International Journal of Health and Pharmaceutical Sciences

ISSN 2278 - 0564

Vol 1, Issue 4, 2012

Research Paper

COMPARATIVE STUDY OF MICRONISED PROGESTERONE VERSUS ISOXSUPRINE IN THE PREVENTION OF PRETERM LABOUR
1
1

Professor, 2,3Resident, Dept of Obstetrics & Gynaecology, JNMC Sawangi, Wardha (India).

Deepti S Shrivastava, 2*Shruti S Goel , 3Sunaina Arya

*Shruti_7589@yahoo.co.in

ABSTRACT: Introduction: Preterm labour is a major public health problem responsible for neonatal morbidity and mortality,hence it is a time felt need to improve the outcome of preterm labor and formulate better methods to prevent it. Aim : Compare the efficacy and safety of micronized progesterone versus isoxsuprine in the prevention of preterm labor. Study design: Prospective ,interventional, case control comparative study of 200 women. Observations & Results: In the study both the drugs were found equally effective in prevention of preterm labour along with micronized progesterone offering a better safety profile. Prevention of preterm labour was equql with both the drugs but sideeffects were significantly less with micronized progesterone i.e. tachycardia ,headache ,palpitation and syncopal attacks were seen in 48%,61%,27%and 23% of women with Isoxsuprine and only 12%, 21%,9% &7% women with micronized progesterone respectively. Conclusion micronized progesterone is almost equally effective with fewer side effects than isoxsuprine in prevention of preterm labour. KEY WORDS: Preterm labour, micronized progesterone , Isoxsuprine . INTRODUCTION: Preterm labor refers to the onset of uterine contractions of sufficient strength and frequency to effect progressive dilatation and effacement of cervix between 20 and 37 weeks of gestation.[1]Preterm delivery affects11% of pregnancies in US or even greater in developing countries(23.3% in India) .[2]It is rising world over because of increased frequency of multiple births due to assisted reproductive techniques (ART), more working mothers, increasing psychological stress and medically induced prematurity. It is a major public health problem in terms of loss of life, long-term disability (cerebral palsy, blindness, deafness, chronic lung disease) and healthcare costs both in the developing and the developed world.[1] Due to continued innovation in neonatal intensive care facilities and obstetric interventions, fetal survival is now possible even at 20 weeks gestation in developed countries[3]. However, in even best setup in developing countries, salvage is rare below 28 weeks of gestation ,so it is better to arrest preterm labour till atleast 34 weeks of gestation to prevent complications like respiratory distress syndrome. [4]
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A myriad of strategies to identify patients at risk have been investigated, and interventions have been considered . [5] Although tocolysis itself is considered to be controversial but it is being tried almost every where with a concern of foetal lung maturity ,till atleast prophylactic steroids given to mother could act. We have conducted this study in a rural setup where the most common drug used for tocolysis is isoxusuprine. In the present study we have tried to compare its efficacy and safety with recently documented effectivity of natural micronized progesterone in various studies. MATERIALS AND METHOD: It was a prospective case control comparative study conducted in the department of Obstetrics and Gynaecology at Acharya Vinoba Bhave Rural Hospital, Sawangi Wardha during the period of 3 years. Institutional ethical committee approved the study. Informed written consent was taken from subjects recruited in the study. 200 antenatal women admitted with preterm labor at less than 37 weeks gestational age were recruited. They were evaluated by history taking, clinical examination, and ultrasonography. ACOG criteria 1997 was taken to document preterm labor and threatened preterm labor viz., four uterine contractions in 20 minutes with or without cervical dilatation greater than 1 cm or effacement 80% or greater. Leaking i.e., rupture of membranes to be diagnosed by speculum examination and were excluded for the study. Women were investigated for haemoglobin,TLC,DLC ,Urine routine microscopy and vaginal swab was sent. INCLUSION CRITERIAL: Women with singleton pregnancy

Women with gestational age between 28 weeks to less than 37th completed weeks Presenting with pain in abdomen Four uterine contractions in 20 minutes Cervical dilatation not more than 1 cm & effacement more than 80 % History of previous preterm birth and recurrent miscarriage Women with a history of cervical insufficiency and a cerclage in place.

EXCLUSION CRITERIA: Women with multiple pregnancy Women with history of recurrent infections/ UTI Women with previously diagnosed oligohydraminos/IUGR Women with confirmed leaking per vaginum or PROM. Amongst the 200 women, GROUP A constituted subjects who were given intravaginally micronized progesterone 200 mg daily. Another group(B) of 100 women , constituted of those, who were given injection isoxsuprine 10 mg intramuscularly and was repeated every 6 hourly for 48 hours, later on switched over to 40 mg oral retard capsules on mantainence therapy once daily.Women with gestational age less than 34 weeks were given 12 mg betamethasone intramuscularly that was repeated after an interval of 24 hours. RESULTS: During the study period, 200 antenatal women admitted with preterm labor at less than 37 weeks gestational age were recruited and studied. Table 1 shows the comparison of the gestational ages amongst two groups. Maximum cases ie 44% in micronized progesterone and 40% in isoxsuprine belonged to the gestational age of 34 to 36 weeks. Table 2 shows distribution of women according to their parity.it was seen that

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maximum cases ie 44% in group A and 40% in group B were second gravida and both the groups were comparable. Table 3 shows micronized progesterone was effective in prolonging the duration of pregnancy to a period of more than 48 hours to 1 week in 46% women while isoxsuprine was successful in prolonging for the same duration in 44% cases .Thus it was found equally efficacious.

Table 4 shows better safety profile with micronized progesterone as but side effects were significantly less with micronized progesterone i.e. tachycardia ,headache ,palpitation and syncopal attacks were seen in 48%,61%,27%and 23% of women with isoxsuprine and only 12%, 21%, 9% &7% women with micronized progesterone respectively while in micronized progesterone the only annoying side effect was excessive vaginal discharge in 58% cases.

Table 1 shows estational age wise distribution of cases Gestational age(wks) 28 -32 32-34 34 -35 3 5 -36 36- <37 Total 16(16%) 32(32%) 44(44%) 4(4%) 4(4%) 100 12(12%) 28(28%) 40(40%) 12(12%) 8(8%) 100 Group A Group B 2value 1.59 0.81 Not Significant p>0.05 P-value

Table 2 shows Parity wise distribution of the cases Parity Primi Group A 40(40%) Group B 40(40%) 0.18 48(48%) 12(12%)
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2-value

p-value 0.91 NS p>0.05

Multigravida Gravida 2 Gravida 3 44(44%) 16(16%)

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Table 3 depicts duration of prolongation achieved with the use of isoxusuprine and micronised progesterone Duration prolongation >6 to 8 weeks >4 to 6 weeks >2 to 4 weeks >1 to 2 weeks >48 hours to 1week <48 hours(failure ) Total 100 100 20(20%) 20 (20%) 4(4%) 04(4%) 04 (4%) 22(22%) 46(46%) 8(8%) 6(6%) 2(2%) 20(20%) 44(44%) 0.51 0.91 P>0.05 NS of Group A Group B 2-value P-value

Table 4 depicts the side effect profile of both the drugs in which micronized progesterone has a better side effect profile as compared to isoxsuprine Side Effects Hypotension Tachycardia Palpitations Syncopal attack Headache Allergy/Rash Abnormal discharge Group A 10(10%) 12(12%) 9(9%) 7(7%) 21(21 %) 20(20%) vaginal 58(58%) nil Group B 40(40%) 48(48%) 27(27%) 23(23%) 61(61%) 8(8%) 05(05%) 2(2%) P value p<0.0001,S p<0.0001,S 0.0015,S 0.0003,S p<0.0001,S 0.0237,S p<0.0001,S 0.4975,NS

Gestational diabetes

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DISCUSSION: Despite years of research into the etiology of spontaneous preterm labor, only few effective treatments have been identified.[1]Unfortunately, there is little evidence confirming the effectiveness of any of these strategies In particular, tocolysis of established preterm labor is at best associated with only small prolongation of pregnancy and has not been shown to decrease perinatal mortality or morbidity. But it is still effective in threatened preterm labour and most commonly practised . Natural micronized progesterone is different from the commonly prescribed synthetic progesterone in that it is not similar to the structure of the natural progesterone in the body but identical. Natural micronized progesterone is shown to have fewer side effects and discomforts such as headaches etc. than with the synthetic variety and is often available over-thecounter. Cochrane review 2004 on preterm labour concludes that tocolysis is definitely indicated before 34 weeks gestational age in their study tocolysis delayed delivery in 39 % of the cases. Another study [6] demonstrated that Spontaneous delivery before 34 weeks of gestation was less frequent in the progesterone group than in the placebo group (19.2% vs. 34.4%; relative risk, 0.56; 95% confidence interval [CI], 0.36 to 0.86). According to some[7] Antenatal administration of progesterone reduces the risk of preterm birth before 37 weeks and 34 weeks, as well as the risk of a newborn

being born with a birth weight of less than 2500 g. In another study [8] conducted suggested that use of oral micronized progesterone was associated with an increase in the mean gestational age at delivery (36.1 2.66 vs. 34.0 3.25 weeks, P < 0.001). Micronized progesterone also had a protective role in preventing preterm birth between 28 and 31 weeks plus 6 days. According to another study [9] the use of vaginal progesterone suppository after successful parenteral tocolysis associated with a longer latency preceding delivery. Progesterone group demonstrated a longer mean latency until delivery (36.1 17.9 vs 24.5 27.2) days. This observed difference was statistically significant .In our study micronized progesterone prolonged duration for more than 48 hours t 1 week in 44% women. In our study we have compared the efficacy of micronized progesterone with the most commonly used betasympathomimmetic, isoxsuprine and found both of them to be equally efficacious .On the other hand micronized progesterone offers better compliance profile as compared to betasympathomimmetics, which are contraindicated in moderate to severe anaemia, thyroid diseases,diabetes and women with heart disease. In our study we found almost similar effectiveness of micronized progesterone as isoxsuprine with advantage of lesser side effects except for the excessive vaginal discharge was annoying to few women and almost nil contraindications for it.

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Table 5: Showing different trials conducted demonstrating efficacy of micronised progesterone

[10]

Authors Progesterone Gestational No. of Subjects % Preterm pregnancy (Year) Dose age of initiation Progesterone Placebo Progesterone Placebo (wks)

O Brien NMVBP gel et al (2007)

18 to 22

309

302

<35-22.7 <32 10.0 <28 3.2

26.5 11.3 3.0 34.4 70.3

De NMVBP gel Fonseca et al (2007)

33.9

125

125

<34 9.2 <37 695

Rouse NMVBP gel et al (2007)

35

325

330

<32 6.9 <27 - 8.0

14.5 6.1

RCOG recommends that if a tocolytic drug is used betasympathomimmetics is no longer the first choice.the choice of tocolytic agent which could improve neonatal outcome with no maternal or neonatal side effect has not yet surfaced.[11] CONCLUSION: Micronized progesterone can serve as a promising option in the prevention of preterm labour as it is equally efficacious and has low side effect profile as compared to betasympathomimmetics. Since it has lesser side effects thereby it provides better patient compliance. REFERENCES: [1] Edwin Chandraharan, Sabaratnam Arulkumaran; Recent advances in

[2] [3]

[4]

[5]

management of preterm labor J Obstet Gynecol India Vol. 55, No. 2 : March/April 2005 Pg 118- 124 Martin JA,Kochank KD et al ,Annual Summary of vital statistics 2003.Pediatrics.2005;115:619-392. Singh Uma, Singh Nisha, Seth Shikha ;A prospective analysis of etiology and outcome of preterm labor; J Obstet Gynecol India Vol. 57, No. 1 : January/February 2007 :48-52. Singh Nisha, Singh Uma; comparative study of nifedipine and isoxsuprine as tocolytics:the journal of obstetrics and gynaecologyof india;sept-oct 2011: 61 (5)512-515. Cahill AG, Odibo AO, Caughey AB, et al. Universal cervical length screening and treatment with vaginal
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[6]

[7]

[8]

progesterone to prevent preterm birth: a decision and economic analysis. Am J Obstet Gynecol 2010; 202:548.e1-8. Eduardo B. Fonseca, Ebru Celik, Mauro Parra, Mande5ep Singh, Kypros H ;Progesterone and the Risk of Preterm Birth among Women with a Short Cervix: N Engl J Med 2007; 357:462-469 Rogelio Gonzalez et al: Prenatal adm. inistration of progesterone for preventing preterm birth in women considered at risk of preterm birth: RHL commentary (last revised: 1 December 2009). The WHO Reproductive Health Library; Geneva: World Health Organization Rai, Pushpanjali; Rajaram, Shalini; Goel Neerja; Gopalakrishnan, Radhika Ayalur; Agarwal, Rachna; Mehta, Sumita Obstetrical & Gynecological Survey:

Oral Micronized Progesterone for Prevention of Preterm Birth May 2009 - Volume 64 - Issue 5 - pp 285-286 [9] Sedigheh Borna M.D., Soghra Khazardoust M.D., Sedigheh Hantoushzadeh, Noshin Sahabi : Effect of progesterone as maintenance tocolytic therapy on the prevention of recurrent preterm labor: Journal of Family and Reproductive Health Summer 2007;1(1):12-17 [10] J. M. O'BrienD. Ada A. DEfranco, Article published online: 26 SEP 2007Progesterone vaginal gel for the reduction of recurrent preterm birth: primary results from a randomized, double-blind, placebo-controlled trial [11] RCOG tocolytic drugs for women in preterm labour.In :clinical guideline no.1[B]:LONDON :RCOG press ;2002

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