AMTSL trial

ACTIVE MANAGEMENT OF THE THIRD

STAGE OF LABOUR WITHOUT
CONTROLLED CORD TRACTION: A
RANDOMIZED NON-INFERIORITY
CONTROLLED TRIAL
HRP Trial: A65554
Justus Hofmeyr, Presented on behalf of the
AMTSL trial Group

Rationale

AMTSL reduces PPH by over 60%

AMTSL components are:
administration of oxytocin,
delayed cord clamping,
controlled cord traction (CCT), and
uterine massage.
Previous WHO guidelines recommended AMTSL, but
Acknowledging the lack of evidence on the effectiveness of
some individual components.
CCT requires manual skills, carries risks (uterine inversion)
If CCT does not have a meaningful impact on blood loss,
then it could be omitted and a simplified package focusing
mainly on the uterotonic could be recommended.

Uterine inversion being reduced with saline

(OSullivans method)

Uterine replacement complete

Systematic review CCT vs no CCT

Outcome: Blood loss>1000ml

WHO AMTSL Trial: Objective

Primary objective: to determine whether

the simplified package of oxytocin 10 IU
IM/IV, without CCT,
is not less effective than the full AMTSL
package
with regard to reducing blood loss 1000
ml in the third stage of labour.

Hypothesis: non-inferiority within a risk

ratio margin of 1.30.

Study design

Hospital-based, multicentre, randomized, non-inferiority controlled

trial.
Participating countries: Argentina, Egypt, India, Kenya, the Philippines,
South Africa, Thailand, Uganda. (16 hospitals, 2 PHC centres)
Sample size ~ 25,000 women
Participants:
- inclusion criteria: women expecting to deliver vaginally
- exclusion criteria: advanced first stage of labour, women too
distressed
to give consent, minors without guardian, planned
caesarean section,
multiple pregnancies, birth considered abortion.
Interventions:
- experimental arm: "simplified package" (Placental delivery
WITHOUT controlled cord traction. i.e. maternal effort, gravidity)
- control arm: "full package" (Placental delivery WITH controlled
cord traction )

Outcome measures

Primary outcome
Severe PPH (blood loss 1000 ml or
more) at one hour or up to 2 hours
for women who continue to bleed
beyond one hour
Secondary outcomes
Blood loss 500 ml or more
Blood transfusion
Additional uterotonics
Maternal death
Manual removal of the placenta
Additional surgical procedures
Maternal death or severe morbidity
Initiation of breastfeeding

Characteristics of women at trial entry

and delivery (mITT population)
Simplified package

Full AMTSL package

n/N* (%)

n/N (%)

253 (56)

253 (56)

Primigravida

5362/11823 (454)

5476/11799 (464)

Gestational age 37 weeks

10713/11815 (907)

10620/11797 (903)

Labour induced/augmented

5923/11815 (501)

5796/11795 (491)

Spontaneous cephalic
vaginal delivery

11266/11818 (953)

11240/11795 (953)

Perineal trauma (episiotomy

or tear requiring suture)

7667/11816 (649)

7616/11791 (646)

3069 (538)

3054 (544)

11661/11818 (987)

11639/11797 (987)

Age (mean, SD)

Birth weight (mean, SD)

Baby alive

Adherence to trial interventions and final delivery

mode of the placenta
Simplified package

Full AMTSL package

n/N

n/N

Adherence
Cord management according to the
protocol*
Oxytocin administered

11253/11861 949

11406/11820 965

11779/11861 993

11751/11820 994

Delayed cord clamping and cutting

9321/11861

9242/11820

782

708

786

Final delivery mode of the placenta**

Hands off/Maternal effort

10668/11776 906

833/11763

CCT

731/11777

621

11389/11766 968

Umbilical vein injection

10/11814

008

10/11794

008

Manual removal of the placenta

153/11814

13

105/11794

089

Curettage

165/11814

14

98/11794

083

Hysterectomy

2/11814

002

6/11794

005

Left in situ

3/11813

003

7/11792

006

Placenta and baby delivered

simultaneously

29/11814

025

23/11797

019

*Hands-off in the simplified package and CCT in the full package in the first 30 minutes
** More than one intervention may have been used for any one patient

Trial outcomes
Simplified package

Full AMTSL package

Risk ratio (95% CI)

% Risk difference
(95% CI)

Outcome
n/N

n/N

Blood loss 1000ml

239/11621

188

017 (-019 to 053)

109 (091 to 131)

Blood loss 500ml

1598/11621 1375 1493/11621 1285

090 (003 to 178)

107 (100 to 114)

Blood loss (ml)(mean difference)

282 (11621)

108 (47 to 169)

Additional uterotonics

2434/11802 2062 2390/11783 2028

206 219/11621

271 (11621)

034 (-069 to 137)

102 (097 to 107)

Blood transfusion

62/11814

052

55/11790

047

006 (-012 to 024)

112 (078 to 162)

Manual removal of placenta

153/11814

130 105/11794

089

040 (014 to 067)

145 (114 to 186)

Third stage duration (min.)(mean

difference)
Maternal death

126 (11662)

61 (11648)

65 (62 to 68)

2/11818

002

1/11798

001

001 (-002 to 004)

200 (018 to 220)

Additional surgical procedures

2/11814

002

9/11790

008

-006 (-011 to 000)

022 (005 to 103)

Maternal death or severe morbidity

20/11616

017

31/11616

027

-09 (-022 to 003)

065 (037 to 113)

10565/11711 9021 10532/11693 9007

014 (-062 to 091)

100 (099 to 101)

Baby put to breast within 30 minutes

Trial outcomes
Simplified package

Full AMTSL package

Risk ratio (95% CI)

% Risk difference
(95% CI)

Outcome
n/N

n/N

Blood loss 1000ml

239/11621

188

017 (-019 to 053)

109 (091 to 131)

Blood loss 500ml

1598/11621 1375 1493/11621 1285

090 (003 to 178)

107 (100 to 114)

Blood loss (ml)(mean difference)

282 (11621)

108 (47 to 169)

Additional uterotonics

2434/11802 2062 2390/11783 2028

206 219/11621

271 (11621)

034 (-069 to 137)

102 (097 to 107)

Blood transfusion

62/11814

052

55/11790

047

006 (-012 to 024)

112 (078 to 162)

Manual removal of placenta

153/11814

130 105/11794

089

040 (014 to 067)

145 (114 to 186)

Third stage duration (min.)(mean

difference)
Maternal death

126 (11662)

61 (11648)

65 (62 to 68)

2/11818

002

1/11798

001

001 (-002 to 004)

200 (018 to 220)

Additional surgical procedures

2/11814

002

9/11790

008

-006 (-011 to 000)

022 (005 to 103)

Maternal death or severe morbidity

20/11616

017

31/11616

027

-09 (-022 to 003)

065 (037 to 113)

10565/11711 9021 10532/11693 9007

014 (-062 to 091)

100 (099 to 101)

Baby put to breast within 30 minutes

The risk of severe postpartum haemorrhage is not increased

Trial outcomes
Simplified package

Full AMTSL package

Risk ratio (95% CI)

% Risk difference
(95% CI)

Outcome
n/N

n/N

Blood loss 1000ml

239/11621

188

017 (-019 to 053)

109 (091 to 131)

Blood loss 500ml

1598/11621 1375 1493/11621 1285

090 (003 to 178)

107 (100 to 114)

Blood loss (ml)(mean difference)

282 (11621)

108 (47 to 169)

Additional uterotonics

2434/11802 2062 2390/11783 2028

206 219/11621

271 (11621)

034 (-069 to 137)

102 (097 to 107)

Blood transfusion

62/11814

052

55/11790

047

006 (-012 to 024)

112 (078 to 162)

Manual removal of placenta

153/11814

130 105/11794

089

040 (014 to 067)

145 (114 to 186)

Third stage duration (min.)(mean

difference)
Maternal death

126 (11662)

61 (11648)

65 (62 to 68)

2/11818

002

1/11798

001

001 (-002 to 004)

200 (018 to 220)

Additional surgical procedures

2/11814

002

9/11790

008

-006 (-011 to 000)

022 (005 to 103)

Maternal death or severe morbidity

20/11616

017

31/11616

027

-09 (-022 to 003)

065 (037 to 113)

10565/11711 9021 10532/11693 9007

014 (-062 to 091)

100 (099 to 101)

Baby put to breast within 30 minutes

The blood loss reduction with CCT is clinically not significant

Trial outcomes
Simplified package

Full AMTSL package

n/N

n/N

% Risk difference
(95% CI)

Blood loss 1000ml

239/11621

206

219/11621

188

017 (-019 to 053)

109 (091 to 131)

Blood loss 500ml

1598/11621

1375 1493/11621 1285

090 (003 to 178)

107 (100 to 114)

Blood loss (ml)(mean difference)

282 (11621)

271 (11621)

108 (47 to 169)

Additional uterotonics

2434/11802

2062 2390/11783 2028

034 (-069 to 137)

102 (097 to 107)

Outcome

Risk ratio (95% CI)

Blood transfusion

62/11814

052

55/11790

047

006 (-012 to 024)

112 (078 to 162)

Manual removal of placenta

153/11814

130

105/11794

089

040 (014 to 067)

145 (114 to 186)

Third stage duration (min.)(mean

difference)
Maternal death

126 (11662)

61 (11648)

65 (62 to 68)

2/11818

002

1/11798

001

001 (-002 to 004)

200 (018 to 220)

Additional surgical procedures

2/11814

002

9/11790

008

-006 (-011 to 000)

022 (005 to 103)

Maternal death or severe morbidity

20/11616

017

31/11616

027

-09 (-022 to 003)

065 (037 to 113)

10565/11711 9021 10532/11693 9007

014 (-062 to 091)

100 (099 to 101)

Baby put to breast within 30 minutes

But, there was an increase in the need of manual removal of placenta

This effect is clustered in Philippines, where ergotamine is widely used for
Prevention of PPH: excluding Philippines data, there is no additional risk of
manual removal of placenta

Sensitivity analysis for the trial outcomes excluding

Philippines
Simplified package
Outcome
n/N

Full AMTSL
package
n/N

% Risk difference
(95% CI)

Risk ratio (95% CI)

Blood loss 1000ml

153/9411

163

140/9420

149

014 (-021 to 049)

109 (087 to 137)

Blood loss 500ml

987/9411

105

927/9420

984

065 (-022 to 151)

107 (098 to 116)

Blood loss (ml)

266 (9403)

Additional uterotonics

1026/9472

108

962/9459

102

066 (-021 to 154)

107 (098 to 116)

Blood transfusion

50/9484

053

34/9463

036

017 (-002 to 036)

147 (095 to 227)

Manual removal of placenta

62/9483

065

64/9470

068

-002 (-025 to 021)

097 (068 to 137)

Third stage duration (min.)

Maternal death
Additional surgical procedures
Maternal death or severe morbidity
Baby put to breast within 30 minutes

256 (9409)

114 (9391)

102 (39 to 164)

62 (9378)

52 (49 to 55)

1/9487

001

1/9471

001

-000 (-003 to 003)

100 (006 to 160)

0/9484

3/9463

003

-003 (-007 to 000)

--

12/9407

013

15/9415

016

-003 (-014 to 008)

080 (037 to 171)

8571/9468

905

8566/9461

905

-001 (-085 to 082)

100 (099 to 101)

Non-inferiority analysis graph showing where the 95%CI for the Risk Ratio
for the primary outcome Blood loss1000ml lies with respect to the point
of no difference and to the preset non-inferiority margin for the RR, =13

Simplified package better

Simplified package worse

Modified ITT
analysis

1.09 (0.91, 1.31)

0.70

0.80

0.90

1.00

RR

1.10

1.20

1.30
=1.3

1.40

Systematic review CCT vs no CCT

Main findings

CCT has minimal added value in terms of reducing blood

loss over and above the uterotonic
Oxytocin 10 IU IM injection after delivery of the baby should
be regarded as the primary intervention for prevention of
PPH
In settings where SBA are not available and oxytocin is used
as routine uterotonic for prevention of PPH, CCT could be
safely omitted during the third stage of labour
In setting where SBA are available, and oxytocin is used as
routine uterotonic for prevention of PPH, practising CCT
may shorten the duration of the third stage of labour
without additional harms or benefits
Even when there is good adherence to a hands-off
management of the umbilical cord and the placenta, about
6% of women will eventually require CCT. Thus, teaching of
CCT for health professionals should continue

Implications for research

The findings of this trial strengthen the

need to focus on strategies to scale up
the use of oxytocin in peripheral levels
of health system as the primary
component of AMTSL.

It is timely to conduct a rigorous

evaluation of the preventive and
therapeutic use of uterine massage.