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A uterotonic, also known as an oxytocic or ecbolic, is a type of medication used to induce contraction or greater tonicity of the uterus. Uterotonics are used both to induce labor and to reduce postpartum hemorrhage. [1]
Labor induction in the third trimester of pregnancy may be required due to medical necessity, or may be desired for social reasons. Generally, labor induction is indicated when the risk of carrying the pregnancy outweighs the risk of delivering. These reason include, but are not limited to, pregnancies that are prolonged, prelabor rupture of the fetal membranes, and concerns about the health and safety of the mother and/or child. There are multiple techniques available to stimulate uterine contractions including mechanical, pharmacological, and alternative medicine methods to initiate contractions prior to spontaneous onset of labor. [2]
Postpartum hemorrhage, also known as PPH, is defined as a loss of 500 mL or greater of blood within 24 hours after giving birth. It is one of the leading causes of maternal mortality in women and adolescent girls worldwide, with mothers from low-resource countries being at a larger risk when compared to mothers of higher-resource countries. Occurring in 5% of all women giving birth, these situations are considered emergencies and require a quick, adequate response and the proper resources to prevent the death of the mother. [3]
Labor and delivery is a sequential process that results in the birth of a fetus and placenta. It is dependent on maternal and fetal chemical signals to stimulate muscles in the uterus to contract and relax. Of such signals include prostaglandins [4] and oxytocin. [5] Uterotonics can be utilized in these chemical pathways in order to medically stimulate contractions in labor induction or to treat postpartum hemorrhage.
Utertonic | Administration | Onset | Duration of Action | Common Side Effects | Contraindications |
---|---|---|---|---|---|
Oxytocin | IV Bolus IV continuous infusion Intramuscularly (IM) | IV: < 1 min IM: 3-5 min | IV: 20 min IM: 30-90 min | IV: Hypotension, tachycardia, arrhythmia IM: Nausea and Vomiting | IV: Hypotension IM: Hemodynamically unstable |
Carbetocin | IV bolus IM | IV & IM: 2 min | IV: 60 min IM: 120 min | IV: Hypotension, tachycardia, arrhythmia IM: Nausea and Vomiting | IV: Hypotension IM: Hemodynamically unstable |
Misoprostol | Oral (PO) Sublingual (SL) Vaginal (PV) Rectal (PR) | PO: 8 min SL:11 min PV: 20 min PR: 100 min | PO: 120 min SL: 180 min PV: 240 min PR: 240 min | Fever Diarrhea Nausea Vomiting | |
Carboprost | IM Intramyometrial (IMM) | IM: 3-5 min IMM: No data | IM: 60-120 min IMM: No data | IM: Bronchospasm IMM: Nausea, vomiting, shivering | IM: Asthma IMM: Caution in liver, kidney or heart disease. |
Ergometrine | IV IM | IV: < 1 min IM: 2-3 min | IV: 45 min IM: 3 hours | IV: Hypertension IM: Nausea and Vomiting | IV: Hypertension IM: Myocardial Ischemia |
Methylergonovine | IV IM | IV: < 1 min IM: 2-3 min | IV: 45 min IM: 3 hours | IV: Hypertension IM: Nausea and Vomiting | IV: Hypertension IM: Myocardial Ischemia |
Oxytocin is a peptide hormone produced in the hypothalamus that plays an important role in many physiological functions. These functions include, enhancing mood and social relationships, promotion of maternal behaviors and stimulations of uterine contractions, among others roles. Uterine muscle contractions are induced via a G-protein pathway stemming from the oxytocin receptor (OXTR), the binding and activation site of oxytocin. [7] When oxytocin binds to its associated receptors in the uterus, a cascade is initiated that results in an increase in calcium and subsequently an increase in muscle contractions. The release of oxytocin helps to facilitate stronger contractions during labor to aid in delivery of the fetus. Additionally, during pregnancy, the uterine muscles have an increased concentration of oxytocin receptors, leading to an increased response to oxytocin as well. [8]
Oxytocin is the most commonly used agent for labor induction. It is given intravenously since it is easily degraded by the body if given orally. While giving oxytocin, it is important to monitor the mother and the fetus, specifically the mother's uterine activity and the fetal heart rate. The more common side effects of oxytocin include tachysystole, hyponatremia, and hypotension. Tachysystole is an increased rate of uterine contractions. If this occurs, it can be managed by lowering the dosage of oxytocin. Hyponatremia is a decreased concentration of sodium in the body as a result of increased fluids. This occurs due to oxytocin's similar structure to vasopressin (antidiuretic hormone), which acts to retain water in the body. Hypotension, or low blood pressure, is also a common side effect due to oxytocin's ability to relax smooth muscle of vessels. In comparison to women in spontaneous labor, women in induced labor on oxytocin experience a longer latent phase, however the duration of labor after reaching active labor (when the cervix has reached 6 cm), the duration of labor is considered equal. [9]
The most common cause of postpartum hemorrhage is a loss of muscle tone in the uterus. Normally, the uterus will contract to constrict blood vessels and decrease the flow of blood to prevent bleeding out. However, if there is a loss of muscle tone, see uterine atony, there is an increased risk of bleeding. Oxytocin is the first-line pharmacological step to help prevent PPH and treat PPH. [8]
Oxytocin plays an integral role in regulation of many of the body's biological processes- especially labor regulation. Since its structure was revealed in 1953, it has been the subject of intensive research. [10] Some of the analogs produced from extensive modification of its chemical structure residues have produced drugs and therapies that are utilized as uterotonics. Similar to oxytocin, analogues bind to oxytocin receptors found along the muscles of the uterus and act as an agonist. During pregnancy, the number of oxytocin receptors increase until reaching their peak near completion of the pregnancy. An important note is that not all analogs of oxytocin work as an receptor agonist or as a uterotonic. Some may oppose uterine contractility such as atosiban. [11]
Carbetocin: A long-acting synthetic analog with a half-life 4 to 10 times longer than natural oxytocin, it is used to control postpartum hemorrhaging or bleeding after giving birth. Heat-stable carbetocin does not require refrigeration unlike oxytocin; a notable advantage for use in low medical resource areas. [12] It is approved for use in 23 various countries around the world (not approved in United States). [11] In Canadian and German guidelines, carbetocin is recommended as a first-line therapy treatment for post-partum hemorrhaging with notable efficacy when used with cesarean section deliveries. [10] Carbetocin has been shown to be more effective than oxytocin in preventing postpartum hemorrhaging as well. Common side effects of carbetocin include vomiting, fever, and hypertension- similar side effect profile to that of oxytocin. [10] Both carbetocin and oxytocin are listed on the World Health Organization's Essential Medicines List. [10]
Demoxytocin is another analog of oxytocin which is also used to induce labor.
Prostaglandins are derived from the cell membrane phospholipids through a series of enzymatic reactions. Phospholipase A2 cleaves arachidonic acid from membrane phospholipids and is eventually converted to prostaglandins by cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2). Due to this mechanism, prostaglandins have a presence in many areas of the body and allow for diverse physiological and pathological functions. Primarily known for its role in mediating inflammation: pain, swelling, redness, and warmth, prostaglandin synthesis is a target for many drugs. Inhibition of COX-1 and COX-2 by aspirin and non-steroidal anti-inflammatory drugs prevents the inflammatory response and can also prevent homeostatic functions of the stomach and GI system that may lead to ulcers and bleeding. [13]
Prostaglandins (PG) have been attributed to partaking in the mechanisms of uterine activity during labor. The presence of prostaglandins and PG receptors increases throughout the pregnancy and increase expression of oxytocin receptors as well. Along with the increase in oxytocin receptors to facilitate labor, prostaglandins also increase the intracellular concentration of calcium. [6] Two PG subtypes, E and F, play fundamental roles in labor, PG E receptors, activated by PGE1 and PGE2 are more uteroselective and will stimulate contraction or relaxation depending on the subtype. PG F receptors will stimulate myometrial contraction, although the stimulus from PG F receptors are inferior to oxytocin. For this reason, injectable PGs are not used as first line treatment. Adverse effects of injectable PGs include hypotension and pulmonary edema. [14]
Misoprostol: an analogue of PGE1, this PG is a popular choice for PPH prophylaxis and treatment. Misoprostol is easily administered, considered safe, and is low cost. The routes of administration include sublingual, oral, vaginal, and rectal with greatest efficacy from sublingual and vaginal administration. Vaginally administered misoprostol had improved outcomes of inducing labor within twenty four hours compared to oxytocin, but was associated with uterine hyperstimulation. [15] Misoprostol is an agonist of EP1 and EP3 receptors, and can cause a greater stimulation at lower concentrations. At higher concentrations, the medication can suppress contractions. [14]
Carboprost: an analogue of PGF 2α, this prostaglandin contains oxytocic properties that permit a longer duration of action than the naturally occurring prostaglandins. The injectable prostaglandin is administered via intramuscularly or intramyometrial, and is used in clinical practice. The drug is contraindicated in those with reactive airway diseases. Side effects of this medication include hypertension, hypotension, pulmonary hypertension, vomiting and diarrhea. [14] [6]
Ergot Alkaloids refer to a set of medications derived from the rye ergot fungus with mixed receptor activity that work to increase uterine muscle tone. [8] Unlike oxytocinergic uterotonics, ergot alkaloids work primarily through agonistic activity of serotonin receptors along the smooth muscles of the uterine wall.
Ergometrine, also known as ergonovine. Ergometrine is the first drug to be isolated from the rye ergot fungus. Ergometrine is often used alongside oxytocin to treat postpartum hemorrhaging and has been found to more effective than the standard of oxytocin treatment alone. [10] Ergometrine has a relatively quick onset of action following intravenous administration (one minute) with the duration of action averaging 45 minutes (rhythmic contracts will persist for up to 3 hours following administration). [8]
Methylergonovine, a synthetic analog of ergometrine that is primarily used to treat postpartum hemorrhaging due to uterine atony. [10] Similar to ergometrine, methylergonovine works through agonism of the serotonin receptors found on the smooth muscles of the uterine wall. It has partial agonist activity on α-adrenergic receptors as well as weak antagonistic activity on dopamine receptors. [8] Methylergonovine is intravenously administered with onset and duration of action similar to that of ergometrine. Its most common side effect is hypertension. Methylergonovine is recommended as a second-line therapy in treating postpartum hemorrhaging due to uterine atony according to both the American College of Obstetricians and Gynecologists (ACOG) and the Royal College of Obstetrics and Gynecology. In 2012, ACOG published a warning regarding use of methylergonovine's usage in people with hypertension where it was suspected to have caused myocardial infarction and ischemia in those individuals. [8]
Prostaglandins (PG) are a group of physiologically active lipid compounds called eicosanoids that have diverse hormone-like effects in animals. Prostaglandins have been found in almost every tissue in humans and other animals. They are derived enzymatically from the fatty acid arachidonic acid. Every prostaglandin contains 20 carbon atoms, including a 5-carbon ring. They are a subclass of eicosanoids and of the prostanoid class of fatty acid derivatives.
Misoprostol is a synthetic prostaglandin medication used to prevent and treat stomach and duodenal ulcers, induce labor, cause an abortion, and treat postpartum bleeding due to poor contraction of the uterus. It is taken by mouth when used to prevent gastric ulcers in people taking nonsteroidal anti-inflammatory drugs (NSAID). For abortions it is used by itself or in conjunction with mifepristone or methotrexate. By itself, effectiveness for abortion is between 66% and 90%. For labor induction or abortion, it is taken by mouth, dissolved in the mouth, or placed in the vagina. For postpartum bleeding it may also be used rectally.
Uterine contractions are muscle contractions of the uterine smooth muscle that can occur at various intensities in both the non-pregnant and pregnant uterine state. The non-pregnant uterus undergoes small, spontaneous contractions in addition to stronger, coordinated contractions during the menstrual cycle and orgasm. Throughout gestation, the uterus enters a state of uterine quiescence due to various neural and hormonal changes. During this state, the uterus undergoes little to no contractions, though spontaneous contractions still occur for the uterine myocyte cells to experience hypertrophy. The pregnant uterus only contracts strongly during orgasms, labour, and in the postpartum stage to return to its natural size.
Labor induction is the process or treatment that stimulates childbirth and delivery. Inducing (starting) labor can be accomplished with pharmaceutical or non-pharmaceutical methods. In Western countries, it is estimated that one-quarter of pregnant women have their labor medically induced with drug treatment. Inductions are most often performed either with prostaglandin drug treatment alone, or with a combination of prostaglandin and intravenous oxytocin treatment.
Cervical dilation is the opening of the cervix, the entrance to the uterus, during childbirth, miscarriage, induced abortion, or gynecological surgery. Cervical dilation may occur naturally, or may be induced surgically or medically.
Bloody show or show is the passage of a small amount of blood or blood-tinged mucus through the vagina near the end of pregnancy. It is caused by thinning and dilation of the cervix, leading to detachment of the cervical mucus plug that seals the cervix during pregnancy and tearing of small cervical blood vessels, and is one of the signs that labor may be imminent. The bloody show may be expelled from the vagina in pieces or altogether and often appears as a jelly-like piece of mucus stained with blood. Although the bloody show may be alarming at first, it is not a concern of patient health after 37 weeks gestation.
Ergometrine, also known as ergonovine and sold under the brand names Ergotrate, Ergostat, and Syntometrine among others, is a medication used to cause contractions of the uterus to treat heavy vaginal bleeding after childbirth. It can be used either by mouth, by injection into a muscle, or injection into a vein. It begins working within 15 minutes when taken by mouth and is faster in onset when used by injection. Effects last between 45 and 180 minutes.
Cervical effacement or cervical ripening refers to the thinning and shortening of the cervix. This process occurs during labor to prepare the cervix for dilation to allow the fetus to pass through the vagina. While this is a normal, physiological process that occurs at the later end of pregnancy, it can also be induced through medications and procedures.
Prostaglandin E2 (PGE2), also known as dinoprostone, is a naturally occurring prostaglandin with oxytocic properties that is used as a medication. Dinoprostone is used in labor induction, bleeding after delivery, termination of pregnancy, and in newborn babies to keep the ductus arteriosus open. In babies it is used in those with congenital heart defects until surgery can be carried out. It is also used to manage gestational trophoblastic disease. It may be used within the vagina or by injection into a vein.
Uterine atony is the failure of the uterus to contract adequately following delivery. Contraction of the uterine muscles during labor compresses the blood vessels and slows flow, which helps prevent hemorrhage and facilitates coagulation. Therefore, a lack of uterine muscle contraction can lead to an acute hemorrhage, as the vasculature is not being sufficiently compressed. Uterine atony is the most common cause of postpartum hemorrhage, which is an emergency and potential cause of fatality. Across the globe, postpartum hemorrhage is among the top five causes of maternal death. Recognition of the warning signs of uterine atony in the setting of extensive postpartum bleeding should initiate interventions aimed at regaining stable uterine contraction.
Postpartum bleeding or postpartum hemorrhage (PPH) is often defined as the loss of more than 500 ml or 1,000 ml of blood following childbirth. Some have added the requirement that there also be signs or symptoms of low blood volume for the condition to exist. Signs and symptoms may initially include: an increased heart rate, feeling faint upon standing, and an increased breathing rate. As more blood is lost, the patient may feel cold, blood pressure may drop, and they may become restless or unconscious. In severe cases circulatory collapse, disseminated intravascular coagulation and death can occur. The condition can occur up to twelve weeks following delivery in the secondary form. The most common cause is poor contraction of the uterus following childbirth. Not all of the placenta being delivered, a tear of the uterus, or poor blood clotting are other possible causes. It occurs more commonly in those who already have a low amount of red blood, are Asian, have a larger fetus or more than one fetus, are obese or are older than 40 years of age. It also occurs more commonly following caesarean sections, those in whom medications are used to start labor, those requiring the use of a vacuum or forceps, and those who have an episiotomy.
Carbetocin, sold under the brand names Pabal among others, is a medication used to prevent excessive bleeding after childbirth, particularly following Cesarean section. It appears to work as well as oxytocin. Due to it being less economical than other options, use is not recommended by NHS Scotland. It is given by injection into a vein or muscle.
A vaginal delivery is the birth of offspring in mammals through the vagina. It is the most common method of childbirth worldwide. It is considered the preferred method of delivery, as it is correlated with lower morbidity and mortality than caesarean sections (C-sections), though it is not clear whether this is causal.
Prostaglandin F2α, pharmaceutically termed dinoprost, is a naturally occurring prostaglandin used in medicine to induce labor and as an abortifacient. Prostaglandins are lipids throughout the entire body that have a hormone-like function. In pregnancy, PGF2α is medically used to sustain contracture and provoke myometrial ischemia to accelerate labor and prevent significant blood loss in labor. Additionally, PGF2α has been linked to being naturally involved in the process of labor. It has been seen that there are higher levels of PGF2α in maternal fluid during labor when compared to at term. This signifies that there is likely a biological use and significance to the production and secretion of PGF2α in labor. Prostaglandin is also used to treat uterine infections in domestic animals.
Oxytocin/ergometrine (trade name Syntometrine) is an obstetric combination drug. The components are synthetically produced oxytocin, a human hormone produced in the hypothalamus, and ergometrine, an alpha-adrenergic, dopaminergic and serotonin (5-HT2) receptor agonist.
Uterine Tachysystole is a condition of excessively frequent uterine contractions during pregnancy. It is most often seen in induced or augmented labor, though it can also occur during spontaneous labor, and this may result in fetal hypoxia and acidosis. This may have serious effects on both the mother and the fetus including hemorrhaging and death. There are still major gaps in understanding treatment as well as clinical outcomes of this condition. Uterine tachysystole is defined as more than 5 contractions in 10 minutes, averaged over a 30-minute period.
Retained placenta is a condition in which all or part of the placenta or membranes remain in the uterus during the third stage of labour. Retained placenta can be broadly divided into:
Placental expulsion occurs when the placenta comes out of the birth canal after childbirth. The period of time starting just after the baby is expelled until just after the placenta is expelled is called the third stage of labor.
Synthetic oxytocin, sold under the brand name Pitocin among others, is a medication made from the peptide oxytocin. As a medication, it is used to cause contraction of the uterus to start labor, increase the speed of labor, and to stop bleeding following delivery. For this purpose, it is given by injection either into a muscle or into a vein.
Pain management during childbirth is the partial treatment and a way of reducing any pain that a woman may experience during labor and delivery. The amount of pain a woman feels during labor depends partly on the size and position of her baby, the size of her pelvis, her emotions, the strength of the contractions, and her outlook. Tension increases pain during labor. Virtually all women worry about how they will cope with the pain of labor and delivery. Childbirth is different for each woman and predicting the amount of pain experienced during birth and delivery can not be certain.