Tocolysis in the management of preterm prelabor rupture of membranes at 22-33 weeks of gestation: study protocol for a multicenter, double-blind, randomized controlled trial comparing nifedipine with placebo (TOCOPROM).

BACKGROUND: Preterm prelabor rupture of membranes (PPROM) before 34 weeks of gestation complicates 1% of pregnancies and accounts for one-third of preterm births. International guidelines recommend expectant management, along with antenatal steroids before 34 weeks and antibiotics. Up-to-date evidence about the risks and benefits of administering tocolysis after PPROM, however, is lacking. In theory, reducing uterine contractility could delay delivery and reduce the risks of prematurity and its adverse short- and long-term consequences, but it might also prolong fetal exposure to inflammation, infection, and acute obstetric complications, potentially associated with neonatal death or long-term sequelae. The primary objective of this study is to assess whether short-term (48 h) tocolysis reduces perinatal mortality/morbidity in PPROM at 22 to 33 completed weeks of gestation. METHODS: A randomized, double-blind, placebo-controlled, superiority trial will be performed in 29 French maternity units. Women with PPROM between 220/7 and 336/7 weeks of gestation, a singleton pregnancy, and no condition contraindicating expectant management will be randomized to receive a 48-hour oral treatment by either nifedipine or placebo (1:1 ratio). The primary outcome will be the occurrence of perinatal mortality/morbidity, a composite outcome including fetal death, neonatal death, or severe neonatal morbidity before discharge. If we assume an alpha-risk of 0.05 and beta-risk of 0.20 (i.e., a statistical power of 80%), 702 women (351 per arm) are required to show a reduction of the primary endpoint from 35% (placebo group) to 25% (nifedipine group). We plan to increase the required number of subjects by 20%, to replace any patients who leave the study early. The total number of subjects required is thus 850. Data will be analyzed by the intention-to-treat principle. DISCUSSION: This trial will inform practices and policies worldwide. Optimized prenatal management to improve the prognosis of infants born preterm could benefit about 50,000 women in the European Union and 40,000 in the United States each year. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03976063 (registration date June 5, 2019).

Tocolysis after preterm premature rupture of membranes and neonatal outcome: a propensity-score analysis.

BACKGROUND: There are conflicting results regarding tocolysis in cases of preterm premature rupture of membranes. Delaying delivery may reduce neonatal morbidity because of prematurity and allow for prenatal corticosteroids and, if necessary, in utero transfer. However, that may increase the risks of maternofetal infection and its adverse consequences. OBJECTIVE: The objective of the study was to investigate whether tocolytic therapy in cases of preterm premature rupture of membranes is associated with improved neonatal or obstetric outcomes. STUDY DESIGN: Etude Epidémiologique sur les Petits Ages Gestationnels 2 is a French national prospective, population-based cohort study of preterm births that occurred in 546 maternity units in 2011. Inclusion criteria in this analysis were women with preterm premature rupture of membranes at 24-32 weeks' gestation and singleton gestations. Outcomes were survival to discharge without severe morbidity, latency prolonged by ≥48 hours and histological chorioamnionitis. Uterine contractions at admission, individual and obstetric characteristics, and neonatal outcomes were compared by tocolytic treatment or not. Propensity scores and inverse probability of treatment weighting for each woman were used to minimize indication bias in estimating the association of tocolytic therapy with outcomes. RESULTS: The study population consisted of 803 women; 596 (73.4%) received tocolysis. Women with and without tocolysis did not differ in neonatal survival without severe morbidity (86.7% vs 83.9%, P = .39), latency prolonged by ≥48 hours (75.1% vs 77.4%, P = .59), or histological chorioamnionitis (50.0% vs 47.6%, P = .73). After applying propensity scores and assigning inverse probability of treatment weighting, tocolysis was not associated with improved survival without severe morbidity as compared with no tocolysis (odds ratio, 1.01 [95% confidence interval, 0.94-1.09], latency prolonged by ≥48 hours (1.03 [95% confidence interval, 0.95-1.11]), or histological chorioamnionitis (1.03 [95% confidence interval, 0.92-1.17]). There was no association between the initial tocolytic drug used (oxytocin receptor antagonists or calcium-channel blockers vs no tocolysis) and the 3 outcomes. Sensitivity analyses of women with preterm premature rupture of membranes at 26-31 weeks' gestation, women who delivered at least 12 hours after rupture of membranes, women with direct admission after the rupture of membranes and the presence or absence of contractions gave similar results. CONCLUSION: Tocolysis in cases of preterm premature rupture of membranes is not associated with improved obstetric or neonatal outcomes; its clinical benefit remains unproven.

Tocolysis for inhibiting preterm birth in extremely preterm birth, multiple gestations and in growth-restricted fetuses: a systematic review and meta-analysis.

This systematic review was to identify available evidence on the effectiveness of tocolysis in inhibiting preterm delivery for women with threatened extremely preterm birth, multiple gestations, and growth-restricted babies, and their infants' outcomes. A comprehensive search using MEDLINE, Embase, the Cochrane Library, CINAHL, POPLINE and the WHO Global Health Library databases was conducted on 14 February 2014. For selection criteria, randomized controlled trials and non-randomized studies that compared tocolysis treatment to placebo or no treatment were considered. Selection of eligible studies, critical appraisal of the included studies, data collection, meta-analyses, and assessment of evidence quality were performed in accordance with the Cochrane Collaboration's guidance and validated assessment criteria. The search identified seven studies for extremely preterm birth, in which three were randomized controlled trials (RCTs) and four were non-randomized studies (non-RCTs). There were no eligible studies identified for women with multiple pregnancy and growth-restricted fetuses. Meta-analyses indicated no significant difference was found for the relative effectiveness of tocolytics versus placebo for prolonging pregnancy in women with extremely preterm birth (RR 1.04, 95% CI 0.83 to 1.31) or reducing the rate of perinatal deaths (RR 2.22, 95% CI 0.26 to 19.24). In summary, there is no evidence to draw conclusions on the effectiveness of tocolytic therapy for women with threatened extremely preterm birth, multiple gestations, and growth-restricted babies.

Pharmacokinetics of nifedipine slow-release during sustained tocolysis.

OBJECTIVE: The pharmacokinetics of nifedipine as a tocolytic agent has not been studied in great detail in pregnant women and has instead focused on immediate release tablets and gastrointestinal therapeutic system (GITS) tablets. The aim of this study was to determine nifedipine slow-release half-life and distribution volume in pregnant women and to compare these with pharmacokinetic parameters of nifedipine in non-pregnant subjects described in the literature. MATERIALS: This is a study parallel to a trial studying women with threatened preterm labor between 26 + 0 and 32 + 2 weeks after initial tocolysis and a completed course of corticosteroids, who were randomly allocated to maintenance nifedipine (slow-release tablets 20 mg 4 times daily) or placebo. Exclusion criteria for the pharmacokinetic study were contra-indications for nifedipine, impaired liver function, and concomitant intake of inhibitors or inducers of the cytochrome P450 3A4 isoenzyme. Blood samples for measuring nifedipine plasma concentrations were drawn at t = 0, t = 12 hours, t = 24 hours, t = 48 hours, t = 72 hours, t = 7 days, and t = 9 days. METHODS: Pharmacokinetic parameters were estimated using iterative two-stage Bayesian population pharmacokinetic analysis by MWPharm© software. The study was designed to establish a correlation between body weight and nifedipine plasma level. RESULTS: The pharmacokinetic parameters of nifedipine slow-release tablets were determined from the data of 8 pregnant women. Nifedipine slow-release had a half-life of 2 - 5 hours, a mean distribution volume of 6.2 ± 1.9 L/kg (calculated while using a fixed biological availability of 0.45 taken from the literature due to lack of intravenous data in this population) compared to a half-life of 6 - 11 hours, and a distribution volume of 1.2 - 1.3 L/kg described in non-pregnant subjects in the literature. None of the women delivered during study medication. Study medication was continued for the duration of the pharmacokinetic study (9 days) in all women. A correlation between nifedipine plasma levels and maternal body weight was not demonstrated. This may have been caused by lack of power. CONCLUSION: Pregnant subjects in this study, using nifedipine slow-release tablets, showed a larger volume of distribution and a shorter elimination half-life than for non-pregnant subjects as published in the literature.

B-type natriuretic peptide measurement for early diagnosis of acute pulmonary edema during pregnancy.

Calcium-channel blockers administered to pregnant women as tocolytic agents can cause acute pulmonary edema. The first signs of this severe complication can be atypical and so delay introduction of appropriate therapy. We describe three cases in whom B-type natriuretic peptide measurements proved to be relevant in early diagnosis and monitoring of pregnant women with acute pulmonary edema. B-type natriuretic peptide measurement in this setting could contribute to timely diagnosis and improve follow-up.

Amnioinfusion before 26 weeks' gestation for severe fetal growth restriction with oligohydramnios: preliminary pilot study.

AIM: The prognosis for severe fetal growth restriction (FGR) with severe oligohydramnios before 26 weeks' gestation (WG) is currently poor; furthermore, its management is controversial. We report the innovative new management of FGR, such as therapeutic amnioinfusion and tocolysis. MATERIAL AND METHODS: For FGR and severe oligohydramnios before 26 WG complicated with absent or reversed umbilical artery end-diastolic flow velocity and/or deceleration by ultrasonography, we performed transabdominal amnioinfusion with tocolysis. Cases with multiple anomalies were excluded. Survival rate and long-term prognosis were analyzed. RESULTS: Among 570 FGR cases, 18 were included in the study. Mean diagnosis and delivery were at 22.6 ± 2.0 and 28.7 ± 3.3 WG. Median birthweight was 625 g (-4.2 standard deviation). Final survival rate was 11/13 (85%). There were five fetal deaths. In seven cases, oligohydramnios improved. Growth was detected in 10/18 fetuses. Furthermore, 8/8 decelerations, 4/12 cases of reversed umbilical artery end-diastolic flow velocity, 7/14 cases of brain-sparing effect, and 6/13 venous Doppler abnormalities were improved. When we detected umbilical cord compression, 8/10 cases were rescued. Eleven infants were followed up for an average of 5 years; one case of cerebral palsy with normal development and 10 cases with intact motor functions without major neurological handicap were confirmed. CONCLUSIONS: In cases of extremely severe FGR before 26 WG with oligohydramnios and circulatory failure, amnioinfusion might be a promising, innovative tool.

[Tocolysis in preterm labour--current recommendations]. / Tokoliza w porodzie przedwczesnym--aktualne wytyczne.

Common use of tocolytic drugs in preterm labor has not been shown to reduce the rate of neonatal mortality and morbidity Currently tocolytics should be administered in the course of a 48-h administration of antepartum glucocorticoids and/or transfer of the gravida to a center with neonatal intensive care unit. Only oxytocin receptor antagonist--atosiban and short-acting beta-agonists--fenoterol are licensed to reduce preterm uterine activity Owing to its safety and efficacy atosiban should be the first-choice tocolytic, especially in women with other diseases or multiple gestations.

[Tocolysis with nifedipin; its use in current practice].

AIM: The aim of the study is to establish the safety and efficacy of calcium channel blocker- Nifedipin as tocolytic agents. A wide range of tocolytics have been utilized for the management of preterm labor Calcium channel blockers, namely nifedipine, gained popularity as tocolytics due to the oral route of administration, availability of immediate- and slow-release preparations, the low incidence of maternal adverse effects associated with their use, and the fact that they are inexpensive. METHODS: 88 pregnant women in preterm labor participated in a prospective longitudinal study Inclusion criteria were: gestational age between 24 and 34 weeks gestation; uterine contractions in 10-15 min interval; single pregnancy, lack of contraindications for tocolysis. In all cases the calcium antagonist Nifedipine was used in dosage 4 x 10 mg per os. The clinical response to tocolysis, gestational age at delivery and potential side effects were analyzed. RESULTS: 91 pregnant women participated in the study. Three were excluded because they refused to participate. 88 pregnancies were finally analyzed. In nine of them maternal contractions persisted despite of treatment. The other 79 pregnancies were delayed 48 hours to receive antenatal corticosteroids. From all these 79 pregancies 66 delayed 7 days. The most common adverse effects were tachycardia, hypotonia, headache, dizziness, but they escape soon after the first dose. CONCLUSION: Nifedipine is an effective oral tocolytic with few maternal side effects.

Evaluation of maternal and neonatal outcomes after maintenance tocolysis: a retrospective study.

AIM: This study aimed to compare maternal and neonatal outcomes after no tocolysis, short-term tocolysis (≤48h), and maintenance tocolysis (>48h). METHODS: This was a retrospective study, conducted from January 2007 to June 2008, of vaginal preterm deliveries admitted to the neonatal intensive care unit (NICU) between 23 and 36 weeks of gestation. Patients were placed in three groups: no tocolysis, tocolysis ≤48h, and tocolysis >48h. The following neonatal parameters were recorded: respiratory distress syndrome, grade III or IV intraventricular hemorrhage, culture-proven sepsis, necrotizing enterocolitis, and length of NICU stay. RESULTS: A total of 162 deliveries were included in the study. Sixty-nine mothers received no tocolysis, 42 received tocolysis ≤48h, and 51 received tocolysis >48h. No adverse maternal outcomes were observed in any of the groups. There were no statistically significant differences in neonatal outcomes between the three groups. The maintenance tocolysis group had a longer pregnancy duration (P<0.0001), but their infants required longer NICU stay (P=0.0020). CONCLUSION: This study showed that maintenance tocolysis prolongs the duration of pregnancy but does not improve neonatal outcomes. Infants of mothers in the maintenance tocolysis group showed an increase in the length of NICU stay. A multicenter randomized control trial should be considered to further evaluate the need for maintenance tocolysis.

Antenatal calcium channel blocker exposure and subsequent patent ductus arteriosus in extremely low-birth-weight infants.

This study aimed to assess whether tocolytic fetal exposure to antenatal calcium channel blockers (aCCB) increases the risk for hemodynamically significant patent ductus arteriosus (hsPDA) in extremely low-birth-weight (ELBW) infants. This case-control study investigated ELBW infants (<1,000 g) without cardiac defects in a level 3 neonatal intensive care unit who had survived at least 7 days. Nifedipine was the only aCCB used for this study population. The measurements included the history of aCCB exposure, selected maternal data, hsPDA diagnosis, gestational age at birth, birth weight, mode of delivery, sex, maternal race, location of birth, Apgar scores, and selected neonatal morbidities. The end point of the study was hsPDA, defined as an echocardiographically confirmed PDA with clinical symptoms. A total of 180 infants met the study criteria. The diagnosis was hsPDA for 56% of these patients, 20% of whom had aCCB exposure. Of the infants without hsPDA, 11% had aCCB exposure (p = 0.09). No statistically significant associations were found between aCCB exposure and hsPDA after adjustment for gestational age (odds ratio [OR], 1.5; 95% confidence interval [CI], 0.6-3.7) or for gestational age and cumulative aCCB exposure of 100 mg or more (OR, 2.0; 95% CI, 0.6-6.5). A history of aCCB exposure does not appear to increase hsPDA risk in ELBW infants. Studies using neonatal serum nifedipine concentrations after antenatal exposure should be performed to confirm this conclusion.

Peripartum cardiomyopathy and acute heart failure associated with prolonged tocolytic therapy in pregnancy: A case report.

RATIONALE: Peripartum cardiomyopathy (PPCM) is a rare and sometimes fatal systolic heart failure that affects women during late pregnancy or the early postpartum period. Heart failure symptoms can mimic the physiological changes of normal pregnancy, and the diagnosis is based on echocardiography. PATIENT CONCERNS: A 38-year-old multiparous woman with a history of cervical incompetence underwent cervical cerclage and received tocolysis for 100 days. DIAGNOSES: She delivered vaginally at 37 weeks of gestation but developed postpartum decompensated acute heart failure with low left ventricular ejection fraction (LVEF: 34%) and was diagnosed with PPCM. INTERVENTIONS: She received standard therapy for acute heart failure. OUTCOMES: The patient's pulmonary edema cleared, and she was fully ambulatory 6 days after admission. A follow-up echocardiogram 3 months later demonstrated recovery of LVEF to 66%. LESSONS: Prolonged tocolysis may contribute to cardiomyopathy and should be used with caution. PPCM management requires standard treatments for acute heart failure with modifications for fetal safety.

Is long-term tocolysis effective for threatened premature labour?

There is some controversy regarding the optimum duration of tocolysis. This retrospective multicentre study was performed to evaluate whether long-term (> 2 days) tocolysis is effective in treating threatened premature labour. A total of 1147 eligible patients were grouped according to whether or not tocolytics were given, and according to route of administration and whether or not ritodrine (the standard tocolytic regimen in Japan) or other tocolytic was given. They were then further stratified into three subgroups, using the Baumgarten and Gruber tocolysis index (TI), to assess the efficacy of tocolysis treatment according to the risk of premature labour. Prolongation of gestation was significantly longer in patients treated with tocolytics for > 2 days compared with the unmedicated, bed-rest group. In women receiving tocolysis, the mean duration of prolonged gestation was 2.2 times longer in the intermediate-risk TI group and 3.1 times longer in the high-risk TI group compared with the unmedicated group. In the patients who received tocolysis, IV ritodrine was used in 86% of cases and was considered safe and effective for prolonging gestation in cases of threatened premature labour.

[Acute pulmonary edema occurred during tocolytic treatment using nicardipine in a twin pregnancy. Report of three cases]. / OEdème aigu du poumon lors d'une tocolyse par nicardipine chez une grossesse gémellaire. A propos de trois observations.

We report three cases of acute pulmonary edema that occurred during treatment by intravenous tocolysis using nicardipine in twin pregnancy patients with no previous heart problems. The three patients were admitted into our unit on account of the risk of premature birth after 29 to 32 weeks of amenorrhea. The treatment by intravenous tocolysis using nicardipine combined with glucocorticoids therapy had been undertaken in the previous maternity ward. The three patients presented symptoms of acute dyspnea 48 hours after the beginning of the treatment. Paraclinical examinations eliminated the diagnosis of pulmonary embolism. The patients'condition improved rapidly with appropriate diuretic treatment and by modifying the tocolysis. There are currently few studies proving the benefits of nicardipine in tocolysis treatment. Few similar cases of acute pulmonary edema have been noted in twin pregnancy patients treated with nicardipine. Haemodynamic modifications specific to twin pregnancy, intravenous hydratation and glucocorticoid maturation may explain a part of this complication. Therefore, it is appropriated to limit the use of intravenous nicardipine in the sole indication of tocolysis in twin pregnancy, and to prefer the use of nifedipine and atosiban, that have proven their effectiveness in this indication.

Emerging tocolytics: challenges in designing and testing drugs to delay preterm delivery and prolong pregnancy.

The global rate of preterm delivery (before 37 completed weeks of pregnancy) is increasing and there are no effective means available to prevent this rise. Prematurity is the principal cause of neonatal mortality and a major cause of pediatric morbidity and long-term disability. Current strategies to prolong pregnancy are based on inhibiting the mechanisms that effect uterine smooth muscle (myometrium) contractions in women who are in preterm labor. Most drugs in this group were developed for other purposes. Newer strategies are designed to maintain a state of uterine quiescence and pregnancy, preventing the myometrium from initiating contractions and entering preterm labor. Again, it may be possible to use existing drugs for pregnancy maintenance. Several financial and practical barriers exist for developing completely new drugs to delay labor. Designing clinical trials to test tocolytics is complicated, as the health of two patients must be considered and the nature of preterm birth and its outcomes are different at early preterm labor (< 28 weeks) and late preterm labor (34 - 36 weeks).

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.

[Tocolysis with calcium-channel blockers and intraventricular hemorrhage]. / Tocolyse par les inhibiteurs calciques et hémorragies intraventriculaires.

OBJECTIVE: To determine the possible association between intraventricular hemorrhage (IVH) in very premature infants and calcium-channel blockers used as tocolytics. MATERIALS AND METHODS: We performed a case-control study (from October 1999 to December 2002) including 51 premature infants under 30 weeks with IVH (all grade) and 112 premature infants under 30 weeks without IVH. In this study only premature infants issued from spontaneous prematurity were included. The exposure frequency to calcium-channel blockers and to other tocolytics were compared between the two groups by univariate analysis and by logistic regression analysis. RESULTS: Calcium-channel blockers were used in monotherapy before birth in 16% of infants without IVH and in 20% of infants with IVH (P=0.55). An exposure to a bitherapy or a tritherapy with a calcium-channel blocker and one or several other tocolytics has been found in 43% of infants with IVH and in 26% of infants without IVH (P<0.05). However this association disappears after adjustment for gestational age. CONCLUSION: We did not find a significant association between calcium-channel blockers used as tocolytics and an increased risk of intraventricular hemorrhage in premature infants less than 30 weeks.

Maintaining and repeating tocolysis: A reflection on evidence.

It is inherent to human logic that both doctors and patients want to suppress uterine contractions when a woman presents in threatened preterm labor. Tocolysis is widely applied in women with threatened preterm labor with a variety of drugs. According to literature, tocolysis is indicated to enable transfer to a tertiary center as well as to ensure the administration of corticosteroids for fetal maturation. There is international discrepancy in the content and the implementation of guidelines on preterm labor. Tocolysis is often maintained or repeated. Nevertheless, the benefit of prolonging pregnancy has not yet been proven, and it is not impossible that prolongation of the pregnancy in a potential hostile environment could harm the fetus. Here we reflect on the use of tocolysis, focusing on maintenance and repeated tocolysis, and compare international guidelines and practices to available evidence. Finally, we propose strategies to improve the evaluation and use of tocolytics, with potential implications for future research.

Acute pulmonary edema during tocolytic therapy with nifedipine.

Calcium channel blockers are becoming more popular as first-line tocolytic agents. Serious side effects have rarely been reported and involved mainly intravenous use of nicardipine. We report the first case of acute pulmonary edema following tocolytic oral nifedipine. Possible contributing factors are mentioned.

Constriction of the ductus arteriosus by selective inhibition of cyclooxygenase-1 and -2 in near-term and preterm fetal rats.

We studied the transplacental ductal constrictive effects of a selective cyclooxygenase (COX)-1 inhibitor (SC560), six selective COX-2 inhibitors including rofecoxib, and a non-selective COX inhibitor (indomethacin). Each drug was administered to the pregnant rats, and fetal ductus arteriosus (DA) was studied with a whole-body freezing method. The inner diameter ratio of the DA to the main pulmonary artery (DA/PA) was 1.02+/-0.03 (mean+/-S.E.M.) in controls. Every drug constricted the DA dose-dependently. In preterm rats on the 19th day of gestation, 10mg/kg of SC560, rofecoxib and indomethacin caused ductal constriction, with DA/PA reduced to 0.76+/-0.02, 0.80+/-0.03 and 0.75+/-0.02, respectively. In near-term on the 21st day, 10mg/kg of them caused ductal constriction, with DA/PA to 0.74+/-0.04, 0.26+/-0.02 and 0.33+/-0.05. In conclusion, both COX-1 and COX-2 selective inhibitors constrict fetal DA. They are not better alternatives for the fetus than non-selective COX inhibitors for tocolysis.