Oxytocin

(BAN, rINN)
Oxytocin Chemical formula
Synonyms: Alpha-hypophamine; Hipofamina; Ocitocina; Oksitocinas; Oksitosiini; Oksitosin; Oxitocin; Oxitocina; Oxytocine; Oxytocinum. Cys-Tyr-Ile-Gln-AsnCys-Pro-Leu-Gly-NH 2 cyclic (1→6) disulphide; [2-Leucine,7-isoleucine]vasopressin.
Cyrillic synonym: Окситоцин.

💊 Chemical information

Chemical formula: C43H66N12O12S2 = 1007.2.
CAS — 50-56-6.
ATC — H01BB02.
ATC Vet — QH01BB02.

Pharmacopoeias.

In Chin., Eur., Jpn, and US.

Ph. Eur. 6.2 (Oxytocin). A cyclic nonapeptide having the structure of the hormone produced by the posterior lobe of the pituitary that stimulates contraction of the uterus and milk ejection in receptive mammals. It is obtained by chemical synthesis and is available in the freeze-dried form as an acetate. A white or almost white, hygroscopic powder. Very soluble in water and in dilute solutions of dehydrated alcohol and of acetic acid. A 2% solution in water has a pH of 3.0 to 6.0. Store at 2° to 8° in airtight containers. Protect from light.

Ph. Eur. 6.2 (Oxytocin Concentrated Solution). A solution of oxytocin with a concentration of not less than 250 micrograms of oxytocin per mL. It may contain a suitable antimicrobial preservative. A clear colourless liquid with a pH of 3.0 to 5.0. Store at 2° to 8°. Protect from light.

USP 31

(Oxytocin). A nonapeptide hormone having the property of causing the contraction of uterine smooth muscle and of the myoepithelial cells within the mammary glands. It is prepared by synthesis or obtained from the posterior lobe of the pituitary of healthy domestic animals used for food by man. Its oxytocic activity is not less than 400 units/mg. Store in airtight containers at 2° to 8°.

💊 Units

12.5 units of oxytocin for bioassay are contained in about 21.4 micrograms of synthetic peptide (with human albumin 5 mg and citric acid) in one ampoule of the fourth International Standard (1978).

💊 Adverse Effects

Oxytocin given in high doses, or to women who are hypersensitive to it, may cause uterine hyperstimulation with hypertonic or tetanic contractions, leading to uterine rupture and soft tissue damage. Effects in the fetus include bradycardia, arrhythmias, asphyxiation, and perhaps death. Maternal deaths from severe hypertension and subarachnoid haemorrhage have occurred. Rapid intravenous injection of oxytocin has produced acute transient hypotension with flushing and reflex tachycardia. Postpartum haemorrhage, fatal afibrinogenaemia, and disseminated intravascular coagulation have been reported, but may be due to complications of labour induction rather than oxytocin itself. High doses of oxytocin infused over prolonged periods can also cause water retention leading to hyponatraemia and intoxication, which may progress to convulsions, coma, and even death. Vasopressin-like activity is more likely with oxytocin of natural origin but may occur even with the synthetic peptide. Other adverse effects include headache, nausea and vomiting, skin rashes, cardiac arrhythmias, pelvic haematoma, and anaphylactic and other hypersensitivity reactions. There are reports of neonatal jaundice and retinal haemorrhage associated with the use of oxytocin in the management of labour. Adverse effects after intranasal use of oxytocin have included nasal irritation, rhinorrhoea, lachrymation, uterine bleeding, and violent uterine contractions.

Inappropriate use.

In a 1988 comment on the misuse of oxytocin in labour,1 it was noted that statements on the management of labour were often misinterpreted as meaning that all women who failed to make adequate progress in terms of cervical dilatation should be given oxytocin. This was only true if poor progress was due to poor uterine action, and would be dangerous where there was disproportion; the decision to use oxytocin required careful assessment by an experienced obstetrician. In the previous 2 years the authors had seen one case of fractured pelvis, 2 of ruptured uterus, and 7 of cerebral palsy from fetal hypoxia, all of which were thought to be due to the ill-advised use of oxytocin to augment labour. More than a decade later the injudicious use of oxytocin during labour, with adverse outcomes including neonatal brain damage and death, continues to be reported. A review2 of obstetric malpractice claims in Sweden found that the incorrect use of oxytocin was obvious in 37 of 54 cases; often, the oxytocin infusion had been increased despite a nonreassuring fetal heart-rate pattern with or without overly frequent uterine contractions, or fetal monitoring was inadequate and hence fetal distress not recognised. For reference to haemorrhage and to neonatal hyperbilirubinaemia occurring after an oxytocin challenge test, see under Uses and Administration, below.
1. Taylor RW, Taylor M. Misuse of oxytocin in labour. Lancet 1988; i: 352
2. Jonsson M, et al. Analysis of malpractice claims with a focus on oxytocin use in labour. Acta Obstet Gynecol Scand 2007; 86: 315–19.

Neonatal jaundice.

Analysis of neonatal jaundice in 12 461 single births confirmed a higher incidence of jaundice in offspring of mothers given oxytocin, independent of gestational age at birth, sex, race, epidural analgesia, method of delivery, and birth-weight, which were also associated with jaundice.1 A later review2 of 12 023 single births also found some of these factors to be associated with neonatal hyperbilirubinaemia, but not epidural analgesia or the use of oxytocin. Another smaller population study3 also concluded that oxytocin was not significantly related to neonatal jaundice. In a total of 90 infants born to mothers after oxytocin-induced labour in 2 studies,4,5 haematological disturbances were noted. These included erythrocyte fragility or reduction in erythrocyte deformability, hyponatraemia, hypoosmolality, and an increase in serum-bilirubin concentration. Glucose injection, used as a vehicle for oxytocin may have further aggravated these changes.5 A comparison6 of women who received oxytocin infusion in either glucose 5% or sodium chloride 0.9% found the use of glucose to be associated with more cases of hyponatraemia in cord plasma, and neonatal hyperbilirubinaemia. In contrast, another study7 found no difference between these diluents, but did report that neonatal bilirubin concentrations were higher when oxytocin had been used for augmentation of labour, compared with labour induction. See also under Oxytocin Challenge Test in Uses and Administration, below.
1. Friedman L, et al. Factors influencing the incidence of neonatal jaundice. BMJ 1978; 1: 1235–7
2. Linn S, et al. Epidemiology of neonatal hyperbilirubinemia. Pediatrics 1985; 75: 770–4
3. Seidman DS, et al. Predicting the risk of jaundice in fullterm healthy newborns: a prospective population-based study. J Perinatol 1999; 19: 564–7
4. Buchan PC. Pathogenesis of neonatal hyperbilirubinaemia after induction of labour with oxytocin. BMJ 1979; 2: 1255–7
5. Singhi S, Singh M. Pathogenesis of oxytocin-induced neonatal hyperbilirubinaemia. Arch Dis Child 1979; 54: 400–2
6. Omigbodun AO, et al. Effect of saline and glucose infusions of oxytocin on neonatal bilirubin levels. Int J Gynecol Obstet 1993; 40: 235–9
7. Oral E, et al. Oxytocin infusion in labor: the effect different indications and the use of different diluents on neonatal bilirubin levels. Arch Gynecol Obstet 2003; 267: 117–20.

Water intoxication.

Oxytocin-induced water intoxication is most likely to arise as a result of prolonged attempts to empty the uterus in missed abortion or mid-trimester termination of pregnancy, but it has also been described after oxytocin infusion in other conditions including induction of labour.1 Irrespective of the oxytocin concentration, patients in virtually all the reported cases have received more than 3.5 litres of infused fluid. Convulsions and somnolence associated with hyponatraemia have also been reported in a patient who was drinking more than 5 litres of herbal tea daily while using intranasal oxytocin 8 times or more daily.2 Another factor contributing to hyponatraemia is the antidiuretic effect of the pethidine and morphine commonly used for analgesia with oxytocin infusions. Water intoxication usually presents with fits and loss of consciousness but in some cases there may be preceding signs such as raised venous pressure, bounding pulse, and tachycardia. Diagnosis is confirmed by profound hyponatraemia; the mechanism appears to be more complex than simply haemodilution by the infused water. Treatment consists of controlling convulsions and maintaining an airway; oxytocin infusion must be stopped and isotonic, or even hypertonic, saline may be infused. Diuresis may then be assisted with furosemide. The prime objective, however, should be prevention; no patient should receive more than 3 litres of fluid containing oxytocin, and a careful fluid balance record is essential.
1. Feeney JG. Water intoxication and oxytocin. BMJ 1982; 285: 243
2. Mayer-Hubner B. Pseudotumour cerebri from intranasal oxytocin and excessive fluid intake. Lancet 1996; 347: 623.

💊 Precautions

Oxytocin should not be given where spontaneous labour or vaginal delivery are liable to harm either the mother or the fetus. This includes significant cephalopelvic disproportion or unfavourable presentation of the fetus, placenta praevia or vasa praevia, placental abruption, cord presentation or prolapse, mechanical obstruction to delivery, fetal distress or hypertonic uterine contractions. It should not be used where there is a predisposition to uterine rupture, as in multiple pregnancy or high parity, polyhydramnios, or the presence of a uterine scar from previous caesarean section. Oxytocin should not be used for prolonged periods in resistant uterine inertia, severe pre-eclampsia, or severe cardiovascular disorders. When given for induction or enhancement of labour particular care is needed in borderline cephalopelvic disproportion, less severe degrees of cardiovascular disease, and in patients over 35 years of age or with other risk factors. Careful monitoring of fetal heart rate and uterine motility is essential so that dosage of oxytocin can be adjusted to individual response; the drug should be given by intravenous infusion, preferably by means of an infusion pump. Infusion should be stopped immediately if fetal distress or uterine hyperactivity occur. Over-vigorous labour should be avoided in cases of intra-uterine fetal death, or where there is meconiumstained amniotic fluid, because there is a risk of amniotic fluid embolism. The risk of water intoxication should be borne in mind, particularly when high doses of oxytocin are given over a long time. Infusion volumes should be kept low, and in such circumstances an electrolyte-based infusion fluid should be used rather than glucose solution. Fluid intake by mouth should be restricted and a fluid balance chart maintained; serum electrolytes should be measured if electrolyte imbalance is suspected.

Oxytocin challenge test.

For the suggestion that oxytocin challenge testing should be used with caution in women whose offspring might be at risk of hyperbilirubinaemia, see under Uses and Administration, below.

💊 Interactions

Oxytocin may enhance the vasopressor effects of sympathomimetics. Some inhalational anaesthetics, such as cyclopropane or halothane, may enhance the hypotensive effect of oxytocin and reduce its oxytocic effect; cardiac arrhythmias may occur. Prostaglandins and oxytocin may potentiate the effects of each other on the uterus; the UK licensed product information for oxytocin states that it should not be started for 6 hours after use of vaginal prostaglandins.

💊 Pharmacokinetics

Oxytocin undergoes enzymatic destruction in the gastrointestinal tract but it is rapidly absorbed from the mucous membranes when given intranasally. It is metabolised by the liver and kidneys with a plasma halflife of only a few minutes. Only small amounts are excreted unchanged in the urine.
1. Seitchik J, et al. Oxytocin augmentation of dysfunctional labor IV: oxytocin pharmacokinetics. Am J Obstet Gynecol 1984; 150: 225–8
2. Perry RL, et al. The pharmacokinetics of oxytocin as they apply to labor induction. Am J Obstet Gynecol 1996; 174: 1590–3.

💊 Uses and Administration

Oxytocin is a cyclic nonapeptide secreted by the hypothalamus and stored in the posterior lobe of the pituitary gland. It may be prepared from the gland of mammals or by synthesis. Oxytocin causes contraction of the uterus, the effect increasing with the duration of pregnancy due to proliferation of oxytocin receptors. Small doses increase the tone and amplitude of the uterine contractions; large or repeated doses result in tetany. Oxytocin also stimulates the smooth muscle associated with the secretory epithelium of the lactating breast causing the ejection of milk but having no direct effect on milk secretion. It has a weak antidiuretic action. Oxytocin is used for the induction and augmentation of labour, to control postpartum bleeding and uterine hypotonicity in the third stage of labour, and to promote lactation in cases of faulty milk ejection. It is also used in missed abortions, but other measures may be preferred. For the induction or augmentation of labour (below) oxytocin may be given by slow intravenous infusion preferably by means of an infusion pump. A solution containing 5 units in 500 mL of a physiological electrolyte solution such as sodium chloride 0.9% has been recommended but more concentrated solutions may be given via infusion pump, and current UK guidelines suggest 10 or 30 units in 500 mL of diluent. Infusion is begun at a recommended initial rate of 1 to 2 milliunits/minute and then gradually increased at intervals of at least 30 minutes, until a maximum of 3 or 4 contractions are occurring every 10 minutes. A rate of up to 6 milliunits/minute is reported to produce plasma oxytocin concentrations comparable to those in natural labour, and 12 milliunits/minute is usually the most that is needed but doses of up to 20 milliunits/minute or more may be required. UK guidelines suggest that 32 milliunits/minute should not be exceeded, and no more than a total of 5 units should be given in 1 day. Oxytocin should not be started for 6 hours after vaginal prostaglandins have been given. Fetal heart rate and uterine contractions should be monitored continuously. Once labour is progressing, oxytocin infusion may be gradually withdrawn. For the treatment and prevention of postpartum haemorrhage (below) oxytocin may be given by slow intravenous injection in a dose of 5 units; this may be followed in severe cases by intravenous infusion of 5 to 20 units in 500 mL of a suitable non-hydrating diluent. The BNF suggests that in the treatment of uterine bleeding, higher doses may also be considered: a single dose of 10 units by slow intravenous injection may be used, followed if necessary by an infusion containing up to 30 units in 500 mL. A single dose of 5 units by slow intravenous injection has also been given during caesarean section, immediately after delivery of the child. An alternative for the prophylaxis of postpartum haemorrhage in the routine management of the third stage of labour is the intramuscular injection of oxytocin 5 units with ergometrine maleate 500 micrograms after delivery of the anterior shoulder, or, at the latest, immediately after delivery of the infant; the BNF suggests a single intramuscular dose of oxytocin 10 units used alone if ergometrine is contra-indicated. In the USA a dose of 10 units of oxytocin, by intravenous infusion at a rate of 20 to 40 milliunits/minute, or as an intramuscular injection, has been recommended for treatment of postpartum haemorrhage. In missed abortion a suggested dose in the UK is 5 units by slow intravenous injection, followed if necessary by intravenous infusion at a rate of 20 to 40 milliunits/minute or higher. Oxytocin nasal spray is used to facilitate lactation; a dose of one spray, delivering 4 units, into one nostril 5 minutes before suckling has been used. However, evidence for its efficacy is limited and there is a danger that the mother may become dependent upon its action; such usage is not generally recommended. An oxytocin challenge test (below) has been used to evaluate fetal distress in pregnant patients at high risk. Synthetic derivatives of oxytocin such as demoxytocin have been used similarly.

Labour induction and augmentation.

There have been numerous studies on the dosage of oxytocin required to induce or augment labour. Various dosage regimens have been tried, and studies have reported using initial doses ranging from 0.5 to 6 milliunits/minute, dose increases of 1 to 6 milliunits/minute, and intervals between increases of 15 to 40 minutes.1 Higher doses and shorter intervals between increases can shorten labour and reduce rates of intra-amniotic infection and caesarean delivery, but result in more uterine hyperstimulation and emergency caesarean deliveries for fetal distress.1 Lowdose regimens are now generally advocated; for example, UK guidelines2 favour a starting dose of 1 to 2 milliunits/minute, increased at intervals of 30 minutes, and titrated against contractions to a maximum of 32 milliunits/minute. WHO3 suggests a starting dose of 2.5 milliunits/minute, increased at intervals of 30 minutes, and titrated against contractions to a maximum of 60 milliunits/minute. However, it has been pointed out that no one regimen has been clearly proved superior.1,4,5
1. Stubbs TM. Oxytocin for labor induction. Clin Obstet Gynecol 2000; 43: 489–94
2. Royal College of Obstetricians and Gynaecologists. Induction of labour: evidence-based clinical guideline number 9 (issued June 2001). Available at: http://www.nice.org.uk/nicemedia/pdf/ inductionoflabourrcogrep.pdf (accessed 30/06/08
3. Department of Reproductive Health and Research. Induction and augmentation of labour. In: WHO. Managing complications in pregnancy and childbirth: a guide for midwives and doctors. Geneva: WHO, 2003: P17–P26. Also available at: http:// www.who.int/reproductive-health/impac/Procedures/ Induction_P17_P25.html (accessed 30/06/08
4. Patka JH, et al. High- versus low-dose oxytocin for augmentation or induction of labor. Ann Pharmacother 2005; 39: 95–101
5. Smith JG, Merrill DC. Oxytocin for induction of labor. Clin Obstet Gynecol 2006; 49: 594–608.

Oxytocin challenge test.

The oxytocin challenge test (OCT) is designed to detect placental insufficiency, and identify fetuses at risk of still-birth or complications during labour. In a study, it was performed on 399 occasions in 305 women with pregnancies at risk and a gestational age of 36 weeks or more.1 Oxytocin 1 milliunit/minute was given by infusion pump and increased every 5 to 10 minutes until a contraction rate of 3 per 10 minutes was achieved. Less than 10% of late or variable decelerations of fetal heart rate (FHR) was judged negative; 10 to 29% was judged equivocal; and 30% or more was judged positive. The finding of a positive or equivocal response to the OCT was considered a prediction of decelerations of the FHR during parturition, though the type of risk might vary. After 100 OCTs in 90 pregnant women considered at risk2 it was concluded that a negative result is a reliable test of fetal well-being which should encourage obstetricians to await spontaneous onset of labour in preference to intervention. However, there have been reports of fetal death occurring despite a negative response to the OCT.3-5Another study6 found that in 239 women with an unequivocal OCT result, a negative response was a reliable test for a good outcome, but that a positive result was not a reliable predictor of poor outcome. Adverse effects associated with the OCT have included haemorrhage occurring in a patient after the second of two tests (the patient was found to have a major placenta praevia)7 and neonatal hyperbilirubinaemia.8 The latter effect led to the suggestion that the OCT should be used with caution in women whose babies might be at risk from hyperbilirubinaemia.
1. Schulman H, et al. Quantitative analysis in the oxytocin challenge test. Am J Obstet Gynecol 1977; 129: 239–44
2. Sellappah S, Wagman H. Oxytocin challenge test as an out patient procedure. Br J Clin Pract 1984; 38: 255–8
3. Marcum RG. False negative oxytocin challenge test. Am J Obstet Gynecol 1977; 127: 894
4. Lorenz RP, Pagano JS. A case of intrauterine fetal death after a negative oxytocin challenge test. Am J Obstet Gynecol 1978; 130: 232
5. Dittman R, Belcher J. False-negative oxytocin challenge test. N Engl J Med 1978; 298: 56.
6. Ocak V, et al. The predictive value of fetal heart rate monitoring: a retrospective analysis of 2165 high-risk pregnancies. Eur J Obstet Gynecol Reprod Biol 1992; 44: 53–8
7. Ng KH, Wong WP. Risk of haemorrhage in oxytocin stress test. BMJ 1976; 2: 698–9
8. Peleg D, Goldman JA. Oxytocin challenge test and neonatal hyperbilirubinaemia. Lancet 1976; ii: 1026.

Postpartum haemorrhage.

Oxytocin is used for the prophylaxis and treatment of postpartum haemorrhage. In the active management of the third stage of labour, the combination of oxytocin and ergometrine may be associated with a small reduction in the risk of postpartum haemorrhage compared with oxytocin alone, but a higher incidence of nausea, vomiting, and hypertension.

Retained placenta.

Oxytocin injected into the vein of the umbilical cord has been used to assist the removal of retained placenta. A meta-analysis1 of 12 studies found evidence that oxytocin reduced the incidence of manual removal of the retained placenta, although there was no apparent benefit in terms of other measures including blood loss, curettage, and infection.
1. Carroli G, Bergel E. Umbilical vein injection for management of retained placenta. Available in The Cochrane Database of Systematic Reviews; Issu
4. Chichester: John Wiley; 2001 (accessed 30/06/08).

💊 Preparations

BP 2008: Ergometrine and Oxytocin Injection; Oxytocin Injection; USP 31: Oxytocin Injection; Oxytocin Nasal Solution.

Proprietary Preparations

Arg.: Hipofisina; Syntocinon; Veracuril; Austral.: Syntocinon; Austria: Syntocinon; Belg.: Syntocinon; Braz.: Naox; Orastina; Oxiton; Syntocinon; Chile: Syntocinon; Denm.: Syntocinon; Fin.: Syntocinon; Fr.: Syntocinon; Ger.: Orasthin†; Syntocinon; Hong Kong: Syntocinon; India: Gynotocin; Pitocin; Syntocinon; Indon.: Induxin; Pitogin; Piton-S; Syntocinon; Irl.: Syntocinon; Ital.: Syntocinon; Malaysia: Syntocinon; Mex.: Oxitopisa; Syntocinon; Xitocin; Neth.: Piton-S†; Syntocinon; Norw.: Syntocinon; NZ: Syntocinon; Philipp.: Estima; Fetusin; NeOxyn; Obcin; Oxitone; Oxtimon; Solvoxine; Syntocinon; Tranoxy; Port.: Syntocinon; S.Afr.: Syntocinon; Singapore: Syntocinon; Spain: Syntocinon; Swed.: Syntocinon; Switz.: Syntocinon; Turk.: Postuitrin; Synpitan; UK: Syntocinon; USA: Pitocin; Venez.: Pitocin†; Syntocinon. Multi-ingredient: Austral.: Syntometrine; Ger.: Syntometrin†; Hong Kong: Syntometrine†; Irl.: Syntometrine; Malaysia: Syntometrine; NZ: Syntometrine; S.Afr.: Syntometrine; UK: Syntometrine.
Published November 08, 2018.