Intrauterine growth restriction

1. Intrauterine Growth
RestrictionPathogenesis &
interventions to improve outcome
DR. PRAMAN KUSHWAH
Neonatology Resident
NICE Hospital, Hyderabad

2. Objectives
1. Definition
2. Health Burden
3. Classification
4. Aetiology
5. Pathophysiology
6. Screening
7. Prevention
8. Diagnosis
9. Intervention & Management

3. Intoduction
“Fetus who does not achieve the expected in utero
growth potential due to genetic or environmental
factors”
Shrunken or "wizened" appearance of an
infant with intrauterine growth restriction

4. Definitions
IUGR / (Fetal growth Restriction)
◦ Fetus who does not achieve the expected in utero
growth potential due to genetic or environmental
factors (Brodsky and Christou, 2004)
◦ An estimated fetal weight <10th percentile
◦ Moderate FGR BW 3rd to 10th percentile
◦ Severe FGR BW < 3rd percentile

5. Small-for-gestational age (SGA)
◦ Majority are constitutionally small and healthy
◦ 10–15% of SGA infants are growth restricted, i.e., with
slow growth velocity in utero (Alberry and Soothill, 2007)

6. Health Burden
10 % of live-born are IUGR
2nd leading cause - perinatal morbidity and mortality
1.5% risk of fetal death

7. Classification

8. The Ponderal index
[birth weight in grams ×100]/[length in centimeters]3
the weight-to-length ratio may be
Used to categorize growth-retarded infants.
Those with asymmetric growth retardation have low
Ponderal index.
Ponderal index for symmetric IUGR may be normal

9. Etiology

11. Fetal Etiologies
◦ Chromosomal etiologies classically, trisomies more common
(5 - 20 %)
◦ Congenital birth defects (e.g. gastroschisis)

12. Maternal Etiologies
Factors affecting Health & reproductive potential
◦ maternal age, parity, or last pregnancy interval
◦ maternal health conditions prior to pregnancy
◦ hypertension and diabetes, either pre-existing or gestational,
◦ pulmonary and renal disease,
◦ autoimmune disease, thrombophilic disorders
◦ congenital heart disease.
Mother’s own diet and access to nutrition
image distortion disorders such as bulimia, anorexia or hyperemesis
gravidarum.

13. Environmental Etiologies
Infections in early pregnancy (5-10%)
• Malaria, rubella, cytomegalovirus,
Toxoplasma gondii, syphilis
• (malaria represents the largest portion of
global burden of IUGR secondary to
infectious etiologies.)
Substance Abuse
• Alcohol, Cocaine, heroin, and narcotic use
during pregnancy
Teratogens, maternal medications, or
maternal substance abuse
• antiepileptic medications (valproic acid),
• antithrombotic agents (e.g., warfarin)
• chemotherapeutic/ antineoplastic agents
(e.g., cyclophosphamide).
Location
• High altitude versus near sea level
• developed versus developing nations.

14. Placental Etiologies (m/c)
Placental disorders
◦ chronic placental abruption, infarction, circumvallate shape, chorioangioma
Umbilical cord abnormalities
◦ velamentous or marginal cord
Multiple gestation
◦ A/w both SGA and prematurity
◦ risk of SGA 25% in twin pregnancies, 60% for triplet and quadruplet
◦ monochorionicity at higher risk of SGA and IUGR (unequal placental sharing,
twin-to-twin transfusion)
Small size placentas and histopathologically hypovascular villi, fibrin
deposition, and/ or trophoblast degeneration
Poor nutrient and oxygen provision to the fetus on a physiologic level

15. Pathophysiology

16. Placental insufficiency
◦ Majority of IUGR neonates ( idiopathic IUGR).
◦ Disruption in normal early vascularization of the placenta
◦ Incomplete spiral artery remodelling  shallow placental
vasculature
◦ Failure of these vessels to appropriately become low-
resistance vessels
◦ Limiting blood flow to the fetus
◦ Limiting nutrient/oxygen provision to the fetus and
placenta itself.

18. Cont.
Hormones - Insulin, thyroid hormones, adrenal hormones, pituitary
hormones
Insulin
◦ control cell number via direct mitogenic effects on cellular
development,
◦ regulate glucose uptake and consumption in somatic tissues
◦ regulate other metabolic pathways, such as protein breakdown.
◦ IGF-1, IGF-2, IGFBP-2 and -3 implicated in the pathophysiology of
IUGR in experimental models
Chromosomal abnormalities
◦ Decreased numbers of fetal cells and poor cellular growth  IUGR

19. Screening
1. Maternal and family history  identify presence of etiologic risk
factors
2. Accurate gestational dating  True SGA from wrong dates
3. Recurrence risk
◦ risk of recurrent SGA 20%
◦ risk of recurrent IUGR is estimated at ~20%-50%
4. Detailed maternal physical exam including Fundal height
measurement

20. Evaluation
1. Fetal ultrasound:
◦ Biometric parameters (1) biparietal diameter, (2) head
circumference, (3) abdominal circumference, and (4)
femur length
◦ To distinguish symmetric from asymmetric IUGR
◦ Abdominal circumference - best “stand-alone” with
specificity and a negative predictive value of almost 90%
for diagnosing IUGR

21. ◦ If EFW < 10th percentile for gestational age
◦ detailed evaluation - Doppler & Amniotic fluid
◦ Evaluation of fetal anatomy
◦ structural and genetic abnormalities (a/w
chromosomal disorders or infections)
◦ ACOG suggest every 3-4 weeks assessment to
minimize false-positive rates

22. 2. Doppler velocimetry, (esp. umbilical artery)
◦ Severity of fetal growth restriction
◦ Reflection of maternal circulation
◦ Placental insufficiency, resistance will increase,
diastolic flow will decrease, absent or reversed end-
diastolic flow in the umbilical artery
◦ absent or reversed end-diastolic flow  poor
prognostic factor a/w increased perinatal Mortality

23. 3. Timing of delivery
• Based on
• Underlying etiology
• Estimated gestational age
• Early delivery of an IUGR fetus
• Aneuploidy or congenital infection no improved
outcomes
• Placental insufficiency - antenatal surveillance helpful

24. RECOMMENDATION (ACOG)
In Isolated fetal growth restriction
oDelivery at 38 0/7 to 39 6/7 weeks in cases of, and
IUGR fetuses with additional risk factors for poor
prognosis
odelivery at 34 0/7 to 37 0/7 weeks
oRisk Factors - oligohydramnios, abnormal umbilical
artery Doppler velocimetry
Delivery ideally should be performed at a center with both
high-risk maternal fetal medicine teams and a neonatal
intensive care unit.

25. Prevention
Very few “preventative” strategies
Altering modifiable risk factors can help. (e.g. Cigarette smoking, diet,
malarial prophylaxis in high-risk areas)
No role - Nutritional and dietary supplementation regimens
Not recommended - Bed rest
New Modality – Aspirin
Efficient in mitigating severe IUGR with abnormal Dopplers
Increased birth weight at delivery
Prolonging gestation
Decreased need for NICU admission
very less existing studies  NOT ROUTINELY INDICATED

26. Postnatal Diagnosis of IUGR
 Problematic (lack of clarity in definition)
1. History
1. Prenatal history
2. Prenatal pattern of growth
3. Prenatal condition - Placental and Fetal structural abnormalities,
abnormal genetic testing, family and previous maternal pregnancy
history, and pregnancy infections
2. Evaluation
1. Histopathologic evaluation of the placenta - structural abnormalities, and
large infarctions.

27. 3. Examination
1. Anthropometric measurements at birth
2. Examination of the infant
◦ Stigmata of “malnourishment”
◦ Features of aneuploidies - dysmorphic facies, congenital anomalies
◦ stigmata congenital infections - microcephaly, petechiae and “blueberry
muffin” rashes
◦ Cardiac murmur – a/w CHD

28. Stigmata of “Malnourishment”
Large and wide anterior fontanelle,
Absent buccal fat
Small and scaphoid abdomen
Thin umbilical cord,
Decreased skeletal muscle &
subcutaneous fat,
Disproportionately large hands and
feet,
Loose and dry skin (axilla &gluteal
regions)
Large head compared to the body
(Asymmetric IUGR)

29. Stigmata of “congenital infections”

30. Interventions to improve
OUTCOME
High risk of stillbirth, neonatal death, and prematurity
5 to 30-fold increase in morbidity and mortality
2.5 times more likely to be born premature
Chances of needing more perinatal intervention like
caesarean delivery, exposure to antenatal steroids, and
admission to NICU

31. POSTNATAL CONCERN OVERALL RISK & ETIOLOGY
MANAGEMENT
RECOMMENDATIONS
Perinatal distress /
asphyxia
• IUGR infants, compared to
AGA, have a 5-30x increase
in morbidity and mortality,
even when born at term
• 2.5x more likely to be born
premature.
• Increased risk for stillbirth
and prematurity makes the
delivery of an IUGR neonate
high risk.
• Increased risk of perinatal
distress given in the setting
of chronic poor blood flow
and hypoxia.
Attendance at delivery by a
skilled team that can
resuscitate a low birth weight
or premature infant, ideally at
a center with a
neonatal intensive care unit

32. POSTNATAL CONCERN OVERALL RISK & ETIOLOGY
MANAGEMENT
RECOMMENDATIONS
Hypoglycemia
<2.6 mmol/L
OR
< 46 mg/dL
• 1/3 of infants with a birth
weight <10% have severe,
recurrent, and/or prolonged
hypoglycemia.
• Due to suboptimal glycogen
stores, impaired
gluconeogenesis.
• Decreased fat, increased
sensitivity to insulin. May be
exacerbated by
polycythemia or
hypothermia.
Serial monitoring for
hypoglycemia soon after birth.
If persistent, prolonged, or
severe: Formula
supplementation, gavage
feeding, provision of dextrose-
containing
intravenous fluids.

33. POSTNATAL CONCERN OVERALL RISK & ETIOLOGY
MANAGEMENT
RECOMMENDATIONS
Respiratory
complications
• Poor in utero growth and
concomitant risk for
prematurity put IUGR infants
at risk for respiratory distress
syndrome in the short term
and chronic lung disease in
the long term.
• IUGR infants exhibit evidence
of pulmonary vascular
remodeling, which may
result in increased risk of
pulmonary hypertension.
Supportive care and
respiratory support, as
necessary.

34. POSTNATAL CONCERN OVERALL RISK & ETIOLOGY
MANAGEMENT
RECOMMENDATIONS
Hypothermia • Decreased brown fat
deposition in utero.
Temperature monitoring,
initiated soon after birth.
• Provision of an exogenous
heat source or incubator
may be required
Necrotizing
enterocolitis/
feeding intolerance
• Severe cases of IUGR (UA
Dopplers), with concomitant
prematurity, may have
increased susceptibility to
NEC and/or feeding
intolerance.
• Breastmilk provision and
avoidance of formula.
• Early initiation of trophic or
small volume feeding.

35. POSTNATAL CONCERN OVERALL RISK & ETIOLOGY
MANAGEMENT
RECOMMENDATIONS
Intraventricular
hemorrhage
• Due to cerebral vascular
remodeling, cerebral
autoregulatory
mechanisms, and overall
hemodynamic instability in
IUGR.
• Surveillance with head
ultrasound.
• Avoiding fluctuations in
cerebral oxygenation using
continuous monitoring such
as near infrared
spectroscopy.
Electrolyte
abnormalities
• Hyperglycemia and
hypocalcemia
• Monitor for and correct
abnormalities
Polycythemia/jaundice • May occur as a response to
long-standing hypoxia in
utero.
• Check for underlying
hematologic abnormalities,
and treat when clinically
indicated.

36. POSTNATAL CONCERN OVERALL RISK & ETIOLOGY
MANAGEMENT
RECOMMENDATIONS
Abnormal innate and
humoral immunity
• Due to bone marrow
suppression secondary to
chronic hypoxia.
• Check for underlying
abnormalities with a
complete blood count and
differential.
• Low threshold for infectious
work-up and aggressive
management of infection

37. Potential targets
for therapy
Malhotra A, Allison BJ, Castillo-Melendez M, Jenkin G, Polglase GR,
Miller SL. Neonatal morbidities of fetal growth restriction:
pathophysiology and impact. Frontiers in endocrinology. 2019 Feb
7;10:55.

38. Complications

39. Neonatal morbidities in IUGR

40. Long Term Outcomes
1. Neurodevelopmental consequences
◦ increased risk for cerebral palsy
◦ lower scores across multiple neurocognitive domains including
cognition, attention, mood, and social skills
◦ decreased brain volume, gray matter, and hippocampal volumes
◦ asymmetric IUGR - brain-sparing appears to be regional, not global
“Optimized postnatal growth seems to portend
better neurocognitive outcomes”

41. 2. Cardiometabolic consequences
Phenomenon of – “Developmental programming”
◦ Based on epidemiologic studies showing that maternal gestation during
periods of famine results in IUGR offspring that are at increased risk for
cardio-metabolic disease during adulthood.
◦ Examples - obesity, cardiovascular disease, and diabetes

42. 3. Other Long term Outcomes
◦ Propensity toward cancer,
◦ schizophrenia,
◦ Alzheimer’s disease,
◦ polycystic ovarian syndrome,
◦ shorter life span
◦ immune dysfunction

43. What's New
1. Behavioral interventions and SGA (December 2021)
◦ Participants were randomly assigned to a structured Mediterranean diet,
mindfulness-based stress reduction, OR usual care from 20 weeks of
gestation to delivery. The rate of SGA births was significantly lower for
both structured diet (14 percent) and stress reduction (16 percent)
compared with usual care (22 percent)
2. Timing of delivery in fetal growth restriction (August 2021)
◦ Infants who were severely small for gestational age (SGA, birth weight
<3rd percentile) and delivered early for suspected FGR had poorer school
outcomes in grades 3, 5, and 7 compared with infants with the same
degree of SGA who were not suspected of having FGR (mean gestational
age at birth: 37.9 versus 39.4 weeks)

44. Take Home Message
IUGR is due to fetal growth less than its genetic potential.
To diagnose, prevent, and develop therapies for intrauterine growth
restriction – A challenge
Broad Aetiologies are: Fetal, Maternal, Environmental and Placental
Prenatal screening largely depends on serial USG & Doppler - still
debate as to how these should be used to dictate prenatal care and
delivery planning
IUGR has significant short- and long-term consequences for the
neonate

45. Thank You

46. Fanaroff and martin's
neonatal-perinatal medicine
www.UpToDate.com