Because Life is Precious
Misoprost - 600 Mcg
Prevents Pph, Saves Lives.

Overview

Maternal deaths arise from the risks attributable to pregnancy and childbirth, as well as because of the poor quality of healthcare services.

In India, the direct causes of maternal mortality still remain haemorrhage, hypertension and sepsis, with anaemia being the most indirect cause.

Postpartum haemorrhage is one of the leading causes of maternal mortality and the most frightening and challenging of all medical emergencies in the world. Postpartum haemorrhage may arise in any pregnancy, without there being any history to it, and may recur in a subsequent pregnancy.

Prevention of postpartum haemorrhage is better than treatment, which can be life-threatening for the woman going through it. For this purpose, different uterotonics, with active management of the third stage of labour, have been routinely used and have been shown to be effective and safe.

Misoprostol is a prostaglandin analogue, which was approved initially for the prevention of Non-Steroidal Anti-Inflammatory Drug (NSAID) induced gastric ulcers. But in later years, it also got approved in indications like abortion (with mifepristone), cervical ripening and, now, in the prevention of postpartum haemorrhage.

Misoprostol is a uterotonic with a known potential for preventing postpartum haemorrhage. Misoprostol can be a promising alternative to the existing, standard uterotonics, especially because many deaths occur in out-of-hospital settings; death can occur within a short space of time, before transfer to a health facility is possible; and the primary methods of prevention and treatment have depended on injectable uterotonics and skilled birth attendants, which are often not available at a community level.

Postpartum Haemorrhage1,3

Postpartum haemorrhage (PPH) means excessive bleeding following the birth of the baby. PPH can be either primary or secondary.

The World Health Organization (WHO) defines PPH as follows -

Primary - Blood loss of >500 ml, from the genital tract, within 24 hours of delivery.
Secondary - Abnormal bleeding from the genital tract, from 24 hours after delivery until 6 weeks postpartum.

PPH occurs unpredictably and is an equal opportunity killer. Uterine rupture can precede death by 24 hours and antepartum haemorrhage may lead to death in half that time, but PPH can be lethal in as little as 2 hours.

Danger of PPH

The danger of PPH is twofold. First, the resultant anaemia weakness in the patient lowers her resistance and predisposes her to puerperal infection. Second, if the loss of blood is not arrested, death will be the final result.

Epidemiology2

Global Burden

Globally, about 5,00,000 women die annually from complications during pregnancy or childbirth. PPH accounts for one-third of maternal deaths. Moreover, 99% of these deaths occur in developing countries in women who rarely receive prophylaxis because they give birth outside of a hospital setting.

Indian Scenario

India is representative of the scope and magnitude of the problem. The maternal mortality rate in India was estimated at 407/1,00,000 live births and PPH accounts for 30% of these deaths. In rural India, 50% of births are at home or in rudimentary facilities without a physician in attendance. This makes it difficult to diagnose and manage PPH and its complications.

Also, given the high prevalence of anaemia (80%), even a small amount of blood loss can be fatal in the absence of prompt and appropriate life-saving care, which adds to the burden of PPH.

Causes4,5

PPH is commonly due to one or a combination of four processes referred to as the "4Ts":

Tone

While the occasional cause of postpartum uterine atony is completely unexpected, in many instances the presence of predisposing factors alerts the observant physician to the possibility of trouble. Atonic uterus is the most common cause of PPH and accounts for 70% of the cases.

Atonic PPH could arise because of the following -

Uterine dysfunction - Primary uterine atony is an intrinsic dysfunction of the uterus.
Mismanagement of the placental stage - Hurrying the third stage by kneading and squeezing the uterus interferes with the physiologic mechanism of placental detachment and may cause partial placental separation with resultant bleeding.
Anaesthesia - Deep and prolonged inhalation of anaesthesia is a common cause that leads to excessive relaxation of the myometrium, failure of contraction and retraction, uterine atony, and PPH.
Ineffective uterine action - Ineffective uterine action during the first two stages of labour is likely to be followed by poor contraction and retraction during the third stage.
Overdistention of the uterus - Overdistended uterus, because of conditions such as a large baby, multiple pregnancy, and polyhydramnios tends to contract poorly.
Exhaustion from prolonged labour - Not only is the tired uterus likely to contract weakly after delivery of the baby, but the worn out mother is less able to withstand the loss of blood.
Multiparity - The uterus that has borne many children is prone to inefficient action during all stages of labour.
Myomas of the uterus - These interfere with proper contraction and retraction, and predispose to haemorrhage.
Operative deliveries - This includes operative procedures such as mid forceps and version and extraction.

Trauma

Considerable bleeding can take place from tears sustained during normal and operative deliveries. The birth canal should be inspected after each delivery so that the sources of bleeding can be controlled.

I. Episiotomy

Blood loss may reach 200 ml. When arterioles or large varicose veins are cut or torn, the amount of blood lost can be considerably more. Hence bleeding vessels should be clamped immediately to conserve blood.

II. Pelvic Haematomas

Blood loss leading to cardiovascular instability is not always visible. Sometimes, lacerations of the blood vessels lead to formation of pelvic haematoma. Pelvic haematomas can be of three types: Vulvar, vaginal, or retroperitoneal.

Vulvar Haematoma

Laceration of vessels in the superficial fascia of either the anterior or posterior triangle results in vulvar haematoma, which presents as vulvar pain or urinary retention. Treatment consists of volume support, a wide linear incision on the mass, and evacuation of blood clots. As this is usually due to small vessel laceration, the vessels may not be identified. Once the clot is evacuated, the dead space is closed with sutures.

Vaginal Haematoma

This usually occurs after forceps delivery. Blood accumulates in the plane above the level of the pelvic diaphragm. The most common complaint is rectal pressure and treatment consists of volume support and evacuation of blood and clots.

Retroperitoneal Haematoma

This is the least common and most dangerous haematoma; symptoms may be vague till the patient collapses. A retroperitoneal haematoma occurs after laceration of one of the vessels originating from the hypogastric artery. This may be because of inadequate haemostatis at the time of a caesarean delivery or after rupture of a low transverse caesarean delivery scar during the trial of labour. Blood may dissect up to the renal vasculature. Treatment involves surgical exploration and ligation of both internal iliac arteries.

III. Uterine Inversion

Occasionally, the third stage of labour is complicated by partial delivery of the placenta followed by the rapid onset of shock because of inversion of the uterus, which is often confused with the placenta or a myoma. Although it is uncommon, it is life-threatening. Inversion of the uterus is incomplete if it has not crossed the cervix and complete if it has crossed the cervix. It usually occurs in fundally-inserted placenta. It should be replaced if possible without uterine relaxation or, otherwise, relaxants should be used. The placenta should be separated only after replacing the uterus.

IV. Uterine Rupture

Although an uncommon event, uterine rupture can be life-threatening for the mother. Conditions that may increase the risk of uterine rupture include surgery to remove fibroid (benign) tumours and a prior caesarean scar in the upper part (fundus) of the uterus. It can also occur before delivery and place the foetus at risk as well.

In addition, other factors operate to cause an excessive loss of blood where there is trauma to the birth canal. These include the following:

Prolonged interval between performance of the episiotomy and delivery of the child.
Undue delay from birth of the baby to repair of the episiotomy.
Failure to secure a bleeding vessel at the apex of the episiotomy.
Neglecting to inspect the upper vagina and cervix.
Neglecting the possibility of multiple sites of injury.
Undue reliance on oxytocic agents accompanied by too long a delay in exploring the uterus.

Tissue

Retention of part or the entire placenta in the uterus interferes with the contraction and retraction, keeps the blood vessels open and leads to PPH.

Once part of the placenta has separated from the uterine wall, there is bleeding from that area. The part of the placenta that is still attached prevents proper retraction and bleeding goes on until the rest of the organ has separated and is expelled.

The retention of the whole placenta, part of it, an accessory lobe, a single cotyledon, or a fragment of placenta can cause PPH. In some cases, there is placenta accreta. There is no correlation between the amount of placenta retained and the severity of the haemorrhage. The important consideration is the degree of adherence. Exploration of the uterine cavity under anaesthesia is essential to exclude or remove retained placental tissue and membranes.

Thrombin

Any of the haemorrhagic diseases (blood dyscrasias) can affect pregnant women and occasionally are responsible for PPH.

Afibrinogenaemia or hypofibrinogenaemia may follow abruptio placentae, prolonged retention in utero of a dead foetus, and amniotic fluid embolism. One aetiologic theory postulates that thromboplastic material arising from the degeneration and autolysis of the deciduas and placenta may enter the maternal circulation and give rise to intravascular coagulation and loss of circulating fibrinogen. The condition, a failure of the clotting mechanism, causes bleeding that cannot be arrested by the measures usually employed to control haemorrhage.

Risk Factors4,7

Any woman undergoing delivery can experience PPH, but having any of the following risk factors can put her in the high risk class of PPH -

Past history of PPH
Anaemia
Obstructed uterus
Chorioamnionitis
Episiotomy
Pre-eclampsia
Prolonged third stage of labour
Multiple deliveries
Foetal macrosomia
Operative delivery

However, since PPH also occurs in women with no risk factors, it is necessary to be prepared to manage this condition at every delivery. Identifying and correcting anaemia before the delivery, being aware of the mother's beliefs about blood transfusions and eliminating routine episiotomy can minimize the effects of PPH. Also, identifying macrosomia and the presence of pre-eclampsia and being aware of the patient's medical history can help manage the third stage effectively.

Signs, Symptoms and Probable Diagnosis19

Complications7

The common complications can be short-term or long-term. Most patients with PPH are quickly identified and successfully treated before major complications develop.

Anaemia - The most common problem is anaemia and loss of iron stores, which results in fatigue in the postpartum period, making maternal care of the newborn more difficult. Postpartum anaemia increases the risk of postpartum depression.

Shock - Many of the complications of severe PPH are related to massive blood loss and hypovolemic shock. Damage to all major organs is possible, such as respiratory (adult respiratory distress syndrome) and renal (acute tubular necrosis) damage.
Renal failure is usually self-limited, and renal function recovers fully. Temporary dialysis is seldom required. If patient is healthy, pulmonary oedema is uncommon; however, it may develop acutely or during the recovery phase because of fluid overload or myocardial dysfunction.

Venous thrombosis - Pregnant women are at increased risk of venous thrombosis and embolic events. Many of the risk factors for PPH are also risk factors for venous thrombosis and embolic events, including operative vaginal delivery, caesarean delivery, and pelvic surgery.

Sheehan Syndrome - Hypopituitarism following severe PPH (Sheehan syndrome) is due to critical ischaemia of the hypertrophied pituitary. This condition should be considered if a failure to lactate occurs. Isolated deficiencies of pituitary tropins and hyperprolactinaemia have also been reported.

Transfusion - Excessive blood loss raises the need for blood transfusion, which comes with risks like infection, transfusion reaction, and development of atypical antibodies.

Obstetric hysterectomy - Rarely, the need for a hysterectomy arises in case of failure of all the measures taken, leading to loss of child-bearing potential.

Diagnosis1

An average woman has 5 litres of blood in her circulation, which can be lost as fast as in a minute due to PPH.
If the woman is in severe shock, the kidneys are the first vital organs that will stop functioning. Hence, diagnosing PPH becomes critical.

PPH is identified either by clinical, visual, or objective assessment.

Clinical

Clinical estimation remains the primary means to diagnose the extent of bleeding and to direct interventional therapy in obstetric practice. The classification of the haemorrhage can be based on a physiological response to the loss of circulating blood volume.

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A woman can progress from Class I into Class II rapidly. At Class III level, unless intervention is rapid and appropriate, the woman may progress to irreversible shock.

Visual

The standard method of observation used for the measurement of blood loss is relatively straightforward and requires no expenditure, but is an inaccurate measure and varies from one care-giver to the other.

The accuracy of this method can be improved by standardization and training. The blood loss is measured using fixed-sized gauze pads of size 10 x 10 cm. The amount of blood loss is determined by seeing how much area of the gauze is covered by the blood. But, the observer needs to be trained in determining the blood loss.

Another method of calculation is by allowing blood to drain into a fixed collecting container for estimation at the end of 1 hour. Blood losses on the delivery table, garments and the floor are also assessed. At the end of 1 hour, the total amount of blood lost is estimated by totalling up the blood in the container, in the sponges and secondary blood spillage on the delivery table, garments and the floor.

Though the visual assessment method enables the birth attendant to correlate findings on an individualized basis, with the clinical presentation, however, significant differences between clinical estimates and actual measurements have been consistently demonstrated.

Failure to collect or note all the blood in stained linen, incomplete extraction from the collection device, ignoring maternal blood within the placenta, confusion related to the mixing of blood contaminated with amniotic fluid and urine, and technical inaccuracies associated with the transfer of the collection to a measuring device give rise to errors in estimating the blood loss.

The most common error is underestimation of blood lost. Observers tend to give a median or average estimate of blood loss. Large blood losses are most often underestimated and, when the losses are less than average, they tend to be overestimated.

Objective

Objective assessment is done by using a "calibrated plastic blood collection drape", a BRASSS-V drape, which measures the amount of blood collected in the immediate postpartum period. The BRASSS-V drape has a calibrated and funnelled collecting pouch, incorporated within a plastic sheet, which is placed under the buttocks of the woman immediately after the delivery of the baby. The upper end of the sheet has a belt, which is loosely tied around the woman's abdomen to optimize blood collection.

This simple tool not only has the potential for a more accurate detection of postpartum blood loss, but it is hypothesized that this approach will lead to earlier interventions, with an ultimate goal of decreasing maternal morbidity and mortality due to PPH.

(The name "BRASSS-V" was coined by combining the first letter of the names of the seven collaborators who developed the drape).

Management4,8,9

PPH can occur unpredictably. Knowing the complications that can occur after the blood loss, it is better to prevent the disaster. Hence, management of the third stage of labour becomes a critical component in the prevention of PPH.

The third stage of labour can be managed in two ways -

Expectant management of the third stage of labour
Active management of the third stage of labour (AMTSL)

Expectant Management

Expectant management is a "leave well alone" approach.
No oxytocic drug is given at delivery.
The cord is not cut until pulsation ceases and only an umbilical clamp is applied. Controlled cord traction is not used.
Once signs of separation have occurred, the placenta will deliver spontaneously either with the aid of gravity, nipple stimulation or asking the woman to make efforts to push the placenta out.

AMTSL

AMTSL has been shown to significantly reduce the incidence and severity of PPH and shorten the third stage of labour. The WHO, the International Confederation of Midwives (ICM) and the International Federation of Gynaecologists and Obstetricians (FIGO) advocate the routine use of active management to reduce maternal morbidity and mortality by decreasing the incidence of early PPH.

AMTSL involves the following -

Administering a uterotonic agent within 1 minute after the baby is born, after ruling out the presence of another baby in the uterus.
After the cord is clamped, the placenta is delivered by controlled cord traction, i.e., by gently pulling on the umbilical cord with counter-traction on the fundus.

3. The fundus is massaged after delivery of the placenta to keep the uterus contracted.

Active versus Expectant Management of the Third Stage of Labour

A Cochrane Review assessed the effects of active versus expectant management on blood loss, PPH and other maternal and perinatal complications of the third stage of labour.

The results showed that compared to expectant management, active management was associated with reduced risks of maternal blood loss, PPH of more than 500 ml and prolonged third stage of labour. No advantages or disadvantages were apparent for the baby.

It was concluded that routine "active management" is superior to "expectant management" in terms of blood loss, PPH and other serious complications of the third stage of labour, and hence, active management should be the routine management of choice for women expecting to deliver a baby by vaginal delivery in a maternity hospital.

Uterotonics4,9,10,11

Since uterine atony is the commonest cause of PPH, a uterotonic drug is recommended to be used to reduce the blood loss. Uterotonics stimulate the myometrium to contract rhythmically, which constricts spiral arteries and decreases blood flow through the uterus.
Routine administration of a uterotonic drug is an integral part of AMTSL and is thought to play the largest role in preventing PPH. The most commonly used uterotonics for prevention or treatment of PPH are given.

Misoprostol1,12,13

Misoprostol is a prostaglandin E₁ analogue with strong uterotonic activity. There is an ease of administration with misoprostol since it can be given orally, sublingually, rectally and vaginally (abortion, induction of labour). Since it is available in a tablet form, it does not need sterile needles and syringes, there are no special storage requirements and it is relatively stable at high temperatures. Also, it is inexpensive.

Pharmacodynamics

Prostaglandin E₁ causes myometrial contractions by interacting with specific receptors on the myometrial cells. This interaction results in a change in the calcium concentration, thereby initiating muscle contraction. By interacting with prostaglandin receptors, misoprostol causes the cervix to soften and the uterus to contract, resulting in the expulsion of the uterine contents.

Pharmacokinetics

In a pharmacokinetic study, misoprostol 600 μg was given orally and rectally as soon as the umbilical cord was clamped. Blood samples were taken at 7.5,15, 30,45, 60, 90, 120, and 240 minutes after drug administration.

Misoprostol tablets are absorbed rectally and sublingually, even though they are formulated for oral use.

In subjects receiving oral misoprostol, the serum concentration rose quickly, peaked between 7.5 and 30 minutes (mean = 18 minutes) after administration and fell steeply by 60 minutes; this C_max, (maximum serum concentration) was reached sooner than misoprostol administered rectally.
The oral route group had a C_max higher than that for the rectal route. This may be important when faster onset of action is required during PPH.

Serum concentration of misoprostol acid in subjects receiving the rectal doses rose gradually, reached a maximum level between 15 and 60 minutes (mean = 40.5 minutes). The area under the curve (AUC) for rectal misoprostol was higher than for oral misoprostol. This indicates a longer half-life of rectally-administered misoprostol, which could prolong uterine contraction, and, thus prevent delayed haemorrhage.

Clinical Studies

Misoprostol Versus Placebo²

Oral misoprostol in preventing postpartum haemorrhage in resource-poor communities: a randomized controlled trial

Aim

To investigate whether oral misoprostol, a potential alternative to oxytocin, could prevent PPH in a community home-birth setting.

Methods

A placebo-controlled trial was undertaken between September 2002 and December 2005.
After delivery of the baby and within 5 minutes of clamping and cutting of the umbilical cord, 1,620 women in rural India were randomized to receive -
- 600 μg (200 μg x 3 tablets) misoprostol orally (n=812); or
- Placebo (n=808)
25 auxiliary nurse midwives undertook the deliveries, administered the study drug, and measured blood loss.
Primary outcome - Evaluate incidence of acute PPH (defined as ≥ 500 ml bleeding within 2 hours of delivery).

Results

Oral misoprostol reduced acute PPH significantly (P<0.0001) by nearly 50% compared with placebo.
It was associated with a significant reduction (P<0.0218) in acute severe PPH of 80%.
It was associated with lesser need for an emergency transfer to a higher level facility, blood transfusion or surgical interventions.
One case of PPH was prevented for every 18 women treated.

Side effects (primarily, shivering and fever) from misoprostol on the mothers were transient.
There was no evidence of adverse effects on the neonates.

Conclusion

Oral misoprostol is associated with significant decreases in the rate of acute PPH and mean blood loss.
It is a safe, effective, stable and inexpensive option for the prevention of PPH.

Misoprostol Versus Oxytocin¹⁴

A randomized controlled trial of misoprostol versus oxytocin in the active management of the third stage of labour

Aim

To compare oral misoprostol with IM oxytocin in the prevention of PPH and whether 600 μg misoprostol could safely replace IM oxytocin without an increase in the incidence of PPH.

Methods

Double-blind, randomized controlled trial.
Women (N=496) were randomized to receive either -
- 600 μg (200 μg x 3 tablets) oral misoprostol immediately after the delivery of the baby and cord clamping (n=247); or
- 10 IU oxytocin IM at the delivery of the anterior shoulder (n=249).
Primary outcome - Measure the incidence of PPH.

Results

In both the groups,
- incidence of blood loss >500 ml, mean estimated blood loss and duration of the third stage of labour was similar;
- no woman had an estimated blood loss >1,000 ml.
The need for additional oxytocics was not significantly higher with misoprostol, nor was the need for manual removal of the placenta.
No women in either group needed blood transfusion.

All not statistically significant

Conclusion

Misoprostol given orally and IM oxytocin appear to be equally effective in the prevention of PPH.
It can replace IM oxytocin in reducing PPH in low-risk women in developing countries, especially as it is administered orally and it is thermostable in tropical conditions.
Apart from thermostability, it offers advantages like ease of administration and minimal side effects such as nausea and vomiting over oxytocin or ergometrine.
It can be administered to hypertensive patients.

Misoprostol Versus Methylergometrine¹⁶

Oral misoprostol for prevention of postpartum haemorrhage by paramedical workers in India

Aim

To study whether paramedical workers from rural primary health centers in India are able to administer oral misoprostol and actively manage the third stage of labour to prevent PPH.

Methods

Cluster randomization was used at 30 peripheral health centres from five states in India.
Women enrolled (N = 1,200) were divided into the following groups -
- 600 formed the intervention group - active management of the third stage of labour with 600 μg (200 μg x 3 tablets) MISOPROST
- 600 formed the comparison group (current government guidelines for the prevention of PPH were followed) -
  - 0.2 mg IM methylergometrine (n = 531)
  - 0.125 mg tablet methylergometrine (n = 58)
  - No treatment (n = 11)
Primary outcome - Evaluate blood loss after delivery, measured using a calibrated blood collection drape.

Results

MISOPROST. was associated with the following -

Significant reduction (P<0.001) in the duration of the third stage of labour.
Significantly lower (P<0.001) amount of blood loss than that observed in the comparison group.
No maternal or neonatal mortality reported.

Conclusion

Active management of the third stage of labour with oral misoprostol led to a significant decrease in blood loss.
Simple interventions can be easily implemented to reduce the blood loss during labour especially in developing countries, where the prevalence of anaemia is high.

Misoprostol Versus Ergometrine + Oxytocin¹⁷

A multicentre randomized controlled trial of oral misoprostol and IM ergometrine + oxytocin in the management of the third stage of labour

Aim

To compare the efficacy and safety of oral misoprostol with IM ergometrine+oxytocin in the management of the third stage of labour.

Methods

A prospective, multicentre, randomized, controlled trial performed in three tertiary training centres in Hong Kong.
Patients having a singleton pregnancy and a vaginal delivery were randomly assigned to receive either -
- 600 μg (200 μg x 3 tablets) of oral misoprostol immediately after delivery of the baby (n = 1,026); or
- 1 ml of 5 units of oxytocin and 0.5 mg ergometrine IM, at delivery of the anterior shoulder of the baby (n = 1,032)
Primary outcome - Evaluate amount of blood loss during delivery and the occurrence of primary PPH.
Maternal BP, pulse and temperature were recorded immediately after delivery and repeated 30 and 60 minutes later.

Results

In both groups,
- there was no significant difference in the amount of estimated blood loss and the incidence of PPH (>500 ml) or severe PPH (≥1,000 ml).
- there was no significant difference in the incidence of delayed haemorrhage within the first 24 hours.
- the incidence of prolonged third stage (≥30 minutes) was similar.
In the misoprostol group,
- there was a significantly lower (P < 0.05) incidence of manual removal of placenta.
- the incidence of hypertension (BP ≥ 140/90 mmHg) after delivery was significantly (P < 0.05) lowered at 30 and 60 minutes.
Misoprostol does not cause hypertension and is associated with a 55-60% reduction in the incidence of hypertension when compared with IM ergometrine + oxytocin.

Conclusion

Misoprostol may be used as an alternative to IM ergometrine + oxytocin in the management of the third stage of labour, especially in situations where IM ergometrine + oxytocin is contraindicated or where storage and parenteral administration of oxytocics is a potential problem.

Benefits of Misoprostol Over Other Uterotonics

Refrigeration is not required
Stable at higher temperatures
Long shelf-life
Ease of administration
Good safety profile
Inexpensive
Can be given to hypertensive, asthmatic patients

Safety of Misoprostol in PPH18

Uterotonics like oxytocin, methylergometrine and carboprost are not within the reach of a vast majority of women in the rural areas of resource-poor countries, where home deliveries, generally conducted by unskilled birth attendants, still account for 30-50% of births.

Misoprostol has proven to be an effective agent in the prevention of PPH. Several studies have reported on the adverse effects of misoprostol and have found that shivering and pyrexia are the common side effects. Though these side effects are of a transient nature and can be managed by giving medications, in most of the cases, no medical treatment is required.

A safety study was carried out to assess side effects on the neonates among mothers who were given misoprostol and who nursed immediately post-delivery. All side effects were assessed for each mother and newborn at both 2 hours and 24 hours.

In this study, 812 women received 600 μg (200μg x 3 tablets) misoprostol and 808 received placebo.

Misoprostol appears to be safe in women with hypertensive disorders and is clearly preferable to ergot derivatives in this subset of women.
Antipyretics, antispasmodics and antihistaminic were the most commonly administered medications. However, in almost all cases, no medical treatment was required by 24 hours.
As misoprostol acid, the pharmacologically active metabolite is excreted in the colostrum (milk produced during pregnancy and continuing through the early days of breastfeeding), it is possible that breast-fed infants could experience side effects associated with the early administration of misoprostol to the mother. In this study, there were no adverse side effects of misoprostol in breast-fed newborns.

Conclusion

600 μg of misoprostol was shown to be safe for both the mother and newborn when used for the prevention of PPH.
It was associated with a transient increase in the rate of postpartum shivering and fever, but no other serious side effects were noted.

Other Procedures19

Balloon Tamponade

The Balloon Tamponade two-way catheter provides temporary control of PPH when conservative management is warranted.

The insertion technique is simple and consists of placing the balloon portion of the Sengstaken, Rüsch or Bakri catheter directly into the uterus, making sure that the entire balloon (500 ml capacity) is inserted past the cervical canal and internal os. Gentle traction on the balloon shaft ensures proper contact between the balloon and the tissue surface and enhances the tamponade effect. Success is judged by a declining loss of blood from the cervix and as seen through the drainage port.

The mean time for leaving the tamponade balloon ranges from 8 to 48 hours. A gradual deflation of the balloon is advised to reduce the potential risk of further bleeding. Tamponade procedures are simple, cheap and easy to use, and are effective measures that should be considered for intractable PPH, especially when other options are not available.

Alternative

An alternative innovative approach uses a sterile rubber catheter fitted with a condom as a tamponade balloon device. The sterile catheter is inserted within the condom and tied near the mouth of the condom with a silk thread; the outer end of the catheter is connected to a saline set. After placement in the uterus, the condom is inflated with 250-500 ml of normal saline according to need, and the outer end of the catheter is folded and tied with a thread after the bleeding has stopped. To keep the balloon in situ, the vaginal cavity is packed with roller gauze. This method represents a cheap, simple and quick intervention, which is invaluable in resource-poor countries.

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Bimanual Compression

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Bimanual compression causes mechanical constriction of myometrial vessels and stimulates uterine contractions. The steps of uterine massage include the following-

Insert a gloved hand into the vagina, and push up against the body of the uterus.
Place the other hand above the uterine fundus on the abdomen and compress the posterior uterine wall against the hand in the vagina.

Bimanual compression also helps to reduce bleeding, thus aiding rapid resuscitation.

Surgical Management Of PPH19

B-Lynch Suture

The B-Lynch suture aims to exert continuous vertical compression on the uterine vascular system. Laparotomy, uterine exteriorization and an opened uterine cavity are necessary. The potential efficacy of the B-Lynch suture should be tested by performing an open bimanual compression to see whether the bleeding stops, before proceeding to place the suture into the uterus. If the bleeding stops on applying such compression, there is a good chance that application of the B-Lynch suture will stop the bleeding.

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Vertical Uterine Compression Sutures

These are an alternative to the B-Lynch technique if no lower segment caesarean incision is present. They may be placed without opening the uterus, using a straight 10 cm needle. Ensure downward bladder retraction and place two to four vertical sutures. Check that the compression sutures have worked by observing blood loss per vaginum before closing the abdomen.

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Cho Multiple Square Compression Sutures

Multiple square sutures are used to cover the whole body of the uterus and may be useful in cases of placenta previa (make sure to leave a drainage portal). Check that the compression sutures have worked by observing the blood loss vaginally before closing the abdomen. Suture through with a straight 10 cm needle.

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Uterine Artery Embolization

Embolization requires an obstetric department that is well aware of its implications in PPH and a proactive protocol providing the obstetricians with easy access to emergency care from the interventional radiology team.
The patient must be sufficiently stable to be transported to the angiography suite. Embolization should be considered early, because it may take time to mobilize services. When embolization is successful, the patient can rapidly recover without undergoing additional surgery. Embolization not only saves the life of the patient, but also the uterus and adnexal organs, thus preserving fertility.

Stepwise Devascularization

The surgical approach starts with ligature of the uterine artery and its distribution to the uterus, either unilaterally or bilaterally, preferably as it emerges from crossing over the ureter or as it approaches the uterine wall to penetrate and establish its divisions and the infundibulo pelvic vessels before it enters the uterus.

Internal Iliac Artery Ligation

Conditions indicating ligation are PPH due to atonic uterus refractory to other measures, abruptio placentae with uterine atony, abdominal pregnancy with pelvic implantation of the placenta, and placenta accreta.

Therapeutic indications include the following -Before or after hysterectomy for PPH; continuous bleeding from the broad ligament base; profuse bleeding from the pelvic side wall or the angle of the vagina; diffuse bleeding without a clearly identifiable vascular bed; ruptured uterus in which the uterine artery may be torn at its origin from the internal iliac artery; and where extensive lacerations of the cervix have occurred following difficult instrumental delivery.

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Hysterectomy

Emergency peripartum hysterectomy is the best option when uterine atony is unresponsive to oxytocics and prostaglandins, where facilities for embolization are not available, and/or the obstetrician is not versed with conservative surgical procedures. Uterine rupture secondary to obstructed labour and a previous caesarean section may be indications. If the rupture is extensive and the haemorrhage cannot be contained by suture of the ruptured area, then a hysterectomy may be necessary.

Misoprost 600

For the use of a Registered Medical Practitioner only

Misoprostol Tablets

MISOPROST 600

Composition

MISOPROST 600
Each uncoated tablet contains
Misoprostol.............600 μg

Dosage Form

Tablets for oral use

Pharmacology

Pharmacodynamics

Misoprostol is a synthetic prostaglandin E_{1. Misoprostol causes the cervix to soften and the uterus to contract.}

Prostaglandin E₁ causes myometrial contractions by interacting with specific receptors on myometrial cells. This interaction results in a change in the calcium concentration, thereby initiating muscle contraction. By interacting with prostaglandin receptors, misoprostol causes the cervix to soften and the uterus to contract, resulting in the expulsion of the uterine contents.

Pharmacokinetics

On oral administration, misoprostol is rapidly and extensively absorbed and undergoes rapid de-esterification to its pharmacologically active metabolite, misoprostol acid which is detectable in plasma. The alpha side chain undergoes beta-oxidation and the beta side chain undergoes omega oxidation followed by reduction of the ketone to give prostaglandin Fanalogs.

In a pharmacokinetic study comparing misoprostol 600 μg given orally and rectally, it was seen that all subjects receiving oral misoprostol, the serum concentration rose quickly, peaked between 7.5 and 30 minutes (mean = 18 minutes) after administration, fell steeply by 60 minutes, and remained low thereafter which may be of clinical significance in postpartum haemorrhage treatment.

On the other hand, serum concentration of misoprostol acid in subjects receiving the rectal doses rose gradually, reached a maximum level between 15 and 60 minutes (mean = 40.5 minutes), and declined slowly in 5 patients and faster in the others.

The longer half-life of rectally administered misoprostol could prolong uterine contraction, thus preventing a delayed haemorrhage.

Misoprostol is primarily metabolized in the liver, and less than 1 % of its active metabolite is excreted in the urine. Patients with hepatic disease should receive a decreased dose, whereas dose adjustment is unnecessary for patients with renal insufficiency who do not require dialysis. Misoprostol has no known drug interactions and does not induce the hepatic cytochrome P450 enzyme system.

Indications

For prevention of postpartum haemorrhage.

Dosage and Administration

One tablet of MISOPROST 600 is given orally immediately after cord clamping.

Contraindications

Known hypersensitivity to misoprostol or other prostaglandins.
During pregnancy.

Warnings and Precautions

The patient should not give misoprostol to anyone else.
Misoprostol has been prescribed for the patient's specific condition, it may not be the correct treatment for another person, and may be dangerous to the other person if she is or were to become pregnant.
For prevention of PPH, MISOPROST 600 should be administered orally immediately after cord clamping.
Exclude second twin before using MISOPROST 600
MISOPROST 600 should be used with caution in the following conditions:-
- Bronchial asthma
- Heart diseases

Drug Interactions

Misoprostol has not been shown to interfere with the beneficial effects of aspirin on the signs and symptoms of rheumatoid arthritis. Misoprostol does not exert clinically significant effects on the absorption, blood levels, and antiplatelet effects of therapeutic doses of aspirin. Misoprostol has no clinically significant effect on the kinetics of diclofenac or ibuprofen. The most common side effects of misoprostol are diarrhoea and abdominal pain. These side effects may be increased if misoprostal is taken concurrently with antacids.

Renal Impairment

Pharmacokinetic studies in patients with varying degrees of renal impairment showed an approximate doubling of T_½, C_max and AUC compared to normal, but no clear correlation between the degree of impairment and the AUC. In subjects over 64 years of age, the AUC for misoprostol acid is increased. No routine dosage adjustment is recommended in older patients or patients with renal impairment, but the dosage may need to be reduced if the usual dose is not tolerated.

Hepatic Impairment

Patients with hepatic disease may require a decreased dose.

Pregnancy

MISOPROST 600 should not be administered during pregnancy. For prevention of PPH, MISOPROST 600 should be administered orally immediately after cord clamping.

Lactation

Although it is not known whether misoprostol or misoprostol acid is excreted in human milk, misoprostol should not be administered to nursing mothers because the potential excretion of misoprostol acid could cause diarrhoea in nursing infants.

Undesirable Effects

Shivering
Hyperthermia
Diarrhoea

Incidence greater than 1%: In clinical trials, the following adverse reactions were reported by more than 1 % of the subjects receiving misoprostol and may be causally related to the drug: Nausea (3.2%), flatulence (2.9%), headache (2.4%), dyspepsia (2.0%), vomiting (1.3%), and constipation (1.1%). However, there were no significant differences between the incidences of these events for misoprostol and placebo.

Causal relationship unknown: The following adverse events were infrequently reported. Causal relationships between misoprostol and these events have not been established, but cannot be excluded:

Body as a whole: aches/pains, asthenia, fatigue, fever, rigors, weight changes.

Skin: rash, dermatitis, alopecia, pallor, breast pain.

Special senses: abnormal taste, abnormal vision, conjunctivitis, deafness, tinnitus, earache.

Respiratory: upper respiratory tract infection, bronchitis, bronchospasm, dyspnoea, pneumonia, epistaxis.

Cardiovascular: chest pain, oedema, diaphoresis, hypotension, hypertension, arrhythmia, phlebitis, increased cardiac enzymes, syncope.

Gastrointestinal (Gl): Gl bleeding, Gl inflammation/infection, rectal disorder, abnormal hepatobiliary function, gingivitis, reflux, dysphagia, amylase increase.

Hypersensitivity: anaphylaxis

Metabolic: glycosuria, gout, increased nitrogen, increased alkaline phosphatase.

Genitourinary: polyuria, dysuria, haematuria, urinary tract infection.

Nervous system/Psychiatric: anxiety, change in appetite, depression, drowsiness, dizziness, thirst, impotence, loss of libido, sweating increase, neuropathy, neurosis, confusion.

Musculoskeletal: arthralgia, myalgia, muscle cramps, stiffness, back pain.

Blood/Coagulation: anaemia, abnormal differential, thrombocytopenia, purpura, erythrocyte sedimentation rate (ESR) increased.

Overdosage

Clinical signs that may indicate an overdose are sedation, tremor, convulsions, dyspnoea, abdominal pain, diarrhoea, fever, palpitations, hypotension, or bradycardia. Symptoms should be treated with supportive therapy. It is not known if misoprostol acid is dialyzable. However, because misoprostol is metabolized like a fatty acid, it is unlikely that dialysis would be an appropriate treatment for overdosage.

Storage and Handling Instructions

Store in a cool, dry place.

Packaging Information

MISOPROST 600 is available as a blister pack of 1 tablet.

Other Indications of Misoprostol

Misoprostol, apart from being used for the prevention for PPH, is also approved for the medical termination of pregnancy along with mifepristone, and for cervical ripening. The dosage is as follows-

image-7-miso_1

References

1. Pitfalls in assessing blood loss and decision to transfer, B. S. Kodkany and R. J. Derman; Chapter 4:35-44
2. Lancet.2006;368(9543):1248-53
3. Obstetrics, Gynaecology & Reproductive Medicine 2009;19(5): 121-126
4. Oxom Foote - Childbirth & Labor - 5^th Edition
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7. emedicine.medscaoe.com /article/796785-ovefview
8. Cochrane Database Syst Rev. 2000;(3):CD000007
9. www.pphprevention.org/files/ICM_FIGO_Joint_Statement.pdf
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11. Micromedex
12 Obstet Gynecol.2003;101(5 Pt 1)968-74
13. BMC Pregnancy Childbirth. 2008;8.40
14. J Obstet Gynaecol. 2003;23(1): 13-6
15. J Obstet Gynaecol 2004;24:40-3
16. Int J Gynaecol Obstet. 2006;92(2): 170-5
17. Hum Reprod. 2001;16(1 ):31-35
18. J Matem Fetal Neonatal Med. 2009;22(1):24-8
19 Guidelines for immediate acton leaflet - Textbook of postpartum hemorrhage