In modern obstetrics, labour induction is considered a way to improve maternal and foetal outcomes ^[1]. In this regard, an increase in the frequency of induced labour has been noted worldwide.^[2] However, some evidence suggests that elective labour induction prolongs hospital stay and may increase costs and resource utilisation.^[3] Considering these provisions, and also the fact that some women prefer to be at home as long as possible before delivery, outpatient cervical ripening could be a reasonable alternative.

It is well known that a “ripe” cervix is the most important predictor of success of labour induction. The use of pharmacological agents or mechanical methods to promote cervical ripening before the initiation of the induction process, known as preinduction, is important for successful induction. The preinduction and induction of labour are essentially linked in the same chain; however, they are different. Preinduction is aimed at ripening of the cervix (softening^,[4] shortening, and initial dilatation) and consists predominantly of remodelling the connective tissue that constitutes the bulk of the uterine cervix. Induction is the process of stimulating the uterine muscle fibres to initiate contractions.^[5] As in the setting of an unfavourable cervix, preinduction requires more time than induction, and it may be beneficial to perform it on an outpatient basis.^[6]

Mechanical methods (balloons or dilators) provide dilatation of the cervix; that is, they are preinduction methods. Pharmacological agents, such as prostaglandins and oxytocin, activate the contractile activity of the uterus; therefore, they should be considered as methods of labour induction.^[7]

Mifepristone, a 19-norsteroid compound, counteracts progesterone at the receptor level and eliminates its inhibitory effect on uterine tissue, increases the synthesis of prostaglandins, and inhibits the action of prostaglandin dehydrogenase ^[8]. The antiprogestogenic effect of mifepristone promotes cervical ripening by increasing cervical collagenase and prostaglandin synthesis, and enhancing the expression of the extracellular matrix-degrading protease stromelysin-1 ^[9]. To achieve the effect of cervical ripening, a sufficiently long period is required, usually 24–72 h. Given that the action of mifepristone is mainly aimed at ripening the cervix and not stimulating uterine contractions, its use should be considered as a preinduction method^.[10]

The efficacy and safety of mifepristone for the preinduction/induction of labour have been confirmed in observational and randomised trials^[11]

Considering that mifepristone is a means of preinduction, and does not directly induce labour, and that it takes up to 24–72 h to achieve the effect, it seems appropriate and convenient to use it on an outpatient basis. However, there are currently no studies comparing the efficacy and safety of mifepristone preinduction of labour on an inpatient and outpatient basis.^[12]

This study aimed to evaluate whether the outpatient use of mifepristone for cervical ripening before the induction of labour at term is efficient and safe.

This study was open-label randomized controlled trial conducted in the Department of Obstetrics and Gynaecology, King George’s Medical University, Lucknow, over a time period of 1 year from August 2018 to August 2019 enrolled women who were admitted to the labor room at term with indications of induction of labor, willing to participate in the trial. The study was approved by Institutional Ethics Committee KGMU Lucknow (Vide letter Ref No.262/Ethics/R.Cel-16, Ref. code:90th ECM II B-Thesis/P35 dated 15-08-2018) and had been performed in accordance with the ethical standards described in an appropriate version of the 1975 Declaration of Helsinki, as revised in 2000

The inclusion criteria were singleton gestation, cephalic presentation, Bishops score ≤ 5, and reactive nonstress test pattern. The exclusion criteria were premature rupture of membrane, previous history of cesarean section or uterine surgery, intrauterine death, any hypersensitivity and contraindication to PGE2 gel such as asthma, glaucoma, and any preexisting cardiovascular diseases, multiple pregnancy, chorioamnionitis, and any febrile morbidity and any contraindication to the induction of labor.

During the study period, a total of 460 pregnant women were admitted for the induction of labor. Out of 460 women, 225 women were excluded who did not met the inclusion criteria and who denied of participating in the study. One hundred and ninety-one women who fulfilled the inclusion criteria were enrolled in the study after written informed consent and were randomized by the simple computer-generated random number table into group A (mifepristone) and group B (Dinoprostone gel). Allocation concealment was done by the distribution of drugs by sequentially numbered opaque sealed envelopes (SNOSE). Group A had 94 women in which six women discontinued the intervention as they denied further induction, and Group B had 97 women in which five women discontinued the intervention as they denied further induction So Group A had 88 women, and Group B had 92 women

All enrolled women were subjected to detailed history; per abdominal and per vaginal examination, including Bishops score; and relevant investigations, which include complete blood count, ABO-RH, viral markers, Diabetes in pregnancy study groups in India (DIPSI), urine routine, and microscopy, Serum thyrotropin hormone (S.TSH) (if previously not done), and further specific investigations were done according to other risk factors.

Labor and delivery details were noted, and outcome was measured : Primary outcomes were change in bishops score and induction to the onset of contractions, and secondary outcomes were induction to delivery interval, mode of delivery, cesarean for failed induction, any adverse events, and fetal outcome

Statistical Analysis

The results were analyzed using descriptive statistics and making comparisons among the various groups. Discrete (categorical) data were summarized as in proportions and percentages (%), while continuous in mean and SD. The chi-square test, arithmetic mean, standard deviation, unpaired t-test, and odds ratio were done using SPSS 23

The age of the patients ranged from 18 to 33 years. The mean age in the Mifepristone group was 25.10±3.50 years, and in the Dinoprostone group, it was 24.80±3.40 years (p=0.685). In the Mifepristone group, 30 (55%) were primigravida, and 25 (45%) were multigravida, while in the Dinoprostone group, 31 (57%) were primigravida, and 23 (43%) were multigravida (p=0.710).

A total of 35 (65%) patients in both groups were at a gestational age of more than 40 weeks. About 12 (22%) patients in the Mifepristone group and 10 (19%) in the Dinoprostone group were at 37–40 weeks, whereas 7 (13%) in the Mifepristone group and 8 (15%) in the Dinoprostone group were at less than 37 weeks of gestation (p=0.930).

The most common indication for induction was prolonged pregnancy (65%), followed by hypertensive disorders (23%) and gestational diabetes mellitus (12%) in both groups (p=1.000). Patients in both groups were comparable, with no significant statistical differences in demographic parameters.

Table 1: Demographic Characteristics of Both Groups (n=460)

Table 2: Bishop’s Score Before and After 24 Hours

Most of the patients in both groups had pre-induction Bishop’s score of 2 to 4. After 24 hours, 78% patients in Mifepristone group and 70% patients in Dinoprostone group had Bishops’s score >6 (Table 3). Comparing the mean gain in Bishop’s score after 24 hours, Mifepristone group had better gain (4.45±1.35) as compared to patients in Dinoprostone group ((4.07±1.34) with p value of 0.159 (Table 3). However, the difference was not statistically significant. The mean duration of labor was longer in Dinoprostone group as compared to Mifepristone group (p=0.247). However, the induction delivery interval (IDI) was lesser in Dinoprostone group (12.28±6.75) as compared to Mifepristone group (14.00±7.00) (Table 4). Half of the patients in group A (48%) and two-third of the patients in group B (70%) required oxytocin for labor induction or augmentation. The mean dose of oxytocin (units) required was higher in Dinoprostone group (2.26±0.17) and lesser in Mifepristone group (3.29±1.35) with p-value of 0.001. This difference was highly significant statistically.

Table 3: Gain in Bishop’s Score over Time

Table 4: Duration of Different Stages of Labor

Table 5: Requirement of Oxytocin for Augmentation

Table 6: Maternal and fetal complications.

There  are  various  methods  of  induction  of  labor  available  but  none  of  them  is ideal. Various studies have been done to evaluate the role of mifepristone at term. So, the purpose of our study was to compare the efficacy of mifepristone with that of PGE2 gel. The rationale behind this study was to utilize the antiprogestrogenic activity  of  mifepristone  at  term  and  to  find  out  whether  it  is  a  suitable  and effective  labor-inducing  agent.  In  our  study,  baseline  characteristics  like  age, booking  status,  socioeconomic  status,  education,  parity,  period  of  gestation, indication for the induction of labor, and Bishops score were comparable in both groups^.[13]

In  the  present  study  we  assessed  the  age  distribution  of  the  study  subjects.  We observed that majority of the study subjects belonged to the age group of 26 to 35 years (55% and 50% in either group), followed by more than 36 years (37.5% and 40%  resp). Wing  et  al11 in  Southern  California,  Los  Angels,  conducted  a randomized  controlled  trial  in  which  88  percent  of  the patients  were  in  the  age bracket  of  21-30  years. Kanan  Yelikar  et  al12 in  their  study  observed  that  the mean  age  of  the  study  subjects  is  22.98  years.  If  we  compare  parity  in  both groups,  the  groups  were  comparable  (p  =  0.310).  Similarly in studies done by Yellikar ET al12, mean parity was 1.48 ± 0.44 and 1.62 ± 0.44 (p= 0.659). Gupta et  al.13 also  compared  the  effectiveness  of  mifepristone,  and  the  groups  were comparable  (p  <0.0310).  In our study, the mean gestation age was comparable (p= 0.239).  In  a  similar  study,  Sah  and  Padhye  discovered  that  there  was  no statistically significant difference in gestational age between the two groups.^[14]

In  this  study  we  assessed  the  gravida  status  among  the  study  subjects.  We observed  that  majority  were  primigravida  (72.5%  and  62.5  resp).In  this  aspect our  study  correlates  with  studies  done by Giacalone  et  al Department  of Obstetrics   and   Gynaecology,   Hospital   Arnaud   de   Villeneuve,   University   of Montepetlier.^[15] Similar  to the Wing  DA  et  al, Elliot  et  al study  and Kanan Yelikar  these  trials  compared  mifepristone  to  placebo,  whereas  herePGE2  gel was used.

In the present study we assessed the Bishops score at the start. We observed that majority of the subjects had score of 3 (70% and 62.5% resp), followed by score 2 (25% and 30% resp).  Our  findings  are  similar  to  those  of Elliot  et  al15, Department  of  Obstetrics  and  Gynecology,  University  of  Edinburgh,  United Kingdom,  1998,  who  included  Bishop's  score  of  4  or  less  in  the  research  group. The mean Bishop's score at the start of our study was 2.72, which is comparable to the mean Bishop's score at the start of Kanan Yelikar's study, which was 2.02.^[16] Yellikar ET al12. And Gupta et al13 compared oral mifepristone versus placebo and found that preinduction Bishop score in both groups was 2.02 ± 0.749 and 2.79 ± 1.29, respectively. In contrast toour study, Sailatha et al16. found that the mean increase   in   post-induction   Bishops   score   at   24   hours   was   4   ±   1.48   in mifepristone  group  and  4.7  ±  1.49  in  PGE2  gel  group,  and  this  was  statistically significant (p = 0.042).^[17]

The literature data indicate that misoprostol does not increase maternal and fetal morbidity. Our findings, on the other hand, indicate an increased rate of cesarean section with repeated use of vaginal misoprostol 50 µg. It is reasonable to think that a lower dose of misoprostol (25 µg versus 50 µg) may reduce tachysystole or hypertonia (as shown in a literature review37) and thereby reduce the rate of cesarean section due to fetal heart rate abnormalities observed in our study. Oral administration may reduce abnormal fetal heart rate.^[18]

In the present study we assessed the mean blood loss among the study subjects. We  observed  that  mean  blood  loss  in  Mifepristone  group  was  187.6  ml,  whereas in  dinorpstone  group  was  comparatively  greater  232.8  ml.  The difference was found to be statistially significant (p value:  <0.0001).  In the present study we assessed the neonatal complications among the study subjects. We observed that Respiratory   distress,   Meconium   aspiration,    TTN,   NICU   admission   were comparatively   found   to   be   lesser   in   mifepristone   group   as   compared   to dinoprostone group.^[19] NICU admission were required more in dinoprostone group (10%), as comapred to mifepristone group (7.5%). Wing DA et al11 discovered that there  was  no  statistically  significant  difference  in  neonatal  outcome  between  the mifepristone-treated  and  control  groups.  Our  findings  are  similar  to  those  of Kanan  Yelikar,  who  found  no  statistically  significant differences  in  perinatal outcomes between two groups. Sandhya Kumari et al24 in their study observed that the NNU admission was less in mifepristone group 9 (10.2%) as compared to PGE2 group 15 (16.3%) and the proportion of NNU admission in group B was relatively more than the group A but no statistically significant difference was noted (p = 0.231).^[21] Three babies in each group  had  an  Apgar score  of  6  at  5  minutes  in  their  study,  and  there  was  no statistically significant difference between them (p= 0.956). Gaikwad et al.23 found that 6 and 14 percent of new-borns in the mifepristone and dinoprostone groups, respectively, required NICU admission, which was similar to our findings. Among the babies, 36% required baby unit admission in mifepristone. In contrast to our findings,  Sah  and  Padhye  discovered  that  in  the  mifepristone  group,  5  (10%) neonates  required  NICU  admission  while  in  the  dinoprostone  group,  1  (2%) babies required NICU admission.^[22]

Misoprostol an analogue of PGE1 appear to be perfect substitute for induction of labour. Its use was found to be associated with reduced time to delivery and high rate of vaginal delivery within 12 and 24 hours of induction. The requirement for oxytocin in augmentation was substantially reduced.

1. Roy RR, Mukhopadhyay A, Mukherjee K. Unexplained still birth. In: Mukherjee CG, Chakravarty S, Pal B, editors. Current Obstetrics and Gynaecology, 1st ed. New Delhi Jaypee Publishers; 2007, Page no; 147-5.

2. Lahra MM, Gordon A, Jeffery HE. Chorioamnionitis and Fetal Response in Still Birth. Am J Obstet Gynecol 2007; 196: 229-32.

3. Bugalho A, Bique C, Machungo F, Faaunder A. Induction of labor with intravaginal misoprostol in intrauterine fetal death. Am J Obstet Gynecol 1994; 171:538-41

4. Silver RM, Fetal Death. Obstet Gynecol 2007; 109: 153-6.

5. Fletcher HM, Wharfe G, Simeon D, Mitchell S, Brown D, Introduction of labor with intravaginal misoprostol versus dinoprostone in intrauterine death: a retrospective study. J Obstet Gynecol 1996; 16:155-8.

6. Nagi SW, Tang OS, Ho PC. Prostaglandins for induction of second trimester termination and intrauterine death. Best Pract Res Clin Obstet Gynecol. 2003; 17:765-75

7. Sitruk Ware, I.M. Spitz. Pharmacological properties of mifepristone: toxicology and safety in animal and human studies: Contraception 2003; 68:409-420.

8. Easmin S, Nahar K, Jahan MK, Rahim R, Nila TA, Nigar K, Khan NA: Intravaginal use of misoprostol for induction of labour in intrauterine death, Mymensingh Med J. 2011;20:566-9.

9. Skjoldebrand-spare, Toljvenstam,T Papadog-iarnakis, N wharan-B, Broliden, Nyman, Parvo virus B19 infection association with third trimester intrauterine foetal death; BJOG 2000;107:476-80.

10. Ranganath S, Shankaregowda HS. Medical Management of Late Intrauterine Death Using a Combination of Mifepristone and Misoprostol [MS thesis]. Bangalore: The Rajiv Gandhi University of Health Sciences; 2006

11.   Vayrynen W, Heikinheimo O, Nuutila M. Misoprostolonly versus mifepristone plus misoprostol in induction of labor following intrauterine fetal death. Acta Obstet Gynecol Scand 2007; 86: 701-5.

12.   Sharma D, Singhal SR, Poonam, Paul A, Kunika. Comparison of mifepristone combination with misoprostol and misoprostol alone in the management of intrauterine death: Condensation – Misoprostol and mifepristone combination is more effective than misoprostol alone in the management of intrauterine death. Taiwan J Obstet Gynecol 2011; 50:322-5.

13.   Praveena G, Shameem VP, Rao A, Rao B. Mifepristone plus misoprostol versus only -misoprostol in induction of labour in intrauterine fetal death. Int J Pharm Biomed Res 2013; 4:108-10.

14.   Newhall EP, Winikoff B. Abortion with mifepristone and misoprostol: regimens, efficacy, acceptability and future directions. Am J Obstet Gynecol 2000; 183:S44- 53. 15. WHO | Safe

15.   abortion: technical and policy guidance forhealth systems [Internet]. WHO. [cited 2014 Sep 16]. Available from: http://www.who.int/reproductivehealth/ publications/unsafe_ abortion/9789241548434/en/. 16. Wagaarachchi

16.   PT, Ashok PW, Narvekar NN, Smith NC, Templeton A. Medical management of late intrauterine death using a combination of mifepristone and misoprostol. BJOG 2002; 109:443-7.

17.   Prasai S. Outcome of induction of labour in primigravida term patient with poor bishop score with or without priming with PGE2 gel. Bangladesh College of Physicians and Surgeons 2000; 2: 76-9.

18.    Chittacharoen A, Herabutya Y, Punyavachira P. A randomized trial of oral and vaginal misoprostol to manage delivery in cases of fetal death. Obstet Gynecol 2003; 101:70-3.

19.   De Heus R, Graziosi GC, Christiaens GC, Bruinse HW, Mol BW. Medical management for termination of second and third trimester pregnancies: a comparison of strategies. Eur J Obstet Gynecol Reprod Biol. 2004; 116:16-21.

20.   Fairley TE, Mackenzie M, Owen P, Mackenzie F. Management of late intrauterine death using a combination of mifepristone and misoprostol experience of two regimens. Eur J Obstet Gynecol Reprod Biol. 2005; 118:/28-31.

21.   Vayrynen W, Heikinheimo O, Nutila M. Misoprostol only versus mifepristone plus misoprostol in induction of labour following intrauterine fetal death. Acta Obstetriciaet Gynecologica Scandinavica 2007; 86: 701–5.

22.   Shetty A, Danielian P, Templeton A. A comparison of oral versus vaginal misoprostol tablets in induction of labour at term.Br J ObstetGynaecol 2001; 108:238-243.