A RANDOMISED PLACEBO CONTROLLED TRIAL TO COMPARE MATERNAL AND
FETAL EFFECTS FOLLOWING DISCONTINUATION VERSUS
CONTINUATION OF OXYTOCIN IN ACTIVE STAGE OF INDUCED LABOURS
A dissertation submitted to the Tamil Nadu Dr. M.G.R.Medical University, Chennai in partial fulfillment of the requirement for the M.S. Obstetrics and Gynaecology degree examination to be held in
May 2020
A RANDOMISED PLACEBO CONTROLLED TRIAL TO COMPARE MATERNAL AND FETAL EFFECTS FOLLOWING DISCONTINUATION VERSUS CONTINUATION OF OXYTOCIN
IN ACTIVE STAGE OF INDUCED LABOURS
Dissertation submitted to
THE TAMIL NADU DR.MGR MEDICAL UNIVERSITY, CHENNAI In partial fulfillment of the requirements for the degree of
MASTER OF SURGERY IN
OBSTETRICS AND GYNAECOLOGY BY
MRUDUL SHASHIKANT SHINGE
REGISTER NUMBER: 221816407
DEPARTMENT OF OBSTETRICS AND GYNAECOLOGY VELLORE
MAY 2020
CERTIFICATE
This is to certify that the dissertation entitled “Randomised placebo controlled trial to compare maternal and fetal effects following discontinuation versus continuation of oxytocin in active stage of induced labours” is the original work of Dr. MrudulShashikantShinge towards the MS branch VI(Obstetrics and Gynaecology) Degree examination of the Tamil Nadu Dr.M.G.R University, Chennai to be held in May 2020.
Signature:
Guide:
Dr. ManishaMadhai Beck Professor and Head of Unit 4 Obstetrics and Gynaecology Christian Medical College Vellore- 632004, India
Co-Guides:
Dr. Liji Sarah David
Dr. Benjamin Jeyanth Ross
Mr. BijeshYadav
CERTIFICATE
This is to certify that the dissertation entitled “ Randomised placebo controlled trial to compare maternal and fetal effects following discontinuation versus continuation of oxytocin in active stage of induced labours” is the original work of Dr. MrudulShashikantShinge towards the MS branch VI (Obstetrics and Gynaecology) Degree
examination of the Tamil Nadu Dr.M.G.R University, Chennai to be held in May 2020.
Signature:
Head of Department:
Dr. Jiji Elizabeth Mathews
Professor and Head of Department Obstetrics and Gynaecology
Christian Medical College
Vellore- 632004
CERTIFICATE
This is to certify that the dissertation entitled “ Randomised placebo controlled trial to compare maternal and fetal effects following discontinuation versus continuation of oxytocin in active stage of induced labours” is the original work of Dr. MrudulShashikantShinge towards the MS branch VI (Obstetrics and Gynaecology) Degree examination of the Tamil Nadu Dr.M.G.R University, Chennai to be held in May 2020.
Signature:
Principal,
Dr. Anna Pulimood
Christian Medical College
Vellore- 632004, India
DECLARATION
This is to certify that the dissertation entitled “ Randomised placebo controlled trial to compare maternal and fetal effects following discontinuation versus continuation of oxytocin in active stage of induced labours” which is submitted by me in partial fulfillment towards M.S. Branch VI (Obstetrics and Gynaecology) Degree examination to be held in May 2020 under the supervision and guidance of Dr.
ManishaMadhai Beck, Professor and Head of Unit 4 Department of Obstetrics and Gynaecology, Christian Medical College, Vellore represents my original research work and information taken from secondary sources has been given due acknowledgement and citation.
SIGNATURE:
MrudulShashikantShinge P G Registrar
Department of Obstetrics and Gynaecology Christian Medical College
Vellore- 632004
PLAGIARISM CERTIFICATE
ACKNOWLEDGEMENTS
I would like to thank God for Hisgrace and leading which enabled me to work to complete this dissertation.
I take this opportunity to express my heartfelt gratitude to my guide Dr.
ManishaMadhai Beck for herinsight, supervision, support and encouragement throughout this study.
I sincerely acknowledge the help of my co guides Dr. Liji Sarah David and Dr Benjamin Jeyanth Ross
I would also like to thank Mrs. Alice, Mrs. Pushpa and Mr. Madhan for their help. I would also like to thank Mr. Dany for the tamil translation and
Mr.Bijesh and Ms. Dona for the statistical analysis in this study.
I thank my family and friends for their prayers, support and encouragement.
I could not have done this study without the consent and co-operation of my
patients and want to thank them for their contribution.
TABLE OF CONTENTS
INTRODUCTION ... 1
METHODS OFLABOUR INDUCTION ... 6
REVIEW OF ... 8
LITERATURE ... 8
AIMS AND OBJECTIVES ... 27
MATERIALS ... 29
AND ... 29
METHODS ... 29
RESULTS ... 40
DISCUSSION ... 63
CONCLUSION ... 73
BIBLIOGRAPHY ... 78
ANNEXURES ... 82
ANNEXURE 1 : CLINICAL RESEARCH FORM ... 82
ANNEXURE 2 : CONSENT FORM ... 85
ANNEXURE 3 : INFORMATION SHEET ... 93
ANNEXURE 4 : IRB APPROVAL ... 94
ANNEXURE 5 :DATA SHEET ... 98
1
INTRODUCTION
2
INTRODUCTION
Induction of labour (IOL) is a common obstetric procedure. It is defined as stimulation of uterus using artificial methods , prior to spontaneous onset of labour , with the aim to deliver the feto-placental unit. (1)
Historically, labour induction dates back to Hippocrates’ time when nipple stimulation and mechanical dilatation of cervix were used for the first time .(2)
Induction of labour is the most common procedure performed in obstetrics in United States (3) In the United Kingdom, Induction of Labour was performed in 22.1% of all deliveries in 2011 and 2012. (4)
In Australia, the procedure was performed in 25.4% of all deliveries during the same time period (5). The frequency of IOL in Latin America and Asian countries is 11.4% and 12.1% respectively. (6)In our setup, 40% pregnancies undergo labour induction at term .
3
INCREASING TRENDS OF ELECTIVE INDUCTION OF LABOUR
There has been an increasing trend in labour induction in the recent years. In the United States, the rate of labour induction has steadily climbed from 9.6% in 1990 to 23% in 2005 In our setup, 40% pregnancies undergo labour induction at term .(7)
Similar trends have been noticed in other developed countries (8)
Various factors have contributed to this increase in induction of labour. These include widespread availability of cervical ripening agents ; routine use of ultrasound during pregnancy ; use of fetal monitoring and rise in medicolegal cases . (9)
Induction of labour is justified in circumstances when the risk of ongoing pregnancy outweighs the risk associated with labour induction. For example, in a post-date pregnancy, it is frequently used to prevent adverse perinatal outcomes.
Elective induction, on the other hand , is defined as labour induction carried out in the absence of medical or obstetrical indications. The American College of Obstetricians and Gynecologists recommend to avoid labour induction unless there is a risk of maternal or fetal compromise with the ongoing pregnancy (7).
4
The Society of Obstetricians and Gynecologists of Canada( SOGC), the Royal College of Obstetricians and Gynaecologists (RCOG), and the National Institute for Clinical Excellence (NICE), have similar guidelines discouraging this practice.(8)(10).
INDICATIONS FOR LABOUR INDUCTION:
Gestational age > 41 completed weeks Prelabour rupture of membranes Post dates pregnancy
Hypertensive disorders in pregnancy Gestational/pregestational diabetes Intrauterine demise
Fetal growth restriction Multiple pregnancy Chorioamnionitis
Antepartum haemorrhage Decreased fetal movements
5
Cholestasis of pregnancy
There are pharmacologic and non pharmacologic methods used for labour induction.
Pharmacologic methods include use of prostaglandins , PGE1 and PGE2, and Oxytocin.
Non pharmacologic methods include
Stretch and sweep; amniotomy and use of mechanical methods such laminaria tents and Foley’s bulb.
As per American College of Obstetricians and Gynecologists (ACOG), the pre induction checklist should include the following : (11)
(1)Ensuring the gestational age is correct (2) determining fetal presentation
(3) estimated fetal weight
(4) assessing pre induction cervical/Bishop score (5) Evaluating fetal heart rate (FHR) pattern
(6) Reviewing pregnancy and medical complications
6
METHODS OFLABOUR INDUCTION
There are many methods used for labour induction. Mechanical methods include laminaria tents and balloon catheters , ACOG and WHO guidelines routinely recommend the use of balloon catheters .(7)
NICE guidelines, on the other hand, state that although mechanical methods may reduce the incidence of hyperstimulation , but do not improve the rate of vaginal birth within 24 hours.(8)
Pharmacological agents used for labourinduction include , prostaglandin E1
(PGE 1) ; Prostaglandin E2( PGE2 ) and oxytocin. ACOG supports the use
of both PGE1 and PGE2 for cervical ripening and induction . They also
support the use of oxytocin for this purpose.(7)
7
NICE guidelines, on the other hand, recommend the use of PGE2 over
PGE1. The use of intravenous oxytocin alone is not recommended by
NICE(8).
8
REVIEW OF
LITERATURE
9
REVIEW OF LITERATURE
Oxytocin is one of the most widely used pharmacological agents used for induction and augmentation of labour. (12)It is an octapeptide amine which was first isolated and synthesized by Vincent van Vigneaud in 1954 (13)
FIGURE A: Oxytocin molecular structure
10
PHARMACOLOGY AND EFFECTS OF OXYTOCIN
Oxytocin is a natural hormone produced in the body by the posterior pituitary gland and is released inlarge amounts following distension of the birth canal and cervical dilatation. It has a half life of 5-12 minutes . A steady state plasma concentration is established in 40 minutes and it has a steadyresponse of the uterus for 30 minutes or so. (1)
It can’t be given orally because the polypeptide is degraded into small, inactive forms by gastrointestinalenzymes . Thus intravenous route is the preferred route of administration.
The pharmacological actions of oxytocin are mediated via high affinity receptors situated in the myometrium. These increase in number as gestation advances and increase by 100 fold at 32 weeks and 300 fold at parturition. (1)The sensitivity of the myometrium to oxytocin is determined by the concentration and the binding kinetics of oxytocin receptors. (14)
11
Known advantages of oxytocin are initiation and augmentation of uterine contractions . Continuous oxytocin infusion given intravenously during labour has been recommended by various guidelines and is being used by obstetricians.(15)
Oxytocin has been used in “high dose” and “low dose” protocols . While the high dose regimens are supposed to result in short labours, they are also associated with increased incidence ofhyperstimulation , resulting in FHR changes (16)
A common complication of its use is uterine hyperstimulation . , which is defined as presence of more than five contractions in 10 minutes. (7)When the contractions are too frequent and too strong the relaxation period between contractions is not enough for fetus to recover sufficient oxygen , leading to fetal compromise , presenting as non reassuring FHR (fetal heart rate) (17)
Bakker et al found that use of oxytocin in labour almost doubles the likelihood of uterine hyperstimulation and triples the likelihood of immediate intervention due to hyperstimulation .(18)
12
Use of oxytocin has also been associated with other adverse effects such as maternal hypotension ;tachycardia and arrhythmias. (19)Oxytocin relaxes vascular smooth muscle , resulting in tachycardia and hypotension when given in doses > 5 units rapid intravenous injection. (20)
Oxytocin , especially when given in high doses, can lead to maternal hyponatremia . This is because it binds to ADH (Anti diuretic hormone ) receptors in maternal kidney and promotes water retention (21)
Fernandez et al found an increased risk of postpartum haemorrhage ;
uterine rupture and unsuccessful breast feeding (22)Recent studies have shown that administration of exogenous oxytocin in labour crosses the placental barrier, suppresses the endogenous production of oxytocin in the fetus, which may have long term implications on the behavioural development of thechild. (23)
Owing to the above mentioned complications of uterine hyperstimulation and uterine rupture, the pregnant woman’s mobility is restricted due to need for continuous monitoring of fetus
13
and mother when the latter is on oxytocin for labour induction and /or augmentation .Hence , theconcept of down regulation of oxytocin receptors in active stage of induced labours has been explored extensively.
FIGURE B :OXYTOCIN VIAL FOR INTRAVENOUS USE
14
FIGURE C : CTG showing tachysystole following oxytocin administration, leading to Fetal bradycardia
15
FIGURE D: Uterine hyperstimulation :,hypertonus , following oxytocin administration resulting in fetal bradycardia
16
FIGURE E: CTG image showing hypertonus with fetal bradycardia, related to oxytocin use
17
FIGURE F: CTG image showing abnormal fetal heart rate (recurrent variable decelerations due to tachysystole (>5 contractions in 10 mins) during labour in a woman on oxytocin infusion
18
STRUCTURE OF OXYTOCIN RECEPTORS(24)
Oxytocin is synthesized by suprachiasmatic and paraventricular nuclei of hypothalamus. The Special anatomical structure of the neurons make dual role of oxytocin as hormone as well as neurotransmitter possible .
Oxytocin receptors are seen in uterus; ovary; testis; adrenal glands; thymus and pancreas. The Oxytocin receptor (OTR)belongs to A-G protein coupled receptor (GPCR) family and containsseventransmembrane alpha helices containing 389 amino acid residues .
Oxytocin receptors can be coupled to subunits such as Gq; Gi1; Gi2; Gi3; GoA;
GoB. Coupling withGq subunit can cause increase in cytosolic calcium concentration whereas coupling with Gi subunit can inhibit adenylatecyclase activity .
19
Oxytocin receptor 5and 6 transmembrane regions are specially recognized by oxytocin .Upon Binding to oxytocin, the receptor undergoes change in affinity, bringing about biological activity or function .
FIGURE G: The oxytocin receptor has seven transmembranealpha helices, containing 389 amino acid residues
20
OXYTOCIN SIGNALING PATHWAY CASCADE(24)
Oxytocin promotes uterine contraction through activation of calcium channels associated withreceptors and release of sarcoplasmic reticulum calcium. Oxytocin binds to the receptors andmediated by second messenger, increases the production of 1,4,5 triphosphate inositol.
This causes release of intracellular calcium in endoplasmic reticulum and sarcoplasmic reticulum .Oxytocin also brings about muscle contraction by producing action potentials through receptor activated,
non selectivecation channels that depolarize cell membranes
CONCEPT OF DOWNREGULATION OF RECEPTORS
Although exogenous oxytocin is used for augmentation of labour, prolonged oxytocin use has been associated with poor uterine contractility ; uterine atony and subsequently dysfunctional labour.
21
This can be explained on the basis of phenomenon of receptor downregulation . Oxytocin binds to receptors in the myometrium and stimulates myometrial contractions and production of prostaglandins in the decidua. (25)(26)
Studies have shown that lower number of receptors are present in laboring women who have beengiven large doses or longer infusions of oxytocin in comparison to those who receive it in smaller doses and for shorter duration. (27)This is because of downregulation of the oxytocin receptors.
Moreover, studies have also shown that after 10 hours of oxytocin use , the myometrium receptorconcentration diminishes and further oxytocin administration may have no or negative effect onmyometrial contractility (28)
CURRENT EVIDENCE IN MEDICAL LITERATURE .
There has been , a concern about the use of oxytocin infusion for labour induction and augmentation. (29)Despite the widespread use of oxytocin, there is no consensus yet on whether it should be continued or discontinued in active labour.
(3, 22- 24)
22
Various studies have been done comparing obstetric outcomes between two groups :discontinuationversus continuation of oxytocin infusion once active labour is reached. (1)(12)(13)(30)(31). While some ofthem found a decrease in the rate of LSCS and uterine hyperstimulation in the women where oxytocin was discontinued in active labour(30)(32)still others found no change or even increase in the LSCS rates (1) (31).
The main concern when discontinuing oxytocin in the active stage of labour is the prolongation of labour in these women. (31)(33). On the other hand, some studies have not found any difference in the duration of active labour between the two groups(34)(30).
23
HOW THE INTERVENTION MIGHT WORK
There have been trials published from clinical practice that support the discontinuation of oxytocin in active labour, hence reducing maternal and neonatal complications. (1)(12)(30)This enables for a more natural childbirth mechanism after an artificial induction of labour and augmentation with oxytocin.
Discontinuation may reduce the risk of uterine tachysystole and the associated risk of decreased fetal oxygen supply causing fetal distress and the need for immediate delivery. Thus in theory, discontinuation of oxytocin during the active phase could be more effective and safer than conventional continuous administration/ infusion.
Theoretically once active labour is established, the endogenous production of hormone from endometrium disrupted by contractions maybe enough to maintain appropriate uterine activity without further stimulation with exogenous oxytocin.
This will enable oxytocin to retain its potency by reducing the oxytocin receptor desensitization.(17)
24
Oxytocin is used injudiciously and has a potential risk of both maternal and fetal adverse effects. Hence, reducing the duration of oxytocin stimulation during labour will probably reduce the risk of caesarean delivery and the number of newborns with asphyxia sequelae, and this in turn will decrease the risk of expensive litigation. According to a survey of liability of cases by Clark et al, approximately 50% of paid liability claims affecting maternity services involved alleged misuse of oxytocin.
JUSTIFICATION FOR THIS STUDY
A Cochrane systematic review and metaanalysis also looked at this area. This included ten RCTs(Randomized Controlled Trial ) involving 1888 women (9) . The authors concluded that discontinuing oxytocin in active stage of labour may decrease the LSCS rates but the evidence is of lowcertainity since the studies were
“at risk of bias”. Hence more RCT’s are needed to draw further conclusions.
The use of placebo in such studies have been used by only3 RCTs(1,22,(35)All of these have have used 500 ml of 0.9% normal saline as a placebo. Our study plans to use placebo in the Group I whereoxytocin is discontinued.
25
With oxytocin use , the American College of Obstetricians and Gynecologists recommend fetal heart rate monitoring and contraction monitoring similar to that for any high risk pregnancy . (7)This may not be possible in a high volume centre like ours where there are 14000 deliveries per annum.
Most of our pregnant women receive oxytocin for augmentation of labour.However , one on one monitoring is not possible and low risk mothers are left with suboptimal monitoring, even when they are on oxytocin. This is potentially hazardous and may lead to serious complications like uterine rupture or perinatal asphyxia. Discontinuation of oxytocin , if found beneficial , will enhance the safety of laboring mothers and decrease the burden of clinical workload.
At present our overall LSCS rate is around 30%. Nearly half of these (43%) are done for fetal distress . If this strategy of discontinuing oxytocin in active labour is found to be effective in reducing LSCS rates without undue prolongation of labour, then it would be incorporated in the standard routine care.
26
Oxytocin is the most widely used drug for induction of labour. Even though oxytocin is used widely, there is no regimen as to its initial dose, dosage increments or the maximal dose.
There is not enough data to comment whether induction or augmentation of labour with oxytocin should be continued or stopped after the onset of active phase of labour. The main adverse effect of oxytocin is hyperstimulation (6 or more uterine contractions in 10 minutes with associated CTG abnormalities) which can lead to fetal compromise, dysfunctional labour and rarely uterine rupture)
The comparison of interest is continued oxytocin (standard care) versus discontinued oxytocin once the active phase of labour is established. Oxytocin will be restarted in cases of slow or no progression of labour.
27
AIMS AND OBJECTIVES
28
AIMS AND OBJECTIVES OF THE STUDY
(1) To compare the LSCS rates in pregnant women undergoing induction of labour and being managed by two different labourprotocols , discontinuation versus continuation of intravenous oxytocin in active stage of induced labours
(2) To compare maternal and neonatal outcomes in both the groups, stoppage versus Continuation of oxytocin infusion in active stage of induced labours
29
MATERIALS AND
METHODS
30
MATERIALS AND METHODS
This was a randomized, single blind, placebo controlled trial carried out in the departments of Obstetrics and Gynaecology , Neonatology and Biostatistics at Christian Medical College, Vellore, a tertiary care perinatal centre. The study duration was from August 10, 2019 to September 30, 2019.
All pregnant women undergoing Induction of Labour at term (≥ 37 weeks of GA) were recruited for the study if they met the eligibility criteria and consented to be a part of the study.
INCLUSION CRITERIA : all pregnant women at term (Gestational age >37 completed weeks ) who were undergoing induction of labour
31
EXCLUSION CRITERIA included:
Multifetal gestation, Gestational age <37weeks
Previous LSCS
Pre eclampsia (Blood pressure ≥ 140/90 mm Hg with proteinuria)
Severe Gestational Hypertension (BP >=160/110mmHg without proteinuria) Placental Abruption
Meconium Stained Amniotic Fluid Intra Uterine Fetal Demise
Fetus with major congenital anomalies.
Women were screened for eligibility and consented for study when they got admitted for induction of labour. Randomisation into groups was carried out only when they entered active labour
32
Cervical ripening prior to labour induction was carried out in all women if Bishop score was <5 . Various methods of cervical ripening included use of PGE1;
Foley’s bulb; PGE1 with Foley’s bulb. Artificial rupture of membranes was done (except in women who were being induced for PROM) in all women and oxytocin was started
The women who consented to be a part of the study ,were randomized into two groups once they entered active labour, defined as cervical dilatation 4-5 cm. In Group I or in intervention arm,oxytocin was discontinued in active labour, and Group II or control arm, where oxytocin was continued till delivery
Randomisation was done using computer generated random numbers. Serially numbered opaque envelopes with treatment allocation were provided to the principal investigator at the time of randomization, i.e when patient entered active labour.These sealedopaque envelopes, had CONTROL or INTERVENTION written inside and patients were randomized based on this allocation . The patient was unaware of the treatment allocation, but the clinician was aware.
33
Once they entered active labour (>= 5 cm dilatation), then, based on their randomization , oxytocin was either discontinued (Group I) or continued till delivery (Group II).Management in both the groups were as follows :
GROUP I (INTERVENTION): Following discontinuation of oxytocin in Group I, plain Ringer Lactate was started. Repeat vaginal examination was done after four hours to assess the progress of labour.If there was no cervical dilatation, oxytocin infusion was restarted. If there was suboptimal progress , defined as cervical dilatation < 1 cm/hour, labour was allowed to continue without oxytocin and repeat vaginalreassessment was carried out after 2 hours. After two hours ,if there was still suboptimal or no cervical change, oxytocin was be restarted and continued till delivery.
GROUP II (CONTROL ARM ): Oxytocin was continued till delivery.Vaginal examinations were carried out every four hours . Oxytocin drip was titrated based on uterine contractions. If there were 3 contractions in 10 minutes each lasting for 40-45 seconds, oxytocinwas not be increased further. Rest of labour and delivery was managed as per routineprotocol. Maternal and fetal outcomes were assessed in both the groups post delivery.
34
The algorithm of clinical management is outlined in Figure E. In both the groups , maternal and neonatal outcomes were entered in the clinical proforma
OUTCOMES ASSESSED
Primary outcome was overall LSCS rate.
Secondary outcomes were : A) Maternal-
1. Mean duration of first stage in minutes 2. Mean duration of second stage in minutes
3. Mean duration between ARM and delivery in minutes
4. Number of women in Group 1 who were restarted back on Oxytocin infusion 5.Number of women in Group II for whom oxytocin had to be stopped.
6. Uterine hyperstimulation- More than 5 uterine contractionsin 10 minutes with associated CTG abnormalities
35
7. Chorioamnionitis- Infection of chorio decidua, characterized by Maternaltemperature >=100.4 degrees Farhenheit, maternal and fetal tachycardia, uterine tenderness and foul smelling liquor.
8. Post-partum haemorrhage- Blood loss more than 1000ml following an LSCS and 500ml following a vaginal delivery
9. Breast feeding
B) Fetal
1. IntrapartumCTG(Cardiotocography) abnormalities- Presence of severe variable decelerations or late decelerations
2. APGAR score < 7 at 5 mins
3. Neonatal Intensive Care Unit admission
36
STATISTICAL ANALYSIS
Data was entered using EPIDATA software and screened for outliers and extreme values using Box- Cox plot and histogram (for shape of the distribution).
Summary statistics was used for reporting demographic and clinical characteristics.
t- test was used for analysis of continuous data with Normal distribution and Mann-Whitney U test for data with non-Normal distribution in intervention and control group.
Chi- square test was performed for categorical variables in intervention and control group. Differences were considered significant at p< 0.05. Multivariate analysis was performed based on the variables which were significant at bivariate levels.
Statistical analysis was done on “ intention to treat “ basis , which means the women were analysed in the groups they were randomized into. All the statistical analysis was performed using SPSS 25.0
37
SAMPLE SIZE CALCULATION
Target sample size and rationale:600 total (300 in each arm). Based on study by Rashwan et al(36)
Two Proportion - Hypothesis Testing - Large Proportion - Equal Allocation Proportion in group I (intervention/discontinuation arm) 0.30
Proportion in group II (control/continuation arm) 0.20
Estimated risk difference 0.10
Power (1- beta) % 80
Alpha error (%) 5
1 or 2 sided 2
Required sample size for each arm 293
Based on the clinical experience the average LSCS rate in CMC was 30%. With
10% reduction in primary
LSCS rate with 80% power and 5% alpha error, the required number of the study would be around 300in each group.
38
39
FIGUREH: ALGORITHM OF STUDY
40
RESULTS
41
RESULTS
Two hundred women were approached for recruitmentafter they met the eligibility criteria. Ten women did not agree to participate in the study. Six women had to be excluded due to presence of intra partum pre eclampsia , suspected abruption etc. (Figure I)
Following randomization, there were 94 (N) in Group I and Group II had 90 women (n=90). The labour and delivery details were available for all randomized women. In Group I , oxytocin was stopped following active labour. In Group II, oxytocin was continued till delivery. However, in Group I, 15.9% (n=15) women required restarting of oxytocin whereas in Group II, 26(28.8%) women had their oxytocin discontinued due to occurrence of hyperstimulation.(Figure I).
Maternal characteristics such as age, Gestational age in weeks , parity , body mass index (BMI) and Bishop score were comparable in both the groups. (Table 1).
Maximum number of women in the study had BMI of 25-29.9 kg/m2(n=72, 39.1%) (Figure 1)
42
The number ofprimiparous women were almost 4 times than multiparous women within each group, Group I and Group II (Figure 2). However, comparing across the groups, there was no significant difference in the parity of women (p value 0.346, Table 1)
43 FIGURE I: CONSORT DIAGRAM OF STUDY
Number of women invited to participate in the study n = 200
Declined to participate n = 10 Excluded due to intrapartum risk factors n = 6
Number of women randomized n = 184
Group 1 (Intervention) N = 94 Group 2 (Control) n = 90
Protocol deviation
14 oxytocin restarted in stage 1 of labour 1 oxytocin restarted in stage 2 of labour Protocol adherence :79
Protocol deviation 26 oxytocin stopped and 11
needed terbutaline Protocol adherence : 64
Intention to treat analysis = 94
Intention to treat analysis = 90
44 TABLE 1: MATERNAL CHARACTERISTICS IN BOTH GROUPS
Maternal
characteristics Group I (N=94) Group II (n=90) P value
Age (years +/- SD) 26.63+/- 4.09 25.56+/- 3.9 0.07
Gestational age (weeks+/- SD)
39.19+/- 0.91 39.2+/-0.91 0.82
BMI (kg/m2 +/- SD)
25.7 +/-4.41 25.73+/-5.26 0.96
Bishop’s score
(n+/- SD) 4.03+/-1.64 3.91+/- 1.29 0.57
Parity (n; %) Primigravidae Multigravidae
72( 76.6) 22( 23.4)
74(82.22) 16(17.78)
0.35
45 FIGURE 1: DISTRIBUTION OF AGE OF WOMEN IN THE STUDY IN PERECENTAGE
Majority of the women belonged to the 19- 25 age category (n = 85, 46.1 %), followed by women in the age group ranging from 26- 30 years (n = 68, 36.9 %)
Age in percentage 0
5 10 15 20 25 30 35 40 45 50
≤ 18 19- 25
26- 30
31- 34
≥ 35
Age in percentage
Age in percentage
46
FIGURE 2: DISTRIBUTION OF BMI OF WOMEN IN THE STUDY IN PERCENTAGE.
Majority of women in the study belonged to overweight category (n=72, 39.1%) followed by women with normal BMI (n=69, 37.5%)
0 10 20 30 40
< 18
18- 24.9
25- 29.9
> 30
BMI in percentage
47
FIGURE 3: DISTRIBUTION OF PARITY AMONG BOTH THE GROUPS.
In both the groups, I and II, the primigravidae were four times than multigravidae.
(76.6%vs 23.4% in Group I and 82.2% vs 17.78% in group II) (p value 0.34, Table 1)
0 10 20 30 40 50 60 70 80 90
PRIMI MULTI
GROUP I GROUP II
48
FIGURE 4: OVERALL INDICATIONS FOR INDUCTION OF LABOUR IN BOTH GROUPS .
The most common indication for labour induction overall was PROM (pre labour rupture of membranes) (n=80, 43.48%). This was followed by past dates pregnancies (n= 45, 24.46%)
Gestational hypertension was the cause for induction in only 2% cases. (n=3)
Past dates 24%
IUGR 5%
HTN 2%
DM PROM 8%
43%
DFM 9%
Others 9%
Indications for IOL
49
FIGURE 5: COMPARISON OF INDICATIONS FOR LABOUR INDUCTION IN BOTH THE GROUPS.
The reasons for labour induction were comparable in both the groups with majority of women being induced for PROM in either group. This was followed by post datespregnancy . Three women were induced for gestational hypertension in Group II in comparison to none in Group I.
0 5 10 15 20 25 30 35 40 45 50
PAST DATES
IUGR HTN GDM PROM DFM OTHERS
GROUP1 GROUP II
50 FIGURE 6: COMPARISON OF BISHOP’S SCORE IN BOTH THE GROUPS.
In both the groups, maximum number of people had Bishop’s score of 3 . This was followed by a score of 4. Hence, majority of women needed pre induction cervical ripening
Group 1 0
10 20 30 40 50
3 4 5 6 7 8 11 12 13
Group 1 Group 2
51
FIGURE 7: COMPARING AGENTS OF CERVICAL RIPENING USED IN BOTH THE GROUPS
The most common agent used in either group was PGE 1(72.3 % vs 66.6% in Group I and Group II). PGE1 and Foley’s were used together in 15.9% and 25.5%
in Group I and Group II respectively.
No agents were used in 9.5% in Group I and 5.5% in Group II. The use of cervical ripening agents were comparable in both the groups.
0 10 20 30 40 50 60 70 80
PGE1 FOLEY'S PGE1
+FOLEY'S
S&S NONE
GROUPI GROUPII
52
Intrapartum characteristics
Group I (N= 94) Group II (n=90) P value
Cervical dilatation at ARM in cm (Mean +/- SD)
2.71+/- 0.17 2.64+/- 0.12 0.75
Duration of first stage in mins (Mean +/- SD)
784.11+/- 400.26 888.67+/- 404.7 0.08
Duration of second stage in mins
(Mean+/- SD) 63.25+/- 45.33 62.36+/- 35.68 0.89 Time interval
between ARM and delivery in mins
(Mean +/- SD) 604. 19+/- 356.58 652.27+/- 349.07 0.35
TABLE 2 : INTRAPARTUM CHARACTERISTICS OF BOTH GROUPS
53
Table 2 describes intrapartum characteristics in both the groups , I and II. The cervical dilatation at the time of rupture of membranes was comparable in both the groups.
The duration of first stage of labour , second stage of labour was comparable between bothgroups (p value 0.08 and 0.89 respectively) (Table 2). Moreover, the duration between rupture of membranes till delivery was also similar in both the groups (p value 0.35)
54
FIGURE 8 : COMPARISON OF CERVICAL DILATATION AT ARM IN BOTH GROUPS.
ARM was needed in 104 women while the rest were being induced for pre labour rupture of membranes .The mean cervical dilatation in Group I and Group II was approximately 3 cm (2.7 versus 2.64 cm respectively)
Group 1 0
20 40 60 80
1 2 3 4 5 6 7 9 10
Cervical dilatation at ARM
Group 1 Group 2
55 FIGURE 9:PROGRESS OF LABOUR AFTER 4HOURS FOLLOWING STOPPING OXYTOCIN IN GROUP I
Optimal 40%
Suboptimal 14%
No change 11%
Delivered 35%
Progress of labour after 4 hours
56
Figure 9 depicts the progress of labour in Group I following stoppage of oxytocin.
Thirty five percent women had already delivered after 4 hours of stopping oxytocin. Optimal progress was seen in 45% women , i. e. cervical dilatation >=
1cm/hour .
Suboptimal change (cervical dilatation <1cm/hour) was seen in only in 14%
women , who were given 2 more hours to progress. Oxytocin was started in 11%
women at 4hours due to lack of any cervical change (Figure 9)
57
MATERNAL COMPLICATIONS
Group I (N=94) Group II(n=90) P value
CHORIOAMNIONITIS (n,%)
2 (2.1) 2(2.2)
HYPERSTIMULATION REQUIRING
TERBUTALINE (n,%)
1(1.06) 11(12.2)
BLOOD LOSS 500- 1000 ml (n, %)
22( 23.4) 22(22.44) 0.86
TABLE 3: COMPARISON OF MATERNAL COMPLICATIONS IN BOTH GROUPS .Equal number of women had chorioamnionitis in both the groups (2.1% versus 2.2%). Hyperstimulation requiring administration of terbutalineoccurred in 12% in Group II in comparison to only 1.06% in Group I . The occurrence of postpartum haemorrhage was also comparable in both the groups (p value 0.86)
58
VARIABLES GROUP I (N=94) GROUP II(n=90) Pvalue MODE OF
DELIVERY VAGINAL
DELIVERY(n,%) LSCS (n,%)
76(80.85) 18(19.15)
73(81.11)
17(18.89) 0.96
BIRTH WEIGHT (kg)(Mean +/-SD)
3.01+/-0.36
3.03+/- 0.37 0.73 SEX OF THE BABY
MALE(n, %) FEMALE (n, %)
55(58.51) 39( 41.49)
47(52.22) 43(47.48)
0.39 APGAR ≤7 AT 5
MINS 0(0) 0(0) -
TRANSFER TO
NICU(n, %) 0(0) 0(0) _
TABLE 4: DELIVERY AND NEONATAL OUTCOMES IN BOTH THE GROUPS
Table 4 depicts the labour and delivery outcomes in both the groups. Vaginal delivery occurred more than four times than LSCS , in both Groups I and II.
(figure 7) Comparing across the groups,the mode of delivery was found to be similar (p value 0.96, Table 4)
59
The mean birth weight and sex of the babies were also comparable in both the groups. There were no adverse outcomes in terms of Apgar score < 7 at 5mins or transfer to Neonatal Intensive Care Unit in either group. (Table 4)
60
FIGURE 10:MODE OF DELIVERY IN BOTH THE GROUPS . In each group , vaginal delivery occurred more than four times than LSCS . Comparing across the groups, the rates were found to be similar (p value 0.96, Table 4)
0 10 20 30 40 50 60 70 80 90
NVD LSCS
GROUP I GROUP II
61
FIGURE 11: OVERALL INDICATIONS FOR LSCS IN BOTH THE GROUPS.
There were 35 LSCS overall in both the groups. Fetal distress and non progress of labour were most common indications of LSCS (n=15, 43%)
*NPOL :Non progress of labour
** CPD: Cephalo pelvic disproportion
Fetal distress 43%
NPOL 43%
CPD 11%
Failed forceps 3%
Overall Indications for LSCS
62
FIGURE 12: COMPARISON OF INDICATIONS OF LSCS IN BOTH GROUPS . Out of 35 LSCS ,Fetal distress was indication for LSCS in 43% women overall.
Out of 15 LSCS done for fetal distress, 60% (9/15) were in Group I and 40%
(6/15) were in Group II.
Non progress of labour was cause for LSCS in 43% women overall. Out of these 50% were in Group I and Group II respectively. One woman underwent LSCS for failed trial of forceps in Group II.
0 1 2 3 4 5 6 7 8 9 10
Fetal distress NPOL CPD Failed forceps
Group 1 Group 2
63
DISCUSSION
64
DISCUSSION
Since oxytocin was first synthesized in 1954, it has become one of the most widely used medications in obstetrics for induction and acceleration of labour.
(37) , affecting approximately one in four women(25)
A common complication of oxytocin use is too frequent uterine contractions or uterine tachysystole .
As per ACOG, tachysystole is defined as more than five contractions in ten minutes .(7) When contractions are too frequent or too long, the relaxation between uterine contractions is too short for the neonate to recover sufficient oxygen, which, in turn, will lead to fetal distress ,requiring immediate delivery .(17)
65
Oxytocin use has also been associated with risk of uterine rupture, postpartum haemorrhage and unsuccessful breast feeding (22) Maternal side effects of the use of oxytocin during labour has been found to be associated with hypotension, tachycardia, arrhythmias, nausea, vomiting, headache and flushing (38)
Rare side effects of large doses of oxytocin include water retention, hyponatraemia, myocardial ischaemia, seizures and coma. (39) Moreover, almost half of medicolegal cases affecting maternity services were found to be associated to alleged misuse of oxytocin (40)
Due to these concerns there has been a renewed interest to study the effect of discontinuing oxytocin once active stage of labour is reached. Discontinuation of oxytocin would shorten the duration of oxytocin infusion, reducing oxytocin receptor desensitization and stimulating production of endogenous oxytocin (17).
This, in turn, will enable oxytocin to retain its potency and maintain effective uterine contractions to bring about progress of labour.
There is still no consensus on whether oxytocin should be stopped once active stage is reached or continued till delivery. (3) (23) (28) (32). Although there has
66
been a Cochrane metaanalysis studying this research question, the studies included in the metaanalysis had an “inherent risk of bias” and hence more RCT’s were recommended to reach a consensus(41).
The concept behind stopping oxytocin in active stage of labour is the fact that with prolonged usage of oxytocin in labour there is downregulation of oxytocin receptors, leading to prolonged labour(1)(25) (19).
Many studies, like ours, have compared maternal and perinatal outcomes in groups discontinuing versus continuing of oxytocin in active stage of labour(1) (3) (30)(36).
All of these studies, like ours, have recruited pregnant women undergoing induction of labour at term for various reasons. Most of our women were induced for PROM followed by Post dates. This is similar to the study by Bor et al (30).
While most of the studies have used 5cm cervical dilatation as cut off for active labour(1)(13)(30) (34), the Cochrane metaanalysis included studies where 4cm
67
cervical dilatation was used as the cut off for active labour(41). In our study also we used 4-5cm as the cut off for defining active labour.
All the studies, including ours recruited term pregnancies. This is in contrast to Rashwan et al who included pregnancies after 35 weeks of gestation. (36)
In both the groups, Primigravidas were four times more than the Multigravidas.
Chopra et al had recruited equal number of primigravidas and multigravidas in their study (1). Whereas Ahmad Rashwan et al recruited more primigravidas than multigravidas like our study (36).
In our study nearly 16% of women in Group I required restarting of oxytocin. Bor et al had reported restarting of oxytocin in 36% women, out of which 64% (n = 23) did not have any clear indication for and restarting oxytocin.
They explained that lack of clear definition of arrested labour and apprehension about non-progress of labour by unblinded care providers might have triggered restarting of oxytocin (30).
68
In our study, we too used cervical dilatation as means for diagnosing progress in labour. We repeated Per vaginal examinations as per our routine protocol , both in intervention and control groups, i.e. every four hours in active stage .
This is in contrast to Bor et al who did PVs every hour to assess cervical changes in the laboring women.(30). Similarly, Rashwan et al also repeated per vaginal examinations every 1-2 hours to assess progress in labour(36).
In our study at the end of 4 hours of stopping oxytocin in Group I, we found 25%
of women having suboptimal progress or no progress, based on cervical change (Figure 9).
However, oxytocin was restarted only in 16% women because we gave additional 2 hours before restarting oxytocin in women with suboptimal progress of labour.
Oxytocin was started immediately in women with no cervical change at first assessment after stopping oxytocin for 4 hours.
69
Thirty percent of women in Group II required discontinuation of oxytocin. More than half of these also needed terbutaline injection for treatment of uterine hyperstimulation (Figure I). In a systematic review and metaanalysis done by Saccone et al, the risk of uterine tachysystole was significantly more in the oxytocin continuation group (6.2% vs 13.1%; RR 0.53, 95% CI 0.33- 0.84)(32).
Rates of maternal chorioamnionitis were similar in both the groups in our study.
(Group I vs Group II , 2.1% vs 2.2% respectively, Table 3). Many of the studies have not looked at maternal chorioamnionitis as an outcome (1)(30)(35)(42).
Diven et al found an increase in chorioamnionitis in the oxytocin continuation group (12).
In spite of most of our women being induced for pre-labour rupture of membranes, we had remarkably low rates of chorioamnionitis in both the groups since we did not change our protocol of doing per vaginal examinations because of the study.
Also, we do not use intrauterine pressure catheters (IUPC) for monitoring uterine contractions as has been used by some authors (12).
70
We did not find any difference in the duration of first and second stage of labour between the two groups (p value 0.08 and 0.89 respectively, Table 2). Moreover, there was no significant difference in the duration between artificial rupture of membranes and delivery between the two groups. This is similar to the findings by Chopra et al (1).
However, other authors found an increase in the duration of active stage of labour in the oxytocin discontinuation group (30)(31)(43). The systematic review and metaanalysis by Saccone et al also found an increase in the duration of active phase of labour in the oxytocin discontinuation group (mean difference was 27.65 minutes, 95% CI 3.94- 51.36) (32).
In our study, the mode of delivery was found to be comparable in both groups (p value 0.96, Table 4).This is in contrast to the results found by Rashwan et al who found a significant decrease in LSCS rates in the oxytocin discontinuation group (36). However, others had similar findings like ours (1)(12)(31).
71
We could not complete the sample size needed to study the difference in the mode of delivery.
A total of 15 women (43%) underwent LSCS for fetal distress in our study, out of these 60% (n = 9) belonged to Group I and 40% (n = 6) belonged to Group II (Figure 12).
This is in contrast to the findings by others who found an increased LSCS rate due to FHR abnormalities in the oxytocin continuation group (35) (31) (33) (43).
However in our study, there were no babies with an APGAR score ≤ 7 at 5 minutes. There were no admissions to NICU in both the groups.
There was no increase in LSCS done for non progress of labour between both the groups. Out of 15 LSCS done for non progress of labour, half were in Group I and the other half in Group II (Figure 12). This is in contrast to what we were expecting to find .
72
STRENGTHS AND LIMITATIONS
Our study was a randomized placebo controlled trial, randomization was done using computer generated random numbers. Statistical analysis was done on the basis of “intention to treat” i.e. women were analysed in the group they were randomized into.
We did not complete the sample size needed to assess reduction in the LSCS rates.
This study was conducted in a busy labour room setting, where management of labour was carried out by the obstetrician on call. The definition of arrested labour was subjective , based only on cervical dilatation , and resulted in restart of oxytocin in Group I.
73
CONCLUSION
74
CONCLUSION
Our RCT did not find any significant differences in maternal and neonatal outcomes between the two groups, Group I (oxytocin stoppage group) and Group II(oxytocin continuation group).
The mean duration of first and second stages of labourwere comparable. There was no significant difference in the rates of maternal complications such as chorioamnionitis ;hyperstimulation and postpartum haemorrhage
The modes of delivery was comparable within both the groups.The LSCS done for fetal distress and non progress of labour was similar in both the groups. There was no difference in the neonatal outcomes between the two groups.
75
We could not complete the sample size , designed to assess the difference in the LSCS rate. This can therefore be , at best, regarded as the interim analysis of our study.
76
GLOSSARY OF ACRONYMS
RCT- Randomized controlled trial BMI – Body mass index
MSAF- Meconium stained amniotic fluid PV- Per vaginal
ARM- Artificial rupture of membranes LSCS- Lower segment caesarean section IUGR- Intra uterine growth restriction IOL- Induction of labour
GA- Gestational age IV- Intravenous
NICU- Neonatal intensive care unit
PROM : Pre labour rupture of membranes NPOL : Non progress of labour
77
CPD :Cephalo pelvic disproportion CTG : Cardio tocography
FHR : Fetal heart rate
IUPC : Intra uterine pressure catheter
ACOG :American College of Obstetricians and Gynecologists SOGC: Society of Obstetricians and Gynecologists of Canada RCOG : Royal College of Obstetricians and Gynecologists WHO : World Health Organisation
PGE1: Prostaglandin E1 PGE2: Prostaglandin E2
78
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82
ANNEXURES
ANNEXURE 1 : CLINICAL RESEARCH FORM
Name: Age:
Hospital Number:BMI :
Parity: 1. Primi 2. Multi Gestational age in weeks:
Reason for labour induction 1.Past dates
2.Fetal growth restriction 3.Hypertension
4.Pregestational/gestational DM 5.Others (specify)
Agent used for cervical ripening:
1.PGE1 2.PGE1 +Foley’s 3.Foley’s 4. Stretch and sweep Bishop’s score:1. ≥6
2. <5 P/V at ARM
Oxytocin started- Yes/No
Dose of oxytocin: Units/drop
GROUP – 1
83
• P/V at time of stopping oxytocin:
• Dose of oxytocin at the time stoppage ________________(u/drops/min)
• Strength and frequency of uterine contractions:
• PV after 4 hours:
• Oxytocin restarted :Yes/No
• If restarted , then in which stage : First/Second
• If no progress, P/V after 2 hours
• Duration of labour in hours:
First stage : Second stage :
• Time interval betweenARM and delivery ________________ hours
• Need for terbutaline : Yes/No
GROUP II
• Total dose of oxytocin : Units/drop
• Duration of labour in hours:
First stage Second stage
• Time period between ARM and delivery : hours
84
• Need to stop oxytocin: Yes/no
• If yes, reason for stopping oxytocin : 1.hyperstimulation
2.fetal distress 3.others (specify) Neonatal details –
Mode of birth -: 1.Vaginal delivery2.LSCS Sex of baby: 1. Male 2.female
Birth weight of baby:
Apgar score at 5 at 7 minutes : Yes/No Transfer to NICU: Yes /No
If Yes , reason : Postpartum Details
• PPH : Yes/No EBL (in ml)
• If yes, interventions
• Breast feeding : Initiated /Not
• If not, reasons :
85
ANNEXURE 2 : CONSENT FORM
86
87
88
89
90
