WHO recommendation on tocolytic therapy for improving preterm birth outcomes

In 2021, the Executive Guideline Steering Group (GSG) for the World Health Organization (WHO) maternal and perinatal health recommendations prioritized updating the then current recommendations on the use of tocolysis as published in the WHO recommendations on interventions to improve preterm birth outcomes. This decision was based on new evidence on the subject that had become available. The recommendations in this document thus supersedes the previous WHO recommendations on the use of tocolysis as published in the 2015 guidelines, WHO recommendations on interventions to improve preterm birth outcomes.

Study protocol for a randomised trial for atosiban versus placebo in threatened preterm birth: the APOSTEL 8 study.

INTRODUCTION: Preterm birth complicates >15 million pregnancies annually worldwide. In many countries, women who present with signs of preterm labour are treated with tocolytics for 48 hours. Although this delays birth, it has never been shown to improve neonatal outcome. In 2015, the WHO stated that the use of tocolytics should be reconsidered and that large placebo-controlled studies to evaluate the effectiveness of tocolytics are urgently needed. METHODS AND ANALYSIS: We designed an international, multicentre, randomised, double-blinded, placebo-controlled clinical trial. Women with threatened preterm birth (gestational age 30-34 weeks), defined as uterine contractions with (1) a cervical length of < 15 mm or (2) a cervical length of 15-30 mm and a positive fibronectin test or (3) in centres where cervical length measurement is not part of the local protocol: a positive fibronectin test or insulin-like growth factor binding protein-1 (Actim-Partus test) or (4) ruptured membranes, will be randomly allocated to treatment with atosiban or placebo for 48 hours. The primary outcome is a composite of perinatal mortality and severe neonatal morbidity. Analysis will be by intention to treat. A sample size of 1514 participants (757 per group) will detect a reduction in adverse neonatal outcome from 10% to 6% (alpha 0.05, beta 0.2). A cost-effectiveness analysis will be performed from a societal perspective. ETHICS AND DISSEMINATION: This study has been approved by the Research Ethics Committee (REC) of the Amsterdam University Medical Centres, location AMC, as well as the REC's in Dublin and the UK. The results will be presented at conferences and published in a peer-reviewed journal. Participants will be informed about the results. TRIAL REGISTRATION NUMBER: Nederlands Trial Register (Trial NL6469).

Differences between evidence-based recommendations and actual clinical practice regarding tocolysis: a prospective multicenter registry study.

BACKGROUND: International guidelines recommend that tocolytic therapy be restricted to a single 48-h application. However, multiple cycles of tocolytic therapy and maintenance therapy that exceeds 48 h appear to play a role in daily clinical practice. We aimed to evaluate current trends in clinical practice with respect to treatment with tocolytic agents and to identify differences between evidence-based recommendations and daily clinical practice in Austria. METHODS: A prospective multicenter registry study was conducted from October 2013 through April 2015 in ten obstetrical departments in Austria. Women ≥18 years of age who received tocolytic therapy following a diagnosis of threatened preterm birth were included, and details were obtained regarding clinical characteristics, tocolytic therapy, and pregnancy outcome. RESULTS: A total of 309 women were included. We observed a median of 2 cycles of tocolytic therapy per patient (IQR 1-3) with a median duration of 2 days per cycle (IQR 2-5). Repeat tocolysis was administered in 41.7% of women, resulting in up to six tocolysis cycles; moreover, 40.8% of the first tocolysis cycles were maintenance tocolysis (i.e., longer than 48 h). Only 25.6% of women received one single 48-h tocolysis cycle in which they received antenatal corticosteroids for fetal lung maturation in accordance evidence-based recommendations. CONCLUSIONS: Here, we report a clear disparity between evidence-based recommendations and daily practice with respect to tocolysis. We believe that the general practice of prescribing tocolytic therapy must be revisited. Furthermore, our findings highlight the need for contemporary studies designed to investigate the effectiveness of performing maintenance and/or repetitive tocolysis treatment.

Clinical guidelines for prevention and management of preterm birth: a systematic review.

BACKGROUND: Clinical practice guidelines (CPG) endorse multiple strategies to prevent or manage preterm birth (PTB). OBJECTIVES: To summarise CPG recommendations for PTB and identify areas of international consensus. SEARCH STRATEGY: In May 2017 we searched for all CPG relevant to PTB without language restrictions. SELECTION CRITERIA: CPG were eligible if the following criteria were met: (1) the guideline was published or current from June 2013; (2) the guideline recommended practices for the prevention or management of PTB relevant to our prespecified clinical questions for screening, medications or surgery and other interventions; (3) publications on methods of guideline development for eligible CPG were included to enable quality assessment. DATA COLLECTION AND ANALYSIS: Two authors classified CPG recommendations relevant to prespecified clinical questions. When more than 70% of CPGs reporting on a topic recommended or rejected an intervention, we regarded this as consensus. We summarised recommendations in tables. MAIN RESULTS: We identified 49 guidelines from 16 guideline developers. We found consensus for several clinical practices: cervical length screening for high-risk women; short-term tocolysis; steroids for fetal lung maturation; and magnesium sulphate for fetal neuroprotection. We found discrepant recommendations for progesterone and fibronectin. No guideline identified an effective strategy for women with multiple pregnancy. CONCLUSIONS: We identified interventions for which there is an international consensus on benefit for PTB. Systematic reviews of CPG using standardised methodology will help avoid duplication and target scarce resources for guideline developers globally. TWEETABLE ABSTRACT: International clinical guidelines agree on the benefits and harmful effects of several important interventions to prevent preterm birth.

In which preterm labor-patients is intravenous maintenance tocolysis effective?

AIM: We evaluated whether maintenance tocolysis (intravenous ritodrine hydrochloride and/or magnesium sulfate) was effective in cases of spontaneous preterm labor with intact membranes. METHODS: One hundred and thirty preterm labor patients who reached 36 weeks of gestation by maintenance tocolysis were selected. Immediate delivery (ID) after ceasing maintenance tocolysis was defined as an 'effective case'. The correlated factors between ID and no immediate delivery (NID) were statistically analyzed. RESULTS: Thirty-six patients delivered < two days after ceasing maintenance tocolysis (27.7%) and were defined as effective cases. Multiple logistic regression analysis revealed that amniotic fluid interleukin-8 at admission (≥ 2.3 ng/mL; odds ratio [OR] 5.6, 95% confidence interval [CI] 2.1-17.6; P < 0.001), pre-pregnancy body mass index (≤ 21.4; OR 5.3, 95% CI 2.0-16.2; P < 0.001) and cerclage (OR 3.6, 95% CI 1.1-11.8; P = 0.028) were independent factors correlated with ID (< 2 days). CONCLUSION: Maintenance tocolysis may be effective in limited cases with mild intra-amniotic inflammation, in lean women and in cerclage cases. Maintenance tocolysis should be ceased in cases without these clinical factors when clinical symptoms disappear.

[Maintenance tocolysis with calcium channel blockers]. / Tocolyse d'entretien par les inhibiteurs calciques.

AIM OF THE STUDY: The objective of initial tocolysis is to prolong pregnancy for 48 hours, in order to allow fetal lung maturation with corticosteroids. Maintenance tocolysis is defined by the prolongation of tocolytic therapy beyond 48 h. Although the 2002 guidelines of the French College did not recommend to prolong tocolysis beyond 48 h, about 60% of obstetricians prescribe maintenance tocolysis. METHOD: Nifedipine is the most frequently used treatment for maintenance tocolysis. Five randomised studies and two metaanalyses have compared maintenance tocolysis with nifedipine, with placebo or no treatment. RESULTS-CONCLUSION: Maintenance tocolysis with calcium channel blockers does not reduce the risk of preterm birth and does not improve perinatal outcome. Tocolytic treatment after 48 hours of initial tocolysis has no beneficial effect (level of evidence 1).

[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.

The quality of randomised trials of tocolysis.

Tocolytic treatment of suspected preterm labour has been evaluated in at least 75 randomised controlled trials. These have been included in six Cochrane reviews. If the trials are poorly designed, such reviews may mislead or, at best, provide weaker evidence than those based on well-designed ones. The objective of this study was to compare the quality of the trials included in the Cochrane reviews of tocolytic therapy. Trial group sizes; the methods used by each trial to avoid selection, performance, attrition, and detection bias; and evidence that the statistical analysis plan was prespecified were abstracted from each Cochrane review. Except where noted, the judgement of the Cochrane reviewers was used. The number of trials graded A (sealed envelopes or third-party randomisation) for allocation concealment was as follows: beta-agonists 5/16, magnesium sulphate 9/23, oxytocin receptor antagonists 6/6, cox inhibitors 12/13, calcium channel blockers 9/12, and nitric oxide donors 5/5. The number blinding the intervention was as follows: beta-agonists 9/16, magnesium sulphate 2/23, oxytocin receptor antagonists 5/6, cox inhibitors 7/13, calcium channel blockers 0/12, and nitric oxide donors 1/5. The number reporting a sample size calculation was as follows: beta-agonists 2/16, magnesium sulphate 3/23, oxytocin receptor antagonists 6/6, cox inhibitors 4/13, calcium channel blockers 4/12, and nitric oxide donors 1/5. The mean sample size of each treatment group was as follows: beta-agonists 53, magnesium sulphate 41, oxytocin receptor antagonists 126, cox inhibitors 31, calcium channel blockers 43, and nitric oxide donors 46. Data on avoiding attrition bias (follow-up rates) are difficult to summarise because there is no agreed standard for 'complete follow up'. Data on avoiding detection bias (blinding of outcome assessments) appeared unreliable because reviewers reported this in different ways. In conclusion, the trials of oxytocin antagonists and beta-agonists were of the highest quality. There remains considerable scope for bias in many of the trials included in the current Cochrane systematic reviews of tocolytics.

Preterm prelabour rupture of the membranes: a survey of current practice.

BACKGROUND: Preterm prelabour rupture of the membranes (PPROM) complicates 1-2% of all pregnancies. Risks of remaining in utero need to be balanced against the risks of iatrogenic prematurity if early birth is planned. AIMS: To assess and further define the current management of women with pregnancies complicated with PPROM in Australia. METHODS: A mail out questionnaire was sent to all Australian Members and Fellows of the Royal Australian and New Zealand College of Obstetricians and Gynaecologists (RANZCOG). RESULTS: There were 731 responses from RANZCOG Fellows and Members. Corticosteroids were used routinely in the setting of PPROM by 99% (95% confidence intervals (CI) 98.4-100.0%) of obstetricians. Tocolysis was used commonly by 75% (95% CI 98.4-100.0%). Antibiotics are also used routinely by 63% (95% CI 58.8-67.3%) of Australian obstetricians. For women presenting with PPROM less than 34 weeks' gestation 56% (95% CI 48.1-60.0%) of obstetricians would plan to deliver these women prior to term, while for women presenting with PPROM greater than 34 weeks' gestation 50% (95% CI 46.0-54.8%) would offer delivery to such women prior to term. CONCLUSIONS: There is significant variation in clinical practice in the management of women who present with PPROM in Australia. There is little consensus regarding the optimal timing of delivery for babies of women with pregnancies complicated with PPROM. The present survey supports the need and feasibility of a randomised controlled trial to assess the appropriate gestation at which to deliver women with PPROM near to term.

The morbidity of the 34- to 35-week gestation: should we reexamine the paradigm?

Algorithms for the management of preterm labor avoid the use of tocolysis beyond 34 weeks' gestation, based in large part on low respiratory morbidity found at this gestational age. We sought to delineate the morbidities, not just respiratory, of this age group in a modern neonatal intensive care unit setting. We prospectively looked at hospital resource use and general morbidity in a consecutive 2-year cohort of 34-weekers at our hospital. The concurrent consecutive 35-week cohort was used as a control. Data were prospectively collected from obstetricians and bedside records. Compared with 35-weekers, the 34-week group had similar obstetric characteristics. Significant differences were seen in use of oxygen, nasal continuous positive airway pressure, methylxanthines, home apnea monitoring, antibiotics, and phototherapy. The 34-week group took longer to come off intravenous lines and were discharged later. Overall, they used approximately twice the resources of the 35-week group. To stop or not use tocolysis at 34 weeks' gestation based mainly on low respiratory morbidity ignores the significant other morbidities. These findings suggest a reconsideration of the paradigm regarding 34-week gestation as a cutoff point in decision making.

[Analysis of adequacy and effectiveness in the use of tocolytics in preterm labor]. / Anlise da adequação e da efetividade do uso de tocolíticos no trabalho de parto prematuro.

The objective of this study was to assess quality of care for premature labor at public maternity facilities in Rio de Janeiro, Brazil, using referents, indicators, and standards of care derived from scientific evidence. The standard utilized in the process analysis for use of betamimetic tocolytics was 100%, considering the related referents. For outcome analysis, the standard applied was the occurrence of premature delivery in 11% of patients within 24 h and in 24% of patients (referent) within 48 h of hospital admission. Use of tocolytics was observed in 18.7% of patients admitted in premature labor. At gestational age from 28 weeks to 33 weeks and 6 days, especially critical for neonatal survival, tocolytics were used in 32.6% of patients. Premature birth occurred in 59% of patients within 24 h and in 64% within 48 h. These outcomes were consistent with the low rate of utilization of tocolytics. Effectiveness of care for preterm labor measured by rate of premature birth was low. Results of the corresponding process and outcomes analysis were consistent.

Análise da adequação e da efetividade do uso de tocolíticos no trabalho de parto prematuro / Analysis of adequacy and effectiveness in the use of tocolytics in preterm labor

O objetivo do presente trabalho foi avaliar a qualidade do atendimento ao trabalho de parto prematuro em maternidades públicas do Rio de Janeiro, utilizando referentes, indicadores e padrões de processo e de resultado derivados de evidências científicas. Na análise de processo, o padrão utilizado para o uso de tocolíticos betamiméticos foi de 100 por cento, considerando os referentes derivados. Na análise de resultados, o padrão foi a ocorrência de parto prematuro em 11 por cento das pacientes dentro de 24 h e em 24 por cento dentro de 48 h da admissão hospitalar. O uso de tocolíticos ocorreu em 18,7 por cento das pacientes admitidas em trabalho de parto prematuro. Na faixa de idade gestacional de 28 a 33 semanas e seis dias, especialmente importante para a sobrevivência neonatal, o uso de tocolíticos foi feito em 32,6 por cento das pacientes. Parto prematuro ocorreu em 59 percet das pacientes dentro de 24 h e em 64 percent das pacientes dentro de 48 h da admissão, resultados consistentes com o baixo uso de tocolíticos observado. A efetividade da assistência ao trabalho de parto prematuro, medida pela taxa de nascimentos prematuros, foi baixa. Os achados das correspondentes análises de processo e resultado foram consistentes

Perinatal outcome following conservative management of mid-trimester pre-labour rupture of the membranes.

OBJECTIVE: To assess perinatal outcome and the effect of antenatal steroid use following conservative management of 86 consecutive singleton pregnancies complicated by pre-labour rupture of membranes (ROM) in the mid-trimester (13-26 weeks; mean 22.8 weeks). METHODOLOGY: Review of obstetric and neonatal case notes between 1 January 1990 and 31 December 1993. RESULTS: The duration of ruptured membranes (latent period) ranged from 1.25 to 105 days (mean 23.8 days; median 14 days) and was inversely related to gestational age at ROM. There was clinical evidence of chorioamnionitis in 39.5% with placental histological changes consistent with chorioamnionitis in 76.6%. All infants were delivered before 33 weeks gestation (mean 26 weeks). Overall, the mortality rate was 43.0% but 62.5% in infants with ROM before 24 completed weeks gestation. Adverse outcome (defined as death, severe intraventricular haemorrhage (IVH) or periventricular leucomalacia (PVL)) occurred in 46.5% and was significantly related to both gestation at delivery and gestation at ROM. In the group (n = 40) with ROM before 24 weeks gestation, adverse outcome occurred in 65% and was inversely related to gestation at ROM independent of gestation at delivery. Antenatal steroid administration resulted in less adverse outcome independent of gestation at delivery (OR 0.31; 95% CI (0.09-0.98; P = 0.046)). CONCLUSION: From the neonatal perspective conservative management is justified for pregnancies with ROM at or after 24 weeks gestation; in this group the use of antenatal steroids prior to delivery may improve perinatal outcome. A poor outcome is associated with ROM that occurs before 24 weeks gestation.

Short-term verus long-term prophylactic tocolysis in patients with preterm premature rupture of membranes.

A randomised prospective clinical trial was conducted over a 7-year period (1987-1993) in the Department of Obstetrics and Gynaecology, University of Patras. The purpose of this study was to compare two management protocols of Preterm Premature Rupture of Membranes (PPROM). Two-hundred forty-one women entered the study and were assigned randomly to one of two groups. Group A consisted of 105 subjects who were managed expectantly (tocolysis used for 48 h only, if necessary, to permit full course of steroid therapy), while Group B consisted of 136 subjects, in whom aggressive tocolysis was utilised. The differences in the latency period (time from rupture of membranes to the onset of labour) were not statistically significant between the two groups. On the contrary, statistically significant differences in the incidence of chorioamnionitis and postpartum endomyometritis were found between the two groups (higher in Group B). Twelve subjects in Group A (12/105, 11.4%) and 40 in Group B (40/136, 29.4%) had chorioamnionitis. The relative risk (RR) was 2.47 (95% C.I. 1.42-4.66, P < 0.001). Endomyometritis was diagnosed in 20 subjects in Group A (20/105, 19%) and in 45 in Group B (45/136, 33.3%). The RR was 1.74 (95% C.I. 1.10-2.75, P < 0.05). These data suggest that long term prophylactic tocolytic therapy in patients with PPROM, while without demonstrated benefit, may result in an increased risk of maternal infectious morbidity, and raise the cost of treatment.

Premature rupture of the membranes: management controversies.

Preterm premature rupture of the membranes continues to be a leading cause of perinatal morbidity and mortality in the United States. In the absence of amnionitis or fetal compromise, expectant management is a reasonable alternative to permit fetal weight gain and to allow for fetal lung maturation. When embarking on an expectant management course, a variety of clinical approaches are available to the practicing clinician.

Placenta previa.

Placenta previa occurs in approximately one in 200 pregnancies. The cause is unknown, but endometrial damage due to prior pregnancy, cesarean section, and other factors predispose to it. Diagnosis is usually made by transabdominal ultrasonography. False-positive diagnoses are common in the second trimester and the term "potential placenta previa" has been proposed to describe this situation. Bleeding with placenta previa is usually associated with uterine contractions, thus the introduction of tocolysis. Placenta accreta is common in the patient with one or more previous cesarean sections and placenta previa in the current pregnancy. Management of placenta previa is expectant and involves avoidance of digital vaginal examination, delay of delivery until 36 weeks' gestation and/or documented fetal lung maturity, transfusion support to maintain maternal hematocrit greater than or equal to 30%, serial ultrasonography, antepartum fetal heart rate monitoring, glucocorticoids, tocolytic therapy, and elective delivery by cesarean section. Maternal mortality is rare with placenta previa. Perinatal mortality is currently 4% to 8% primarily related to complications of prematurity.