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Intrauterine Growth RestrictionUpdate

Danny Wu, MBChBKaiser PermanentePerinatology

Oct 2013

Disclosure

• No commercial interests related to topics presented

Pretest Question 136 year old G1P0 with history of chronic hypertensionBP well controlled with labetalol 100mg BIDSingleton pregnancy IUGR at 37 weeksEFW at 9th percentile by Hadlock Normal amniotic fluid. Normal NST. Normal Doppler of umbilical arteryShould delivery be offered?

Yes

No

90%

10%

1. Yes2. No

Pretest Question 2Patient diagnosed with IUGR (3rd percentile ) at 28 weeksNormal amniotic fluid. Normal NSTUterine artery Doppler shows absent end diastolic flowDelivery should be offered

Ye

s

No

42%

58%

1. Yes2. No

2

Pretest Question 3G1P0 at 38 weeksIUGR at 3rd percentile Induction of labor is associated with an increased risk of cesarean section compared with expectant management

Tru

e

Fa

lse

28%

72%

1. True2. False

Pretest Question 430 year old G2P1 healthy individualPrior pregnancy was only complicated by IUGR near termInduced labor at 39 weeks to deliver a low birth weight infantLow dose aspirin will modify recurrence risk

Tru

e

Fals

e

55%

45%1. True2. False

Outline

• Definition• Implications of IUGR• Etiology• Diagnosis

– Growth Curves• Management

– Fetal cardiovascular changes by Doppler– Umbilical artery, MCA, Venous

• Timing of delivery– RCTs

• Recurrence

In-utero Growth Restriction

• ACOG defined IUGR as EFW < 10th percentile• 4 million birth per year -- 400,000 babies are

IUGR• Consequences

– At birth and in infancy– Childhood and adult life : Barker Hypothesis

• Risk of hypertension, hypercholesterolemia, coronary heart disease, impaired glucose tolerance and diabetes

• Enormous burden

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Etiology• Maternal

– Chronic disease ( eg cHTN, DM, SLE, APLS )– Pregnancy related hypertension

– Smoking and substance abuse ( eg alcohol, cocaine ) – Malnutrition– Teratogens (eg anticonvulsants)

• Fetal– Genetic disorder: chromosomal ( eg T13,T18 T21), genetic

syndromes– Structural ( eg gastroschisis, CHD ) – Infection: eg CMV, toxo, rubella ( <5% of all IUGR )

– Multiple ( more common in mo/di than di/di )• Placental

– Chorangioma, Confined placental mosaicism– Abruption

Perinatal Mortality and Morbidity

Perinatal Morbidity

• Increased risk of spontaneous or induced preterm births– Preterm infants: NEC, need for respiratory

support• Neonatal Complications:

– Neonatal asphyxia– Meconium aspiration– Hypoglycemia– Metabolic abnormalities– Polycythemia

Long Term Sequelae

• Low et al– 218 “high risk neonates” followed up age 11– 77 (35%) learning difficulties– IUGR independent risk factor (30/77)

• Blair et al– Strong association of CP and IUGR among

neonates >33 weeks

Low JA, Handley-Derry MH, Burke SO, et alAm J Obstet Gynecol 1992; 167:1499.

Blair E, Stanley F:Am J Obstet Gynecol 1990; 162:229.

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Barker Hypothesis

• Barker et al found an increased risk of cardiovascular disease and low birthweight in UK

• Insulin resistance, obesity

• Others have reported association with bone density, schizophrenia, breast cancer and asthma

Barker DJP, Robinson RJ, ed. Fetal and Infant Origins of Adult Disease, London: British Medical Journal; 1992.

Gluckman PD, Hanson MA, ed. Developmental Origins of Health and Disease, Cambridge: Cambridge University Press; 2007.

Screening for IUGR

• All pregnant patients should be screened for risk factors

• Fundal heights after 24 weeks– Sensitivity 27-86% specificity 80-90%– Limitations with obesity, multiple gestation,

fibroid

• Consider USS if risk factors present

ACOG Technical Bulletin No. 134 May 2013

Screening for IUGR

• Routine 3rd trimester USS – For low risk unselected populations does not

confer benefit on mother or baby.– 8 trials recruiting 27024 women were included– Screened group has a higher C-section rate,

but not statistically different– Not recommended

Bricker et al Cochran Database Syst Review 2008

Growth Curve

Customized or not ?

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Growth Curves : Population Customized Growth Curve

• Gardosi et al – proposed standards according to individual

growth potential calculated for each pregnancy

– Standard are adjusted according to maternal characteristics ( ht, wt, parity, ethnic origin ) are considered

– Pathological process are excluded ( eg DM, smoking and prematurity )

Customized Growth Curve

Gardosi J, Francis A. Adverse pregnancy outcome and association with smallness for gestational age by customised and population based birthweight percentiles .AmJ Obstet Gynecol 2009;201:28.e1-8.

Customized growth curve

• Other studies do not find it beneficial– Hutcheon et al1

• Cohort of 783303 births• Use of customized curve showed no advantage

– Grobman et al 20132

• Secondary analysis of the BEAM study• Individualized growth curve does not improve the

association or prediction of CP or death by age 2

1. J. A. Hutcheon et al “Customised birthweight percentiles: does adjusting for maternal characteristics matter?” International Journal of Obstetrics and Gynaecology, vol. 115, no. 11, pp. 1397–1404, 2008 2. Grobman et al. The association of cerebral palsy and death with small-for-gestational-age birthweight in preterm neonates by individualized and population-based percentiles. Am J Obstet Gynecol 2013;209:340.e1-5.

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Symmetric vs Asymmetric

• Symmetric– All parts have same degree of growth

• Asymmetric– Head sparing

• Doppler studies probably more helpful

Doppler

Umbilical Artery (UA)Middle Cerebral Artery (MCA) Ductus Venosus (DV)

Fetal Circulation Dopplers

placenta

ArterialUmbilical Artery

MCA

VenousUmbilical Vein

Ductus Venosus

Uterine artery

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Umbilical Artery Doppler

Doppler waveform represents downstream impedance to flow

Doppler Waveform Analysis

Umbilical Artery Doppler

• As placental insufficiency worsens, diastolic flow progressively decreases

Morrow RJ; Adamson SL; Bull SB; Ritchie JW SOAm J Obstet Gynecol 1989 Oct;161(4):1055-60.

Decreased Absent Reversed

30% 70%Abnormal Vasculature

Absent End Diastolic Flow

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Reversed End Diastolic Flow Perinatal Outcomes

• Absent or reversed flow is associated with adverse perinatal outcome

• It may be present for weeks before additional sign of fetal compromise occurs

Doppler in High Risk Pregnancy

• Eleven RCTs involving nearly 7000 women were included

• Reduction in perinatal deaths (OR 0.71)

• Fewer inductions of labor (OR 0.83)

• Fewer admissions to hospital • No difference fetal distress in labor

• No difference caesarean delivery

Cochrane Database Syst Rev. 2000;(2):CD000073

Routine Doppler in Low Risk Pregnancy

• Not Recommended• Five trials were included which recruited

14,338 women• No benefit

Cochrane Database Syst Rev. 2008

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PhysiologicalChanges

Increased placental vascular resistance

Shunting to vital organs“Brain-sparing”

Impaired cardiacfunctions

UA S/D increases

MCA P/I decreases

Abnormal venous flow

Doppler Changes

MCA Doppler

Brain Sparing Effect

Cerebral Circulation“Brain Sparing Effect”

Cerebral Blood Flow

• Hypoxemia

• Hypoxemia + Acidemia

MCA Doppler1. Fetus at rest2. Circle of Willis3. Zoom – MCA 50% of

screen4. Sample volume 1mm

placed between origin of carotid and the middle of the artery

5. Angle between USS and blood flow = 0°

6. Consistent waveforms7. Repeat 3 times

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Doppler Waveform Analysis Example of an MCA Doppler tracing at 27 weeks

Middle Cerebral ArteryIUGR

MCA PI PO2

MCA PI PO2 2 – 4 SD

MCA PI PO2 < 4 SD

Venous Dopplers

Reflects fetal cardiac function

Predictive of adverse perinatal outcome

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Ductus Venosus

Qualitative Assessmnet

• Blood flow should always be antegrade

• Absent or reversed flow is alwaysabnormal

SD

A

Semi-quantitative Assessment

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Outcomes related to Doppler changes

Baschat et al Ultrasound Obstet Gynecol 2006; 27: 41–47

Venous Doppler abnormalityis the strongest predictor

Doppler Abnormality Perinatal Mortality

SD elevated 5.6%

AEDF/REDF 11.5%

Venous 38.8%

Baschat.Ultrasound Obstet Gynecol 2004; 23: 111–118

Survival Rate by GA

Baschat et al Obstet Gynecol vol 109 , no.2(1), 2007

Neonatal Mortality

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Intact Survival ACOG Opinion on Doppler Use in IUGR

• Recommend Umbilical artery Doppler– In conjunction with standard fetal surveillance

(NST, BPP)– It provide insight into underlying etiology– May affect timing of delivery

• Role of assessments of MCA and DV remains uncertain

Timing of Delivery

• Limited options:1) Wait2) Deliver

• Gestational age remains a major factor for adverse perinatal outcome especially in very preterm infants

Optimal Timing of Delivery

• Despite over 10000 publications on the topic, confusion remains– Definition– IUGR is not a homogenous group – Retrospective data with different threshold for

delivery

• Timing of delivery for early IUGR is highly controversial

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Growth Restriction Intervention Trial GRIT Study

• 548 preterm IUGR ( 24 – 36 wks )

• Uncertainty regarding delivery

• Randomized to delivery or observation until clinical course is clear

• No difference in mortality• No difference in long term outcome

– Age 6 to 9 years of age

1. The GRIT Study Group. A randomized trial of timed delivery for the compromised preterm fetus: short term outcomes and Bayesian inter- pretation. BJOG 2003;110:27-32. 2. Walker et al : The Growth Restriction Intervention Trial: long-term outcomes in a randomized trial of timing of delivery in fetal growth restriction. Am J Obstet Gynecol 2011;204:34.e1-9.

DIGITAT Study

• Disproportionate Intrauterine Growth Intervention Trial at Term

• Multicenter trial done in the Netherlands• Women with singleton pregnancy beyond 36+

weeks with suspected IUGR– 321 randomised to induction

– 329 randomised to expectant monitoring

• Primary outcome – composite measure of adverse neonatal outcome ( not powered to detect difference in stilbirth )

Boers et al BMJ 2010;341:c7087

DIGITAT

• Result– No difference – C-section rate similar in both groups

• 14.0% induction vs 13.7% expectant

– Follow-up studies• Neonatal morbidity1

– No difference

• Neurodevelopment and behavior2

– No difference

1. Boers KE, van Wyk L, van der Post JAM, et al. Neonatal morbidity after induction vs expectant monitoring in intrauterine growth restriction atterm: a subanalysis of the DIGITAT RCT. Am J Obstet Gynecol 2012;206:344.e1-72. van Wyk L, Boers KE, van der Post JAM, et al. Effects on (neuro)developmental and behavioral outcome at 2 years of age of induced laborcompared with expectant management in intrauterine growth-restricted infants: long-term outcomes of the DIGITAT trial. Am J Obstet Gynecol 2012;206:406.e1-7.

Trial of Umbilical and Fetal Flow in Europe

( TRUFFLE )

• Trial performed between 2005-2010

• Participants– Singleton fetus 26-32 weeks– AC < 10th percentile with elevated UA PI

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TRUFFLE• Randomise to delivery by

– CTG abnormality– Early venous abnormality– Late venous changes

• Primary outcome – neurodevelopment age 2

• 511 patients entered randomization– 2005 and 2010– Information of intervention not disclosed yet

Lee et al : Ultrasound Obstet Gynecol 2013; 42: 400–408

What Does ACOG Recommend?

• Isolated IUGR– Deliver at 38 0/7 to 39 6/7 weeks

• IUGR with additional risk factors– eg oligohydramnios, abnormal Doppler,

maternal risk factors or co-morbidities– Deliver between 34 0/7 – 37 6/7 weeks

ACOG Technical Bulletin no 134 May 2013

ACOG

• If delivery for IUGR is anticipated before 34 weeks– NICU– MFM– Steroid– If under 32 weeks, magnesium for

neuroprotection

ACOG Technical Bulletin no 134 May 2013

Intrapartum Management

• Uteroplacental insufficiency may be exacerbated by labor

• Oligohydramnios

• Higher risk of cesarean section

• Close monitoring in labor is indicated• Obtain cord gases

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Recurrence

• Recurrence risk – Netherlands 1999-20071

• 12943 women identified with IUGR in first pregnancy

• The risk of SGA in the second pregnancy (23% vs 3.4%; adjusted odds ratio, 8.1)

– Recurrence risk is related to severity of IUGR in first pregnancy2

1. Voskamp et al. Recurrence of small-for-gestational-age pregnancy: analysis of first and subsequent singleton pregnancies in The Netherlands.Am J Obstet Gynecol. 2013;208(5):374.e12. Patterson et al . Birth weight percentile and perinatal outcome: recurrence of intrauterine growth retardationObstet Gynecol. 1986;68(4):464

Prevention

• Avoid modifiable risk factors ( eg smoking, poor nutriton )

• Aspirin has not been shown to be effective by larger RCT1

• Dietary changes, supplements, bedrest do not prevent FGR

1. CLASP: a randomised trial of low-dose aspirin for the prevention and treatment of pre-eclampsia among 9364 pregnant women. CLASP (Collaborative Low-dose Aspirin Study in Pregnancy) Collaborative Group. Lancet. 1994;343(8898):619

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