preterm labour

preterm labour is a major obstetrical syndrome
we need to understand and try to prevent and treat preterm labour for better outcomes

1. Tocolysis in Preterm Labour Narendra Malhotra Jaideep malhotra Neharika Malhotra Bora [email protected] www.rainbowhospitals.org

2. Preterm Labor Preterm labor is defined as the onset of uterine contraction of adequate strength and frequency to cause progressive dilatation and effacement of cervix between 20 and 37 weeks of gestation 1 Preterm labor is one of the leading cause of perinatal morbidity and mortality 2 Preterm delivery effects almost 23% pregnancies in developing countries like India 3 Revisiting the use of Isoxsuprine in Preterm Labor – Indian Consensus Document by ISSRF BJOG. Volume 120, Issue 13 December 2013 Pages 1588–1598 International Journal of Basic and Applied Medical Sciences ISSN: 2277 : An Open Access, Online International Journal2015 Vol. 5 (3) September 2

3. Epidemiology -The WHO 2013 fact sheet 3 Internet: 15 Million babies born too soon. http://www.who.int/mediacentre/news/releases/2012/preterm_20120502/en/ : Accessed on 14 Jan 2017

4. Epidemiology of Preterm birth. Globally, prematurity is the leading cause of newborn deaths and the second leading cause of death after pneumonia in children under the age of five. India is the biggest contributor to the world ’ s prematurity burden, with almost 3.6 million premature births—accounting for 23.6% of the around 15 million global pre-term births—reported each year. Of these, 13% are live pre-term births.

5. Causes of PRETERM births

6. The Lancet Editorial 2006;368:339

7. IOM Report – July 2006 “ Babies born before 32 weeks have the greatest risk for death and poor health outcomes, however, infants born between 32 and 36 weeks, which make up the greatest number of preterm births, are still at higher risk for health and developmental problems compared to those infants born full term IOM Report page 72

8. Frequency of preterm birth by gestational age < 28 weeks : 0.82 % < 32 weeks: 2.2 % 33-36 weeks: 8.9 % < 37 weeks: 11.2 IOM Report-July 2006- page 72/2006 Alexander GR et al 2006 (under review) Cold Stress Hypoglycemia RDS Jaundice Sepsis Complications of “ Late Preterm or Near Term Infants ”

9. Clinical Circumstances Associated with Preterm Birth Spontaneous preterm labor with intact membranes Preterm PROM Indicated preterm delivery Maternal (e.g. pre-eclampsia) Fetal (e.g. SGA/fetal compromise)

10. Risk Factors Revisiting the use of Isoxsuprine in Preterm Labor – Indian Consensus Document by ISSRF 11

11. Mechanism of Preterm Labor Causes Mechanism • Stress • Premature activation of physiological effectors Activation of maternal-fetal HPA-axis • CRH → Fetal adrenal androgens • Placental estrogen and progesterone • Inflammation and infection • Pro-inflammatory cytokines • Fetal inflammatory response syndrome • Ischemia or hemorrhage • Thrombin activation • Pathological Uterine distension • Increased gap junction along with contraction associated protiens and upregulation of prostaglandins and oxytocin receptors Revisiting the use of Isoxsuprine in Preterm Labor – Indian Consensus Document by ISSRF 12

12. Common Uterine Features of Term and Preterm Labor Increased myometrial contractility Cervical ripening (dilatation and effacement) Decidual /membrane activation Romero R, Mazor M, Munoz H et al: The Preterm Labor Syndrome. Ann NY Acad Sci 1994;734:414 Term Labor Preterm Labor

13. Common Pathway of Parturition Anatomic, physiologic, biochemical, endocrinologic, immunologic, and clinical events in the mother and/or fetus in both term and preterm labor Romero R, Mazor M, Munoz H et al: The Preterm Labor Syndrome. Ann NY Acad Sci 1994;734:414

14. Synchronous and Asynchronous Activation of Labor Cervical Ripening Uterine Contractility Membrane- Decidual Activation Preterm PROM Preterm Contractions Cervical Insufficiency © VR RR MM

15. Common Terminal Pathway Normal Term Labor Physiologic Activation Preterm Labor Pathologic Activation © VR RR MM

16. What causes pathologic activation of the pathway ?

17. Placental Pathology in Prematurity Arias et al. Obstet Gynecol 1997;69:285. © PJS

18. And one of the 5 “p” syndromes (AOFOG) preterm,premature,prom,pih,pph “ Great Obstetrical Syndromes ” Romero R J Prenat Neonat Med 1996;1:8-11

19. The Preterm Parturition Syndrome Uterine Overdistension Vascular Infection Cervical Disease Hormonal Immunological © VR RR MM Unknown

20. Frequent: 25 % (at presentation) Sub-clinical Fetal disease FIRS Host defense Intraamniotic Infection

21. 12% of preterm labor 20% of preterm PROM Sub-clinical Clinical Chorioamnionitis

22. Severe neonatal morbidity Impending preterm delivery Fetal multisystem involvement FIRS © VR RR MM

23. Fetal Inflammatory Response Syndrome Hematologic Abnormalities Endocrine System Cardiac Dysfunction Pulmonary Injury Renal Dysfunction Brain Injury (PVL)

24. Prediction of preterm labor 1. Risk factors . 2. Home uterine activity monitoring (HUAM) . 3. Cervical ultrasonography ( Cx . Length assessment) . 4. Salivary estriol . 5. Screening for bacterial vaginosis (BV) . 6. Screening for fetal fibronectin ( fFN ) . ( Edwin and Sabaratnam . 2005)

25. Screening for PRETERM labour Uterine contraction monitoring Colton and Associates US preventive service task force Cervical screening by TVS( sogc ) Cervical length (less than 25mm) Cervical Funneling Fetal Fibronectin ( 50ng/ml ) RCOG 23 rd edition Williams Obstetrics ACOG Practice Bulletin Vol.120 no.4 N Engl J Med 1998;338:15–9. (Level I)

26. Preterm Management Management Preventive Definitive

27. Prevention of Preterm Labor/Delivery Important and desirable goal Only proven beneficial strategy is eradication of asymptomatic bacteriuria Limited attributable risk Patients with previous preterm birth are at increased risk for recurrence Role of prophylactic isoxsuprine (retard preperations ) Potential beneficial effect of progesterone administration 17OHP-C and vaginal progesterone Cerclage in short cervix

28. The Preterm Parturition Syndrome Uterine Overdistension Vascular Infection Cervical Disease Hormonal Immunological © VR RR MM Unknown

29. Component Test Treatment Myometrium Uterine Monitor Tocolysis Ultrasound Cerclage Cervix Approaches for the Prevention of Preterm Birth Fetal Fibronectin Antibiotics Membrane/Decidua © VR RR MM Is preterm labor simply “ labor before its time ” ?

30. Prevention PROHYLACTIC TOCOLYSIS There is no clear evidence that tocolytic drugs improve outcome and therefore it is reasonable not to use them. However, tocolysis should be considered if the few days gained would be put to good use, such as completing a course of corticosteroids or in utero transfer.

31. Progesterone in Pregnancy Maintenance Myometrial quiescence Down-regulate gap junction formation Inhibit cervical ripening

32. Short Cervix with TVS Singleton Multiple Low risk Group Vaginal Progesterone offered if Cx 20mm or less at or before 24 weeks High risk Group and receiving progesterone since 16-34wks Cerclage should be considered if cervical length is less than25 mm before24 weeks of gestation No intervention improves outcome ACOG

33. Cervical Circlage History Indicated Circlage Only if 3 or more previous preterm or 2 nd Trimester loss (15% vs 32% p<0.005) Not offered if 2 or less previous preterm or 2 nd trimester loss (14% vs 17% & 12% vs 14%) H/O painless cervical dilatation, rupture of membrane before onset of contraction and additional risk factors are not helpful for decision to place History indicated circlage Usg Indicated If Cx is ≤25mm circlage is not indicated if no H/O spontaneous preterm or 2 nd trimester loss ( 22% vs 26%; RR 0.84; 95% CI 0.54 -1.3; p=0.44) Women with singleton pregnancy without Spontaneous Midterm loss or preterm birth should not be offered usg indicated circlage IF Cx is ≤25mm before 24 weeks gestation USG indicated circlage not recommended for funneling of cervix in absence of cervical shortening≤25mm Rescue Cerclage – Cx dilated >1-2cm with or without perceived ut . Contractractions ( with or wihtout membrane bulging)

34. “ Progesterone deficient state ” has been proposed to be a Mechanism of Disease in Preterm Labor

35. Progesterone is “ indispensable ” for normal pregnancy Progesterone withdrawal is a prerequisite of normal pregnancy termination

36. A progesterone withdrawal “ prepares ” the uterus for the action of uterotonic agents

37. Working Classifications < 28 weeks Cerclage /progesterone/ tocolysis 28 - < 32 weeks Progesterone/ tocolysis 32 - < 37 weeks tocolysis The majority of the preterm infants belong to the late preterm subgroup ( Marken et al., 2008) .

38. Criteria for Efficacy Prevention of preterm birth 37 weeks 35 weeks 32 weeks Prolongation of pregnancy Neonatal morbidity and mortality

39. Obstet Gynecol 2003;102:1115-6

40. Obstet Gynecol 2003;102:1115-6

41. FIGO IS NOW TRYING TO FIND A TEST TO PREDICT..FUNDED BY MARCH OF DIMES A key way to reduce pre-term numbers is to find ways to help all pregnancies continue to full term. A number of risk factors for pre-term birth have been identified, including a prior history of pre-term birth, being underweight/overweight, diabetes, hypertension, smoking, infection, maternal age (either under 17 or more than 40), genetics, multi- foetal pregnancy, and pregnancies spaced too closely together.

42. Criteria for PTL James 4 th Edition High Risk Pregnancy Chap. 61 pg-1075

43. Signs and symptoms of preterm labour Frequent contractions (more than four per hour) Cramping Pelvic pressure Excessive vaginal discharge Backache and Low back pain Non-specific symptoms Am Fam Physician. 1998 May 15;57(10):2457-2464 46

44. Diagnosis Clinical diagnosis is based on uterine contractions and vaginal examination: regular contractions (at least 1/10 minutes) which are associated with effacement and/or dilatation of the cervix. A cervical length <15 mm on TVS—is associated with an increased risk of spontaneous preterm birth. Uterine contractions monitoring by tocometer . Contractions of sufficient frequency and intensity to effect progressive effacement and dilation of the cervix: active preterm labor . Revisiting the use of Isoxsuprine in Preterm Labor – Indian Consensus Document by ISSRF 47

45. Diagnosis Continued …. Markers for Diagnosis of Preterm Labor Transvaginal ultrasonographic scanning (TVUSS) of cervical length. Assessment of cervicovaginal fetal fibronectin (FFN) levels has shown a sensitivity of about 80%. Revisiting the use of Isoxsuprine in Preterm Labor – Indian Consensus Document by ISSRF 48

46. Fetal fibronectin testing Sample : from the posterior fornix of the vagina Indications: 1 - Symptomatic preterm labour 24 - 36 weeks 2- Intact membranes and 3- Cervical dilatation less than 3 cm Contraindications: 1- Ruptured membranes 2- Vaginal bleeding 3- Cervical cerclage insitu Relative Contraindications: 1- After the use of lubricants or disinfectants 2- Within 24 hours of coitus or vaginal examination (The Royal Australian and New Zealand College of Obstetricians and Gynaecologists 2008)

47. Management of Preterm Labor Am Fam Physician. 1999 Feb 1;59(3):593-602 v Specific management Strategy Asses the patient 50

48. Management Contd ….. Revisiting the use of Isoxsuprine in Preterm Labor – Indian Consensus Document by ISSRF 51

49. Management Contd ….. Revisiting the use of Isoxsuprine in Preterm Labor – Indian Consensus Document by ISSRF 52

50. Treatment of premature labor Inhibition of uterine contractions with tocolysis Corticosteroids to induce fetal lung maturation Treatment of infection with antibiotics Bed rest and hospitalization. (Schleußner.2013)

51. Definitive Corticosteroid Administration Single dose antenatal corticosteroids to women between 24-34 weeks with High risk of preterm birth (level 1++) Ante-natal corticosteroid can be considered for women between 23 rd and 23 +6 (level 2) Ante-natal corticosteroid should be given to all women whom an elective caesarean section planned prior to 38weeks. (level 2) Green-top Guideline no.7 RCOG

52. Antibiotics : In PROM Routine use reduces maternal and neonatal morbidity (level 1a) Choice of antibiotic any penicillin (except co- amoxiclav ) or erythromycin for 10days In Preterm Labour (membrane intact) Use of antibiotic is not at all recommended Kenyon & colleagues study shows neonatal exposure to antibiotic more prone to cerebral palsy at age 7 than non exposed

53. Neuroprotection Magnesium Sulphate Administration of MgSO 4 significant reduction in cerebral palsy in gestation age before 28weeks ( rouse et al ) Administration of MgSO 4 before 30weeks of gestation ( University of Adelaide ) Administration even for multiple gestation For expected delivery within 24hour Even in PROM Can be administer 4hour before delivery ( Australian guidelines )

54. The perfect tocolytic is uniformly effective with complete fetomaternal safety Does it exist ?? does not exist

55. Tocolysis : There is no clear evidence that tocolytic drug improve outcome therefore it is reasonable not to use them. (level A) - Use them only to gain few days would be put to good use such as corticosteroid course or in- utero transfer Tocolytic drug not associated with clear reduction in perinatal or neonatal mortality or morbidity (level A) Not recommended in suspected preterm labour who had otherwise uncomplicated pregnancy Only in those who benefit by gaining time to Hosiptal or NICU transfer or not completed steroid course

56. Tocolysis Aim of tocolysis : Suppress uterine contractions and delay preterm delivery to : 1-allow in- utero transfer to an appropriate level facility . 2-allow for the administration of corticosteroids and MAG SULF for neuroprotection (King .,et al.2003)

57. Tocolysis Tocolytic therapy may offer some short-term benefit in the management of preterm labor. Can offer time to Administer corticosteroids to enhance pulmonary maturity Reduce the severity of fetal respiratory distress syndrome, and To reduce the risk of intraventricular haemorrhage. Facilitate transfer of the patient to a tertiary care center . Am J Obstet Gynecol. 2004;190:702-706

58. Tocolysis Contd …. Revisiting the use of Isoxsuprine in Preterm Labor – Indian Consensus Document by ISSRF 61

59. Tocolysis Contraindications : Gestation > 34 weeks Labour is too advanced In utero fetal death Lethal fetal anomalies Suspected fetal compromise Placental abruption Suspected intra-uterine infection Maternal hypotension: BP < 90 mmHg systolic Relative contraindications : pre- eclampsia . Multiple pregnancy placenta praevia . Rupture of membrane (Di Renzo et al., 2007) c

60. Tocolytic Drugs Class Examples Beta agonists Isoxsuprine, Ritodrine, Terbutaline Oxytocin Antagonist Atosiban Nitric oxide donors GTN Calcium Channel Blockers Nifedipine Others Magnesium Sulphate Drugs. 1983 Sep;26(3):243-61 International Journal of Basic and Applied Medical Sciences ISSN: 2277 An Open Access, Online International Journal 2015 Vol. 5 (3) Septembe 63

61. Tocolytic Drugs contd … MECHANISMS OF ACTION OF DIFFERENT TOCOLYTIC DRUGS Beta mimetic s CCBs and Magnesium NO donors Oxytocin antagonists COX inhibitors 64

62. Tocolytic Drugs : Nifedepine and Atosiban has comparable effectiveness ( levelA ) Compared to β agonist nifedepine improves neonatal outcome ( levelA ) β agonist have higher side-effects ( levelA ) Nifedepine , Atosiban and COX inhibitor lesser side-effects( levelA ) comparing effectiveness is unclear There is insufficient evidence for any firm conclusions about whether or not tocolysis leads to any benefit in preterm labour in multiple pregnancy Maintenace therapy in threatened preterm is not recommended

63. Calcium channel blockers ( Nifedipine ) Dosage and administration : 30 mg loading dose,|then 10–20 mg every 4–6 h . Contraindications : . Cardiac disease . . Renal disease . . Maternal hypotension (< 90/50 mm Hg) . . Avoid concomitant use with magnesium sulphate . Maternal side effects : . Flushing, headache . . Nausea . . Transient hypotension . . Transient tachycardia . Fetal and neonatal side effects : . Sudden fetal death . . Fetal distress . ( Conde et al.,2011)

64. Atosiban ( Tractocile ) Dosage and administration : Initial bolus dose 6.75 mg over one minute, followed by an Infusion of 18 mg/h for 3 h and then 6 mg/h for up to 45 h. Contraindications : . None . Maternal side effects : . Nausea . . Allergic reaction . . Headache . Fetal and neonatal side effects : . None ( De Heus et al.,2009 )

65. Prostaglandin synthetase inhibitors ( Indomethacin ) Dosage and administration : loading dose of 50 mg rectally or 50-100 mg orally, then 25-50 mg orally every 6 hr × 48 hr. Contraindications : . Renal or Hepatic impairment Maternal side effects : . Nausea, heartburn gastritis . Renal impairment function . Increased PPHge . Headache, dizziness Fetal and neonatal side effects : . Constriction of ductus arterious . Pulmonaryhypertension . Oligohydramnios , . Intraventricularhemorrhage . Hyperbilirubinemia , . Necrotizing enterocolitis ( Haas et al.,2009 )

66. Nitric oxide dono rs Dosage and administration : 10 mg patch for every 12 hr continuing until contraction cease up to 48 hours Contraindications : . Headache Maternal side effects : . Headache . . Hypotension . Fetal and neonatal side effects : . Neonatal hypotension ( Smith et al.,2007 )

67. Magnesium sulfate Dosage and administration : Loading dose: 4g MgSO 4 as a SLOW BOLUS over 15-30 minutes Maintenance dose: 1g/hr. for 24/hr. ( Stop infusion if: RR<12 ,Hypotension ,loss of Patellar reflexes & UOP<100ml in 4hours ) Contraindications : 1- Hypersensitivity . 2- Hypermagnesemia & Hypercalcemia . 3- Myocardial damage, Diabetic coma, Heart block . Side effects : Magnesium toxicity include : 1- Hypotension & Hypothermia . 2- Cardiac and Central nervous system depression 3- Respiratory paralysis . ( Overdose is treated with 10ml of 10% Calcium Gluconate i.v . over 10 minutes ) (Lowes 2013)

68. Betamimetics Dosage and administration : 1- Terbutaline 0.25 mg subcutaneously every 20 min. to 3 hr . 2- Ritodrine initial dose of 50-100 μ g/min i.v ., increase 50 μ g/min every 10 min until contractions cease or side effects develop, maximum dose = 350 μ g/min Contraindications : . Uncontrolled thyroid desease , & diabetes mellitus . Cardiac arrythmias ( Anotayanonth et al.,2010 ) Maternal side effects : . Hypokalemia . Hyperglycemia . Hypotension . Pulmonary edema . Arrhythmias . Myocardial ischemia Fetal and neonatal side effects : . Tachycardia. . Hyperinsulinemia . Hyperglycemia

69. Isoxsuprine Beta- sympathomimetics have been most frequently used to arrest preterm labour Isoxsuprine hydrochloride was the first beta-agonist used to arrest preterm labour Potent Vasodilator DCGI Approved drug ACOG Recommends Beta Sympathomimetic as first line treatment in the management of preterm labor Evidence includes positive reviews on tolerability of the drug when used both as acute and maintenance therapy R evisiting the use of Isoxsuprine in Preterm Labor – Indian Consensus Document by ISSRF 72

70. Isoxsuprine Dose IV infusion : 0.2 to 0.5 mg /min to be adjusted to the patient’s response until symptoms are controlled 6 X 2ml ampoules can be diluted in 500 ml of 5% dextrose The drip rate should be 30 to 45 drops /min , gradually increased to 50 to 80 drops/min Monitor the BP Dose can be titrated as per the response of the patient Prescribing Information of Duvadilan 73

71. Contd …. I.M injections : Administered at the onset of premature labor , only if facilities for IV administration are not available and continued until control is obtained on symptoms of preterm labor . Dose is 10 mg every 1-2 hours Oral: Oral administration of isoxsuprine should be subsequent to IV or IM administration provided uterine activity has completely subsided . 60 to 80 mg daily in divided doses is the usual maintenance dos e Prescribing Information of Duvadilan 74

72. Adverse Effects Central Nervous System - Dizziness. Cardiovascular - Low blood pressure, palpitations, tachycardia, and flushing. Gastrointestinal - Nausea, vomiting and abdominal distress.   Miscellaneous - Rash and allergic reactions such as hives, difficulty breathing, tightness in the chest. Obs and Gynecology . 2002 : VII : 10 75

73. Contraindications General Contraindications of Tocolytics Known lethal congenital or chromosomal abnormalities Intrauterine infections Severe pre-eclampsia Placental abruption Advanced cervical dilatation Fetal demise Chorioamnionitis Revisiting the use of Isoxsuprine in Preterm Labor – Indian Consensus Document by ISSRF 76

74. Regulatory Status Revisiting the use of Isoxsuprine in Preterm Labor – Indian Consensus Document by ISSRF 77

75. Regulatory Status of Tocolytics Ministry of Health and Family Welfare (MOHFW) Indicated in preterm labor Schedule H drug (prescription drug) approved by CDSCO Monograph given in National Formulary list 2016 published by Indian Pharmacopoeia Commission, Ministry of Health and Family Welfare Note: In India use of nifedipine for preterm labor is off label Revisiting the use of Isoxsuprine in Preterm Labor – Indian Consensus Document by ISSRF 78

76. Regulatory Status Contd …. European Medicines Agency (EMA) Assessment –– EMA assessment report for short-acting beta-adrenergic agonists (salbutamol, terbutaline, fenoterol , ritodrine , hexoprenaline , isoxsuprine ) containing medicinal products for obstetric indication (2013) concluded that benefits of parenteral formulations outweigh risk in short-term management of uncomplicated tocolysis –– Parenteral products should only be administered for up to 48 hours, in patients between 22 weeks and 37 weeks of gestation Revisiting the use of Isoxsuprine in Preterm Labor – Indian Consensus Document by ISSRF 79

77. Regulatory Status Contd … WHO Guidelines –– Evidence-based guidelines for preterm labor —WHO recommendations (2015) on interventions to improve preterm birth outcomes have stated that tocolytic treatment, acute and maintenance are not recommended for women at risk of imminent preterm birth for the purpose of improving newborn outcomes. --- Conditional recommendations are given based on very low quality evidence Revisiting the use of Isoxsuprine in Preterm Labor – Indian Consensus Document by ISSRF 80

78. ACOG Recommendations Practice Bulletin interim update on Management of Preterm Labor Jan2016 – Evidence Supports Beta – adrenergic drug as the first line therapy in Preterm Labor Practice Bulletin interim update on Management of Preterm Labor Oct2016 – Evidence Supports Beta – adrenergic drug as the first line therapy in Preterm Labor 81

79. Isoxsuprine Vs Nifedipine: Clinical study Success rates in delaying delivery Isoxsuprine (%) Nifedipine %) P - Value Less than 24 hours 61% 70% Not significant 7 days 36% 31% Not significant Upto 34 weeks 27% 29% Not significant Both drugs had similar success in inhibiting PTL . Maternal side effects were higher in the Isoxsuprine group in this study Cepeda T D et al. Tocólisis con clorhidrato de isoxuprina o nifedipina en la amenaza de parto pretérmino . NIFEDIPINA Vol. 70, Nº 1, marzo 2010 11 Rev Obstet Ginecol Venez 2010;70(1):11-17 For internal Abbott use only

80. Take Home Message TVS preferred modality for Cx length at 20 weeks and also at 13 weeks NT NB scan Fibronectin level positivity between 24-34 wks- asso with PTL No usefulness of routine uterine monitoring ( cost-benefit ) Vaginal Progesterone recomm . for singleton pregnancy( lowrisk ) with CxL <2cm at 24 weeks or more High risk group should given 17alpha Hydroxy Progesterone Caproate Only if 3 or more previous preterm or 2 nd Trimester loss - History indicated cerclage Tocolysis used to buy time ………. isoxsuprine in India the largest experience,and clinically may be first line … If pain is there then oral isoxsuprin is a reasonale startup choice Administration of MgSO4 before 30weeks of gestation for Fetal neuroprotection .

81. Take home message Fetal fibronectin is a promising predictive test. (Honest et al.,2009) but it may have limited accuracy in predicting preterm birth within 7 days for women with symptoms of preterm labour . (Sanchez-Ramos et al.,2009) Ultrasound assessment of cervical length is also a promising predictive test for symptomatic women . ( Crane and hutchens .2008)

82. Take home message There is no indication in routine clinical practice for continuing tocolytic therapy for more than 48 hours. Except in some cases (e.g., placenta previa hemorrhage, amniotic sac prolapse ). (Schleußner.2013) Using multiple tocolytic drugs associated with a higher risk of adverse effects and should be avoided. Use isoxsuprin as first line is accepted (experience) (De Heus et al.,2009)

83. Take home message Atosiban and Nifedipine appear to have comparable effectiveness in delaying delivery, with fewer adverse effects than alternatives such as Ritodrine or Indomethacin . (RCOG Green-top Guideline. 2011) Ritodrine and Atosiban are licensed in the UK. for the treatment of threatened preterm labour . Although the use of Nifedipine for preterm labour is an unlicensed indication, it has the advantages of oral administration and a low price. (British National Formulary)

84. Take home message FDA warns against magnesium sulfate injections to pregnant women for more than 5-7 days to stop preterm labor, as this agent can lead to hypocalcemia and bone abnormalities in the fetus. (Lowes.2013) Antenatal corticosteroid therapy should be initiated between 24 and 34 weeks gestation to reduce fetal morbidity. (Porto et al.,2011)

85. Take home message Routine administration of antibiotics in premature labor without premature rupture of the membranes is not recommended .because the rate of maternal infection is lower , but pregnancy is not prolonged, nor reduction of the neonatal complications . ( Subramaniam et al.,2012) There is no evidence that bed rest actually lowers the rate of preterm birth. ( Crowther and Han. 2012)

86. Revisiting the use of tocolytics in the Management of Preterm Labor Certain questions need to be answered ?

87. Why tocolysis ? To allow for a course of corticosteroids To allow for in utero transfer (women go to tertiary center)

88. Questioning T ocolysis !!!! Patient oriented outcome: neonatal mortality ????

89. What a surprise!!! No clear evidence was found for the relative effectiveness of any tocolytic versus placebo being beneficial for neonatal mortality

90. No evidence !! No evidence of beneficial effect does not mean Evidence of no value No evidence could be due to small number of patients (type II error), or heteregeneity of studies, or different entry point at time of study

91. What to do now?? we have become accustomed to the fact that tocolytics buy us time. The question is : Does it Worth?

92. To get an answer is a large scale multi- centred randomised non-blinded trial, analysed by intention to treat.

93. Till then Tocolysis will continue So use the most cost effective modality : CCB THIS IS OFF LABEL IN INDIA Or simpler to use are B mimetics (agonists)( isoxsuprine ) specialy the retrad oral preperations

94. Thank you