hofmeyr_who trial on active management of the third stage of labor

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


n/N % n/N %

% Risk difference









12·6 (11662) 6·1 (11648) 6·5 (6·2 to 6·8)




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


n/N % n/N %

% Risk difference









12·6 (11662) 6·1 (11648) 6·5 (6·2 to 6·8)





•The blood loss reduction with CCT is clinically not significant

Trial outcomes


n/N % n/N %

% Risk difference









12·6 (11662) 6·1 (11648) 6·5 (6·2 to 6·8)





•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


n/N % n/N %



Blood loss (ml) 266 (9403) 256 (9409) 10·2 (3·9 to 16·4)



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.

hofmeyr_who trial on active management of the third stage of labor

Documents

controlled

final delivery

systematic

full amtsl

full package

simplified

uterine massage

uterine inversion