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Intrauterine growth restriction

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intrauterine growth restriction
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Intrauterine growth restriction
What are the risks to a baby born with IUGR?
Types of intrauterine growth restriction (IUGR)
Asymmetrical intrauterine growth restriction
Asymmetric IUGR causes
Symmetrical intrauterine growth restriction
Intrauterine growth restriction causes
IUGR risk factors
Intrauterine growth restriction prevention
Intrauterine growth restriction symptoms
Table 1. Intrauterine growth restriction (IUGR) neonatal complications
Intrauterine growth restriction (IUGR) complications
Intrauterine growth restriction diagnosis
Intrauterine growth restriction treatment
Intrauterine growth restriction prognosis

Intrauterine growth restriction

Intrauterine growth restriction also called IUGR, fetal growth restriction or Small-for-Gestational-Age (SGA), has been defined in several ways, but in general IUGR describes a condition in which the fetus exhibits poor growth in utero where the fetal weight is below the 10th percentile or less than 2 standard deviation for that population reference for gestational age as determined through an ultrasound 1, 2, 3, 4. This means that a baby with intrauterine growth restriction (IUGR) is smaller than 90% other babies of the same gestational age. Intrauterine growth restriction (IUGR) occurs when a baby does not grow well in the mother’s uterus (womb) because of problems with the placenta, the mother’s health, or birth defects. IUGR occurs when the fetus does not receive the necessary nutrients and oxygen needed for proper growth and development of organs and tissues. IUGR can begin at any time in pregnancy. Early-onset IUGR is often due to chromosomal abnormalities, maternal disease, or severe problems with the placenta. Late-onset growth restriction (after 32 weeks) is usually related to other problems.

Intrauterine growth restriction (IUGR) affects approximately 10% of pregnancies worldwide and is a leading cause of perinatal mortality and morbidity 5, 6, 7. Intrauterine growth restriction (IUGR) affects nearly 30%–50% of extremely preterm neonates 8.

Babies with intrauterine growth restriction (IUGR) may be born early or full-term; premature babies  (born before 37 weeks of pregnancy) with IUGR may be very small and physically immature, and full-term (37 to 41 weeks) babies with IUGR may be physically mature but weak. Infants born after undiagnosed IUGR have 2–9 times higher risk of perinatal death and severe neurological complications to those diagnosed prenatally 9, 10.

Intrauterine growth restriction (IUGR) babies may appear physically and neurologically mature but are smaller than other babies of the same gestational age. Intrauterine growth restriction (IUGR) babies may be proportionately small (equally small all over) or they may be of normal length and size but have lower weight and body mass.

One of the most important things when diagnosing IUGR is to ensure accurate dating of the pregnancy. Gestational age can be calculated by using the first day of your last menstrual period (LMP) and also by early ultrasound calculations. Once gestational age has been established, the following methods can be used to diagnose IUGR:

  • A fundal height that does not coincide with gestational age
  • Measurements calculated in ultrasound are smaller than would be expected for the gestational age
  • Abnormal findings discovered by a Doppler ultrasound

Despite new research, the optimal treatment for intrauterine growth restriction (IUGR) remains problematic. Up till now, no effective methods are available to reverse the pathological intrauterine condition or to accelerate the growth of fetuses in pregnancies complicated by IUGR 11. Most likely the treatment will depend on how far along you are in your pregnancy.

  • If gestational age is 34 weeks or greater, health care providers may recommend being induced for early delivery.
  • If gestational age is less than 34 weeks, health care providers will continue monitoring until 34 weeks or beyond. Fetal well-being and the amount of amniotic fluid will be monitored during this time.
  • If either of these becomes a concern, then immediate delivery may be recommended. Depending on your health care provider, you will likely have appointments every 2 to 6 weeks until you deliver. If delivery is suggested prior to 34 weeks, your health care provider may perform an amniocentesis to help evaluate fetal lung maturity.

Figure 1. Intrauterine growth restriction (IUGR)

intrauterine growth restriction

Footnote: Example of a IUGR (2nd centile weight for age, yellow), and an appropriately grown (50th centile weight for age, blue) infant born at 37 weeks gestation.

[Source 12 ]

What are the risks to a baby born with IUGR?

  • Increased risk for cesarean delivery
  • Increased risk for hypoxia (lack of oxygen when the baby is born)
  • Increased risk for meconium aspiration, which is when the baby swallows part of the first bowel movement. This can cause the alveoli to be over distended, a pneumothorax to occur, and/or the baby can develop bacterial pneumonia.
  • Hypoglycemia (low blood sugar)
  • Polycythemia (increased number of red blood cells)
  • Hyperviscosity (decreased blood flow due to an increased number of red blood cells)
  • Increased risk for motor and neurological disabilities

Types of intrauterine growth restriction (IUGR)

There are two different types of IUGR (Figure 2) 13, 14:

  1. Symmetric or primary IUGR is characterized by all internal organs being reduced in size. Symmetric IUGR accounts for 20% to 25% of all cases of IUGR. Symmetric IUGR is usually early onset with intrinsic genetic disorder or infections to fetus as the main causal factors. Ponderal index is normal, whereas biparietal diameter (BPD), femur length (FL), head and abdominal circumference (HC and AC) are proportionally reduced. Prognosis is poor.
  2. Asymmetric or secondary IUGR is characterized by the head and brain being normal in size, but the abdomen is smaller. Asymmetric IUGR incidence is 70–80%. Typically this is not evident until the third trimester. Ponderal index is low (< 3), whereas biparietal diameter (BPD), head circumference (HC) and femur length (FL) are normal. Abdominal circumference is decreased. Brain sparing growth is there, with advancing pregnancy, and features of malnutrition are exaggerated. Prognosis is better.
  3. Mixed IUGR. Initially symmetric but later on asymmetric. Etiology is mixed.

Footnotes:

  • Ponderal index is an anthropometric measure of body mass index, defined as person’s weight in kilograms divided by the cube of height in meters (mass/height³). This is regarded as less satisfactory than the body mass index (BMI) where person’s weight in kilograms divided by the square of height in meters (mass/height²)
  • Biparietal diameter (BPD) is one of the basic biometric parameters used to assess fetal size.
  • Biparietal diameter (BPD) together with head circumference (HC), abdominal circumference (AC), and femur length (FL) are computed to produce an estimate of fetal weight. In the second trimester this may be extrapolated to an estimate of gestational age and an estimated due date (EDD).
  • Head circumference (HC) is one of the basic biometric parameters used to assess fetal size. Head circumference (HC) together with biparietal diameter (BPD), abdominal circumference (AC), and femur length (FL) are computed to produce an estimate of fetal weight. In the second trimester, this may be extrapolated to an estimate of gestational age and an estimated due date (EDD).

Figure 2. Types of intrauterine growth restriction 

IUGR types

Footnotes: Representation of the physical presentation of symmetrical and asymmetrical IUGR and a short list of clinical characteristics and causes. * note that incidence data are from high-resource settings. A third phenotype is proposed in low-resource settings, that includes characteristics of malnutrition and late gestation placental insufficiency 15, not shown. Delphi criteria from Gordijn et al. 16.

# Ponderal index is an anthropometric measure of body mass index, defined as person’s weight in kilograms divided by the cube of height in meters (mass/height³). This is regarded as less satisfactory than the body mass index (BMI) where person’s weight in kilograms divided by the square of height in meters (mass/height²)

Abbreviations: HC = head circumference; AC = Abdominal circumference; GW = gestational weeks; AC = abdominal circumference; EFW = Estimated fetal weight.

[Source 17 ]

Asymmetrical intrauterine growth restriction

Asymmetric IUGR is the commonest IUGR with an incidence of 70–80%. Asymmetrical intrauterine growth restriction is a type of intrauterine growth restriction (IUGR) is characterized by the head and brain being normal in size due to the result of “brain sparing,” a process whereby brain growth is less affected than body growth due to the redistribution of cardiac output, but the abdomen is smaller. While brain sparing does not completely prevent the damaging effects of IUGR on brain development 18, 19, it is nonetheless associated with better neurological outcomes than when brain sparing does not occur 20. Typically asymmetric IUGR is not evident until the third trimester. Ponderal index is low (< 3), whereas biparietal diameter (BPD), head circumference (HC) and femur length (FL) are normal. Abdominal circumference is decreased. Brain sparing growth is there, with advancing pregnancy, and features of malnutrition are exaggerated. Prognosis is better.

Classically, in asymmetrical intrauterine growth restriction, there is relative preservation of the fetal brain (fetal head sparing theory), which is pathologically characterized by an increased brain-to-liver ratio (BLR) 21. This can also result in decreased fetal subcutaneous fat 22, 23. A rare paradoxical situation is with maternal cocaine use, where the head circumference (HC) is reduced out of proportion to other biometric parameters 24.

Brain sparing can be detected prenatally based on the Doppler pulsatility index (PI) in the middle cerebral artery (MCA); PI is reduced by the decreased cerebral resistance which allows a greater fraction of the cardiac output to perfuse the brain. However, this compensatory process of blood distribution can become “decompensatory” because the increase of brain blood flow and blood volume themselves become damaging 25. Understanding when and how the alteration of relative cerebral blood flow is switched from a compensatory to decompensatory response is clearly important for devising the most appropriate interventions and therapies. It is worth noting that brain sparing does not reduce the consequences of IUGR on later health, such as increased adiposity, diabetes, and cardiovascular risks, 26, 27.

Asymmetric IUGR causes

  • Placental insufficiency: one of the commonest causes of asymmetrical IUGR
  • Pre-eclampsia 23

Associations

  • The incidence of concurrent karyotypic abnormalities is low or minimal, especially if asymmetrical IUGR is detected late in pregnancy 28.
  • Syndromes that can give an asymmetrical IUGR picture include: Russell-Silver syndrome

Symmetrical intrauterine growth restriction

Symmetrical or primary IUGR is characterized by all internal organs being reduced in size. Both length and weight parameters are reduced. Symmetric IUGR accounts for 20% to 25% of all cases of IUGR. As a general rule, fetuses with symmetrical IUGR pattern may present at an earlier stage in gestation compared with the asymmetrical IUGR pattern. Symmetric IUGR is usually caused intrinsic genetic disorder or infections to fetus. It is also worth noting that mortality is higher in IUGR with symmetric growth even after adjusting for possible cofounding factors 18.

Symmetrical IUGR causes:

  • Aneuploidic syndromes
    • Triploidy. Triploidy is a rare lethal chromosomal (aneupliodic) abnormality caused by the presence of an entire extra chromosomal set.
    • Trisomy 13
    • Trisomy 18
  • Fetal infections, e.g. toxoplasmosis, rubella cytomegalovirus (CMV), herpes simplex (HSV), and human immunodeficiency virus (HIV) [TORCH] 29
  • Other
    • topical use of maternal fluorinated glucocorticoid (rare) 30
    • external agents, e.g. nicotine, alcohol, heroin, ionizing radiation 29

Ponderal index is normal, whereas biparietal diameter (BPD), femur length (FL), head and abdominal circumference (HC and AC) are proportionally reduced. Prognosis is poor.

Intrauterine growth restriction causes

The primary cause of IUGR is widely considered to be placental insufficiency; i.e., inability of the placenta to adequately support fetal growth. However, the causes of placental insufficiency are many and over-lapping, and include constricted spiral arteries and increased coagulation leading to fetal hypoxia (as in maternal hypertension), and inappropriate substrate availability due to maternal under-nutrition or over-nutrition (see Figure 3) 31, 32. The leading causes of IUGR are maternal malnutrition and chronic maternal diseases, followed by placental insufficiency due to vascular or circulatory placental damage 33. Hypoxia, infections during pregnancy, fetal malformations, smoking, pollution, and chronic alcoholism are also causative factors, though less common 34, 35. It is thought that 40% of birth weight is ascribable to genetic factors and that the remaining 60% is due to fetal environmental exposures 1. Therefore, it is clear that poor macronutrient provision modified by micronutrient supply to the fetus is a critical component in the pathogenesis of IUGR. Nutrient provision is largely dependent on availability of nutrients to the fetus via maternal circulation, and as facilitated by placental transport 36.

Some factors that may contribute to intrauterine growth restriction (IUGR) include the following

Maternal factors that may contribute to IUGR include the following:

Factors involving the uterus and placenta that may contribute to IUGR include the following:

  • Decreased blood flow in the uterus and placenta (abnormal uteroplacental circulation)
  • Placental abruption (placenta detaches from the uterus). Chronic low-grade abruption leading to multiple subchorionic hemorrhages, abruption, infarction, calcifications, villitis, chronic villitis of unknown etiology, hemorrhagic endovasculitis, avascular villi, syncytial knots
  • Placenta previa (placenta attaches low in the uterus)
  • Congenital infection, including: CMV, rubella, toxoplasmosis, malaria, congenital HIV infection, syphilis
  • Weight of placenta (weight < 350 g at term)
  • Abnormalities in trophoblastic invasion: preeclampsia and placenta accreta
  • Tumors: chorioangiomas, placental hemangiomas, abnormal umbilical cord or abnormal umbilical cord insertion
  • Placental genes: over-expression of IGFBP-3 and placenta IGF-2 and under-expression of placental IGF1 and epidermal growth factor (EGF) 37

Factors related to the developing baby (fetus):

  • Multiple gestation (for example, twins or triplets)
  • Intrauterine infections 38
    • TORCH group:
      • in utero toxoplasmosis infection / congenital toxoplasmosis infection:
        • congenital cerebral toxoplasmosis
      • in utero rubella infection
      • in utero cytomegalovirus infection: most common in utero infection
      • in utero herpes simplex virus (HSV) infection
    • in utero syphilis infection
    • in utero parvovirus B19 infection
    • in utero varicella zoster virus (VZV) infection
    • AIDS embryopathy / in utero HIV infection
  • Birth defects, including: cardiac, e.g., Tetralogy of Fallot, transposition of the great vessels and gastroschisis
  • Genetic abnormalities (chromosomal anomalies):
  • Constitutional small
  • Genetic syndromes like, Rubenstein-Taybi syndrome, Russell-Silver syndrome, Seckel syndrome, Cornelia de Lange syndrome, Brachmann-de Lange syndrome, Bloom syndrome, Dubowitz syndrome, Johanson–Blizzard syndrome, Roberts syndrome, Fanconi syndrome and Mulibrey Nanism syndrome
  • Fetal genetic factors: low nitric oxide, genetic deletion of IGF1, under-expression of N-terminal parathyroid hormone-related protein, high urinary protein S100B 37
  • In utero substance exposure e.g. fetal hydantoin syndrome

Figure 3. Intrauterine growth restriction causes

IUGR causes

Footnotes: Outline of the causes of IUGR including contributions from maternal, placental and umbilical cord, and fetal dysfunction or injury.

[Source 17 ]

IUGR risk factors

Pregnancies that have any of the following conditions may be at a greater risk at developing IUGR:

  • Maternal weight less than 100 pounds
  • Poor nutrition during pregnancy
  • Birth defects or chromosomal abnormalities
  • Use of drugs, cigarettes, and/or alcohol
  • Pregnancy-induced hypertension (gestational hypertension)
  • Placental abnormalities
  • Umbilical cord abnormalities
  • Multiple pregnancies
  • Gestational diabetes in the mother
  • Low levels of amniotic fluid or oligohydramnios

Intrauterine growth restriction prevention

Prenatal care is important in all pregnancies, and especially to identify problems with fetal growth. Stopping smoking and use of substances such as drugs and alcohol are essential to a healthy pregnancy and can reduce the risk for sudden infant death syndrome (SIDS) and other sleep-related infant deaths. Eating a healthy diet in pregnancy may also help.

Intrauterine growth restriction symptoms

Babies with intrauterine growth restriction (IUGR) may have problems at birth including the following:

  • Decreased oxygen levels
  • Low Apgar scores (an assessment that helps identify babies with difficulty adapting after delivery)
  • Meconium aspiration (inhalation of the first stools passed in utero) which can lead to difficulty breathing
  • Hypoglycemia (low blood sugar)
  • Difficulty maintaining normal body temperature
  • Polycythemia (too many red blood cells)

After birth, IUGR infants are more likely to spend a significantly longer time in neonatal intensive care unit (NICU) compared to gestation age-matched infants 39.

Intrauterine growth restriction (IUGR) infants demonstrate elevated rates of intolerance to feeds/ milk, feeding difficulties and necrotizing enterocolitis 12. Necrotizing enterocolitis is predominantly seen in infants who are born preterm, but late preterm infants are more likely to develop necrotizing enterocolitis if they were growth restricted 40. It is likely that in-utero chronic fetal hypoxia and subsequent cardiovascular redistribution of blood flow away from the gastrointestinal tract contribute to immature gut development 41. Intrauterine growth restriction (IUGR) newborns, especially with abnormal flows in the umbilical artery prior to birth, are shown to have more feed intolerance when compared to their well-grown preterm counterparts 42. Superior mesenteric artery blood flows have been used as a marker for splanchnic perfusion in neonates and decreased flows correlate with feed intolerance 43. Application of near infra-red spectroscopy in the neonatal period as an assessment tool for monitoring gut perfusion can detect changes in splanchnic oxygen delivery, which may be reduced in intrauterine growth restriction (IUGR) infants and may predict feeding intolerance and development of necrotizing enterocolitis 44. Studies have shown that preterm intrauterine growth restriction (IUGR) infants do not tolerate enteral feeds in the first few days of life 45 but conversely there is evidence that delaying enteral feeds in preterm intrauterine growth restriction (IUGR) infants does not confer any protection against feed intolerance or necrotizing enterocolitis 46. In fact, it may delay establishment of feeds and increase length of stay in the neonatal unit 47.

Malnutrition and low birth weight puts intrauterine growth restriction (IUGR) infants at an increased risk of a number of transient neonatal morbidities including hypothermia, altered glucose metabolism (hypoglycemia, hyperglycemia), hypocalcemia, polycythemia, jaundice and sepsis 48. Increased risk of infection is also common, potentially related to depressed immunological state and competence 49. IUGR infants born preterm also have an increased risk of retinopathy of prematurity 50. IUGR is linked to altered nephrogenesis, due to suboptimal tubular development caused by intrauterine hypoxia 51, and in turn, urinary Cystatin-C excretion is increased in intrauterine growth restriction (IUGR) infants compared to appropriately-grown infants which is seen to reflect reduced renal volume 52. It is therefore suggested that increased secretion of Cystatin-C signifies nephron loss as a result of the negative impact of intrauterine growth restriction (IUGR) on kidney development. Factors involved in nephron loss may include intrauterine hypoxia, decreased antioxidant capacity, and altered levels of growth factors.

Table 1. Intrauterine growth restriction (IUGR) neonatal complications

Cardiovascular morbidityRespiratory morbidityNeurological morbidityOthers
Neonatal period
  • Early hypotension
  • Persistent fetal circulation/persistent pulmonary hypertension
  • Structural heart changes
  • Vessel wall rigidity
  • Cardiac function issues
  • Late systemic hypertension
  • Secondary pulmonary hypertension
  • Increased need for respiratory/ventilator support
  • Meconium aspiration syndrome
  • Pulmonary hemorrhage
  • Bronchopulmonary dysplasia
  • Perinatal asphyxia
  • Microcephaly
  • Cranial ultrasound abnormalities (intraventricular hemorrhage, periventricular leukomalacia)
  • White matter and gray matter changes on MRI
  • Functional and diffusion tensor imaging MRI changes
  • General movement assessment abnormalities
  • EEG abnormalities
  • Poor transition
  • Hypoglycemia
  • Hypocalcemia
  • Hypothermia
  • Sepsis
  • Jaundice
  • Polycythemia
  • Prolonged NICU stay
  • Feed intolerance
  • Delay in establishment of feeds
  • Necrotizing enterocolitis
  • Renal tubular injury
  • Retinopathy of prematurity
Long term impact
  • Hypertension
  • Ischemic heart disease
  • Stroke
  • Atherosclerosis
  • Chronic respiratory insufficiency
  • Reactive airway disease
  • Neurodevelopmental issues
  • Behavioral problems
  • Learning difficulties
  • Cerebral palsy
  • Dementia
  • Mental health issues
  • Failure to thrive
  • Obesity
  • Immune dysfunction
  • Osteoporosis
  • Metabolic syndrome
  • Renal issues
  • Hormonal issues
  • Cancer
  • Shortened life span
[Source 12 ]

Intrauterine growth restriction (IUGR) complications

Intrauterine growth restriction (IUGR) complications are many and may include the following:

Antepartum (before childbirth) complications:

  • stillbirth
  • iatrogenic prematurity (medically induced prematurity)
  • placental abruption
  • perinatal stroke

Intrapartum (during childbirth – a time period from the onset of labor through delivery of the placenta) complications:

  • abnormal fetal status (fetal heart rate tracing)
  • asphyxia
  • emergency Cesarean section
  • need for active neonatal resuscitation
  • perinatal stroke

Neonatal (newborn infant under 28 days of age) complications:

Pediatric complications:

  • Increased risk of:
    • short stature
    • cerebral palsy
    • developmental delay
    • behavioral and emotional problems
    • lower IQ scores
    • chronic lung disease
    • future cardiovascular disease and hypertension

Intrauterine growth restriction diagnosis

The baby with intrauterine growth restriction (IUGR) is often identified before birth. During pregnancy, a baby’s size can be estimated in different ways. The height of the fundus (the top of a mother’s uterus) can be measured from the pubic bone. This measurement in centimeters usually corresponds with the number of weeks of pregnancy after the 20th week. If the measurement is low for the number of weeks, the baby may be smaller than expected.

Although many intrauterine growth restriction (IUGR) babies have low birthweight, they are not all premature and may not experience the problems of premature babies. Other intrauterine growth restriction (IUGR) babies, appear thin, pale, and with loose, dry skin. The umbilical cord is often thin, and dull-looking rather than shiny and fat.

Other diagnostic procedures may include the following:

  • Ultrasound. Ultrasound (a test using sound waves to create a picture of internal structures) is a more accurate method of estimating fetal size. Measurements can be taken of the fetus’ head and abdomen and compared with a growth chart to estimate fetal weight. The fetal abdominal circumference is a helpful indicator of fetal nutrition.
  • Doppler flow. Another way to interpret and diagnose IUGR during pregnancy is Doppler flow, which uses sound waves to measure blood flow. The sound of moving blood produces wave-forms that reflect the speed and amount of the blood as it moves through a blood vessel. Blood flow through blood vessels in both the fetal brain and the umbilical cord can be checked with Doppler flow studies.
  • Mother’s weight gain. A mother’s weight gain can also indicate a baby’s size. Small maternal weight gains in pregnancy may correspond with a small baby
  • Gestational assessment. Babies are weighed within the first few hours after birth. The weight is compared with the baby’s gestational age and recorded in the medical record. The birthweight must be compared to the gestational age. Some doctors use a formula for calculating a baby’s body mass to diagnose intrauterine growth restriction (IUGR).

Intrauterine growth restriction treatment

Specific treatment for intrauterine growth restriction (IUGR) will be determined by your baby’s doctor based on:

  • Your baby’s gestational age, overall health, and medical history
  • Extent of the condition
  • Your baby’s tolerance for specific medications, procedures, or therapies
  • Expectations for the course of the condition
  • Your opinion or preference

Despite new research, there are currently no effective medical interventions for IUGR, management consists of close surveillance aimed at determining the most appropriate time for delivery. Up till now, no effective methods are available to reverse the pathological intrauterine condition or to accelerate the growth of fetuses in pregnancies complicated by IUGR 11. Most likely the treatment will depend on how far along you are in your pregnancy.

  • If gestational age is 34 weeks or greater, health care providers may recommend being induced for early delivery.
  • If gestational age is less than 34 weeks, health care providers will continue monitoring until 34 weeks or beyond. Fetal well-being and the amount of amniotic fluid will be monitored during this time.
  • If either of these becomes a concern, then immediate delivery may be recommended. Depending on your health care provider, you will likely have appointments every 2 to 6 weeks until you deliver. If delivery is suggested prior to 34 weeks, your health care provider may perform an amniocentesis to help evaluate fetal lung maturity.

The STRIDER-UK study (multicentre, randomized, double-blind, 156 participants) tested the use of sildenafil in women with severe early-onset IUGR and found that treatment did not prolong pregnancy or cause any adverse effects, but did not improve pregnancy outcomes 53. However, this study is part of a more extensive international study, and in isolation, it does not have the power to adequately assess outcomes in this very high-risk cohort (45% of recruited infants in this study died) 54. A meta-analysis (nine studies, total of 576 treated patients) has shown that arginine supplementation increases gestational length and birth weight in IUGR pregnancies, except for infants born preterm (<32 weeks post-conceptional age) with severe IUGR 55; there were no reported side effects. The proposed mechanisms of action of arginine include the increased production of placental insulin that acts as a fetal trophic factor.

Creatine may also be a potential treatment for IUGR 56, 57, with recent studies showing a positive correlation of birth weight to placental creatine load 58, and the discovery that the human placenta expresses the enzymes to synthesize and transport creatine 59. Creatine is an energy substrate which protects ATP turnover during periods of oxidative stress 60 and as such may be a potential prophylactic treatment for IUGR outcomes 56, 57. Creatine readily crosses the placenta in humans and some other omnivores (but not in sheep, an herbivore), suggesting that maternal creatine supplementation could be used to increase placental creatine transfer and promote fetal growth in a hypoxic uterine environment. Supporting data include a number of pre-clinical studies 61, 62. Whilst there has been extensive animal research suggesting creatine’s potential to protect the fetus against periods of oxygen deprivation in several animal models, and there is a strong rationale for moving toward clinical trials for maternal creatine supplementation to reduce or prevent IUGR, no intervention studies have yet been undertaken in pregnant women. IUGR is also proposed to be a disorder of insulin-like growth factor-1 (IGF-1) deprivation. Of particular note is an extensive preclinical study of prenatal IGF-1 treatment in a sheep model of IUGR (41 controls, 66 IUGR + saline, 28 IUGR + IGF-1, powered for sex-specific analysis and long term follow-up) which show that prenatal IGF-1 treatment improves prenatal and postnatal indices of growth and biochemical dysfunction in IUGR 63, 64.

Intrauterine growth restriction prognosis

Intrauterine growth restriction (IUGR) affects approximately 10% of pregnancies worldwide and is a leading cause of perinatal mortality and morbidity 5, 6, 65, 66. IUGR fetuses are at increased risk of stillbirth, fetal compromise, early neonatal death, and neonatal morbidity 67. IUGR survivors are at increased risk of cardiovascular diseases and neurodevelopmental deficits, with lifelong neurological deficits ranging from behavioral and motor disabilities to cerebral palsy 68, 69, 70, 71. Underlying these functional impairments, IUGR also compromises brain development and is commonly associated with reduced myelination and decreased total brain cell number 72, 73.

The appropriate growth of the fetal brain is highly dependent on the availability of growth factors. Brain Derived Neurotrophic Factor (BDNF), a member of the neurotrophin family, is widely expressed in the developing fetal brain and plays a vital role in neuronal survival, neuronal differentiation, and synaptic plasticity 74. Brain Derived Neurotrophic Factor (BDNF) is downregulated in cord blood from IUGR neonates clinically 75 and lower levels of BDNF receptors have been demonstrated in cortical neurons of IUGR rats, leading to reduced cell viability and synaptic function 76.

Additionally, the IUGR neonates have been shown to be highly prone to developing metabolic syndrome (e.g., obesity and type 2 diabetes) due to the increasing hepatic gluconeogenic capacity and impairing beta-cell function 77, 78. Children with IUGR, especially if they achieve catch-up growth in childhood, as well as SGA subjects, are at a higher risk for long-term developmental consequences or developing diseases later in life such as short stature, hypertension, dyslipidemia, insulin resistance, and cardiovascular disease 79, 80, 81.

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