The Journal of Maternal-Fetal & Neonatal Medicine

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Intrauterine growth restriction – part 2

Deepak Sharma, Nazanin Farahbakhsh, Sweta Shastri & Pradeep Sharma

To cite this article: Deepak Sharma, Nazanin Farahbakhsh, Sweta Shastri & Pradeep Sharma
(2016) Intrauterine growth restriction – part 2, The Journal of Maternal-Fetal & Neonatal
Medicine, 29:24, 4037-4048, DOI: 10.3109/14767058.2016.1154525

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Published online: 15 Mar 2016.

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J Matern Fetal Neonatal Med, 2016; 29(24): 4037–4048

! 2016 Informa UK Limited, trading as Taylor & Francis Group. DOI: 10.3109/14767058.2016.1154525

REVIEW ARTICLE

Intrauterine growth restriction – part 2

Deepak Sharma1, Nazanin Farahbakhsh2, Sweta Shastri3, and Pradeep Sharma4
1
Department of Pediatrics, Pt B.D. Sharma, Post Graduate Institute of Medical and Sciences, Rohtak, Haryana, India, 2Department of Pediatrics,
Shiraz University of Medicine, Shiraz, Iran, 3Department of Pathology, N.K.P Salve Medical College, Nagpur, Maharashtra, India, and 4R.N.T Medical
College, Udaipur, Rajasthan, India

Abstract Keywords
Small for gestational age (SGA) infants have been classically defined as having birth weight less Asymmetrical IUGR, foetal insulin hypothesis
than two standard deviations below the mean or less than the 10th percentile of a population- and MODY genes, foetal origin of adult
specific birth weight for specific gestational age, whereas intrauterine growth restriction (IUGR) disease, IUGR, symmetrical IUGR, thrifty
has been defined as a rate of foetal growth that is less than normal for the population and for genotype, thrifty phenotype (Barker
the growth potential of a specific infant. SGA infants have more frequent problems such as Hypothesis)
perinatal asphyxia, hypothermia, hypoglycaemia, polycythaemia and many more when
compared with their appropriate for gestational age counterpart. They too have growth History
retardation and various major and subtle neurodevelopmental handicaps, with higher rates of
perinatal and neonatal mortality. With the advent of newer technologies, even though the Received 22 December 2015
perinatal diagnosis of these SGA/IUGR foetuses has increased, but still perinatal morbidity and Revised 9 February 2016
mortality rates are higher than normal foetuses and infants. In this part, we have covered Accepted 11 February 2016
neonatal IUGR classification, postnatal diagnosis, short-term and long-term complications faced Published online 11 March 2016
by these IUGR infants.

Introduction  Moderate: Birth weight in the 3–10 percentile

Intrauterine growth restriction (IUGR) is defined as a rate of
foetal growth that is less than normal for the growth potential of
a specific infant because of genetic or environmental factors.
These neonates who are born with IUGR have different types
of short-term and long-term problems making them vulnerable
to mortality and morbidity, both immediately and also on long-
term follow-up. These neonates need to be followed up for
delayed onset of neurological problem so that early interven-
tion can be started on both neurological and physical aspect
and lead to better outcome of this group. The preterm IUGR is
more susceptible to these problems as they are faced with more
perinatal insult as compared with term IUGR and these preterm
IUGR also face other problems of prematurity. In this part, we
have covered the classification of IUGR with their short-term
and long-term morbidities. In this article, IUGR and small for
gestational age (SGA) are used interchangeably though there
are some subtle difference [1,2].
Definition
SGA refers to a weight below the 10 percentile for gestational
age as per the population growth charts. It can be further
classified as [3]
Address for correspondence: Dr Deepak Sharma, Department of
Pediatrics, Pt B.D. Sharma, Pt. B.D. Sharma Post Graduate Institute of
Medical and Sciences, Rohtak, Haryana, India. E-mail:
dr.deepak.rohtak@gmail.com
 Severe: Birth weight less than 3 percentile
Classification of IUGR
There are three types of IUGR, namely symmetrical IUGR
(hypoplastic small for date), asymmetrical IUGR (malnour-
ished babies) and mixed IUGR based on the clinical and
anthropometric features. There are multiple differentiating
features between symmetrical IUGR and asymmetrical IUGR
(Table 1). A third variety is also seen in developing countries
termed as mixed IUGR. This is characterized by both
reduction in cell number and cell size and has clinical
features of both symmetrical and asymmetrical IUGR. This
occurs when early IUGR is affected further by placental
causes in late pregnancy [4].
Postnatal diagnosis of IUGR
The postnatal diagnosis of IUGR involves myriad of compo-
nents such as clinical examination, anthropometry, Ponderal
Index, Clinical assessment of nutrition (CAN) score,
Cephalization index, mid-arm circumference (MAC) and
mid-arm/head circumference (HC) ratios.
Anthropometry
Assessment of weight at birth less than 10 centile labels a
neonate IUGR. There are controversies over the type of
growth chart to use as these growth curves may not be true
4038 D. Sharma et al.
Table 1. Features of symmetrical and asymmetrical IUGR.
Characteristics Symmetrical IUGR
Period of insult Earlier gestation
Incidence of total IUGR cases 20–30%
Etiology Genetic disorder or infection intrinsic to foetus
Antenatal scan (head circumference, abdominal All are proportionally reduced
circumference, biparietal diameter and femur
length)
Cell number Reduced
Cell size Normal
Ponderal Index Normal (more than 2)
Postnatal anthropometry (Weight, length and Reductions in all parameters
head circumference)
Difference between head and chest circumfer- Less than 3 cm
ence in term IUGR
Features of malnutrition Less pronounced
Prognosis Poor
representation of the total population because of small sample
size and heterogeneity of population. It has been proved that
customized growth charts that account for maternal charac-
teristics such as height, weight or body mass index (BMI),
ethnicity, parity and neonatal sex are more accurate at
diagnosing foetal and neonatal IUGR [5]. In symmetrical
IUGR, weight, HC and length will be less than 10 centile
whereas in asymmetrical IUGR only weight will be less than
10 centile and rest will be as per gestation age [6].
Clinical examination
IUGR newborns have varied typical features of malnutrition
(Figure 1). These include
 Weight less than expected for the gestational age
 Relatively large heads compared with rest of the body
 Large Anterior fontanelle because of decreased mem-
branous bone formation
 Loss of buccal fat, face has a typical shrunken or
‘‘wizened’’ appearance (Old Man Look)
 Small or scaphoid appearing abdomen, thin umbilical
cord often stained with meconium
 Decreased skeletal muscle mass and subcutaneous fat
tissue with thin arms and legs
 Skin is loose, dry and easy to be peeled away
 Long finger nails
 Relatively large hands and feet compared with body with
increased skin creases
 Loose folds of skin in the nape of neck, axilla, inter-
scapular area and groins
 Anxious and hyper alert
 Diminished breast bud formation and immature female
genitalia due to loss of subcutaneous fat.
In the case of symmetrical IUGR examine such neonate for
any associated dysmorphic features, congenital anomalies
(suggestive of chromosomal abnormality, syndrome or intra-
uterine drug exposure) and features of congenital viral
infection especially TORCH group (microcephaly, petechiae,
blue-berry muffin, cardiac defect, hepatosplenomegaly, chor-
ioretinitis and cataracts).
The physical component of the Ballard scoring system for
gestational age assessment is misleading in these IUGR
infants because of diminished vernix caseosa, skin is
J Matern Fetal Neonatal Med, 2016; 29(24): 4037–4048
Asymmetrical IUGR
Later gestation
70–80%
Utero-placental insufficiency
Abdominal circumference-decreased biparie-
tal diameter, head circumference and
femur length- normal
Normal
Reduced
Low (less than 2)
Reduction in weight length and head cir-
cumference-normal (brain sparing growth)
More than 3 cm
More pronounced
Good
continuously exposed to amniotic fluid leading to cracking
and peeling of the skin which leads to more mature sole
crease pattern, less well-formed ear cartilage, diminished
breast bud (due to decreased blood flow, low estradiol level
and low subcutaneous fat), and less mature-appearing female
genitalia (due to reduced fat deposit in the labia majora). The
neurologic component of the Ballard scoring system is less
affected in IUGR and can be used more accurately to confirm
gestational age assessment of these infants [1,2].
Ponderal index
Ponderal Index is also used to determine the degree of foetal
malnutrition. It is calculated as ratio of body weight in grams
to length in cm expressed as (PI ¼ [weight (in g) 
100] 7 [length (in cm)3]). PI of less than 10 percentile
reflects foetal malnutrition; PI of less than 3 percentile
indicates severe foetal wasting [7,8].
Mid-arm circumference and MAC/HC ratios
(Kanawati and McLaren’s index)
The normal value of MAC/HC ratios is 0.32–0.33 and in a
term IUGR infants, value less than 0.27 is considered as
features of foetal malnutrition [9].
Clinical assessment of nutrition score (CAN Score)
CAN score was developed by Metcoff J and used in
assessment of nutritional status in newborns at birth. It
includes nine parameters, namely, hair, cheeks, neck and chin,
arms, legs, back, buttocks, chest and abdomen. The maximum
score is 36 with each parameter given maximum score of 4
and minimum score is 1, in which 4 denotes normal nutrition
and 1 denotes malnutrition. A neonate with CAN score of less
than 25 is considered to be malnourished (Table 2) [10]. CAN
score has been shown better than anthropometry, Ponderal
index, weight for age, MAC/HC and BMI [11–13].
Cephalization index
This was first studied by Harel et al. and they coined the term
cephalization index. This is calculated as ratio of HC to body
weight. They postulated that higher the brain:body ratio, the
more severe is the IUGR and higher cephalization index
DOI: 10.3109/14767058.2016.1154525 Intrauterine growth restriction – part 2 4039

Figure 1. Clinical features of infants at birth that are having intrauterine growth restriction. Figure Copyright Deepak Sharma.

Table 2. The nine signs for CAN status in the newborn.

Hair Large amount, smooth, silky, easily groomed [4], Thinner, some straight, ‘‘staring’’ hair [3], still thinner, more straight,
‘‘staring’’ hair which does not respond to brushing [2], Straight ‘‘staring’’ hair with depigmented stripe (flag sign) [1]
Cheeks Progression from full buccal pads and round face [4], to significantly reduced buccal fat with narrow, flat face [1]
Neck and chin Double or triple chin fat fold, neck not evident [4]; to thin chin. No fat fold, neck with loose, wrinkled skin, very evident [1]
Arms Full, round, cannot elicit ‘‘accordion’’ folds or lift folds of skin from elbow or tricep area [4]; to a striking ‘‘accordion’’ folding
of lower arm, elicited when examiner’s thumb and fingers of the left hand grasp the arm just below the elbow of the baby
and thumb and fingers of the examiners right hand circling the wrist of the baby are moved towards each other; skin is loose
and easily grasped and pulled away from the elbow
Legs Like arms
Back Difficult to grasp and lift skin in the interscapular area [4]; to skin loose, easily lifted in a thin fold from the interscapular area
[1]
Buttocks Full round gluteal fat pads [4]; to virtually no evident gluteal fat and skin of the buttocks and upper posterior high loose and
deeply wrinkled [1]
Chest Full, round, ribs not seen [4]; to progressively prominence of the ribs with obvious loss of intercostal tissues [1]
Abdomen Full, round, no loose skin [4]; to distended or scaphoid, but with very loose skin, easily lifted, wrinkled and ‘‘accordion’’ folds
demonstrable

Adopted from Ref. [10].

reflected a greater degree of brain vulnerability and increased
likelihood of cerebral palsy and severe psychomotor retard-
ation. The mean HC: body weight ratio for preterm IUGR was
0.0209 ± 0.001 (SD ¼ 0.0045) and for term IUGR was
0.0170 + 0.00059 (SD ¼ 0.003). The cephalization index
may serve as an additional screening device for the future
risk categorization of an IUGR infant [14].
Short-term complications of IUGR neonates
These newborns are faced with many problems after birth.
Severely affected IUGR infants, deprived of oxygen and
nutrients, may have difficult cardiopulmonary transition
with perinatal asphyxia, meconium aspiration or persistent
pulmonary hypertension (PPHN). Immediate neonatal com-
plications include hypothermia, hypoglycaemia, hypergly-
caemia, hypocalcaemia, polycythaemia, jaundice, feeding
difficulties, feed intolerance, necrotizing enterocolitis, late
onset sepsis, pulmonary haemorrhage and so on (Table 3 and
Figure 2) [2].
Perinatal mortality is high in these neonates as compared
with their appropriate for gestational age (AGA) counterpart.
This is seen because of adverse effect prolonged intra-uterine
hypoxia, birth asphyxia, sudden sentinel events, including
abruption, cord prolapse and associated congenital anomalies
seen in this group [15,16]. Perinatal asphyxia is the result of
acute foetal hypoxia superimposed on chronic foetal hypoxia
and acidosis, placental insufficiency/preeclampsia and asso-
ciated glycogen deficiency [17]. The prevention of perinatal
asphyxia includes regular ante-natal and intrapartum moni-
toring, regular foetal growth monitoring by ultrasound,
biophysical profile, conducting delivery at appropriate time
and early identification of complications with prompt referral
and efficient neonatal resuscitation. The management of
hypoxia includes multi-organ system support, controlling
seizures, maintaining adequate perfusion, glucose, calcium
4040 D. Sharma et al. J Matern Fetal Neonatal Med, 2016; 29(24): 4037–4048

Table 3. Immediate complications of intrauterine growth restricted newborn.

Morbidity Pathogenesis/pathophysiology Prevention/treatment

Asphyxia Acute foetal hypoxia superimposed on Regular antepartum and intrapartum monitoring
chronic foetal hypoxia and acidosis Foetal growth monitoring by USG
Placental insufficiency/preeclampsia Biophysical profile
Glycogen deficiency Delivery at appropriate time
Efficient neonatal resuscitation
Hypothermia Impaired thermoregulation Protect against increased heat loss during resuscita-
Increased surface area tion
Decreased body and subcutaneous fat store Thermo-neutral environment
Catecholamine depletion Nutritional support including aggressive breastfeed-
Hypoxia ing
Hypoglycaemia Warm transport, Kangaroo care
Hypoglycaemia Decreased stores of glycogen of hepatic/ Monitoring of blood glucose 6 hourly for the first
muscle 72 h
Decreased alternative energy sources Early and scheduled feeding
Comorbidities like hypoxia, hypothermia Early intravenous glucose support when needed
Decreased production of glucose
Decreased counter-regulatory hormones
Increased insulin sensitivity
Hyperglycaemia Low insulin secretion rate Strict glucose monitoring
Excessive glucose delivery Avoiding high glucose infusion
Increased catecholamine and glucagon effects Insulin administration
Polycythaemia/hyperviscosity Chronic intra-uterine hypoxia Monitoring of haematocrit at 12 and 24 h after birth
Maternal-foetal transfusion Partial volume exchange and fluid supplementation
Increased erythropoiesis due to hypoxia if symptomatic
Persistent pulmonary hypertension Chronic hypoxia Avoiding hypoxia
(PPHN) Remodelling of pulmonary vasculature Cardiovascular support
Secondary hypocalcaemia, polycythaemia, Mechanical ventilation, nitric oxide
infections
Meconium aspiration Hypoxia Resuscitation as per the NRP 2015 guidelines
includes avoiding tracheal suctioning for
depressed and vigorous newborn and early
establishment of respiration
Feed intolerance/necrotizing enterocolitis Decreased intestinal perfusion Avoiding rapid increase in feeds
Focal ischemia Cautious enteral feeding
Hypoperistalsis Only breast milk (either mothers or donor milk)
Renal dysfunction Hypoxia/ischemia Cardiovascular support
Renal tubular injury Maintenance of perfusion
Immunodeficiency Immunological immaturity Early, aggressive and optimal nutrition
Malnutrition Prevention of sepsis
Congenital infection Specific antibiotic and immune therapy
Decreased T and B peripheral lymphocytes
Pulmonary haemorrhage Hypothermia, polycythaemia Avoid cold stress
Asphyxia Gentle ventilation
Infection/DIC
Mortality Increased incidence due to associated other Adequate post-natal care
comorbidities
Intrauterine foetal death Chronic hypoxia Antenatal surveillance
Placental insufficiency Regular foetal monitoring
Malformation Delivery for severe/worsening foetal distress
Infection
Sudden sentinel events including abruption,
cord prolapse
Infarction/preeclampsia

Adapted from Ref. [1].

and blood pressure and therapeutic hypothermia [18]. Ananth
and Vintzileos in their study showed that the rate of score
Apgar57 at 5 min of life was significantly high in SGA
infants when compared with AGA (RR ¼ 2.0; 95% CI ¼ 1.9–
2.1) [19].
Neonatal mortality is higher in the SGA neonates because
of the associated co-morbidities and also because of antenatal
and perinatal insults faced by these infants [20]. Katz et al. in
a pooled analysis of 20 cohorts from developing population
showed that in comparison with term AGA infants, the RR for
neonatal mortality was 1.83 (95% CI 1.34–2.50) and post-
neonatal mortality RR was 1.90 (1.32–2.73) for SGA infants.
The risk of neonatal mortality was maximum in babies who
were both preterm and SGA in comparison to babies who
DOI: 10.3109/14767058.2016.1154525
Figure 2. Immediate neonatal complications seen in intrauterine growth restricted neonates. Figure Copyright Deepak Sharma.
were either SGA or preterm alone (15.42; 9.11–26.12) [21].
The risk for mortality increases further in preterm SGA when
compared with preterm AGA. In study conducted by Sharma
et al. results showed that when controlling for GA, premature
SGA infants were at a higher risk for mortality (Odds ratio
3.1, p ¼ 0.001) and at lower risk of respiratory distress
syndrome (OR ¼ 0.71, p ¼ 0.02) than AGA infants [22].
Hypoglycaemia is seen because of decreased glycogen
stores, gluconeogenesis, increased sensitivity to insulin,
decreased fat (adipose tissue) and decreased ability to oxidize
free fatty acids and triglycerides effectively. Hypoglycaemia
could also be a result of asphyxia, polycythaemia or
hypothermia. The risk of hypoglycaemia is more in initial
few days because of sudden disruption of the maternal
glucose supply and delay in post-natal adaptation. These
neonates need sugar monitoring with early feeding after birth
with monitoring of sign and symptoms of hypoglycaemia
[2,23]. Whole blood glucose levels persistently less than
40–45 mg/dL and not responding to enteral feeding or
symptomatic hypoglycaemia and any asymptomatic infant
with very low glucose concentrations (less than 20–25 mg/dL)
requires immediate intravenous glucose and strict monitoring
[24]. Doctor et al. in their study showed that SGA infants had
significantly higher rates of hypothermia (18% versus 6%)
and symptomatic hypoglycaemia (5% versus 1%) [25].
Similar results were reported by Deorari et al. from India
who reported incidence of hypoglycaemia as 17% and
polycythaemia as 10% [26].
Hyperglycaemia is also seen sometimes in these IUGR
infants because of result of low insulin secretion rate,
excessive exogenous glucose delivery and increased catechol-
amine and glucagon effects [23]. Management includes
regular monitoring of sugar level and avoiding too much
glucose infusion [27].
Hypothermia is a common complication in these IUGR
infants if proper care of temperature maintenance is not done
Intrauterine growth restriction – part 2 4041
after birth [25]. There are multiple causes for predilection for
hypothermia which includes relatively large body surface
area, decreased body and subcutaneous tissue fat, impaired
thermoregulation and catecholamine depletion. In addition,
simultaneous occurrence of either hypoxia or hypoglycaemia
can interfere with heat production. For the prevention of
hypothermia we should deliver and nurse these infants in
thermo-neutral environment (use of warmer) and ensure
nutritional support, including aggressive breastfeeding and
warm transport, and kangaroo mother care [28].
Polycythaemia defined as venous haematocrit more than
65% is seen in these IUGR infants. This polycythaemia and
leukoneutropenia is due to increased synthesis of erythropoi-
etin secondary to chronic intra-uterine hypoxia and some-
times because of maternal-foetal transfusion [29,30]. This
polycythaemia can lead to myriad of symptoms and involve
all the system of the infant. These IUGR infants should be
monitored for haematocrit at 2, 12 and 24 h after birth. If the
infant is symptomatic, polycythaemia can be managed with
partial volume exchange and fluid supplementation [31,32].
IUGR/SGA is prone to develop early onset hypocalcaemia,
because of decreased transfer of calcium in-utero and also
sometimes secondary to hypophosphatemia induced by
chronic hypoxia [33]. Muhammad et al. in their prospective
study, that enrolled 100 SGA and 100 AGA very preterm
babies and reported that SGA had significant increase in
hypocalcaemia (24% versus 10%, p ¼ 0.02) were compared
AGA infants [34]. The incidence of hypocalcaemia is highest
at 48–72 h of life and needs monitoring [35]. Hypocalcaemia
needs management with either intravenous or oral supple-
mentation depending on whether it is symptomatic or
asymptomatic [36].
PPHN is seen in these IUGR infants because of chronic
hypoxia in these infants that lead to remodelling of pulmonary
vasculature, with extension of muscularis layer of blood
vessels to intra-acinar arteries. This PPHN could also be a
4042 D. Sharma et al.
secondary with associated hypocalcaemia, polycythaemias,
hypoglycaemia or infections, seen in them. Management of
PPHN involves avoiding hypoxia and hyperoxia, normaliza-
tion of metabolic milieu, cardiovascular support, pulmonary
vasodilator and mechanical ventilation [37,38]. FGR has also
been seen as an independent risk factor for chronic lung
disease in preterm IUGR infants [39,40].
Meconium aspiration syndrome (MAS) is seen in these
IUGR infants because of chronic hypoxia leading to meco-
nium-stained liquor (MSL) and aspiration. The severity can
vary from mild to severe MAS requiring ventilation.
Management includes intra-partum foetal monitoring and
early detection of MSL. There is no role of amnio-infusion for
prevention of MSL except in places where facilities for
perinatal surveillance are limited [41]. Treatment involves
adequate ventilation with prevention of hypoxia, adequate
lung recruitment and management of PPHN [42]. These
infants develop secondary surfactant deficiency, hence few
infants may benefit with surfactant instillation [43]. Routine
tracheal suctioning in non-vigorous MSL infants have been
removed from latest neonatal resuscitation programme (NRP-
2015) [44].
Pulmonary haemorrhage is seen because of abnormal
vasculature and also because of other comorbidities such as
hypothermia, polycythaemia, asphyxia and infection/DIC.
Management involves prevention of hypothermia and gentle
ventilation and supportive care for pulmonary haemorrhage
[45].
Feed intolerance and necrotizing enterocolitis (NEC) is
seen frequently in these neonates [46]. These are due to in-
utero decreased intestinal perfusion due to shunting of blood
in response to hypoxia to vital organs, including heart, brain
and adrenals, focal ischemia and hypoperistalsis [47]. The
incidence of NEC is increased further in IUGR infants with
absent or reversed end diastolic flow in the umbilical artery
Doppler’s [48]. Management includes avoiding rapid increase
in feeds, cautious enteral feeding, minimal enteral nutrition
and only breast milk (either mothers or donor milk) [49].
Dogra et al. from India, in their prospective observational
study reported that there was a trend towards more feed
intolerance (22% versus 12%, p ¼ 0.183) and NEC (12%
versus 6%, p ¼ 0.295) in SGA group and these babies also had
significantly more hypoglycaemia (p ¼ 0.000) and polycy-
thaemia (p ¼ 0.032) and longer hospital stay (p ¼ 0.017) [50].
Renal dysfunction is seen usually secondary to hypoxia/
ischemia leading to renal tubular injury and usually manifest
as oliguria and deranged renal parameters. Management
includes cardiovascular support and maintenance of renal
perfusion [26].
Immunodeficiency seen in these IUGR infants makes them
more prone for post-natal infection. The pathogenesis of
immunodeficiency is immunological immaturity, associated
malnutrition, congenital infection and decreased T and B
peripheral lymphocytes. Management includes prevention of
postnatal infection by asepsis measurement, enhancing
immunity with early, aggressive and optimal nutrition and
treatment of postnatal infection with antibiotics and immune
therapy [51,52].
Retinopathy of prematurity (ROP) incidence is increased
in these infants because of intrauterine hypoxia, altered levels
J Matern Fetal Neonatal Med, 2016; 29(24): 4037–4048
of growth factors, and diminished antioxidant capacity [16].
Bardin et al. showed that SGA infants (less than 27 weeks
gestation) were at greater risk for developing severe ROP
(stage4/¼III) (65% versus 12% for AGA) [53].
Neuro-behavioural abnormalities are also seen in this
group of infants. In a study conducted by Padidela et al. who
evaluated the neuro-behaviour of term appropriate for gesta-
tional and SGA babies during the first two weeks of life using
Brazelton neuro-behavioural assessment scale reported that
the behaviour performance of SGA babies on day 3, compared
with AGA babies, was lower in all the clusters except
orientation where they performed much better. The percent-
age improvement of scores in SGA babies was higher than in
AGA babies and by day 14, SGA babies were scoring higher
than AGA babies in orientation, autonomic stability and
regulation of state [54].
Low serum ferritin is seen in these infants, secondary to
decreased transport through placenta and also because of
increased prematurity seen in this group. Mukhopadhyay et al.
in their study to evaluate the iron status at birth and at four
weeks in preterm-SGA infants in comparison with preterm
and term-AGA infants reported low cord serum ferritin levels
in preterm-SGA group as compared with preterm-AGA
group. The proportion of the infants with ‘‘low’’ serum
ferritin was significantly more in preterm-SGA than in
preterm-AGA, with similar results in follow-up too [55].
Long-term morbidities
IUGR infants are at risk for impaired growth and neurode-
velopment and are prone to develop adult onset disease in
their infancy (Figure 3).
Long-term physical growth
There are many postnatal factor that determine the postnatal
growth of IUGR baby like cause of the growth retardation
(most important), the postnatal nutritional intake, economic
status of parents, and the surrounding social environment. The
IUGR infants who are symmetrical IUGR have poor growth
postnatally and remain small throughout life as they have
reduced cell number at the time of birth. In compared to
symmetrical IUGR, asymmetrical IUGR has better prognosis
and they have good postnatal growth as the cell number is
normal and only defect in cell size is there, but the growth
depends upon the optimal environment and adequate post-
natal caloric intake provided to such neonates [56–58]. Leger
et al. in their follow-up study from birth to puberty of IUGR
infants showed that individual final height and individual
height gain in the IUGR infant could be explained at birth
from mother’s height, father’s height and birth length [59].
A study conducted from India by Chaudhari et al. in which
the growth and sexual maturation of low birth weight infants
was assessed at 12 year of age enrolled 180 LBW infants
who were grouped as preterm SGA (n ¼ 73), full term SGA
(n ¼ 33) and preterm AGA (n ¼ 74). Ninety full term AGA
infants were taken as controls. The result of this cohort study
showed that preterm SGA children had significantly less
anthropometric measurement compared with the others two
group. There was no significant difference in sexual maturity
and onset of menarche [60].
DOI: 10.3109/14767058.2016.1154525 Intrauterine growth restriction – part 2 4043

Figure 3. Long term physical and neurodevelopmental problems faced by intrauterine growth restricted neonates when they reach their childhood and
adulthood. Figure Copyright Deepak Sharma.

Table 4. Various foetal origin of adult disease

Chaudhari et al. followed the above cohort till age of 18 (FOADs).
years and the population of this LBW infant cohort consisted
of preterm SGA (n ¼ 61), full term SGA (n ¼ 30) and preterm  Hypertension
AGA (n ¼ 70) infants. Seventy-one full term AGA infants  Ischemic heart disease/stroke
were the controls. They reported that preterm SGA males had  Type 2 diabetes
height which was significantly less than that of controls.  Kidney disease
Preterm children had short stature in spite of normal mid-  Liver disease
parental height. Preterm SGA and AGA children had smaller  Hypercholesterolemia
HC [61].  Metabolic syndrome X
 Obesity
Long-term neurodevelopmental outcome (Figure 3)  Lung abnormalities- reactive airways disease
 Cancer breast, ovarian, colon, lung, and blood
These IUGR infants have high probability of having subtle to  Schizophrenia/Parkinsonism
major cognitive and neurodevelopmental abnormalities when  Alzheimer disease
compared with their AGA counterparts of same gestational  Polycystic ovarian syndrome, premature pubarche
age. The neurodevelopmental outcome of IUGR infants  Shortened life span
depends upon the type of IUGR, perinatal events like  Depression, anxiety, bipolar disorder
maternal hypertension [62], Doppler abnormalities [63,64],  Immune dysfunction
and perinatal asphyxia and also on the postnatal course like  Osteoporosis
hypoglycaemia, neonatal sepsis, meningitis, hypoxic-ische-  Social problems
mic encephalopathy and necrotizing enterocolitis [65]. The  Poor cognitive performance
common neurological problems seen in these children include
[66–69]:
 Lower scores on cognitive testing
 School difficulties or requirement of special education  Lower Intelligence
 Gross motor and minor neurologic dysfunction  Poor perceptual performance.
 Behavioural problems (attention deficit hyperactivity Grantham-McGregor studied association between IUGR
syndrome) and cognitive development and behaviour in the first six years
 Growth failure of life and found out that performance deficits was early in
 Reduced strength and work capacity onset and begins to appear between 1 and 2 years of age with
 Cerebral Palsy more deficits in high risk subgroups though the size of the
 Low social competence difference was less at 4–7 years of age [70]. Martorell et al. in
 Poor academic performance their systematic review of 12 studies reported that IUGR
4044 D. Sharma et al. J Matern Fetal Neonatal Med, 2016; 29(24): 4037–4048

Figure 4. Figure showing various adult diseases the IUGR infant is prone to develop in his adulthood as per FOAD. IUGR infants undergo epigenetic
modification in-utero and postnatally have abnormal nutrition and growth leading to various diseases of adulthood in these infants. Figure Copyright
Deepak Sharma.

Figure 5. Barker Hypothesis (thrifty phenotype) explaining the FOAD in IUGR infants. Figure Copyright Deepak Sharma.

males and females performed poorly on tests of strength and
hence could apply approximately 2–3 kg less force to a hand
grip dynamometer and had lower work capacity in compari-
son to their normal counter-parts [71]. In a recently published
study, the investigator showed that SGA was associated with
hyperactive behaviour, but not with cognition and neurode-
velopmental impairment [72].
In a study from India, cohort of 161 low birth weights
(weight 52000 g at birth) were followed from birth till 18
years of age. The authors reported that among the enrolled
infants PT SGA subjects had the lowest IQs (percentile 35.5)
although within the normal range for age. PT SGA infants
were also poor in visuo-motor perception, motor incompe-
tence, reading and mathematics learning [73].
DOI: 10.3109/14767058.2016.1154525
Figure 6. Follow-up programme of infants who are born with intrauterine growth restriction. Copyright of image: Deepak Sharma.
Foetal origin of adult disease
Barker observed that babies who were born in the 1920s and
1930s and were low weight at birth or at age of one year, when
grew to age of 50–70 years had high incidence of coronary
heart disease, Diabetes mellitus, hyperinsulinemia and hyper-
cholesterolemia [74–76]. Similar findings were observed by
other investigators and proposed that insult during foetal life
give pathway to these adult diseases [77–79]. Three different
hypotheses have been purposed for this association, namely
foetal insulin hypothesis and mature onset diabetes of the
young (MODY) genes, thrifty genotype and thrifty phenotype
(Barker Hypothesis) and the last one is the most accepted one
[80]. These IUGR infants are susceptible to number of adult
disease in their life [81] (Table 4 and Figure 4).
Foetal insulin hypothesis and MODY genes
Hattersley and Tooke purposed this theory of and purposed
the possibility of genes causing both low birth weight and
increased risk of type 2 diabetes. They stated that genetically
determined insulin resistance results in impaired insulin-
mediated growth in the foetus and also is responsible for
insulin resistance in adult life leading to susceptibility to type
2 diabetes. Due to the result of this insulin resistance, there is
Intrauterine growth restriction – part 2 4045
abnormal vascular development during foetal life and early
childhood, leading to increased risk of hypertension and
vascular disease. They concluded that predisposition to type 2
diabetes and vascular disease is common output of both
genetic and foetal environmental factors. This foetal insulin
hypothesis is supported by individuals who suffer from
MODY type 2. These individuals have mutations in the
glucokinase gene that results in decreased insulin secretion,
reduced foetal growth and MODY2 [82].
Thrifty genotype
This theory was purposed by Neel in 1962. The investigator
stated that genes which are responsible for causing diabetes
had been retained in the genome of all individual as a result of
natural selection, as they are beneficial to the infant. These
genes result in a greater capacity to store fat during times of
starvation and undernourishment, and recently these genes
have become detrimental because of overeating and lack of
exercise, henceforth leading to early onset of obesity [83,84].
Thrifty phenotype (barker hypothesis)
This is the most accepted hypothesis for explanation of foetal
origin of adult disease (FOAD). This hypothesis suggested
4046 D. Sharma et al.
that when the intrauterine environment was poor due to any
reason like maternal, placental or foetal, the foetus gets
adopted to this hostile environment to survive in-utero. These
include prioritization of brain growth at the expense of other
tissues such as muscle, liver and pancreas, reduced production
and sensitivity to the foetal insulin and insulin-like growth
factor-1 and also by up-regulation of the hypothalamo–
pitutary–adrenal axis. The metabolic programming (epigen-
etic modification) occurs at the crucial time of foetal
development; hence, they become permanent or ‘‘pro-
grammed’’. These changes make the foetus to adapt to poor
postnatal nutrition, but when nutrition during postnatal life is
normal or excessive, which is opposite the foetal program-
ming leads to abnormal growth and make them susceptible to
FOAD (Figure 5) [85].
Conclusion
SGA describes a neonate who is born with weight less than 10
centile for gestational age. IUGR is characterized by foetal
growth less than normal for the population and growth
potential of a given infant. There are mainly two types of
IUGR, symmetrical and asymmetrical depending upon the
gestation of onset and etiology of IUGR. These IUGRs have
both short-term and long-term complications which make
them high risk neonate. The short-term problems include
perinatal asphyxia, meconium aspiration, PPHN, hypother-
mia, hypoglycaemia, hyperglycaemia, hypocalcaemia, poly-
cythaemia, jaundice, feeding difficulties, feed intolerance,
necrotizing enterocolitis, late onset sepsis and pulmonary
haemorrhage. The long-term problems include abnormal
physical growth and neurodevelopmental outcome. These
infants are more likely to develop adult onset disease because
of foetal epigenetic changes. These infants need to be
monitored for both short-term and long-term complications
and should have a regular follow-up for early identification of
any complications (Figure 6).
Declaration of interest
The authors report no conflicts of interest. The authors alone
are responsible for the content and writing of this article.
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