ulla britt wennerholm_ptb
TRANSCRIPT
Preterm Birth and Cervical Length Measurements
Ulla-Britt Wennerholm Bo Jacobsson
Henrik Hagberg Pihla Kuusela
Sahlgrenska University Hospital, Gothenburg, Sweden
Background
� 15 million preterm neonates born yearly � 1.1 million neonates die from complications of
preterm birth
Liu et al., Lancet 2012 ACOG, Obstet Gyn 2012
PTB: 70% of neonatal mortality (25)-50% of long-term neurological impairment
Background � PTB complications one of the
10 leading causes of disability-adjusted life years, DALYs (the number of years lost because of ill health, disability or early death) Murray et al., Lancet 2012)
� PTB: Social and psychological trauma of families affected Singer et al., JAMA, 1999
� PTB: High costs: $26.2 billion per year (USA) Romero et al., Science, 2014
Early neonatal death (day 0-6) per1000 live births in relation to gestational age Number of deaths per 1000 live births
Gestational age, weeks
160
140
120
100
80
60
40
20
0 -27 2 8- 29 30 - 31 32 - 33 34 - 35 36 - 37 38 - 39 40 - 41 42 - 43
Hagberg et al., Acta Paediatr 1996
Cerebral palsy in relation to gestational age
Preterm birth
Morken et al., AOGS 2005
80 %
1/4 3/4
Preterm labor: One syndrome, many causes
Romero et al., Science 2014
0 %
1.0%
2.0%
3.0%
4.0%
5.0%
6.0%
7.0%
1975 1980 1985 1990 1995 2000
Year
Preterm birth (%)
Sweden
8.0%
9.0%
10.0%
11.0%
12.0% USA (all)
USA (white)
2010
USA (black)
Preterm birth in Sweden and USA
13.0%
Strategies to prevent preterm birth
75% 50%
Prevention/management of spontaneous preterm birth
Patients with symptoms of preterm labour
• Tocolytic therapy • Antibiotics • Corticosteroids • Magnesium sulfate Patients without symptoms • Progesterone supplementation • Cervical cerclage • Cervical pessary • Prevention of cigarette smoking • Judicious use of fertility treatment • Nutritonal interventions • Treatment of periodontal disease
Progesterone
Women with a past history of PTB Metaanalysis:11 studies, 1899 women
RR 95% CI
◦ PTB <34 weeks 0.31 0.14-0.69 ◦ PTB <37 weeks 0.55 0.42-0.74 ◦ PNM 0.50 0.33-0.75 ◦ BW <2500 g 0.58 0.42-0.79 ◦ NEC 0.30 0.10-0.89 ◦ Assisted ventilation 0.40 0.18-0.90 ◦ NICU 0.24 0.14-0.40
Dodd et al., Cochrane Database Syst Rev, 2013
Meis et al., 2003
RCT women with previous spontaneous PTB (<37 weeks) 16-20 weeks (18.3 ) to 36 weeks weekly im injections of 250 mg 17 α-hydroxyprogesterone caproate (17P) or placebo (2:1)
Meis et al, NEJM 2003
Problems…
� Only 8-12% of PTB occur in women with a previous PTB
� Therefore we need another strategy…..
Lancet, 2004
47 123 women with singleton pregnancies were screened at 22-24 weeks (12 hospitals in Europe, South America and South Africa) 470 (1%) had a CL ≤15 mm RCT: Patients: 253 (54%) women with CL ≤15 mm Intervention: 127 cerclage Control: 126 no cerclage Primary outcome: PTB <33 weeks: 22% in cerclage group and 26% in the no cerclage group RR 0.84, p=0.44. No difference in perinatal or maternal mortality or morbidity
1.7%
61%
Women with CL ≤15 mm Vaginal progesterone capsules 200 mg or placebo each night 24 weeks to 33+6 weeks
1.7%
20-25 weeks
2.3% Women with CL 10-20 mm Vaginal progesterone gel 90 mg or placebo each night 20+0 – 23+6 weeks until 36 weeks
19-24 weeks
?
Sweden, Gothenburg, Autumn 2011
Universal screening of cervical length with TVU? New Scandinavian study?
OPPTIMUM- UK study 2010 - May 2013
� International multicenter RCT � 750 (375 per group) women with a singleton
pregnancy and a short cervix (≤25 mm) or history of PTB+pos FFN
� Vaginal progesterone 200 mg or placebo each night from 22-24 weeks to 34 weeks
� Primary endpoints: ◦ Delivery <34+0 weeks ◦ Neonatal mortality and morbidity (CLD or brain
injury on cerebral ultrasound) ◦ Childhood development at 2 years (Bayley III test) ◦ Economic evaluation
� Results???
Our results from the OPPTIMUM trial
March 2015
August 2012-May 2013 SU, Gothenburg and NÄL,Trollhättan 2122 women screened with TVU, at 16+0-23+1 weeks, (98.8% between 17+0 and 22+0 weeks)
Distribution of cervical length (CL) (in mm) at TVU at 16-23 weeks in 2122 asymptomatic women with singleton pregnancies
Kuusela et al., AOGS 2015
Mean CL (SD) 39.9 (6.5) mm at median 18+4 weeks CL ≤25 mm: 11 women (0.5%) CL ≤30 mm: 73 women (3.4%)
Our results from OPPTIMUM trial
March 2015
2122 women screened 7/11 women included in the OPPTIMUM trial 35 women with an iatrogenic PTB 19 women lost to follow up 2061 women were analysed for the risk of PTB< 34 and 37 weeks
Maternal characteristics in screened and not screened women
Screened vs. unscreened population: Spontaneous PTB <34 weeks: 1.1% vs. 1.0% (p=0.65) Spontaneous PTB <37 weeks: 4.2% vs. 3.7% (p=0.31)
Kuusela et al., AOGS 2015
Univariable logistic regression analysis of selected maternal characteristics for the risk of spontaneous PTD <34 weeks
Kuusela et al., AOGS 2015
Percentiles of cervical length and the relative risk of spontaneous PTB <34 weeks
Kuusela et al., AOGS 2015
Prediction of spontaneous PTB <34 weeks
Kuusela et al., AOGS 2015
Study Week for cervical
screening
Setting/population Number of women screened
Cut off CL mm
Preva-lence
To 22-24 UK, Greece, Slovenia South America, South Africa
47 123 <15 1.1%
Fonseca 20-25 UK, Greece South America
1.8% twin pregnancies
24 620 <15
1.7%
Hassan 20-23 USA, Europe South America, South Africa,
Asia
32 091 10-20 2.3%
Heath 22-23 UK 2 713 <25 8.1%
Goya 18-22 Spain 11 518 <25 6.4%
Taipale 18-22 Finland 3 694 <25 0.2%
Sahlgrenska/ NÄL
16-23 Sweden 9% previous PTB
2 122 ≤25 0.5%
Sahlgrenska/ NÄL
16-23 Sweden 9% previous PTB
2 122 ≤30 3.4%
van Os/Mol 18-22 The Netherlands No previous PTB
20 234 <30 1.8%
Grobman 16-22 USA Nulliparous
15 435 <30 10%
Summary of studies on cervical length
<15 mm
10-20 mm
≤25 mm
≤30 mm
Conclusions
� The prevalence of short CL (≤25 mm) 0.5% was much lower than in other studies
� To find 750 women to a RCT on progesterone (if 0.5% with CL ≤25 mm) we need to screen 150 000 women.
� If 30% participation rate we need to screen 500 000 women!
1. Na%onal observa%onal study on cervical length
2. Na%onal RCT on progesterone?
Sweden, Spring 2013
?
18+0 - 20+6 weeks 21+0 - 23+6 weeks <33+0 weeks
Swedish multicenter observational study on transvaginal sonographic measurement of cervical length in the second
trimester in women with singleton pregnancies
11000 women 100 women
+
Vaginal progesterone in asymptomatic women with a singleton pregnancy and a sonographic short cervix in the mid-pregnancy IPD metaanalysis, 4 RCTs, 723 women
RR 95% CI
◦ PTB <28 weeks 0.51 0.31-0.85 ◦ PTB <33 weeks 0.56 0.40-0.80 ◦ PTB <35 weeks 0.67 0.51-0.87 ◦ RDS 0.47 0.27-0.81 ◦ NNM and morbidity 0.59 0.38-0.91 ◦ BW <1500 g 0.52 0.34-0.81 ◦ NICU 0.67 0.50-0.91
Romero et al., AJOG, 2012
Why? • Progesterone treatment to asymptomatic women with a ”short” cervix: Results mainly based on 2 RCTs (Fonseca 2007, Hassan 2011), performed in countries with a higher rate of PTB and different race/ethnic distribution
• The rate of ”short” cervix in the Nordic countries seems to be 10-30 times lower
• Sensitivity and specificity for ”short” cervix and PTB much lower in the Scandinavian studies
Swedish multicenter observational study on transvaginal sonographic measurement of cervical length in the second
trimester in women with singleton pregnancies
Swedish multicenter observational study on transvaginal sonographic measurement of cervical length in the second
trimester in women with singleton pregnancies
General aim To estimate if, in asymptomatic women with a singleton pregnancy, screening for PTB with CL measurement with TVU in the second trimester and treatment with progesterone if CL is ”short” is cost-effective in Sweden Specific aims 1. Estimate the prevalence of ”short” cervix 2. Find the optimal CL cut off to predict PTB 3. Estimate the sensitivity and specificity (using different measurement techniques and definitions) 4. Define the optimal gestational weeks between 18+0-23+6 weeks to measure CL 5. Investigate if a shortening of the CL between 18-20 and 21-23 weeks is more predictive than a single measurement 6. Based on these results and the PTB rate in Sweden calculate the sample size of a RCT to investigate the effect o PTB and neonatal outcome of screening of CL and progesterone treatment if cervix is ”short”
Malmö/Lund
Göteborg NÄL
Örebro Stockholm
Falun
Swedish multicenter observational study on transvaginal sonographic measurement of cervical length in the second
trimester in women with singleton pregnancies
33 500 eligible women per year
Swedish multicenter observational study on transvaginal sonographic measurement of cervical length in the second
trimester in women with singleton pregnancies
Sample size 11000 women: 100 of these women (0.9% of 11000) are expected to give birth before 33+0 gestational weeks, which gives a reasonable 95% CI for estimated sensitivity of ”short cervix” to predict PTB before 33+0 gestational weeks
Ethical approval in November 2013
Certification of midwives (n=13)
Study started May 2014
April 10, 2015: 2800 women (25%) screened
Swedish multicenter observational study on transvaginal sonographic measurement of cervical length in the second
trimester in women with singleton pregnancies
Thank you!