1. Fetal Growth Restriction
Jason L Picconi, MD, PhD, FACOG, FACMG
Avera Medical Group
Maternal Fetal Medicine
19 September 2019

2. Disclosures
No conflicts of interest

3. Objectives Definition of fetal growth restriction
Why is growth restriction important?
Management of fetal growth restriction
Antenatal surveillance
Doppler changes in FGR
Timing of delivery

4. Definition Fetal Growth Restriction (FGR)
Failure of the fetus to reach its growth potential in-utero
Often used interchangeably with IUGR, Placental Insufficiency
Different from SGA which is a postnatal measurement
“Placental insufficiency is the umbrella that covers our ignorance in terms of etiology and pathogenesis of the utero-placental chronic dysfunction”
Nicholas S Assali ( )
Growth disorders are difficult to predict since each fetus has a different growth potential
SGA refers to a neonate whose birth weigh is <10th% for GA.

5. Biometric Parameters
Estimated fetal weight is calculated by 4 biometric parameters
BPD: Level of the thalami, the septum cavum pellucidum, and the third ventricle (outer and inner edge of calvarium)
AC: Umbilical vein, 1 rib on each side , stomach and spine.
FL: Only the long axis of the femur
Ultrasound Lecture Series, AIUM

6. Commonly Used Sonographic Formulas
At least 30 formulas for EFW have been published. The most popular ones are Warsof’s with Shepard’s classification and Hadlocks
Ultrasonography in Obstetric and Gynecology Callen, P 5th ed. 2008

7. EFW by GA

8. Growth Rates Across Gestation
5 g /d (14-15 weeks)
10 g/d (20 weeks)
30-35 g/d (32-34 weeks)
Resnik, R Obstet Gynecol 2002;99:490-96
There is a normal variation in the rates of growth across gestation…>34 weeks the growth rate decreases.
Growth rates for singletons and mutiples differ as shown by this figure taken from median growth rate curves California births
15-30% of twin gestations have IUGR.
Williams, R et al. Obstet Gynecol 1982;59:624-32

9. Definition
The most accepted definition of fetal growth restriction is an estimated fetal weight less than the tenth centile for gestational age.
This accepts that many constitutionally small fetuses will be misdiagnosed.
3-10% of fetuses <10% EFW are FGR
Approximately 70% are Constitutionally small
Ethnicity
Parity
Weight
Height
The confusion comes because the terminology for classifying fetuses and newborns with growth abn is inconsistent and of the lack of a uniform definition.
The most commonly accepted definition in the US is an EFW below the 10th percentile for gestational age.
This definition does not take into account the individualized growth potential of each fetus and may result in the misdiagnosis of growth restriction for constitutionally small fetuses.
There are debates regarding the value of customized vs population based curves, however Cochrane database reviews concluded that despite large observational studies suggesting that customized growth charts better differentiated the constitutionally small, normal fetus from the pathologically growth restricted one, there was insufficient randomized trial evidence to draw definitive conclusions.
ACOG Practice Bulletin No Obstet Gynecol 2019;133:e97-109

10. Etiology Genetic Structural anomalies Congenital Infections (TORCH)
Multiple gestation
Inadequate maternal nutrition
Environmental factors (Teratogens, drugs, tobacco)
Placental factors/umbilical cord abnormalities
Maternal vascular disease (DM, HTN, Lupus)
40% of birth weight variations are due to genetic contributions from mother and fetus and 60% due to the fetal environment
20-25% of fetuses with anomalies have IUGR
Infections such as rubella and CMV have been associated with IUGR

11. Genetics/Anomalies Genetic causes for growth restriction are often:
Early onset (<24 weeks)
Severe (<5% EFW)
Symmetric
Common Causes:
Trisomy 13 and 18:
50% have IUGR
Confined placental mosaicism (10% of idiopathic FGR)
Structural anomalies
Cardiac
GI (gastroschisis: 25% FGR)
ACOG Practice Bulletin No Obstet Gynecol 2019;133:e97-109

12. Congenital Infections
Primary etiology in 5-10% of FGR cases
Toxoplasmosis, Rubella, CMV, HSV, Varicella
Malaria
Zika
Malaria accounts for most of infectious related cases of IUGR worldwide
ACOG Practice Bulletin No Obstet Gynecol 2019;133:e97-109

13. Multiples Twins account for 2-3% of live births in the US
But responsible for 10-15% of adverse neonatal outcomes
Risk of SGA
Twins: 25%
Triplets: 60%
SGA is a neonatal term referring to birthweight <10th%
ACOG Practice Bulletin No Obstet Gynecol 2019;133:e97-109

14. Placental/Umbilical cord abnormalities
Placental disorders
Most common pathology
Abruption, infarction, hemangioma
Vasculopathy
Syncytial knots
Thickened basement membrane
Cord abnormalities
Velamentous/marginal insertion, SUA
Abnormal placentation that results in poor placental perfusion is the most common pathology associated with fetal growth restriction.
ACOG Practice Bulletin No Obstet Gynecol 2019;133:e97-109

15. Why is this important? Before 1960s: Lubchenco et al. Pediatrics 1963:
All newborns with BW <2,500g were premature
Lubchenco et al. Pediatrics 1963:
There is a cohort of newborns that do not achieve their growth potential.
Their failure to achieve proper growth imparts a significant burden of increased perinatal mortality and short term and long term morbidity.

16. Why is it important? Stillbirth Risk >10% 0.7% <10% 1.5%
>10% %
<10% %
<5% %
Lubchenco first demonstrated that for any given GA at birth, a weight <10th% increased the mortality risk dramatically.
Manning et all in the 1990s showed that perinatal morbidity and mortality increased markedly as birth weight falls from the 10th% to the 1st%.
There is continuing debate as to whether the 10th, 5th or 3rd birthweight percentile should be used as a cutoff for designation of SGA.
Therefore it becomes the challenge of the Obstetrician to optimize the outcome of these at risk infants by identifying when inadequate growth occurs, determining its cause and severity, counseling the parents, consulting with our Neonatal colleagues and selecting the appropriate time and mode of delivery.
The lower the percentlile, the higher the risk of poor outcome
Modified from Manning F. Fetal Medicine, 1995;7:307

17. Importance of Diagnosing FGR
Fetal
Oligohydramnios
NRFHT / CD
Death
Hypoxia/metabolic acidosis in labor (low Apgar, UA pH <7.0)
Recurrence risk of 20%
Neonatal
Preterm Birth (RDS, IVH, NEC, sepsis, meconium aspiration, etc.)
Hypothermia, hypoglycemia, electrolyte imbalances, polycythemia
Neurodevelopmental delay
Impact or importance
Low Apgar scores, UA pH <7.0
Fetal death: 5-6 fold increase, directly related to degree of FGR
Growth restricted fetuses are predisposed to the development of cognitive delay in childhood
Neonatal morbidity (RDS etc) not just related to PTB
Hypothermia, with higher brain weight compared to body, due to less body fat
Hypoglycemia, decreased glycogen and adipose tissue stores, may require glucose IV
Hypocalcemia, polycythemia (increased erythropoietin level from chronic hypoxia)
Immune deficiency, with decrease IgG, lysozymes, neutropenia, sepsis
Coagulopathy, liver insufficiency, apnea
Chronic intrauterine hypoxia/hypoxemia acidemia gives rise to hypoxic ischemic encephalopathy, seizures, perinatal stroke

18. Importance of Diagnosing FGR
Infant and child
Poor gross motor development, CP
Lower intelligence quotient, mental delay
Speech/reading/learning deficits
Poor academic achievement
Social and financial problems

19. Barker’s Hypothesis David Barker 1989: Fetal Programming
Complex interaction between genetics and environment determines growth and susceptibility to disorders in adult life
Complex interaction between genetic constitution and prenatal/early postnatal environment determines the growth and development of the fetus and defines the susceptibility to certain disorders in adult life
A trial compared cardiac function in 80 children (mean age 5 years) with fetal growth restriction with 120 controls. Children who had growth restriction in utero had increased transverse diameters and more globular ventricles, decreased stroke volume (despite normal left ventricular ejection fractions), and decreased myocardial peak velocities. They were also observed to have higher blood pressures. These findings were linearly related to the severity of growth restriction. Findings such as these may alter future obstetric management with respect to timing of delivery.
References
1. Crispi F, Bijnens B, Figueras F, et al: Fetal growth restriction results in remodeled and less efficient hearts in children. Circulation  2010; 121(22):
Crispi et al. Circulation 2010;121(22):

20. Importance of Diagnosing FGR
Long-term adult consequences
Hypertension
Coronary artery disease
Diabetes
Obesity

21. Management

22. Non-stress test
Recognizes the coupling of fetal neurologic status to cardiovascular reflex responses
NST should not be used in isolation to determine the antenatal status of FGR
Can be combined with assessment of amniotic fluid volume (modified BPP)
Any abnormality in the NST (non-reactive, occasional decels, decreased variability, persistent “minor decels” calls for a complete USG.
NST alone is not the standard of care for high risk fetuses.
Creasy, R. Maternal Fetal Medicine 2009

23. Ultrasound Biophysical profile:
Multidimensional survey of fetus
Looks at both acute and chronic physiologic parameters
Fetal death within 1 wk of a normal BPP is rare
0.726 per 1,000 (14/19,221)
4/4,380 were FGR Manning, FA et al. AJOG 1987
Amniotic Fluid Maximum Vertical Pocket:
Normal MVP is less frequently associated with demise
Low MVP as a result of decreased renal blood flow
Ultrasound remains the best method for evaluating the growth restricted fetus.
4 biometric measures (BPD, HC,AC, FL), combine to give the EFW, however the estimate may deviate from the birth weight by 20% in 95% of cases and 5% may deviate by >5%.
Manning et al described years ago that oligohydramnios has been associated with a high risk of fetal compromise.

24. Factors Affecting BPP Drugs: Cigarettes: decreases breathing
Sedatives/Aldomet: diminishes activity
Betamethasone: diminishes breathing
Indomethacin: diminishes MVP
Cigarettes: decreases breathing
Hypoglycemia: decreases movement/tone
Creasy, R. Maternal Fetal Medicine 2009

25. Antenatal Assessment
Evaluation of fetal oxygenation and acid-base equilibrium is crucial for management of FGR fetus
One of the challenges when faced with the diagnosis of IUGR is the need to balance prolongation of pregnancy with the risks of iatrogenic prematurity or IUFD.

26. Fetal Circulation
Gabbe’s Obstetrics

27. Christian J. Doppler Austrian Physicist, 1803-53
Director of Prague Institute
Color effect of double stars
(1842)

28. Doppler Velocimetry
Doppler USG is based on the principle of the Doppler effect (named after Johann Doppler who discovered it in 1842)
When energy is reflected from a moving boundary (blood flow), the frequency of the reflected energy varies in relation to the velocity of the moving boundary

29. Independent Indices PI = pulsatility index RI = resistance index
Doppler we can assess the velocity. This slide shows the various indices.
These angle correctors are used since we cannot consistently obtain zero degree measurement of velocity.
Most commonly used are S/D ration and PI. However if there is absent diastole (number is zero).
PI = pulsatility index
RI = resistance index
S = peak systolic velocity
D = end-diastolic velocity
M = mean velocity
Courtesy of AIUM

30. Doppler Velocimetry
Primary surveillance tool for monitoring pregnancies affected by FGR
Identification of fetuses at risk of adverse outcome
Identification of blood flow redistribution
Role in timing of delivery
Fundamental role in diagnosis
Doppler USG of UA and MCA in combination with biometry, provides the best tool to identify fetuses at risk of adverse outcome
Doppler studies of the fetal cardiovascular system allow assessment of the blood flow redistribution observed in IUGR (increased UA PI and decreased MCA PI) which suggests increased vascular resistance of the UA and cerebral vasodilation.

31. Why are Dopplers important?
The rate of perinatal death is reduced by as much as 29% when the umbilical artery Doppler is added to standard antepartum testing in the setting of FGR
Absent or reversed end diastolic flow in the UA is associated with an increased risk of perinatal mortality.
Points to consider:
This refers to persistent.
When this occurs earlier in gestation the risk is great.
If there is oligohydramnios.
Just because you see this finding does not always indicate mortality, one must keep in mind the context.
Alfirevic, Z et al. Cochrane Database, 2010

32. Dopplers Weekly UA Dopplers Improves outcomes of FGR fetuses:
In conjunction with standard surveillance
Non-stress test + Amniotic Fluid Assessment
Biophysical profile
Although Umbilical artery Doppler velocimetry plays an important role in management of the IUGR fetus its use in conjuction with standard fetal surveillance.
Alfirevic, Z et al. Cochrane Database, 2010

33. Umbilical Artery Arise from the common iliac arteries
Represent the dominant outflow of the distal aortic circulation
Reflect downstream resistance of the placenta
Resistance falls throughout pregnancy
As early as 14 weeks, low impedance in the UA permits continuous flow through the cardiac cycle.

34. Umbilical Artery Doppler
Assesses resistance to blood perfusion of the placenta
Maternal/placental conditions that obliterate small muscular arteries result in progressive decreased in EDF until absent or reversed during diastole
In pathologic cases, when resistance increases, diastolic velocities fall and ultimately become absent.
As resistance rises even more, an elastic component is added to the placenta which will induce REDF as the rigid placental circulation recoils after being distended by the pulse pressure.
Trudinger, B et al. AJOG 1987

35. Umbilical Artery
The fetal response in IUGR is manifested by various cardiovascular adaptive changes. Changes in blood flow favor essential organs
Doppler interrogation of the fetal arterial system provides an indirect assessment of placental resistance and can aid in the assessment of the progression of IUGR prior to FHR abnormalities and IUFD
In appropriately grown fetuses, Diastolic component increases with advancing gestational age. IUGR: low diastole, absence or revasl of diastolic flow
Changes seen at the level of the umbilical artery are… When 70% of the villous vessels are abnormal, AEDV or REDV can be seen

36. PI >95th% abnormal

37. Umbilical Artery Doppler
AEDF may exist in equilibrium
Weeks (as high as 14 weeks prior to delivery)
Oftentimes progresses to REDF
Associated with obliteration of >70% of arteries in the placental tertiary villi
Usually seen in severe (<3rd%) and oligo
Waveforms may be obtained anywhere throughout the cord, h owever, samples near the placental end reflect downstream resistance and tend to show higher end diastolic velocity.
For uniformity may suggest obtaining sample at abdominal cord insertion.
PI or S/D should only be obtained when the waveforms are uniform and in the absence of fetal breathing or movement.

38. Middle Cerebral Artery
Major branch of the Circle of Willis
Most accessible vessel for USG in the fetus
Carry >80% of the cerebral circulation
There is increased blood flow to the brain in FGR (cephalization or brain-sparing effect)

39. A B C D E F JUM 2005; 24:425 Steps to measure MCA.
Transverse plane of the fetal head at the base of the skull. MCA should occupy more than 50 % of screen, the blood vessel must be seen for its entire legnth (to ensure that zero degrees) and sample volume must be soon after the origin of the interna carotid.
There is no real difference if sampled elsewhere, but the inter and intra observer variability is lower. The waveforms should be the same and should be repeated three times. Less than 5 mins
It is easy to sample the
MCA with an angle of 0, which allows for the
real velocity of the blood flow to be determined. . E F
JUM 2005; 24:425

40. Mari G et al Am J Obstet Gynecol 1992;166:1262
The MCA sampled soon after its origin from the internal carotid artery in the absence of fetal movement or breathing, is used and the PI and PSV obtained
Diastole is much higher in IUGR than appropriate grown fetus (Brain sparing effect)
The use of an angle corrector increases the intra- and inter-observer variability; therefore, its use is not
recommended
in anemic fetuses High MCA-PSV is related to decreased fetal hemoglobin decreases blood viscosity consequently increasing cardiac output.
In IUGR the MCA-PSV increase is related to hypoxemia and hypercapnia (Brain autoregulation)
Mari G et al Am J Obstet Gynecol 1992;166:1262
Courtesy of AIUM

42. Ductus Venosus Connects the umbilical vein to the IVC
Reflects the physiologic status of the right ventricle.

43. Ductus Venosus
3 peaks, first is ventricular systole, second is diastole with rapid passive filling of ventricles and third is the nadir which represents the atrial kick.
If there is increased afterload (umbilical artery resistance), the “a” wave becomes progressively deeper. “a” wave retrograde signifies the onset of significant cardiac impairment.
Retrograde conduction of the “a-wave” is frequently associated with umbilical venous pulsations.

44. S D S D a a
Ductus Venosus
Hemodynamically, these phases (S, D, a) reflect the rapid chronologic change in pressure gradients between the umbilical vein and the right atrium

46. Umbilical Vein

47. Vessels Abnormalities Preceding NRFT or Fetal Demise
Y- mean days from onset of abnormality of particular vessel

48. Therefore, the management of FGR fetuses is often subjective.
There is no robust data on how to manage and when to deliver FGR fetuses.
Therefore, the management of FGR fetuses is often subjective.
Courtesy of AIUM Curriculum

49. Fetal Growth Restriction Surveillance
Ultrasound assessment for interval growth every 3-4 weeks after diagnosis
Doppler assessment of umbilical arteries and amniotic fluid assessment weekly after diagnosis
Biophysical profile weekly once fetal breathing is noted
Transfer to tertiary care center for inpatient surveillance and antenatal corticosteroid administration once oligohydramnios or elevated umbilical artery Dopplers are identified
Doppler interrogation of other vessels (MCA, DV, UV) and increased frequency of testing, depending on capability

50. Timing Delivery Abnormality Frequency of BPP Decision to deliver
Elevated indices
Weekly
Abn. BPP, term or >36w and no growth
AEDF
Twice weekly
Abn. BPP, or >34w if progression to REDF
REDF
Daily
BPP<10/10, or >32w after steroids
REDF/UV
TID
BPP<10/10, or >28w after steroids
Harman, CR 1999

51. GRIT(2003) Growth Restriction Intervention Trial
Only randomized study of FGR fetuses:
24-36 weeks randomized to immediate (n=296) vs expectant management (n=291)
Perinatal survival was similar and the 6-12 year follow up was similar between the two groups
Lack of standard criteria for intervention
GRIT Study Group. Lancet 2014

52. DIGITAT (2010) Disproportionate Intrauterine Growth Intervention Trial at Term
Prospective study of 650 women >36 wks
Randomly assigned to delivery vs expectant
No difference in the composite neonatal outcome between the two groups
Cohort not large enough to see if perinatal death was affected by the different approaches
randomly assigned 650 pregnant women over 36.0 weeks of gestation with suspected FGR to induction of labor or expectant monitoring [60-62]. The primary outcome was a composite measure of adverse neonatal outcome (death before hospital discharge, five-minute Apgar score <7, umbilical artery pH <7.05, or admission to the intensive care unit) [60].
Boers, K et al. BMJ 2010

53. TRUFFLE (2015) Trial of Randomized Umbilical and Fetal Flow in Europe
Prospective study of 503 women weeks gestation with fetal growth restriction
Randomly assigned to three groups with delivery for:
Abnormal FHTs
Elevated PI in DV Doppler studies
Absent A wave in DV Doppler waveform
No significant differences in adverse outcomes
Lees et al, Lancet 2015:385:2162

54. So when should we deliver?
No adequately powered randomized trials to determine the optimal timing of delivery
Expert Consensus 2019:
NICHD
SMFM
ACOG

55. NICHD

56. Management of FGR Fetuses: Caution
Delivery at less than 25 weeks gestation or 500 grams EFW is almost universally fatal
Delivery after 29 weeks gestation is rarely fatal
Mari G, et al. J Ultrasound Med 2007; 26:555

57. Management of FGR Fetuses: Important Consideration
Between 25 and 29 weeks’ gestation, for each week the fetus remains in-utero, the perinatal mortality decreases by 48%.
Mari G, et al. J Ultrasound Med 2007; 26:555

58. Management of FGR Fetuses: Important Consideration
FGR fetuses have been considered a homogeneous group, and this has hampered our understanding of the FGR process.
Mari G, et al. J Ultrasound Med 2007; 26:555

59. Fetal Growth Restriction Delivery
38 0/7 – 39 6/7 weeks - Fetal growth restriction without oligohydramnios or abnormal umbilical artery Dopplers
32 0/7 – 37 6/7 weeks – Fetal growth restriction with oligohydramnios or abnormal umbilical artery Dopplers
Less than 32 weeks gestation – Fetal growth restriction with severe abnormalities in Doppler vessels and/or abnormal fetal heart rate tracing

60. Conclusion
FGR fetuses are at increased risk of demise and long term morbidity.
It is important to not only identify the FGR fetus but appropriately manage them.
Timing delivery should be individualized and should involve a multidisciplinary approach.
Doppler ultrasound is used as an adjunctive tool to help time delivery.

61. Thank you