Molecular basis of IUGR. – 1. Atypical expression of enzymes governed by TGFβ causes the placental apoptosis and altered expression of TGFβ due to hyper alimentation causes impairment of lung function. 2. Crosstalk of cAMP with protein kinases plays a prominent role in the regulation of cortisol levels. 3. Increasing levels of NOD1 proteins leads to development of IUGR by increasing the levels of inflammatory mediators. 4. Increase in leptin synthesis in placental trophoblast cells is associated with IUGR. A positive history for risk factors of IUGR can raise the problem of an increased surveillance with the specific goal of an early detection of growth insufficiency [23]. Further diagnostic tests could have a better relevance in a selected high-risk population Serum markers linked to IUGR The placentation process starts with the migration of trophoblastic cells that invade the walls of spiral arteries and transform them from small caliber high resistant vessels into wide caliber low resistant vessels that deliver blood at low pressure to the intervillous space. Then, the utero-placental circulation develops in two stages: the first stage (until the 10th week of gestation) consists in endovascular plugging of the spiral arteries by trophoblastic cells, subsequently followed by invasion and destruction of the intradecidual spiral arteries; the second stage (between 14-16 weeks of gestation) consists in the invasion of the inner miometrial part of the spiral arteries [27]. The impaired spiral artery transformation is leading to weak development of the utero-placental circulation and is implied in the pathology of preeclampsia and IUGR Pregnancy associated plasma protein A (PAPP-A), an Insulin–like Growth Factor Binding Protein Protease whose levels depend on placental volume and function, was assessed in several studies with congruent results. In 2000, Ong et al. evaluated 5584 singleton pregnancies at 10-14 weeks of gestation and measured maternal serum free beta human chorionic gonadotropin (β-hCG) and PAPP-A, concluding that low levels of maternal serum PAPP-A or β-hCG were associated with subsequent development of pregnancy

1. Dr Alka Mukherjee Nagpur 1
INTRAUTERINE GROWTH RESTRICTION:
WHEN TO DELIVER?
DR ALKA MUKHERJEE
DR APURVA MUKHERJEE
NAGPUR M.S. INDIA

2. DR ALKA MUKHERJEE
MBBS DGO FICOG FICMCH PGDCR PGDMLS MA(PSY)
Director & Consultant At Mukherjee Multispecialty
Hospital
MMC ACCREDITATED SPEAKER
MMC OBSERVER MMC MAO – 01017 / 2016
Present Position
 Director of Mukherjee Multispecialty Hospital
 Hon.Secretary INTERNATIONAL COUNCIL FOR HUMAN
RIGHTS
 Hon.Secretary NARCHI NAGPUR CHAPTER (2018-2020)
 Hon.Secretary AMWN (2018-2021)
 Hon.Secretary ISOPARB (2019-2021)
 Organizing secretary AMWICON – 2019
 Life member, IMA, NOGS, NARCHI, AMWN &
Menopause Society, India, Indian medico-legal &
ethics association(IMLEA), ISOPARB, HUMAN RIGHTS
 Founder Member of South Rapid Action Group,
Nagpur.
 On Board of Super Specialty, GMC, IGGMC, AIIMS
Nagpur, NKPSIMS, ESIS and Treasury, Nagpur for “
WOMEN SEXUAL HARASSMENT COMMITTEE.”
mukherjeehospital@yahoo.com
www.mukherjeehospital.com
https://www.facebook.com/
Mukherjee Multispeciality
https://www.instagram.com/
Achievement
 Winner of NOGS GOLD MEDAL – 2017-18
 Winner of BEST COUPLE AWARD in Social
Work - 2014
 VIDARBHA RATNA PURASKAR - 2019
Past Position
 Vice President of NOGS(2016-2017)
 Organizing joint secretary ENDO-GYN
 Vice President IMA Nagpur (2017-2018)
 Organizing joint secretary ENDO-GYN 2019

3. INTRODUCTION
• Pregnancies with intrauterine growth restriction (IUGR) - a
major obstetric problem
• Associated with increased neonatal morbidity and mortality
• Adverse intrauterine environment may increase disease risk
of hypertension, diabetes, coronary heart disease, and
stroke in adulthood.
• Affects up to 10% of all pregnancies.
• Majority of such pregnancies will have a physiologically
normal foetus that is simply small for gestational age (sga),
the ability to differentiate such a foetus from the
pathologically growth-restricted foetus is limited.”

5. • The management of growth restriction depends on the
cause. In 40% of cases, however, the cause is not definite
which also necessitates management.

6. Causes of Intrauterine Growth Restriction
• Maternal causes:
• Chronic hypertension
• Pregnancy-associated
hypertension
• Cyanotic heart disease
• Class F or higher diabetes
• Hemoglobinopathies
• Autoimmune disease
• Protein-calorie malnutrition
• Smoking
• Substance abuse
• Uterine malformations
• Thrombophilias
• Prolonged high-altitude
exposure
• Placental or umbilical cord
causes of IUGR include the
following:
• Twin-to-twin transfusion
syndrome
• Placental abnormalities
• Chronic abruption
• Placenta previa
• Abnormal cord insertion
• Cord anomalies
• Multiple gestations

9. PATHO-PHYSIOLOGY OF
IUGR
• IUGR occurs when gas exchange and nutrient delivery to the fetus
are not sufficient to allow it to thrive in utero.
• This process can occur primarily because of maternal disease
causing decreased oxygen-carrying capacity (eg, cyanotic heart
disease, smoking, hemoglobinopathy),
• A dysfunctional oxygen delivery system secondary to maternal
vascular disease (eg, diabetes with vascular disease, hypertension,
autoimmune disease affecting the vessels leading to the placenta),
• Or placental damage resulting from maternal disease (eg, smoking,
thrombophilia, various autoimmune diseases).
• Evaluation of causative factors for intrinsic disorders leading to poor
growth may include a fetal karyotype, maternal serology for
infectious processes, and an environmental exposure history.

14. Perinatal Implications
• IUGR causes a spectrum of perinatal complications:
• fetal morbidity and mortality,
• iatrogenic prematurity,
• fetal compromise in labor,
• need for induction of labor, and
• cesarean delivery.
• a increase in late fetal deaths among very small fetuses.
• Almost 40 0% of stillborn fetuses not malformed are SGA.
• Fetuses with IUGR who survive the compromised I-U
environment - increased risk for neonatal morbidity -
increased rates of necrotizing enterocolitis, renal failure
thrombocytopenia, temperature instability - occur as a result
of the alteration of normal fetal physiology in utero.

16. The brain-sparing effect
• With limited nutritional reserve, the fetus redistributes
blood flow to sustain function and to help in the
development of vital organs - and results in increased
relative blood flow to the brain, heart, adrenals, and
placenta, with diminished relative flow to the bone marrow,
muscles, lungs, gastrointestinal (GI) tract, and kidneys - may
result in different fetal growth patterns.
• Symmetrically small fetuses - early global insult (eg,
aneuploidy, viral infection, fetal alcohol syndrome).
• Asymmetrically small fetuses -small secondary to an
imposed restriction in nutrient and gas exchange.

18. • Greater predisposition to develop a metabolic syndrome later in
life - obesity, hypertension, hypercholesterolemia, cardiovascular
disease, and type 2 diabetes - thrifty GENE HYPOTHESIS -
intrauterine malnutrition results in insulin resistance, loss of
pancreatic beta-cell mass, and an adult predisposition to type 2
diabetes.
• Prepubertal individuals who had IUGR at birth show a greater
insulin response than prepubertal individuals who had healthy
growth as infants - increased risk of type 2 diabetes in adults who
had restriction as infants stems, instead, from increased
peripheral insulin resistance that allows the brain-sparing
physiology to occur but with a permanent reduction in skeletal-
muscle glucose transport.
• This ultimately results in beta-cell burnout.
• The causative pathophysiology is uncertain, the risk of a metabolic
syndrome in adulthood is clearly increased among individuals who
had IUGR

24. • ? An association between low birth weight and adult risk of
ischemic heart disease.
• ? Adult kidney function is adversely affected by restricted
intrauterine growth.
• ? Mental health problems morbidity academic impairment
and poorer general health impaired fetal circulation, as
demonstrated by Doppler studies, in association with IUGR
results in worsened cognitive function in adulthood.

25. DETECTION OF INTRAUTERINE GROWTH
RESTRICTION
• Diagnosis by maternal physical examination - inaccurate 50%
of cases.
• A single fundaI height measurement at 32-34 weeks' -65-
85% sensitive and 96% specific for detecting the growth-
restricted foetus.
• When IUGR is suspected by maternal fundaI height,
ultrasound for estimated foetal weight (EFW) assessment
should be performed.

26. Diagnosis and Surveillance
Criteria for diagnosis of IUGR
• An EFW at or below the 10th percentile is used to identify
fetuses at risk. (Short maternal or paternal height, the
neonate's ability to maintain growth along a standardized
curve, and a lack of other signs of uteroplacental
insufficiency (eg, oligohydramnios, abnormal doppler
findings) can be reassuring)
• USG -an initial scan may be obtained in the middle of the
second trimester (at 18-20 weeks) to confirm dates, evaluate
for anomalies, and identify multiple gestations. A repeat
scan may be scheduled at 28-32 weeks' gestation to assess
fetal growth, evidence of asymmetry, and stigmata of brain-
sparing physiology (eg, oligohydramnios, abnormal doppler
findings).

27. • If the EFW is below the 10th centile, further sonographic
evaluation should be performed, including Doppler flow
studies, amniotic fluid assessment, and evaluation for
structural abnormalities.
• During initial evaluation, it is important to note whether
growth restriction is symmetric, asymmetric, or a mixed
pattern.
• Intrinsic insults occurring early in pregnancy result in a
symmetric growth restriction.
• Extrinsic insults occurring later in pregnancy will likely result
in asymmetric growth restriction.
• Every tool must be used to identify the aetiology of IUGR.

29. THERAUPTIC OPTIONS
• First, behavioral strategies to quit smoking result in a lower
rate of low birth weight in babies at term among mothers
who smoke.
• Second, balanced nutritional supplements in
undernourished women and magnesium and folate
supplementation (in some studies) decrease the rate of SGA
newborns.
• Third, if malaria is the etiologic agent, maternal treatment of
malaria can increase fetal growth.

30. The administration of steroids
• The only intervention that has been shown to decrease neonatal
morbidity and mortality is the administration of steroids to
premature fetuses when delivery is anticipated.
• Odds ratio reduction with steroids, from Bernstein et al, is as
follows [7] :
• Relative risk of death, 0.54; 95% CI, 0.48-0.62
• Relative risk of respiratory distress syndrome, 0.51; 95% CI, 0.44-
0.58
• Relative risk of intraventricular hemorrhage, 0.67; 95% CI, 0.61-
0.73
• Relative risk of severe intravascular hemorrhage, 0.5; 95% CI,
0.43-0.57
• Relative risk of necrotizing enterocolitis, no difference noted

31. The IUGR fetuses can be grouped as follows:
• Small for gestational age (SGA): Small foetuses with no
discernible pathology and with normal umbilical artery and
middle cerebral artery Doppler results.
• Growth restriction: Small foetuses with recognisable
pathology/abnormal Doppler studies.
• Idiopathic growth restriction: Small foetuses with no
identifiable pathology/ abnormal Doppler studies.

32. STAGING SYSTEM
• Staging of IUGR based on foetal biometry, Doppler
cardiovascular changes, amniotic fluid volume, and clinical
parameters. In addition, the staging system is applicable to
pregnancies at any gestational age. The staging system is as
follows:
• Stage 0: Foetuses with EFW or an AC <10th percentile.
Normal Doppler of the umbilical artery and middle cerebral
artery.
• Stage I: Foetuses whose EFW or AC is <10th percentile plus
abnormal Dopplor flow of the umbilical artery or middle
cerebral artery.

33. • Stage II: Foetuses whose EFW or AC is <10th percentile plus
absent or reversed
• Doppler flow of the umbilical artery.
• Stage III: Fetuses whose EFW or AC is <10th percentile plus
absent or reverend
• Doppler flow of the ductus venosus.
• Based on the amniotic fluid index (AFI), each IUGR foetus
will be either (AFI <5 cm) or B (AFI 25 cm).

34. SITUATION-WISE MANAGEMENT
• Situation 1
• Test results – AC less than fifth percentile, low AC growth
rate, high ratio of head circumference to AC; BPS greater
than or equal to 8 and AFV normal; abnormal UV and/or
cerebroplacental ratio; normal MCA.
• Interpretation – IUGR diagnosed, asphyxia extremely rare,
increased risk of intrapartum distress.
• Recommended management – Intervention for obstetric or
maternal factors only, weekly BPS, multivessel Doppler
every 2 weeks.

35. STAGING SYSTEM AND MANAGEMENT
• Stage 0: SGA foetuses have a good prognosis ,
• managed as outpatient with dietary supplementation (NO
donors, arginine granules, Protein supplementation) and
• Doppler assessment every 2 weeks.
• If the Doppler Teams normal, delivery at term.
• If the Doppler becomes abnormal, these fetuses are
managed as Stage I IUGR fetuses.

36. • Situation 2
• See the list below:
• Test results – IUGR criteria met, BPS greater than or
equal to 8, AFV normal, UA with absent or reversed
end-diastolic velocities, decreased MCA.
• Interpretation – IUGR with brain sparing, hypoxemia
possible and asphyxia rare, at risk for intrapartum
distress.
• Recommended management – Intervention for
obstetric or maternal factors only; BPS 3 times a
week; weekly UA, MCA, and venous Doppler.
SITUATION-WISE MANAGEMENT

37. • Stage 1: Fetuses having mild IUGR, affected mothers
without pre-eclampsia are usually managed as outpatients.
• Antenatal corticosteroids
• In these fetuses - twice-weekly antenatal testing
• If the non-stress testing (NST) remains reactive and the AFI
remains >5 cm - delivery at 37 weeks' gestation.
• If the umbilical artery Doppler becomes absent/reversed -
manage as Stage II IUGR.
STAGING SYSTEM AND MANAGEMENT

38. • Situation 3
• See the list below:
• Test results – IUGR with low MCA PI; oligohydramnios; BPS
greater than or equal to 6; normal IVC, DV, and UV flow.
• Interpretation – IUGR with significant brain sparing, onset of
fetal compromise, hypoxemia common, acidemia/asphyxia
possible.
• Recommended management – If at more than 34 weeks'
gestation, deliver (route determined by obstetric factors). If
at less than 34 weeks' gestation, administer steroids to
achieve lung maturity and repeat all testing in 24 hours
SITUATION-WISE MANAGEMENT

39. • Stage II: IUGR fetuses managed as inpatients.
• During hospital management - twice-daily NST and daily
biophysical profile (BPP).
• If the NST reassuring and the BPP score between 6 and 8 -
continuation of expectant management &
• Antenatal corticosteroids at 28 weeks.
• Delivery at 34 weeks.
• If NSTs become non- reassuring or if the BPP score is <4/8 on
2 occasions at least 4 hours apart - immediate delivery By
Caesarean delivery because fetuses with an
absent/reversed flow of the umbilical artery may not
tolerate labor induction.
STAGING SYSTEM AND MANAGEMENT

40. • Situation 4
• See the list below:
• Test results – IUGR with brain sparing, oligohydramnios, BPS
greater than or equal to 6, increased IVC and DV indices, UV flow
normal.
• Interpretation – IUGR with brain sparing, proven fetal
compromise, hypoxemia common, acidemia/asphyxia likely.
• Recommended management – If at more than 34 weeks'
gestation, deliver (route determined by obstetric factors and
oxytocin challenge test [OCT] results). If at less than 34 weeks'
gestation, individualize treatment with admission, continuous
cardiotocography, steroids, maternal oxygen, and/or
amnioinfusion and then repeat all testing up to 3 times a day
depending on status.
SITUATION-WISE MANAGEMENT

41. • Stage III: IUGR fetuses are managed the same as stage II
except for delivery at 32 weeks' gestation, regardless of
gestational age at time of diagnosis.
• As with stage I and II - antenatal corticosteroids
The advantage of the above scoring system is its simplicity.
Only foetal biometry. Doppler evaluation, and the amniotic
fluid index are needed.
STAGING SYSTEM AND MANAGEMENT

42. • Situation 5
• See the list below:
• Test results – IUGR with accelerating compromise, BPS less
than or equal to 6, abnormal IVC and DV indices, pulsatile
UV flow
• Interpretation – IUGR with decompensation, cardiovascular
instability, hypoxemia certain, acidemia/asphyxia common,
high perinatal mortality, death imminent
• Recommended management – If fetus is considered viable
by size, deliver as soon as possible at tertiary center. Route
determined by obstetric factors and OCT results. Fetus
requires highest level of neonatal ICU care.
SITUATION-WISE MANAGEMENT

43. • If the umbilical artery and middle cerebral artery Doppler
are normal, Doppler study of the ductus venosus is
unnecessary because it will be normal as well.
• The presence MGR in the setting of pre-eclampsia should
not deter standard management of pre-eclampsia.
STAGING SYSTEM AND MANAGEMENT

44. • The diagnosis of severe IUGR before 32 weeks' gestation is
associated with a poor prognosis, and therapy must be
highly individualized.
• Once a decision has been made to effect delivery, the mode
of delivery is governed by evidence of acidemia, gestational
age, and Bishop score.
• Cesarean delivery without a trial of labor may be
appropriate (1) in the presence of evidence of fetal distress
by nonstress testing or reversed diastolic flow or (2) for
traditional obstetrical indications for cesarean delivery (ie,
malpresentation, prior cesarean delivery).

45. IMPORTANT CAUSES OF IUGR AND THEIR
MANAGEMENT
• The most important factor -when to deliver an IUGR fetus.
• Repeat the investigations according to the extent IUGR and
• Close monitoring is absolutely essential on a case-to-case
basis and to delay delivery as close to fetal maturity as
possible.
• Gestational diabetes mellitus and the degree of glucose
intolerance has to be identified during pregnancy. A
diagnostic 75 g oral glucose tolerance test (OGTT) after
overnight fast at least 8 hours should be tested at 24-28
weeks and must be repeated periodically to monitor glucose
control.

46. • Patients with (GDM) must be taught the importance of self
glucose monitoring (capillary).
• Pre-pregnancy counselling and
• Antenatal management are essential for optimising of
glycaemic control, keeping glycosylated hemoglobin (HbA1C)
less than 6.5-7%.
• Dietary control, oral hypoglycaemic agents or properly
chosen insulin and its dosage along with frequent
monitoring -optimum results.
• Try to prevent every complication of diabetes.

47. DIAGNOSIS
• Diagnose - Abnormalities affecting the structure and
function of the foetus as early as possible.
• Screening methods for chromosomal abnormalities have
improved over years, e.g. biochemical markers in 1 st and
2nd trimester of pregnancy,
• Advances in ultrasonography, colour Doppler and 3D and 4D
screening for birth defects;
• Invasive tests such as amniocentesis, CVS, cordocentesis for
foetal cord blood sampling

48. • Noninvasive prenatal foetal chromosomal study from
maternal blood is available only at some centers.
• Preimplantation genetic diagnosis is rarely utilized for
couples with high risk of transmitting an inherited condition.
• Depending on the case and type of anomaly, discontinuation
of pregnancy may be decided after counseling.
• Chronic urinary infection in pregnancy needs proper
diagnosis and long-term treatment.

49. • Overall general health of the patient and
• management of anaemia, hypothyroidism and infections
• Investigate - Thromboembolic disease during pregnancy
especially when there is recurrent IUGR.
• Appropriate treatment by anti thrombotic and thrombolytic
agents such as low molecular weight heparin, aspirin,
steroids are given almost through the pregnancy and
decision to deliver the patient depends on the results of
monitoring.

50. • Hypertension during pregnancy causes placental ischaemia with
endothelial dysfunction and IUGR.
• Chronic reduction in uteroplacental perfusion - detect by series of
tests—clinical, biochemical, sonographic and Doppler
• Management with antihypertensive agents, nitric oxide donors, L-
arginine treatment, low-dose aspirin - effective along with very
close monitoring timely treatment and delivery.
• Endothelial cell dysfunction - main component of the patho
physiology of pre-eclampsia and in spite of medical treatment, the
decision for timely delivery is most important.

51. Management of twins
• Delivery depends on chorionicity, prenatal screening for
chromosomal and structural abnormalities and placental
evaluation.
• Cervical length measurements and foetal growth studies in
IUGR in twin pregnancy - most important especially in
discordant and monochorionic twins.
• A careful approach to diagnosis and management – for
better outcomes, preventing unanticipated stillbirth and
allowing appropriate timing of delivery.

52. • Integration of different testing modalities allows adjustment of
monitoring interval based on Doppler parameters and a more
precise prediction of acid-base, status based on biophysical
variables.
• The presence of a well-equipped neonatal intensive care unit
(NICU) and a well-trained neonatologist – must.
• For the obstetrician and the neonatologist - the balance of fetal
risks of continuation of pregnancy the neonatal risks after birth
that dictates the timing of delivery.

53. TIMING OF DELIVERY
• There is a temporal sequence of Doppler changes preceding
the onset of late decelerations.
• Early Doppler changes occur in all the IUGR fetuses,
• Whereas late Doppler changes occur in idiopathic IUGR and
only in a few IUGR cases diagnosed in patients with pre-
eclampsia.
• In pre eclamptic patients - the changes are unpredictable,
and can occur in a few hours, and in most cases, do not
occur because delivery is done for maternal indication.

55. TIMING OF DELIVERY FOR VERY PREMATURE
GROWTH-RESTRICTED FOETUSES
• At the current time, it is not possible to identify optimal
timing of delivery in very premature IUGR fetuses.
• Mostly, the decision to deliver a growth-restricted foetus
based on abnormal antenatal testing, an abnormal BPP or
NST, or abnormal Doppler study.
• In terms of survival rate, the growth-restricted foetus
delivered at >25 and <30 weeks - most problematic.

56. • The very early IUGR foetuses are delivered in the presence
of either NST or an abnormal BPP (<4/8 confirmed at 2 hours
apart).
• Fetuses diagnosed with stage I or higher IUGR involving
abnormal Doppler studies should be monitored closely.
• Still delivery solely on the basis of abnormal Doppler studies
has not been proven beneficial and, in most cases, fetuses
with abnormal Doppler studies do well in the setting of
reassuring antenatal testing.

57. MODE OF DELIVERY FOR IUGR FOETUSES
• Data seems to support caesarean delivery for a growth-
restricted foetus when there is absent or reversed flow of
the umbilical artery because these fetuses rarely tolerate
attempts at vaginal delivery.

58. Future Directions and Prevention
• Decline in the rate of IUGR from 61.5% in the historic controls to 13.3% in
those treated with aspirin and dipyridamole.
• A small decrease in the rate of preeclampsia but not IUGR (at the risk of
increased chance of abruption)
• using 150 mg of aspirin in pregnant women with abnormal UA Doppler
findings. (increase in birth weight and an increase in placental weight.)
• Beginning 100-150 mg/d of aspirin at less than 17 weeks' gestation
decreased the rate of IUGR by approximately 65% and the rate of
perinatal mortality by approximately 60%.
• Despite the theoretical benefit of aspirin in many studies, the role of
aspirin, if any, in the prevention of IUGR is still unclear.

59. SUMMARY
• Intrauterine growth restriction (IUGR) secondary to placental
insufficiency - a major cause of perinatal morbidity and
mortality worldwide.
• No single test that appears superior to the other available
tests for determining the timing of delivery of the growth-
restricted fetus.
• The presence of a well trained neonatologist at the time of
delivery - valuable.
• A few days gained by the foetus in utero between 25 weeks
and 30 weeks gestation, can make a difference in the future
of the IUGR baby.