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!