Cervical ripening and labour induction

1. CERVICAL RIPENING AND LABOUR INDUCTION Dr. N. SRAVANTHI Dr. RENUKA

2. Induction of labor – Implies stimulation of contractions before the spontaneous onset of labor, with or without membranes. Augmentation refers to stimulation of spontaneous that are considered to be inadequate because of failed cervical dilatation and fetal descent

3. Evaluation before induction of labour MATERNAL FETAL Confirm indication for induction   Review contraindications to labor and/or vaginal delivery   Perform clinical pelvimetry to assess pelvic shape and adequacy of bony pelvis   Assess cervical condition (assign Bishop score)   Review risks, benefits and alternatives of induction of labor with patient Confirm gestational age   Assess need to document fetal lung maturity status   Estimate fetal weight (either by clinical or ultrasound examination)   Determine fetal presentation and lie   Confirm fetal well-being

4. WHO RECOMMENDATIONS FOR INDUCTION OF LABOUR Induction of labour should be performed only when there is a clear medical indication for it and the expected benefits outweigh its potential harms. In applying the recommendations, consideration must be given to the actual condition, wishes and preferences of each woman, with emphasis being placed on cervical status, the specific method of induction of labour and associated conditions such as parity and rupture of membranes .

5. Induction of labour should be performed with caution since the procedure carries the risk of uterine hyperstimulation and rupture and fetal distress. Wherever induction of labour is carried out, facilities should be available for assessing maternal and fetal well-being

6. Women receiving oxytocin, misoprostol or other prostaglandins should never be left unattended Failed induction of labour does not necessarily indicate caesarean section Wherever possible, induction of labour should be carried out in facilities where cesarean section can be performed

7. Indications Indicated when benefits to mother or fetus outweighs those of continuing the pregnancy

8. ACCEPTED ABSOLUTE INDICATIONS Hypertensive disorders Pre-eclampsia/eclampsia Maternal medical conditions Diabetes mellitus Renal disease Chronic pulmonary disease Pre- labor rupture of membranes Chorioamnionitis Fetal compromise Fetal growth restriction Isoimmunization Non-reassuring antepartum fetal testing Oligohydramnios Fetal demise Prolonged pregnancy(>42weeks)

9. RELATIVE INDICATIONS Hypertensive disorders Chronic hypertension Maternal medical condition Systemic lupus erythematosus Gestational diabetes Hypercoagulable disorders Cholestasis of pregnancy Polyhydramnios Fetal anomalies requiring specialized neonatal care Logistic factors Risk of rapid labor Distance from hospital Psychosocial indications Advanced cervical dilatation Previous still birth Post term pregnancy(>41weeks)

10. CONTRAINDICATIONS ABSOLUTE Prior classic uterine incision or transfundal uterine surgery   Active genital herpes infection Placenta or vasa previa   Umbilical cord prolapse Transverse or oblique fetal lie Absolute cephalopelvic disproportion (as in women with pelvic deformities) RELATIVE Cervical carcinoma Funic presentation Malpresentation (breech)

11. RELATIVE INDICATIONS Hypertensive disorders Chronic hypertension Maternal medical condition Systemic lupus erythematosus Gestational diabetes Hypercoagulable disorders Cholestasis of pregnancy Polyhydramnios Fetal anomalies requiring specialized neonatal care Logistic factors Risk of rapid labor Distance from hospital Psychosocial indications Advanced cervical dilatation Previous still birth Post term pregnancy(>41weeks)

12. CONTRAINDICATIONS ABSOLUTE Prior classic uterine incision or transfundal uterine surgery   Active genital herpes infection Placenta or vasa previa   Umbilical cord prolapse Transverse or oblique fetal lie Absolute cephalopelvic disproportion (as in women with pelvic deformities) RELATIVE Cervical carcinoma Funic presentation Malpresentation (breech)

13. Risks CESAREAN DELIVERY especially increased in nulliparas two- to threefold risks rates are inversely related with favorability of the cervix at induction, that is, the Bishop score. CHORIOAMNIONITIS UTERINE ATONY Postpartum atony and hemorrhage are more common in women undergoing induction or augmentation Intractable atony was the indication for a third of all cesarean hysterectomies

14. CERVICAL RIPENING

15. Cervical ripening : A prelude to the onset of labour whereby the cervix becomes soft and compliant. This allows its shape to change from being long and closed, to being thinned out (effaced) and starting to open (dilate). It either occurs naturally or as a result of physical or pharmacological interventions NICE 2008

16. MECHANISM INVOLVED IN CERVICAL RIPENING Cervix is a complex and heterogeneous organ, that undergoes extensive changes throughout gestation and parturition. Chronic process, which begins within the first trimester of pregnancy and progressively proceeds until term Softens, dilates and effaces the cervix This remodeling process is extremely complex and involves properly timed biochemical cascades, interaction between cellular and extra cellular components, and infiltration by inflammatory cells.

17. Hyperplasia of cellular components in early gestation physiologic cell death, in advanced pregnancy Up gradation of Decorin -Invasion by neutrophils and macrophages -Nitric oxide – regulates MMPs and releases PGs. COLLAGEN REMODELLING

18. Extra-cellular changes Dispersion and Disorganization of Collagen Collagenases, Proteases and Elastases (produced by fibroblast and PMN) MMP 1 and 8 – source: stromal cells and neutrophils Proteoglycans e.g. Decorin Inflammatory cells--- increase in degradative enzymes Hyaluronic acid (GAG)- increase water content

19. Collagenases, MMP 1 & 8, elastases Source – stromal cells, neutrophils and macrophages Activity enhanced by cytokines like IL-1B, IL-8 - Tissue inhibitors of MMPs, alpha 2 macroglobulin

20. AFFECTING ELEMENTS CYTOKINES – e.g . interleukin-1 β enhance the activity of collagenases and interleukin 8, Platelet activating factor, monocyte chemotactic factor-1 HORMONAL INFLUENCES – Estrogens increases collagenases Progesterones inhibit collagenases, hyaluronic acid & IL-8 NITRIC OXIDE stimulates leukocytes infiltration induce prostaglandin secretion

21. PREINDUCTION CERVICAL RIPENING The condition of the cervix influences the success of inducing labor. A cervical examination is essential before labor induction is initiated. In 1964, Bishop developed a scoring system to evaluate multiparous women for elective induction at term. The scoring system is based on properties of the cervix that may be assessed clinically at the time of pelvic examination such as dilatation, effacement, consistency, and position as well as the station of the fetal presenting part

22. “Bishop Scoring System” Used for Assessment of Inducibility SCORE DILATATION (cm) EFFACEMENT (%) STATION (–3 to +2) CERVICAL CONSISTENCY CERVICAL POSITION CLOSED 0 - 30 -3 FIRM POSTERIOR 1 1-2 40 - 50 -2 MEDIUM MID POSITION 2 3-4 60 - 70 -1 SOFT ANTERIOR 3 >/= 5 >/=80 +1, +2 - -

23. Bishop score is now widely used to predict the success of labor induction. The higher the Bishop score, the more “ripe” or “favorable” the cervix is for labor induction. A low Bishop score, usually considered less than or equal to 6, is “unripened” or “unfavorable” and will benefit from cervical ripenin g

24. fFN in cervical secretions: Not more predictive than Bishop’s score Other predictors

25. Other scoring systems Field’s system Burnett modification of bishops score Weighted Bishop’s score by Friedman Pelvic score by Lange However, despite this none of the modifications have shown improved predictability.

26. ULTRASOUND IMAGING Adv. Over digital examination: more objective and assesses the entire length of the cervix. Both bishop’s score and TVUS predicted successful induction. Bishop’s score predicted delivery within 24 hrs. and TVUS within 48 hrs. Cervical length related to latent phase of labor, funneling related to both latent and active phase of labor. ( Am. J of Obs. Gynecol. 1994;171.) Some other studies have not found any USG parameter predictive, and consider bishop’s score to be superior.

27. METHODS OF CERVICAL RIPENING Unfortunately, women too frequently have an indication for induction but with an unfavorable cervix. As favorability or Bishop score decreases, there is an increasingly unsuccessful induction rate. Methods used for cervical ripening include pharmacological preparations and various forms of mechanical cervical distension.

28. Non pharmacologic means of cervical ripening Herbal supplements: evening primrose oil, blue and black cohosh, raspberry leaves. Breast stimulation: causes oxytocin release. Adv–non invasive, inexpensive, simple Disadv. – causes FHR abnormalities. Castor oil, hot baths, enemas Miscellaneous - acupuncture , sexual intercourse

29. (HYGROSCOPIC DILATORS): Natural osmotic dilators – Laminaria japonicum Laminaria digitata Isapgol Synthetic osmotic dilators Lamicel Dilapan They absorb endocervical and local tissue fluids, causing the device to expand within the endocervix and provide mechanical pressure. cause mechanical dilation and release of prostaglandins. Swell up to 4 – 5 times. Most rapidly in first 4-6 hours but continue to swell up to 24 hours later.

30. ADVANTAGES DISADVANTAGES Cheap Outpatient placement Easy for placement No need for fetal monitoring Rapid improvement of cervical status Skill needed for proper placement in internal os. Delay in obtaining maximum effect. Patient discomfort . Inability of tents to be molded without compromising mechanical integrity. Lack of manufacturer specifications for natural dilators. Potential for incomplete sterility . ETO gas does not eradicate spores in the interstices of the sea weed stem

31. Membrane stripping: Release of endogenous PGs. and mechanical dilation. results in < labor inductions < post dated pregnancies > spontaneous onset of labor - inexpensive, safe, efficacious in promoting labor over several days

32. Balloon devices : Single / Double balloon First described in 1967 Safe Cheap ADVANTAGES : The combination of balloon catheter plus oxytocin is recommended as an alternative method when prostaglandins (including misoprostol) are not available or are contraindicated (previous caesarean) May be useful for outpatient ripening. Can be inserted in presence or absence of membranes. Associated with favorable Bishop scores and no additional side effects.

33. Single Balloon Devices A fluid filled balloon is inserted inside the cervix .  A Foley catheter (26 Fr) or specifically designed balloon devices can be used Mechanism of action: The mechanism by which Foley' s catheter improves the cervical state is by its mechanical action. It strips the fetal membranes from the lower uterine segment, causing rupture of lysosomes , release of phospholipase A and formation of prostaglandins.

34. Technique of Balloon Placement After sterilization and draping, the catheter is introduced into the endocervix either by direct visualization or blindly by sliding it over fingers through the endocervix into the potential space between the amniotic membrane & the lower uterine segment. The balloon is inflated with 30 to 50 mL of normal saline and is retracted so that it rests on the internal os. Constant pressure may be applied over the catheter. e.g. a bag filled with 1 L of fluid may be attached to the catheter end / An intermittent pressure may also be exerted on the catheter end 2 -4 times per hour .

35. Catheter is removed at the time of rupture of membranes or may be expelled spontaneously which indicate a cervical dilatation of 3 - 4 Centimeters.

36. PHARMACOLOGICAL TECHNIQUES Prostaglandins PGE2 : Dinoprostone PGE1 : Misoprostol Oxytocin Others Estrogen Relaxin Hyaluronic acid Progesterone receptor antagonist

37. PROSTAGLANDINS The chemical precursor is arachidonic acid PGs are endogenous compounds found in the myometrium, deciduas, and fetal membranes during pregnancy. Cervical production of PGE2, PGI2, PGF increases at term. Modulate fibroblast activity - Increase hyaluronic acid production Acting as chemotactic agents, Inflammatory cells further release degradative enzymes, causing cervical ripening.

38. Prostaglandins administration results in dissolution of collagen bundles and an increase in sub mucosal water content of the cervix. These changes in cervical connective tissue at term are similar to those observed in early labor. Unlike oxytocin, response to prostaglandins does not change throughout gestation .

39. Preparations PGE2 : Dinoprostone PGE1 : Misoprostol Vaginal gel : Prepidil, Cerviprime TM Removable tampon : Cervidil TM Vaginal pessary : Prostin E2 TM Misoprost TM Cytotec TM

40. Prostaglandin E2: (Dinoprostone)

41. PROSTAGLANDIN E2 (DINOPROSTONE): CERVIPRIME GEL - is commonly used for cervical ripening . is available in a 2.5-mL syringe for an intracervical application of 0.5 mg of dinoprostone. With the woman supine, the tip of a pre-filled syringe is placed intracervically, and the gel is deposited just below the internal cervical os. After application she remains reclined for at least 30 minutes. Doses may be repeated every 6 hours, with a maximum of three doses recommended in 24 hours .

42. Prepidil Intracervical placement

43. Dinoprostone should only be administered at hospital. Continuous Uterine activity & FHR monitoring. If optimal response is not achieved by 6 hours, another dose can be administered. The maximum allowed dose is 3 doses be administered per 24 hours. Oxytocin should not be initiated until 6 to12 hours after the last dose because of the potential for uterine hyperstimulation with concurrent oxytocin and prostaglandin administration .

44. Cervidil placed in posterior vaginal fornix

45. Vaginal insert containing 10 mg of dinoprostone in a timed-release formulation. The vaginal insert administers the medication at 0.3 mg/h and may be left in place for up to 12 hours . ADVANTAGE : the insert may be removed with the onset of active labor, rupture of membranes, or with the development of uterine hyperstimulation .

46. Vaginal pessary : Prostin E2TM

47. COCHRANE REVIEW vaginal PGE2 No Rx / Placebo risk ratio (RR ) 95% confidence interval (CI) risk of the cervix remaining unchanged/ unfavourable after 12 to 24 hours 5 trials, 467 women 21.6% 40.3%, 0.46 0.35 to 0.62 reduction in failure to achieve vaginal delivery within 24 hours 2 trials, 384 women 18.1% 98.9%, 0.19 0.14 to 0.25 use of oxytocin augmentation 12 trials, 1321 women 35.1% 43.8% 0.83 0.73 to 0.94 Uterine hyperstimulation with FHR changes 14 trials, 1259 women 4.4% 0.49%, 4.14 1.93 to 8.90 Hyperstimulation without FHR changes 13 trials, 3636 Women 1.4% 0.4% 2.48 1.17 to 5.26 Vaginal Prostaglandin E2 versus placebo/no treatment (37 trials, 6511 women)

48. COCHRANE REVIEW Vehicle comparisons PGE2 gel is as efficacious as PGE2 tablets. PGE2 gel does reduce the need for oxytocin augmentation, Gel was associated with less uterine hyperstimulation. Sustained release pessaries in comparison with gel have not been shown to significantly reduce caesarean section rates have not been shown to improve adverse neonatal or maternal outcomes. There is reduction in the use of oxytocin augmentation and the reduction in instrumental delivery rates. The frequency of vaginal examinations is reduced when using sustained release pessaries.

49. INTRACERVICAL PGE2: although this route of administration is effective, it offers no advantages when compared to other methods of administration, namely the vaginal route. Intracervical prostaglandins are effective compared to placebo, but appear inferior when compared to intravaginal prostaglandins.

50. PGE2 can cause Uterine hyperstimulation, Fetal distress and Cesarean section. Uterine hyperstimulation : - More common with intra vaginal application . - 1-5%, similar to low dose oxytocin <=4mu/ml. - Begins within 1 hr - Removal, irrigation of Cervix, vagina : not helpful - Rapidly reversed with terbutaline or removal of insert. - Hence fetal heart rate monitoring is needed for 2 hours following single dose and longer if contractions persist after that.

51. A retrospective study of case notes ( n = 3099) investigated women who underwent induction with PGE2 (vaginal tablet, gel and intracervical gel). Uterine hyperstimulation (defined as contraction frequency being more than five in 10 minutes or contractions exceeding 2 minutes in duration ) occurred in 5.8% patients, of which 31.5% were associated with FHR abnormalities. Administration of tocolytic treatment with β2-adrenergic drugs (hexoprenaline at 0.3 micrograms/minute OR single dose of terbutaline 250 micrograms intravenously or subcutaneously) successful in normalising uterine contractions and reversing any FHR abnormality in (98.3%). Improvement usually began within 5 minutes regardless of hyperstimulation patterns. NICE 2008

52. Systemic effect Nausea Vomiting Diarrhea Caution in Glaucoma hepatic and renal disease Asthma

53. Safety in induction for VBAC Concern is with uterine rupture caused by uterotonic effects. In largest cohort study of 5022 patients willing for VBAC 453 patients received intra vaginal gel The rates of rupture were, 1.3% with PGE2 and 0.7 without its use. ~ not statistically significant . Am J of Perinatol. 1997;14:157-160

54. Two studies have expanded on the differences in adverse outcomes between prostaglandin and non-prostaglandin (such as intracervical Foley catheter) based induction regimens. In the NICHD study, prostaglandin induction compared with non-prostaglandin induction incurred a non-significantly higher risk of uterine rupture (140/10,000 versus 89/10,000; P = 0.22). In an analysis of nationally collected data from Scotland, prostaglandin induction compared with non-prostaglandin induction was associated with a statistically significantly higher uterine rupture risk (87/10,000 versus 29/10,000) and a higher risk of perinatal death from uterine rupture(11.2/10,000 versus 4.5/10,000). This compares with 6/10,000 risk of perinatal death in women with an unscarred uterus induced by prostaglandin identified by a Cochrane review. RCOG

55. Given these risks and the absence of direct robust evidence, it is important not to exceed the safe recommended limit for prostaglandin priming in women with prior caesarean birth. RCOG 2007

56. Use with Premature Rupture of Membranes at term. It has not been shown to decrease neonatal infections when compared with expectant management. It could decrease time to delivery, but this can be achieved equally with optimum oxytocin dosing. More important intervention to decrease maternal infectious morbidity is decreasing number of PV examinations.

57. Misoprostol Dosing 25 mcg 50 mcg Very cheap Easy to store

58. Pharmacokinetics Route of administration: Oral, vaginal and sublingual route for induction. Bioavailability: Extensively absorbed from the GIT Metabolism: De-esterified to prostaglandin F analogs Half life: 20–40 minutes Excretion: Mainly renal 80%, remainder is fecal: 15% maximum plasma conc. with 400µg miso. - 34 mins. after oral , 80 mins. After vaginal - rapid onset and greater peak action with oral miso. - longer action with vaginal miso.

59. Clinical trials indicate that the safe optimal dose and dosing interval is 25 mcg intravaginally every 4-6 hours. ACOG 1999 A maximum of 6 doses was suggested.

60. VAGINAL MISOPROSTOL (comparison) Vaginal misoprostol versus Trials/ No. of women Outcomes Placebo/ Expectant management 5 trials/ 769 participants Reduced risk of not achieving vaginal birth within 24 hrs of induction Intravenous oxytocin 9 trials/1200 participants 25trials/3074 participants 13 trials/1906 participants Reduced risk of not achieving vaginal birth Fewer cesarean sections Fewer infants with apgars below 7 at 5mins Other prostaglandins - a reduced risk of vaginal birth not achieved within 24 hours fewer caesarean sections increased risk of uterine hyperstimulation with fetal heart rate changes

61. Compared with higher doses of vaginal misoprostol, lower doses (25 μg, 6-hourly) were associated with a reduced risk of uterine hyperstimulation with fetal heart rate changes (16 trials, 2540 participants, RR 0.51, 95% CI 0.37–0.69). The risk of vaginal birth not being achieved within 24 hours was similar with both higher and lower doses

62. Oral misoprostol versus Trials/ No. of women Outcomes Placebo/ Expectant management 1 trials/96 participants 6 trials/629 participants Reduced risk of not achieving vaginal birth within 24 hrs of induction Reduced cesarean births Intravenous oxytocin 8 trials/1026 participants Similar w. r, t. the risk of priority outcomes Intracervical prostaglandins More effective in achieving vaginal birth within 24 hrs Vaginal prostaglandins Reduction in cesarean rates ORAL MISOPROSTOL

63. Lower doses of oral misoprostol (up to 50 μg) were associated with similar outcomes compared with higher doses (100 μg)

64. Oral misoprostol versus vaginal misoprostol Similar with regard to priority outcomes except Oral misoprostol was associated with a lower risk of Apgar score being less than seven at 5 minutes of life (14 trials, 3270 participants, 94 events, RR 0.65, 95% CI 0.44–0.97).

65. Vaginal misoprostol versus sublingual/ buccal misoprostol : similar with regard to all the priority outcomes Oral versus sublingual/buccal misoprostol: Data are limited

66. Recommendations Oral misoprostol (25 μg, 2-hourly) is recommended for induction of labour. (Moderate-quality evidence. Strong recommendation.) Vaginal low-dose misoprostol (25 μg, 6-hourly) is recommended for induction of labour. (Moderate-quality evidence. Weak recommendation.) Misoprostol is not recommended for women with previous caesarean section. (Low-quality evidence. Strong recommendation.)

67. Misoprostol vs Dinoprostone The mean time to vaginal delivery was significantly shorter in the misoprostol group (925.8 versus 1577.6 minutes), and the mean duration of the active length of labour was significantly shorter in the misoprostol group (353.7 versus 496.8 minutes) Less likely to require a repeated dose of prostaglandin for cervical priming and oxytocin for augmentation of labour. no difference in the rate of Caesarean section More hyperstimulation during labour in the misoprostol group Aust N Z J Obstet Gynaecol. 2001 May;41(2):145-52

68. Oxytocin for cervical ripening : comparison Intravenous Oxytocin versus Trials / No women Outcome Expectant management 25 trials; 6660 women Intravenous oxytocin reduced the failure to achieve vaginal delivery within 24 hours when compared with expectant management (8.4% versus 54%) Vaginal PGE2 27 trials; 4564 women compared with vaginal PGE2, oxytocin was associated with more failures to achieve vaginal delivery within 24 hours (70% versus 21%) Intracervical PGE2 14 trials; 1331 women Oxytocin was associated with increased unsuccessful vaginal deliveries within 24 hours when compared with intracervical PGE2 (50.4% versus 34.6%) Increase in cesarean sections (19% versus 13.7%)

69. CONCLUSION Comparison of oxytocin with either intravaginal or intracervical PGE2 reveals that the prostaglandin agents probably increase the chances of achieving vaginal birth within 24 hours. Oxytocin induction may increase the rate of interventions in labour. NICE 2008

70. Risks CESAREAN DELIVERY especially increased in nulliparas two- to threefold risks rates are inversely related with favorability of the cervix at induction, that is, the Bishop score. CHORIOAMNIONITIS UTERINE ATONY Postpartum atony and hemorrhage are more common in women undergoing induction or augmentation Intractable atony was the indication for a third of all cesarean hysterectomies