Ulla Britt Wennerholm, NNFM Nordic Network of Fetal Medicine meeting in Gothenburg 14-16th of April 2015.

1. Preterm Birth and
Cervical Length Measurements
Ulla-Britt Wennerholm
Bo Jacobsson
Henrik Hagberg
Pihla Kuusela
Sahlgrenska University Hospital, Gothenburg, Sweden

2. 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

3. 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

4. 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

5. Hagberg et al., Acta Paediatr 1996
Cerebral palsy in relation to gestational age

6. Preterm birth
Morken et al., AOGS 2005
80 %
1/4 3/4

7. Preterm labor:
One syndrome, many causes
Romero et al., Science 2014

8. 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%

9. Strategies to prevent preterm birth

10. 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

11. 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

12. 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)

13. Meis et al, NEJM 2003

14. Problems…
— Only 8-12% of PTB occur in women with
a previous PTB
— Therefore we need another strategy…..

15. 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

16. 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

18. 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

21. ?
Sweden, Gothenburg, Autumn 2011
Universal screening of
cervical length with TVU?
New Scandinavian study?

22. 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???

23. 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)

24. 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%)

25. 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

26. 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

27. Univariable logistic regression analysis of selected
maternal characteristics for the risk of
spontaneous PTD <34 weeks
Kuusela et al., AOGS 2015

28. Percentiles of cervical length and the relative risk
of spontaneous PTB <34 weeks
Kuusela et al., AOGS 2015

29. Prediction of spontaneous PTB <34
weeks
Kuusela et al., AOGS 2015

30. 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

31. 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!

32. 1. Na%onal
observa%onal
study
on
cervical
length
2. Na%onal
RCT
on
progesterone?
Sweden, Spring 2013
?

33. 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
+

34. 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

35. 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

36. 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”

37. 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

38. 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

39. 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

40. Thank you!