Misoprostol, a Good Alternative for Preventing Postpartum Haemorrhage

Abstract

Postpartum haemorrhage is the leading cause of maternal mortality. There are ways to prevent it and reduce the risk of maternal mortality. Oxytocin is the drug of first choice recommended by the WHO but poses problems in its conservation and management. Increasingly, misoprostol is recommended in place of oxytocin given the similar and sometimes superior results; it offers in preventing PPH and the ease of storage, transport, and ease of use that it offers. It offers comparison to oxytocin. Several studies have shown the effectiveness of misoprostol and its acceptance by both patients and medical staff.

1. Introduction

Maternal mortality is a global public health problem, with approximately 830 women dying every day worldwide from complications related to pregnancy or childbirth [1]. The maternal mortality ratio in developing countries in 2015 was 239 per 100,000 births, compared to 12 per 100,000 in developed countries [2].

Postpartum haemorrhage (PPH) is one of the leading causes of maternal death in sub-Saharan Africa. In developing countries, postpartum haemorrhage is responsible for 30% of maternal deaths [3].

Despite the identification of risk factors, postpartum haemorrhage (PPH) is most often unpredictable. The main causes of postpartum haemorrhage are uterine atony, placental insertion anomalies, and coagulation disorders [4].

Risk factors include multiple pregnancies, fetal macrosomia, primigravida, grand multiparity, older age, preterm births, genital tract injuries, non-use of uterotonic for PPH prophylaxis, labor induction, cesarean delivery, and intrauterine fetal deaths a history of postpartum haemorrhage. Uterotonics are used both for the prevention and treatment of postpartum haemorrhage if the cause is obviously uterine atony. Since then, several uterotonics have been proposed, some being more effective than others. Among the uterotonics, some require more complex and rigorous storage conditions. The routes of administration are also different for most of them. The WHO standard is “All women should benefit from the administration of a uterotonic at delivery to prevent delivery haemorrhage” [5, 6].

2. Anatomical reminders

The pregnant uterus at term consists of three muscular layers of unequal values. Due to pregnancy changes, the myometrium loses its complexity and approaches the embryonic and tubal structure. The superficial layer is specific to the uterine body. It is thin, subperitoneal, formed by longitudinal bundles in the midline and oblique laterally. The deep layer is made up of two sub-layers which are sandwiched in an intermediate zone. During pregnancy, this intermediate zone is covered by a rich venous plexus and muscular bundles whose predominant direction is transverse. Furthermore, these muscle bundles adhere to and surround the vessels. Thus, during contraction of the uterus the lumen of the vessels is erased. This device reduces haemorrhage to relatively small proportions of normal delivery.

Regarding vascularization, the uterine artery stretches, unwinds its turns, and increases its length, which triples or even quadruples. It is after delivery that the retraction of the uterine artery causes an increase in its caliber. It must be remembered that the flow rate of each uterine artery reaches 300 ml/min at the end of pregnancy (Figure 1) [7].

Figure 1.

Muscle layers of the myometrium on a gravid uterus [7].

3. Physiological reminder

3.1 Physiology of the third phase of childbirth

Deliverance is the expulsion of the placenta and membranes from the genital tract. It progresses in three phases: placental abruption, expulsion of the placenta, and hemostasis.

Placental abruption phase: Placental abruption is dependent on uterine retraction which prepares it and uterine contractions which provoke it. Uterine retraction is a passive phenomenon, corresponding to the reduction in uterine volume during fetal expulsion. It results in an increase in thickness of the uterine walls respecting the area opposite the placental insertion which remains thin. This results in a physiological intermingling of the placenta, essential for its separation. Uterine contractions gradually increase in intensity. The physiologically enchatonated placenta, the perimeter of which is surrounded by a thicker muscular ring, undergoes concentric pressures which tend to make it bulge toward the cavity Uterine. This creates detachments in places, which will quickly lead to a retro-placental hematoma. Retroplacental hematoma results in complete cleavage between the uterine decidua (Superficial layer of the gravid uterine mucosa) and the deep mucosa layer which, remaining undamaged, will be the basis for the subsequent regeneration of the uterine mucosa.

Phase of migration and expulsion of the placenta: Under the influence of uterine contractions and its own weight, increased by the blood retained by the membranes still adhering to the uterine walls, the placenta falls into the lower segment which unfolds, lifting the uterine body. Then, the detached placenta then migrates through the cervix toward the vagina to be expelled to the vulva: Most frequently, through the fetal side of the placenta (BAUDELOCQUE mode), which occurs more often if the placenta is fundal or fairly high up; more rarely by its maternal side (DUNCAN mode), especially if it is low inserted. This method of delivery would promote complications (retained membranes, lower segment haemorrhage), requiring increased monitoring.

Uterine retraction phase: The phase of uterine retraction this time concerns the placental wound where it ensures hemostasis: the vessels are enclosed and closed by the contraction of the fibers Muscular; thrombosis occurring in these vessels is facilitated by coagulation factors, which are increased in late pregnancy. Blood loss is often underestimated.

3.2 Physiological hemostasis

Three factors are involved in uterine hemostasis:

Muscle factor: This is the most important mechanism because it is a fundamental locking system to stop bleeding. Hemostasis is essentially ensured by uterine retraction. The very strong retraction of the uterus closes the uterine vessels as they pass through the myometrium, closing the mesh of the plexiform layer. All the utero-placental vessels which until then nourished the placenta bleed but by contracting, the uterus tightens these vessels, and the bleeding ends up decreasing. At the area of insertion of the placenta in particular, the maternal vessels will find themselves enclosed and collapsing by the active contraction of the fibers of the myometrium which create a true physiological tourniquet or “living Pinard ligature”. This is physiological vascular ligation of Pinard. Compression of the spiral arteries therefore limits intrauterine haemorrhage while compression of the venous sinuses will prevent the intrusion of amniotic fluid, tissue debris, air, and thromboplastinic substances into the maternal circulation. This uterine retraction will only be possible after complete evacuation of the uterus. It is this mechanism, and not the coagulation process, which is responsible for the rapid cessation of bleeding, so much so that, if the hemorrhagic risk is significant, it is useful to amplify this mechanism using utero tonics to reduce blood loss less than 150 ml (“directed” or “assisted” delivery).

Vascular factors: Prostaglandins, released by the endometrium after placental abruption, cause vasoconstriction. This reflex vasoconstriction reduces both the caliber and the flow.

Hemostatic factor: This factor can only work if the other two (2) are present. Thrombosis occurring in these vessels is facilitated by coagulation factors (fibrinogen, factors VII, VIII, and X) which are increased at the end of pregnancy.

3.3 Hormones and hemostasis

The essential phenomenon which explains physiological hemostasis is the contraction of the uterine muscles which occurs after childbirth. This contraction is induced by the action of certain hormones both to induce labor and to control the rhythm of uterine contractions and after expulsion, to ensure hemostasis by compressing the vessels that remain open. Two hormones play an important role in this phenomenon. These are oxytocin and prostaglandin. Oxytocin is a peptide hormone best known for its role in childbirth and breastfeeding. It is released in large quantities by the pituitary gland during labor and causes contractions of the uterus to facilitate birth. It also stimulates contractions during the third stage of labor: the separation of the placenta from the uterine wall and the compression of the maternal blood vessels after placental expulsion. When uterine contractions are not strong enough to compress the blood vessels, postpartum haemorrhage can threaten a woman’s life. In this case, a woman will receive a utero tonic medication, to stimulate contractions and stop bleeding. Prostaglandins have recently appeared in the therapeutic armamentarium as an alternative to the surgical technique of hemostasis hysterectomy. Many authors have shown that plasma levels of endogenous prostaglandins reach a maximum at the time of delivery, 5–10 min after birth, and thus play a crucial role in uterine retraction [7]. The action of prostaglandins is more powerful and earlier than that of methylergometrine and oxytocin on the myometrium. Currently the mechanisms of action by which prostaglandins cause physiological hemostasis are known. Three types of prostaglandins are concerned: prostaglandins E2 and F 2 Alpha. These 2 types of prostaglandin are synthesized at the level of the amniochoreal membrane and the decidua. It crosses the placental barrier to trigger uterine contractions. Prostaglandin I 2 or prostacyclin is synthesized in the myometrium, and its role is to regulate uterine contractions. The uterine contractions induced by these two groups of prostaglandins will contribute to the regularity of labor and after the expulsion of the fetus and its appendages, to the reduction of haemorrhage by causing the uterine contractions which are at the origin physiological hemostasis by compression of the vessels.

4. Prevention of delivery haemorrhages

Preventing postpartum haemorrhage remains an absolute priority in obstetrics. Prevention of PPH is essential outside of a maternity ward as well as in the delivery room. Physiological means as described above are not enough to guarantee effective hemostasis and avoid haemorrhage which is the leading cause of maternal mortality despite prevention and treatment. Among postpartum haemorrhages (PPH), those during delivery are the most dangerous. This fear is reinforced by the fact that they represent the leading cause of maternal mortality and that their preventable nature reaches 50–80%, hence the importance of prevention by means that are effective and easy to handle. However, it should be noted that a haemorrhage of 500–1,000 ml is generally well tolerated with a clinical impact often only apparent beyond 1,000 ml of blood loss [7]. The prevention and even the management of haemorrhages during delivery use the means which make it possible to amplify the phenomenon of uterine contraction to achieve ligation of the uterine vessels by the plexiform muscles. For this purpose, utero tonics are used.

5. A toned uterus

(An oxytocic) is a product/medication that increases the tone of the muscles of the uterus. It stimulates the contraction of the uterine muscles. Drugs such as oxytocin and ergometrine have important uterotonic properties and have been used to treat uterine atony since their discovery. Oxytocin is the first-line medication for the management of postpartum haemorrhage. But more and more, misoprostol is used with results highly appreciated by many researchers.

5.1 Oxytocin and prevention of postpartum haemorrhage

SYNTOCINON® is a synthetic analogue of natural post-pituitary oxytocin. Oxytocin—or called oxytocin—is a cyclic nonapeptide. Physiologically, this hormone is synthesized by the hypothalamus, which projects its neuronal extensions into the posterior pituitary gland. This is where ADH and oxytocin will be stored to be released into the bloodstream when needed. Throughout pregnancy, and especially in the third trimester, stretching of the uterus and cervix sends impulses through afferent fibers to the hypothalamus. The latter responds by synthesizing oxytocin and delivering it through the posterior pituitary gland. Furthermore, its secretion is increased by stimulation of the breast and is reduced by taking ethanol. Its half-life in plasma is 5–10 min, and it is degraded by an amniopeptidase or oxytocinase and is eliminated by the kidney. It is at the end of pregnancy where we see an increase in estrogen levels which, on the one hand, stimulates the synthesis of oxytocin receptor in myometrial cells, and on the other hand, antagonizes the influence of progesterone. This is how the effectiveness of oxytocin increases during gestation: the uterus becomes more and more sensitive to its presence, due to the multiplication of receptors on the surface of muscle cells. Thus, oxytocin has the effect of acting mainly on the uterine smooth muscle and the mammary glands, by inducing an increase in the intracellular calcium concentration by stimulation of phospholipase C [1]. On the smooth muscle fiber, by increasing the intracellular calcium concentration, oxytocin increases the strength and frequency of muscle contractions. Indeed, once the hypothalamus is involved, positive feedback from oxytocin induces an increase in its secretion, and therefore, uterine contractions intensify and send feedback to the hypothalamus, and so on. Its action is coupled with that of prostaglandins, the synthesis of which by the placenta is induced by the secretion of oxytocin itself. It is therefore essential to avoid interfering with their production, for example, by using anti-prostaglandin drugs such as ibuprofen, which can then inhibit the first period of labor [8, 9]. Marketed under the name SYNTOCINON®, its composition is 5 IU of oxytocin per 1 mL ampoule.

5.1.1 Use in obstetrics and constraint

All women should benefit from the administration of a uterotonic during delivery to prevent PPH, and the recommended uterotonic is oxytocin (10 IU IV/IM). However, oxytocin requires a number of conditions for its conservation. The temperature sensitivity of oxytocin in solution requires that the injectable product be supplied and stored under refrigerated (2–8°C) (it should never be frozen) or cool (<25°C) to minimize degradation of oxytocin and maintain quality. This condition involves heavy logistics and rigor in conservation. In developed countries, this is already a significant challenge. In many low-resource countries temperatures will exceed 25°C, and cold chain infrastructure may be lacking or unreliable [10]. In some developing countries, the manufacture of oxytocin is not regulated as in developed countries; in addition, it is not always stored under proper temperature control, leading to deterioration of effectiveness, especially when exposed to sunlight and high temperatures. Oxytocin exists in injectable form only and requires the use of sterile consumables such as syringes, infusions, kits, etc., for its administration. It also requires the availability of trained medical personnel and medical supervision during its administration. Pain during injection is another factor that must be taken into account for the comfort of the patient.

5.2 Prostaglandins

Prostaglandins, natural and intrinsic substances, are revolutionizing all modern therapy. Since their discovery in 1913, they have continued to arouse a certain scientific curiosity on the part of researchers. In 1930, two American gynecologists, Kurszrok and Lieb, discovered that uterine strips from hysterectomized patients contracted or relaxed when exposed to human sperm [1]. A few years later, in 1934, Goldblatt in England and Von Euler in Sweden reported that seminal fluid and reproductive glands stimulated smooth muscle contraction. Von Euler identified the active material as a fat-soluble acid, capable of contracting certain smooth muscles and lowering blood pressure. He named this acid prostaglandin, believing that this hormone was secreted by the prostate. Von Euler’s discovery was logical: we now know that seminal fluid is rich in prostaglandins, of the order of mg per ml. Everywhere else, their concentration is of the order of ng per ml [7]. In 1957, Bergstrôm’s team isolated PGEl and PGFla in crystalline form. In 1964, this same team synthesized PGE2 from arachidonic acid. Therefore, numerous studies are devoted to the physiological effects of prostaglandins and make it possible to clarify, thanks to a series of discoveries, their role in the cardiovascular, digestive, respiratory, genitourinary systems, and the endocrine and nervous systems.

In 1968, Karim artificially induced labor in a woman, using an IV infusion of PGE2. But it was in the field of reproduction that prostaglandins aroused the interest of researchers in the 1970s. Their oxytocic properties and their action on the maturation and dilation of the cervix therefore gave rise to great hopes concerning their application in evacuation of uterine contents, prevention of postpartum haemorrhage, the process of cervical ripening, and artificial induction of labor.

5.2.1 Mechanism of action of prostaglandins

• Membrane action

At the cellular level, the initial step in the response to endogenous or exogenous prostaglandins appears to be binding to specific membrane receptors or to certain intracellular sites. The action of prostaglandins is essentially membrane-based, with the basis of controlling the activity of adenyl cyclase and/or guanyl cyclase, to form cAMP at the origin of the biological response from ATP or GTP. Other membrane enzymes (ATP-ases in particular) see their activity modulated by prostaglandins which thus intervene on membrane permeability to Ca²⁺ ions, hence the generation and propagation of action potentials at the origin of muscle contraction (Figure 2) [9].

Figure 2.

Cellular mechanism of action of prostaglandins [9].

• Calcium and contractile system

The myometrial response consists of an increase in the frequency of phasic contractile responses and an increase in baseline tone. Phasic contractions depend on the transmembrane influx of Ca²⁺ ions associated with brush action potentials: the ascending phase of the action potential is linked to the rapid entry of sodium and calcium. It is the concentration of intracellular calcium that regulates the contractile system. Calcium is essential for the establishment of uterine contraction, the sliding relative to each other of actin and myosin filaments requiring energy provided by hydrolysis of ATP. This hydrolysis is the result of a protein kinase having Ca²⁺ as a co-factor. Carsten demonstrated that for contractile proteins to be activated (by phosphorylation of a myosin light chain allowing the establishment of anchoring bridges between the myofilaments), the intracellular Ca²⁺ must be greater than 10-7 M [7].

On the other hand, the use of an inhibitor of an endoplasmic reticulum-dependent Ca²⁺-ATPase, tBHQ (2,5-di(tert-butyl)-1,4-hydroquinone), led to a drop in the flux extracellular calcium and consequently a cessation of muscle contractions in vitro [8].

• Messenger systems

The cellular mechanism of action of prostaglandins at the level of myometrial cells can be explained by considering on the one hand the fundamental role attributed to calcium, but also on the other hand by highlighting the role of other messenger systems regulating contractile activity: – PGE2 and PGI2 stimulate adenyl cyclase and cAMP, – Phosphatidyl inositol (PI) promotes Ca²⁺ movements, di-acyl-glycerol (DAG) activates phospholipase A2, the importance of which is known for the synthesis of prostaglandins, and – Inositol tri phosphate (IP3), by mobilizing intracellular calcium, activates Ca²⁺-Calmodulin-dependent protein kinases (Carsten) (Figure 3).

Figure 3.

Phosphatidyl inositol pathway with the second two [9]. PI, phosphatidyl inositol; PIP, phosphatidyl inositol 4-phosphate; PIP2, phosphatidyl inositol 4-5-phosphate; PKC, protein kinase C; IP3, inositol triphosphate; DAG, diacylglycerol; DAG, diacylglycerol.

Messengers: IP3 and DAG, according to Tournaire.

Finally, we will note the contradiction manifested by prostaglandins E which cause both a contraction of the uterine fibers and an increase in intracellular cAMP. (cAMP causes the activation of a cAMP-dependent phosphorylase kinase involved in the inhibition of myosin light chain phosphorylation, promoting relaxation) (Figure 4).

Figure 4.

Mode of action of certain myocontracting or muscle-relaxing substances whose final point of impact is the cAMP system, according to Tournaire. Cliquez ou appuyez ici pour entrer du texte. Aucune source spécifiée dans le document actif [9].

Aucune source spécifiée dans le document actif [9].

5.2.2 Misoprostol and prevention of postpartum haemorrhage

Misoprostol is a medicine from the prostaglandin family. It is a synthetic prostaglandin, analogous to natural PGE1. Formerly used in the treatment of ulcers stomach and duodenum and to prevent or treat gastritis due to non-steroidal anti-inflammatory treatment (NSAIDs). Today he has a double marketing authorization(AMM) for its use also in gynecology and obstetrics.

• Therapeutic action

In gynecology, at recommended doses, misoprostol causes contractions of the smooth muscle fibers of the myometrium and relaxation of the cervix. The uterotonic properties of misoprostol should facilitate the opening of the cervix and the expulsion of intrauterine debris. Through this mechanism, it allows hemostasis to be achieved also after childbirth. At recommended doses, misoprostol is not expected to cause cardiac, hepatic, or renal adverse effects. Misoprostol comes in tablets of 25 and 200 μg. Its use in gynecology and obstetrics is very broad. It is used both in the termination of pregnancy, the induction of labor, and in the prevention and treatment of postpartum haemorrhage. In the prevention of postpartum haemorrhage, doses of 200, 400, and 600 μg have been used according to the authors and research reaching similar conclusions but with different dose-dependent effectiveness. Studies using 600 μg had greater effectiveness in preventing postpartum haemorrhage. In the treatment of postpartum haemorrhage, FIGO recommends a dose of 800 μg.

• Use in obstetrics and advantages

Although the World Health Organization recommends the use of oxytocin for the prevention of PPH, the use of misoprostol is becoming more common due to its benefits in the management and treatment administration. Misoprostol, presented in tablet form, is indeed very easy to manage compared to oxytocin. Misoprostol does not need a cold chain, and it can be kept at room temperature below 25°C, which makes it easy to store and transport. Misoprostol can be stored for longer. It also offers several routes of administration. Misoprostol can be administered sublingually, rectally, and vaginally. Its administration does not require the presence of highly qualified personnel. At recommended doses, it has few side effects. For the treatment of postpartum haemorrhage, the rectal route is used when the sublingual route is impossible. A theoretical advantage of sublingual misoprostol could be better bioavailability achieved by avoiding first-pass metabolism [11]. Misoprostol appears to be a good alternative, but there is insufficient data on the comparative effectiveness of oxytocin 10 IU IM and sublingual misoprostol, particularly at the recommended dose of 600 mcg, for the prevention of PPH during active labor management.

6. Misoprostol, an evidence-based alternative

Oxytocin is rightly considered a first-line drug in the management of postpartum haemorrhage. This is because of the results obtained from its use and the fact that it is the most used medication throughout the world to prevent or treat postpartum haemorrhage. Misoprostol has been offered for several years as an alternative, especially in low-resource countries. Some practitioners remain skeptical, and scientists cite the absence of sufficient data to conclude. Since then, several studies have been conducted on the effectiveness of misoprostol in the prevention and management of postpartum haemorrhage. To be an alternative, misoprostol must provide at least the same level of effectiveness as oxytocin to be ethically accepted. Several studies were then carried out to verify this. The studies whose results are presented in this chapter consisted of comparing the effectiveness of misoprostol versus oxytocin in the prevention of postpartum haemorrhage. The samples included two groups. One group consisted of women given oxytocin treatment to prevent postpartum haemorrhage, and the other consisted of women given misoprostol treatment for the same cause. A study conducted on a sample of 652 cases, by Ballad et al., found that sublingual misoprostol was more effective than intramuscular oxytocin in reducing PPH [9]. A systematic review analysis carried out in Taiwan by Zümrüt Bilgin and Nuran Komürcü in 2019 that included 12 randomized controlled articles (n = 6290) concluded that in the misoprostol group, the rate of blood loss >500 mL was lower than that in the oxytocin group (p < 0.05). Misoprostol was found to be more effective than oxytocin in 10 out of 12 studies [12]. Another study conducted in India between 2012 and 2014, although on a small sample, noted a higher number of haemorrhages in the oxytocin group than in the misoprostol group [13]. A study conducted in the Democratic Republic of Congo, comparing misoprostol 600 μg sublingual to 10 IU of oxytocin IM in the prevention of postpartum haemorrhage, showed similar results. The study found that the proportion of PPH was higher in the group of women who received oxytocin 6.96% versus 2.87% in the group of women who received misoprostol (measured blood loss greater than 500 ml at 2 h).

After adjustment of this logistic regression model, a high probability of the occurrence of postpartum haemorrhages was noted in the groups of women who received oxytocin with a risk multiplied by 2.51 times that in the group of women having received misoprostol with a statistically significant difference (p < 0.001) [14]. Some studies have found that misoprostol is clinically equivalent to oxytocin when used to stop excessive postpartum bleeding suspected of being due to uterine atony in women who received oxytocin prophylactically at during the third phase of labor. A study done in Uganda in 2014 found a modest benefit from oxytocin compared to misoprostol. The Ugandan study found no significant differences in the rate of severe PPH, need for blood transfusion, postpartum hemoglobin, hemoglobin change, or use of supplemental uterotonics between the groups. study. The same study concludes that “the significant results between treatment groups also offer promising preliminary data that sublingual misoprostol at a dose of 600 mg is likely to be of significant benefit where oxytocin is not available”.

These studies found that sublingual misoprostol was more effective than intramuscular oxytocin in reducing PPH [15, 16, 17]. The sublingual mode and/or powder formulation may increase the effectiveness of misoprostol and make it superior to injectable oxytocin for the prevention of PPH.

Other studies with a different objective to these have been carried out in certain areas of Asia and Africa. Among these studies, some have studied the practicality of misoprostol use by midwives who attend home births. Others have studied the possibility of distributing it to pregnant women living in remote areas, who do not have access to health facilities and who most often give birth in their homes. These are critical situations which unfortunately still exist in certain corners of the world. In a study carried out in the North-East department of Haiti, on “access to misoprostol for the prevention of postpartum haemorrhage at the level of health institutions and at home, the results clearly showed that the distribution community-based misoprostol is generally accepted by all stakeholders from the two municipalities. The satisfaction expressed by users of this product was also observed at all levels, whether providers, health workers, or community leaders. More than three quarters of women, or 79.2%, used misoprostol correctly after childbirth. The results revealed that the majority of women who received misoprostol in ANC and who delivered at home used it correctly” (USAID).

Misoprostol is easier to distribute among the local population than a less stable injectable medicine, such as oxytocin, to prevent or treat severe bleeding in women after childbirth (postpartum haemorrhage).

7. Conclusion

Misoprostol is a good alternative to oxytocin and offers more benefit in management, use, and distribution. For the prevention of PPH, a single dose of 600 μg (3 tablets of 200 μg) sublingual may be indicated, after the birth of the child, for the treatment of PPH secondary to uterine atony.