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27

STANDARD MEDICAL THERAPY F. Breathnach and M. Geary

INTRODUCTION successful until the early 20th century, when Barber and Dale isolated ergotoxine in 19062. Failure of the uterus to contract and retract Initially thought to be a pure substance, this following has for centuries been agent was subsequently found to comprise four recognized as the most striking cause of post- alkaloids and in 1935 Moir and Dudley were partum hemorrhage. is a condi- credited for isolating , the active tion which, in spite of the presence of effective aqueous extract ‘to which ergot rightly owes medical interventions, still claims thousands of its long-established reputation as the pulvis maternal lives. In the developing world, lack of parturiens’5,6. Moir reported on its clinical use access to therapies that have been in 1936, stating6: available for almost a century represents one of the most glaring disparities in obstetric care ‘. . . the chief use of ergometrine is in the preven- today. tion and treatment of postpartum haemorrhage. In the 19th century, uterine atony was Here the ergometrine effect is seen at its best. If after the delivery of the placenta the uterus is treated by intrauterine placement of various unduly relaxed, the administration of ergo- agents with the aim of achieving a tamponade metrine, 1 mg by mouth or 0.5 mg by injection, effect. ‘A lemon imperfectly quartered’ or ‘a will quickly cause a firm contraction of the organ. large bull’s bladder distended with water’ were If severe haemorrhage has already set in, it is employed for this purpose, with apparent suc- highly recommended that the drug should be cess. Douching with vinegar or iron perchloride given by the intravenous route. For this purpose was also reported1,2. Historically, the first utero- one-third of the standard size ampoule may be tonic drugs were ergot alkaloids, followed by injected or, for those who wish accurate dosage, and, finally, . a special ampoule containing 0.125 mg is manu- Ergot, the alkaloid-containing product of the factured. An effect may be looked for in less than fungus Claviceps purpurea that grows on rye, was one minute.’ recognized for centuries as having uterotonic Oxytocin, the hypothalamic polypeptide hor- properties and is the substance referred to by mone released by the posterior pituitary, was John Stearns in 1808 as ‘pulvis parturiens’ (a discovered in 1909 by Sir Henry Dale7 and syn- powder [for] childbirth), at which time it was thesized in 1954 by du Vigneaud8. The develop- used as an agent to accelerate labor3. By the end ment of oxytocin constituted the first synthesis of the 19th century, however, recognition of the of a polypeptide hormone and gained du potential hazards associated with ergot use in Vigneaud a Nobel prize for his work. labor, namely its ability to cause uterine hyper- The third group of comprises stimulation and stillbirth, had tempered enthu- the ever-expanding family. The siasm for its use. Focus was diverted toward prostaglandins were discovered in 1935 by a its role in preventing and treating postpartum group led by Swedish physiologist Ulf von hemorrhage at a time when, according to an Euler9 who found that extracts of seminal vesi- 1870 report, maternal mortality in England cles or of human semen were capable of causing approached one in 20 births4. Attempts to iso- contraction of uterine tissue and lowering blood late the active alkaloids from ergot were not pressure. The term ‘prostaglandin’ evolved

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from von Euler’s belief that the active material Ta bl e 1 Risk factors for uterine atony came exclusively from the prostate gland. This Factors associated with uterine overdistension family of ‘’, 20-carbon fatty acids, Multiple pregnancy was subsequently found to be produced in a Polyhydramnios variety of tissues and capable of mediating a Fetal macrosomia myriad of physiologic and pathologic processes. Prostaglandins, by virtue of their ability to cause Labor-related factors strong myometrial tetanic activity, are increas- Induction of labor Prolonged labor ingly being employed as adjunctive therapy Precipitate labor to standard oxytocin and ergometrine to treat Oxytocin augmentation postpartum hemorrhage resulting from uterine Manual removal of placenta atony (see Chapter 12). This chapter is devoted to critical evaluation Use of uterine relaxants of the standard pharmacological methods avail- Deep anesthesia (especially halogenated anesthetic able to overcome uterine atony, with particular agents) focus on agent selection based on effectiveness, safety profile, ease of administration, cost and Intrinsic factors applicability in low-resource settings. Previous postpartum hemorrhage Antepartum hemorrhage (abruptio or previa) Obesity UTERINE ATONY Age > 35 years Powerful efficient contractions of the myo- metrium are essential to arrest blood loss after delivery. The resultant compression of the uter- hemorrhage confers a 2–4-fold increased risk of ine vasculature serves to halt the 800 ml/min hemorrhage compared to women without such blood flow in the placental bed. Recognition of a history12,13. a soft, boggy uterus in the setting of a post- It is appropriate that women with these pre- partum bleed alerts the attendant to uterine disposing risk factors should deliver in a hospital atony. The contribution that uterine atony with adequate facilities to manage postpartum makes toward postpartum hemorrhage is so hemorrhage. Prophylactic measures adopted well-known that a universal reflex action when include appropriate hospital booking for women faced with excessive is at risk, active management of the third stage of to massage a . Prompt labor, intravenous access during labor and recognition of this condition and institution of ensuring the availability of cross-matched uterotonic therapy will effectively terminate the blood. However, it is noteworthy that uterine majority of cases of hemorrhage. Once effective atony occurs unpredictably in women with uterine contractility is assured, persistent bleed- no identifiable predisposing risk factors. This ing should prompt the search for retained underpins the need for strict protocols for the placental fragments, genital tract trauma or a management of postpartum hemorrhage to be bleeding diathesis (see Chapters 9 and 25). in place in every unit that provides obstetric Astute risk assessment is crucial in identify- care. ing women at increased risk of uterine atony, thereby allowing for preventive measures to OXYTOCIN be instituted and for delivery to take place where transfusion and anesthetic facilities are With timely and appropriate use of uterotonic available. The established risk factors associated therapy, the majority of women with uterine with uterine atony are outlined in Table 1. It is atony can avoid surgical intervention. Stimula- worth noting that multiparity, hitherto believed tion of uterine contraction is usually achieved in to be a significant risk factor, has not emerged the first instance by bimanual uterine massage as having an association with uterine atony and the injection of oxytocin (either intra- in recent studies10-12. Previous postpartum muscularly or intravenously), with or without

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ergometrine. The mode of action of oxytocin of action of 2–5 min. Metabolism is via the involves stimulation of the upper uterine seg- hepatic route and the mean plasma half-life ment to contract in a rhythmical fashion. Owing is 30 min. Nonetheless, the clinical effect of to its short plasma half-life (mean 3 min), a ergometrine persists for approximately 3 h. The continuous intravenous infusion is required in co-administration of ergometrine and oxytocin order to maintain the uterus in a contracted therefore results in a complementary effect, with state14. The usual dose is 20 IU in 500 ml oxytocin achieving an immediate response and of crystalloid solution, with the dosage rate ergometrine a more sustained action. adjusted according to response (typical infusion Common side-effects include nausea, vomit- rate 250 ml/h). When administered intra- ing and dizziness and these are more striking venously, the onset of action is almost instanta- when given via the intravenous route. As a result neous and plateau concentration is achieved of its vasoconstrictive effect via stimulation after 30 min. By contrast, intramuscular admin- of α-adrenergic receptors, hypertension can istration results in a slower onset of action occur. Contraindications to use of ergometrine (3–7 min) but a longer lasting clinical effect (up therefore include hypertension (including to 60 min). pre-eclampsia), heart disease and peripheral Metabolism of oxytocin is via the renal and vascular disease. If given intravenously, where hepatic routes. Its antidiuretic effect, which its effect is seen as being almost immediate, it amounts to 5% of the antidiuretic effect of should be given over 60 s with careful monitor- , can result in water toxicity if given ing of pulse and blood pressure. Relevant to the in large volumes of electrolyte-free solutions. developing world in particular is its heat lability. This degree of water overload can manifest itself It is both heat- and light-sensitive and should with headache, vomiting, drowsiness and con- be stored at temperatures below 8°C and away vulsions. Furthermore, rapid intravenous bolus from light. administration of undiluted oxytocin results in The product Syntometrine® (5 units oxy- relaxation of vascular , which can tocin and 0.5 mg ergometrine) combines the lead to . It is therefore best given rapid onset of oxytocin with the prolonged intramuscularly or by dilute intravenous infu- effect of ergometrine. The mild vasodilatory sion. Oxytocin is stable at temperatures up property of oxytocin may counterbalance the to 25°C but refrigeration may prolong its vasopressor effect of ergometrine. shelf-life. First-line treatment of uterine atony, there- A disadvantage of oxytocin is its short half- fore, involves administration of oxytocin or life. The long-acting oxytocin analog ergometrine as an intramuscular or diluted has been studied in this context as its more intravenous bolus, followed by repeat dosage sustained action, similar to that of ergometrine if no effect is observed after 5 min and comple- but without its associated side-effects, may offer mented by continuous intravenous oxytocin advantages over standard oxytocic therapy15. infusion. Atony that is refractory to these Comparative studies of carbetocin for the first-line oxytocics will warrant prostaglandin prevention of postpartum hemorrhage have therapy. identified enhanced effectiveness of this analog when compared with an oxytocin infusion16,17.

Carboprost (15-methyl PGF α) acts as a ERGOMETRINE 2 smooth muscle stimulant and is a recognized In contrast to oxytocin, the administration of second-line agent for use in the management ergometrine results in a sustained tonic uterine of postpartum uterine atony unresponsive to contraction via stimulation of myometrial oxytocin/ergometrine. It is an analog of PGF2α α-adrenergic receptors. Both upper and lower (dinoprost) with a longer duration of action uterine segments are thus stimulated to contract than its parent compound, attributed to its in a tetanic manner14. Intramuscular injection resistance to inactivation by oxidation at the of the standard 0.25 mg dose results in an onset 15-position. Available in single-dose vials of

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0.25 mg, it may be administered by deep intra- or sublingual route. The results of an inter- muscular injection or, alternatively, by direct national multicenter, randomized trial of oral intramyometrial injection. The latter route of as a prophylactic agent for the third administration is achieved either under direct stage of labor showed it to be less effective vision at Cesarean section or transabdominally at preventing postpartum hemorrhage than or transvaginally following vaginal delivery and parenteral oxytocin21. Fifteen percent of women has the advantage of a significantly quicker in the misoprostol arm required additional onset of action18,19. Peripheral intramuscular uterotonics compared with 11% in the oxytocin injection yields peak plasma concentrations at group. This may be due to its longer onset of 15 min in contrast to less than 5 min for the action (20–30 min to achieve peak serum levels intramyometrial route. Using a 20-gauge spinal compared to 3 min for oxytocin). However, needle, intravascular injection can be avoided owing to the fact that its more prolonged time by pre-injection aspiration, and intramyometrial interval required to achieve peak serum levels rather than intracavitary placement of the may make it a more suitable agent for pro- needle can be confirmed by observing resistance tracted uterine bleeding, there is mounting on injection, as described by Bigrigg and interest in its role as a therapeutic rather than a colleagues20. The dose may be repeated every prophylactic agent. 15 min up to a maximum cumulative dose of The use of rectal misoprostol for the treat- 2 mg (eight doses), although, in reported case ment of postpartum hemorrhage unresponsive series, the majority of patients require no more to oxytocin and ergometrine was first reported than one dose. by O’Brien and colleagues22 in a descriptive Reported efficacy is high. Successful arrest study of 14 patients. Sustained uterine contrac- of atonic hemorrhage is reported in 13/14 tion was reported in almost all women within patients by Bigrigg and colleagues20. The largest 3 min of its administration. However, there case series to date19 involved a multicenter sur- was no control group included for comparison. veillance study of 237 cases of postpartum hem- A single-blinded, randomized trial of miso- orrhage refractory to standard oxytocics and prostol 800 µg rectally versus Syntometrine® reported an efficacy of 88%. The majority of intramuscularly plus oxytocin by intravenous women in this study required a single dose only. infusion found that misoprostol resulted in Owing to its vasoconstrictive and broncho- cessation of bleeding within 20 min in 30/32 constrictive effects, carboprost can result in cases (93%) compared to 21/32 (66%) for nausea, vomiting, diarrhea, pyrexia and the comparative agents23. A Cochrane review bronchospasm. Contraindications therefore supports these findings, suggesting that rectal include cardiac and pulmonary disease. The misoprostol in a dose of 800 µg could be a use- cost of carboprost makes it unsuitable for ful ‘first-line’ drug for the treatment of primary consideration in low-resource settings. Further- postpartum hemorrhage24. more, it is both light- and heat-sensitive and A strong need exists for high-dose miso- must be kept refrigerated at 4°C. prostol to be evaluated in randomized control trials. As an alternative to the aforementioned uterotonics, misoprostol has the significant MISOPROSTOL advantage of low cost, thermostability, light Misoprostol is a synthetic analog of prostaglan- stability and lack of requirement for sterile din E1 which selectively binds to myometrial needles and syringes for administration, making EP-2/EP-3 receptors, thereby pro- it an attractive option for use in the developing moting uterine contractility. It is metabolized world. It has a shelf-life of several years. via the hepatic route. It may be given orally, Side-effects of misoprostol are mainly gastro- sublingually, vaginally, rectally or via direct intestinal and are dose-dependent. A frequently intrauterine placement. The rectal route of reported side-effect of misoprostol is the occur- administration is associated with a longer onset rence of shivering and pyrexia. Side-effects are of action, lower peak levels and a more favorable less marked when the rectal route of administra- side-effect profile when compared with the oral tion is used.

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OTHER PROSTAGLANDINS However, to date there is only one case report in the literature of the use of this agent in the set- Dinoprost (prostaglandin F α) has been used 2 ting of postpartum hemorrhage; that particular via intramyometrial injection at doses of case involved a placenta accreta where the 0.5–1.0 mg with good effect25. Low-dose source of the persistent bleeding was the lower intrauterine infusion via a Foley catheter has uterine segment and the uterine body was also been described, consisting of 20 mg dino- described as being well contracted31. The dose prost in 500 ml saline at 3–4 ml/min for 10 min, employed was 1 g given intravenously 4-hourly then 1 ml/min. The bleeding was arrested in to a cumulative dose of 3 g. all but one of 18 patients and no adverse The use of recombinant activated factor VII outcome was reported. As mentioned earlier, (rFVIIa) as a hemostatic agent for refractory however, this agent has a shorter duration postpartum hemorrhage has recently been of activity than carboprost and indeed has described in a number of case reports32,33. The been unavailable in the US since the 1980s mode of action of this agent involves enhance- where its withdrawal was attributed to financial ment of the rate of thrombin generation, leading reasons. to formation of a fully stabilized fibrin plug that (dinoprostone), in spite 2 is resistant to premature lysis. Reported cases of its vasodilatory properties, causes smooth involve hemorrhage unresponsive to a myriad muscle contraction in the pregnant uterus, thus of conventional treatments including hysterec- making it a potentially suitable uterotonic agent. tomy and pelvic vessel ligation, where use of this Its principal indication is in pre-induction agent was remarkably successful at arresting cervical priming, but intrauterine placement of seemingly intractable bleeding within a matter dinoprostone has been successfully employed of minutes. Doses of 60–120 µg/kg intra- as a treatment for uterine atony26. The vaso- venously were used. A more complete discus- dilatory effect of dinoprostone, however, ren- sion of this agent is found in Chapter 26. ders it unsuitable for use in the hypotensive or hypovolemic patient. It may, however, be of use in women with cardiorespiratory disease in CONCLUSIONS whom carboprost is contraindicated. The identification of ‘substandard care’ in 71% Experience with , a prostaglandin of maternal deaths attributed to hemorrhage E analog, in pessary formulation delivered 1 in the 2000–2002 Confidential Report (UK)34 directly into the uterine cavity or placed in underscores the need for a standard of care to the posterior vaginal fornix, is again largely be established in every unit where childbirth anecdotal27-29. Its mode of action resembles takes place and for all relevant health-care work- that of PGF α. Rectal administration has 2 ers to be keenly familiar with that standard (see also been reported. A retrospective series of Chapter 22). Integral to any protocol on man- 14 cases in which rectal gemeprost 1 mg was agement of postpartum hemorrhage will be a used for postpartum hemorrhage unresponsive stepwise approach to achieving effective uterine to oxytocin and ergometrine reported prompt contractility. The successful management of cessation of bleeding in all cases, with no uterine atony will depend on staff being familiar apparent maternal adverse sequelae30. with the pharmacologic agents available to them with respect to dosage, route of administration and safety profile (Table 2). Application of such HEMOSTATICS: TRANEXAMIC ACID protocols has been shown to achieve successful AND RECOMBINANT ACTIVATED reduction in the morbidity associated with FACTOR VII postpartum hemorrhage35. The antifibrinolytic agent tranexamic acid, It is tempting to credit the second- or which prevents binding of plasminogen and third-line agent with successfully controlling a plasmin to fibrin, may well have a role in the postpartum hemorrhage; however, it is certainly control of intractable postpartum hemorrhage, plausible that a synergistic effect is observed particularly where coagulation is compromised. where a combination of uterotonics is used.

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Ta bl e 2 Medical uterotonic therapy

Agent Dose Cautions Oxytocin (Pitocin®, 10 IU i.m./i.v. followed by i.v. Hypotension if given by rapid i.v. Syntocinon®) infusion of 20 IU in 500 ml bolus. Water intoxication with crystalloid titrated versus response large volumes (e.g. 250 ml/h) Ergometrine (Ergonovine®) 0.25 mg i.m./i.v. Contraindicated in hypertensive patients. Can cause nausea/ vomiting/dizziness

Carboprost (15-methyl PGF2α) 0.25 mg i.m./myometrial. Can be Bronchospasm (caution in patients (Hemabate®) repeated every 15 min. Max. 2 mg with , hypertension, cardiorespiratory disease)

Dinoprost (PGF2α) 0.5–1 mg intramyometrial or 20 mg Bronchospasm, nausea, vomiting ® (Prostin F2α ) in 500 ml N/saline infused via Foley and diarrhea can occur catheter into uterine cavity Dinoprostone (Prostin®/ 2 mg p.r. 2-hourly Hypotension Prepidil®) Gemeprost (Cervagem®) 1–2 mg intrauterine placement/ Gastrointestinal disturbance 1 mg p.r. Misoprostol (Cytotec®) 600–1000 µg p.r./intracavitary Gastrointestinal disturbance, shivering, pyrexia Tranexamic acid 1 g 8-hourly i.v. Can increase risk of thrombosis (Cyclokapron®) rFVIIa (Novoseven®) 60–120 µg/kg i.v. , hypertension

i.m., intramuscularly; i.v., intravenously; p.r., per rectum

The global quest for an ‘ideal’ uterotonic 2. De Costa C. St Anthony’s fire and living liga- agent must take into account the fact that what tures: a short history of ergometrine. Lancet is applicable in one setting may have no rele- 2002;359:1768–70 vance in another. This is particularly true of the 3. Thoms H. John Stearns and pulvis parturiens. need to study the potential of a low-cost agent Am J Obstet Gynecol 1931;22:418–23 4. Edgar JC. The Practice of Obstetrics. Philadelphia: such as misoprostol for use in the developing Blakiston, 1913:475-7 world. The cost and instability of standard 5. Dudley HW, Moir C. The substance responsible oxytocic drugs are prohibitive in many for the traditional clinical effect of ergot. Br Med low-resource settings. Safety and parallel effi- J 1935;1:520–3 cacy should therefore suffice as parameters 6. Moir C. Clinical experiences with the new whereby an agent such as misoprostol is judged alkaloid, ergometrine. Br Med J 1936;ii:799–801 rather than demonstration of clinical superiority 7. Dale HH. The action of extracts of the pituitary over established uterotonics. body. Biochem J 1909;4:427–47 8. duVigneaud V, Ressler C, Swan JM, et al. The synthesis of an octapeptide amide with the hormonal activity of oxytocin. J Am Chem Soc 1954;75:4879–80 References 9. von Euler H, Adler E, Hellstrom H, et al. On the 1. Davis DD. The Principles and Practice of Obstetric specific vasodilating and plain muscle stimulat- Medicine. London: Rebman, 1896:602 ing substance from accessory genital glands in

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man and certain animals (prostaglandin and 23. Lokugamage AU, Sullivan KR, Niculescu I, et al. vesiglandin). J Physiol (London) 1937;88:213–34 A randomized study comparing rectally adminis- 10. Stones RW, Paterson CM, Saunders NJ. Risk tered misoprostol versus syntometrine combined factors for major obstetric haemorrhage. Eur J with an oxytocin infusion for the cessation of Obstet Gynaecol Reprod Biol 1993;48:15–18 primary postpartum haemorrhage. Acta Obstet 11. Tsu VD. Postpartum haemorrhage in Zimba- Gynecol Scand 2001;80:835–9 bwe: a risk factor analysis. Br J Obstet Gynaecol 24. Mousa HA, Alfirevic Z. Treatment for primary 1993;100:327–33 postpartum haemorrhage. Cochrane Database of 12. Waterstone M, Bewley S, Wolfe C. Incidence Systematic Reviews 2003;1 CD 003249 and predictors of severe obstetric morbidity: 25. Kupferminc MJ, Gull I, Bar-Am A, et al. case-control study. Br Med J 2001;322:1089–94 Intrauterine irrigation with prostaglandin F2α for 13. Hall MH, Halliwell R, Carr-Hill R. Concomi- management of severe postpartum haemorrhage. tant and repeated happenings of complications of Acta Obstet Gynecol Scand 1998;77:548–50 the third stage of labour. Br J Obstet Gynaecol 26. Peyser MR, Kupferminc MJ. Management of 1985;92:732–8 severe postpartum hemorrhage by intrauterine 14. Dollery C, ed. Therapeutic Drugs, 2nd edn. irrigation with . Am J Obstet Edinburgh: Churchill Livingstone, 1999 Gynecol 1990;162:694–6 15. Hunter DJ, Schulz P, Wassenaar W. Effect of 27. Barrington JW, Roberts A. The use of gemeprost carbetocin, a long-acting oxytocin analog on the pessaries to arrest postpartum haemorrhage. Br J postpartum uterus. Clin Pharmacol Ther 1992;52: Obstet Gynaecol 1993;100:691–2 60–7 28. El-Lakany N, Harlow RA. The use of gemeprost 16. Boucher M, Nimrod CA, Tawagi GF, et al. pessaries to arrest postpartum haemorrhage. Br J Comparison of carbetocin and oxytocin for the Obstet Gynaecol 1994;101:277 prevention of postpartum hemorrhage following 29. Bates A, Johansen K. The use of gemeprost pes- vaginal delivery: a double-blind randomized saries to arrest postpartum haemorrhage. Br J trial. J Obstet Gynaecol Can 2004;26:481–8 Obstet Gynaecol 1994;101:277–8 17. Dansereau J, Joshi AK, Helewa ME, et al. 30. Craig S, Chau H, Cho H. Treatment of severe Double-blind comparison of carbetocin versus postpartum haemorrhage by rectally adminis- oxytocin in prevention of uterine atony after tered gemeprost pessaries. J Perinat Med 1999; . Am J Obstet Gynecol 1999; 27:231–5 180:670–6 31. Alok K, Hagen P, Webb JB. Tranexamic acid in 18. Jacobs M, Arias F. Intramyometrial PGF2α in the management of postpartum haemorrhage. Br treatment of severe postpartum hemorrhage. J Obstet Gynaecol 1996;103:1250 Obstet Gynecol 1980;55:665–6 32. Segal S, Shemesh IY, Blumenthal R, et al. Treat- 19. Oleen MA, Mariano JP. Controlling refractory ment of obstetric hemorrhage with recombinant postpartum hemorrhage with hemabate sterile activated factor VII (rFVIIa). Arch Gynecol Obstet solution. Am J Obstet Gynecol 1990;162:205–8 2003;268:266–7 20. Bigrigg A, Chui D, Chissell S, et al. Use of 33. Bouwmeester FW, Jonkhoff AR, Verheijen RH, intramyometrial 15-methyl prostaglandin F2α et al. Successful treatment of life-threatening to control atonic postpartum haemorrhage postpartum hemorrhage with recombinant following vaginal delivery and failure of conven- activated factor VII. Obstet Gynecol 2003;101: tional therapy. Br J Obstet Gynaecol 1991;98: 1174–6 734–6 34. Why Mothers Die. Report on Confidential 21. Gulmezoglu AM, Villar J, Ngoc NT, et al. WHO Enquiry into Maternal Deaths in the United multicentre randomised trial of misoprostol in Kingdom 2000–2002. London: RCOG Press, the management of the third stage of labour. 2004 Lancet 2001;358:689–95 35. Rizvi F, Mackey R, Geary M, et al. Successful 22. O’Brien P, El-Refaey H, Geary M, et al. Rectally reduction of massive postpartum haemorrhage administered misoprostol for the treatment by use of guidelines and staff education. Br J of postpartum haemorrhage unresponsive to Obstet Gynaecol 2004;111;495–8 oxytocin and ergometrine: a descriptive study. Obstet Gynecol 1998;92:212–14

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