Presented by Dr. Pyone Myat Mon Intravaginal dinoprostone versus misoprostol in induction of labour for late intrauterine fetal death in Central Women’s Hospital Presented by Dr. Pyone Myat Mon

Introduction A baby delivered without signs of life after 24 completed weeks of pregnancy - defined as late intrauterine fetal death (NICE guideline (2013) , RCOG Green-top Guideline No. 55, November 2010) 2.6 million stillbirths occur worldwide each year (The Lancet, 2011) Stillbirth rate in Myanmar - 20 per 1000 live births (WHO, Myanmar, 2014) 207 intrauterine fetal death cases admitted to Central Women’s Hospital Yangon in 2014

Intrauterine fetal death - a tragic event for the parents and a great cause of stress for the caregiver Important to identify the probable etiology of fetal death and the series of events that eventually lead to fetal demise Helps in formulating preventive policies, protocols, counselling and consoling the grieving parents Options for management of intrauterine fetal death - expectant delivery or induction of labour

Spontaneous labour occurs within three weeks of IUFD in >90% Risk of disseminated intravascular coagulopathy (DIC) due to gradual release of thromboplastin from the products of conception into maternal circulation and intrauterine infection in case of ruptured membrane unless the labour starts Combination of mifepristone and prostaglandins recommended to induce labour (WHO and RCOG guidelines for IUFD)

Prostaglandins without priming with mifepristone commonly used Success rate ranges from 67% to 100% (Wagaarachchi PT et al, 2002) Findings from this study - to find better management and improve the choice of optimum prostaglandins effectively which in turn will reduce the emotional distress and the complications of IUFD

Aim To detect the efficacy and safety of intravaginal dinoprostone (PGE2) and misoprostol (PGE1) in induction of labour in late intrauterine fetal death

Materials and Method Hospital-based comparative study carried out in Central Women’s Hospital, Yangon from 1st January to 31st December 2016 Total 76 eligible pregnant women with IUFD after 24 weeks of gestation who admitted to obstetrics wards Exclusion criteria – grandmultip any scar on uterus severe asthma placenta praevia cardiac dieases abnormal lie previous LSCS allergic to drugs

Two prostaglandins drugs (dinoprostone and misoprostol) used Informed consent and allocation concealment ramdomization Explained detailed procedure and risks Took written consent after excluding any contraindications

Baseline data such as name, age, address, registration number, date of admission, gravida, parity, gestational age obtained by proper history taking and examination including vaginal examination to assess Bishop score Usual investigations done before the procedure

One group - dinoprostone (PGE2) 3mg intravaginally six hourly (maximum two doses in 24 hours) Another group - 100µg misoprostol (PGE1) inserted vaginally six hourly before 26 weeks and 25-50µg four hourly at 27 weeks or more (maximum four doses in 24 hours) Repeated course given until delivery provided no complications after 24 hours later

Vital signs (temperature, blood pressure, pulse rate), uterine contraction - monitored at the baseline and each and everytime before and after insertion of vaginal tablet Vaginal examination & cervical scoring assessed every four hourly and six hourly

Results Background characteristics ( age, gravida, gestational age) – comparable between two groups

  Bishop score Study group Total Dinoprostone Misoprostol Favourable Unfavourable 36 (94.7%) 2 (5.3%) 35 (92.1%) 3 (7.9%) 71 (93.4%) 5 (6.6%) 38 (100.0%) 76 (100.0%)

Number of repeated course Study group   Total Dinoprostone Misoprostol 1 2 3 4 30 (78.9%) 7 (18.4%) 1 (2.6%) 0 (0.0%) 33 (86.8%) 3 (7.9%) 2 (5.3%) 63 (82.9%) 10 (13.2%) 1 (1.3%) 2 (2.6%) 38 (100.0%) 76 (100.0%)

Mean duration - 16. 4 ± 14. 2 hrs (misoprostol group),18. 9 ± 16 Mean duration - 16.4 ± 14.2 hrs (misoprostol group),18.9 ± 16.5 hrs (dinoprostone group) (p=0.470)

Mean time between two groups - 20. 9 ± 16. 6 hrs and 18. 4 ± 14 Mean time between two groups - 20.9 ± 16.6 hrs and 18.4 ± 14.5 hrs respectively (p=0.468)

 Mode of delivery Study group   Total Dinoprostone Misoprostol SVD LSCS 38 (100.0%) 0 (0.0%) 37 (97.4%) 1 (2.6%) 75 (98.7%) 1 (1.3%) 76 (100.0%)

Uterine hyperstimulation  Complications Study group   P value Dinoprostone Misoprostol Shivering 1(2.6%) 2(5.2%) 0.5484 Pyrexia 3(7.8%) 0.3035 Diarrhoea - Uterine hyperstimulation Uterine rupture PPH 0.1530 Nausea 1.000 Vomiting

Discussion Induction of labour - widely used obstetrical practice for different indications Success of induction - dependent on the cervical status assessed by Bishop’s score Death of a fetus at any stage of pregnancy - a tragic event Induction of labour in late IUFD using pharmacological agents with known safety profile recommended by most of the guidelines

Prostaglandins - used for induction of labour and the therapeutic effects and side effects are depended on type of prostaglandins and route of administrations Changes of Bishop’s score after induction , dinoprostone group - more effective in changes in Bishop’s score (94.7%) than misoprostol group (92.1%) Ah-Mar (1999) and Mya-Mya-Aye (1997) studies- misoprostol more efficacy in changes in Bishop’s score than syntocinon

Total dose required for successful induction - less need in dinoprostone compared to misoprostol As a result of reduced sensitivity of progesterone receptors subsequent to fetal death (p value=0.364) Edward and Hassan (1990) - overall doses needed significantly fewer in sulprostone group compared with dinoprostone group

In current study - one repeated course of induction in dinoprostone group was 30 women (76.9%) and 33 women (86.8%) in misoprostol group (p value=0.192) Mean induction to onset of labour – shorter in misoprostol group than dinoprostone group (18.9 ± 16.5 hours vs 16.4 ± 14.2 hours) (p=0.470) Mya-Mya-Aye (1997) - shorter in misoprostol group than syntocinon group (7.36 ± 5.1 vs 9.5 ± 4.5 hours)

Mean induction to delivery – shorter in misoprostol than dinoprostone (18.4 ± 14.5 vs 20.9 ± 16.6 hours) Biwas (2014) – dinoprostone gel had higher induction to delivery time than misoprostol (14.32 ± 2.46 vs 8.13 ± 1.62) (p = <0.0001) Mode of delivery – dinoprostone had successful vaginal delivery than misoprostol (100% vs 97.4%) Edward and Hasson (1990) – complete expulsion in dinoprostone group

Maternal complications – more in misoprostol group (18.4% vs 10.4%) Biwas (2014), Ah-Mar (1999) and Mya-Mya-Aye (1997) – side effects more in misoprostol May be due to different dosage, different routes, different monitoring systems, different hospital protocols and guidelines in their respective hospitals

Further studies still needed in order to establish optimal dose, dosing interval and route of administration for management of IUFD Both drugs are safe and effective in induction of labour for late IUFD Dinoprostone - more expensive and needs refrigeration store Dinoprostone - a lincensed drug proved by FDA and misoprostol - an unlicensed drug Good points of dinoprostone over misoprostol - less maternal side effects and encouraging effect in induction

REFERENCE Ah-Mar (1999). A comparative study of the effects of syntocinon and prostaglandin E1 analogue in induction of delivery in intrauterine fetal death cases. A dissertation submitted for the degree of M.Med.Sc (O & G), University of Medicine, Mandalay. Centre for Maternal and Child Enquiries (CMACE) (2011). Perinatal Mortality (2009).  Edward A. Kidess, Hassan S. Ba’Aqeel (1990). Management of intrauterine fetal death after 12 weeks of gestation: Comparison of two prostaglandins. Annals of Saudi Medicine, 10(4)  Hospital Statistics. Central Women’s Hospital, Yangon (2014)

Mya-Mya-Aye (1997). A Comparison of intravaginal misoprostol and oxytocin infusion in intrauterine fetal death. A dissertation submitted for the degree of M.Med.Sc (O & G), Institute of Medicine (1), Yangon.  Nation Institute for Health and Clinical Excellence (2013) Clinical guideline no.70: Induction of labour  Royal College of Obstetricians and Gynaecologists. Green-top Guideline No.55 (2010). Late intrauterine fetal death..  Titol Biwas (2015). Misoprostol (PGE1) versus dinoprostone gel (PGE2) in induction of labour in late intrauterine fetal death with unfavourable cervix: a comparative study. Int J Reprod Contracept Obstet Gynaecol; 4:35-37  Wagarrachchi PT, Ashok PW, Narvekar NN, Smith NC, Templeton A (2002). Medical management of late intrauterine fetal death using a combination of mifepristone and misoprostol. Br J Obstet Gynaecol: 109:443-447  World Health Organization (WHO) (2014): Global Health Observatory Data Repository, Myanmar.

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