universal screening the future direction of prevention?

Universal screening The future direction of prevention?

Prevention of very preterm birth

Working together: Annual conference of the Perinatal and Maternal Mortality Review Committee (PMMRC) Tuesday 28 June 2016 Te Papa Tongarewa Wellington

Dr Katie Groom, MFM Subspecialist National Women’s Health and

University of Auckland

Should we do routine cervical length screening at the time of

the anomaly scan?

Universal screening

Principles and Practice of Screening for Disease James Maxwell Glover Wilson & Gunner Jungner 1968

“The central idea of early disease detection and treatment is essentially simple. However, the path to its successful achievement (on the one hand, bringing to treatment those with previously undetected disease, and, on the other, avoiding harm to those persons not in need of treatment) is far from simple though sometimes it may appear deceptively easy.”

Wilson and Jungner defined screening criteria to guide the selection of conditions that would be suitable for screening based on the capacity to detect the condition

at an early stage and the availability of an acceptable treatment

Principles of screening

1. Important health problem 2. Suitable treatment for condition 3. Facilities for diagnosis and treatment available 4. There should be a latent phase of the disease 5. Suitable test or examination for the condition 6. The test (and treatment) should be acceptable to the population 7. The natural history of the disease should be understood 8. There should be an agreed policy on who to test and treat 9. Costs of case finding economically balance costs of condition 10. Case finding must apply to all and be continuous

Andermann et al. WHO Bulletin 2008 http://www.who.int/bulletin/volumes/86/4/07-050112/en/

Wilson & Jungner 1968

Updated criteria 2008

http://www.who.int/bulletin/volumes/86/4/07-050112/en/

Should we do it? Limitations of screening:

• Cost & use of medical resources on a majority who do not need

intervention • Adverse effects of screening (e.g. stress/anxiety, discomfort,

surgical/radiation/chemical exposure) • Stress & anxiety of a false positive result • Unnecessary investigation & treatment of false positive result • Stress & anxiety of a positive result by prolonging knowledge of

problem without improving outcome • False sense of security with false negative, may delay final

diagnosis & treatment

Can we do it?

Universal Screening to Prevent Preterm Birth

1. Important health problem

7- 10% of all deliveries 1% deliver <32 weeks 0.005% deliver 23-25 weeks

Preterm birth

NWH data 23-31weeks 2003-2015

RDS, IVH, ROP, NEC, sepsis

CLD, CP, blindness

Developmental delay

Metabolic syndrome

Major cause of morbidity and mortality

National Women’s Health ACR 2014 http://nationalwomenshealth.adhb.govt.nz

Important health problem 7. Natural history of disease understood

Iatrogenic or indicated preterm delivery At least 30% of deliveries <37 weeks are clinically indicated

Preeclampsia, IUGR, diabetes, APH, fetal anomalies

Spontaneous preterm labour/PPROM Large variety of aetiologies

Often multi-factorial

Final common pathway

Uterus/myometrium PGF 2 IL-8 PGF 2α IL1b Contractions

Fetal membranes PGE 2 IL-8 IL1b

ROM

Cervix PGE 2

IL-8 NO

Cervical ripening

Labour is an inflammatory process

Screening will only be effective if can detect disease in a latent phase where intervention is still possible

Labour is an inflammatory process – involving cervix, membranes & myometrium Progressive change which ultimately leads to an open cervix, membrane rupture and myometrial contractility and preterm birth

Cervical shortening likely to proceed PPROM and contractions in many cases of spontaneous PTL/PPROM – this may be the ‘latent phase’

4. Latent phase of the disease

TA scan less sensitive to identify short cervix

Sensitivity to identify TV 25mm length TA 25 mm - 45% TA 36 mm - 96%

Important health problem 5. Suitable test/examination for the condition

Salomon UOG 2009 Transvaginal (TV) cervical length

Heath UOG 1998

• TV is the gold standard • Unaffected by maternal obesity, cervical position,

and fetal part shadowing

• Safe • Reproducible <10% intra- & inter observer variability • Reported nomograms and normal ranges

SMFM Consult Series#40. AmJOG 2016 in press

Important health problem TV Cervical Length Heath UOG 1998

Cervical length (mm)

Del <33/40

(% )

Cervical length

Delivery <33 weeks

≤15mm 52%

15mm 4%

5mm 78%

The shorter the cervix the higher the risk

PREGNANT trial – placebo 16% del <33 weeks (CL 10-20mm at 19-24weeks) Fonseca Study – placebo 34% del <33 weeks (CL≤15mm at 22 weeks)

1st centile = 23mm

Hassan UOG 2011 DOI: 10.1002/uog.9017

Fonseca NEJM 2007; 357:462-9

Important health problem

2. Suitable treatment for condition

Cervical Cerclage? Progesterone? Cervical Pessary?


Cervix open Membranes exposed

Cervical barrier breached

Allows ascending infection

Further stimulation of inflammation

Vicious circle ensues with further cervical ripening and ascending infection

Ultimately leads to membrane rupture and myometrial contractility & PTL

Cervical funnelling

Normal cervix

Phases of parturition and cervical change

Labour is an inflammatory process

Cerclage may offer benefit whether the cervix is a primary or

secondary problem

Important health problem Cerclage for a short cervix

4 RCTs n=607 (low and high risk, twins and triplets) CL≤15mm or <25mm in 3 studies

IPD meta-analysis ‘Cerclage’ vs ‘no cerclage’

Berghella Obstet Gynecol 2005

Del <35w 29% vs 35% (RR 0.8 95%CI 0.7-1.1)

Del <35w 23% vs 39% (RR 0.6 95%CI 0.4-0.9)

Del <35w 25% vs 34% (RR 0.7 95%CI 0.6-0.96)


Cerclage for a short cervix in a general population

Recognised and accepted benefit in women with multiple prior PTB and women with short cervix and prior PTB

Limited evidence to support effectiveness in a general population

No Prior PTB

CL <25mm RR del <35w 0.84 (95% CI 0.6-1.2)

Berghella UOG 2010 DOI: 10.1002/uog.7547

USS indicated cerclage has limited role in a general

population, most beneficial in singleton pregnancies with risk factors for PTB

Contraction associated protein (CAP) OTR, connexin 43, gap junctions

PGF2α R, COX-2, PGDH

Phase 0 Phase 1 Phase 2 Phase 3 Conception

Uterus

Cervix

Contractile unresponsiveness

Preparation for labour

Active labour

Uterine involution

Anabolic metabolism Ripening Catabolic metabolism

Remodelling

Initiation of parturition

Onset of labour

Delivery of fetus

Fertility restored

Membranes Anabolic metabolism Weakening Rupture

Suppressive action on pro-labour CAP genes Inhibits gap junction formation Decreases uterine OT sensitivity Inhibits prostaglandin activity

Inhibitory effect on pro-labour factors allows uterus to enlarge

without increasing uterine contractility

Progesterone

Phases of parturition and progesterone

Progesterone therapy may be effective treatment for preventing PTB

Important health problem Progesterone for a short cervix in a general population

Many studies of progesterone use in women with prior history of PTB

Evidence specific to a singleton general population with a short cervix

• 5 trials in 775 women • Twin pregnancies

included (total 827 infants)

• Mixed risk population

Hassan UOG 2011 DOI: 10.1002/uog.9017 Fonseca NEJM 2007; 357:462-9

Romero AmJOG 2012; 206:124.e1-19


Singleton Pregnancy RR 0.56 (95%CI 0.4-0.8) No benefit in twin pregnancies Significant reduction in short term neonatal outcomes – RDS, NICU, mechanical ventilation No data on long term outcomes and insufficient numbers to test survival

Delivery <33 weeks


Norman Lancet 2016 http://dx.doi.org/10.1016/S0140-6736(16)00350-0

Largest RCT comparing obstetric, neonatal, and childhood outcomes in high-risk women with singleton pregnancy treated with vaginal progesterone to prevent preterm birth Included 256 women with short cervix <25mm

Rates of preterm birth were higher with CLL <25mm and <15mm but no significant interactions between CL and the effect of progesterone on any obstetric, neonatal, or childhood outcomes

Important health problem Cervical pessary for a short cervix?

Goya Lancet 2012

Spontaneous PTB Pessary Expectant RR (95%CI)

Del <34 weeks 12 (6%) 51 (27%) 0.24* (0.13–0.43)

Del <28 weeks 4 (2%) 16 (8%) 0.25* (0.09–0.73)

Del <37 weeks 41 (22%) 113 (59%) 0.36* (0.27–0.49)


Pessary Expectant OR (95%CI)

55 (12%) 50 (10.8%) 1.1 (0.8–1.7)

Important health problem Cervical pessary for a short cervix?

Nicolaides N Engl J Med 2016;374:1044-52. DOI: 10.1056/NEJMoa1511014

• 932 singleton pregnancies • CL ≤25mm at 20+0 – 24+6 weeks • Pessary or expectant management • All received progesterone if <15mm

Delivery <34 weeks (primary outcome)

Gestational age at delivery

Pessary Expectant p value

38.9 weeks 38.7 weeks 0.4

Important health problem 6. The test (& treatment) should be acceptable

TV cervical length Acceptable to most

Progesterone PV pessaries nocte to 36 weeks Some reports of vaginal itching/ulceration

75% uptake More likely to accept if: - nulliparous versus multiparous (83% vs 68%, p<0.001) - sonographer female versus male (83% vs 42%, p<0.001) No difference if: - "opt-out" vs "opt-in" approach (76% vs 75%, p=0.81) Similar findings in NZ population in the SCOPE study

Compliance within clinical trials Return of unused drug – investigator reported 93% compliance Patient reported compliance diaries – 66% compliant >80% of drug administration

Hassan UOG 2011 DOI: 10.1002/uog.9017

Norman Lancet 2016 http://dx.doi.org/10.1016/S0140-6736(16)00350-0

Orzechowski Am J Perinatol 2014;31:1057–1062

Important health problem 3. Facilities for test/treatment available

Integration into anomaly scan visit- hospital and private USS provider Published Best Practice Guidelines for measurement Current level of experience insufficient for image acquisition and interpretation

TV cervical length

Quality control study of CL measurements in US academic MFM centres: 25% did not meet published quality criteria

Need standardised formal education and accreditation programme

Iams AmJOG 2013;209:365.e1-5

Progesterone

Utrogestan 100mg pessaries available (200mg dose)

NZ Special Authority (short cervix or prior PTB)

Important health problem 8. Agreed policy on who to test/treat

SMFM Consult Series#40. AmJOG 2016 in press

• Universal screening remains an ‘object of debate’

• ‘cannot yet be universally mandated’ • ‘can be viewed as reasonable and

considered by individual practitioners’

Recommendations • Routine TV CL screening for women with singleton pregnancy & history of prior

spontaneous PTB (grade 1A) • Routine TV CL screening should not be performed for women with cervical cerclage,

multiple gestation, PPROM, or placenta previa (grade 2B) • Sonographers and/or practitioners receive specific training in the acquisition and

interpretation of cervical imaging during pregnancy (grade 2B)

2015 survey of US institutions with MFM Fellowship Programs • Implementation of universal CL screening (singleton with no prior spPTB) • 68% implemented a programme, 47% using TV US

Kahlifeh Obstet Gynecol 2016;127:7s

Important health problem 8. Agreed policy on who to test/treat

• No evidence of long term benefit for the baby • May not just be “absence of evidence” (delay may have adverse

effects if the fetus remains in an adverse intrauterine environment). https://www.rcog.org.uk

https://www.rcog.org.uk/en/guidelines-research-services/guidelines/gtg60/

RCOG endorses current recommendations: In women at high risk of preterm delivery, progesterone administration should be restricted to clinical trials to determine whether its use is associated with improved fetal, neonatal and/or infant outcome

RANZCOG College statement highlights issues only

Australia Making a move to routine universal screening. WA initiative

NZMFMN Statement Not currently endorsing universal screening

Important health problem 9. Economic costs

Case finding must at least economically balance the cost of disease treatment and management

Prematurity has enormous financial costs and so an EFFECTIVE screening test AND intervention is likely to have financial advantages

Limited cost analysis study based on RCT data • No data on outcomes of screen negative so only implied • Accounted for costs of increased morbidity in preterm births on placebo but study did not show increase in neonatal morbidity

Important health problem 10. Continuous case finding

Must be on-going process Apply screening to whole population

Universal Screening to Prevent Preterm Birth

1. Important health problem

2. Suitable treatment for condition

3. Facilities for diagnosis and treatment available

4. There should be a latent phase of the disease

5. Suitable test or examination for the condition

6. The test (and treatment) should be acceptable to the population

7. The natural history of the disease should be understood

8. There should be an agreed policy on who to test and treat

9. Costs of case finding economically balance costs of condition

10. Case finding must apply to all and be continuous

Important health problem Is there a solution?

No single screening test or single treatment to prevent

all preterm births

Screen and treat/manage the modifiable risks

Pre-pregnancy Fertility treatment Smoking and drug use Obesity Management of TOP and miscarriage Caution with LETZ Optimise medical conditions such as; hypertension, diabetes

In pregnancy Aspirin for IUGR and PET risk Smoking and drug use (marijuana) Treat asymptomatic bacteruria Screen and treat chlamydia Control of medical conditions such as; hypertension, diabetes

Cervical length screening with use of progesterone (+/- cerclage) may have a role as part of a prevention programme

Important health problem Preterm Birth Prevention Programme

State-wide campaign which aims to safely lower the rate of preterm birth by combining the latest evidence-based clinical practice with educational outreach programs for health care practitioners and the general public

Western Australian Preterm Birth Prevention Initiative

Collaborative Project: • State Government funding • Women and Newborn Health Service • Women and Infants Research Foundation • University of Western Australia Support from: • State-wide Obstetric Services Unit • Australian Medical Association • RANZCOG • RACGP

Important health problem Preterm Birth Prevention Key Interventions

Research, education (mothers and health care professionals) and implementation

1. Preconception care – BMI, smoking, drug & alcohol use, folate use, optimise medical conditions

2. Individualised management guidelines – identify as low, medium or high risk 3. Progesterone treatment (16-36 weeks) – for women with prior spontaneous PTB 20 -34w

Cervical cerclage - for women with prior spontaneous PTB 20 -34w 4. Measurement of cervical length – routine part of 18-20w scan, TA scan , <35mm proceed

to TV scan. Cervix 10-20mm treat with progesterone, ≤10mm use cerclage 5. Avoid non-medically indicated later preterm birth - No delivery until at least 38 weeks,

unless there are medical or obstetric reasons justifying earlier intervention 6. Reduce tobacco exposure - harness the many strategies available to minimise the chance

of pregnant women smoking, or being exposed to second-hand cigarette smoke 7. Judicious use of fertility treatment – reduce multiple pregnancies 8. Preterm Birth Prevention Clinic –cases at high risk of preterm birth (single centre pilot)

Important health problem Summary

• Individualise the care we provide

• Aim to screen and identify risks for all forms of PTB

• Target the use of effective interventions to reduce risk

Should we do universal screening for PTB for all women?

In the future this may include routine cervical length screening at the time of the anomaly scan

Essentials of a screening programme 1. Screening programme should respond to a recognised need 2. Objectives of screening should be defined at the outset 3. A defined target population 4. Scientific evidence of screening programme effectiveness 5. Programme should integrate education, testing, clinical services & programme

management 6. Quality assurance, with mechanisms to minimize potential risks of screening 7. Should ensure informed choice, confidentiality and respect for autonomy 8. Should promote equity and access to screening for the entire target population 9. Programme evaluation should be planned from the outset 10.Overall benefits of screening should outweigh the harm

Emerging screening criteria since 1968

Andermann et al. WHO Bulletin 2008 http://www.who.int/bulletin/volumes/86/4/07-050112/en/




universal screening the future direction of prevention?

Documents