3 centres collaboration

Preterm Labour

Table of contents




    This guideline aims to provide consistent evidence-based advice on the management of preterm labour (PTL) at the three level six (tertiary) maternity services in Victoria. Namely, Mercy Hospital for Women, Monash Medical Centre and The Royal Women’s Hospital.

    This will be of significant benefit to the women being treated and for the service providers, who receive advice and support from these tertiary maternity hospitals.

    It is anticipated that this guideline will be used as a basis for the development of guidelines at other hospitals; which will take into account local service provision and the needs of the local population.

    Search and appraisal

    The following methods of search and appraisal were used: An Ovid platform database selection was made using Medline, Embase and Cochrane databases for evidence published in English, mostly from the year 2000 onwards.

    Professional body websites were also used, namely: American College of Obstetricians and Gynecologists (ACOG), Royal Australian and New Zealand College of Obstetricians and Gynaecologists (RANZCOG), Royal College of Obstetricians and Gynaecologists (RCOG), Society of Obstetricians and Gynaecologists of Canada (SOGC).

    Other websites accessed were: National Health and Medical Research Council (NHMRC), National Institute for Health and Clinical Excellence (NICE) and BMJ Best practice.

    Where international guideline groups have cited levels of evidence, these have been referred to in the summary boxes at the conclusion of each section. Also see Appendix 4. Evidence tables.

    Search terms used were: "Threatened preterm labour" (labor), "premature", "cervical insufficiency", "cervical shortening", "tocolytics", "preterm birth", "progesterone", "corticosteroids", "neuroprotection" and "fetal fibronectin".

    In the compilation of these recommendations, international guidelines and the results of systematic reviews were used to compare facets of care. Contemporary reviews and recommendations from professional bodies were also used. Individual randomized controlled trials were used if they were a high level of evidence using NHMRC evidence level grading criteria.

    Published guidelines from each of the three level six (tertiary) maternity hospitals were gathered, then compared and contrasted against the international reviews and guidelines.

    Following an iterative consultation process among key stakeholders from the three level six hospitals, a consensus of opinion was gained in most instances. In cases of conflicting points of view, a variance process was initiated whereby the Co-Chairs of the 3centres Collaboration made the final decision. 



    The World Health Organization defines preterm or premature birth as the birth of an infant before 37 completed weeks of gestation.1 However preterm birth at the earlier gestations have the most clinical impact. 

    Preterm labour can be confirmed in the following order: by gestation, (where accurate gestational dating is available from an early ultrasound scan) by the last menstrual period or in preterm birth, by fetal weight. The following generally accepted classifications can be useful for planning on-going management and predicting or discussing neonatal outcomes. 

    34- 37 weeks gestation: Preterm
    28-34 weeks gestation: Very preterm
    <28 weeks gestation: Extremely preterm

    There is no set lowest gestation to this definition, but 23–24 weeks gestation is widely accepted, which approximates to an average fetal weight of 500g.2 

    The care and management of women in labour on the cusp of viability (22-23 weeks) will not be covered in this guideline.


    Around 10% of all births in Australia are before 37 weeks gestation.3 Preterm birth, particularly at the lower gestations, is associated with an increased risk of perinatal mortality and morbidity, including disability in surviving children.4  

    Risk Factors

    One in three preterm births are unexplained and spontaneous (30%) however, one known association for idiopathic preterm labour, is low socioeconomic status.5,6,7

    Known risk factors for preterm labour and birth include: 

    • previous preterm birth
    • preterm rupture of membranes
    • multiple pregnancy 
    • antepartum haemorrhage
    • systemic infections 
    • genital tract infections 
    • cervical insufficiency
    • congenital uterine abnormalities

    Around 15-20% of preterm births are due to iatrogenic or elective preterm births, usually for maternal medical complications including hypertensive disorders or fetal growth restriction.8 

    Immediate management of threatened preterm labour

    If a preterm birth appears imminent and the woman is not aready in a hospital that
    can provide neonatal services appropriate for her gestation, immediately inform:



    On presentation, a thorough assessment of the woman should be undertaken and include:

    • the estimated date of delivery (EDD). The current gestational age should be established preferably by early ultrasound, (<14 weeks) which overrides the calculation of the EDD using the last normal menstrual period (LMP). If the first ultrasound has been performed >14 weeks, and differs by >7 days from the LMP, the EDD should be calculated from the LMP.9 
    • predisposing risk factors for preterm labour or birth 
    • symptoms of labour, such as contractions, ascertain their duration, strength and regularity
    • associated symptoms of labour, for example lower back pain
    • symptoms of ruptured membranes, antepartum haemorrhage or a “show”


    A maternal examination should be performed with a focus on the following:

    • maternal observations i.e. temperature, blood pressure and pulse.
    • abdominal palpation to assess uterine tone, tenderness or contractions; to assess duration, strength and regularity. 
    • palpation to assess fetal size, lie, presentation and station. 
    • vaginal speculum examination using sterile gloves and a sterile speculum. Sterile water should be used as a lubricant to allow the fetal fibronectin (fFN) test to be performed accurately (see below).10 
    • high vaginal swabs should be taken be taken for bacteriological assessment and a low vaginal/ano-rectal swab for group b streptococcus screen. 
    • digital vaginal examination to assess effacement, dilatation and station. If the membranes are thought to be ruptured, a digital examination should be avoided until labour is established. (also see www.3centres.com.auhttp://3centres.com.au/guidelines/PPROM)

    Note – In all situations, it is advisable to avoid a digital cervical examination until after a speculum examination has been performed so that a fFN test can be carried out; as a digital examination will affect the result of this test. 

    If the woman has a cervical suture and is in established preterm labour, confirmed by the presence of regular (painful) contractions, accompanied by cervical change or has preterm prelabour rupture of the membranes, prompt removal of the cerclage is indicated.  

    If time permits and transfer to a hospital that is able to provide neonatal services appropriate for her gestation is required, following consultation with PERS, it may be prudent to consider leaving the cerclage in situ and using tocolysis in transit.

    Fetal Fibronectin Test (fFN)

    Fetal fibronectin (fFN) is an appropriate screening test to use in women presenting with preterm uterine activity, to predict the likelihood of birth within the next 7 days. It may also assist in the decision-making regarding transfer of a woman to a hospital with neonatal facilities appropriate for her gestation.11

    A negative fFN test has a very high negative predictive value: 99.5% of women with a negative result will not give birth spontaneously in the 7 days following the test. 

    Because of the high negative predictive value for preterm birth, there is no evidence to support keeping a woman in hospital with a negative fFN test, unless her circumstances require admission or clinical situation changes significantly. 

    The predictive value of a positive fFN test is less clinically useful and may not enhance clinical decision making, with the positive predictive value of 13-30% for preterm birth in the next 7 days.12 

    Any cervical manipulation within the previous 24 hours, such as coitus, digital vaginal examination and transvaginal ultrasound examination, may affect the test outcome.

    Fetal fibronectin is also found in blood, semen and liquor, the presence of which may also cause a false positive result. However, this should not dissuade the clinician from performing the test, as a negative result in these circumstances can still be relied upon.

    If a symptomatic woman with a positive fFN result is not already in a hospital with appropriate neonatal facilities for her gestation, is symptomatic with a positive fFN result, the clinician is advised to consult with the Victorian Perinatal Emergency Referral Services (PERS) regarding the appropriateness for transfer. Tel: 1300137650.

    Fetal fibronectin table


    Other investigations

    Maternal investigations

    Dependent upon the woman’s gestation and if time permits, an ultrasound scan may be used to confirm presentation, assess fetal weight, morphology (if not already performed) and amniotic fluid index (AFI).

    A Full Blood Count (FBC) should be considered as part of a general screen for infection as a cause of preterm labour.

    A mid stream urine for laboratory culture and sensitivity should be collected. Other sources of infection should be considered and investigated as necessary.

    Fetal Investigations

    Cardiotocograph (CTG); Continuous electronic fetal heart rate monitoring should be used when a woman is in preterm labour.13 There is a possibility that fetal compromise has been the trigger for preterm labour and it is also possible that the preterm fetus will have reduced reserves and may be more susceptible to hypoxia associated with contractions. 

    CTG monitoring between 26-28 weeks is more difficult to interpret, as the physiological adaptations that affect the heart rate pattern in a term fetus, have not yet fully matured at this gestation. Preterm infants have a baseline heart rate towards the upper end of the range 110-160bpm. Accelerations have less amplitude and are of shorter duration.

    History, examination and investigations summary table




    If preterm birth less than 34 weeks is anticipated within the next 7 days, corticosteroids should be administered as soon as possible, unless birth is imminent. 

    Corticosteriods are now widely administered for prophylaxis against neonatal respiratory distress syndrome, a single course of betamethasone is given to women with a gestation of between 23 to 34 weeks. The course is administered as two intramuscular (I.M.) injections of 11.4 mg of betamethasone given 24 hours apart.14

    While there is compelling evidence that antenatal corticosteroids improve neonatal outcomes when used before 34 weeks gestation, to date the evidence for the optimal drug, dose, route and timing remain unclear.

    Antenatal corticosteroid use reduces neonatal death even when infants are born less than 24 hours after the first dose has been given.

    The results from one small trial suggest that dexamethasone is more effective in reducing the rate of neonatal intraventricular hemorrhage when compared with betamethasone. 

    Therefore, should betamethasone be unavailable, clinicians may choose to use dexamethasone as an alternative. It is administered as 6mg I.M. every 12 hours for 4 doses.15 

    There is currently insufficient evidence regarding the potential risks and long-term effects to recommend the use of repeated doses of corticosteroids in clinical practice, and results from trials with long-term follow-up are required. If a repeat dose of antenatal corticosteroid is contemplated, then caution is advised and senior obstetric opinion should be sought. 

    If the original indication for the risk of a premature birth is resolved, or 34 weeks gestation is reached, then no further doses are required.

    The results from the Australasian Collaborative Trial of Repeat Doses of Corticosteroids for the Prevention of Neonatal Respiratory Disease (ACTORDS) trial will further assist in guiding practice.16



    If the woman’s membranes are intact and there is no other indication for use, antibiotics should not be routinely given, as there is no evidence that they prolong gestation or improve neonatal outcomes. 

    Further, there is some evidence that suggests antibiotics in this instance are implicated in possible harm, with an increase in the number of children with functional impairment whose mothers were exposed to erythromycin. The use of amoxicillin/clavulanic acid in women with intact membranes has also been associated with an increase in the numbers of babies born with cerebral palsy and is therefore not recommended until further evidence can guide practice.17

    Antibiotics for systemic infection

    If there are signs of systemic infection or chorioamnionitis, the antibiotic treatment should be broad and given according to local protocols. There is no definitive drug or duration of treatment however, an example of a common treatment regimen is: 

    Amoxicillin or ampicillin 2 grams intravenously I.V. every 6 hours;

    Gentamicin 4 to 6mg/kg I.V. for one dose then a maximum of one or two further doses, based on renal function;

    Metronidazole 500 mg I.V. every 12 hours to provide additional anaerobic coverage. 

    In women allergic to penicillin, give: Clindamycin or Lincomycin 600mg I.V. every 8 hours.18

    Systemic infection antibiotics summary box


    Prophylactic antibiotics for Group B Streptococcus (GBS)

    If the woman is being treated for a systemic infection, the antibiotics prescribed should replace GBS-specific antibiotic prophylaxis.

    GBS specific antibiotics: Penicillin 1.2g I.V. bolus followed by 600mg I.V. every 4 hours. If the woman is allergic to penicillin, give Clindamycin or Lincomycin 600mg  I.V. every 8 hours.

    If a woman’s GBS status is unknown the following risk factors for GBS infection should guide treatment with appropriate antibiotics.

    • previous infant with early-onset GBS disease
    • GBS bacteriuria in the current pregnancy
    • Positive for GBS on a low vaginal anorectal swab in the current pregnancy
    •  prolonged rupture of membranes (an interval of 18 hours or more between rupture and birth)
    • preterm labour at less than 37 weeks of gestation
    • maternal temperature higher than 38 ̊C.

    Antibiotics are not indicated in the following circumstances:

    • regardless of GBS status- antibiotics are unnecessary if the membranes are intact, providing there is no systemic infection and if labour is not established.
    • antibiotic prophylaxis for GBS is also unnecessary for women with preterm rupture of membranes unless she is in established labour.  

    Prophylactic antibiotics for GBS summary box  




      The use of tocolysis to prolong pregnancy has not shown to improve perinatal morbidity or mortality. The primary indication of tocolytic treatment for women who are in preterm labour is to postpone birth for 48 hours in order to allow the optimal effect of maternal corticosteroid treatment. If required, it will also facilitate in the transfer of a woman to a hospital with neonatal facilities appropriate for her gestation.

      There is currently no evidence to support the role of maintenance therapy beyond the initial 48 hours.

      There is no high quality evidence to show that tocolysis improves perinatal outcomes. By suppressing labour in a potentially adverse fetal environment or with an unknown cause for the preterm labour, it could be harmful. For this reason some clinicians may choose not to use tocolysis. 


      If tocolysis is used, the tocolytic agent of choice unless contraindicated, is the calcium channel blocker nifedipine. While nifedipine is not approved for use in pregnancy and is classified as a risk category C drug by the Australian Drug Evaluation Committee, it is the most commonly used first line tocolytic therapy.19

      The onset of action is usually 30 – 60minutes. It is not recommended that a second line tocolytic drug be considered in the first two hours after giving nifedipine.


      Give an initial dose of 20mg of nifedipine tablet orally (not slow or controlled release nifedipine). 

      After 30 minutes, if contractions persist, give another 20mg nifedipine oral dose. 

      After a further 30 minutes, if still contracting, follow up with a further 20mg orally.

      If the woman’s blood pressure is stable, a maintenance dose of 20mg nifedipine orally, eight hourly for 48 hours may be given where indicated. The maximum dose of nifedipine is 160mg/day. 


      Half hourly maternal pulse and blood pressure until the contractions cease. Maternal hypotension should be treated with IV fluids in the first instance.

      Continuous electronic fetal heart rate monitoring should be carried out until contractions have settled. 


      Tocolysis should be used with extreme caution and in consultation with experienced advice in suppression of labour where there is an antepartum haemorrhage (APH), preeclampsia, abnormal fetal CTG recording, maternal cardiac disease including cardiac conduction defects, left ventricular failure and hypotension. 

      Clinicians must weigh the possibility of a preterm birth and the sequelae of a preterm infant against the risk of suppressing labour in order to gain time for fetal lung maturation, but with the possibility of a precarious maternal or fetal situation evolving. 

      While seldom reported in clinical practice, there is a potential interaction between magnesium sulphate (MgSO4) and nifedipine, resulting in hypotension and neuromuscular blockade effects. If severe hypotension occurs, nifedipine and MgSO4 administration should be ceased.

      Side effects 

      Numerous side effects to nifedipine use have been reported. These include: 

      • hypotension that may affect blood supply to the uteroplacental bed and cause an alteration in fetal heart rate. Maternal hypotension should be treated promptly and CTG monitoring used to observe the fetal effect. 
      • maternal facial flushing, headache, nausea, tachycardia, dizziness, and hypotension. 

      The clinician, in consultation with the woman must decide whether the benefits outweigh these unpleasant side-effects.

      Nifedipine regimen


      Tocolysis summary box


      Magnesium sulphate for neuroprotection

      Although high-level evidence is limited regarding the use of magnesium sulphate as a neuroprotectant, recent meta-analyses have suggested that magnesium sulphate given before preterm birth may be neuroprotective for the fetus.20

      It is not recommended that magnesium sulphate for neuroprotection is used for those women who are awaiting transfer or who are in transit to an appropriate hospital.

      Magnesium sulphate may be considered for use in women at high risk of birth before 30 weeks gestation, or whose birth is planned or anticipated within 24 hours and who are already in a hospital where neonatal facilities are appropriate for her gestation, irrespective of:

      • the number of babies in utero 
      • the reason the woman is in preterm labour
      • the parity
      • the anticipated mode of birth
      • whether or not corticosteroids have been given   

      If it has been decided to give MgSo4 then the recommended dosing regimen is: 

      • a 4g loading dose given intravenously, slowly over 20-30 minutes
      • a 1 g/hour maintenance dose. 
      • This should be continued up until birth or for 24 hours, whichever comes first. 
      • If birth no longer appears to be imminent the infusion is stopped, but can be restarted as indicated.21

      While seldom reported in clinical practice, there is a potential interaction between magnesium sulphate (MgSO4) and nifedipine, resulting in hypotension and neuromuscular blockade effects. If severe hypotension occurs, nifedipine and MgSO4 administration should be ceased.

      Magnesium sulphate for neuroprotection summary box



      Ensure that all documentation is contemporaneous and thorough. 


      If time permits, the woman and her family should have the opportunity to discuss the birth, management plan and expected outcomes for the infant once it is born. It is important to ensure the woman and her family are all adequately informed of the clinical situation, in a manner that they will understand.

      Longer term management of threatened preterm labour

      When the immediate assessment and management is complete and contractions have ceased, consider a transvaginal ultrasound examination for cervical length and assessment of fetal wellbeing, including biometry. If the fetus is found to be growth restricted, umbilical artery Dopplers to assess fetal well-being can also be performed.

       Subsequent pregnancy

      Women who have previously experienced a preterm birth, should be reviewed by an obstetric consultant in the next pregnancy. Dependant upon the circumstances of the preterm birth, additional tests, investigations and management options should be discussed and considered. 


      [1] World Health Organisation. Available from: www.who.int/reproductivehealth
      [2] Haas DM, Preterm Birth, BMJ Clin Evid (Online). 2008 Jun 2; 2008. www.clinicalevidence.bmj.com
      [3] Laws PJ, Li Z & Sullivan EA 2010. Australia’’s mothers and babies 2008. Perinatal statistics series no. 24. Cat. no. PER 50. Canberra: AIHW.
      [4] The Consultative Council on obstetric and paediatric Mortality and Morbidity (CCopMM) Annual report available from www. health.vic.gov.au/ccopmm/downloads/ccopmm_annrep07.pdf
      [5] Bloom SL, Yost NP, McIntire DD, et al. Recurrence of preterm birth in singleton and twin pregnancies. Obstet Gynecol 2001;98:379–385.
      [6] Durnwald CP, Walker H, Lundy JC, Iams JD. Rates of recurrent preterm birth by obstetrical history and cervical length. Am J Obstet Gynecol. Sep 2005;193(3 Pt 2):1170-4
      [7] Goldenberg R. et al, Epidemiology and causes of preterm birth The Lancet, 2008, Volume 371, Issue 9606, Pages 75-84
      [8] Iannucci TA, et al. Etiology and outcome of extremely low-birth-weight infants. Am J Obstet Gynecol 1996;174:1896–1902
      [9] Maternity and Newborn Clinical Network, Victorian standard for induction of labour. Depart. Of Health, Victoria. (undated) Available from: www.health.vic.gov.au/clinicalnetworks/downloads/maternity/victorian_standard_for_induction_of_labour.pdf
      [10] www.ffntest.com/pdfs/SpecimenCollectionMultilingual.pdf
      [11] Capability framework for maternity and newborn services, Dept. of Health, Victoria. Available from: www.health.vic.au/maternitycare
      [12] The Royal Australian and New Zealand College of Obstetricians and Gynaecologists, Use of cervical fetal fibronectin as a screening tool for preterm birth. College Statement. C-Obs 26. 2008 [Cited November 2010]. Available from: http://www.ranzcog.edu.au/publications/statements/C-obs26.pdf
      [13] RANZCOG Intrapartum Fetal Surveillance Clinical Guidelines. Available from: www.ranzcog.edu.au/fsep/practical_guide.shtml
      [14] Brownfoot FC, Crowther CA, Middleton P. Different corticosteroids and regimens for accelerating fetal lung maturation for women at risk of preterm birth. Cochrane Database of Systematic Reviews 2008, Issue 4. Art. No.: CD006764. DOI: 10.1002/14651858.CD006764.pub2
      [15] Elimian A, Antenatal betamethasone compared with dexamethasone (betacode trial): a randomized controlled trial. Obstet Gynecol. 2007 Jul;110(1):26-30
      [16] Crowther CA, Doyle LW, Haslam RH, Hiller JE, Harding JE, Robinson JS for the Australasian Collaborative Trial of Repeat Doses of Steroids (ACTORDS) Study Group  Outcomes at Age 2 Years following a Randomized Trial of Repeat Doses of Antenatal Corticosteroids, N Engl J Med 2007;357:1179-89
      [17] Kenyon S et al. Childhood outcomes after prescription of antibiotics to pregnant women with spontaneous preterm labour: 7-year follow-up of the ORACLE II trial. Lancet. 2008 Oct 1;372(9646):1319-27
      [18] Pelvic inflammatory disease: Severe infection [revised June 2010]. In: eTG complete [Internet]. Melbourne: Therapeutic Guidelines Limited; Accessed Feb. 2010 www.tg.org.au
      [19] King JF, Flenady V, Papatsonis D, Dekker G, Carbonne B. Calcium channel blockers for inhibiting preterm labour. Cochrane Database of Systematic Reviews 2003, Issue 1. Art. No.: CD002255. DOI: 10.1002/14651858.CD002255
      [20] Doyle LW, Crowther CA, Middleton P, Marret S, Rouse D. Magnesium sulphate for women at risk of preterm birth for neuroprotection of the fetus. Cochrane Database of Systematic Reviews 2009, Issue 1. Art. No.: CD004661. DOI: 10.1002/14651858.CD004661.pub3
      [21] The Antenatal Magnesium Sulphate for Neuroprotection Guideline Development Panel. Antenatal Magnesium Sulphate Prior to Preterm Birth for Neuroprotection of the Fetus, Infant and Child: National Clinical Practice Guidelines 2010 Feb. Available at: www.adelaide. edu.au/arch/antenatalMagnesium_SulphateGuidelines.pdf .

      Additional references sourced

      ACOG, Society for Maternal-Fetal Medicine. Committee Opinion No. 455: Magnesium sulphate before anticipated preterm birth for neuroprotection. Obstet Gynecol. 2010 Mar;115(3):669-71.

      V, Hayes E, Visintine J, Baxter JK. Fetal fibronectin testing for reducing the risk of preterm birth. Cochrane Database Syst Rev 2008:CD006843.

      Berghella V, et al, Gestational age at cervical length measurement and incidence of preterm birth. Obstet Gynecol. 2007 Aug;110(2 Pt 1):311-7

      Bloom SL, Yost NP, McIntire DD, et al. Recurrence of preterm birth in singleton and twin pregnancies. Obstet Gynecol 2001;98:379–385.

      Conde-Agudelo A, Romero R. Antenatal magnesium sulphate for the prevention of cerebral palsy in preterm infants less than 34 weeks' gestation: a systematic review and metaanalysis. Am J Obstet Gynecol. Jun 2009;200(6):595-609.

      Crowther CA. Hiller JE. Doyle LW. Haslam RR. Australasian Collaborative Trial of Magnesium Sulphate (ACTOMg SO4) Collaborative Group  - Effect of magnesium sulfate given for neuroprotection before preterm birth: a randomized controlled trial. JAMA. 290(20): pp. 269-76 (2003) 

      Farine D, et al, Maternal Fetal Medicine Committee, Society of Obstetricians and Gynaecologists of Canada. The use of progesterone for prevention of preterm birth. J Obstet Gynaecol Can 2008 Jan;30(1):67-71.

      Honest H, Bachmann LM, Gupta JK, Kleijnen J, Khan KS. Accuracy of cervicovaginal fetal fibronectin test in predicting risk of spontaneous preterm birth: systematic review. BMJ. 2002 Aug 10;325(7359):301

      Jobe AH, Soll RF. Choice and dose of corticosteroid for antenatal treatments. Am J Obstet Gynecol. 2004;190:878.

      Newnham J, et al. Should we be prescribing repeated courses of antenatal corticosteroids? Semin Fetal Neonatal Med. 2009 Jun;14(3):157-63. Epub 2008 Dec 21. Gynecol. 2007 Aug;110(2 Pt 1):311-7.

      Queensland Statewide Maternity and Neonatal Clinical Guideline: Assessment and management of preterm labour Available from: www.health.qld.gov.au/cpic/documents/matguide_preterm4.2.pdf.

      The Royal Australian and New Zealand College of Obstetricians and Gynaecologists (2006) Intrapartum Fetal Surveillance Clinical Guidelines available from: www.ranzcog.edu.au/publications/womenshealth

      Appendix 1. Assessment and management of preterm labour: Flowchart

      (Print as a pdf)


      Appendix 2. Levels and grades of evidence

      NHMRC body of evidence matrix

        RCOG levels and grades of evidence 


        SOGC levels of evidence


        BMJ Clinical Practice evidence levels


        BMJ Clinical Evidence search and appraisal June 2007. The following databases were used to identify studies for this systematic review: Medline 1966 to June 2007, Embase 1980 to June 2007 and The Cochrane Library (all databases) 2007, Issue 2. Additional searches were carried out using these websites: NHS Centre for Reviews and Dissemination (CRD) for all databases, Turning Research into Practice (TRIP), and NICE. Abstracts of the studies retrieved from the initial search were assessed by an information specialist. Selected studies were then sent to the author for additional assessment, using pre-determined criteria to identify relevant studies. Study design criteria for inclusion in this review were: published systematic reviews and RCTs in any language, at least single blinded (if possible), and containing at least 20 individuals of whom more than 80% were followed up. There was no minimum length of follow-up required to include studies. We excluded all studies described as “open”, “open label”, or "not blinded" unless blinding was impossible. In addition we use a regular surveillance protocol to capture harms alerts from organisations such as the FDA and the UK Medicines and Healthcare products Regulatory Agency (MHRA), which are added to the reviews as required. We have performed a GRADE evaluation of the quality of evidence for interventions included in this review.