Intrauterine Growth Restriction: Comparison
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Please note this is a comparison between Version 1 by Daniel Hardy and Version 2 by Vicky Zhou.

Intrauterine growth restriction (IUGR) is a pathological condition by which the fetus deviates from its expected growth trajectory, resulting in low birth weight and impaired organ function. The developmental origins of health and disease (DOHaD) postulates that IUGR has lifelong consequences on offspring well-being, as human studies have established an inverse relationship between birth weight and long-term metabolic health. While these trends are apparent in epidemiological data, animal studies have been essential in defining the molecular mechanisms that contribute to this relationship. One such mechanism is cellular stress, a prominent underlying cause of the metabolic syndrome. 

Intrauterine growth restriction (IUGR), or fetal growth restriction, refers to poor growth of a fetus while in the womb during pregnancy. IUGR is defined by clinical features of malnutrition and evidence of reduced growth regardless of an infant's birth weight percentile. The causes of IUGR are broad and may involve maternal, fetal, or placental complications. At least 60% of the 4 million neonatal deaths that occur worldwide every year are associated with low birth weight (LBW), caused by intrauterine growth restriction (IUGR), preterm delivery, and genetic abnormalities, demonstrating that under-nutrition is already a leading health problem at birth. Intrauterine growth restriction can result in a baby being small for gestational age (SGA), which is most commonly defined as a weight below the 10th percentile for the gestational age. At the end of pregnancy, it can result in a low birth weight.
  • intrauterine growth restriction (IUGR)
  • metabolism
  • cell stress
  • cell death
  • metabolic syndrome

1. Introduction

The metabolic syndrome refers to a group of physiological symptoms that increase an individual’s risk for cardiovascular disease and type II diabetes. These symptoms, including dyslipidemia, obesity, hyperglycemia, and hypertension, are often assessed independent of each other; however, their simultaneous occurrence is synergistic toward onset of the metabolic syndrome. It is well known that these symptoms are influenced by factors such as genetics and lifestyle, but the role of developmental priming is often overlooked. The developmental origins of health and disease (DOHaD) posits that there is an inverse relationship between birth weight and long-term metabolic health, as adverse events in utero may permanently influence the function of metabolic organs. Infants affected by intrauterine growth restriction (IUGR) exhibit impaired organ growth with metabolic disease in adulthood, as early epidemiological studies by Sir David Barker and colleagues determined that low birth weight individuals have high rates of obesity, glucose intolerance, and coronary artery disease [1][2][3]. These studies have since led to widespread investigation of the underlying causes of IUGR, as well as the metabolic pathologies that arise in response to impaired organ development.
IUGR occurs as a consequence of utero-placental insufficiency, whereby the placenta does not meet metabolic requirements set by the fetal genome [4]. When placental tissue is unable to support proper nutrient and oxygen exchange, select fetal organs exhibit reduced growth and decreased cell size [5]. This ‘organ-sparing’ effect occurs such that vital organs (i.e., the heart and brain) receive greater shares of available resources at the expense of other organs, such as the liver [6]. Utero-placental insufficiency is often secondary to insults of maternal origin, including maternal malnutrition, drug use, and infection among others; therefore, maternal lifestyle has a significant influence on offspring health [4][5]. Importantly, the postnatal environment has also been demonstrated to play an indirect role in provoking long-term metabolic dysfunction, as offspring born into an environment that is ‘mismatched’ from that in utero are subject to maladaptive changes in fetal programming [7]. Animal studies have revealed several mechanisms that govern this relationship, including epigenetic regulation of gene expression, the microbiome, and the hypothalamus-pituitary-adrenal axis. In addition, cellular stress is known to have a major role in causing adverse metabolic health across various models of IUGR.
Fetal growth and development consist of intricate cellular processes that are highly sensitive to intra- and extracellular stressors. Because of this, it is plausible that the presence of metabolic disease in adult IUGR offspring is attributed in part to cellular stress and programmed cell death. While events of cell stress and cell death are often protective, they can also be destructive and contribute to the development of metabolic disease. Studies have demonstrated that a suboptimal prenatal environment initiates cell stress and cell death in the placenta, giving rise to compromised fetal growth. This may further lead to cellular stress and dysfunction in metabolic organs, including oxidative stress and mitochondrial dysfunction, endoplasmic reticulum (ER) stress, inflammation, apoptosis, and autophagy. Alternatively, the occurrence of rapid postnatal weight gain (i.e., catch-up growth) in low birth weight offspring can lead to cellular stress and metabolic disease in an indirect manner. 

2. Programmed Cell Death and Metabolism in IUGR Offspring

As mentioned previously, cell stress often occurs in a protective manner. That said, an organism’s response to cell stress is dependent on the type and severity of the gestational insult. When an insult is severe and/or chronic enough that the resulting cell stress is overwhelming, cellular death may occur. Programmed cell death is a controlled cellular response that works to eliminate damaged or dysfunctional cells, either by means of apoptosis or autophagy.

2.1. Apoptosis

Apoptosis is a highly regulated form of cell death consisting of morphological changes that are distinct from other forms of cell death. Apoptotic cells undergo cell shrinkage, membrane blebbing, and fragmentation of nuclei and chromatin, often without inducing inflammation. This is what distinguishes apoptosis from necrosis, a type of uncontrolled cell death that provokes an immune response. While apoptosis is an essential part of many developmental processes, it is also a large contributor to the impaired function of metabolic organs. For example, the apoptotic loss of pancreatic β-cells is believed to be a driving factor of type II diabetes, particularly after the pancreas experiences oxidative stress or ER stress [8]. Although apoptosis does not cause inflammation, it has been demonstrated to occur as a result of upregulated immune cell function and pro-inflammatory cytokines (as reviewed by Quan et al., 2013) [9]. Finally, the loss of cardiomyocytes via apoptosis may also contribute to chronic heart failure, as early studies have shown that apoptosis exists in myocardial tissue samples taken from patients following myocardial infarction, cardiomyopathy, and end-stage heart failure [10][11][12][13]. Taking all of this into account, the occurrence of apoptosis in IUGR offspring seems to be cause for concern when assessing for risk of the metabolic syndrome.

2.2. Autophagy

Autophagy, also known as “self-eating”, is a form of programmed cell death that aims to clear out damaged organelles, misfolded or aggregated proteins, and intracellular pathogens. Following the identification of unwanted intracellular cargo, an isolation membrane called the phagophore engulfs cell material to form the autophagosome structure. Through fusion with lysosomes, the autophagosome then becomes an autolysosome and permits enzymatic degradation of its contents. While highly complex and not as well understood as apoptosis, autophagy is important in the balance of energy sources during development or times of metabolic stress. Because of this, activation of the AMP-activated protein kinase (AMPK) pathway is recognized as being a promotor of autophagy, while the mammalian target of rapamycin (mTOR) pathway is inhibitory. Dysregulated autophagy in the pancreas and liver has been previously associated with obesity and diabetes, and it is for this reason that autophagy has become of interest in the field of DOHaD. Much like apoptosis, most studies to date concerning the developmental consequences of autophagy tend to focus on its role in the placenta. That said, there has been some investigation of autophagy in the IUGR heart, pancreas, and liver. In the fetal baboon heart, autophagy occurs as a result of maternal caloric restriction [14]. Furthermore, male IUGR offspring display increased levels of autophagy-related 7 (ATG7) protein and LC3BII, along with fibrosis of the left ventricle [14]. 

3. Conclusions

Epidemiological studies have provided astonishing evidence for the role of developmental programming in affecting susceptibility to the metabolic syndrome. It is clear that the perinatal period is a critical window for fetal reprogramming, while the early postnatal environment also has influence on offspring metabolic health. Animal studies have established that the inverse relationship between birth weight and long-term metabolism is mediated by mechanisms of cell stress, including oxidative stress, mitochondrial dysfunction, ER stress, and inflammation. When cell stress goes unresolved, this can lead to programmed cell death and the failure of metabolic organs. That said, there are many other factors involved in this relationship that remain poorly understood. For example, androgen levels have been demonstrated to promote both oxidative stress and ER stress [15][16]; therefore, sex-specific differences of postnatal cell stress may exist due to altered estrogen and testosterone signaling. Furthermore, recent studies have begun to elucidate a paternal contribution to IUGR and postnatal cellular stress; paternal obesity has been demonstrated to alter placental vascular structure and postnatal liver development, likely due to the induction of ER stress in both of these organs [17]. Overall, future studies are warranted to further investigate all of these factors, and novel technologies will be required to validate the molecular findings of animal studies in human IUGR cohorts. By better understanding the origins of cell stress and programmed cell death in IUGR offspring, postnatal therapeutic measures could be developed to reduce risk for the metabolic syndrome during adult life. Neonatal administration of exendin-4, an agonist of the glucagon-like peptide 1 receptor, has been previously shown to prevent hepatic oxidative stress in male offspring at 7–9 weeks of age, and in doing so mitigated hepatic insulin resistance [18]. The therapeutic benefits of exendin-4 have been explored in several clinical trials, and it is currently used as a treatment for type II diabetes; however, its safety and efficacy as a treatment in infants remains unknown. Similarly, the ER stress inhibitor tauroursodeoxycholic acid (TUDCA) ameliorates the incidence of type II diabetes in obese rats, so it is possible that TUDCA could be effective in treating IUGR-induced diabetes when administered in early life like exendin-4 [19]. Finally, this evolving field of research has great potential to guide clinical policy and protocols that exist during prenatal care. The cooperation of health care professionals with pregnant women is essential in preventing IUGR, and this could contribute to reduced rates of the metabolic syndrome across the adult demographic.

1. Types

There are two major categories of IUGR: pseudo IUGR and true IUGR With pseudo IUGR, the fetus has a birth weight below the tenth percentile for the corresponding gestational age but has a normal ponderal index, subcutaneous fat deposition, and body proportion. Pseudo IUGR occurs due to uneventful intrauterine course and can be rectified by proper postnatal care and nutrition. Such babies are also called small for gestational age. True IUGR occurs due to pathological conditions which may be either fetal or maternal in origin. In addition to low body weight they have abnormal ponderal index, body disproportion, and low subcutaneous fat deposition. There are two types-symmetrical and asymmetrical.[9][10] Some conditions are associated with both symmetrical and asymmetrical growth restriction.

Asymmetrical

Asymmetrical IUGR accounts for 70-80% of all IUGR cases.[11] In asymmetrical IUGR, there is decreased oxygen or nutrient supply to the fetus during the third trimester of pregnancy due to placental insufficiency.[12] This type of IUGR is sometimes called "head sparing" because brain growth is typically less affected, resulting in a relatively normal head circumference in these children.[13] Because of decreased oxygen supply to the fetus, blood is diverted to the vital organs, such as the brain and heart. As a result, blood flow to other organs - including liver, muscle, and fat - is decreased. This causes abdominal circumference in these children to be decreased.[13] A lack of subcutaneous fat leads to a thin and small body out of proportion with the liver. Normally at birth the brain of the fetus is 3 times the weight of its liver. In IUGR, it becomes 5-6 times. In these cases, the embryo/fetus has grown normally for the first two trimesters but encounters difficulties in the third, sometimes secondary to complications such as pre-eclampsia. Other symptoms than the disproportion include dry, peeling skin and an overly-thin umbilical cord. The baby is at increased risk of hypoxia and hypoglycemia. This type of IUGR is most commonly caused by extrinsic factors that affect the fetus at later gestational ages. Specific causes include:

  • Chronic high blood pressure
  • Severe malnutrition
  • Genetic mutations, Ehlers–Danlos syndrome

Symmetrical

Symmetrical IUGR is commonly known as global growth restriction, and indicates that the fetus has developed slowly throughout the duration of the pregnancy and was thus affected from a very early stage. The head circumference of such a newborn is in proportion to the rest of the body. Since most neurons are developed by the 18th week of gestation, the fetus with symmetrical IUGR is more likely to have permanent neurological sequelae. Common causes include:

  • Early intrauterine infections, such as cytomegalovirus, rubella or toxoplasmosis
  • Chromosomal abnormalities
  • Anemia
  • Maternal substance use (prenatal alcohol use can result in Fetal alcohol syndrome)

2. Causes

IUGR is caused by a variety of factors; these can be fetal, maternal, placental or genetic factors.[11]

Maternal

  • Pre-pregnancy weight and nutritional status
  • Poor weight gain during pregnancy
  • Malnutrition
  • Anemia
  • Substance use: smoking, alcohol, drugs including marijuana or cocaine
  • Medication: warfarin, steroids, anticonvulsants
  • Inter-pregnancy interval of less than 6 months
  • Assisted reproductive technologies
  • Pre-gestational diabetes
  • Gestational diabetes
  • Pulmonary disease
  • Cardiovascular disease
  • Kidney disease
  • Hypertension
  • Celiac disease increases the risk of intrauterine growth restriction by an odds ratio of approximately 2.48[14]
  • Subclinical hypothyroidism[15]
  • Blood clotting disorder/disease (e.g., Factor V Leiden)

Uteroplacental

  • Preeclampsia
  • Multiple gestation
  • Uterine malformations
  • Placental insufficiency

Fetal

  • Chromosomal abnormalities
  • Vertically transmitted infections: TORCH, Malaria, congenital HIV infection, Syphilis
  • Erythroblastosis fetalis
  • Congenital abnormalities

Genetic

  • Placental genes
  • Maternal genes: Endothelin-1 over-expression, Leptin under-expression
  • Fetal genes

3. Pathophysiology

If the cause of IUGR is extrinsic to the fetus (parental or uteroplacental), transfer of oxygen and nutrients to the fetus is decreased. This causes a reduction in the fetus’ stores of glycogen and lipids. This often leads to hypoglycemia at birth. Polycythemia can occur secondary to increased erythropoietin production caused by the chronic hypoxemia. Hypothermia, thrombocytopenia, leukopenia, hypocalcemia, and bleeding in the lungs are often results of IUGR.[5] Infants with IUGR are at increased risk of perinatal asphyxia due to chronic hypoxia, usually associated with placental insufficiency, placental abruption, or a umbilical cord accident.[16] This chronic hypoxia also places IUGR infants at elevated risk of persistent pulmonary hypertension of the newborn, which can impair an infant's blood oxygenation and transition to postnatal circulation.[17] If the cause of IUGR is intrinsic to the fetus, growth is restricted due to genetic factors or as a sequela of infection. IUGR is associated with a wide range of short- and long-term neurodevelopmental disorders.

Cardiovascular

In IUGR, there is an increase in vascular resistance in the placental circulation, causing an increase in cardiac afterload. There is also increased vasoconstriction of the arteries in the periphery, which occurs in response to chronic hypoxia in order to preserve adequate blood flow to the fetus' vital organs.[18] This prolonged vasoconstriction leads to remodeling and stiffening of the arteries, which also contributes to the increase in cardiac afterload. Therefore, the fetal heart must work harder to contract during each heartbeat, which leads to an increase in wall stress and cardiac hypertrophy.[19] These changes in the fetal heart lead to increased long-term risk of hypertension, atherosclerosis, cardiovascular disease, and stroke.[19]

Pulmonary

Normal lung development is interrupted in fetuses with IUGR, which increases their risk for respiratory compromise and impaired lung function later in life. Preterm infants with IUGR are more likely to have bronchopulmonary dysplasia (BPD), a chronic lung disease that is thought to be associated with prolonged use of mechanical ventilation.[19]

Neurological

IUGR is associated with long-term motor deficits and cognitive impairment.[19] In order to adapt to the chronic hypoxia associated with placental insufficiency, blood flow is redirected to the brain to try to preserve brain growth and development as much as possible. Even though this is thought to be protective, fetuses with IUGR who have undergone this brain-sparing adaptation have worse neurological outcomes compared with those who have not undergone this adaptation.[20] Magnetic resonance imaging (MRI) can detect changes in volume and structural development of infants with IUGR compared with those whose growth is appropriate for gestational age (AGA). But MRI is not easily accessible for all patients.[19] White matter effects – In postpartum studies of infants, it was shown that there was a decrease of the fractal dimension of the white matter in IUGR infants at one year corrected age. This was compared to at term and preterm infants at one year adjusted corrected age. Grey matter effects – Grey matter was also shown to be decreased in infants with IUGR at one year corrected age.[21] Children with IUGR are often found to exhibit brain reorganization including neural circuitry.[22] Reorganization has been linked to learning and memory differences between children born at term and those born with IUGR.[23] Studies have shown that children born with IUGR had lower IQ. They also exhibit other deficits that point to frontal lobe dysfunction. IUGR infants with brain-sparing show accelerated maturation of the hippocampus which is responsible for memory.[24] This accelerated maturation can often lead to uncharacteristic development that may compromise other networks and lead to memory and learning deficiencies.

4. Management

Mothers whose fetus is diagnosed with intrauterine growth restriction can be managed with several monitoring and delivery methods. It is currently recommended that any fetus that has growth restriction and additional structural abnormalities should be evaluated with genetic testing.[6] In addition to evaluating the fetal growth velocity, the fetus should primarily be monitored by ultrasonography every 3–4 weeks.[6] An additional monitoring technique is an Doppler velocimetry. Doppler velocimetry is useful in monitoring blood flow through the uterine and umbilical arteries, and may indicate signs of uteroplacental insufficiency.[25] This method may also detect blood vessels, specifically the ductus venosus and middle cerebral arteries, which are not developing properly or may not adapt well after birth.[25] Monitoring via Doppler velocimetry has been shown to decrease the risk of morbidity and mortality before and after parturition among IUGR patients.[26] Standard fetal surveillance via nonstress tests and/or biophysical profile scoring is also recommended.[25][6] Bed rest has not been found to improve outcomes and is not typically recommended.[27] There is currently a lack of evidence supporting any dietary or supplemental changes that may prevent the development of IUGR.[6] The optimal timing of delivery for a fetus with IUGR is unknown. However, the timing of delivery is currently based on the cause of IUGR[6] and parameters collected from the umbilical artery doppler. Some of these include: pulsatility index, resistance index, and end-diastolic velocities, which are measurements of the fetal circulation.[26] Fetuses with an anticipated delivery before 34 weeks gestation are recommended to receive corticosteroids to facilitate fetal maturation.[6][28] Anticipated births before 32 weeks should receive magnesium sulfate to protect development of the fetal brain.[29]

5. Outcomes

Postnatal complications

After correcting for several factors such as low gestational parental weight, it is estimated that only around 3% of pregnancies are affected by true IUGR. 20% of stillborn infants exhibit IUGR. Perinatal mortality rates are 4-8 times higher for infants with IUGR, and morbidity is present in 50% of surviving infants.[30] Common causes of mortality in fetuses/infants with IUGR include: severe placental insufficiency and chronic hypoxia, congenital malformations, congenital infections, placental abruption, cord accidents, cord prolapse, placental infarcts, and severe perinatal depression.[5] IUGR is more common in preterm infants than in full term (37–40 weeks gestation) infants, and its frequency decreases with increasing gestational age. Relative to premature infants who do not exhibit IUGR, premature infants with IUGR are more likely to have adverse neonatal outcomes, including respiratory distress syndrome, intraventricular hemorrhage, and necrotizing enterocolitis. This association with prematurity suggests utility of screening for IUGR as a potential risk factor for preterm labor.[31] Feeding intolerance, hypothermia, hypoglycemia, and hyperglycemia are all common in infants in the postnatal period, indicating the need to closely manage these patients' temperature and nutrition.[32] Furthermore, rapid metabolic and physiologic changes in the first few days after birth can yield susceptibility to hypocalcemia, polycythemia, immunologic compromise, and renal dysfunction.[33][34]

Long-term consequences

According to the theory of thrifty phenotype, intrauterine growth restriction triggers epigenetic responses in the fetus that are otherwise activated in times of chronic food shortage. If the offspring actually develops in an environment where food is readily accessible, it may be more prone to metabolic disorders, such as obesity and type II diabetes.[35] Infants with IUGR may continue to show signs of abnormal growth throughout childhood. Infants with asymmetric IUGR (head-sparing) typically have more robust catch-up postnatal growth, as compared with infants with symmetric IUGR, who may remain small throughout life. The majority of catch-up growth occurs in the first 6 months of life, but can continue throughout the first two years. Approximately 10% of infants who are small for gestational age due to IUGR will still have short stature in late childhood.[36] Infants with IUGR are also at elevated risk for neurodevelopmental abnormalities, including motor delay and cognitive impairments. Low IQ in adulthood may occur in up to one third of infants born small for gestational age due to IUGR. Infants who fail to display adequate catch-up growth in the first few years of life may exhibit worse outcomes.[37][38] Catch-up growth can alter fat distribution in children diagnosed with IUGR as infants and increase risk of metabolic syndrome.[39] Infants with IUGR may be susceptible to long-term dysfunction of several endocrine processes, including growth hormone signaling, the hypothalamic-pituitary-adrenal axis, and puberty.[40] Renal dysfunction, disrupted lung development, and impaired bone metabolism are also associated with IUGR.[41]

6. Animals

In sheep, intrauterine growth restriction can be caused by heat stress in early to mid pregnancy. The effect is attributed to reduced placental development causing reduced fetal growth.[42][43][44] Hormonal effects appear implicated in the reduced placental development.[44] Although early reduction of placental development is not accompanied by concurrent reduction of fetal growth;[42] it tends to limit fetal growth later in gestation. Normally, ovine placental mass increases until about day 70 of gestation,[45] but high demand on the placenta for fetal growth occurs later. (For example, research results suggest that a normal average singleton Suffolk x Targhee sheep fetus has a mass of about 0.15 kg at day 70, and growth rates of about 31 g/day at day 80, 129 g/day at day 120 and 199 g/day at day 140 of gestation, reaching a mass of about 6.21 kg at day 140, a few days before parturition.[46]) In adolescent ewes (i.e. ewe hoggets), overfeeding during pregnancy can also cause intrauterine growth restriction, by altering nutrient partitioning between dam and conceptus.[47][48] Fetal growth restriction in adolescent ewes overnourished during early to mid pregnancy is not avoided by switching to lower nutrient intake after day 90 of gestation; whereas such switching at day 50 does result in greater placental growth and enhanced pregnancy outcome.[48] Practical implications include the importance of estimating a threshold for "overnutrition" in management of pregnant ewe hoggets. In a study of Romney and Coopworth ewe hoggets bred to Perendale rams, feeding to approximate a conceptus-free live mass gain of 0.15 kg/day (i.e. in addition to conceptus mass), commencing 13 days after the midpoint of a synchronized breeding period, yielded no reduction in lamb birth mass, where compared with feeding treatments yielding conceptus-free live mass gains of about 0 and 0.075 kg/day.[49] In both of the above models of IUGR in sheep, the absolute magnitude of uterine blood flow is reduced.[48] Evidence of substantial reduction of placental glucose transport capacity has been observed in pregnant ewes that had been heat-stressed during placental development.[50][51]

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