Nifedipine versus atosiban for threatened preterm birth (APOSTEL III): a multicentre, randomised controlled trial 

Preterm birth is associated with 50% of neonatal morbidity and50–75%ofneonatalmortalityworldwide,1–5andaffects 5–13% of all pregnancies in high-income countries.2–5 Additionally, preterm birth can cause long-term physical and developmental impairment and thereby has a substantialimpactoninfant,parents,families,andhealth- care costs.1,2 To improve outcomes in preterm babies, women in labour before 34 weeks of gestation receive antenatal corticosteroids to enhance fetal lung maturation.6 Toallowoptimaleffectofmaternalsteroidadministration, most perinatal centres attempt to delay birth by administrating tocolytic drugs for 48 h.7 Previous meta- analyses have shown that tocolytic drugs are effective in delaying delivery by 48 h and 7 days.8,9 Several types of tocolyticdrugsareusedastreatmentinpretermlabour, including β adrenoceptor agonists, cyclooxygenase inhibitors (COX), magnesium sulphate, calcium-channel blockers and oxytocin receptor antagonists. Uncertainty remains over which tocolytic should be drug of choice.

Studies of β adrenoceptor agonists have shown contradictory results for its ability to postpone delivery and decrease neonatal mortality compared with placebo,9,10 and their use has been largely abandoned in clinical practice due to a substantial side-effect profile. For COX inhibitors, no effect on perinatal mortality and morbidity has been reported and some concerns exist about potential adverse effects on neonatal outcomes; a recent meta-analysis found an increase in intra- ventricular haemorrhage, necrotising enterocolitis, and periventricular leukomalacia with administration of COX inhibitors compared with placebo.11,12 For initial tocolysis, calcium-channel blockers or oxytocin antagonists for 48 h are recommended because they have the best efficacy to side-effect ratio; however it has not yet been established which drug leads to the best outcomes.13–15 Three small randomised trials comparing the calcium-channel blocker nifedipine with the oxytocin antagonist atosiban have shown contradictory results.16–18 One study (n=145) found a lower prevalence of delivery within 7 days, but a higher prevalence of delivery within 48 h after nifedipine tocolysis compared with atosiban.18 The two other trials (n=80 and n=63) did not find a significant difference in the ability of either drug to delay delivery for 48 h.16,17 Salim and colleagues18 showed a shorter length of stay at the neonatal intensive care unit for babies from women in the nifedipine group as compared with those from women in the atosiban group. The two trials that reported on neonatal outcome did not show a significant difference, but were underpowered. 17,18

In view of this uncertainty, we started the Assessment of Perinatal Outcome after Specific Tocolysis in Early Labour (APOSTEL-III) study, a multicentre randomised clinical trial in which we aimed to compare the calcium- channel blocker nifedipine with the oxytocin antagonist atosiban in women with threatened preterm birth. 

Methods

Study design and participants

We did this multicentre, randomised controlled trial in 19 centres (ten tertiary care centres with a neonatal intensive care unit facility and nine secondary centres) in 18 cities in the Netherlands and Belgium that collaborate in the Dutch Consortium for Healthcare EvaluationandResearchinObstetricsandGynecology.

The protocol has been published previously.19 Women were eligible if they were aged 18 years or older and had threatened preterm birth at between 250/7 weeks and 340/7 weeks of gestation. Threatened preterm birth was defined as at least three uterine contractions per 30 min and presence of one of the following: cervical length of 10mmorless,bothacervicallengthof11–30mmanda positive fetal fibronectin test, or presence of ruptured amniotic membranes. Women with singleton or multiple pregnancies were eligible. Exclusion criteria were a contraindication for tocolysis (severe vaginal bleeding or signs of intrauterine infection), hypertension or current use of antihypertensive drugs, history of myocardial infarction or angina pectoris, cerclage, cervical dilatation greater than 5 cm, tocolytic treatment for more than 6 h before arrival in a participating centre, or a previous episode of tocolytic treatment. Women with a fetus showing signs of fetal distress or a fetus suspected of chromosomal or structural anomalies were not included. Eligible women were identified and counselled by the local staff or research coordinators in the participating hospitals.

This study was approved by the ethics committee of the Academic Medical Centre Amsterdam (reference number MEC AMC 09/258) and the boards of management of all participating hospitals. All women provided written informed consent.

Randomisation and masking

An independent data manager used a web-based computerised program to randomly assign women to nifedipine or atosiban in a 1:1 ratio, with assignment done in permuted blocks of four and stratified by centre. Because of the nature of the interventions, oral medication, and intravenous medication, clinical staff or women were not masked.

Procedures

In the nifedipine group, the initial dose was 20 mg nifedipine (two 10 mg capsules) orally in the first hour, followed by 20 mg slow-release nifedipine per 6 h for the next 47 h. In the first hour after the start of nifedipine administration, blood pressure and heart rate were measured every 15 min. If blood pressure remained within the normal limits, treatment continued with blood pressure and heart rate measured four times every 24 h. In the atosiban group, women received a bolus injection of 6·75 mg intravenous in 1 min, followed by 18 mg/h for 3 h, followed by a maintenance dosage of 6 mg/h for 45 h. Antenatal corticosteroids were administered according to guidelines from the Dutch Society of Obstetrics and Gynecology (NVOG) for management of preterm birth, which advise antenatal corticosteroids to women with threatened preterm birth at less than 34 weeks gestation. We gave magnesium sulphate for neuroprotection to women with threatened preterm birth at less than 32 weeks gestation, according to guidelines from NVOG. The provision of prophylactic antibiotics was at the discretion of the attending physician.

Trained research staff documented demographic characteristics, obstetric and medical history, and data for pregnancy and delivery until the day of discharge from hospital of both mother and baby. Data were entered in an online electronic case report form by research nurses and midwives (Oracle Clinical version 4.5.3; Redwood City, CA, USA).

Bronchopulmonary dysplasia was diagnosed according to the international consensus guideline as described by Jobe and Bancalari at time of discharge home or at 36 weeks of corrected gestational age.20 Culture-proven sepsis was diagnosed based on clinical signs and a positive culture of the blood sample. Intraventricular haemorrhage and periventricular leukomalacia were diagnosed by repeated neonatal cranial ultrasound by the neonatologist according to the guidelines on neuroimaging described by de Vries and colleagues21 and Ment and colleagues.22 Necrotising enterocolitis was staged by methods reported by Bell.23

All perinatal deaths were assessed by a panel of two neonatologists and two consultant obstetricians who were not involved in the trial. The members individually reviewed all cases of perinatal death while remaining blinded to the administered study drug. They assessed whether the perinatal deaths could be causally related to the study drug using WHO categories of: certain, probable, possible, unlikely, conditional, and non- assessable.24 When at least a 75% consensus was reached the conclusion was considered valid.

Outcomes

The primary outcome measure was a composite of adverse perinatal outcome composed of perinatal in- hospital mortality and the following severe perinatal morbidities: bronchopulmonary dysplasia, culture- proven sepsis, intraventricular haemorrhage higher than grade 2, periventricular leukomalacia higher than grade 1, and necrotising enterocolitis higher than Bell’s stage 1 

Figure 1: Study profile 

All babies with one or more of these outcomes before hospital discharge were deemed to have met the primary outcome criteria. Prespecified secondary outcome measures on the maternal level were gestational age at delivery; time from randomisation to delivery (prolongation of pregnancy); and rates of maternal death and side-effects leading to discontinuation of study drug. Prespecified secondary outcomes on the neonatal level were the individual components of the composite perinatal outcome (bronchopulmonary dysplasia, culture- proven sepsis, intraventricular haemorrhage higher than grade 2, periventricular leukomalacia higher than grade 1, and necrotising enterocolitis higher than stage 1); days of stay in a neonatal intensive-care unit (NICU) after birth; days of ventilation support after birth; total days in hospital until corrected age 3 months; number of babies with apnoea; number of babies with asphyxia; number of babies with proven meningitis; number of babies with pneumothorax; and number of babies with convulsions.
Secondary outcomes were assessed up to discharge of the baby from hospital unless otherwise specified.

Statistical analysis

We designed the trial to detect a reduction in the prevalence of the primary outcome from 25% to 15%. We calculated that we would need to enrol 500 women (250 in each group) to provide a power of 80% at a two-sided significance level of 0·05.

Primary and secondary outcomes were analysed in the modified intention-to-treat population; all women and babies with follow-up data were included. We assessed the primary outcome on a neonatal level with a generalised estimating equations model (GEEs) for binomial data with a log-link function and using an unstructured correlation matrix, resulting in a calculated relative risk (RR) and 95% CI. We accounted for interdependence between outcomes in multiple pregnancies by considering the mother as a cluster variable.25 Secondary outcomes on 

the neonatal level were calculated in a similar way to the primary outcome. Continuous outcomes on the neonatal level were assessed with linear quantile mixed models with mother as the grouping variable, resulting in a median difference with 95% CI. Prolongation of pregnancy and gestational age at delivery were evaluated by Cox proportional hazards regression and Kaplan-Meier estimates, accounting for differing gestational age at entry, and tested with the log-rank test. Gestational age at delivery was censored at 37 weeks of gestation because the interest of the effectiveness of tocolytic therapy is mainly focused on preterm birth and not necessarily on overall gestational age at delivery. The proportional hazards assumption was verified by plotting Schoenfeld residuals over time.26 Outcomes on the maternal level were assessed by a binomial regression model with log-link function.

We analysed the following subgroups: PPROM status (PPROM vs intact membranes), gestational age at randomisation (<30 weeks vs ≥30 weeks), number of fetuses (multiple vs singleton pregnancies), and history of preterm birth (yes vs no). Subgroup effects were investigated for adverse perinatal outcome and prolongation of pregnancy. Subgroup effects were assessed by including an interaction term between the subgrouping variable and treatment allocation as covariate to the regression model. When the interaction term was statistically significant (pinteraction<0·05) a stratified subgroup analysis was done to study the effect of treatment in different strata of the subgroups. Furthermore, the effect of the treatment was assessed in women with a positive fibronectin test, and those with a cervical length <10 mm.

We did a planned interim analysis based on the outcomes of 145 women, at which the data safety monitoring committee noted no conditions to stop the trial. All analyses were adjusted for the interim analyses with the O’Brien- Fleming α spending function. As a result, we deemed a nominal p value of less than 0·049 as indicative of statistical significance. We corrected 95% CIs to account for this by using an α of 0·049 instead of 0·05 for their calculation.

Serious adverse events (perinatal death, maternal mortality or severe maternal morbidity, including intensive-care unit admission) were reported to the central committee on research involving human subjects and to the ethics committee of the Academic Medical Centre, Amsterdam. We analysed data with R, version 3.1.1; specifically, we did GEE using the gee library and did linear quantile mixed models using the lqmm library. We used a data safety and monitoring committee composed of four independent academics from the Acadamic Medical Centre, Amsterdam and the University Medical Centre, Leiden. The study is registered at the Dutch Clinical Trial Registry, number NTR2947.

Role of the funding source

The funder of the study, ZonMw, had no role in study design, data collection, data analysis, data interpretation, 

Figure 2: Time to delivery HR=hazard ratio. 

or writing of the report. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication.

Results

Between July 6, 2011, and July 7, 2014, we enrolled 510 women. We randomly assigned 254 women to the nifedipine group and 256 to the atosiban group (figure 1, table 1). The last measure of outcomes was on Sept 11, 2014. Outcome data were available for 248 women in the 

Figure 3: Time to delivery in women without PPROM PPROM=preterm premature rupture of membranes. HR=hazard ratio.

nifedipine group and 255 in the atosiban group, corresponding to 297 and 294 babies, respectively (figure 1).

In the primary analysis, 42 (14%) of 297 babies in the nifedipine group and 45 (15%) of 294 in the atosiban group had the adverse perinatal outcome (RR 0·91, 95% CI 0·61–1·37; table 2). Gestational age at delivery was similar between the groups (table 2). Median prolongation of pregnancy was 7 days (IQR 1·0–40·0) for women in the nifedipine group and 4 days (1·0–38·0) for those in the atosiban group, with the Kaplan-Meier curve of time to pregnancy showing no significant difference (figure 2). The Schoenfeld residuals for gestational age at delivery and prolongation of pregnancy showed a random pattern with time, indicating the proportional hazards assumption is realistic (data not shown).

The individual rates of bronchopulmonary dysplasia, sepsis, intraventricular haemorrhage, periventricular leukomalacia, and necrotising enterocolitis were similar between groups (table 2). 16 (5%) babies died in the nifedipine group and seven (2%) babies died in the atosiban group (RR 2·20, 95% CI 0·91–5·33). A panel of experts independently assessed these deaths and classified all as unlikely to be caused directly by the study drug (appendix).

In the nifedipine group, 155 (52%) babies were admitted to the NICU, compared with 182 (62%) in the atosiban group (RR 0·85, 95% CI 0·73–0·99, table 2). 42 (14%) of the babies in the nifedipine group needed ventilation support, compared to 53 (19%) babies in the atosiban group (RR 0·76, 95% CI 0·51–1·12). Days on ventilation, time in hospital, and rates of apnoea, asphyxia, meningitis, and pneumothorax in babies also did not differ (table 2). We did not collect data for convulsions because the study group decided it was not clinically relevant.

No women died. 74 women (30%) in the nifedipine group and 75 (29%) in the atosiban group discontinued the study drug (RR 1·01, 95% CI 0·77–1·32), mainly due to progression into labour (table 2). Side-effects leading to discontinuation of study drug were reported in 15 (6%) women in the nifedipine group and seven (3%) in the atosiban group (table 2). Side-effects and adverse events in women were similar between group assignments and are listed in table 3.

In women without PPROM at study entry, time to delivery was longer in women assigned to treatment with nifedipine (median 24 days, IQR 4·0–54·8) than for those assigned to atosiban (14 days, 2·0–51·5; figure 3; appendix). Adverse perinatal outcome rates did not differ between group assignments in women with and without PPROM (RR 0·90, 95% CI 0·56–1·43). No significant interactions were found between drug allocation and the adverse perinatal outcomes or prolongation of pregnancy for the other subgroups (appendix); hence no effect sizes were calculated in different strata of the subgroups. No significant effects of treatment assignment were found in women with a positive fibronectin test or a cervical length smaller than 10 mm (appendix). 

Discussion

In this multicentre, randomised controlled trial, we show that 48 h of tocolysis with nifedipine and atosiban resulted in similar rates of adverse perinatal outcomes in babies born to women with threatened preterm birth. Unexpectedly, a non-significant higher perinatal mortality rate was found in the nifedipine group (table 2). This finding is of concern and warrants more investigation into the use of this tocolytic drug. Almost all neonatal and maternal secondary outcomes were similar; however, NICU admittance rates were lower in the nifedipine group (52%) than in the atosiban group (62%; RR 0·85, 95% CI 0·73–0·99).

Our study has several strengths. First, our primary outcome measure reflects the main goal of tocolysis, which is to improve neonatal outcome and not prolongation of pregnancy in itself. Previous trials on this topic were not sufficiently powered to examine neonatal outcomes.16–18 Second, to our knowledge this is the largest randomised controlled trial to directly compare the effectiveness and safety of the widely used tocolytic drugs nifedipine and atosiban in a multicentre setting. Third, we aimed to include women at high risk of preterm delivery. Indeed, more than half of the women in our study delivered within 7 days after inclusion, and more than 75% delivered preterm, a contrast with previous trials in which most women did not deliver shortly after randomisation.^17,18 

Our study also has some limitations. Because of the different administration routes of the interventions (oral vs intravenous), our study was not masked. This factor might have caused bias, although it is unlikely to have an impact on the main outcomes of the study since all women received an active drug and since our outcome measures could be objectively assessed. Second, perinatal death was part of our composite outcome measure. Although the use of a composite outcome is common practice and can help to make statistically reliable comparisons with a smaller population, it also has a limitation since it ignores clinical differences in the components of the composite outcome, and considers more severe (eg, death) and less severe outcomes (eg, bronchopulmonary dysplasia) as equal. Also, certain mechanisms can have different effects on parts of the composite outcome; for example, prolongation of pregnancy could improve respiratory perinatal outcome but lead to more fetal deaths due to circulatory instability. Our study was not powered to reliably assess the treatment effect on the level of the individual components of the composite outcome.

Subgroup analyses showed a longer duration of pregnancy in women without ruptured membranes who were treated with nifedipine (appendix). However, this prolongation of pregnancy did not improve perinatal outcomes. A statistically non-significant, but possibly clinically relevant, increase in neonatal death was noted in the nifedipine group, although the expert panel could not find a direct causal association between the drugs and mortality (table 2; appendix). It could be postulated that the administration of nifedipine in pregnant women has an adverse effect on the fetus, for example by lowering maternal blood pressure and reducing placental perfusion. Animal studies have described changes in uterine blood flow and occurrence of fetal acidaemia, but studies in humans showed no adverse effects on umbilical artery blood flow or fetal movements.28–35 Investigators have reported fetal death after tocolysis with nifedipine, most likely due to maternal hypotension.36 A prospective cohort study from the Netherlands and Belgium concluded that maternal adverse events, mainly hypotension and tachycardia, were more frequent with the use of nifedipine.37 In our study, no severe maternal side-effects were observed and review of the charts of the perinatal deaths did not reveal any deaths in which mothers had severe hypotension (appendix). However, the safety of nifedipine in pregnancy has not been studied extensively, and worldwide nifedipine is not registered for use in pregnancy.38 This fact is of concern, especially since nifedipine is recommended as a first-line tocolytical drug in international guidelines.39,40 Since our expert panel could not find a direct causal association between the drug and deaths, we could not find evidence in our study for a clinical effect of the proposed pathophysiological mechanism.

Atosiban has a favourable reported adverse event profile and is registered for the use in pregnancy in many countries; however, it is not readily available throughout the world. The costs of atosiban also exceed the costs of other tocolytic drugs such as nifedipine. Most importantly, the debate about the effectiveness and safety of tocolysis in general is inconclusive. There is little proof that tocolysis, and thereby prolongation of pregnancy in threatened preterm birth in general, improves perinatal outcome and it might even be harmful.13,41 This dearth was recognised by an international panel of experts who advised in the new WHO guidelines against the use of any tocolytics other than to facilitate intrauterine transfer.42 We therefore recommend the initiation of large placebo-controlled trials to assess treatment of preterm labour, with adverse perinatal outcome being the primary outcome.

Contributors

MAO, BWM, BCO, and JHK conceived of and designed the study. MAO, BWM, TAJN, ES, and EOGvV drafted the manuscript and analysed and interpreted the data. All authors are members of the APOSEL III study group or collaborators, were local investigators at the participating centres, and participated in the design of the study during several meetings. All authors edited the manuscript and read and approved the final draft.

Declaration of interests

BWM is a consultant for ObsEva, Switzerland; payments go to The Robinson Research Institute, Adelaide. All other authors declare no competing interests.

Acknowledgments

This study was funded by ZonMw, the Netherlands Organization for Health Research and Development Healthcare Rational Medicine program, project number 836011005. We thank the research nurses, midwives, and administrative assistants of our consortium; and the residents, nurses, midwives, and gynaecologists of the participating centres for their help with participant recruitment and data collection. We give special thanks to the members of the data safety monitoring committee J G P Tijssen, F M Helmerhorst, T R de Haan, and

J H van der Lee, for monitoring the trial and evaluating the interim analysis. We thank H A A Brouwers, J J H M Erwich, L van Toledo, and A C C Evers for their evaluation of perinatal mortality in our study.
We give many thanks to all the women who participated in this study. 

References

1. Blencowe H, Cousens S, Chou D, et al. Born too soon: the global epidemiology of 15 million preterm births. Reprod Health 2013; 10 (Suppl 1): S2.

2. Treyvaud K, Lee KJ, Doyle LW, Anderson PJ. Very preterm birth influences parental mental health and family outcomes seven years after birth. J Pediatr 2014; 164: 515–21.

3. Bolisetty S, Bajuk B, Abdel-Latif ME, Vincent T, Sutton L, Lui K. Preterm outcome table (POT): a simple tool to aid counselling parents of very preterm infants. Aust N Z J Obstet Gynaecol 2006; 46: 189–92.

4. Ananth A, Cintzileos A. Epidemiology of preterm birth and its clinical subtypes. J Matern Fetal Neonatal Med 2006; 19: 773–82.

5. Goldenberg RL, Culhane JF, Iams JD, Romero R. Epidemiology and causes of preterm birth. Lancet 2008; 371: 75–84.

6. KeirseMJ.Thehistoryoftocolysis.BJOG2003;110(suppl20):94–97. 

7. Hehiri MP, O’Connor HD, Kent EM, et al. Early and late preterm delivery rates—a comparison of differing tocolytic policies in a single urban population. J Matern Fetal Neonatal Med 2012; 25(11): 2234–36.

8. Haas DM, Imperiale TF, Kirkpatrick PR, Klein RW, Zollinger TW, Golichowski AM. Tocolytic therapy: a meta-analysis and decision analysis. Obstet Gynecol 2009; 113: 585–94.

9. Haas DM, Caldwell DM, Kirkpatrick P, McIntosh JJ, Welton NJ. Tocolytic therapy for preterm delivery: systematic review and network meta-analysis. BMJ 2012; 345: e6226. 

10. Berkman ND, Thorp JM Jr, Lohr KN, et al. Tocolytic treatment for the management of preterm labour: A review of the evidence.
    Am J Obstet Gynecol 2003; 188: 1648–59.

11. Reinebrant HE, Pileggi-Castro C, Romero CL, et al. Cyclo-oxygenase (COX) inhibitors for treating preterm labour. Cochrane Database Syst Rev 2015; 6: CD001992.

12. Hammers AL, Sanchez-Ramos L, Kaunitz AM. Antenatal exposure to indomethacin increases the risk of severe intraventricular hemorrhage, necrotizing enterocolitis, and periventricular leukomalacia: a systematic review with metaanalysis. Am J Obstet Gynecol 2015; 212(4): 505–13. 

13. van Vliet EO, Boormans EM, de Lange TS, Mol BW, Oudijk MA. Preterm labour: current pharmacotherapy options for tocolysis. Expert Opin Pharmacother 2014; 15: 787–97.

14. Flenady V, Wojcieszek AM, Papatsonis DN, et al. Calcium channel blockers for inhibiting preterm labour and birth.
    Cochrane Database Syst Rev 2014; 6: CD002255.

15. Flenady V, Reinebrant HE, Liley HG, Tambimuttu EG,
    Papatsonis DN. Oxytocin receptor antagonists for inhibiting preterm labour. Cochrane Database Syst Rev 2014; 6: CD004452.

16.  Kashanian M, Akbarian AR, Soltanzadeh M. Atosiban and nifedipin for the treatment of preterm labour. Int J Gynaecol Obstet 2005; 91: 10–14.

17. Al-Omari WR, Al-Shammaa HB, Al-Tikriti EM, Ahmed KW. Atosiban and nifedipine in acute tocolysis: a comparative study.
    Eur J Obstet Gynecol Reprod Biol 2006; 128: 129–34.

18. Salim R, Garmi G, Nachum Z, Zafran N, Baram S, Shalev E. Nifedipine compared with atosiban for treating preterm labour:
    a randomised controlled trial. Obstet Gynecol 2012; 120: 1323–31.

19. van Vliet EO, Schuit E, Heida KY, et al. Nifedipine versus atosiban in the treatment of threatened preterm labour (Assessment of Perinatal Outcome after Specific Tocolysis in Early Labour: APOSTEL III-Trial). BMC Pregnancy Childbirth 2014; 14: 93.

20. Jobe AH, Bancalari E. Bronchopulmonary dysplasia.
    Am J Respir Crit Care Med 2001; 163: 1723–29.

21. de Vries LS, Eken P, Dubowitz LM. The spectrum of leukomalacia using cranial ultrasound. Behav Brain Res 1992; 49: 1–6.

22. Ment LR, Bada HS, Barnes P, et al. Practice parameter: neuroimaging of the neonate: report of the Quality Standards Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society. Neurology 2002; 58: 1726–38.

23. Bell MJ. Neonatal necrotizing enterocolitis. Ann Surg 1978; 187: 1–7. 

24. Meyboom RH, Hekster YA, Egberts AC, Gribnau FW, Edwards IR. Causal or casual? The role of causality assessment in pharmacovigilance. Drug Saf 1997; 17: 374–89.

25. Gates S, Brocklehurst P. How should randomised trials including multiple pregnancies be analysed? BJOG 2004; 111: 213–19. 

26. Schoenfeld D. Residuals for the proportional hazards regression model. Biometrika 1982, 69: 239–241.

27. Alfirevic Z. Tocolytics: do they actually work? BMJ 2012; 345: e6531.

28. Furuhashi N, Tsujiei M, Kimura H, Yajima A. Effects of nifedipine on normotensive rat placental blood flow, placental weight and fetal weight. Gynecol Obstet Invest 1991; 32: 1–3.

29. Harake B, Gilbert RD, Ashwal S, Power GG. Nifedipine: effects on fetal and maternal hemodynamics in pregnant sheep.
    Am J Obstet Gynecol 1987; 157: 1003–08.

30. Holbrook RH, Lirette M, Katz M. Cardiovascular and tocolytic effects of nicardipine HCl in the pregnant rabbit: comparison with ritodrine HCl. Obstet Gynecol 1987; 69: 83–87.

31. Blea CW, Barnard JM, Magness RR, Phernetton TM, Hendricks SK. Effect of nifedipine on fetal and maternal hemodynamics and blood gases in the pregnant ewe. Am J Obstet Gynecol 1997; 176: 922–30.

32. Mari G, Kirshon B, Moise KJ, Lee W, Cotton DB. Doppler assessment of the fetal and uteroplacental circulation during nifedipine therapy for preterm labour. Am J Obstet Gynecol 1989; 161: 1514–18.

33. Pirhonen JP, Erkkola RU, Ekblad UU, Nyman L. Single dose of nifedipine in normotensive pregnancy: nifedipine concentrations, hemodynamic responses, and uterine and fetal flow velocity waveforms. Obstet Gynecol 1990; 76: 807–11.

34. Guclu S, Saygili U, Dogan E, Demir N, Baschat AA. The short-term effect of nifedipine tocolysis on placental, fetal cerebral and atrioventricular Doppler waveforms. Ultrasound Obstet Gynecol 2004; 24: 761–65.

35. de Heus R, Mulder EJ, Derks JB, Visser GH. The effects of the tocolytics atosiban and nifedipine on fetal movements, heart rate and blood flow. J Matern Fetal Neonatal Med 2009; 22: 485–90.

36. van Veen AJ, Pelinck MJ, van Pampus MG, Erwich JJ.
    Severe hypotension and fetal death due to tocolysis with nifedipine. BJOG 2005; 112: 509–10.

37. de Heus R, Mol BW, Erwich JJ, et al. Adverse drug reactions to tocolytic treatment for preterm labour: prospective cohort study. BMJ 2009; 338: b744.

38. Khan K, Zamora J, Lamont RF, et al. Safety concerns for the use of calcium channel blockers in pregnancy for the treatment of spontaneous preterm labour and hypertension: a systematic review and meta-regression analysis. J Matern Fetal Neonatal Med 2010; 23: 1030–38.

39. Management of preterm labour. American College of Obstetricians and Gynecologist; Committee on Practice Bulletins. Obstet Gynecol 2012; 119: 1308–217.

40. RCOG. Tocolysis for women in preterm labour. London: Royal College of Obstetricians and Gynaecologists, 2011. https://www. rcog.org.uk/globalassets/documents/guidelines/gtg1b26072011.pdf (accessed May 12, 2015).

41. Simhan HN, Caritis SN. Prevention of preterm delivery. N Engl J Med 2007; 357: 477–87.

42. Vogel JP, Oladapo OT, Manu A, Gülmezoglu AM, Bahl R.
    New WHO recommendations to improve the outcomes of preterm birth. Lancet Glob Health 2015; 3: e589–90.