Oxytocin and Its Congeners in Obstetrics Practice: An Update on Carbetocin

Abstract

There are no standardised recommendations for the use of oxytocin in obstetric indications. To prevent postpartum haemorrhage (PPH), the routine administration of oxytocin is standard practice. Failure of prophylactic therapy with oxytocin occurs commonly, necessitating the use of further oxytocin or other treatments to maintain haemodynamic stability. Oxytocin has its limitations as it requires cold storage and transport, and in low-resource settings, the cold chain is not commonly available. By modifying the oxytocin molecule, its half-life has been prolonged and its enzymatic degradation reduced. The modified molecule is named carbetocin. Heat-stable carbetocin is a promising alternative to oxytocin, which can overcome the persistent problems with oxytocin quality as it does not require a cold chain for storage and transport.

1. Introduction

Oxytocin is used for induction of labor, augmentation of labor, and to reduce the risk of postpartum haemorrhage (PPH) [1]. Optimal management of oxytocin infusion requires effective interprofessional communication and collaboration. Oxytocin is a peptide generated from the hypothalamus in a pulsatile manner and secreted through the posterior pituitary, stimulating myometrial cells in the uterus and the myoepithelial cells around the mammary alveoli [2]. Oxytocin has a central role in labour. The oxytocin levels gradually increase during pregnancy, and the oxytocin receptors in the uterine muscles also gradually increase in number and become more sensitive to oxytocin in late pregnancy [3, 4]. During the labour initiation, there are fluctuations in the levels of oestrogen and progesterone alongwith changes in their receptors distribution. The effacement of the cervix happens during first stage of labour.

The uterus is supplied by the autonomic nervous system, which has a significant effect on the labour. Parasympathetic stimulation enhances contractility and circulation to the uterus and fetus, while sympathetic activation triggers ineffective contractions and inhibits uterine circulation [5]. Surroundings perceived as safe, familiar and friendly (e.g. a woman’s own home) and a supportive environment (e.g. one to one nursing care) are likely to increase oxytocin release by parasympathetic stimulation and facilitate the progression of labour, as well as lead to the beneficial central actions caused by oxytocin.

1.1 Induction of labour with oxytocin

Induction of labour (IOL) with oxytocin is the artificial initiation of uterine contractions which leads to progressive effacement and dilatation of the uterine cervix, and descent of the fetus. While IOL with oxytocin alone is indicated in women with ruptured membranes, it is not recommended in women with intact membranes [6]. The objective of this intervention is to give the minimum effective dose until optimal myometrial contractions are achieved. Oxytocin can be added to normal saline for infusion, but large volumes of oxytocin infusion must not be administered due to the risk of hyponatremia. Oxytocin infusion has a half-life of 30 minutes, and by 40 minutes achieves steady-state levels. Therefore, oxytocin dose is increased at intervals of about 40 minutes [7]. There is no evidence to show whether a low-dose or a shigh-dose oxytocin regimens are optimal, and this compounds the confusion in clinical practice [5].

Oxytocin has very variable effects in terms of uterine contractions and fetal hypoxia in different subjects, which results in unpredictability of response in clinical setting. During increments, a close monitoring of labour progress becomes essential, anticipating that adverse effects of oxytocin on uterine activity and the fetus are exclusively dose-related [5]. The attention must be on uterine contractions and the fetus rather than the dosage of oxytocin.

Synthetic oxytocin is frequently used for IOL [5]. But its use has not been standardised and reported to be used improperly. Desirable effects on the brain that are demonstrated with physiologic oxytocin are absent with exogenous oxytocin infusions. It is advised that a protocol and algorithms with oxytocin, needs to be followed [5]. It is recommended by various authors to have an interval of 40 minutes between increments while observing the uterine contractions and the fetus closely. The use of oxytocin needs continuous supervision [5].

1.2 Oxytocics (also known as uterotonics)

These are agents that stimulate the myometrium or promote uterine contractions and hence increase the tone of the uterus. Uterotonics are used to induce or augment labour to stimulate delivery of the placenta and to prevent or treat PPH. Common uterotonic agents are synthetic oxytocin, synthetic oxytocin analogue carbetocin, methylergometrine, carboprost and misoprostol.

1.3 Postpartum haemorrhage

PPH is the leading cause of maternal morbidity and mortality globally, with atony of the uterus responsible for up to 80% of cases, thereby being the single most common cause [8, 9]. As is clear from Figure 1, retraction of uterine muscle fibres clamps the blood vessels and helps to stop bleeding postpartum. Therefore, uterine atony will result in clinical PPH. Figure 2 shows why it is normal to expect bleeding postpartum, as placental site has a large surface area with cut blood vessels.

Figure 1.

Uterine contractions are essential to control bleeding after childbirth.

Figure 2.

Placental separation results in large wound that bleeds after childbirth.

Conventionally, PPH is defined as blood loss of at least 500 ml after vaginal delivery and blood loss of >1000 ml after Caesarean section [10]. The American College of Obstetricians and Gynaecologists (ACOG) revitalise initiative defined PPH as cumulative blood loss of >1000 ml (irrespective of the route of delivery) or blood loss accompanied by signs or symptoms of hypovolemia within 24 hours after the birth process.

It contributes greatly to significant maternal morbidity, long-term disability, and many other severe maternal conditions, which involve significant blood loss. These include anaemia, cardiac failure, and sepsis.

Carbetocin is a drug that precludes for additional uterotonic drugs in women at increased risk of PPH. Better trials are underway to evaluate carbetocin in preventing PPH in high-risk women [11].

1.4 Therapies for PPH

Oxytocin is the current standard drug for the prevention of PPH. Oxytocin availability in developing nations is limited by the requirement for temperature-regulated storage and administration by skilled nursing staff [12]. PPH prophylaxis with oxytocin fails commonly, necessitating the use of further oxytocin or other treatments to maintain stability [13]. The efficacy of uterotonics in causing uterine contractions to prevent haemorrhage can be impaired by improper storage. Where access to sustained cold-chain is unavailable, the efficacy of oxytocin cannot be ascertained as it is susceptible to heat [14, 15]. Being a short half-life drug, a continuous IV infusion is necessary for a sustained uterotonic effect. Boluses of oxytocin are associated with adverse effects like hypotension, nausea, vomiting, dysrhythmias, ST-T changes, pulmonary oedema and severe water intoxication with convulsions. Miscellaneous uterotonics include ergometrine/methylergometrine, and misoprostol. Ergometrine degrades on exposure to heat or light. Misoprostol degrades rapidly when exposed to moisture [16]. When degraded, the level of active ingredient is reduced, resulting in a loss of efficacy. The classication of uterotonic drugs is given in Figure 3.

Figure 3.

Classification of uterotonic drugs.

2. Carbetocin: a therapy advance for the prevention of postpartum haemorrhage

Carbetocin is a novel drug, developed as long-acting congener of oxytocin.

It has shown similar pharmacologic traits as oxytocin, but around 10-times longer half-life than oxytocin. Carbetocin does not show variation in dose response, it lacks receptor desensitisation, and thus is an advance over oxytocin in this space [17].

As shown in Figure 4, the amino group and the disulfide bond, which were altered to create carbetocin, are indicated. The amino group was removed and the sulphur atom was replaced by a carba group.

Figure 4.

Modification of oxytocin molecule.

Its long uterine activity is beneficial in the management of the third stage of labour. The side-effect profile of carbetocin is better than oxytocin and other uterotonics. Heat-stable carbetocin has demonstrated to maintain stability for 36 months at 30°C and 75% relative humidity [18].

2.1 Pharmacological properties of carbetocin

As a novel analogue of oxytocin, carbetocin has uterotonic activity by binding to oxytocin receptors on the myometrial cells. The main disadvantage of oxytocin is its short half-life (3–17 minutes) [19]. By modifying the oxytocin molecule, its half-life has been prolonged. Because of alterations, carbetocin has more pronounced pharmacological effects [20].

Carbetocin is a synthetic oxytocin analogue, with a potency of about one-tenth that of oxytocin [21]. Its plasma half-life is approximately 40 minutes, which is about 10 times longer than that of oxytocin [22]. It causes an increase in the intracellular concentration of calcium that promotes uterine contractility, via inositol phosphates signalling pathways [23].

The onset of action is rapid, with a firm contraction being obtained within 2 minutes in around 90% of patients. The duration of action of a single iv injection is about 1 hour, and approximately 2 hours when given as an IM injection. Carbetocin induces a prolonged uterine response, in parameters like amplitude and frequency of contractions.

Adverse reactions: The adverse reactions are the same as those with the use of oxytocin. Carbetocin was associated with nausea, abdominal pain, pruritus, flushing, and tremor (11%) [24].

2.2 Carbetocin to prevent haemorrhage after vaginal birth

Widmer et al. enrolled women across 23 sites in a randomised trial comparing IM injections of heat-stable carbetocin with oxytocin after vaginal birth [25]. The endpoints included the proportion of patients with blood loss of 500 ml or the additional uterotonics use, and patients with blood loss of 1000 ml. The authors concluded that carbetocin was non-inferior to oxytocin.

2.3 Carbetocin to prevent haemorrhage after caesarean delivery

This study enrolled women at risk of PPH after Caesarean section [26]. More than 1200 women were included. Around 750 received oxytocin first and around 480 received carbetocin first. It was demonstrated that compared with oxytocin, carbetocin reduced the need for uterotonics or interventions in high-risk patients.

2.4 Agents for in PPH prophylaxis meta-analysis

The uterotonics use during the third stage of labour for preventing PPH were compared with a control groups. The study demonstrated that ergometrine plus oxytocin combination, carbetocin, and misoprostol plus oxytocin combination were most efficacious in evaluated parameters. Carbetocin showed the best side-effect profile among the studied groups [27, 28].

The WHO did not include carbetocin in its 2012 guideline for PPH [29]. But in its update published in 2018, it has included carbetocin to the Essential Medicines List [30]. Carbetocin is recommended for the prevention of bleeding after all births when oxytocin is unavailable or its quality cannot be assured. Carbetocin remains effective at warm temperatures [31], while oxytocin has to bestored and transported at 2°C–8°C.

2.5 Carbetocin in emergency caesarean delivery

Patients were randomised to an iv injection of oxytocin or carbetocin after Caesarean delivery. Add-on uterotonics use was lower in the carbetocin group. Carbetocin was superior to oxytocin in evaluated parameters by 12% [32].

2.6 Dose and method of administration of carbetocin

• CARBETOCIN should be administered as a single dose only.

• Caesarean section: A single dose of 100 μg (1 ml) of CARBETOCIN injection should be administered iv as a bolus. CARBETOCIN can be administered either before or after delivery of the placenta.

• Vaginal delivery: A single dose of 100 μg (1 ml) of CARBETOCIN injection should be administered after delivery of the infant as an im or iv bolus injection slowly over 1 minute.

3. Miscellaneous uterotonics

3.1 Methyl-ergometrine

It is a vasoconstrictor and induces uterine contraction. It runs the risk of hypertension, coronary artery spasm and bronchospasm. Thus, it should not be used in concomitant cardiopulmonary diseases and pre-eclampsia. It may be used when the response to oxytocin is insufficient.

3.2 Carboprost

Carboprost is used as IM injection in 250 μg doses; can be repeated up to eight such doses (i.e. maximum 2 mg). Side effects are nausea, vomiting, diarrhoea, fever, bronchospasm and hypertension. It is used as a last resort. It should also be used with caution in active hepatic or cardiovascular disease.

3.3 Misoprostol

This prostaglandin analogue can replace oxytocin, if not available. It is used at a dose of 600 μg orally or sublingually in PPH. Diarrhoea, shivering, pyrexia and headache are some of the side effects. The drug is second-line agent when methyl-ergometrine is contraindicated such as in preeclampsia.

4. Conclusion

Failure of prophylaxis with oxytocin in PPH (as demonstrated by the need for a rescue uterotonic) occurs commonly, necessitating the use of further oxytocin or other treatments to maintain haemodynamic stability. Uterotonics include ergometrine/methylergometrine & misoprostol, as shown in Figure 3. The major disadvantages of oxytocin are its short half-life (3–17 minutes) and its requirements for cold storage and transport. By modifying the oxytocin molecule, its half-life has been prolonged and its enzymatic degradation reduced. Carbetocin has more pronounced pharmacological effects. Its main advantage over oxytocin is a longer uterotonic activity, which obviates the need of a continuous infusion and has a standardised dosing of single injection recommendation, carbetocin can address the variations in dosing regimen as is with oxytocin.

The posology of carbetocin has tremendous benefit for the patient. Carbetocin selectively binds to oxytocin receptors present on the myometrium of the uterus, resulting in rhythmic contractions, increased frequency of existing contractions, and increased uterine tone. Another feature to note is that carbetocin selectively has a pronounced effect on the pregnant and immediate postpartum uterus.

Points to Remember

• Oxytocin is limited by the needs for cold storage and transport, and especially in low-income nations, this hampers its quality as there is a lack of such facilities.

• Because of its heat stability, carbetocin is an effective alternative in such a scenario.

• A more uniform dosing regimen of single injection, carbetocin can address the variations in the dosing (cf oxytocin).

• Carbetocin, is added to WHO Essential Medicines List for the prevention of excessive bleeding after childbirth.

• Carbetocin is a new paradigm in the prophylaxis of uterine atony.

Acknowledgments

Authors would like to express sincere gratitude to their mentors and esteemed teachers Dr. SC Chopra and Dr. (Mrs) Chanchal Gupta, former Heads, Department of Pharmacology of Dayanand Medical College, Ludhiana for providing the necessary support in getting the required information for this study. This chapter is dedicated to the faculty & staff of Department of Pharmacology of Dayanand Medical College, Ludhiana and the executives & staff of Uniza Healthcare LLP, Ahmedabad.

Competing interests

Author has declared that no competing interests exist.

Abbreviations

PPH	postpartum haemorrhage
IOL	induction of labour
ACOG	American College of Obstetricians and Gynaecologists
iv	intravenous
IM	intramuscular