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Prevention of preterm birth in twin
pregnancy
NORSTAMP meeting
October 2008
Prof Jane Norman
University of Edinburgh
Multiple births in Scotland 1855 - 2005
Perinatal outcomes in twin births
Singleton
Twin
Triplet
Perinatal
mortality
5.4
14.8
51.8
Stillbirth rate
7.7
28.2
83.3
Infant
mortality
4.5
21.6
61.8
Preterm birth and neonatal unit stay in
multiples
Singleton
Twin
Triplet
Percentage of all
babies
97.2
2. 7
0.1
Percentage of all
preterm births
5.8
48.1
83.3
Percentage of
neonatal cot stays
75
21.6
3.4
Preterm birth and neonatal unit stay in
multiples
Singleton
Twin
Triplet
Percentage of all
babies
97.2
2. 7
0.1
Percentage of
neonatal cot stays
75
21.6
3.4
Percentage of all
preterm births
5.8
48.1
83.3
Preterm birth and neonatal unit stay in
multiples
Singleton
Twin
Triplet
Percentage of all
babies
97.2
2. 7
0.1
Percentage of
neonatal cot stays
75
21.6
3.4
Percentage of all
preterm births
5.8
48.1
83.3
Singleton neonatal deaths by obstetric classification
Scotland 2006
Figure 3a(2): Singleton Neonatal Deaths by Obstetric Classification: 2006
Unexplained <2500G (36%)
Congenital anomaly (31%)
Unexplained >2500G (15%)
Antepartum haemorrhage (4%)
Hypertension of pregnancy (1%)
Postnatal cause only (4%)
Maternal disorder (5%)
Miscellaneous (1%)
Trauma/mechanical (2%)
Multiple neonatal deaths by obstetric classification
(2006)
Figure 3b(2): Multiple Neonatal Deaths by Obstetric Classification: 2006
Unexplained <2500G (74%)
Congenital anomaly (12%)
Miscellaneous (9%)
Postnatal cause only (3%)
Antepartum haemorrhage (3%)
Spontaneous preterm birth is increasing
Langhoff-Roos et al 2006 BMJ 332: 937
Prediction of preterm birth (before 32 weeks) in twin
pregnancy
fFN
Both
Sensitivity
Cervical
length
(< 30mm)
75 %
43 %
83 %
Specificity
85 %
94 %
81 %
PPV
32 %
38 %
25 %
NPV
97%
95 %
99 %
McMahon et al 2002 Am J Obstet Gynecol 186: 1137
Prevention of preterm delivery
• 1. Antibiotics
• 2. Cervical cerclage
• 3. Progesterone therapy
Odds of preterm birth in after treatment with
antibiotics (AB)
OR
95% CI
Any AB
1.03
0.86 – 1.24
Clindamycin
1.02
0.69 – 1.48
Metronidazole
1.06
0.81 – 1.39
AB in women with a history of
PTB
0.99
0.72 – 1.37
AB in women with abnormal
vaginal flora
0.97
0.78 – 1.21
Simcox et al 2007 Aust N Z J Obstet Gynecol 47: 368
What about women presenting in
preterm labour with intact membranes?
• Oracle II study showed no benefit in
preventing preterm labour
• Giving antibiotics to women with intact
menbranes in preterm labour not generally
recommended in the UK
• Until recently no good evidence that this
strategy was harmful
Evidence of harm in children aged 7 after antibiotics
in women with PTL and intact membranes
OR
95 % CI
Any functional impairment
Erythromycin
1.18
1.02 - 1.37*
Co-amoxiclav
1.03
0.89 - 1.19
Erythromycin
1.93
1.21 - 3.09*
Co-amoxiclav
1.69
1.07 - 2.67*
Cerebral palsy
Kenyon et al 2008 Lancet
What about women with pPROM?
Antibiotics improve outcome in women with
PPROM
• In women with preterm ruptured membranes, antibiotics
reduce risk of birth within 48 hrs (RR 0.71, 95% CI 0.58 –
0.87) and of birth within seven days (RR 0.80, 95% CI
0.71- 0.90)
• Neonatal morbidity, neonatal infection, use of surfactant,
oxygen therapy and incidence of abnormal cerebral
ultrasound scan also reduced
• Suggested regimen: erythromycin 250mg IV 6hrly for 48
hrs followed by 330mg 8hrly orally thereafter for 5 days
Kenyon et al 2003 Cochrane Database Syst Rev CD001058
Antibiotics for pPROM in twin pregnancy
• 453 (out of 4826) women in ORACLE 1 had a
multiple pregnancy
• No significant differences in outcome between the
antibiotic and placebo groups
• Uncertainty therefore about whether singelton
pPROM advice (to give antibiotics) is relevant for
multiples
Prevention of preterm delivery
• 1. Antibiotics
• 2. Cervical cerclage
• 3. Progesterone therapy
Cerclage for short cervix on ultrasound –
individual patient meta-analysis
Outcome of PTB < Cerclage Control
35 weeks for
subgroup:
All pregnancies
29.2%
38.4%
RR (95%CI)
0.84 (0.67 – 1.06)
Singletons
24.8 %
33.9%
0.74 (0.57 – 0.96)
Singletons with
previous PTB
38.3%
60.4%
0.63 (0.48 – 0.85)
Berghella et al 2005 Obstet Gynecol 106: 181
Cerclage for short cervix on ultrasound –
individual patient meta-analysis
Singleton gestations in women with a prior preterm birth at 16 –36 weeks
Berghella et al 2005 Obstet Gynecol 106: 181
Cerclage for short cervix on ultrasound –
individual patient meta-analysis
Outcome of PTB < Cerclage Control
35 weeks for
subgroup:
All pregnancies
29.2%
38.4%
RR (95%CI)
0.84 (0.67 – 1.06)
Singletons
24.8 %
33.9%
0.74 (0.57 – 0.96)
Singletons with
previous PTB
38.3%
60.4%
0.63 (0.48 – 0.85)
Twin pregnancy
75 %
36 %
2.15 (1.15 – 4.01)
Berghella et al 2005 Obstet Gynecol 106: 181
Prevention of preterm delivery
• 1. Antibiotics
• 2. Cervical cerclage
• 3. Progesterone therapy
Use of progesterone in clinical practice
• Meta-analysis of progesterone suggests
reduction in incidence of preterm birth –
OR 0.5 (95% CI 0.3 – 0.85) Keirse 1990
• Progesterone not mentioned in chapter on
treatment / prevention preterm birth in
“High Risk Pregnancy”
James/Steer/Weiner/Gonik 2nd edn 1999
Is the use of progesterone to prevent preterm
delivery biologically plausible?
• increasing evidence that labour associated with functional
progesterone withdrawal
• antiprogestogens used to stimulate abortion and labour
induction
• progesterone inhibits prostaglandin production and has other
anti-inflammatory properties (eg upregulates IL-10)
• progesterone inhibits the stimulatory effect of estrogen on
gap junction formation
• some evidence that progesterone may sensitise the uterus to
the action of exogenous tocolytics
Acute effect of progesterone on myometrial
contractions in vitro
Anderson et al, unpublished data
Acute tocolytic effect seen for progesterone but not
17 OHP
Anderson et al, unpublished data
Meta-analysis of progestational agents to prevent PTB
(singletons with previous PTB) - Primary outcomes
Outcome
Odds ratio
95% CI
Perinatal death
0.65
0.38–1.11
PTB < 34
weeks
0.15
0.04–0.64**
Developmental
delay
0.97
0.55–1.73
Dodd et al 2008 Obstet Gynecol 112: 127
Meta-analysis of progestational agents to prevent PTB
(Singletons with previous preterm birth)
Selected secondary outcomes
Outcome
Odds ratio
95% CI
IVH
0.54
0.12–2.47
RDS
0.79
0.57–1.10
Fetal death
1.13
0.35–3.59
Dodd et al 2008 Obstet Gynecol 112: 127
Meta-analysis of progestational agents to prevent PTB
Short cervix
Outcome
Odds ratio
95% CI
Perinatal death
0.38
0.10–1.40
PTB < 34
weeks
0.58**
0.38–0.87
IVH
0.51
0.05–5.53
Dodd et al 2008 Obstet Gynecol 112: 127
Meta-analysis of progestational agents to prevent PTB
Multiple pregnancy
Outcome
Odds ratio
95% CI
Perinatal death
1.95
0.37–10.33
PTB < 37
weeks
1.01
0.92–1.12
Dodd et al 2008 Obstet Gynecol 112: 127
Double blind RCT of 17 OHP for prevention
of preterm birth in twins
661 women with twin pregnancy
–
–
–
–
–
–
Mean age 30 yrs
66% Caucasian
45% nulliparous
65% spontaneous conception
8 % previous preterm delivery
82 % dichorionic
Rouse DJ et al NEJM 2007 357: 454
Double blind RCT of 17 OHP for prevention
of preterm birth in twins
• Women randomised to weekly 17 OHP
250mg IM or placebo starting at 16 -20
weeks gestation and continuing till 34
weeks gestation
• Primary outcome: delivery before 35 weeks
gestation (80% power to detect a 33%
reduction on baseline rate of 35%)
Rouse DJ et al NEJM 2007 357: 454
Proportion of women remaining pregnant with two
live fetuses
Rouse DJ et al NEJM 2007 357: 454
The STOPPIT study
• Investigators: Norman / Mackenzie/ Owen / Norrie/
Hanretty/ Danielian / Cooper/ Mires/ Mactier/ Sturgiss /
Petrou
• ISRCTN: 35782581
• Funding: Chief Scientist Office, Scottish Executive
• Study sponsor: Greater Glasgow Health Board
(NGUHD) and University of Glasgow
• https://medserv.abdn.ac.uk/stoppit/index.php
Study power
– Rate of delivery in twins before 34 weeks is 20%
– RR after Rx between 0.3 and 0.5
– Assume RR is 0.5, sample size of 500 has 85% power at 5%
significance level to show reduction in rate of PTD from
20% to 10%.
– Alternatively 98% power to show reduction from 20% to 7%
(RR 0.3)
– So sample size of 500 would be needed
– (Altman’s nomogram / nQuery advisor / statistician)
Subjects
• Women with twin pregnancy from following
hospitals recruited over 30 months
– PRM, QMH, Forresterhill in Aberdeen, Ninewells
Dundee, NRIE in Edinburgh, RVI in Newcastle
– Aim for 500 women during this time
– Number of twins per year in these hospitals is 498
– Need to recruit 45%
• Some ineligible
• Inward referrals from other hospitals could add a further 300
subjects over 30 months
Treatment regimen
• Vaginal progesterone gel, 90mg daily from
24 – 34 weeks gestation
• Route of administration IM / vaginal
• Dose
• Source of drugs
Use of placebo
• Allows blinding
• Reduces bias (subject / investigator / others
managing patient)
• Placebo has to appear similar
Inclusion / exclusion
• Inclusion
– Twin pregnancy,
– Gestation established by scan before 20 weeks
– Known chorionicity
• Exclusion
–
–
–
–
–
Significant structural / chromosomal fetal abn
Contraindications to progesterone
Planned cervical suture
Planned elective delivery before 34 weeks gestation
Intervention for twin to twin transfusion before 22 wks
Recruitment / randomisation
Formally recruit at 22 weeks
Randomisation stratified by hospital and
chorionicity
Randomisation thro’ CHaRT in Aberdeen
Study number allocated
Pharmacy (WIG) to make up treatment packs
Interventions
• Vaginal progesterone 90mg daily from
24+0 weeks to 33+6 weeks inclusive
Or
• “Placebo” vaginal progesterone 90mg daily
from 24+0 weeks to 33+6 weeks inclusive
Outcomes
• Primary
– no of women in each group delivering before 34 weeks
gestation
• Secondary
– Perinatal mortality and morbidity
– Pregnancy duration in each group
– Maternal complications inc LSCS rates, duration of
labour, vaginal bleeding, PPROM
– Neonatal complication rates
– Maternal side effects
– Acceptability of Rx and alternative
– Costs
Indications for stopping treatment
• Planned elective preterm delivery
• Fetal membrane rupture
• Symptomatic placenta praevia
• NB admission in PTL not indication for
stopping
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Midwife of the year!
STOPPIT results
• Final data collection nearing completion
• Data lockdown and code breaking 1st Nov
• Results late Nov 2008
Is there proof that anything works in
twin pregnancy?
Use of corticosteroids in twin pregnancy
Outcome
RR
95 % CI
No of
studies
No of
babies
RDS
0.85
0.60 – 1.20
4
320
Cerebrovascular
haemorrahge
0.39
0.07 – 2.06
1
127
Roberts D, Dalziel S (2006) Cochrane Database Syst Rev. CD004454
Conclusion
• Twins are at increased risk of spontaneous preterm
birth
• Preterm birth is a major cause of perinatal
morbidity and mortality in twins
• Currently no effective therapies
• STOPPIT soon to report
• More research (RCT and epidemiology) needed
• OPPTIMUM study in singletons
(www.opptimum.org.uk)
Acknowledgements
• STOPPIT collaborators and study midwives
• Chief Scientist Office, Scottish Executive
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