Update on Fetal Growth Restriction Brian L. Shaffer, MD Associate - - PowerPoint PPT Presentation

6/14/2019 1

Update on Fetal Growth Restriction

Brian L. Shaffer, MD Associate Professor Maternal Fetal Medicine Doernbecher Fetal Therapy June 13, 2019

Disclosures

• I have nothing to disclose

Disclosures

• I have nothing to disclose

Objectives: Update on Fetal Growth Restriction

• Definition/Terminology

– Prenatal vs. Neonatal

• Outcomes associated with FGR
• Diagnosis
• Etiology
• Work-up
• Surveillance/Management
• Treatment?

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Fetal growth restriction: Birthweight?

Birthweight: Sum of physiologic & pathologic processes during gestation – growth potential +/- environment Influences on Birthweight: Many!

• Maternal characteristics: Height & Weight, Parity, Geo

ancestry, Social, Nutrition, etc.

• Paternal genes, Conflict between maternal/paternal
• Intrinsic fetal characteristics – Genetics, Fetal Sex
• Others: Altitude, Air quality, Pollution
• Medical (Maternal/Fetal/Placental) – Etiology

FGR: Scope of the issue

Stillbirth: 1.5%  2.5% at <5th%

• Greatest risk (severe, early onset)
• Absolute risk of SGA ↑ with decreasing GA

Morbidity: IVH, NEC, RDS, Asphyxia, Pulmonary HTN, Seizures, Hypoglycemia, Hyperbilirubinemia, Hypothermia Neonatal Mortality - ↑preterm, ↑<5th, ↑↑<3rd Childhood: Neurodevelopment - ↓ Motor, Cognitive & Language performance Adult onset: HTN, ↑ Lipids, CAD, DM, Obesity

SGA: Define in Neonates?

Small for Gestational Age (SGA) - Neonatal Birthweight Who is at risk for poor outcome?

• <10th for GA (most common)
• Importance of

Gestational age

• 2500gm  NICU
• Controversy!

Buene 2017 J Pediatrics

SGA: Define in Neonates?

Small for Gestational Age (SGA) - Neonatal Birthweight Who is at risk for poor outcome?

• <10th for GA (most common)
• Importance of

Gestational age

• 2500gm  NICU
• Controversy!

Buene 2017 J Pediatrics

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FGR: Methods of Screening

Fundal Height: FH >3cm from GA – measuring 33 at 37 weeks FH Chart - Intergrowth-21st

• International cohort to determine norms for FH
• Low risk, normal outcome pregnancies

Limitations: multiples, obesity, fibroids  US

Papageorghiou AT BMJ 2016

FGR: Screening FGR: Definition for Fetal Growth Restriction

Prenatal US: <10th centile – most common US: Fetal biometry-EFW: HC, BPD, AC, FL, +/- HL Number of different growth charts (e.g., Hadlock) Rationale: Timely intervention to ↓ morbidity & mortality Screening  Intervention (monitoring/IOL), Anxiety, $, F+ Does not take into account:

• Any maternal biometric characteristics, maternal/paternal

BW, geographic ancestry, etc.

• Any measure for constitutionally small vs. restricted

growth potential

FGR: Geo Ancestry

5th% (grams) White 2790 Hispanic 2633 Black 2622 Asian 2621 White curve 15% - IUGR (<5th)

Buck Louis. Am J Obstet Gyencol 2015

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FGR: Geo Ancestry

Buck Louis. Am J Obstet Gyencol 2015

FGR: Rationale & Challenges of screening via US

Traditional screening: fail to identify ~80% Definition <10th centile (US)

• EFW 25th% - “programmed” for 85th% -- Miss
• EFW ↓ from 68th 17th% from 28-32 weeks -- Miss
• EFW 10th – constitutionally 10th – False Positive

No clear evidence of benefit

Gardosi J 2011 Paediatr Perinat Epidemiol; Figueras F 2011 AJOG

FGR: Rationale & Challenges of screening via US

Difficult?

FGR: Challenges with parental screening via US

Customized growth chart? Maternal height, pre-pregnancy weight, parity, ethnicity, fetal sex  Fetal growth potential Rationale: Distinguish FGR from Constitutional Improve detection? Lower unnecessary intervention? Very Promising No clear evidence of benefit Not recommended by ACOG/SMFM

Gardosi J 2011 Paediatr Perinat Epidemiol; Figueras F 2011 AJOG Berkley E, et al. for SMFM AJOG 2012

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FGR: Importance of Centile/Fluid and Doppler

<10th vs. <5th vs. <3rd (PORTO) Prospective, n>1100, 5% FGR, ~25% went to NICU

Adverse Outcomes: IVH/PVL, NEC, HIE, BPD, Sepsis, Death (2.5%)

3rd-10th%  2% adverse outcomes, no mortality <3rd%  6% adverse outcomes, 1% mortality <3rd & Oligo  10% adverse outcomes <3rd & Abnl UA  17% adverse outcome Abnl UA - ↑ PI, Absent EDF

PORTO Unterscheider J 2015 AJOG

FGR: Importance of Symmetry

Symmetrical: ~20-30% All biometry restricted

• Potential global impairment early in gestation

Asymmetrical: ~70-80% Response late in gestation to pathologic process  Fetus favors vital organs – redistributed nutrients (brain/heart) rather than abdominal (Liver, fat, kidneys)

FGR - Etiology

Intrinsic Fetal Maternal Environment Maternal Placenta

Audience Poll

29 yo G2P1001 at initial prenatal visit. LMP c/w 8 weeks sono. Prior pregnancy with FGR and SGA at 37 weeks. Neonate spent 14 days in NICU. What is chance of recurrence?

• A. 2-5% if there are no modifiable risk factors
• B. 10-12% and if so your child will have

neurodev delays

• C. Can’t determine that until 20 weeks

ultrasound

• D. 18-20% if there are no modifiable risk factors
• E. 35-40% if normal maternal/paternal size &

BW

37% 2% 7% 42% 12%

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FGR - Etiology

Intrinsic Fetal

Genetic – Aneuploidy (T13 & T18), Single gene, UPD, Syndromes (Russel-Silver) Infection – CMV, Toxo, HSV, Varicella, Malaria (worldwide), Rubella, Syphilis. Structural malformation – gastroschisis,

• mphalocele, CDH, congenital cardiac

malformation

FGR - Etiology

Placenta

Aneuploidy Confined placental mosaicism Placental mesenchymal dysplasia Ischemic placental disease Infection – CMV, Malaria Cord – Velamentous, Marginal, SUA Structural –Bilobate, circumvallate, hemangioma (weak association) Morbidly adherent placenta/previa not associated with FGR

FGR - Etiology

Maternal

Maternal

Medical – Numerous cHTN, CRI, DM, Lupus, APA syndrome, Cardiac, Pulmonary, Anemia, Sickle cell, Uterine Malformation, Radiation Obstetric – Pre-e, Abruption, Multiples Substance – Tobacco, EtOH, drugs, Pollution Teratogen – Medications, Radiation Weight/Nutrition – Poor gain, Nutrition Risk – ART, Interpregnancy interval, Altitude, Age, Biochemical markers SGA not associated with thrombophilia

FGR: Work-up & Management – 2nd Trimester

Diagnostic

US +/- Echocardiogram

• Fetal Survey  Structural malformation, Aneuploidy, Syndrome

Amniocentesis, PUBs, Cord blood – CMA, Karyotype, Gene

• Early (20-24 wks), Severe (<5th), Symmetric
• Soft marker(s), Structural malformation (Cardiac, CDH)

Serum Screening: cf DNA (high suspicion for trisomy 18) Infection: Maternal hx, US features Serum/Amniocentesis

• CMV, toxoplasmosis, rubella, varicella, malaria, zika
• Titers, PCR amniotic fluid

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FGR: Work-up & Management 3rd trimester

3rd trimester – FGR/Uteroplacental insufficiency Ultrasound

Assess for structural malformations Serial biometry q2-4 weeks

Surveillance

BPP &/or NST/AFI Doppler – Umbilical artery, +/- Ductus Venosus

Management: Admit/BMZ/More frequent surveillance Delivery timing APA: <34 (Placental insufficiency, Pre-eclampsia)

FGR: Management Dopplers Umbilical Artery Ductus Venosus

Umbilical Vein Middle Cerebral Artery

Kennedy AM 2019 Radiographics

Audience Poll

31 yo G1 at 37 weeks with FGR. EFW is <10% (7th centile) with normal UA S:D ratios/PI index, no structural

• malformations. AFI is 6cm with 2.1cm pocket,

Please choose optimal management

• A. A: Continue weekly UA doppler and NST/AFI, 39

wk IOL

• B. B: IOL now - oligohydramnios
• C. C: Counsel regarding low risk of adverse
• utcome, expectant management until 41 weeks
• D. D: NST/BPP – NPO for Cesarean if ≤8/10
• E. E: Contraction stress test – CD if positive

nonreactive

64% 25% 4% 4% 3%

FGR: Management

Ultrasound-Doppler

Normal Umbilical Artery (S:D ratio, Pulsatility Index) – low likelihood of adverse outcome (1-2%)

Features with greater rates of adverse outcome/death

UA: Absent EDF or reversal DV waveform abnormalities MCA – Possible adjunct / Cerebro Placental Ratio – CPR PI MCA/PI UA

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FGR: Management

Ultrasound-Doppler

Normal Umbilical Artery (S:D ratio, Pulsatility Index) – low likelihood of adverse outcome (1-2%)

Features with greater rates of adverse outcome/death

UA: Absent EDF or reversal DV waveform abnormalities MCA – Possible adjunct / Cerebro Placental Ratio - CPR

Kennedy AM 2019 Radiographics

FGR: Management

Features with greater rates of adverse outcome/death

UA: Absent EDF or reversal DV waveform abnormalities MCA – Possible adjunct / Cerebro Placental Ratio - CPR

FGR: Management

Features with greater rates of adverse outcome/death

UA: Absent EDF or reversal DV waveform abnormalities MCA – Possible adjunct / Cerebro Placental Ratio - CPR

Kennedy AM 2019 Radiographics

FGR: Management

Features with greater rates of adverse outcome/death

DV waveform abnormalities MCA – Possible adjunct / Cerebro Placental Ratio - CPR

Kennedy AM 2019 Radiographics

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FGR: Management

Features with greater rates of adverse outcome/death

MCA – Possible adjunct Cerebro Placental Ratio

• CPR

PI MCA/PI of UA Lower CPR  Adverse outcomes

Berkley E, et al. for SMFM Am J Obstet Gynecol 2012

FGR: Management GA, Doppler and BPP

Delivery timing: GRIT, DIGITAT, TRUFFLE Maximize GA/growth and Minimize adverse outcomes Etiology (aneuploidy/infection) Gestational Age

<32 weeks, <28 weeks, Term Mortality ↓ 1-2%/day remain in utero (26-29 weeks) Nonintervention – 23-25 weeks severe IUGR/Palliative

Doppler – UA and DV BPP – fluid

Audience Poll

28 yo G1 at 35 weeks with FGR (EFW <10th) centile. She is 5’9” and weighed 9lbs at birth. The fetus is a male. PMHx is negative. She uses tobacco – 1/2ppd. Your management?

• A. A: UA Doppler but warn of increases in

interventions/IOL

• B. B: NST – if nonreactive - UA doppler
• C. C: UA Doppler, if normal IOL at 39 weeks
• D. D: 2/week NST/AFI, delivery at 37 weeks
• E. E: UA Doppler but warn of increased risk of

CD

17% 12% 2% 28% 41%

FGR: Importance of UA Doppler in FGR

UA Doppler ↓ IOL (RR 0.9) ↓ CD (RR 0.9) ↓ Perinatal death (RR 0.7) NNT – 203 No increase in unnecessary intervention

Berkley E, et al. for SMFM Am J Obstet Gynecol 2012

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FGR: Management GA, Doppler and BPP

Recommend Delivery Any GA - Abnormal Ductus Venosus 32 wks UA - Reversed end diastolic flow 34 wks UA – Absent diastolic flow 37 wks – Increased S:D/Pulsatility index with Oligo 38-40 wks – Normal UA Doppler None past 40 weeks

Berkley E, et al. for SMFM Am J Obstet Gynecol 2012

FGR: What can be done to treat/prevent FGR?

Nutritional regimen – individualized counseling

• ↑ Consumption of fish, low fat meat, grains, fruits, vegs
• Low salt diet
• Supplementation: Fe, Zinc, Ca, protein, Mg, Vitamin D
• Baby ASA (can prevent a subset of pre-e), LMWH

Not likely effective, not likely harmful. Inpatient or outpatient Bed rest/Limitation of activity Not effective & harmful ↑ VTE, Negative psychosocial effects, Deconditioning

FGR: What can be done to treat FGR?

Phosphodiesterase-5 enzyme inhibitor – Tadalafil/Sildenafil

Early onset, severe FGR Improved fetal growth (Sildenafil) Early, non-randomized reports

• Pregnancy with pre-e, FGR  Lower BPs
• Improved growth velocity, reduce CD (Tadalafil) ?safety

Dutch RCT STRIDER

No benefit; ↑ Neonatal death – Pulm HTN

FGR: What can be done to treat FGR?

Statins – Pravastatin

Prevent fetal glucocorticoid response – improve growth Improve pre-e, improved survival (APS) Limited data to date

Antihypertensive in chronic HTN

No improvement in fetal growth

Smoking Cessation ~13% of FGR

RR 1.3-10 for SGA infant Eliminate smoking - Total SGA infants ↓ by 12%

Quit in 1st TM – no impact on birthweight

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Conclusions – FGR

• FGR is associated with adverse perinatal outcomes
• Fundal height/Increased risk for FGR – Utilize US
• Definition: <10th centile

– Continued interest in individualized growth curve

• Workup- Maternal/Fetal/Placental

– GA, US, Severity, Serum/Diagnostic testing

• Early (Symmetric/Severe -<3rd%)  Poor outcomes
• Normal growth trajectory, anatomy, UA & AFV

– Likely constitutionally small fetus / minimal fetal impact

• Surveillance for idiopathic FGR: NST/BPP/US-Doppler/EFW

Conclusions – FGR

• FGR  Umbilical artery Doppler studies q1-2 weeks

– If normal, may be less frequent

• Umbilical artery in FGR  Improves outcomes

– ↓ IOL, CD, Death; No ↑ increase in intervention; NNT=203

• DV abnl  Advanced state of fetal compromise  Delivery
• MCA abnl  poorer outcomes, adjunct test
• Antenatal corticosteroids  UA absent/reversed EDF

– Clear benefit <34 weeks, extended to 36 6/7

• Magnesium for neuroprotection  <32 weeks
• No clear nutritional/supplement/treatment to treat IUGR

– Smoking cessation & No Bed rest

References

• Fetal Growth Restriction. ACOG Practice Bulletin No. 204 American College of Obstetricians and
• Gynecologists. Obstet Gynecol 2019:133:e97-109.
• Berkley E, et al. SMFM Clinical consensus guideline. Doppler assessment of the fetus with

intrauterine growth restriction. Am J Obstet Gynecol 2012;206:300-8.

• Papageorghiou AT et. al, International standards for symphysis-fundal height based on serial

measurements from the Fetal Growth Longitudinal Study of the INTERGROWTH-21st Project: prospective cohort study in eight countries. BMJ. 2016;355:i5662. Epub 2016 Nov 7.

• Unterscheider J et. al. Optimizing the definition of intrauterine growth restriction: the multicenter

prospective PORTO Study. Am J Obstet Gynecol. 2013;208(4):290.e1.

• Gardosi J et. al, The customised growth potential: an international research tool to study the

epidemiology of fetal growth. Paediatr Perinat Epidemiol. 2011;25(1):2.

• Figueras F & Gardosi J. Intrauterine growth restriction: new concepts in antenatal surveillance,

diagnosis, and management. Am J Obstet Gynecol. 2011;204(4):288.

• Kennedy AM, Woodward PJ. A Radiologist's Guide to the Performance and Interpretation of

Obstetric Doppler US. Radiographics 2019;39:893-910.

• The GRIT Study Group. When do obstetricians recommend delivery for a high-risk preterm growth-

retarded fetus?. Growth Restriction Intervention Trial. Eur J Ob Gyn Reprod Biol. 1996;67(2):121.

• Boers KE, et. al. Induction versus expectant monitoring for intrauterine growth restriction at term:

randomised equivalence trial (DIGITAT). BMJ. 2010;341:c7087. Epub 2010 Dec 21.

Thank you

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Thank you