Archives of Medicine and Health Sciences

ORIGINAL ARTICLE
Year
: 2020  |  Volume : 8  |  Issue : 2  |  Page : 202--207

Effect of mifepristone-misoprostol versus misoprostol in the management of intrauterine fetal death: A comparative study


TR Sindhuri1, Sunita Samal2, Shweta Gupta3, Seetesh Ghose4,  
1 Mother Hood Women Center, Coimbatore, Tamil Nadu, India
2 Department of Obstetrics and Gynecology, SRM MCH and RC, Chennai, Tamil Nadu, India
3 Aster Specialty Medical Center, International City, Dubai, UAE
4 Department of Obstetrics and Gynecology, MGMC and RI, Puducherry, India

Correspondence Address:
Dr. Sunita Samal
Department of Obstetrics and Gynecology, SRM MCH and RC, Kattankulathur, Chennai, Tamil Nadu
India

Abstract

Background and Aim: The most undesirable consequence of pregnancy is intrauterine fetal death (IUFD) which causes a lot of emotional and medical distress for which medical induction of labor, by routinely used prostaglandins, is recommended. Therefore, the main aim of the study was to determine the management of IUFD using misoprostol alone and mifepristone-misoprostol combination. Materials and Methods: The study included 57 women of gestational age >24 weeks with IUFD, who were divided into two groups. Women between 24–34 and >34 weeks of gestation received 200 μg and 100 μg of misoprostol, respectively. Group A received misoprostol alone and Group B received oral mifepristone (200 mg), 24 h prior to receiving misoprostol. IUFD duration, number of misoprostol doses, induction-delivery interval (IDI), and bishop score were recorded. A majority of 23 patients in Group A had a bishop score <3 while 28 in Group B had a score between 4 and 6 at 0 h. The IUFD duration varied between 1 and 2 weeks in both the groups. Results: Group A received 4 doses and Group B received 1 dose of misoprostol (P < 0.001). Delivery induction was successfully achieved between 3.3–5 h (48.27%) and 5–8.3 h (51.72%) in Group B and between 11.6 and 16.6 h (57.1%) in Group A (P < 0.001). IDI was found to be shorter with increasing gestational age. Conclusion: It was observed that a lesser number of misoprostol doses and shorter duration of IDI in the combination therapy of mifepristone-misoprostol was a more effective and safer approach to induce labor than misoprostol alone in women with IUFD.



How to cite this article:
Sindhuri T R, Samal S, Gupta S, Ghose S. Effect of mifepristone-misoprostol versus misoprostol in the management of intrauterine fetal death: A comparative study.Arch Med Health Sci 2020;8:202-207


How to cite this URL:
Sindhuri T R, Samal S, Gupta S, Ghose S. Effect of mifepristone-misoprostol versus misoprostol in the management of intrauterine fetal death: A comparative study. Arch Med Health Sci [serial online] 2020 [cited 2021 Jun 23 ];8:202-207
Available from: https://www.amhsjournal.org/text.asp?2020/8/2/202/304715


Full Text



 Introduction



One of the most devastating outcomes of pregnancy is intrauterine fetal death (IUFD), encountered in 1% of pregnancies, which could be the result of hemoglobinopathies, diabetes mellitus, hypertensive, and medical disorders during pregnancy. Fetal causes include infections, Rh factor iso-immunization, malformation, and placental dysfunction.[1],[2],[3] The WHO has defined IUFD as the death of fetus at or after 28 weeks of gestation and at 1000 g weight.[4]

Over 90% of women with IUFD deliver spontaneously within 3 weeks of the event. The risk of coagulopathy and intrauterine infections is about 10% after this time period along with many ill effects on physical, psychological, and social aspects. Recommendation of medical induction thereby proves to be a safer option.[5],[6],[7] The ideal drug to terminate IUFD-related pregnancies should be safe, effective, and affordable to mainly avoid any further financial burden already arising from the pregnancy.[8]

The use of prostaglandins has been widely investigated for inducing labor in IUFD, mostly when the cervix is unripe, thereby proving them to be safe and effective.[6] Oral administration of misoprostol, a prostaglandin E1 analog, for labor induction was first described in Sao Paulo, Brazil in 1987.[9] It is preferred for its low cost, stability at room temperature, and ease of administration. It causes cervical ripening, softening, and dilation causing induction of labor. However, repeated doses cause unwanted systemic side effects such as nausea, shivering, fever, and diarrhea along with uterine hyperstimulation.[10] Mifepristone is a progesterone antagonist that has been administered prior to misoprostol which increases the uterine sensitivity to prostaglandins causing cervical ripening, thereby allowing lower doses of misoprostol to induce labor which has proven beneficial.[11],[12],[13],[14] Although various studies using the combination regimen in the management of IUFD have been reported, the optimum dose with good outcomes has not yet been established. Hence, the current study was conducted with an aim to compare the mifepristone-misoprostol combination with misoprostol alone in the management of IUFD at a tertiary care center in Puducherry, India.

 Materials and Methods



Study design

This comparative study was conducted at a tertiary care center in Pondicherry, India, between March 2013 and June 2014 after obtaining the institutional ethical committee clearance.

The study included 57 pregnant women (singleton pregnancy) of gestational age >24 weeks with IUFD. Women with multiple pregnancies, multipara, contraindication to vaginal delivery, scarred uterus after 34 weeks of gestation, IUFD in the active phase of labor, having medical conditions such as glaucoma or heart disease were excluded from the study. Sampling was achieved by computer-generated random method.

Data collection

Information on patient's age, parity, obstetric history, duration of IUFD, height, weight, and body mass index (BMI) were documented. Gestational age was verified by history, clinical examination, and ultrasound. IUFD was confirmed by the absence of cardiac activity on ultrasound. Patients in the current study were divided into two groups. Group A (n = 28) included patients with a gestational age of 24–34 weeks who received 200 μg of misoprostol and patients with a gestational age of >34 weeks who received 100 μg of misoprostol vaginally. Group B (n = 29) included patients who received 200 mg of oral mifepristone as outpatient medication irrespective of their gestational age. After 24 h, patients were admitted to the labor room. Patients with a gestational age of 24–34 weeks received 200 μg of misoprostol and patients with a gestational age of >34 weeks who received 100 μg of misoprostol in the posterior vaginal fornix.

After the injection of misoprostol to patients, additional doses of misoprostol (200 μg) were administered every 4 h up to a maximum of 4 doses until patients entered active labor. Bishop score was assessed after misoprostol administration.[15]

The induction-delivery interval (IDI) and the total number of misoprostol doses received by patients were also recorded. Achieving a successful induction of labor was the primary outcome of this intervention study. Maternal complications such as postpartum hemorrhage and retained placenta, side effects such as nausea, vomiting, diarrhea, and fever were also noted.

Statistical analysis

The statistical analysis was done using R v386 3.6.0 software. Student's t-test (two-tailed, independent) and Wilcoxon Rank-Sum test to define the significance of study parameters on continuous scale between two groups on metric parameters and Chi-square/Fisher's Exact test to define the significance of study parameters on categorical scale between two or more groups was performed. Results on categorical measurements were presented in number (%) and continuous measurements were represented as mean ± standard deviation with P = 0.05 considered as statistically significant.

 Results



The patients included in the study were between 19 and 30 years of age. The mean age of patients in Group A was 24.1 ± 3.36 years, and in Group B was 24.4 ± 3.08 years. The majority of the patients were between the age group 21 and 30 years with 78.57% in Group A and 79.31% in Group B followed by 17.86% and 20.69% in Group A and Group B respectively who were <20 years of age (P = 0.547), as shown in [Figure 1]a. The BMI of patients ranged from 18 to 30 kg/m2. The mean BMI of patients in group A was 22.8 ± 1.85 kg/m2, and in group B was 22.2 ± 1.58 kg/m2. Majority of the women had their BMI ranged between 18.5 and 23 kg/m2 with 42.86% and 62.07% of them in Group A and Group B respectively followed by 50% and 34.48% in Groups A and B, respectively with their BMI ranging between 23 and 25 kg/m2 (P = 0.143), as shown in [Figure 1]b. The number of primigravida women was 46.43% and 51.72% and of multigravida were 53.57% and 48.28% in Group A and Group B, respectively (P = 0.892), as shown in [Figure 1]c. The gestation period of the women under study ranged between 25 and 40 weeks. The mean gestational age in Group A was 33.4 ± 4.10 weeks and in Group B was 34.0 ± 3.75 weeks. The majority of the patients were between gestational age 29 and 32 weeks with 42.86% in Group A and 31.03% in Group B followed by 25% in Group A and 31.03% in Group B in gestational age group >33 weeks (P = 0.561), as shown in [Figure 1]d.{Figure 1}

The number of patients with duration of IUFD of <1 and 1–2 weeks, was 50% each in Group A. In Group B, 58.62% and 41.38% of patients had IUFD duration of <1 and 1–2 weeks respectively, which was statistically insignificant (P = 0.698), as shown in [Figure 2]a. With respect to the gender of the dead fetuses, 42.86% and 57.14% were female and male respectively in Group A. In Group B, 55.17% and 44.83% of the dead fetuses were female and male respectively, as shown in [Figure 2]b. The majority of the dead fetuses weighed between 1500 and 2500 g with 53.57% in Group A and 44.83% in Group B, as shown in [Figure 2]c.{Figure 2}

Majority (82.1%) of patients were with bishop score <3 in Group A at 0 h, 46.4% at 4 h and with just 1 patient in Group B. Majority of the patients with bishop score 4–6 in Group A were 53.6% at 4 h, 78.6% at 8 h and in Group B, 96.55% at 0 h and 100% at 4 h after drug administration. Bishop score of >6 was in 57.15% patients in Group A at 16 h and 86.2% in Group B at 8 h. The association between the bishop score and the number of patients with respect to time interval was found to be highly significant (P < 0.001), as shown in [Table 1].{Table 1}

After the first dosage of misoprostol, 82.1%, 57.1%, and 53.6% patients required the 2nd, 3rd, and 4th dose respectively in Group A. In Group B, only 10.7% of patients required the 2nd dose and none of them required the 3rd or 4th dose of misoprostol. The mean number of doses of misoprostol required was 2.93 ± 1.25 and 1.1 ± 0.31 in Groups A and B respectively with a statistical significance value of P < 0.001.

Majority of patients (57.1%) in group A delivered between 11.6 and 16.6 h followed by 21.43% between 8.3 and 11.6 h after misoprostol administration. In Group B, 48.27% of patients delivered within 3.5–5 h and the rest of them (51.72%) between 5 and 8.3 h after misoprostol administration. The mean IDI was 13.19 ± 3.67 h and 5.52 ± 1.04 h in Groups A and B respectively with their association being highly significant (P < 0.001), as shown in [Table 2].{Table 2}

Gastrointestinal side effects were observed in 8 patients in Group A with 3 of them exhibiting fever, 2 of them for vomiting, chills, and rigor and only 1 complaining of diarrhea. In Group B, only 3 patients exhibited side effects with 2 of them complaining of vomiting and 1 patient with fever.

The patients in Group A with bishop score <3 had mean IDI of 12.91 ± 3.61 h and those with bishop >3 had 14.51 ± 4.11 h. The association was statistically insignificant with a P value of 0.32 within Group A. The patients with bishop score >3 in Group B had a mean IDI of 5.48 ± 1.04 h. However, the association is not applicable because of just one patient with bishop score <3 in Group B. Patients with gestational age <34 weeks in both the Groups A and B respectively had mean IDI of 14.81 ± 2.53 h and 5.53 ± 1.04 h and those with gestational age >34 weeks had 11.33 ± 3.98 h and 5.51 ± 1.07 h. The IDI was shorter with increased gestational age in Group A (P = 0.02) but in Group B, it did not vary with gestational age (P = 0.89). All the primigravida women had mean IDI of 14.27 ± 3.51 h and 5.55 ± 0.86 h while multigravida had an interval of 12.26 ± 3.68 h and 5.5 ± 1.25 h in Groups A and B, respectively. The parity had insignificant effect on IDI in both the groups (Group A, P = 0.11; Group B, P = 0.80), as shown in [Table 3].{Table 3}

 Discussion



The major cause of prenatal mortality, mostly in developing countries is IUFD. With various complications that follow IUFD, induction of labor is of high priority. With misoprostol being widely used, earlier reports indicate successful induction of labor using mifepristone.[16] It was also observed in earlier studies that mifepristone-misoprostol when used in a combination, proved to be a safe and effective regime to induce labor in IUFD.[17],[18]

In the current study that was conducted over 57 pregnant women, the efficacy and safety of mifepristone-misoprostol combination with misoprostol alone in the management of IUFD. Previously conducted preliminary trials resulted in no side effects while using mifepristone to induce labor at a mean gestational age of >18 weeks.[16],[19],[20] Regarding its safety aspect, the current study included women of gestational age >24 weeks.

The mean age of patients in the current study was 24.1 ± 3.36 years in Group A (misoprostol alone) and 24.4 ± 3.08 years in Group B (combination). The age distribution in the present study was comparable with the other studies reported.[13],[10],[21] The BMI of patients was well within normal limits, with a mean BMI of 22.8 ± 1.85 and 22.2 ± 1.58 kg/m2 in Groups A and B, respectively. The range limit was comparable with other reports.[8],[22] The majority of the women in the study were multigravida. The mean gestational age in the study (33.4 ± 4.10 weeks for Group A and 34.0 ± 3.75 weeks for Group B) was comparable with other reports.[10],[14],[18],[21] The duration of IUFD among the women varied between 1 and 2 weeks and the majority of the fetuses weighing between 1500 and 2500 g, comparable to those observed in other reports.[22],[23] However, the association of women with respect to their age, BMI, gestational age, and IUFD duration was found to be nonsignificant (P > 0.05).

Successful delivery induction was achieved between 3.3–5 and 5–8.3 h in 48.27% and 51.72% women respectively in the combination group. With respect to the misoprostol group, the majority of 57.1% of women delivered between 11.6 and 16.6 h. Similar results were observed in a study conducted by Panda et al., Sharma et al., and Trivedi et al.[18],[21],[24] However, the longer duration for delivery induction (>15 h) in both misoprostol alone and combination group has been reported.[8],[10] Therefore, IDI was much shorter in the combination group as compared to misoprostol alone (P < 0.001) which may be attributed to the priming effect of mifepristone. The mean number of doses of misoprostol administered to the women in the current study was less in the combination group (1.1 ± 0.31) in comparison to the misoprostol group (2.93 ± 1.25), owing to the effective cervical ripening facilitating the expulsion of the products of conception by prior injection of mifepristone. The effect was found to be statistically significant (P < 0.001). Similar dosage levels were reported in earlier studies.[17],[21]

Among the 57 women included in the study, 23 from Group A and all in Group B had a bishop score <3 at the initial assessment period. However, after drug administration, the combination group had improved bishop's score as compared to the misoprostol group which was statistically significant (P < 0.001) at every 4 h interval. Earlier studies support the data.[17],[21] Due to the longer time gap between mifepristone dose and the following misoprostol dosage administration, 24 h in the current study, the number of subsequent doses of misoprostol was more in comparison to other studies.[14] The administration interval between mifepristone and misoprostol is 36–48 h but certain complications such as uterine bleeding and psychological issues may occur during this time period which can be altered to a shorter administration time interval.[25]

Although the number of doses in the current study (up to 4 doses in Group A and 2 doses in Group B) was comparable to that observed in the study conducted by Maheshwari and Borgohain[8] Mild gastrointestinal side effects such as fever, vomiting, diarrhea, chills, and rigor were observed more in the misoprostol group. Complications such as postpartum hemorrhage, uterine tachysystole, retained placenta, and coagulopathy were not encountered during the study comparable with previous reports.[20],[21] On comparing IDI with bishop score and parity, the association was insignificant in both the groups. However, the IDI association with the gestational age in group A women was significant with a P = 0.02 but insignificant in group B with a P = 0.89. IDI was found to be shorter with increasing gestational age comparable to that observed in other studies.[17],[20],[26] However, in some studies, no significant difference was achieved.[21],[27]

This study with an average dose, fewer side effects, and shorter IDI may be used as a standard regimen for the management of IUFD. In India, majority of the people belong to low socioeconomic status. Thereby, the delivery cost must be cost-effective for any appropriate regimen. Although only misoprostol regimen was cheap, side effects and IDI were more within this group. Therefore, the combined regimen of mifepristone-misoprostol should be considered as an option for delivery induction in IUFD, after counseling the women for its benefits and cost.

 Conclusion



In the current study, which was aimed to manage the IUFD through misoprostol alone and mifepristone in combination with misoprostol, successful induction was achieved with the combination therapy leading to a shorter IDI. The requirement of subsequent doses of misoprostol was significantly less in patients pretreated with mifepristone along with an improvement in the bishop score. Therefore, the combination therapy was found to be more effective than misoprostol alone for labor induction in women with IUFD which constituted to be safe and more efficacious. However, the study needs to be performed with a larger sample size along with varying dosage levels of misoprostol to define the optimum management of IUFD.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

References

1Roy RR, Mukhopadhyay A, Mukherjee K. Unexplained still birth. In: Mukherjee CG, Chakravarty S, Pal B, editors. Current Obstetrics and Gynecology. 1st ed. New Delhi: Jaypee Publishers; 2007. p. 147-53.
2Lahra MM, Gordon A, Jeffery HE. Chorioamnionitis and fetal response in stillbirth. Am J Obstet Gynecol 2007;196:229.e1-4.
3Silver RM. Fetal death. Obstet Gynecol 2007;109:153-67.
4WHO. Maternal, Newborn, Child and Adolescent Health. Available from: https://www.who.int/maternal_child_adolescent/epidemiology/stillbirth/en/. [Last accessed on 2020 Jan 06].
5Rådestad I, Steineck G, Nordin C, Sjögren B. Psychological complications after stillbirth Influence of memories and immediate management: Population based study. BMJ 1996;312:1505-8.
6Gomez R. Misoprostol for intra uterine fetal death. Int J Gynaecol Obstet 2007;99 Suppl 2:S190-3.
7Mandal M, Chaudhuri A, Banerjee D, Kanrar P, Hazra SK. Impact of management protocols of intrauterine fetal death on perceived stress: A comparative study. J Sci Soc 2017;44:121-5.
8Maheshwari S, Borgohain D. Methods of induction of labor in intrauterine fetal demise: A comparative study. Int J Reprod Contracept Obstet Gynecol 2017;6:3911-4.
9Mariani Neto C, Leao EJ, Barreto EM, Kenj G, de Aquino MM, Tuffi VH. Use of misoprostol for labour induction in still birth. Rev Paul Med 1987;105:325-8.
10Arjunan Y, Nichanahalli KS, Pampapati V, Maurya DK, Subrahmaniyan SR. Oral misoprostol with mifepristone versus misoprostol alone for inducing labor in intrauterine fetal death: A randomized placebo-controlled trial. Int J Adv Med Health Res 2017;4:23-6.
11Robbins A, Splitz IM. Mifepristone: Clinical pharmacology. Clin Obstet Gynecol 1996;39:436-50.
12Ngoc NT, Shochet T, Raghavan S, Blum J, Nga NT, Minh NT, et al. Mifepristone and misoprostol compared with misoprostol alone for second-trimester abortion: A randomized controlled trial. Obstet Gynecol 2011;118:601-8.
13Nagaria T, Sirmor N. Misoprostol vs mifepristone and misoprostol in second trimester termination of pregnancy. J Obstet Gynaecol India 2011;61:659-62.
14Abbasi S, Siddiqua SF, Alam MN, Jesmin S, Siddiqui MM, Rahman MT. Role of combined mifepristone and misoprostol verses misoprostol alone in induction of labour in patients with intrauterine foetal death – A randomized comparison between their outcome. Anwer Khan Mod Med Coll J 2017;8:50-4.
15Wormer KC, Williford AE. Bishop Score. In: StatPearls. Treasure Island (FL): StatPearls Publishing; 2019. Available from: https://www.ncbi.nlm.nih.gov/books/NBK470368/. [Last acces?sed on 2019 Jan 07].
16Cabrol D, Dubois C, Cronje H, Gonnet JM, Guillot M, Maria B, et al. Induction of labor with mifepristone (RU 486) in intrauterine fetal death. Am J Obstet Gynecol 1990;163:540-2.
17Väyrynen W, Heikinheimo O, Nuutila M. Misoprostol-only versus mifepristone plus misoprostol in induction of labor following intrauterine fetal death. Acta Obstet Gynecol Scand 2007;86:701-5.
18Panda S, Jha V, Singh S. Role of combination of mifepristone and misoprostol verses misoprostol alone in induction of labour in late intrauterin fetal death: A prospective study. J Family Reprod Health 2013;7:177-9.
19Fairley TE. Management of intrauterine fetal death using a combination of mifepristone and misoprostol – Experience of two regimens. Eur J Obstet Gynecol Reprod Biol 2005;118:28-31.
20Wagaarachchi 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.
21Sharma D, Singhal SR, Paul A. Comparison of mifepristone combination with misoprostol and misoprostol alone in the management of intrauterine death. Taiwanese Journal of Obstetrics and Gynecology. 2011;50(3):322-5.
22Modak R, Roy S, Biswas DK, Pal A, Mandal TK. Role of combination of mifepristone and misoprostol versus misoprostol alone in induction of labor in late intrauterine fetal death: A randomized trial. Int J Clin Obstetr Gynaecol 2018;2:78-82.
23Chaudhuri P, Datta S. Mifepristone and misoprostol compared with misoprostol alone for induction of labor in intrauterine fetal death: A randomized trial. J Obstet Gynaecol Res 2015;41:1884-90.
24Trivedi K, Swati A, Shrivastava P, Singh S. Mifepristone followed by prostaglandin vs prostaglandin alone for induction of labour in intrauterine foetal death at or more than 28 weeks of pregnancy. Int J Contemp Med Res 2019;6:J5-9.
25Wedisinghe L, Elsandabesee D. Flexible mifepristone and misoprostol administration interval for first-trimester medical termination. Contraception 2010;81:269-74.
26El-Gharib MN, El-Ebyary MT, Alhawary TS, Elshourbagy SH. Low dose vaginal misoprostol in the management of women with intrauterine fetal death. Clin Med Insights: Women's Health 2010;3:15-21.
27Tharihalli C, Bhat S. Study of vaginal misoprostol for labour induction in intra uterine fetal demise. Int J Reprod Contracept Obstet Gynecol 2017;6:479-84.