for preterm labour.

Hyperinsulinism of infancy is a major cause of persistent hypoglycaemia in the newborn period. Transient mild self-limiting hyperinsulinaemia and hypoglycaemia have been described in neonates born to mothers taking ritodrine therapy for premature labour. Ritodrine crosses the placental barrier and enters the fetal circulation readily but the mechanism of how it causes hyperinsulinaemia and hypoglycaemia is unclear. We report the case of severe prolonged hyperinsulinaemic hypoglycamia in a neonate born to a mother taking ritodrine therapy from 16 weeks' gestation for preterm labour. The hyperinsulinaemic hypoglycaemia was managed with oral nifedipine as diazoxide was contraindicated due to fluid overload. Possible mechanisms of ritodrine-induced hypoglycaemia and insulin secretion are discussed.

Maternal admission characteristics as risk factors for preterm birth.

OBJECTIVE: The aim of this study is to identify a subset of women presenting with preterm labor not responding upon tocolytic therapy, eventually resulting in preterm birth. STUDY DESIGN: The maternal admission characteristics of 185 women with preterm labor receiving tocolysis were analysed for risk factors that could predict which women will deliver within 48 h after the start of tocolysis, or before 34 weeks gestation. Univariate analysis and multivariate logistic regression analysis was performed. RESULTS: Logistic regression analysis identified the following risk factors for delivery within 48 h after the start of tocolysis: cervical dilatation at admission (odds ratio (OR, cm(-1)) 1.47; 95% confidence interval (CI), 1.44-1.49), elevated leukocyte count at admission (per 10(3) leukocytes/mm(3)) (OR 1.27; 95% CI, 1.26-1.28), use of nifedipine (OR 0.49; 95% CI, 0.26-0.49), and developing signs suggestive of chorioamnionitis following admission (OR 2.12; 95% CI, 1.04-4.33). For delivery before 34 weeks of gestation the following risk factors were identified: use of steroids (OR 5.87; 95% CI, 2.34-14.7), use of nifedipine (OR 0.46; 95% CI, 0.27-0.85), developing signs suggestive of chorioamnionitis following admission (OR 10.6; 95% CI, 3.1-35.9), and preterm premature rupture of the membranes (OR 12; 95% CI, 4.1-35.2). CONCLUSIONS: Risk factors associated for delivery within 48 h after starting tocolysis are: cervical dilatation at admission, elevated leukocyte count at admission, and developing signs suggestive of chorioamnionitis following admission. Use of nifedipine was associated with a delay of delivery >48 h. Risk factors associated for delivery within 34 weeks gestation are: use of steroids, developing signs suggestive of chorioamnionitis following admission, and ruptured membranes. Use of nifedipine was associated with a delay >34 weeks.

Neonatal effects of nifedipine and ritodrine for preterm labor.

OBJECTIVE: We compared nifedipine and ritodrine for treatment of preterm labor with respect to neonatal outcome. METHODS: We conducted an open randomized multicenter study of neonatal outcome in 185 women who received either oral nifedipine (n = 95) or intravenous (IV) ritodrine (n = 90) for treatment of preterm labor. Secondary outcome measures included neonatal mortality and morbidity, especially neonatal intensive care unit (NICU) admission, respiratory distress syndrome (RDS), and intracranial bleeding. RESULTS: There were no significant differences in umbilical artery pH values and Apgar scores between groups. Nifedipine was associated with lower admission rates to the NICU (49% versus 66%; odds ratio 0. 51, confidence interval 0.28, 0.93) compared with ritodrine, and lower incidences of RDS (21% versus 37%; 0.46, 0.24, 0.89), intracranial bleeding (18% versus 31%; 0.48, 0.24, 0.96), and neonatal jaundice (52% versus 67%; 0.53, 0.29, 0.97). Logistic regression analysis showed that even after correction for gestational age at birth, newborn risk of RDS, intracranial bleeding, or neonatal jaundice was significantly lower in the nifedipine group than the ritodrine group. CONCLUSION: Nifedipine for treatment of preterm labor was associated with a lower incidence of neonatal morbidity than ritodrine. That difference appeared to be partly because of the higher tocolytic efficacy of nifedipine and partly because of an intrinsic beneficial effect of nifedipine, or the lack of harmful effects when compared with ritodrine.

Nifedipine versus ritodrine for suppression of preterm labor; a meta-analysis.

BACKGROUND: Since large randomized clinical trials comparing the effectiveness of nifedipine and ritodrine in the suppression of preterm labor are lacking, we performed a meta-analysis on the subject. METHODS: We searched the databases Medline and EMBASE using the keywords 'nifedipine', 'ritodrine' and 'randomized' or 'randomised'. The studies were scored for blinding, method of randomization and type of analysis ('intention-to-treat' versus 'par protocol'). Subsequently, two by two tables were constructed using 'delay of labor by 48 hours or more', 'delay of labor beyond 36 weeks gestation', perinatal mortality, respiratory distress syndrome and admission to a neonatal intensive care unit as end points. Homogeneity between the studies was tested with a Breslow-Day test. Pooled odds ratios were calculated in case homogeneity could not be rejected. RESULTS: We could detect ten studies that were published between 1986 and 1998, incorporating data of 681 patients. Nifedipine reduced the risk of delivery within 48 hours compared to ritodrine, but this difference was not statistically significant (odds ratio 0.85, 95% confidence interval 0.54 to 1.1). Nifedipine also reduced the risk of delivery before 36 weeks compared to ritodrine, and this difference was statistically significant (odds ratio 0.59, 95% confidence interval 0.39 to 0.90). We are not aware of studies reporting on long-term outcome. CONCLUSION: Since studies reporting on long-term outcome are lacking, the choice between nifedipine and ritodrine can only be based on obstetrical and short-term neonatal outcomes. From that perspective, nifedipine should be the drug of first choice for the suppression of preterm labor.

A randomized comparison of nifedipine and ritodrine for suppression of preterm labor.

OBJECTIVES: To compare the efficacy and safety of nifedipine and ritodrine in preventing preterm labor, and to evaluate maternal side effects and neonatal outcome. STUDY DESIGN: Non-blind, randomized controlled trial RESULTS: A randomized trial of 102 pregnant women with gestational ages under 34 weeks, including 24 with twin pregnancies and 45 on betasympathicomimetic drugs, who had regular uterine contractions with either observed cervical changes or preterm rupture of membranes. After stratification women were randomly assigned to receive either ritodrine intravenously or nifedipine orally. Fifty-five women were randomized to the nifedipine group and 47 to the ritodrine group. As expected, both groups were comparable in terms of several entry variables, including mean gestational age, ruptured membranes, treatment with tocolytic drugs, cervical examination, contraction frequency, age, and twin gestation. Delivery of women in the nifedipine group was delayed for 48 h, 7 days, and until 34 weeks gestation in 33 (60%), 26 (47%) and 21(38%) cases, respectively, compared with 31 (66%), 21(45%) and 11(23%) women in the ritodrine group (no significant difference). Maternal side effects were significantly less common in the nifedipine group than in the ritodrine group, however after 7 days of therapy there was no difference between the two groups. Neonatal outcome was similar in the two groups, with four neonatal deaths in the nifedipine and five in the ritodrine group. CONCLUSIONS: Nifedipine seems to be as effective as ritodrine in the treatment of preterm labor and is associated with less frequent side effects.