Desarrollo teórico del sistema.

Background

There has never been any attempt at using prostaglandins orally for prophylactic management of the third stage of labour. Scientific dogma indicated that oral absorption of any medication would be too slow to act quickly enough for prevention of PPH. The only attempt examining the oral approach for prophylactic management of the third stage of labour was that by De-Groot et al.

(1996), investigating the use of oral methylergometrine, which was not found to be an appropriate alternative to parenteral oxytocics. It was associated with unpredictable pharmacokinetic and dynamic properties, and demonstrated no clinical effect in reducing postpartum blood loss.

The concept of using misoprostol as a prophylactic agent for management of the third stage of labour arose from its confirmed uterotonic properties and their application in various obstetric circumstances. The physiological intrauterine pressure study confirmed that oral misoprostol has a powerful uterotonic effect when used in the postpartum period. To ascertain whether misoprostol would be successful as a prophylactic oxytocic agent in the third stage of labour, a randomised controlled clinical trial would have to be conducted to determine its efficacy in comparison with other oxytocics proved to be effective in this field.

Doubts about the efficacy of oral misoprostol, however, led us to approach this work carefidly. With an ethical viewpoint, preliminary observational studies had first to be conducted to investigate the efficacy of different misoprostol dosages. The appropriate effective dosage, associated with the least side effects, that could safely and ethically be used in a randomised trial had to be determined. This was implemented by means of two consecutive observational pilot studies.

The choice of misoprostol dose to be used in the pilot study was a central issue, since the appropriate dosage required to achieve the desired clinical response with minimum side effects was uncertain. Successful choice of an accurate dosage depends on a balance of three main factors; the clinical indication, efficacy to achieve the desired outcome, and minimisation of side effects. The issue of choice of dosage of misoprostol for a specific clinical indication has been a problem that is clearly highlighted by different studies in the literature. When used in the treatment of gastroduodenal ulcers, a dosage of 1 2 0 0 p,gm of oral misoprostol,

administered in divided doses over 24 hours, was found to be safe, well tolerated, and associated with minimal side effects (Herting & Nissen, 1986; Collins 1990). However, when used in the third trimester of pregnancy, a relatively small dose of 50 |igm of misoprostol administered vaginally could successfully induce labour in 79% of cases (Marguilies et al., 1992). First trimester abortion studies indicate that sole administration of misoprostol dosages up to 800 |igm without mifepristone leads to partial or complete abortion in only 11% of cases, (Rabe et ai, 1987), and when used after pre-treatment with mifepristone, the success rate rises to over 90% (Aubeny & Baulieu, 1991). Aubeny and Baulieu (1991) demonstrated that a single oral dose of 400 pgm of misoprostol, administered following pre-treatment with 600 mg of mifepristone, followed 3 hours later by an additional 200 pgm, achieved successful abortion in 97.6% of women between 42 and 49 days of amenorrhea, but expulsion of the products of conception within 4 hours occurred in only 69% of cases. In second trimester abortion, oral misoprostol doses of up to 800 pgm have been reported to achieve a 30% success rate, and doses up to 1200 jigm achieve a 77% successful abortion rate, following pre-treatment with 600 mg of mifepristone (El-Refaey et al, 1993).

The safety of single doses of 200 pigm of misoprostol and total daily doses of 800 pgm has been established in previous studies. At first, lower doses of 2 0 0 and 400

pgm were used for fear of side effects, after which an 800 pgm dosage was used in later studies.

In a study investigating the use of misoprostol in second trimester abortion (El- Refaey et ai, 1995 a), an 800 pgm dosage was administered vaginally, followed by subsequent 400 jigm oral doses at three hourly intervals, up to a maximum of four doses, achieved a 95% successful abortion rate. Nulliparous women were found to require a higher dosage than multiparous women; 2 0 0 0 pgm ( 1 2 0 0 -

2400 pgm) compared to 1200 pgm (800 - 1600 jigm) respectively. Reported side effects were mainly gastrointestinal. Nausea occurred in 50% of patients, 40% had vomiting, 15% required antiemetic therapy, 20% reported having mild diarrhoea, and 45% developed pyrexia. Side effects were reported to occur more frequently among nulliparous women as a result of the higher dosage they received.

El-Refaey and Templeton (1994 b) demonstrated the efficacy of 800 pgm of oral misoprostol whether administered as a single dose or divided into smaller dosages in early abortion. In a randomised study, an 800 pgm dosage of oral misoprostol was administered to 150 women undergoing early abortion (56 days gestation or less), after pre-treatment with mifepristone. Women first received 200 mg of mifepristone, followed 36 to 48 hours later with either a single oral dose of 800 pgm of misoprostol or two sequential doses of 400 pgm administered two hours apart. The overall success rate was 93.3% (95% Cl of 89.3 to 97.3). The higher single dose achieved a 95% success rate, compared to 92% with the sequential regimen, but the difference was not statistically significant (p-value = 0.52).

Gastrointestinal side effects occurred more frequently among patients receiving the single oral dosage; vomiting in 40%, nausea in 6 8%, and abdominal pain in

36% of patients, compared to 31%, 59% and 39% respectively among those receiving the sequential regimen, but the differences were not statistically significant. Diarrhoea occurred in 33% of women receiving the single higher dose, compared to 2 1% in the second group, and was significantly higher both in

incidence (p-value = 0.049) and severity (p-value = 0.034). The larger dosage of misoprostol was associated with a small but significant fall in blood pressure within four hours of drug administration (p-value = 0.025). Although it appeared that administration of the drug in a sequential manner may decrease the frequency of side effects, but it was noted that, other than diarrhoea, the frequency of side effects did not differ significantly between the two studied groups.

In another study, El-Refaey and Templeton (1995 b) compared a 600 pgm dosage of misoprostol administered orally and vaginally, and demonstrated its efficacy in achieving second trimester pregnancy termination. In a randomised study of 70 women undergoing mid-trimester abortion, 600 |igm of misoprostol was administered 36 to 48 hours after pre-treatment with 600 mg of oral mifepristone. In the first group, women received all the doses vaginally; the initial 600 pgm dosage, followed by 400 pgm doses every three hours. In the second group, women received the first dose of 600 pgm vaginally, followed by the 400 pgm in oral doses administered every three hours. Dosages of up to 2200 pgm were used over a 12-hour interval and were well tolerated. The median dosage used for the first group was 1000 pgm, and that for the second group was 1400 pgm. The overall success rate of the two groups was similar; 97% (Cl of 90 to 1 0 0%). Side

effects reported were vomiting (57% versus 61%) and diarrhoea (29% versus 35%), which were not significantly different between the two studied groups.

In miscarriage, the combination of mifepristone and 600 pgm of oral misoprostol has been shown to have a success rate of 93%. El-Refaey et al (1992) demonstrated the efficacy of this dosage in the management of missed abortion and anembrionic pregnancy. Women first received a single oral dose of 600 mg of mifepristone, followed 36 to 48 hours later by 600 pgm of misoprostol, administered orally in a divided dose of 400 pgm, followed two hours later by a further 200 jrgm. Successful abortion was achieved in 84.3% (43/51) of patients after receiving that dosage. A dosage lower than 600 pgm, however, might not have been sufficient to achieve the desired outcome, while a higher dose might have been associated with unacceptable side effects.

The disparity in the response of the uterus to misoprostol may be explained by variations in uterine responsiveness to prostaglandins at different gestations, in addition to the route of administration of the drug, which is an important consideration. It also appears that the incidence of gastrointestinal side effects increases the higher the dosage administered. The incidence of vomiting, for example, is 10% with an oral misoprostol dose of 400 pgm (Aubeny & Baulieu, 1991), which increases to 40% with an 800 pgm dosage (El-Refaey & Templeton, 1994 b).

A major problem that faced us with these studies was in accurate determination of the most important outcome variable; postpartum blood loss. Accurate assessment of blood loss in the third stage of labour was a very important factor in predicting the success of these studies. As discussed in the Introduction (chapter 1), discrepancies among reports of PPH rates occur as a result of the different methods used for blood loss measurement, whether quantitatively or visually (Newton et al 1961; Brant, 1967; Razvi et al, 1996). However, subjective

estimation of blood loss in parturient women is still the most common method applied in the UK. Major studies in the literature investigating management of the third stage of labour have used subjective assessment of blood loss to report rates of PPH. In line with other landmark papers (Nieminen & Jarvinen, 1963; Dumoulin, 1981; Prendiville et al, 1988; Begley, 1990; McDonald et al, 1993; Mitchell & Elboume, 1993; Khan et al, 1995; Yuen et al, 1995), we have also employed clinical assessment of postpartum blood loss in our studies.

The first pilot study was a prospective observational study investigating the efficacy of 600 pgm of orally administered misoprostol for management of the third stage of labour and prevention of PPH. This particular dosage was chosen to begin with, on the basis of previous abortion studies using misoprostol orally. The main objective of this study was to investigate the rate of PPH in a group of women receiving 600 jrgm of oral misoprostol at the end of the second stage of labour, and to assess the associated clinical effects of its use for management of the third stage of labour. Two hundred and thirty seven (237) consecutive women were recruited for this study.

Results of the first pilot study revealed a high incidence of shivering, which was the main side effect. This incited us to investigate whether the incidence of shivering was dose related. It was therefore decided to follow the first pilot study up with a second study in which smaller misoprostol dosages were used.

The second pilot study was also an observational study that examined the rate of PPH and perceived incidence of side effects in two further groups of women receiving two lower doses of oral misoprostol; 400 and 500 pgm. A further two hundred and eight (208) women were recruited for this study (103 received 400

jagm, and 105 received 500 jigm doses). These two groups were then compared with the first group who had received the 600 pgm dosage, in terms of PPH rate, events in the third stage of labour, and side effects associated with each dosage.