Umbilical vein oxytocin for the treatment of retained placenta (Release Study): a double-blind, randomised controlled trial

doi:10.1016/S0140-6736(09)61752-9

The Lancet

Volume 375, Issue 9709, 9–15 January 2010, Pages 141-147

https://doi.org/10.1016/S0140-6736(09)61752-9 Get rights and content

Summary

Background

Retained placenta is associated with post-partum haemorrhage. Meta-analysis has suggested that umbilical injection of oxytocin could increase placental expulsion without the need for a surgeon or anaesthetic. We assessed the effect of high-dose umbilical vein oxytocin as a treatment for retained placenta.

Methods

In this double-blind, placebo-controlled trial, haemodynamically stable women with a retained placenta for more than 30 min were recruited from 13 sites in the UK, Uganda, and Pakistan. 577 women were randomly assigned by a computer-generated randomisation list stratified by centre to 30 mL saline containing either 50 IU oxytocin (n=292) or 5 mL water (n=285), which was injected into the placenta through an umbilical vein catheter. All trial participants, study workers, and data handlers were masked to individual allocations. The primary outcome was the need for manual removal of the placenta. Analysis was by intention to treat. This study is registered, number ISRCTN 13204258.

Findings

The primary outcome was recorded for all participants. We detected no difference between the groups in the need for manual removal of placenta (oxytocin 179/292 [61·3%] vs placebo 177/285 [62·1%]; relative risk 0·98, 95% CI 0·87–1·12; p=0·84). The need for manual removal was higher in the UK (overall 250/361 [69%]) than in Uganda (90/190 [47%]) or Pakistan (16/26 [62%]). Adverse events did not differ between the two groups.

Interpretation

Umbilical oxytocin has no clinically significant effect on the need for manual removal for women with retained placenta.

Funding

WHO, WellBeing of Women, Pakistan Higher Education Commission.

Introduction

Retained placenta complicates 0·1–2% of deliveries.¹ The rate has increased in Europe since the 1920s and is now nearly ten times that of resource-poor settings.¹ Without prompt treatment, women are at high risk of haemorrhage. At present, treatment is by manual removal of placenta, which needs an operating theatre, a surgeon, and an anaesthetist—facilities that are often unavailable to women in resource-poor settings. As a result, this condition has a case fatality rate of nearly 10% in rural communities.¹ An effective, cheap, low technology treatment is urgently needed.²

Ultrasound studies have shown that the usual cause of retained placenta is a failure of retroplacental myometrial contraction.³ As the retroplacental myometrium contracts and shortens, the relatively inflexible placenta shears off and is expelled. The delivery of oxytocin to the retroplacental myometrium via the umbilical vein and placenta is a low-cost solution. A Cochrane review⁴ suggests that this intervention could be beneficial, even though the largest study⁵ recorded no benefit and the reduction in rates of retained placenta did not differ significantly to that obtained with expectant management (odds ratio 0·86, 95% CI 0·72–1·01).

When undiluted oxytocin is injected directly into the vein, little of the oxytocin reaches the placental bed.⁶ To be effective, at least 30 mL of solution needs to be injected through an umbilical vein catheter—a technique not used in any previous study. Furthermore, analysis of previous trials suggested that studies were more successful when high doses of oxytocin were injected.¹ This finding accords with the outcome of the Release pilot study, for which a dose of 50 IU injected through an umbilical catheter had a success rate of 66% (six of nine attempts; Weeks AD, unpublished data). The Release Study therefore aimed to assess the technique of umbilical vein oxytocin as a treatment for retained placenta, with an injection of 50 IU oxytocin diluted with 25 mL of saline.

Section snippets

Study setting and participants

This double-blind, placebo-controlled, multicentre trial was undertaken in 13 teaching hospitals in the UK (four sites), Uganda (six sites), and Pakistan (three sites), between Dec 30, 2004, and May 13, 2008. Before the start of the trial, all staff recruiting women into the trial (doctors and midwives) underwent training in the technique of umbilical injection and consent procedures.

Women who had a retained placenta for at least 30 min, who were not bleeding, and who were haemodynamically

Results

Figure 1 shows the trial profile. 577 women were recruited and randomly assigned: 292 to oxytocin and 285 to placebo. 361 (63%) were recruited in the four UK sites, 190 (33%) from Uganda, and 26 (5%) from Pakistan.

The recruitment rates were audited at the two largest sites: Liverpool Women's Hospital, UK; and Mulago Hospital, Uganda. In the Liverpool site there were 287 retained placentas between August, 2005, and August, 2006, of which 60 (21%) were recruited to the trial. Of those not

Discussion

Findings from the Release Study have shown that umbilical vein oxytocin had no clinically significant effect on the need for manual removal of the placenta or any other clinical outcome. Furthermore, the confidence intervals were narrow and did not include the 20% reduction needed for manual removal that was regarded as clinically significant before the study.

The strength of the Release Study is its high quality. It was undertaken under the stringent regulations introduced as part of the

References (22)

A Weeks
The retained placenta
Best Pract Res Clin Obstet Gynaecol
(2008)
AD Weeks et al.
The retained placenta—new insights into an old problem (editorial)
Eur J Obstet Gynecol Reprod Biol
(2002)
A Herman et al.
Dynamic ultrasonographic imaging of the third stage of labor: new perspectives into third stage mechanism
Am J Obstet Gynecol
(1993)
G Carroli et al.
Umbilical vein injection for management of retained placenta
Cochrane Database Syst Rev
(2001)
G Carroli et al.
Intra-umbilical vein injection and retained placenta: evidence from a collaborative large randomised controlled trial
Br J Obstet Gynaecol
(1998)
A Pipingas et al.
Umbilical vessel oxytocin administration for retained placenta: in-vitro study of various infusion techniques
Am J Obstet Gynecol
(1993)
A charter for ethical research in maternity care
(1997)
G Vernon et al.
Issues of informed consent for intrapartum trials: a suggested consent pathway from the experience of the Release trial [ISRCTN13204258]
Trials
(2006)
A Weeks et al.
The Release Trial: a randomised controlled trial of umbilical vein oxytocin versus placebo for the treatment of retained placenta
BJOG
(2005)
L Calderale et al.
Is intraumbilical vein administration with oxytocin useful for the treatment of retained placenta?
Giornale Italiano di Ostetricia e Ginecologia
(1994)

JM Frappell et al.

Intra-umbilical vein oxytocin in the management of retained placenta: a random, prospective, double blind, placebo controlled study

J Obstet Gynaecol

(1988)

Cited by (36)

Pharmacologic intervention for the management of retained placenta: a systematic review and meta-analysis of randomized trials
2020, American Journal of Obstetrics and Gynecology
Citation Excerpt :
The quality of included studies as evaluated by the Cochrane Collaboration’s tool for the assessment of risk of bias is presented in Table 2. Although overall bias was low, 9 studies5,11,15–17,20,23,24,26 were identified as being at indeterminate or high risk for performance bias, and 15 studies3,5,11,15–17,20–24,26,29 were at indeterminate or high risk for detection bias. Most commonly, this was secondary to a limited ability to blind providers and participants to study group allocation with possible impact on outcome reporting.
Retained placenta affects 2% to 3.3% of all vaginal deliveries and is one of the leading causes of postpartum hemorrhage worldwide. Despite the prevalence of this condition, there is limited guidance on its management.
A systematic review and meta-analysis were performed to evaluate the efficacy of pharmacologic interventions for the management of retained placenta.
PubMed, ClinicalTrials.gov, Cochrane Library, Web of Science, and Scopus were searched for full-text publications in English. Search terms included “retained placenta” AND “treatment” OR “therapy” OR “disease management” OR “Pitocin” OR “misoprostol” OR “Cytotec” OR “dinoprostone” OR “nitroglycerin” OR “carbetocin” OR “ergotamine,” with no restriction on publication dates. Only randomized controlled trials were included. The primary outcome was the need for manual extraction of the placenta or dilation and curettage. Reviewers evaluated the quality of included articles using the Cochrane Collaboration’s tool for assessing the risk of bias. Pooled risk ratios were estimated based on random- and fixed-effects analyses. Interstudy heterogeneity was considered when I²≥50%.
The literature search identified 29 randomized controlled trials that met the inclusion criteria (2682 subjects). The most commonly used agent across the studies was oxytocin administered via umbilical vein injection; there was high heterogeneity among these studies (I²=62%). Oxytocin was inferior to carbetocin (risk ratio, 1.61; 95% confidence interval, 1.03–2.52) and prostaglandins (risk ratio, 2.63; 95% confidence interval, 1.18–5.86) for the primary outcome. For oxytocin, prostaglandin agents, and nitroglycerin, there was a trend toward favoring the study drug for the primary outcome compared with control or placebo. Compared with placebo or control, estimated blood loss was lower if pharmacologic interventions were administered, with a mean difference of 121.5 mL (95% confidence interval, −185.7 to −52.3). There was no difference in postpartum hemorrhage or the need for blood transfusion between pharmacologic interventions and placebo or control.
Pooled estimates for oxytocin via umbilical vein injection, prostaglandin agents, and nitroglycerin performed favorably compared with placebo or control for the management of retained placenta. Carbetocin and prostaglandin agents were superior to oxytocin in reducing the need for manual extraction or dilation and curettage.
The Windmill technique avoids manual removal of the retained placenta—A new solution for an old problem
2017, European Journal of Obstetrics and Gynecology and Reproductive Biology
The primary objective is to assess the reduction in manual removal of placenta with the Windmill technique of placenta delivery in patients with retained placenta.
The Windmill technique involves the application of continuous 360° umbilical cord traction and rotation in such a manner as to be perpendicular to the direction of the birth canal at the level of the introitus. This rotation through 360 ° is repeated slowly with movement akin to the motion of the blades of a windmill.
We performed a 3-year retrospective case-control study at the Charité University Hospital in Berlin. Patients with a retained placenta more than 30 min following failed traditional interventions were consented and offered the Windmill technique of placenta delivery. Study cases were compared to controls where an operative manual removal of placenta was performed. Patients with suspected placenta implantation problems, uterine atony, bleeding due to vaginal tract injury and coagulation disturbances were excluded.
Over the study period 14 patients were recruited to the study arm and 17 patients were in the control group. With the Windmill technique for retained placenta, 86% (12/14, p < 0.001) of patients avoided invasive operative manual removal of the placenta in theatre.
There was a statistically significant reduction in mean blood loss (429 ml vs 724 ml, p = 0.001) and mean postoperative fall in hemoglobin values (1.3 g/dl vs 2.5 g/dl, p = 0.04). There was a reduction in the time to delivery of the placenta, antibiotic prophylaxis and use of general anesthesia.
The Windmill technique for the delivery of the retained placenta is a simple, safe, effective and easy to teach technique that reduces invasive operative manual removal of the placenta, postpartum blood loss and delay in the placenta delivery. This innovative technique can also be a lifesaving intervention especially in areas with limited or no access to operative facilities.
Initial obstetrical management of post-partum hemorrhage following vaginal delivery
2014, Journal de Gynecologie Obstetrique et Biologie de la Reproduction
L’objectif de ce travail est d’établir les étapes initiales de la prise en charge obstétricale d’une hémorragie du post-partum (HPP) après un accouchement par voie basse.
La recherche bibliographique a été effectuée à l’aide des bases de données informatiques Medline, de la Cochrane Library et par la consultation des recommandations de la HAS, le RCOG, la SOGC, l’ACOG et l’OMS.
En cas d’HPP avérée, la mise en place d’un sac de recueil est recommandée (accord professionnel). Les acteurs (sage-femme, obstétricien, équipe anesthésique) doivent être appelés simultanément dès le diagnostic (accord professionnel). Si l’HPP survient avant la délivrance, le premier geste à réaliser est une délivrance artificielle alors qu’on pratiquera une révision utérine si le placenta est expulsé (accord professionnel). Le traitement médical consiste en une injection de 5 à 10 UI d’oxytocine par voie intraveineuse lente ou intramusculaire suivie d’une perfusion d’entretien de 5 à 10 UI/h pendant 2 heures (accord professionnel). Dans certaines situations à risque ou si l’HPP persiste après les gestes endo-utérins, la filière génitale doit être examinée avec des valves (accord professionnel). Il est du ressort de chaque service de former à la gestion de l’hémorragie du post-partum les professionnels susceptibles d’y être confrontés (accord professionnel). L’étude rétrospective critique des dossiers d’HPP est à encourager (accord professionnel).
Le traitement d’une HPP à sa phase initiale implique un travail multidisciplinaire permettant d’aboutir le plus souvent à un arrêt des saignements en moins de 30 minutes (accord professionnel).
To define initial steps of obstetrical treatment of post-partum hemorrhage (PPH) after vaginal delivery.
We searched the Medline and the Cochrane Library and checked the international guidelines: HAS, RCOG, SOGC, ACOG and WHO.
In case of PPH, the use of a collecting bag is recommended (professional consensus). All the concerned professional (midwife, obstetrician, anesthesiology team) must be warned immediately (professional consensus). If placenta is retained, manual removal needs to be performed and after placental delivery, manual uterine exploration is recommended (professional consensus). At the same time, a dose of 5 or 10 IU of oxytocin must be administrated IV over at least 1 minute or directly by an intramuscular injection followed by an infusion of 5 to 10 UI/h during 2 hours (professional consensus). In some situations at risk of cervical and high vaginal laceration, the low genital tract needs to be carefully examined (professional consensus). Appropriate management of PPH has to be known by the concerned professional (professional consensus). Retrospective study of each case of PPH should be done (professional consensus).
The PPH initial treatment involves a team work that, most of times, leads to stop the bleeding in least than 30 minutes (professional consensus).
Clinical and pharmacological procedures for the prevention of postpartum haemorrhage in the third stage of labor
2014, Journal de Gynecologie Obstetrique et Biologie de la Reproduction
Décrire les méthodes de prévention clinique et pharmacologique de l’hémorragie du post-partum (HPP).
Revue de la littérature entre décembre 2004 et mars 2014 à partir des bases de données Medline, de la Cochrane Library et des recommandations internationales issues des sociétés savantes.
Accouchement voie basse : l’administration préventive d’utérotoniques est le seul moyen efficace de réduire l’incidence des HPP et l’oxytocine est le traitement à privilégier dès lors qu’il est disponible (grade A). Elle peut être administrée soit au dégagement des épaules ou rapidement après la naissance soit après la délivrance (grade B). La dose de 5 ou 10 UI peut être administrée (grade A), par voie IV ou IM (accord professionnel). En IV, l’injection doit être réalisée sur une durée d’environ une minute sauf en cas de risque cardiovasculaire avéré où la durée d’injection doit être d’au moins 5 minutes afin de limiter les effets hémodynamiques (accord professionnel). Les mesures mécaniques n’ont pas d’impact sur l’incidence des HPP. L’utilisation systématique d’un sac de recueil est laissée au choix des équipes (accord professionnel). Une perfusion d’entretien systématique par oxytocine n’est pas recommandée (accord professionnel). Accouchement par césarienne : il n’y a pas d’argument pour privilégier une technique de césarienne à une autre pour prévenir l’HPP (accord professionnel). L’hystérotomie segmentaire est recommandée (grade B). Les techniques d’agrandissement de l’hystérotomie sont laissées au choix de l’opérateur (accord professionnel). La délivrance par traction contrôlée du cordon est associée à des pertes sanguines moins importantes que la délivrance manuelle (grade B). Une injection en IV lente sur au moins une minute de 5 à 10 UI d’oxytocine est recommandée (grade A) sauf en cas de risque cardiovasculaire avéré où la durée d’injection doit être d’au moins 5 minutes afin de limiter les effets hémodynamiques (accord professionnel). Un traitement d’entretien systématique par une perfusion IV d’oxytocine peut être entrepris sans dépasser 10 UI/h (accord professionnel). La carbétocine diminue le risque d’HPP mais en l’absence d’essai de non-infériorité, l’oxytocine constitue le traitement préventif de référence pour la prévention de l’HPP pour les césariennes (accord professionnel).
To describe the clinical and pharmacological procedures for the prevention of Postpartum Haemorrhage (PPH).
We searched the Medline and the Cochrane Library (1st December 2004 to 1st March 2014) and we checked the international guidelines.
Vaginal birth: only the use of uterotonics reduces the incidence of PPH. Oxytocin is the treatment of choice if it is readily available (grade A). Oxytocin can be used either after the shoulders expulsion or rapidly after the placental delivery (grade B). A dose of 5 or 10 IU must be administrated IV over at least 1 minute or directly by an intramuscular injection (professional agreement) except in women with documented cardiovascular disease in which the duration of the IV perfusion should be over at least 5 minutes (professional agreement). Mechanical procedures have no significant impact on PPH. The decision to use a collector bag is left to the medical team (professional agreement). A systematic complementary oxytocin perfusion is not recommended (professional agreement). Caesarean delivery: There is no evidence to recommend a particular type of caesarean technique to prevent PPH (professional agreement) but a lower uterine section is recommended (grade B). All types of incision expansion may be used (professional agreement). A controlled cord traction is associated with lower blood losses than manual removal of the placenta (grade B). A dose of 5 or 10 IU can be injected (IV) over 1 minute, and over 5 minutes in women with cardiovascular disease (professional agreement). Carbetocin reduces the incidence of PPH but there is presently no inferiority study comparing oxytocin and carbetocin so that oxytocin remains the gold standard therapy to prevent PPH in C-section (professional agreement).
A randomized controlled trial on the value of misoprostol for the treatment of retained placenta in a low-resource setting
2013, International Journal of Gynecology and Obstetrics
Citation Excerpt :
The observed rate of spontaneous expulsion of the placenta between 30 and 60 minutes (60% in the misoprostol group and 67% in the placebo group) was close to the value of 56% used in the power calculation. These values are higher than those observed in another recent trial (the “Release Trial”) in which 38% of spontaneous expulsion was reported [15]. Both the present study and the Release Trial treated patients 30 minutes after delivery of the newborn.
To evaluate the efficacy and safety of misoprostol among patients with retained placenta in a low-resource setting.
A prospective, multicenter, randomized, double-blind, placebo-controlled trial was carried out in Tanzania between April 2008 and November 2011. It included patients who delivered at a gestational age of 28 weeks or more and had blood loss of 750 mL or less at 30 minutes after delivery. Sublingual misoprostol (800 μg) was compared with placebo as the primary treatment. Power analysis showed that 117 patients would be required to observe a reduction of 40% in the incidence of manual removal of the placenta (MRP; P = 0.05, 80% power), the primary outcome. The secondary outcomes were blood loss and number of blood transfusions.
Interim analysis after recruitment of 95 patients showed that incidence of MRP, total blood loss, and incidence of blood transfusions were similar in the misoprostol (MRP, 40%; blood loss, 803 mL; blood transfusion, 15%) and placebo (MRP, 33%, blood loss 787 mL, blood transfusion, 23%) groups. The trial was stopped because continuation would not alter the interim conclusion that misoprostol was ineffective.
Treatment with misoprostol was found to have no clinically significant beneficial effect among women with retained placenta.
Clinical Trial Registration: Current Controlled Trials ISRCTN16104753
Mechanisms and management of normal labour
2013, Obstetrics, Gynaecology and Reproductive Medicine

View all citing articles on Scopus

View full text

ArticlesUmbilical vein oxytocin for the treatment of retained placenta (Release Study): a double-blind, randomised controlled trial

Summary

Background

Methods

Findings

Interpretation

Funding

Introduction

Section snippets

Study setting and participants

Results

Discussion

The retained placenta

Best Pract Res Clin Obstet Gynaecol

The retained placenta—new insights into an old problem (editorial)

Eur J Obstet Gynecol Reprod Biol

Dynamic ultrasonographic imaging of the third stage of labor: new perspectives into third stage mechanism

Am J Obstet Gynecol

Umbilical vein injection for management of retained placenta

Cochrane Database Syst Rev

Intra-umbilical vein injection and retained placenta: evidence from a collaborative large randomised controlled trial

Br J Obstet Gynaecol

Umbilical vessel oxytocin administration for retained placenta: in-vitro study of various infusion techniques

Am J Obstet Gynecol

A charter for ethical research in maternity care

Issues of informed consent for intrapartum trials: a suggested consent pathway from the experience of the Release trial [ISRCTN13204258]

Trials

The Release Trial: a randomised controlled trial of umbilical vein oxytocin versus placebo for the treatment of retained placenta

BJOG

Is intraumbilical vein administration with oxytocin useful for the treatment of retained placenta?

Giornale Italiano di Ostetricia e Ginecologia

Intra-umbilical vein oxytocin in the management of retained placenta: a random, prospective, double blind, placebo controlled study

J Obstet Gynaecol

Articles
Umbilical vein oxytocin for the treatment of retained placenta (Release Study): a double-blind, randomised controlled trial