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
Sep 08, 2014
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
(O’Sullivan’s 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
n/N* (%)
Full AMTSL package
n/N (%)
Age (mean, SD) 25·3 (5·6) 25·3 (5·6)
Primigravida 5362/11823 (45·4) 5476/11799 (46·4)
Gestational age ≥ 37 weeks 10713/11815 (90·7) 10620/11797 (90·3)
Labour induced/augmented 5923/11815 (50·1) 5796/11795 (49·1)
Spontaneous cephalic vaginal delivery
11266/11818 (95·3) 11240/11795 (95·3)
Perineal trauma (episiotomy or tear requiring suture)
7667/11816 (64·9) 7616/11791 (64·6)
Birth weight (mean, SD) 3069 (538) 3054 (544)
Baby alive 11661/11818 (98·7) 11639/11797 (98·7)
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* 11253/11861 94·9 11406/11820 96·5
Oxytocin administered 11779/11861 99·3 11751/11820 99·4
Delayed cord clamping and cutting 9321/11861 78·6 9242/11820 78·2
Final delivery mode of the placenta**
Hands off/Maternal effort 10668/11776 90·6 833/11763 7·08
CCT 731/11777 6·21 11389/11766 96·8
Umbilical vein injection 10/11814 0·08 10/11794 0·08
Manual removal of the placenta 153/11814 1·3 105/11794 0·89
Curettage 165/11814 1·4 98/11794 0·83
Hysterectomy 2/11814 0·02 6/11794 0·05
Left in situ 3/11813 0·03 7/11792 0·06
Placenta and baby delivered simultaneously 29/11814 0·25 23/11797 0·19
*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 Outcome
n/N % n/N %
% Risk difference
(95% CI) Risk ratio (95% CI)
Blood loss ≥1000ml 239/11621 2·06 219/11621 1·88 0·17 (-0·19 to 0·53) 1·09 (0·91 to 1·31)
Blood loss ≥500ml 1598/11621 13·75 1493/11621 12·85 0·90 (0·03 to 1·78) 1·07 (1·00 to 1·14)
Blood loss (ml)(mean difference) 282 (11621) 271 (11621) 10·8 (4·7 to 16·9)
Additional uterotonics 2434/11802 20·62 2390/11783 20·28 0·34 (-0·69 to 1·37) 1·02 (0·97 to 1·07)
Blood transfusion 62/11814 0·52 55/11790 0·47 0·06 (-0·12 to 0·24) 1·12 (0·78 to 1·62)
Manual removal of placenta 153/11814 1·30 105/11794 0·89 0·40 (0·14 to 0·67) 1·45 (1·14 to 1·86)
Third stage duration (min.)(mean difference)
12·6 (11662) 6·1 (11648) 6·5 (6·2 to 6·8)
Maternal death 2/11818 0·02 1/11798 0·01 0·01 (-0·02 to 0·04) 2·00 (0·18 to 22·0)
Additional surgical procedures 2/11814 0·02 9/11790 0·08 -0·06 (-0·11 to 0·00) 0·22 (0·05 to 1·03)
Maternal death or severe morbidity 20/11616 0·17 31/11616 0·27 -·09 (-0·22 to 0·03) 0·65 (0·37 to 1·13)
Baby put to breast within 30 minutes 10565/11711 90·21 10532/11693 90·07 0·14 (-0·62 to 0·91) 1·00 (0·99 to 1·01)
Trial outcomes
Simplified package Full AMTSL package Outcome
n/N % n/N %
% Risk difference
(95% CI) Risk ratio (95% CI)
Blood loss ≥1000ml 239/11621 2·06 219/11621 1·88 0·17 (-0·19 to 0·53) 1·09 (0·91 to 1·31)
Blood loss ≥500ml 1598/11621 13·75 1493/11621 12·85 0·90 (0·03 to 1·78) 1·07 (1·00 to 1·14)
Blood loss (ml)(mean difference) 282 (11621) 271 (11621) 10·8 (4·7 to 16·9)
Additional uterotonics 2434/11802 20·62 2390/11783 20·28 0·34 (-0·69 to 1·37) 1·02 (0·97 to 1·07)
Blood transfusion 62/11814 0·52 55/11790 0·47 0·06 (-0·12 to 0·24) 1·12 (0·78 to 1·62)
Manual removal of placenta 153/11814 1·30 105/11794 0·89 0·40 (0·14 to 0·67) 1·45 (1·14 to 1·86)
Third stage duration (min.)(mean difference)
12·6 (11662) 6·1 (11648) 6·5 (6·2 to 6·8)
Maternal death 2/11818 0·02 1/11798 0·01 0·01 (-0·02 to 0·04) 2·00 (0·18 to 22·0)
Additional surgical procedures 2/11814 0·02 9/11790 0·08 -0·06 (-0·11 to 0·00) 0·22 (0·05 to 1·03)
Maternal death or severe morbidity 20/11616 0·17 31/11616 0·27 -·09 (-0·22 to 0·03) 0·65 (0·37 to 1·13)
Baby put to breast within 30 minutes 10565/11711 90·21 10532/11693 90·07 0·14 (-0·62 to 0·91) 1·00 (0·99 to 1·01) •The risk of severe postpartum haemorrhage is not increased
Trial outcomes
Simplified package Full AMTSL package Outcome
n/N % n/N %
% Risk difference
(95% CI) Risk ratio (95% CI)
Blood loss ≥1000ml 239/11621 2·06 219/11621 1·88 0·17 (-0·19 to 0·53) 1·09 (0·91 to 1·31)
Blood loss ≥500ml 1598/11621 13·75 1493/11621 12·85 0·90 (0·03 to 1·78) 1·07 (1·00 to 1·14)
Blood loss (ml)(mean difference) 282 (11621) 271 (11621) 10·8 (4·7 to 16·9)
Additional uterotonics 2434/11802 20·62 2390/11783 20·28 0·34 (-0·69 to 1·37) 1·02 (0·97 to 1·07)
Blood transfusion 62/11814 0·52 55/11790 0·47 0·06 (-0·12 to 0·24) 1·12 (0·78 to 1·62)
Manual removal of placenta 153/11814 1·30 105/11794 0·89 0·40 (0·14 to 0·67) 1·45 (1·14 to 1·86)
Third stage duration (min.)(mean difference)
12·6 (11662) 6·1 (11648) 6·5 (6·2 to 6·8)
Maternal death 2/11818 0·02 1/11798 0·01 0·01 (-0·02 to 0·04) 2·00 (0·18 to 22·0)
Additional surgical procedures 2/11814 0·02 9/11790 0·08 -0·06 (-0·11 to 0·00) 0·22 (0·05 to 1·03)
Maternal death or severe morbidity 20/11616 0·17 31/11616 0·27 -·09 (-0·22 to 0·03) 0·65 (0·37 to 1·13)
Baby put to breast within 30 minutes 10565/11711 90·21 10532/11693 90·07 0·14 (-0·62 to 0·91) 1·00 (0·99 to 1·01)
•The blood loss reduction with CCT is clinically not significant
Trial outcomes
Simplified package Full AMTSL package Outcome
n/N % n/N %
% Risk difference
(95% CI) Risk ratio (95% CI)
Blood loss ≥1000ml 239/11621 2·06 219/11621 1·88 0·17 (-0·19 to 0·53) 1·09 (0·91 to 1·31)
Blood loss ≥500ml 1598/11621 13·75 1493/11621 12·85 0·90 (0·03 to 1·78) 1·07 (1·00 to 1·14)
Blood loss (ml)(mean difference) 282 (11621) 271 (11621) 10·8 (4·7 to 16·9)
Additional uterotonics 2434/11802 20·62 2390/11783 20·28 0·34 (-0·69 to 1·37) 1·02 (0·97 to 1·07)
Blood transfusion 62/11814 0·52 55/11790 0·47 0·06 (-0·12 to 0·24) 1·12 (0·78 to 1·62)
Manual removal of placenta 153/11814 1·30 105/11794 0·89 0·40 (0·14 to 0·67) 1·45 (1·14 to 1·86)
Third stage duration (min.)(mean difference)
12·6 (11662) 6·1 (11648) 6·5 (6·2 to 6·8)
Maternal death 2/11818 0·02 1/11798 0·01 0·01 (-0·02 to 0·04) 2·00 (0·18 to 22·0)
Additional surgical procedures 2/11814 0·02 9/11790 0·08 -0·06 (-0·11 to 0·00) 0·22 (0·05 to 1·03)
Maternal death or severe morbidity 20/11616 0·17 31/11616 0·27 -·09 (-0·22 to 0·03) 0·65 (0·37 to 1·13)
Baby put to breast within 30 minutes 10565/11711 90·21 10532/11693 90·07 0·14 (-0·62 to 0·91) 1·00 (0·99 to 1·01)
•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
Outcome
Simplified package Full AMTSL
package % Risk difference
(95% CI) Risk ratio (95% CI)
n/N % n/N %
Blood loss ≥1000ml 153/9411 1·63 140/9420 1·49 0·14 (-0·21 to 0·49) 1·09 (0·87 to 1·37)
Blood loss ≥500ml 987/9411 10·5 927/9420 9·84 0·65 (-0·22 to 1·51) 1·07 (0·98 to 1·16)
Blood loss (ml) 266 (9403) 256 (9409) 10·2 (3·9 to 16·4)
Additional uterotonics 1026/9472 10·8 962/9459 10·2 0·66 (-0·21 to 1·54) 1·07 (0·98 to 1·16)
Blood transfusion 50/9484 0·53 34/9463 0·36 0·17 (-0·02 to 0·36) 1·47 (0·95 to 2·27)
Manual removal of placenta 62/9483 0·65 64/9470 0·68 -0·02 (-0·25 to 0·21) 0·97 (0·68 to 1·37)
Third stage duration (min.) 11·4 (9391) 6·2 (9378) 5·2 (4·9 to 5·5)
Maternal death 1/9487 0·01 1/9471 0·01 -0·00 (-0·03 to 0·03) 1·00 (0·06 to 16·0)
Additional surgical procedures 0/9484 0 3/9463 0·03 -0·03 (-0·07 to 0·00) --
Maternal death or severe morbidity 12/9407 0·13 15/9415 0·16 -0·03 (-0·14 to 0·08) 0·80 (0·37 to 1·71)
Baby put to breast within 30 minutes 8571/9468 90·5 8566/9461 90·5 -0·01 (-0·85 to 0·82) 1·00 (0·99 to 1·01)
Non-inferiority analysis graph showing where the 95%CI for the Risk Ratio
for the primary outcome Blood loss≥1000ml lies with respect to the point
of no difference and to the preset non-inferiority margin for the RR, Δ=1·3
1.09 (0.91, 1.31)Modified ITT
analysis
0.70 0.80 0.90 1.00 1.10 1.20 1.30 1.40
RR ∆=1.3
Simplified package better Simplified package worse
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.