Prevention of StillbirthManagement of Risk Factors

Alexander HeazellProfessor of Obstetrics

Tommy’s Maternal and Fetal Health Research CentreUniversity of Manchester, UK

@MCR_SB_Research

Stillbirth in HICs: Variation in stillbirth rate

Variation in annual rate reductionsince 2000 across 49 countries

• Fastest decline in rates: Netherlands = 6.8% per annum

• Slowest decline in rates: Slovenia = +0.5% increase

• UK = 1.4% per annum (lowest third of rate of decline in HICs)

Fall Rate Flenady et al. Lancet. 2016 Feb 13;387(10019):691-702.

Conceptual Model – Improving Care and Prevent Stillbirth

Heazell, Recent Advances in Obstetrics and Gynaecology, 2014

Some Risk factors for Stillbirth

Increased Maternal Age

ObesityLow Socioeconomic Group

Smokers

Poor educational attainment

English not first language

Drug Use

Ethnic Minorities Reduced fetal movements

Teenagers

Hypertension

Diabetes

Renal diseasePrevious Stillbirth

Excessive Alcohol

Congenital Anomaly Thrombophilia

High AFP Low PAPP-A

IUGR

Risk factors and Stillbirth

• The majority of stillbirths occur in women with no risk factors (81%)

• Majority confer moderately increased risk– Advanced maternal age (>40) (1.6 - 3.6x)

– Diabetes (2.7x), Hypertension (2.0x)

– Cigarette smoking (1.3-1.6x), Alcohol >5u/wk (2-3x)

– Reduced Fetal Movements (2-3x)

– Small for Gestational Age (19.8x)

– Previous Stillbirth (5x)

Salihu et al. J Obs Gyn Res 2008, Reddy et al. Obstet Gynecol 2010, Heazell and Froen, J Obs Gyn 2005,Kesmodel et al. Am J Epidemiol 2002, McCowan et al. ANZJOG 2007, Gardosi et al. BMJ ,2013.

Observational Studies to identify Associations (Risk Factors)

• Ideal – A prospective cohort study of whole population to study the outcome of interest

• Challenging for infrequent outcomes

• To identify 291 women with late stillbirth (≥28 weeks) would require 100,300 participants

• Alternative approach – Case-control design

• Attempt to minimise bias by conducting study in same populations

MiNESS Case Control Study

• 296 women with late stillbirth (>28 weeks) and 734 controlswere recruited to Midland and North of England Stillbirth Study

Methods• Case - late stillbirth - ≥28 week gestation

• Controls – recruited at same gestation as expected stillbirth profile

• Singleton pregnancy

• No significant congenital abnormality (FASP definition)

• Over 16 years old and able to give informed consent

•Data were collected using a researcher-administeredquestionnaire which included questions on sleep practicesbefore pregnancy, and in the four weeks prior to and onthe night before the interview/stillbirth.

MiNESS Flow Diagram

Results Sleep position – last nightCases Controls Univariable OR Multivariable OR

Sleep duration last night<5.49 129 (44.3) 227 (31.0) 1.94 (1.44 to 2.61) 1.83 (1.24 to 2.68)5.5-8.49 121 (41.6) 413 (56.3) 1.00 (Reference)8.5-9.49 20 (6.9) 55 (7.5) 1.24 (0.72 to 2.15) 1.04 (0.52 to 2.07)9.5+ 19 (6.5) 36 (4.9) 1.80 (1.00 to 3.26) 1.49 (0.72 to 3.08)Number of times up to toilet last night1.0 91 (31.3) 120 (16.4) 2.34 (1.70 to 3.21) 2.81 (1.85 to 4.26)2.1+ 199 (68.4) 613 (83.6) 1.00 (Reference)Maternal going-to-sleep position last night (before stillbirth / interview)Left 140 (48.1) 383 (53.3) 1.00 (Reference)Right 73 (25.1) 220 (30.0) 0.91 (0.65 to 1.26) 0.67 (0.44 to 1.02)Back 19 (6.5) 24 (3.3) 2.17 (1.15 to 4.08) 2.31 (1.04 to 5.11)Tummy 3 (1.0) 4 (0.5) 2.05 (0.45 to 9.28) 1.01 (0.13 to 7.81)Propped 9 (3.1) 15 (2.0) 1.64 (0.70 to 3.84) 0.44 (0.13 to 1.49)Variable 32 (11.0) 76 (10.4) 1.15 (0.73 to 1.82) 0.93 (0.51 to 1.69)Unknown 15 (5.2) 11 (1.5) 3.73 (1.67 to 8.32) 3.33 (1.13 to 9.84)

Results Sleep position – last night

Cases Controls Univariable OR Multivariable ORMaternal Daytime naps in last 4 weeksNever 58 (19.9) 157 (21.4) 1.00 (Reference)Occasionally 49 (16.8) 153 (20.9) 0.87 (0.56 to 1.35) 0.95 (0.54 to 1.66)1-2 per week 47 (16.1) 180 (24.6) 0.71 (0.46 to 1.10) 0.65 (0.38 to 1.13)3-4 per week 44 (15.1) 110 (15.0) 1.08 (0.68 to 1.72) 1.48 (0.83 to 2.64)5-6 per week 22 (7.6) 39 (5.3) 1.53 (0.84 to 2.79) 1.64 (0.77 to 3.47)Everyday 71 (24.4) 93 (12.7) 2.07 (1.34 to 3.18) 2.22 (1.26 to 3.94)Unknown 0 (0.0) 1 (0.1) - -

MiNESS - Population Attributable Risk

Risk Factor Population

exposed

OR PAR 95% CI

Small for Gestational Age 13.8% 7 45.3% 33.6% 56.8%

Nulliparous 40.4% 2.37 35.6% 23.5% 46.8%

3+ parity 7.0% 2.63 10.2% 4.0% 18.9%

Smoking during pregnancy 17.3% 1.94 14.0% 22.3% 37.1%

Obesity 19.5% 1.7 12.0% 3.8% 21.5%

Overweight 29.5% 1.3 8.1% -1.5% 19.5%

No educational

qualifications

4.0% 2.61 6.1% 1.8% 13.0%

Supine going to sleep

position

3.3% 2.17 3.7% 0.5% 9.2%

Bradford-Hill Criteria for CausationCriteria Observation

Analogy The parallel with infant sleeping prone and risk of SIDS is striking.

Biological Gradient These case control studies do not record proportion of the night spent supine, so a biological gradient cannot be determined.

Coherence Coherence between epidemiological and laboratory findings increases the likelihood of an effect. Maternal supine position results in changes indicative of fetal adaptation to hypoxic stress.

Consistency Four case control studies showing association between supine going-to-sleep position

and late stillbirth, the effect size appears to be similar in three different populations

(Australia, UK, New Zealand)

Experiment Evidence of a fall in late stillbirth in New Zealand in the last 5 years which may be due, at

least in part, to documented changes in maternal going-to-sleep position

Plausibility Two biologically plausible mechanisms have been proposed, namely sleep disturbed breathing which is more common in the supine position and/ or inferior vena caval compression and resultant fetal hypoxia.

Specificity There are no data to determine whether the effect of supine-going-to sleep position is

specific for late stillbirth.

Strength The magnitude of the OR is moderate

Temporality Maternal sleep position occurs before the death of the baby.

Comparison with published data

Study Univariate OR for supine sleep

Multivariate OR for supine sleep

Auckland 2011 3.28 (1.46 - 7.34) 2.54 (1.04 - 6.18)

Sydney 2015 6.26 (1.2 - 34)

MCSS 2017 3.63 (1.87 - 7.04) 3.67 (1.74 - 7.78)

MiNESS 2017 2.17 (1.15 - 4.08) 2.31 (1.04 - 5.11)

Potential mechanism

Maternal cardiac output is highest on left, lowest in supine and intermediate on right side in late pregnancy

Fetal oxygen saturation -Changes with maternal position in labour have similar effect

Cardiac Output

4.8

5

5.2

5.4

5.6

5.8

6

6.2

6.4

6.6

6.8

Left lateral Right lateral Supine

L/m

in

Fetal oxygen saturation

42

44

46

48

50

52

54

Left lateral Right lateral Supine

%

Milsom I, et al Am J Obstet Gynecol 1984;148:764-

Carbonne B, et al O+G:1996:88,797

IVCAorta

Awareness of FM associated with Stillbirth

Heazell et al. BMC Pregnancy and Childbirth 2017

MiNESS - FM

• Similar effects seen in case-control studies and large retrospective cohort

• Frequent FMs and hiccups were protectiveHeazell et al. BMJ Open 2018

Placental morphology and function differs in RFM

Density of syncytial knots RFM Normal

Warrander et al. PLoS One 2012

Villous vascularity

45+ years↑ Chronic maternal disease e.g. hypertension, gestational diabetes

↑ and Pre-eclampsia

↑ Increased rates C/S

↑ Postpartum haemorrhage

↑ Postpartum fever

↑ Blood transfusion

↑ Prolonged hospitalisation

↑ Increased preterm delivery↑ Very low BW

↑ NICU admission for neonates↑Stillbirth

↑Neonatal death

>35 years↑ Low birth weight

↑ Preterm birth↑ SGA

↑ Stillbirth•Peak risk at 37-41 weeks

(late stillbirth)

>40 years↑ Low birth weight

↑Preterm birth↑ SGA

↑antepartum and intrapartum stillbirth

2010 vs 1980 Births≥35 years = 20% vs 6%≥40 years = 4% vs 1%

0

50,000

100,000

150,000

200,000

250,000

<20 20-24 25-29 30-34 35-39 >40

Nu

mb

er

of

Pre

gnan

ceis

Maternal Age (Years)1980

2010

Maternal Age and Pregnancy Outcome

Placentas from “normal” uncomplicated pregnancies show evidence of placental dysfunction

Women of AMA:

• 1:43 rate of stillbirth (>40 years)

• Reduced placental efficiency

• Altered placental morphology

• Increased placental nutrient uptake

• Aberrant placental artery function

Lean et al. 2017, Scientific Reports

Social and Behavioural FactorsAdjusted OR

Multiple Deprivation quintile P=0.0025

1 – most deprived 3.01 (1.47, 6.20)2 1.08 (0.50, 2.33)3 1.77 (0.83, 3.77)4 1.22 (0.56, 2.6)5 – least deprived Reference

Work P=0.034

Working ReferenceMaternity leave 1.63 (0.95, 2.80)Non paid work 1.91 (1.01,3.61)Unemployed 2.79 (1.29, 6.02)

Perceived Social stress in last month P=0.01

High 2.09 (1.20, 3.66)

Low Reference

Intimate partner violence P<0.001

No ReferenceNo answer 4.19 (2.61, 6.71)Yes 2.21 (0.69, 7.03)

Summary

• Observational data has identified many associations with stillbirth

– With the exception of SGA and prior stillbirth most risk factors have aOR <3.

• Some important risk factors not within scope of maternity care (but might be ameliorated by it)

• Additional data from Confidential Enquiries

• Develop and test strategies to reduce stillbirth in women with risk factors

Intervention - A Power(ful) Problem

• To detect a 10% fall in stillbirth from 4 per 1,000 to 3.6 per 1,000 would require 371,404 participants in each arm of a trial

• To detect a 10% increase in induction of labour from 30% to 33% would require 3,763 participants

• A trial to demonstrate a 10% reduction in stillbirth could detect a 1% increase in IOL

Borders

Inverness

Dumfries

Stirling

Aberdeen

Dundee

Glas & Ayrshire

Edinb & Fife

Jan April June Oct Dec Mar June Oct Dec April July

2014 2015 2016

AFFIRM Study –Stepped Wedge Cluster Trial

InterventionWritten information for women and education for clinicians Standardised management of women presenting to hospital with decreased FM

AFFIRM ComparisonComponent Control (based on RCOG guideline) Intervention

Information RCOG developed leaflet – picked up by Tommy’s/MAMA

Academy and Kick’s Count.

Women should be advised to be aware of their baby’s

individual pattern of movements. If they are concerned about

a reduction in or cessation of fetal movements after 28

weeks of gestation, they should contact their maternity unit.

No formal FM counting.

AFFIRM Study leaflet given before 24 weeks’ gestation.

More information about when fetal movements should start.

Babies developing a pattern of movements.

Why are babies’ movements important?

Women advised to contact maternity unit if they are

concerned., no gestation specified on the leaflet.

Manageme

nt

Take a history Take a history

FH Auscultate FH to exclude fetal death (Only action if <28w) Auscultate FH to exclude fetal death (Only action if <26w)

CTG CTG to exclude fetal compromise if the pregnancy is over

28+0

weeks of gestation.

CTG to exclude fetal compromise if the pregnancy is over 26+0

weeks of gestation (to be performed within 2h of

presentation).

USS Ultrasound scan assessment should be undertaken as part of

the preliminary investigations of a woman presenting with

RFM after 28+0 weeks of gestation if the perception of RFM

persists despite a normal CTG or if there are any additional

risk factors for FGR/stillbirth. No role for biophysical profile

When a woman recurrently perceives RFM, ultrasound scan

assessment should be undertaken as part of the

investigations. Follow SGA guideline if baby small on USS.

Ultrasound scan for liquor volume within 12h

Ultrasound scan for fetal biometry next working day + LV if not

done and umbilical artery Doppler.

If recurrent RFM, twice weekly CTG and weekly LV and

umbilical artery Doppler.

Delivery No recommendation to deliver infants for RFM alone Consider IOL for women >40w on first presentation with RFM

Consider IOL for women with recurrent RFM >37w with RFM

AFFIRM results

• Study had information from large number of births

– Intervention (n=227,860), Control (n=157,692), Washout (n=23,623) Total (n=409,175)

• Intention to treat analysis of SBs ≥24 weeks

– 4.06 vs 4.4 per 1,000 livebirths aOR 0·90 (0·75–1·07)

– 5 fewer (11 fewer to 3 more)

• On treatment analysis

– 3.09 vs 4.31 per 1,000 livebirths aOR 0.88 (0.76-1.02)

Norman et al. Lancet 2018

AFFIRM Results – Secondary Outcomes

Norman et al. Lancet 2018

Maternal Age - 35-39 study

• Offer of IOL at 39 weeks’ gestation to women over the age of 35

• Primary outcome – Caesarean birth

• Not powered to assess ability to prevent SB

• CS 98/304 in the IOL vs. 103/314 expectant management group (RR 0.99, 0.87–1.14)

• No other adverse effects identified

• A cost–utility analysis based upon quality of life measures and estimates of resource use found that IOL at 39 weeks had cost-saving of £263

Walker et al. NEJM 2016Walker et al. BJOG 2017

Maternal Age – National Data Review

• Potential effect of IOL in nulliparous women at least 35 years of age compared with expectant management using routinely collected data from English hospitals (n=77,327, 2009-14)

• 33% had IOL at 40 weeks

• IOL lower incidence of perinatal death compared to expectant management (0.08 vs. 0.26% (aRR 0.33, 0.13– 0.80) and lower risk of meconium aspiration syndrome (0.44 vs. 0.88%, aRR0.52, 0.35–0.78)

• Increased risk of instrumental delivery (aRR 1.06, 1.01–1.11) and emergency Caesarean section (aRR 1.05, 1.01–1.09).

• High number needed to treat for women aged at least 35, 562 IOLs need to be performed to reduce one perinatal death (would be ~200 for women >40).

The Saving Babies’ Lives Care Bundle

Brings together four key elements of care that are recognised as evidence-based and/or practice:

1. Reducing smoking in pregnancy

2. Risk assessment and surveillance for fetal growth restriction

3. Raising awareness of reduced fetal movements

4. Effective fetal monitoring during labour

30

Launched by NHSE in April 2015 to reduce stillbirth rates –

Pilot sites started intervention from March 2014

Implementing the Care Bundle

Change in Stillbirth over time

Pre/post SBLCB rates

SBLCB launch in Early Implementers

Trend over time

2013 2014 2015 2016 2017

02

46

810

Tot

al S

tillb

irths

/100

0

Pre Rate

4.14

Post Rate

3.31

RR 0.80 (0.71-0.91) p<0.001

Element 1 - Cigarette smoking

2013 2014 2015 2016 2017

510

15

20

Sm

okin

g a

t D

eliv

ery

(%

)

Pre/post SBLCB rates

SBLCB launch in Early Implementers

Trend over time

Pre Rate

14.3

Post Rate

11.8

RR 0.83 (0.80-0.85)

p<0.001

• 56% of women were referred to smoking cessation services (Aim 100%)

• No evidence for improvement in smoking cessation

• Electronic records stated 28.7% of women ceased smoking before SBLCB and 27% after

• 38% of women who smoked reported stopping smoking before birth

Element 2 – Detecting SGA babies

Pre/post SBLCB rates

SBLCB launch in Early Implementers

Trend over time

2013 2014 2015 2016 2017

12

34

56

7

US

scans/w

om

an b

ooked

Pre Rate

3.5

Post Rate

4.4

RR 1.24 (1.20-1.28)

p<0.001

• Increased SGA detected from 33.7% to 53.7% (RR 1.59 1.32-1.92, p<0.001)• Adjusted Rate Ratio of -0.14 (SE 0.06) SB per additional scan P=0.026

Element 3 – Management of RFM

Outcome n Number

% of

women

RFM leaflet received 19 1735 74.4

RFM checklist used 17 339 52.2

Attendances for RFM 19 2171 36.5

Women with RFM who attended 19 1026 77.3

Scanned at every RFM visit 17 322 21.1

Scanned at any RFM visit 17 322 64.9

Women scanned for RFM (patient reported) 19 793 29.4

Heart trace for RFM 19 793 73.5

Monitoring at every RFM visit 17 339 97.4

Monitoring at every RFM visit 17 338 54.7

Women induced due to RFM 18 344 54.7

• 91% of women said they felt they received the right amount of information about monitoring baby’s movements.

• 96% said they monitored their baby’s movements

Secondary Outcomes – Change Over Time

Outcome n

Number

Deliveries

Pre

Rate

Post

RateRR (95% CI)

P

value

Preterm births 17 446,378 7.42 7.90 1.06 (1.03-1.09) <0.001

Preterm singleton

births17 446,378 6.3 6.6 1.05 (1.02-1.08) 0.002

Elective CS 17 452,944 9.86 11.78 1.20 (1.17-1.23) <0.001

Emergency CS 15 386,817 13.7 15.0 1.10 (1.07-1.12) <0.001

Induced Deliveries 18 473,889 26.3 31.4 1.20 (1.18-1.21) <0.001

Instrumental Deliveries 18 473,889 12.3 12.4 1.01 (0.99-1.04) 0.245

Spontaneous

Deliveries18 473,889 63.4 60.4 0.95 (0.95-0.90) <0.001

Ultrasound scans

(per pregnancy)14 449,357 3.5 4.4 1.24 (1.20-1.28) <0.001

NICU admissions§ 14 384,584 3.5 4.1 1.19 (1.11-1.26) <0.001

n; number of Trusts providing data§; from term singleton deliveries (per 100 births)

Conclusions

• UK needs to address stillbirth rates (alongside other challenges in maternity care)

• Significant challenges generating informative data

• Changes in the rate of stillbirth over time

• Changes in other important secondary outcomes

• Incorporate changes iteratively in quality improvement cycle

• Medical / technical solutions do not provide complete solution

Acknowledgements• MiNESS

– All the women who kindly participated

– Recruiting midwives, nurses and obstetricians

– Study funders

• SBLCB Evaluation– Kate Widdows

– Steve Roberts

– Elizabeth Camacho

– Holly Reid

– Matthew Jolly, Julia Walker–Brown and NHSE team

• MBRRACE

• Stakeholder organisations

38