Role of isosorbide mononitrate in induction of labour: A single arm clinical trial at a tertiary care hospital

Introduction and Aim: Isosorbide mononitrate, a nitric oxide donor, induces the enzyme cyclo-oxygenase-2, leading to production of local prostaglandins in human cervix and leads to structural rearrangement of the collagen network and thereby the cervix ripens. The aim of this study was to determine the role of Isosorbide mononitrate in induction of labour, determine induction delivery interval and obstetric and neonatal outcome. Materials and Methods: This study was an interventional study on 40 pregnant women conducted for a period of one year. Women requiring induction of labour, who met the inclusion criteria, were enrolled. Isosorbide mononitrate (40 milligrams) was inserted in the posterior fornix. If Bishop's score did not change after 24 hours of the initial dose, failure of induction of labour was considered. Those patients in whom labour pains started after isosorbide mononitrate alone were considered to be in successful group(A) while those who required additional drugs like prostaglandins were considered to be in the failed group(F). Results: The mean (SD) Bishop score after 1dose of isosorbide mononitrate in the successful group (A) was 6.04 (2.16) and in the failed group (F) was 3.81 (0.83). There was a significant difference in terms of Bishop Score after 1 Dose of IMN (W = 310.000, p = 0.001) and in terms of induction-delivery time in hours (t = -2.386, p = 0.023). Conclusion: This study concludes that Isosorbide mononitrate has significant role for induction of labor in terms of Bishop score changes and induction delivery interval.


INTRODUCTION
nduction implies stimulation of contractions before the spontaneous onset of labour, with or without rupture of membranes (1). With recent advances in fetal as well as maternal monitoring antenatally, the indications for induction of labour is increasing. Also, resource-constrained facilities refer high risk patients to higher centres, leading to more inductions at tertiary hospitals (2). Most important factor guiding successful induction is condition of cervix i.e., Bishop's score (3). In case of Intrauterine fetal death, mode of birth is largely dependent on fetal gestational age and maternal clinical history, with consideration of the couple's personal preference (4). There is a basket of choices for ripening of cervix, such as oxytocin infusion, intracervical Foley's catheter insertion, intravaginal prostaglandins analogue like misoprost and Dinoprostone gel.
Isosorbide mononitrate, a nitric oxide donor, induces the enzyme cyclo-oxygenase-2, leads to production of local prostaglandins in human cervix and structural rearrangement of the collagen network and thereby the cervix ripes (5)(6)(7). This drug does not cause uterine hyperstimulation as is met with prostaglandin analogues. Thus, fetal distress is less observed compared to prostaglandin analogue. It can also be used in induction of labour in those with scarred uterus (8)(9)(10)(11). Side effects of isosorbide mononitrate are few like nausea, vomiting, light-headedness (12). Use with vasodilating drugs like sildenafil is contraindicated (13,14). The aim and objectives of our study were to determine the role of isosorbide mononitrate in induction of labour, induction delivery interval and obstetric and neonatal outcome. Women requiring induction of labour, who met the inclusion criteria, were enrolled. Detailed history, general and obstetrical examination was taken. Vaginal examination was done to rule out cephalopelvic disproportion and to assess the Bishop's score. Confirmation of gestational age was done by Naegle's formula and first trimester ultrasonography. Ultrasonography was done in labour room to assess amniotic fluid index, period of gestation, estimated fetal weight and reconfirm fetal presentation and placental localisation.

MATERIALS AND METHODS
Complete blood count, maternal blood grouping, routine examination of urine, blood sugar levels and viral markers were done, if not done before. Admission Non stress test as taken.
After taking consent, Isosorbide mononitrate (40 milligrams) was inserted in the posterior fornix. Second dose was repeated after 6 hours, if needed. Fetal heart rate and uterine contraction monitoring were done according to standard guidelines. Maternal pulse rate and blood pressure were also monitored. After 12 hours, if cervix was more than 3 cm dilated, oxytocin infusion was started at the rate of 2mU/min with increments of 2 mU/min every 30 minutes up to a maximum dose of 8 mU/min. If Bishop's score did not change after 24 hours of the initial dose, failure of induction of labour was considered. Depending upon the reason of induction, prostaglandin analogue PGE2, 2 doses was given if not contraindicated. LSCS was done for fetal distress or other obstetric indications.
Different outcomes measured were changes in Bishop Score, Induction-Delivery interval, Mode of delivery (spontaneous vaginal, instrumental vaginal or LSCS), Neonatal outcome (APGAR score, Birth weight and Neonatal intensive care unit admission).

Statistical analysis
Sample size calculation: The sample size was calculated Sample size N = 4*Zα 2 σ 2 /δ 2 The sample size for the study was based on a study by Agarwal et al., (16)

RESULTS
The mean (SD) age (years) in the induction with IMN alone: Successful (A) group was 25.12 (2.92). The mean (SD) age (years) in the induction with IMN alone: Failed (F) group was 25.25 (4.12). 65.2% of the participants in the succeeded group were primigravida. 34.8% of the participants were multigravida. There was no significant difference between the various groups in terms of age (t = -0.105, p = 0.917) and parity (X^2 = 0.321, p = 0.571). (Table-1) 45.8% of the participants in the succeeded group were of term pregnancy and 54.2% were of postdated. There was no significant difference between the various groups in terms of period of gestation (X^2 = 0.017, p = 0.897).

DISCUSSION
The induction of labour requires when the risks overweigh the benefits of continuing pregnancy. The condition or the favourability of cervix is an important prognostic factor in the success of induction of labour. Several studies are being done to identify the ideal cervical ripening agent. A significant number of women complained of headache but all responded to analgesics.
In our study, the mean (SD) Bishop Score after 1Dose of IMN in group A was 6.04 (2.16)  None of the neonate's in-group A of our study required NICU admission. In study done by Krishnamurthy et al., (17), only 1 neonate was admitted in NICU and discharged after 2 days.
The limitation of our study was its small sample size and so further research is needed on a larger population so that results can be externally validated.

CONCLUSION
Labour induction is needed by many pregnant women. Though prostaglandin gel is considered to be quite effective in inducing labour, this study shows the utility of Isosorbide mononitrate as cervical ripening and labour inducing agent. This drug is cheap and does not require refrigeration. These are its advantages over Prostaglandin gel. Fetal distress is often seen with prostaglandins. But in this study, Isosorbide Mononitrate proved to be safe for the neonate. Headache is one significant side-effect which the patients need to be counselled beforehand and is amenable to treatment.