Background: Labour induction is one of the most common medical procedures in obstetrics. The aim is to end the pregnancy when continuity is a risk to mother or fetus. Its main side effect is the increase in the cesarean rate, compared to spontaneous onset deliveries. On the other hand, mortality and morbidity in cesareans are higher. The most common pharmacological drugs used for induction are prostaglandins: dinoprostone and misoprostol. The “gold standard” for labour induction is vaginal misoprostol. The oral route is also effective and also has several benefits like faster onset and easear administration. In recent years several publications state that the administration of misoprostol oral solution, given in doses gradually, is associated with a lower cesarean and hyperstimulation rate than the cases where vaginal misoprostol has been used in pregnant women with unripe cervix. Furthermore, being its half life shorter, it may be very useful in case of uterine hyperstimulation and, probably, a high percentage of women prefer this oral administration to the vaginal one. The objective of this study is to compare the efficacy, safety and side effects on mother and fetus on use of oral versus vaginal administration for induction of labour for prolonged gestation (41 weeks) and premature rupture of membranes, both with live fetus. Methods/Design: Design: double blind controlled trial. Study population: Pregnant women whose labour will be induced due to premature rupture of membranes or prolonged gestation. Inclusion Criteria: 1) Bishop Test equal to or less than 7; 2) Single pregnancy; 3) Pregnancy at term (37 - 42 weeks); 4) No history of uterine surgery; 5) Cephalic presentation; 6) Live fetus; 7) No prostaglandins contraindications. Discussion: Nowadays induction rates are very high, ranging from 25% to 30% approximately. In these cases caesarean rates are higher than when the delivery starts spontaneously. That is one of the main reasons why caesareans have increased, mainly in the cases of nuliparous women with immature cervix. If we can prove the hypothetical good results obtained through the use of dosed oral misoprotol, we will be able to reduce the number of induced deliveries by cesarean, and so improve the levels of security for the mother and the foetus, and, as a consequence, provide a higher quality of medical attention to the newborn and the mother.
Induction of labour is one of the most common medical procedures in obstetrics. In the U.S. its frequency has increased steadily from 9.5% in 1990, to 19.4% in 1998 [
Increase of the cesarean delivery rate is one of the main potential adverse effects of induction, compared with spontaneous onset of labour. That happens very often in the case of nulliparous women [3,4] specially within those with unripe cervix [5-8].
The cost of surgery is 76% higher in cesarean delivery than that with vaginal birth, regardless of the readmission rate.
Ideally, the cesarean rate in the induced labours should be as similar as possible to the one of spontaneous deliveries. To obtain this outcome we should find the right drug and dosage to achieve these results.
The methods that have been used for labour induction have been numerous. If we just focus on drugs, we could mention, according to its importance, oxytocin and prostaglandins and within the latter dinoprostone and misoprostol. Oxytocin has the disadvantage of high failure rate when the cervix is immature.
Prostaglandins have been gaining ground to oxytocin in recent decades, mainly for preinduction/induction of labour, when the cervix is immature, but to choose between one or the other it is necessary to know which one works more efficiently and which one has got the safer maternal-fetal profile too.
Hofmeyr [
Other data in favour of misoprostol are: it is cheap and it can be kept at room temperature, however dinoprostone is expensive and needs to be in a fridge.
Subsequent works such as Austin [
Therefore, nowdays, the “gold standard” for cervical ripening and induction of labour is vaginal misoprostol at doses of 25 mcg every 4 - 6 hours [13-16].
Misoprostol may be administered by various routes: oral, vaginal, rectal and sublingual. In general, the vaginal route appears to be as effective as the other. However, the vaginal route seems to be associated with a higher incidence of uterine hyperstimulation than the rest of them, which can compromise fetal safety. This fact seems to be related to the dose provided.
The oral route is also effective and besides it has the benefit of the route of administration, which is better tolerated by women.
Alfirevic [
Obtaining a safe dose ranging below 50 mcg, just by dividing a misoprostol pill of 200 mcg, is inaccurate and therefore unreliable. It has been found out that only in 56% of the cases we would get the desired dose by dividing the pill into eight portions (if we want a 25 mcg dose). This imprecision in the dosage would lead to insufficient or excessive dose that would cause an induction failure or a hyper-stimulation [
From a pharmacokinetic point of view, misoprostol in aqueous solution begins its action (4 minutes, range 2 - 5 min.) faster than if we use pills (6 min., Range 4 - 10 min) or use the vaginal route (20 minutes), statistically significant and relevant differences (p = 0.01) [
Zieman [
Based on these attractive pharmacokinetic characteristics for oral solution described above, several articles have come out in recent years analyzing this via. Moreover, some articles have used the attribute of this new track, which can be dosed according to uterine response.
Cheng [
Kundodyiwa [
Souza [
Shi-Yann Cheng [
Based on all these works we can say that it seems that the administration of misoprostol oral solution, administering dosage having in mind uterine response, is associated with a lower cesarean rate and lower incidence of hyperstimulation than using the vaginal misoprostol, gold standard for the preinduction/induction of labour in pregnant women with unripe cervix. Furthermore, being its life span very short, it can be useful in case of uterine hyperstimulation and besides a high percentage of women probably prefer this route to induce delivery than the vaginal version.
Once the misoprostol oral solution—administered in dosage according to uterine response—has proved its effectiveness and its satisfactory safety profile to induce labour in general, we need to check these features in our environment and in specific clinical situations such as gestation in the process of extension or in case of premature rupture of membranes, with a live fetus, situations that represent 60% of the inductions.
The main objective of this reseach is to compare the efficiency, safety and side effects on the mother and fetus of dosed misoprostol oral solution, depending on uterine response, as this is different for each pregnant woman, compared with the vaginal misoprostol, “gold standard” for preinduction/induction of labour, and doing it in our environment and in specific clinical situations, which represents 75% of the causes of the inductions, the gestation process of extension (41 weeks) and premature rupture of membranes .
Hypothesis: There are differences in the rate of vaginal delivery within the first 24 hours when induced with dosed misoprostol oral solution versus vaginal misoprostol.
To compare dosed misoprostol oral solution efficiency and safety, compared to the present-day “gold standard” vaginal misoprostol, in our environment and in specific clinical situations: extending gestation processes (41 weeks) and premature rupture membranes.
Primary objectives: Estimating the following parameters: 1) Rate of vaginal births in the first 24 hours. 2) Severe perinatal morbidity rate. 3) Severe maternal morbidity rate.
Secondary objectives: Estimating the following parameters: 1) General cesarean section rate. 2) Hyperstimulation syndrome rate. 3) Delivery rate with thick meconium. 4) Delivery rate when oxytocin is needed. 5) Adverse maternal side effects rate: vomiting, diarrhea or fever. 6) Time interval between first dose and delivery. 7) Women’s satisfaction with the route of drug administration.
Dosed misoprotol oral solution. Misoprostol oral solution in doses of 20 mcg/hour (20 ml), during the first 4 hours. Increase to 40 mcg/h, for the next four hours. Increase 60 mcg/hour for the next 4 hours. A new dose will be provided, if no correct dynamic were achieved. To prepare the solution, dissolve a 200 mcg misoprostol pill into a in a container with 200 ml of water so that the concentration is 1 mcg/ml. Administer a placebo: vaginal pill each 4 hours.
Misoprostol vaginal pill. Compressed 25 mcg vaginal misoprostol every 4 hours until adequate dynamic, maximum dose: 6 pills in 24 hours. Placebo: Oral solution of water with the same dosage as indicated previously.
Double blinded controlled clinical trial. The medication is prepared by the hospital pharmacy. The delivery room staff and pregnant women are unaware of the medication that is being used. Randomization is performed at the time of induction, using sealed opaque envelopes, generated by computer sequence.
Gynaecologic Clinic Management Unit. Hospital La Inmaculada (Huercal-Overa) that belongs to the Northern Health Management Area from Almeria (Andalusia Health Service). Andalusia (Spain).
The number of users which correspond to the health area is 120,000. The population is predominantly rural, working primarily in agriculture and the service sector. With a high rate of female migrants/foreigners; the percentage of these in 2010 accounted for 30% of the new mothers. The main regions/countries of origin are: Morocco, South America and English speaking countries. During 2012 1216 deliveries were done, being the rate of inductions 21% and of C-sections 16%. The perinatal mortality rate was 4.81 per thousand. Specifically, the reference population would be pregnant women whose delivery will be treated in our unit.
Pregnant women whose labour will be induced due to the fact that they have premature rupture of membranes or a gestation of 41 weeks, cases which represent more than 75% of our causes for induction.
Pregnant women whose labour will be induced by any of the following two reasons: premature rupture of membranes or in the process of prolonging gestation (41 weeks) and that meet the following criteria:
Bishop Test for less than or equal to 7. Single Pregnancy. Term gestation in the case of ruptured membranes (37 - 41 weeks). No history of uterine surgery. Cephalic presentation. Live fetus. No contraindications to the use of prostaglandins (asthma, glaucoma or allergies).
Excluded from the study those pregnant women who have any of the following requirements:
Pregnant women under 18. History of uterine scar. Multiparous with more than 3 deliveries. Multiple pregnancy.
Prior fetal monitoring prior unsatisfactory. Placenta previa. Antepartum genital bleeding when cause of bleeding is unkown. Obstetric Pathology: intrauterine growth retardation (less than or equal to the 10th percentile), ligohydramnios (low amniotic sac less than 2 to 1) and hypertensive pregnancy disease. Contraindications for the use of prostaglandins (asthma or glaucoma). Malpresentation: Transverse situation. Breech presentation.
For sample size calculation it has been taken into account the following assumptions: the rate of vaginal births in the first 24 hours when induced with vaginal misoprostol is 59% and the rate of vaginal birth with dosed oral misoprostol is 71% (data from the bibliography). The statistical power of the study is 80% and the confidence level of 5%. With these data the sample size should be 194 cases. On the other hand it has been calculated an expected proportion of losses of 15%, therefore the sample, adjusted to the possible losses, is 229.
Losses will be due mainly to dropouts, being the main reason that pregnant woman requests a caesarean section, without medical indication there, once induction has been started.
The distribution of pregnant women between the two groups, experimental and control will be held at 1:1 ratio.
Main dependent variables: 1) Vaginal delivery in the first 24 hours. 2) Severe perinatal morbidity. 3) Severe maternal morbidity.
Secondary dependent variables: 1) Form delivery culmination: Vaginal or cesarean. 2) Hyperstimulation syndrome. 3) Presence of thick meconium 4) Adverse maternal side effects: vomiting, diarrhea or fever. 5) Deliveries that require oxytocin. 6) Time interval between the first dose and delivery 7) Women's satisfaction with the route.
Main independent variable: Dosed oral misoprostol use/vaginal misoprostol use.
Secondary independent variables: Maternal age. Gestational age in days. Parity. Body Mass Index. Bishop Score. Length of the Uterine Cervix. Epidural anaesthesia
For informed consent, midwife or obstetrician, explain the pregnant woman the research project and they give her an informed consent form that meets the conditions set out in Law 14/2007 of 3 July Biomedical Research and the Law 15/1999 of December 13, Protection of Personal Data. The form explains the purpose of the research, the intervention to be performed and the results expected from it. It also will ensure the confidentiality of data and anonymity of the participants. If she agrees to participate in the study, she will have to do so by means of a written consent. The informed consent form is also in Arabic and English. The study has been approved by the Coordinating Committee on Ethics in Research of Andalusia.
The researcher is committed to follow the research standards and rules according to the Declaration of Helsinki and subsequent amendments to the 59th General Assembly, Seoul, Korea, October 2008, and to report adverse reactions as provided in RD 1344/2007 of 11 October. Likewise, attendance of pregnant women will be held under the rules of good clinical practice.
Nowadays induction rates are very high, ranging from 25% to 30% approximately. In these cases caesarean rates are higher than when the delivery starts spontaneously, the rate almost double. That is one of the main reasons why caesareans have increased, mainly in the cases of nuliparous women with immature cervix. The increase in the number of cesarean deliveries causes among mothers: higher levels of morbidity, higher incidence and risk of nosocominial infections, higher needs of blood transfusions, a much slower pace of recovery; among new-born babies: lower levels of breast feeding, higher frequency of respiratory distress, compared to the normal vaginal delivery.
On the other hand, the rate of nuliparous women is increasing dramatically. The percentage is above 50% nowadays.
If we can prove the hypothetical good results obtained through the use of dosed oral misoprotol, we will be able to reduce the number of induced deliveries by cesarean, and so improve the levels of security for the mother and the foetus, and, as a consequence, provide a higher quality of medical attention to the new born and the mother.
LA conceived the project and all the authors contributed to design of the study. LA, MS and MG initially drafted the protocol and all authors were involved in critical revision of the intellectual content. VG, RF and AB obtained ethics approval for the trial. LD and ER negotiated access to population health data for outcome assessment. All authors approved the final protocol.