prevention of stillbirth management of risk factors
TRANSCRIPT
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
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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
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