A historical narrative review through the field of tocolysis in threatened preterm birth.

Preterm birth presents a significant challenge in clinical obstetrics, requiring effective strategies to reduce associated mortality and morbidity risks. Tocolytic drugs, aimed at inhibiting uterine contractions, are a key aspect of addressing this challenge. Despite extensive research over many years, determining the most effective tocolytic agents remains a complex task, prompting better understanding of the underlying mechanisms of spontaneous preterm birth and recording meaningful outcome measures. This paper provides a comprehensive review of various obsolete and current tocolytic drug regimens that were instituted over the past century, examining both historical contexts and contemporary challenges in their development and adoption. The examination of historical debates and advancements highlights the complexity of introducing new therapies. While the search for effective tocolytics continues, questions arise regarding their actual benefits in obstetric care and the necessity for ongoing exploration. The presence of methodological limitations in current research emphasizes the importance of well-designed randomized controlled trials with robust endpoints and extended follow-up periods.In response to these complexities, the consideration of shifting towards prevention strategies aimed at addressing the root causes of preterm labor becomes more and more evident. This potential shift may offer a more effective approach than relying solely on tocolytics to delay labor initiation.Ultimately, effectively managing threatened preterm birth necessitates ongoing investigation, innovation, and a willingness to reassess strategies in pursuit of optimal outcomes for mothers, neonates, and long-term child health.

Trends in preterm birth in the Netherlands in 2011-2019: A population-based study among singletons and multiples.

INTRODUCTION: Preterm birth (PTB) is the leading cause of infant mortality and morbidity worldwide. Rates of PTB in the Netherlands are declining, possibly due to the implementation of preventive strategies. In this study we assessed the overall trend in PTB rates in the Netherlands in recent years, and in more detail in specific subgroups to investigate potential groups that require scrutiny in the near future. MATERIAL AND METHODS: Based on the national perinatal registry, we included all pregnancies without severe congenital abnormalities resulting in a birth from 24 to 42 completed weeks of gestation between 2011 and 2019 in the Netherlands. We assessed PTB rates in two different clinical subtypes (spontaneous vs. iatrogenic) and in five gestational age subgroups: 24-27+6 weeks (extreme), 28-31+6 weeks (very), 32-33+6 weeks (moderate, 34-36+6 weeks [late] and, in general, 24-36+6 weeks [overall PTB]). Trend analysis was performed using the Cochran Armitage test. We also compared PTB rates in different subgroups in the first 2 years compared to the last 2 years. Singleton and multiple gestations were analyzed separately. RESULTS: We included 1 447 689 singleton and 23 250 multiple pregnancies in our study. In singletons, we observed a significant decline in PTB from 5.5% to 5.0% (p < 0.0001), mainly due to a decrease in iatrogenic PTBs. When focusing on different gestational age subgroups, there was a decrease in all iatrogenic PTB and in moderate to late spontaneous PTB. However, in spontaneous extreme and very PTB there was an significant increase. When assessing overall PTB risk in different subgroups, the decline was only visible in women with age ≥25 years, nulliparous and primiparous women, women with a medium or high socioeconomic status and hypertensive women. In multiples, the rate of PTB remained fairly stable, from 52.3% in 2011 to 54.1% in 2019 (p = 0.57). CONCLUSIONS: In the Netherlands, between 2011 and 2019, PTB decreased, mainly due to a reduction in late PTB, and more in iatrogenic than in spontaneous PTB. Focus for the near future should be on specific subgroups in which the decline was not visible, such as women with a low socioeconomic status or a young age.

Impact of ethnicity and neighborhood deprivation on preterm birth: How does urban living play a role?

OBJECTIVE: Women of Black and other non-Western ethnicity and women who live in deprived neighborhoods are at increased risk for preterm birth (PTB). These women may live clustered in certain urban areas. If ethnicity reflects a biological rather than a socioeconomic risk factor, women should have a PTB risk independent of the urban area where they live. In this study we explored the association between urban living and the risk of PTB, combined with knowledge on ethnicity and neighborhood deprivation in these specific urban areas in the Netherlands. STUDY DESIGN: National cohort study of 935,381 women (2014-2019) with a singleton pregnancy resulting in live birth between 24.0 and 42.6 weeks. Antepartum death and severe congenital anomalies were excluded. We performed logistic regression analysis and analyzed the impact of living in one of the four main urban areas on PTB. We adjusted for maternal age, parity and fetal gender. We tested for interaction between ethnicity, neighborhood deprivation index (NDI) and urban living. RESULTS: Mean PTB rate among singleton pregnancies in The Netherlands is 5.1%. There was a strong ethnic difference in PTB risk, with the highest prevalence among South Asian women (7.9%) and African women (6.6%). In the most deprived neighborhoods the PTB risk was 5.7%. We found a significant interaction between ethnicity and urban living, and between NDI and urban living. South Asian and African women living in urban areas had the greatest risk of PTB, between 7.0% and 8.8%. CONCLUSION: Ethnicity remains a fixed biological risk for PTB that cannot be fully explained by socioeconomic status or neighborhood deprivation. Independent of ethnicity and neighborhood deprivation, urban living has a great influence on the risk of preterm birth. Future studies and policies should focus on population-based interventions in those urban areas where South Asian and African ethnic groups live and where the preterm birth risk is the highest.

Tocolysis with nifedipine versus atosiban and perinatal outcome: an individual participant data meta-analysis.

BACKGROUND: Worldwide, nifedipine and atosiban are the two most commonly used tocolytic agents for the treatment of threatened preterm birth. The aim of this study was to evaluate the effectiveness of nifedipine and atosiban in an individual participant data meta-analysis (IPDMA). METHODS: We investigated the occurrence of adverse neonatal outcomes in women with threatened preterm birth by performing an IPDMA, and sought to identify possible subgroups in which one treatment may be preferred. We searched PubMed, Embase, and Cochrane for trials comparing nifedipine and atosiban for treatment of threatened preterm birth between 240/7 and 340/7 weeks' gestational age. Primary outcome was a composite of perinatal mortality and neonatal morbidities including respiratory distress syndrome, intraventricular haemorrhage, periventricular leucomalacia, necrotising enterocolitis, and sepsis. Secondary outcomes included NICU admission, prolongation of pregnancy and GA at delivery. For studies that did not have the original databases available, metadata was used. This led to a two-stage meta-analysis that combined individual participant data with aggregate metadata. RESULTS: We detected four studies (N = 791 women), of which two provided individual participant data (N = 650 women). The composite neonatal outcome occurred in 58/364 (16%) after nifedipine versus 69/359 (19%) after atosiban (OR 0.76, 95%CI 0.47-1.23). Perinatal death occurred in 14/392 (3.6%) after nifedipine versus 7/380 (1.8%) after atosiban (OR 2.0, 95%CI 0.80-5.1). Nifedipine results in longer prolongation of pregnancy, with a 18 days to delivery compared with 10 days for atosiban (HR 0.83 (96% CI 0.69-0.99)). NICU admission occurred less often after nifedipine (46%) than after atosiban (59%), (OR 0.32, 95%CI 0.14-0.75). The sensitivity analysis revealed no difference in prolongation of pregnancy for 48 hours (OR 1.0, 95% CI 0.73-1.4) or 7 days (OR 1.3, 95% CI 0.85-5.8) between nifedipine and atosiban. There was a non-significant higher neonatal mortality in the nifedipine-exposed group (OR 1.4, 95% CI 0.60-3.4). CONCLUSIONS: In this IPDMA, we found no differences in composite outcome between nifedipine and atosiban in the treatment of threatened preterm birth. However, the non-significant higher mortality after administering nifedipine warrants further investigation of the use of nifedipine as a tocolytic drug. STUDY REGISTRATION: We conducted this study according to a prospectively prepared protocol, registered with PROSPERO (the International Prospective Register of Systematic Reviews) under CRD42016024244.

Deprived neighborhoods and spontaneous preterm birth: A national cohort study.

OBJECTIVE: Spontaneous preterm birth is the leading cause of infant morbidity and mortality in the developed world. Environmental socio-economic factors, such as neighborhood deprivation, are known to negatively affect birth outcomes, including overall preterm birth. However, the role of neighborhood deprivation in spontaneous preterm birth (SPTB) is unclear. The aim of the study is to 1) to determine the effect of neighborhood deprivation on SPTB birth and 2) to investigate the trend in rates of SPTB between 2010 and 2019 for each quintile of neighborhood deprivation. STUDY DESIGN: Based on the national perinatal registry, we included 1,584,225 singleton pregnancies resulting in a birth from 22 to 42 completed weeks of gestation between 2010 and 2019 in the Netherlands. Deprivation scores per neighborhood were derived from the Netherlands Institute of Social Research and were linked to the perinatal registry data, using the woman's home address. The scores were divided into quintiles (Q). Rates of SPTB were calculated, categorized into <37 weeks, <32 weeks and <28 weeks of gestation. We used logistic regression analysis to adjust for maternal age, parity and ethnicity. RESULTS: Compared to the most affluent neighborhoods (Q1), women in all other quintiles had a statistically significant increased risk for SPTB. The largest effect was observed in the most deprived neighborhoods (Q5); adjusted odds ratio 1.16 (95% confidence interval 1.13 - 1.19). From 2010 to 2019, we observed an overall decrease of 0.21% in SPTB < 37 weeks (p < 0.0001). All quintiles showed a decrease in SPTBs < 37 weeks, but only in Q1, Q2 & Q5 this decline in SPTB was statistically significant. CONCLUSIONS: Pregnant women in deprived neighborhoods in the Netherlands are more at risk for spontaneous preterm birth. From 2010 to 2019, the rate of spontaneous preterm birth decreased. Efforts should be made by both governmental and medical professionals to develop intervention programs to reduce spontaneous preterm birth in more deprived neighborhoods.

Omega-3 Fatty Acid Supplementation for Perinatal Depression: A Meta-Analysis.

OBJECTIVE: Several randomized controlled trials (RCTs) investigated omega-3 polyunsaturated fatty acids (PUFAs) (ie, fish oil) in perinatal depression, but their efficacy remains unclear. We performed a meta-analysis of RCTs on omega-3 PUFAs for perinatal depression, comparing a priori defined subgroups: pregnant women vs postpartum women and prevention vs treatment of perinatal depression. METHODS: We searched Web of Science, Embase, PsycINFO, and the Cochrane Library, combining omega-3 PUFAs and perinatal depression terms and including publications up to February 18, 2019, for RCTs on omega-3 PUFAs compared to placebo or any active comparator. RESULTS: Data from 18 RCTs on 4,052 participants showed an overall significant small beneficial effect of omega-3 PUFAs on depressive symptoms compared to placebo (-0.236 standardized difference in means [SDM]; 95% CI = -0.463 to -0.009; P = .042). Heterogeneity was considerable (I² = 88.58; P < .001), with significant subgroup differences explaining 55% of between-study variance (P = .001). In depressed women, omega-3 PUFAs showed a medium effect (SDM = -0.545; 95% CI = -1.182 to 0.093; P = .094) vs no effect in nondepressed women (SDM = -0.073). Moreover, the effect was medium to large in postpartum women (SDM = -0.656; 95% CI = -1.690 to 0.378; P = .214) compared to a negligible effect during pregnancy (SDM = -0.071). RCTs specifically studying postpartum depression showed the largest effect (SDM = -0.886; 95% CI = -2.088 to 0.316; P = .149). CONCLUSIONS: Omega-3 PUFAs have an overall significant small beneficial effect on perinatal depression, with important subgroup differences. We advise against prescribing omega-3 PUFAs for the treatment or prevention of depressive symptoms during pregnancy, given a lack of effect with low heterogeneity. In contrast, omega-3 PUFA supplementation may be a promising (add-on) treatment for postpartum depression.

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).

Fetal fibronectin status and cervical length in women with threatened preterm labor and the effectiveness of maintenance tocolysis.

OBJECTIVE: To assess the effect of maintenance tocolysis in women who are at high or low risk for preterm delivery according to fetal fibronectin (fFN) status and cervical length (CL). STUDY DESIGN: We compared the risk of preterm delivery in fFN pos and fFN neg women and in women with a CL <15 mm and ≥15 mm, by using the Cox regression. Differences between the effectiveness of maintenance tocolysis in high- and low-risk women were assessed by using an interaction term. RESULTS: 122 fFN tests were taken, of which 50 were fFN pos. CL was measured in 236 women, of whom 52 women had a CL <15 mm. The median gestational age at delivery was lower in fFN pos women; fFN pos women had a higher hazard for preterm delivery at any point of time (HR 4.7; 95% CI 2.9 to 7.6). Comparable results were seen for CL. Neither fFN status nor CL did alter the effect of maintenance tocolysis, which was ineffective in the total randomized group, on the risk of preterm delivery (p for interaction = 0.87 for fFN and 0.18 for CL). CONCLUSION: Maintenance tocolytic therapy with nifedipine is ineffective and not dependent on fFN or CL status.

Predictive Factors for Delivery within 7 Days after Successful 48-Hour Treatment of Threatened Preterm Labor.

Objective The aim of this study was to assess which characteristics and results of vaginal examination are predictive for delivery within 7 days, in women with threatened preterm labor after initial treatment. Study Design A secondary analysis of a randomized controlled trial on maintenance nifedipine includes women who remained undelivered after threatened preterm labor for 48 hours. We developed one model for women with premature prelabor rupture of membranes (PPROM) and one without PPROM. The predictors were identified by backward selection. We assessed calibration and discrimination and used bootstrapping techniques to correct for potential overfitting. Results For women with PPROM (model 1), nulliparity, history of preterm birth, and vaginal bleeding were included in the multivariable analysis. For women without PPROM (model 2), maternal age, vaginal bleeding, cervical length, and fetal fibronectin (fFN) status were in the multivariable analysis. Discriminative capability was moderate to good (c-statistic 0.68; 95% confidence interval [CI] 0.60-0.77 for model 1 and 0.89; 95% CI, 0.84-0.93 for model 2). Conclusion PPROM and vaginal bleeding in the current pregnancy are relevant predictive factors in all women, as are maternal age, cervical length, and fFN in women without PPROM and nulliparity, history of preterm birth in women with PPROM.

Impact of a randomized trial on maintenance tocolysis on length of hospital admission of women with threatened preterm labor in The Netherlands.

INTRODUCTION: The APOSTEL-II trial was a multicenter randomized placebo-controlled trial, assessing the effectiveness of maintenance tocolysis with nifedipine. The trial showed maintenance tocolysis not to have an effect on perinatal outcome. Objective of the current study is to evaluate the effect of a negative trial on the length of hospital admission of women with threatened preterm labor. MATERIALS AND METHODS: We evaluated length of hospital admission of all patients admitted with threatened preterm labor with a gestational age <32 weeks in 8 perinatal centers that participated in the APOSTEL-II trial. We studied only the first admission with threatened preterm labor, readmissions were excluded. We distinguished between the period before, the period during and the period after the trial. In a subgroup analysis, we differentiated for the group of women who delivered and for the group of women who did not deliver during the initial admission. RESULTS: The mean length of hospital admission was 9.3 days before the start of the trial, 8.4 days during the recruitment period and 8.1 days after the trial was completed. The difference in mean length of hospital admission before and during the recruitment period was significantly different (p<001). COMMENTS: The length of hospital admission of women with threatened preterm labor is found to be reduced during the recruitment period of the APOSTEL-II trial. This shows that the conduct of a randomized controlled trial itself has the potential to change daily practice.

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.

The NIFTY study: a multicentre randomised double-blind placebo-controlled trial of nifedipine maintenance tocolysis in fetal fibronectin-positive women in threatened preterm labour.

OBJECTIVE: In an unselected group of women with signs of preterm labour, maintenance tocolysis is not effective in the prevention of preterm birth and does not improve neonatal outcome. Among women with signs of preterm labour, those who are fetal fibronectin positive have an increased risk of preterm birth. We investigated whether maintenance tocolysis with nifedipine would delay delivery and improve neonatal outcome in women with threatened preterm labour and a positive fetal fibronectin status. STUDY DESIGN: Women with a singleton pregnancy in threatened preterm labour (24(+0) to 33(+6)  weeks) with a positive fetal fibronectin test were randomised to nifedipine or placebo. Study medication was continued until 36 completed weeks' gestation. The primary endpoint was prolongation of pregnancy of seven days. Secondary endpoints were gestational age at delivery and length of NICU admission. RESULTS: Of the 60 participants, 29 received nifedipine and 31 placebo. Prolongation of pregnancy by >7 days occurred in 22/29 (76%) in the nifedipine group and 25/31 (81%) in the placebo group (relative risks, RR 0.94 [0.72-1.2]). Gestational age at delivery was 36.1 ± 5.1 weeks for nifedipine and 36.8 ± 3.6 weeks for placebo (P = 0.027). Length of NICU admission [median (interquartile ranges, IQR)] was 27 (24-41) days and 16 (8-37) days in nifedipine and placebo groups, respectively (P = 0.17). CONCLUSION: In women with threatened preterm labour who are fetal fibronectin positive, maintenance tocolysis with nifedipine does not seem to prolong pregnancy, nor reduce length of NICU admission.

Effect of maintenance tocolysis with nifedipine in threatened preterm labor on perinatal outcomes: a randomized controlled trial.

IMPORTANCE: In threatened preterm labor, maintenance tocolysis with nifedipine, after an initial course of tocolysis and corticosteroids for 48 hours, may improve perinatal outcome. OBJECTIVE: To determine whether maintenance tocolysis with nifedipine will reduce adverse perinatal outcomes due to premature birth. DESIGN, SETTING, AND PARTICIPANTS: APOSTEL-II (Assessment of Perinatal Outcome with Sustained Tocolysis in Early Labor) is a double-blind, placebo-controlled trial performed in 11 perinatal units including all tertiary centers in The Netherlands. From June 2008 to February 2010, women with threatened preterm labor between 26 weeks (plus 0 days) and 32 weeks (plus 2 days) gestation, who had not delivered after 48 hours of tocolysis and a completed course of corticosteroids, were enrolled. Surviving infants were followed up until 6 months after birth (ended August 2010). INTERVENTION: Randomization assigned 406 women to maintenance tocolysis with nifedipine orally (80 mg/d; n = 201) or placebo (n = 205) for 12 days. Assigned treatment was masked from investigators, participants, clinicians, and research nurses. MAIN OUTCOME MEASURES: Primary outcome was a composite of adverse perinatal outcomes (perinatal death, chronic lung disease, neonatal sepsis, intraventricular hemorrhage >grade 2, periventricular leukomalacia >grade 1, or necrotizing enterocolitis). Analyses were completed on an intention-to-treat basis. RESULTS: Mean (SD) gestational age at randomization was 29.2 (1.7) weeks for both groups. Adverse perinatal outcome was not significantly different between groups: 11.9% (24/201; 95% CI, 7.5%-16.4%) for nifedipine vs 13.7% (28/205; 95% CI, 9.0%-18.4%) for placebo (relative risk, 0.87; 95% CI, 0.53-1.45). CONCLUSIONS AND RELEVANCE: In patients with threatened preterm labor, nifedipine-maintained tocolysis did not result in a statistically significant reduction in adverse perinatal outcomes when compared with placebo. Although the lower than anticipated rate of adverse perinatal outcomes in the control group indicates that a benefit of nifedipine cannot completely be excluded, its use for maintenance tocolysis does not appear beneficial at this time. TRIAL REGISTRATION: trialregister.nl Identifier: NTR1336.

Making GRADE accessible: a proposal for graphic display of evidence quality assessments.

When generating guidelines, quality of evidence is frequently reported in tabulated form capturing several domains, for example, study design, risk of bias and heterogeneity. Increasingly, this is done using the Grading of Recommendations Assessment, Development and Evaluation approach. As assimilating large amount of tabulated data across several comparisons and outcomes spread over many pages (sometimes hundreds) is not easy, there is a need to present evidence summaries in a more effective way. A graphic display plotting the several domains used in evidence grading on equiangular spokes starting from the same point, the data length of each spoke proportional to the magnitude of the quality, succinctly captures tabulated information. These plots allow easy identification of deficiencies, outliers and similarities in evidence quality for individual and multiple comparisons and outcomes, paving the way for their routine use alongside tabulated information.

Assessment of perinatal outcome after sustained tocolysis in early labour (APOSTEL-II trial).

BACKGROUND: Preterm labour is the main cause of perinatal morbidity and mortality in the Western world. At present, there is evidence that tocolysis for 48 hours is useful in women with threatened preterm labour at least before 32 weeks. This allows transfer of the patient to a perinatal centre, and maximizes the effect of corticosteroids for improved neonatal survival. It is questionable whether treatment with tocolytics should be maintained after 48 hours. METHODS/DESIGN: The APOSTEL II trial is a multicentre placebo-controlled study. Pregnant women admitted for threatened preterm labour who have been treated with 48 hours corticosteroids and tocolysis will be eligible to participate in the trial between 26+0 and 32+2 weeks gestational age. They will be randomly allocated to nifedipine (intervention) or placebo (control) for twelve days or until delivery, whatever comes first.Primary outcome is a composite of perinatal death, and severe neonatal morbidity up to evaluation at 6 months after birth. Secondary outcomes are gestational age at delivery, number of days in neonatal intensive care and total days of the first 6 months out of hospital. In addition a cost-effectiveness analysis will be performed. Analysis will be by intention to treat. The power calculation is based on an expected 11% difference in adverse neonatal outcome. This implies that 406 women have to be randomised (two sided test, beta 0.2 at alpha 0.05). DISCUSSION: This trial will provide evidence as to whether maintenance tocolysis reduces severe perinatal morbidity and mortality in women with threatened preterm labour before 32 weeks. CLINICAL TRIAL REGISTRATION: http://www.trialregister.nl, NTR 1336, date of registration: June 3rd 2008.