LATEST POSITION & APPOINTMENT

• Clinical Senior Lecturer, Division of Obstetrics and Gynaecology, The

University of Western Australia (2016 to present)
• Maternal Fetal Medicine Specialist, King Edward Memorial Hospital,
Western Australia (2016 to present)

EDUCATIONAL BACKGROUND
• Bachelor of Medicine and Bachelor of Surgery, The University of
Western Australia (2002)
• Doctor of Philosophy, The University of Western Australia (2017)
• Fellow, Royal Australian and New Zealand College of Obstetricians and
SCOTT WHITE Gynaecologists (2014)
• Certification in Maternal Fetal Medicine, Royal Australian and New
King Edward Memorial Hospital
Zealand College of Obstetricians and Gynaecologists (2016)
 Antenatal interventions to
prevent adverse neurological
outcomes for the at-risk fetus
Dr Scott White
MBBS PhD FRANZCOG CMFM

Senior Lecturer in Maternal Fetal Medicine, The University of Western Australia

Maternal Fetal Medicine Specialist, King Edward Memorial Hospital, Western Australia
Overview
• Which fetus is at risk?
• What we know now
• What is being investigated
Identifying the at-risk fetus
• Preterm and early term
• Monochorionic twins and higher order multiples
• Placental dysfunction
• Early-onset fetal growth restriction
• Intrapartum asphyxia
• Genetic conditions and structural anomalies
• Specific complications of pregnancy
Preterm birth
Adverse neurological outcome by gestational age at birth
4

3.5

3
Hazard ratio

2.5

1.5

1
24-27 28-31 32-34 35-36 37-38 39-41 >41
Bourke … White, et al. JAMA Pediatr [Under review 2019]
 Percent of all births

5
6
7
8
9

1994
1995
1996
Preterm birth

1997
1998
1999
2000
2001
2002
2003
2004
Year 2005
2006
2007
2008
2009
2010
2011
Australian preterm birth rate 1994 - 2016

2012
2013
2014
2015
2016
“Early term” birth
• 37 week term/preterm dichotomy is a myth
• Relationship between gestation and outcome extends
beyond 37 weeks
• Neurodevelopmental outcomes in particular
“Early term” birth
Rate of adverse neurological outcome by gestational age at birth
3.5

3
Percent wirh outcome

2.5

1.5

1
32-34 35-36 37-38 39-41 >41
Gestational age at birth (weeks)

Bourke … White, et al. JAMA Pediatr [Under review 2019]

“Early term” birth
• 37 week term/preterm dichotomy is a myth
• Relationship between gestation and outcome extends
beyond 37 weeks
• Adverse sequelae occur across the offspring’s lifecourse:
• Neonatal
• Childhood
• Adulthood
“Early term” birth
• Cortical volume increases by 50% from 34-40 weeks

Serag 2011
www.brain-development.org
“Early term” birth
• Cortical volume increases by 50% from 34-40 weeks
• Increased need for educational assistance
1.4

1.3
Hazard ratio

1.2

1.1

1
37 38 39 40
Gestation at birth MacKay PLoS Med 2010;7(6):e1000289
“Early term” birth
• Cortical volume increases by 50% from 34-40 weeks
• Increased need for educational assistance
• Increased risk of being below educational standard
 “Early term” birth
Risk of being below NAPLAN standard by gestation at birth
1.15

1.1
Hazard ratio

Reading
Writing
1.05 Spelling
Numeracy

1
37 38 39 40
Gestation at birth
Searle ADC Fetal Neonatal 2017;102(5):F409
“Early term” birth
• Cortical volume increases by 50% from 34-40 weeks
• Increased need for educational assistance
• Increased risk of being below educational standard
• Decreased reading score
“Early term” birth
Reading score by gestation at birth

Noble Pediatr 2012;130(2):e257

“Early term” birth
• Cortical volume increases by 50% from 34-40 weeks
• Increased need for educational assistance
• Increased risk of being below educational standard
• Decreased reading score
• Decreased mental and psychomotor development
indices
“Early term” birth
Mental development index Psychomotor development index
by gestation at birth by gestation at birth

Espel PLoS One 2014;9(11):e113758

Multiple pregnancies
• Neurodevelopmental risk determined by:
• Chorionicity:
• Cerebral palsy 8% MC vs 1% DC twins
• Other neurological morbidity 15% MC vs 3% DC twins

Adegbite AJOG 2004;190(1):156; Bolch BMC Pediatr 2018;18:256

Multiple pregnancies
• Neurodevelopmental risk determined by:
• Chorionicity:
• Cerebral palsy 8% MC vs 1% DC twins
• Other neurological morbidity 15% MC vs 3% DC twins
• Birth weight discordance:
• Abnormal neurodevelopment 42% discordant vs 8% concordant MC
• Abnormal neurodevelopment 5% discordant vs 1% concordant DC

Adegbite AJOG 2004;190(1):156; Bolch BMC Pediatr 2018;18:256

Multiple pregnancies
• Neurodevelopmental risk determined by:
• Chorionicity:
• Cerebral palsy 8% MC vs 1% DC twins
• Other neurological morbidity 15% MC vs 3% DC twins
• Birth weight discordance:
• Abnormal neurodevelopment 42% discordant vs 8% concordant MC
• Abnormal neurodevelopment 5% discordant vs 1% concordant DC
• MC complications:
• CP/PVL/microcephaly/severe IVH following laser for TTTS 5-20%
• Abnormal neurodevelopment in 60% of survivors single fetal demise
Adegbite AJOG 2004;190(1):156; Bolch BMC Pediatr 2018;18:256
Antenatal interventions and CP
Antenatal interventions and CP
• Effective
• Magnesium sulfate for preterm birth neuroprotection
• RR 0.68 (0.54, 0.87; 5 studies, N=6145)
Antenatal interventions and CP
• Effective
• Magnesium sulfate for preterm birth neuroprotection
• RR 0.68 (0.54, 0.87; 5 studies, N=6145)
• Probably ineffective
• Repeat AN corticosteroids (vs single)
• RR 1.03 (0.71, 1.50; 4 studies, N=3800)
Antenatal interventions and CP
• Effective
• Magnesium sulfate for preterm birth neuroprotection
• RR 0.68 (0.54, 0.87; 5 studies, N=6145)
• Probably ineffective
• Repeat AN corticosteroids (vs single)
• RR 1.03 (0.71, 1.50; 4 studies, N=3800)
• Ineffective, probably harmful
• Antibiotics for threatened preterm labour with intact membranes
• RR 1.82 (0.99, 3.34; 1 study, N=3173)
• Immediate delivery (vs delayed) for suspected fetal compromise
• RR 5.88 (1.33, 26.02; 1 study, N=507)
Antenatal interventions and CP
• Insufficient evidence
• Antenatal corticosteroids (vs placebo)
• RR 0.60 (0.34, 1.03; 5 studies, N=904)
• Early delivery vs deferred delivery in severe preeclampsia
• RR 6.01 (0.75, 48.14; 1 study, N=262)
• Continuous CTG vs intermittent auscultation in labour
• RR 1.75 (0.84, 3.63; 2 studies, N=13,252)
• Progesterone for prevention of preterm birth
• RR 0.14 (0.01, 3.48; 1 study, N=274)
• Beta-mimetic tocolysis for preterm labour
• RR 0.19 (0.02, 1.63; 1 study, N=246)
Antenatal interventions and CP
• Insufficient evidence
• Antenatal corticosteroids (vs placebo):
• RR 0.60 (0.34, 1.03; 5 studies, N=904)
Antenatal interventions and CP
• Insufficient evidence
• Antenatal corticosteroids (vs placebo):
• RR 0.60 (0.34, 1.03; 5 studies, N=904)

• Antenatal corticosteroids for fetal lung maturation:

• 30 studies, N=8154

Roberts Cochrane Database Syst Rev 2017;3:CD004454

Studies assess different outcomes
Antenatal corticosteroids in PTB:
• Significantly reduced intraventricular haemorrhage
• RR 0.55 (0.40, 0.76; 16 studies, N=6000)
• Strong trend to reduced cerebral palsy
• RR 0.60 (0.34, 1.03; 5 studies, N=904)
• Insufficient evidence for neurodevelopmental delay
• RR 0.64 (0.14, 2.98; 1 study, N=82)

Roberts Cochrane Database Syst Rev 2017;3:CD004454

Long-term outcomes aren’t long-term
Long-term outcomes aren’t long-term
Long-term outcomes aren’t long-term
• Neuroprotective magnesium sulfate
• At 2 years:
• Decreased cerebral palsy RR 0.68 (0.54, 0.87)
• At school age (6-11 years):
• No difference in cerebral palsy, OR 1.26 (0.84, 1.91)
• No difference in abnormal motor function, OR 1.16 (0.88, 1.52)
• Possible reduction in mortality, no harm

Crowther PLoS Med 2017;14(10):e1002398

Doyle JAMA 2014;312(11):1105
Interventions in current use
• Preterm birth
• Harm-minimisation strategies
• Neuroprotective MgSO4
• Antenatal corticosteroids
Interventions in current use
• Preterm birth
• Harm-minimisation strategies
• Neuroprotective MgSO4
• Antenatal corticosteroids
• Prevention strategies
• Tocolysis
• Allowing time for corticosteroids
• Permitting transfer to an appropriate facility
• No direct benefit in preterm birth reduction
• Progesterone in asymptomatic cervical shortening
• IPD meta-analysis shows survival advantage and greater reductions in PTB at earlier gestations
• Likely to translate to reductions in long-term complications but not adequately studied
 The State of Western Australia

9.0%
GA: <37

8.0%

7.0%

6.0%
2013 2014 2015

Initiative

PTB singleton rates:

• 2012: 7.4%
• 2013: 7.5%
In 2015, the rate of PTB was reduced by 7.6%
• 2014: 7.2%
• 2015: 6.9%
Newnham, White AJOG 2017;261(5):443
 The State of Western Australia

0.9% GA: 20-27 GA: 28-31

0.7%

0.7%

0.5%
0.5%

0.3% 0.3%
2013 2014 2015 2013 2014 2015

Initiative Initiative

GA: 32-36
7.0%
The rates of PTB were decreased:
• 32 – 36 week group
6.0% • 28 – 31 week group
• 20 – 27 week (but not stat sig.)
5.0%
2013 2014 2015

Initiative

Newnham, White AJOG 2017;261(5):443

Number of preterm births averted in 2015 compared with 2013

GA (w) 20-27 28-31 32-36 <37

Cases 25 22 150 196

Newnham, White AJOG 2017;261(5):443

 King Edward Memorial Hospital
28%

26%

Singleton preterm birth rate

24%

22%

20%

18%

16%

14%

12%

10%

8%
2013 2014 2015 2016 2017

* Preliminary data, unpublished

Interventions in current use
• Anti-D prophylaxis
• Dramatic reduction in severe fetal anaemia
• Neonatal alloimmune thrombocytopaenia
• Severe bleeding complications in 1:11,000 pregnancies
• Weekly IVIG prevents ICH in 98.7% of at risk pregnancies
• Intrauterine platelet transfusion effective but has 11% complication rate, 26% of
which were fatal
Interventions in current use
• Twin-twin transfusion syndrome
• Complicates 10-15% of monochorionic twin pregnancies
• Half severe enough to warrant treatment
• Untreated severe TTTS has >90% mortality rate for both twins
• Generally occurs between 16 and 24 weeks
• Fetoscopic laser photocoagulation vs serial amnioreduction:
• 6 year neurodevelopmental assessment
• Severe morbidity less in laser than amnioreduction, HR 0.61 (0.49, 0.90)
• Solomon vs selective technique
• Reduction in recurrent TTTS, TAPS, death, neurological disability

Senat NEJM 2004;351(2):136

Interventions in current use
• Universal cord lactate measurement
• Introduction of routine umbilical cord gas analysis to a tertiary unit in
Western Australia
• Subsequent reduction in acidaemia and high lactate
• pH < 7.12: OR 0.75 (0.59, 0.96)
• Lactate > 6.7: OR 0.37 (0.29, 0.49)
• Reduction in neonatal nursery admissions, likely to translate to improved
neurodevelopmental outcomes
Interventions in current use
• Universal cord lactate measurement
• Introduction of routine umbilical cord gas analysis to a tertiary unit in
Western Australia
• Subsequent reduction in acidaemia and high lactate
• pH < 7.12: OR 0.75 (0.59, 0.96)
• Lactate > 6.7: OR 0.37 (0.29, 0.49)
• Reduction in neonatal nursery admissions, likely to translate to improved
neurodevelopmental outcomes
• Prospective study in South Africa
• Reduction in acidosis at birth and perinatal mortality following
introduction of universal lactate measurement White ANZJOG 2010;50(4):318
Allanson, abstract presented, as yet unpublished
Future possibilities
• Reproductive carrier screening
• Australian bodies now recommend offering preconception genetic
carrier screening to all couples
• Potentially will allow preimplantation diagnosis to avoid
pregnancies affected by severe neurological conditions
Future possibilities – melatonin
• Placental dysfunction associated with free oxygen radical generation and
oxidative stress
• Melatonin has antioxidant activity:
• Direct free radical scavenger
• Upregulator of antioxidant enzymes
• Maternal melatonin in FGR associated with reduced oxidative stress and lipid
peroxidation in ovine model
• Histological brain injury ameliorated
• Neurodevelopmental outcomes normalised
• RCT currently in progress (PROTECT-Me)
• Severe FGR, 23-32 weeks melatonin vs placebo, 332 participants total
Future possibilities – sildenafil
• Sildenafil and intrapartum fetal distress
• Up to 20% of cerebral palsy may have intrapartum origin/contribution
• Sildenafil promotes pelvic vasodilatation and may increase uterine blood
flow
• Postulated that this will reduce intrapartum fetal compromise and either
caesarean section or fetal asphyxia
• Small pilot study showed promise
• RCT currently in progress (RIDSTRESS)
• 1000 women, uncomplicated term pregnancies
Future possibilities
• Preventing preterm birth may not prevent its complications
• Prolonging exposure to hostile intrauterine environment may not be in
the fetus’s best interests
• Anti-inflammatory agents effective in reducing intrauterine
inflammation in chorioamnionitis
Future possibilities
• Novel placenta-permeable antibiotics with appropriate antimicrobial
spectrum may treat intrauterine infection
Future possibilities
Future possibilities
Future possibilities

Intravenous Intra-amniotic
Future possibilities

Intravenous Intra-amniotic
Keelan et al Front Immunol 2016
Social determinants of health
Summary
• Assessment of efficacy of interventions is challenging
• Different end-points
• Short follow-up times
• Heterogeneous participants with superficially similar condition
• Current interventions
• Genetic conditions – preconception screening
• Structural anomalies – prenatal diagnosis improving
• Preterm birth, intrauterine inflammation and infection
• Some success in prevention, but much still to do
• Harm minimisation strategies: MgSO4, AN corticosteroids beneficial
• Risk of prolonged exposure to an adverse intrauterine environment
• Rare conditions with specialist treatments
• NAIT, TTTS, Rh(D) isoimmunisation
• Social determinants of health
Summary
• The future
• Better prediction and prevention of preterm birth
• Treating intrauterine inflammation
• Treating intrauterine infection
• Antioxidant therapy
• Vasodilators to avoid intrapartum asphyxia