Review Lit Part 1

7/26/2019 Review Lit Part 1

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Physiology of onset of labour and cervical

ripening.

Normal labour is a process defined as the onset of persistent regular

uterine contractions along with progressive cervical dilatation and

effacement in which the foetus is born between 37 to 42 completed

weeks of pregnancy by vertex. It is a physiological event involving a

seuential! integrated set of changes within the myometrium! decidua!

and uterine cervix that occur gradually over a period of days to weeks

leading to expulsion of products of conception per vaginum.

"rogesterone is found to be essential in establishing and maintaining

pregnancy and inhibiting myometrial contractility #$aralis et al!

%&&'(. In most mammals! at the onset of parturition! a fall in maternal

progesterone is seen along with a rise in oestrogen levels but in

humans fall in the level of maternal progesterone has not been

observed! rather its action is blocked by an endogenous antiprogestin

whose secretion from foetal kidney rises markedly at the end of

pregnancy. In women! concentration of progesterone plateaus while

oestrogen concentration increases prior to onset of labour and results

in increase in oestrogen)progesterone ratio causing a rise in the

prostaglandin production in the uterine tissue #*isra +enu! 2,%4(.

-here is also an increase in the expression of several receptors in the

uterus like oxytocin receptors! prostaglandin receptors! primary gap

unction proteins and prostaglandin endoperoxide / synthetase

#"0/12( which are essential for the initiation of labour. -hey cause



an increase in the myometrial sensitivity to oxytocin and

prostaglandins #*isra +enu! 2,%4(. xytocin induces myometrial

contractions and via receptors in decidua stimulates prostaglandin

synthesis leading to onset of labour #/usslein "! %&4(. -he cervix is

mainly made up of collagen! a fibrous connective tissue that under

goes extensive remodelling and anatomic and physiologic alterations

throughout pregnancy. -he changes occurs in four stages 5 softening!

ripening! dilatation and postpartum repair #*yers! 2,,&(.

"rostaglandins along with uterine contractions play a role in ripening

of the cervix and leads to cervical dilatation and effacement. -here is

an increase in the local production of prostaglandins seen in the

cervical tissue during late pregnancy and labour which suggests its

effect on cervical ripening #6llwood! %&,(. iochemical connective

tissue changes in the uterine cervix appears to precede uterinecontractions and cervical dilatation #Norwit8! 2,%9( but sometimes

these changes does not occur and labour is not initiated at term or due

to some reason pregnancy needs to be terminated before term. :hen

the uterine contractions are initiated before its spontaneous onset then

it is known as induction of labour.

Induction of Labour

Induction of labour is a procedure where labour is induced artificially

to stimulate uterine contraction and ripening of cervix before its

spontaneous onset! with or without ruptured membranes

#;unningham et al! :illiams bstetrics! 2,%4( with an intention of



achieving vaginal delivery when labour is not initiated at term or due

to some reason pregnancy needs to be terminated before term. It is

one of the most common procedures being performed in obstetrics. Its

rate in the <nited 1tates has more than doubled from &.9= in %&&% to

23.2= in 2,%% #*artin! 2,%3(. It is indicated when benefits of

delivery to either mother or foetus is more than the risk of continuing

pregnancy #1anche8+amos! 2,,9(. -he various indications of

induction of labour are postdated pregnancy! pregnancyinduced

hypertension! premature rupture of membranes! intrauterine growth

restriction! chorioamnionitis! +hisoimmunisation! oligohydramnios!

abruption placentae! malformed foetus and intrauterine foetal demise

#1anche8+amos! 2,,9(.

/istory of Induction of >abour

/istory of induction of labour goes back to the time of Hippocrates

who described mammary stimulation and mechanical dilation of

cervical canal as a means to induce labour #de +ibes ;! %&(.

?rtificial rupture of membrane was practiced as early as 2nd century

?.@ by Soranus for induction of labour. *anual dilatation of cervix

was first described by Moshion and Bourgeois used strong enemas

and mixtures of several folk medicines for induction and

augmentation of labour #0raham! %&9,(. *echanical methods were

commonly used from the 2nd through the %7th century. In the %th

century in a meeting in >ondon! physicians discussed the use of

artificial rupture of membranes to induce labour. In the beginning of



%&th century amniotomy and other mechanical methods were the most

commonly used methods for the induction of labour #1anche8+amos

and $aunit8! 2,,&(.

In the beginning of 2,th century! Dale observed that "itocin extracted

from infundibular lobe of pituitary gland causes myometrial

contractions. In %&,& Blair Bell used it as hormonal method for

labour induction. -his method for induction of labour had become

popular among obstetricians. It was used by intramuscular or

subcutaneous routes but due to numerous adverse effects reported like

uterine rupture and maternal deaths! its use declined as it was not

available in pure form. Kurzro and Lieb #%&3,( noted that human

sperm was able to cause uterine contractions. !lf von "uler #%&37(

first isolated a compound from the seminal fluid of monkey! sheep

and goat and he named it prostaglandin believing it to be a secretion

from male prostate gland. +esearch on prostaglandins remained

dormant until after :orld :ar II when work was reinitiated in this

area by scientists in $arolinska institute in 1weden #;ollins! %&&,(.

*eanwhile "age #%&43( suggested that pituitary extract oxytocin may

be given by intravenous route. In %&93! structural formula of oxytocinwas discovered and synthetic oxytocin has been used for induction of

labour since %&99 #1anche8+amos and $aunit8! 2,,&(. 1uccess of

induction depends upon the status of cervix which is measured by

ishop score! a standardi8ed scoring system developed in %&'4 for

assessing the status of cervix before induction. It included cervical

dilatation! effacement! consistency! position of the cervix within the



pelvis and station of the head in relation to ischial spines. -he original

ishop score was modified by ;alder in %&74 which is known as the

*odified ishop score. In this effacement of the cervix was replaced

by its length in centimetres. -he maximum possible score is %2. -he

total cervical score indicates the probability of spontaneous onset of

labour. -he less the cervical score the lesser are the chances of vaginal

delivery. xytocin alone is not a good choice for inducing labour in

women with a poor ishop score! especially if the score is less than '.

In such cases! a cervical ripening agent is reuired which causes

softening and distensibility of cervix for successfully inducing labour.

#-enore! 2,,3(. In women with unfavourable cervix! prostaglandins

have been shown to be more successful for induction of labour.

-he two prostaglandins commonly used are dinoprostone and

misoprostol. @inoprostone #"062( is available in gel form! which can

be used either by intracervical route #,.9mg( or intravaginal route

#2mg(! and as a %,mg slow release vaginal insert. @inoprostone has

the disadvantage of being costly and reuires refrigeration.

*isoprostol #"06%( is the latest addition to the prostaglandins used in

obstetrics. It is useful in inducing abortion and labour and is also usedas a lifesaving drug in postpartum haemorrhage. -he :/ has

included it in its Alist of essential drugsB in *arch 2,,9. It is very

effective for cervical ripening and induction of labour although it has

not been labelled by the <1C@? for this indication #-enore! 2,,3(

but its offlabel use for induction of labour is endorsed by ?;0 as

well as +;0 #?;0 2,,3 website www.acog.org! +;0 2,,%

http://www.acog.org/

http://www.acog.org/



website www.rcog.uk accessed on %')%)%'(. It has several advantages

over dinoprostone as it is cheap! has a longer shelflife and can be

stored at room temperature so it can be used in underdeveloped and

developing countries where supply of electricity is always a problem.

Structure of Prostaglandins

"rostaglandin belongs to bioactive autacoids known as eicosanoids#1erhan and levy! 2,,3(. "rostaglandin 62 was the first eicosanoid

elucidated. -he term prostaglandin was first coined by <lf von 6uler

in %&39 #Don 6uler! %&7(. ergstrom in %&97 elucidated the structure

of prostaglandin 6% and C%E. In the early %&',s! ergstrom et al and

Dan @orp et al independently identified arachidonic acid as a

precursor to prostaglandins by mass spectrophotometry #1erhan and

>evy! 2,,3(. In the late %&',s and early %&7,s ;orey synthesi8ed

prostaglandins for the first time #1erhan and >evy! 2,,3(. >ater

1amuelsson and colleagues #%&'4( discovered the chemical structure

of prostaglandins and its biosynthetic pathways.

"rostaglandins are a 2,carbon fatty acid molecule derived from

dietary fatty acid. It consists of a cyclopentane ring with a fatty acid

moiety attached at 2 adacent carbons #Brien! %&&9(. "rostaglandins

are classified into & groups according to the structure or substitution

of the cyclopentane ring from ? to I.

http://www.rcog.uk/

http://www.rcog.uk/



"rostaglandins of 6 series consist of a ketone group at ;& position

and hydroxyl group at ;%%. "rostaglandin 6% has a transdouble bond

between ;%3 and ;%4 while prostaglandin 62 has an additional cis

bond at ;9;' position #;ollins! %&9(. "rostaglandin C is a prosta9!

%3dien%oic acid substituted by hydroxy groups at position &! %% and

%9.



"rostaglandins #"0s( act like hormones. -hey may be autocrine

#acting on same cell( or paracrine #affecting a neighbouring cell( in

action. -hey act by binding to membrane receptors of cells leading to

an increase in cyclic adenosine monophosphate #c?*"( #1usan et al!

2,%3(. -o exert a biological effect "0s must interact with receptors

specific to the type of prostaglandin as determined by its pentane ring!

termed as " receptors. -he "06sensitive receptors are termed as 6"

receptors and "0C2Esensitive receptors are designated C" receptors

#1enior! %&&3(. 6" receptors have been further sub divided into 6"%!

6"2 and 6"3 #1enior! %&&3(. *yometrial samples in term pregnancy

show maximum 6" and C" receptor concentrations at the fundus of

uterus with a decrease in concentration towards the cervix #1enior!

%&&3(. "0C2E has been shown to produce a purely contractile



response of myometrium. "06 shows a biphasic effect with initial

excitation followed by a doserelated inhibition #1enior! %&&3(.

"rostaglandin 6 seems to play a greater role in the process of

parturition and has a more potent action on uterine activity than

"0C2E #$eirse and -urnbull! %&79( but it is chemically unstable

because of propensity for F/ ketone system in cyclopentane ring

which undergoes elimination of water to form E! Funsaturated ketone

system of "0? #;ollins! %&&,(. In early %&7,s! synthesis of analogues

of "06% was started to improve its pharmacological profile.

*isoprostol is a %9deoxy%'hydroxy%'methyl prostaglandin 6%

analogue and produces its biphasic effect by acting on 6"%6"3

receptors #1enior! %&&3(.

*I1"+1->

Naturally occurring "06% was found to inhibit gastric acid secretion

in %&'7 by Robert et al but it had several disadvantages. It underwent

rapid metabolism and therefore could not be given orally. :hen given

parenterally it had a short duration of action. It was chemically

unstable leading to a short shelflife besides having numerous side

effects like headache! abdominal cramps! diarrhoea! hyperthermia!

hypotension! shivering and uterotonic effects # Bergestrom et al !

%&'9(. Its duration of action was also found to be short. -o overcome

its shortcomings *isoprostol! a synthetic "06% analogue! was

synthesi8ed at 0. @. 1earle G company in %&73. It differs structurally

from natural "06 by a methyl ester at ;% which increases the



antisecretory potency and duration of action! a methyl group at ;%'

and a hydroxyl group at ;%' #which was originally at ;%9( which

improves its safety profile and helps prolong the duration of action

#-ang and @anielsson! 2,,7(. -his structural change increased the

biological activity of the drug by 39 times by intravenous route and

had improved oral activity. *isoprostol is a viscous oil highly

susceptible to degradation to prostaglandin ? ust like natural "06%.

It was seen that a dispersion of misoprostol on hydroxyl propyl

methyl cellulose #/"*;( is more stable than its pure form.

;onventional tablets are prepared from the dispersion and have a

shelf life of several years at room temperature #;ollins! %&&,(.



1tructure of misoprostol and naturally occurring prostaglandin 6.

*isoprostol has been found useful in the treatment of both gastric and

duodenal ulcers and its efficacy in preventing and treating



nonsteroidal antiinflammatory drugs #N1?I@s( induced

gastrointestinal ulcer has been proven. It is the first drug found

effective in N1?I@induced gastropathy and is approved by the <1

C@? for this purpose. #;ollins! %&&,(. It has been marketed in <1?

since %& #1anche8+amos! 2,,9(. It was also found to have

uterotonic activity which could not be eliminated and was used for

first trimester abortion #/erting and Nissen! %&'(. *arianiNeto et al

#%&'( used this property for induction of labour in still birth #+ev.

paul. *ed! %&7( and *arguiles et al used it for induction of labour in

live fetus in %&&2. ?lthough it has not been approved by <1C@? but

now it is being used in obstetrics and gynaecology for induction of

labour! cervical ripening before hysteroscopy and in the management

of postpartum haemorrhage #?llen! 2,,&(.

"harmacokinetics of misoprostol

*isoprostol is currently being administered through various routes

orally! vaginally! sublingually! buccal and rectal. "harmacokinetic

profiles of the various routes of administration of misoprostol have

been studied taking the following parameters into consideration the

peak concentration of drug attained in plasma #;max(! the time taken

to reach the peak concentration #-max( and the area under the serum

concentration versus time curve #?<;(.



CigH Mean plasma concentrations of misoprostol acid

over time by various routes.

*isoprostol! after its oral administration is rapidly absorbed and

converted by deesterification to *isoprostol ?cid which is its

primary active metabolite. -his metabolite possesses significant

properties of the original drug. #1choenhard! %&9(. It is further

metabolised over time by Foxidation of the Eside chain! oxidation

of the Fside chain and by reduction to prostaglandin C analogues

#1choenhard! %&9(. -he plasma protein binding of *isoprostol ?cid

#*"?( is approximately 9= and is independent of age! drug

concentration or any other drug commonly coadministered with it!

except for salicylic acid #;ollins! %&&,(.



CigH *etabolism of *isoprostol

Collowing a meal #high fat diet( rate of absorption of the drug #;max(

was significantly reduced. -he plasma elimination halflife of *"? in

humans is about 2, minutes #$arim! %&7(. It was excreted twice the

amount in urine as compared to faeces #;ollins! %&&,(. -ang et al

#2,,2( found that after a single dose of 4,,Jg oral misoprostol! the

plasma peak concentration is attained in about 3, minutes. It rapidly

declines in %2, minutes and remains low thereafter #-ang and

0em8ell@anielsson! 2,,7(.

Daginal route was found more effective in studies as compared to oral

route. Kieman et al #%&&7( found that on vaginal administration!

plasma concentration of *"? increases gradually reaching its peak



concentration after 7,, minutes before slowly declining. @etectable

drug levels are still present in plasma even after ' hours. 1ystemic

bioavailability of the drug was three times greater by vaginal route as

compared to oral route #Kieman et al! %&&7( but absorption of the drug

vaginally is inconsistent as seen by the greater coefficient of variation

of the area under curve #?<;(. ? direct effect on the uterus and

cervix may possibly explain the higher efficacy of this route

#@anielsson et al! %&&&(.

In the buccal route of drug administration the tablet is placed between

the teeth and the cheek. -he absorption curve for the buccal and

vaginal route are similar and the time taken to attain maximum

concentration is also similar but the peak plasma concentration levels

of the buccal route are lower #*eckstroth et al! 2,,'(.

?nother route by which misoprostol can be administered is the

sublingual route. -he tablet is placed under the tongue and it dissolves

within 2, minutes. -ang et al #2,,2( found that after administration of

4,, Jg misoprostol! sublingual route had the shortest time to peak

concentration #3, minutes(! the highest peak concentration and the

greatest bioavailability as compared to other routes. -he area under

curve of misoprostol is four times greater with the sublingual as

compared to the buccal route #1chaff et al! 2,,4(. -his is probably

due to the abundant blood supply under the tongue as well as

bypassing firstpass metabolism through the liver. -he greater ?<;

and the peak concentration attained in plasma may be the reason for



the higher freuency of adverse effects reported with sublingual route

#1chaff et al! 2,,4(.

+ectal route of administration is mainly used in the management of

postpartum haemorrhage. -he time taken to achieve peak plasma

concentration is 2, minutes but the area under the curve is ust one

third of the vaginal route #-ang et al! 2,,7(.

6ffects of misoprostol on the uterus

-he initial effect of misoprostol on uterine contractility is an increase

in uterine tone irrespective of the dose and route of administration

#?ronsson et al! 2,,4(. -his effect was seen to start earlier and was

more pronounced when misoprostol was given orally #7.L3 minutes(

as compared to the vaginal route #2,.&L9.3( #@anielsson et al! %&&&(.

?lthough the initial rise in uterine tone was delayed after vaginal

administration of misoprostol! regular uterine contractions were

established after % to 2 hours which increased gradually and lasted

even up to 4 hours #@anielsson et al! %&&&(. *eckestroth et al #2,,'(

found that uterine activity was similar with both vaginal and buccal

routes of administration of misoprostol even though serum levels of

misoprostol were much higher with vaginal route. +ectal route was

seen to have the lowest uterine contractility as well as delayed onset

of action.

?ronsson et al #2,,4( compared its effect on uterine contractility

when administered sublingually with oral and vaginal routes. -hey



observed that the sublingual route had the advantage of rapidly

increasing the uterine tone and with intensity comparable to oral

route. 1imilar to the vaginal route! regular uterine contractions were

established %2 hours after sublingual administration but it was seen

to last for 3 hours only as compared to 4 hours with vaginal route.

1o it can be concluded that regular uterine contractions are established

irrespective of the route of administration. If administered

sublingually! its action starts earlier than other routes but lasts only for

3 hours #-ang et al! 2,,7(.

6ffects of misoprostol on cervix

-he cervix is mainly made up of connective tissue. ;ervical ripening

reuires a decrease in total collagen content with an increase in

collagenolytic activity. -he extracellular ground substance of the

cervix is degraded by an influx of inflammatory cells in the stroma

which produce cytokines and prostaglandins and leads to degradation

of collagen and conseuent cervical softening #?ronsson et al! 2,,4(.

"l#efaey et al #%&&4( studied the effect of prostaglandin analogues!

misoprostol and gemeprost! on cervical priming before surgically

induced abortion and noted that both caused disintegration and

dissolution of collagen in the connective tissue stroma leading to

cervical dilatation before evacuation but misoprostol was preferred

due to less side effects. $gai et al #%&&9( found oral misoprostol

effective in cervical dilatation before vaccum aspiration in first

trimester abortions. -he mean cervical dilatation was significantly



greater in the misoprostol group as compared to placebo treated group

in both nulliparous as well as multiparous females. Danielsson et al

#%&&&( noted that all the patients between %% weeks of pregnancy

enrolled in their study who had received misoprostol either orally or

vaginally had a dilated cervical canal. %ronsson et al #2,,4( noted

that irrespective of the route and dosage when misoprostol was

administered prior to vaccum aspiration in first trimester of pregnancy

all patients had a dilated cervical canal. ?ll these studies prove the

efficacy of misoprostol in cervical priming. Now misoprostol is being

widely used for its ripening effect on cervix before induction of

labour and vaccum aspiration in early pregnancy.

1ide 6ffects of *isoprostol

*isoprostol is a safe and well tolerated drug with a safety margin of

at least 9,,%,,, fold between lethal dose in animals and therapeutic

dose in human beings #$otsonis et al! %&9(. No clinically significant

adverse effect affecting any of the organ systems has been reported as

yet with the use of misoprostol #-ang and 0em8ell@anielsson! 2,,7(

*isoprostol has the following side effects at therapeutic dosageH

&astrointestinal side effects'

>umbiganon et al #2,,2( studied the side effects of ',,Jg of oral

misoprostol during first 24 hours when used in the management of

third stage of labour. -hey reported that in 9= of the women

diarrhoea started one hour after delivery and peaked between 2'



hours. Its incidence declined thereafter to ,.%= between %&24 hours

following ingestion of the drug. -hey have also observed mild nausea

and vomiting after its use but have not mentioned the incidence.

1chaff et al #2,,4( found that 4,= users had mild nausea! 2,= had

diarrhea and 9,= experienced abdominal cramps following

sublingual administration of ,,Jg misoprostol.

*eckestroth et al #2,,'( observed that after administration of 4,,Jg

misoprostol irrespective of route! 3= of the participants experienced

abdominal pain and %2.9= women had nausea out of which 9=

vomited.

-ang G 0em8ell@anielsson #2,,7( in their review article on

misoprostol have stated diarrhoea as a consistent maor adverse

reaction which is usually mild and selflimiting.

6lati G :eeks #2,,&( in their review article on use of misoprostol in

obstetrics G gynaecology for different indications like first and

second trimester termination of pregnancy! missed abortion!

intrauterine foetal death! induction of labour! management of

postpartum haemorrhage! before any transcervical procedures! with

dosage ranging from 2,',,Jg have stated that nausea! vomiting and

diarrhoea are common adverse reaction of misoprostol intake

affecting about 39= of women. -he gastrointestinal side effects are

more common after oral or sublingual administration. @iarrhoea is the

commonest side effect but usually mild and selflimiting within a day.

Domiting usually resolves within ' hours of delivery. ?bdominal



cramps may start within ten minutes of administration of misoprostol

and continue for a few hours. N1?I@1 can be given for pain relief.

(ever and shivering are commonly associated with the use of

misoprostol but are transient and can be controlled with the use of

antipyretics and physical cooling. >umbiganon et al #%&&&( studied

the doserelated side effect of misoprostol versus oxytocin in the

management of third stage of labour. oth shivering and pyrexia

#-emperatureM 3( were found more commonly in ',,Jg

misoprostol group as compared to 4,,Jg misoprostol and oxytocin

group #2= and 7.9=! respectively(.

>umbiganon et al #2,,2( studied the effects of ',,Jg oral

misoprostol in the management of third stage of labour and observed

that incidence of shivering peaked within one hour of delivery which

was %3.'= as compared to 2.%= in the oxytocin group. It then

gradually subsided within 2' hours. "yrexia peaked at 2' hours after

delivery with an incidence of %%.3= in the misoprostol group as

compared to %.= in the oxytocin group.

-ang and 0em8ell@anielsson #2,,7( in their review article of

different studies conducted by others #/o et al! 2,,9O :alraven et al!

2,,9O @erman et al! 2,,'( on the use of oral or sublingual misoprostol

for the management of third stage of labour or for postpartum

haemorrhage have reported chills in 3297= women! hyperpyrexia

#-emperatureM4,;( with the use of ',,Jg misoprostol and

hyperpyrexia with delirium when ,,Jg misoprostol was used.



6lati G :eeks #2,,&( in their review article stated that transient chills

and fever are common side effects of misoprostol. /yperpyrexia

#-emperatureM4,( are usually seen to be associated with higher dose

#,,Jg(! freuent intervals and oral or sublingual route of

administration of misoprostol.

!terine Hypersti)ulation

<terine hyperstimulation syndrome is diagnosed when tachysystole #'

or more uterine contractions in %, minutes( or hypertonus #single

contraction lasting over a 2 minute period( occurs along with foetal

heart rate changes. :eeks et al #2,,7( in their review article of

misoprostol for induction of labour with a live foetus have found that

incidence of uterine hypercontractility is high with misoprostol as

compared with oxytocin but serious sideeffects are primarily seen

with too high doses or where wrong dosage freuency has been used.

:hen misoprostol is used in low doses! 29Jg vaginal misoprostol 4

hourly! 9,Jg oral misoprostol 4 hourly or 2,Jg oral misoprostol

solution 2 hourly it is as safe and effective! with no excessive uterine

stimulation! as vaginal dinoprostone.

6lati G :eeks #2,,&( in their review article on use of misoprostol in

obstetrics and gynaecology too have stated that hyperstimulation may

occur from the use of excessive or repeated doses of misoprostol and

incidence of hyperstimulation is similar to dinoprostone gel when

used in lower doses like 29Jg vaginal or 2,Jg oral misoprostol



solution. *etaanalysis of oral misoprostol shows higher rates of

hyperstimulation with high doses. /yperstimulation is not seen with

lower doses. 9,Jg misoprostol or less by oral route have same

efficacy and rate of hyperstimulation as vaginal dinoprostone.

!terine #upture

-he risk of uterine rupture in vaginal birth after previous caesarean

delivery is reported between '%2= #:ing et al! %&&( #"laut et al!

%&&&(. <terine rupture has been reported after induction of labour

with misoprostol especially in women with a previous uterine scar

#-ang G 0em8ell@anielsson! 2,,7(. -herefore! it is not

recommended to administer it in cases with a previous uterine scar

#6lati G :eeks! 2,,&(.

Meconiu) staining of li*uor

/ofmeyr et al #%&&&( have concluded in their review article on the use

of misoprostol for induction of labour! in which 3% trials of vaginal

misoprostol and 9 trials of oral misoprostol were analysed! that

incidence of meconium stained liuor was increased when

misoprostol was used for induction of labour in third trimester as

compared to dinoprostone gel #++ %.3! &9= ;I %.,'%.7&(. -hey

also reported that incidence of meconium stained liuor was same

when 29Jg misoprostol was given 3 hourly or ' hourly. -he ;ochrane



review #2,,3( have reported increased incidence of meconium stained

liuor at doses more than 29Jg of misoprostol. :eeks et al #2,,7( in

their review article have also stated that incidence of meconium

stained liuor is significantly more with the use of misoprostol as

compared to other prostaglandins. *econium passage may occur in

response to uterine hyperstimulation or as a direct effect of absorbed

misoprostol metabolites on the foetal gastrointestinal system.

Maternal and perinatal outco)es

"rostaglandins are now being extensively used for induction of labour

at term and they have the advantage of causing both cervical ripening

and uterine contractions as opposed to oxytocin which is effective in

women with a favourable bishop score. xytocin has been found to

be safe for this purpose and several trials are being conducted to

prove the efficacy and safety of prostaglandins on the perinatal

outcomes #*acer et al! %&4(

1anche8+amos et al #%&&3( conducted a randomised trial to compare

the safety and efficacy of 9,Jg intravaginal misoprostol with

intravenous oxytocin for induction of labour at term. "rior cervical

ripening was done with prostaglandin 62 gel in the women #49=(

given oxytocin! if reuired. <terine tachysystole was seen to occur

more commonly in the misoprostol group than in the oxytocin group

#34.4=! p ,.,9( but no other significant differences were observed in˂

the perinatal outcomes including uterine hyperstimulation syndromes!

rate of caesarean section or maternal and neonatal adverse effects.



Induction to delivery interval was significantly shorter in the

misoprostol group #pP,.,,4(. It was therefore concluded that

intravaginal misoprostol is a safe and effective alternative for

induction of labour at term while minimi8ing the expenses associated

with intravenous oxytocin use.

/ofmeyer et al #%&&&( in their review article studied the effectiveness

and safety of misoprostol for cervical ripening and labour induction at

term. -hey analysed several clinical trials on misoprostol

administered orally and vaginally in various dosages and in

comparison with oxytocin and dinoprostone. In the trials comparing

misoprostol with oxytocin infusion! no differences in the maternal and

neonatal outcomes were observed. -he rate of caesarean section was

inconsistent varying from significant reduction in rates in misoprostol

group to no significant difference. In another trial comparing vaginal

misoprostol with dinoprostone gel! it was observed that although the

rate of vaginal deliveries was more and oxytocin augmentation

reuirement was less in the misoprostol group! uterine

hyperstimulation with and without foetal heart rate changes and

meconium staining of liuor was more freuently observed withmisoprostol. ;aesarean rate was overall similar and there were no

significant differences in the perinatal or maternal outcomes. In a trial

comparing lower dosage regimen of 29Jg misoprostol given 3 hourly

versus ' hourly! there were no differences in mode of delivery!

meconium stained liuor or maternal or perinatal effects.



Keba *un8ar #2,%9( conducted a randomised controlled trial to

compare the safety and efficacy of oral misoprostol #%,,Jg given 4

hourly( with prostaglandin 62 vaginal tablet #3mg(. *ore than one

fourth #2=( women in the misoprostol group ended up with

caesarean section out of which = were done for foetal distress.

*econium staining of liuor was seen in %,= women and 4= had

uterine hyperstimulation but these were not statistically significant.

Neonatal outcomes were also similar in both the groups. It was

therefore concluded that misoprostol is as efficacious as prostaglandin

62 with similar maternal and neonatal outcomes and is a much

cheaper alternative to prostaglandin 62.

?8ubuike et al #2,%9( compared the safety and effectiveness of 29Jg

misoprostol versus 9,Jg misoprostol both given vaginally for

induction of labour at term. -hey concluded that there were no

significant differences between the two groups as far as

hyperstimulation syndromes and other maternal and neonatal

outcomes were observed.

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Review Lit Part 1

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