MISOPROSTOL USE IN OBSTETRICS AND GYNAECOLOGY
DR OBIOKONKWO, A.C.[MBBS, U. PHARCOURT]
DEPARTMENT OF OBSTETRICS AND GYNAECOLOGYFEDERAL MEDICAL CENTRE BIRNIN KEBBI
KEBBI STATE
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Outline
Introduction Pharmacology Uses in obstetrics and gynaecology Other uses Controversies Conclusion & Recommendations References
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Introduction
Drug use is almost as old as man. Records - Sumerians use dating as far back as 5000 B.C. [1]
Some drugs were found to be harmful, but others found to be extremely useful
Misoprostol belongs to the useful group and in 2011, was added to the WHO model list of essential medicines
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Introduction
Developed by G.D. Searle & Company in 1973
Originally approved by the Food and Drug Administration (FDA) for the prevention of stomach ulcers in patients taking nonsteroidal anti-inflammatory drugs
Currently used for a variety on on- and off-label indications
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Pharmacology [2]
Synthetic analogue of prostaglandin E1 (PgE1)
Formular – C22H38O5 ; molar mass – 382.534 g/mol
Routes of admin - oral, vaginal, sublingual, buccal, rectal
Extensively absorbed, 80 – 90% protein bound
Metabolized in the liver, excreted in urine (80%)
Elimination half life 20 – 40 minutes
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Pharmacology [2]
15-deoxy-16-hydroxy-16-methyl-PgE1
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Pharmacology [2]
Cheap and heat-stable, able to stimulate uterine contractility in early pregnancy & at term
There are no known drug interactions with misoprostol [3]
Pregnancy category X
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Pharmacology [2]
It is considered a teratogen. [3] Absolute risk – 1%
Congenital malformations thought to be due to vascular disruptions secondary to uterine contractions caused by misoprostol
Defects: skull defects, bladder extrophy, arthrogryposis, CN palsies, facial malformations, limb defects, Moebius sequence
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Pharmacology [2]
Adverse effects...
Uterine hyperstimulation
Hyperthermia
Chills
Vaginal bleeding
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Pharmacology [2]
...Adverse effects
Diarrhoea
Abdominal pain
Clinical exacerbation of inflammatory bowel disease
Anaphylaxis
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Use in Obstetrics and Gynaecology
Obstetric uses Cervical ripening and induction of labour (IOL) Post partum haemorrhage (PPH)
Gynaecological uses Termination of pregnancy (medically) Cervical ripening before instrumentation
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Cervical ripening and induction of labour
Low dose oral misoprostol (20-25µg 2-hourly) is safer and more effective than vaginal misoprostol [4]
Vaginal misoprostol in doses >25µg 4-hourly is associated with a greater risk of uterine hyperstimulation [4]
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Cervical ripening and induction of labour
Misoprostol vs placebo...
10 trials [4] involving 1141 women
Vaginal misoprostol – less failure to deliver within 24 hours
Uterine hyperstimulation without foetal heart changes was increased
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Cervical ripening and induction of labour
...Misoprostol vs placebo
Oral misoprostol - more likely to deliver in 24 hours, less need for oxytocin use, lower caesarean delivery rate
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Cervical ripening and induction of labour
Misoprostol vs oxytocin...
25 trials [4] involving 3074 participants
Vaginal misoprostol more effective than oxytocin for IOL
Use of less than 50µg misoprostol showed no reduction in failure to deliver within 24 hours
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Cervical ripening and induction of labour
...Misoprostol vs oxytocin
Uterine hyperstimulation without foetal heart changes commoner in the misoprostol group
No difference in perinatal or maternal adverse outcome between groups
Increase in meconium-stained liquor in oral misoprostol vs intravenous oxytocin
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Cervical ripening and induction of labour
Misoprostol vs other prostaglandins (especially dinoprostone)...
38 trials,[4] 7022 participants
Failure to deliver vaginally within 24 hours less in misoprostol group
Uterine hyperstimulation with FHR changes and meconium-stained liquor more with misoprostol
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Cervical ripening and induction of labour
...Misoprostol vs other prostaglandins
Oral misoprostol less likely than vaginal dinoprostone have a caesarean delivery
Oral misoprostol group less likely to deliver within 24 hours vs vaginal dinoprostone
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Cervical ripening and induction of labour
Recommended dosing [5]
Intravaginally, 25µg 6-hourly or
Orally, 25µg 2-hourly
Contraindicated in women with a previous uterine scar
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Safe single doses of vaginal misoprostol for producing uterine contractions at various
gestations
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Post-partum haemorrhage
Useful for both the prevention and treatment of PPH
For treatment, evidence[6] shows that...
Oral route of admin fast uptake, but shortest duration of action
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Post-partum haemorrhage
...For treatment, evidence[6] shows that
Rectal route has slow uptake with a prolonged duration of action
Buccal and sublingual routes have rapid uptake, prolonged duration of action and greatest total bioavailability
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Post-partum haemorrhage
PPH prophylaxis [7]
Oral dose of 600µg stat Not as effective as oxytocin Exclude second twin before administration
PPH treatment [8]
Sublingual dose of 800µg stat
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Termination of pregnancy
First trimester medical abortion...
Indicated for induced, missed or incomplete abortion
FDA-approved regimen can be initiated up to 49 days from 1st day of last menstrual period
Involves use of misoprostol alone or in combination with mifepristone or methotrexate
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Termination of pregnancy
...First trimester medical abortion
Mifepristone, 600µg PO stat + misoprostol, 400µg PO on day 3
Methotrexate, 50 mg/m2 IM + misoprostol 800µg PV on day 5
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Termination of pregnancy
Second trimester... [9]
Indicated for IUFD and congenital anomalies incompatible with life
Vaginal misoprostol more effective than oral misoprostol [10] in T2 and T3
Also as effective as the traditionally used gemeprost
IUFD:13-17 weeks, 200µg 6-hourly vaginally x4 max
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Termination of pregnancy
...Second trimester [9]
18-26 weeks. 100µg 6-hourly vaginally, x4 max
Interruption of pregnancy: 400µg vaginally or sublingually 3-hourly x5 max
Caution in women with uterine scars
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Cervical ripening pre-instrumentation[9]
First trimester
Vaginally or sublingually, 400µg 3 hours prior to procedure
Indications Insertion of IUD Surgical termination of pregnancy Hysteroscopy
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Other uses
Currently ONLY approved by the Food and Drug Administration (FDA) for prevention of gastric ulcers resulting from chronic administration of non-steroidal anti-inflammatory drugs eg in the elderly
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Known issues in our environment...
Difficulty in compounding recommended dose
Easy access to misoprostol by health and non-health workers
Self administration by some at home for self induction of labour or abortions
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...Known issues in our environment
The small chance of developing Moebius syndrome in failed misoprostol-induced abortion
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Controversies
Manufacturers of Cytotec™ issued letters in 2000 warning against use of misoprostol in pregnant women
Safety of misoprostol versus other agents used for IOL
Political tussle of pro- versus anti-abortion hardliners
Mifepristone versus misoprostol for TOP
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Recommendations
Consider oral route for IOL with misoprostol
Evidence[6] shows the sublingual route to be the most promising. Consider this for treatment of PPH
Consider local compounding of oral misoprostol to easily administer the recommended dosage
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Conclusion
The discovery of misoprostol could easily be regarded as one of the best things in modern medicine secondary to antibiotics
Though the use in ObGyn is off-label, it's legal and have been highly recommended by several authorities
Misoprostol use in obstetrics is a double-edged sword – our duty
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THANK YOU FOR LISTENING!
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References
1. The Schaffer Library of Drug Policy: A summary of Historical events. Available from http://www.druglibrary.org/schaffer/history/histsum.htm
2. Hoogerwerf WA, Pasricha JP. Pharmacotherapy of gastric acidity, peptic ulcers, and gastroesophageal reflux disease. In: Brunton LL, Lazo JS, Parker KL, editors. Goodman & Gilman's The Pharmacological Basis of Therapeutics. 11th ed. Chicago: McGraw-Hill; 2006
3. Goldberg AB, Greenberg MB, Darney PD. Misoprostol and pregnancy. N Engl J Med. 2001; 334:38-47
4. Abdel-Aleem H. Misoprostol for cervical ripening and induction of labour: RHL commentary (last revised: 1 May 2011). The WHO Reproductive Health Library; Geneva: World Health Organization.
5. WHO recommendations for induction of labour, 2011. Retrieved from http://www.misoprostol.org/dosage-guidelines/
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References
6. Hofmeyr GJ, Walraven G, Gulmezoglu AM, Maholwana B, Alfirevic Z, Villar J. Misoprostol to treat postpartum haemorrhage: a systematic review. BJOG 2005; 112: 547-53 doi: 10.1111/j.1471-0528.2004.00512.x pmid: 15842275.
7. FIGO Guidelines: Prevention of PPH with misoprostol, 2012. Retrieved from http://www.misoprostol.org/dosage-guidelines/
8. FIGO Guidelines: Treatment of PPH with misoprostol, 2012. Retrieved from http://www.misoprostol.org/dosage-guidelines/
9. WHO/RHR. Safe abortion: technical and policy guidelines for health systems (2nd edition), 2012. Retrieved from http://www.misoprostol.org/dosage-guidelines/
10. Matthews JE. Misoprostol for induction of labour to terminate pregnancy in the second or third trimester for women with a fetal anomaly or after intrauterine foetal death: RHL commentary (last revised: 1 October 2010). The WHO Reprobuctive Health Library; Geneva: World Health Organization.