Definition
Birthweight is a measure of fetal growth in pregnancy but is imprecise because it represents fetal growth at only one time point, at the end of gestation. Birthweight provides limited insight into the fetal growth pattern throughout gestation.
Low birthweight (LBW) is defined as a birthweight less than 2500 g but does not take gestational age into consideration. Thus, some babies who are classified as LBW may in fact be normally grown because they are preterm. Similarly the descriptor of very low birthweight (VLBW), defined as less than 1500 g at birth, will include a number of babies of older gestation with poor growth in utero.
Intrauterine growth restriction (IUGR) is the failure to attain optimal intrauterine growth, whereas small for gestational age (SGA) describes an infant whose weight is lower than population norms (3rd, 5th, or 10th percentiles).
SGA infants are most often defined as having a birthweight below the 10th percentile for gestational age.
The ponderal index, defined below, can be used to identify infants whose mass is below normal for their linear development, ie, a measure of “thinness.” A ponderal index <10th percentile has been used to identify IUGR infants at birth.
Bithweight×100Crown−Heel Length3
Thus, all IUGR infants may not be SGA, and all SGA infants may not be small as a result of fetal growth restriction.
Ultimately, crossing of growth centiles in utero on multiple ultrasound assessments is the only true measure of IUGR, but such information is rarely available and so the proxies described above are used.
IUGR may be further thought of as symmetrical or asymmetrical.
Symmetric IUGR occurs when head circumference, height, and weight are all proportionately reduced (<10%) for gestational age. This is due to either decreased growth potential of the fetus (normal genetic variation or genetic disorders) or extrinsic conditions that are active early in pregnancy (metabolic conditions, congenital infection, early nutritional insults, or adverse in utero conditions).
Asymmetric IUGR occurs when the head circumference and length are closer to the expected percentiles for gestational age than is the weight. In these infants, there is some degree of sparing of brain growth relative to body weight. The usual causes are uteroplacental insufficiency, maternal undernutrition or malnutrition, or extrinsic conditions applied late in pregnancy.
Incidence
LBW affects about 15% worldwide whereas 3% to 10% of all pregnancies are associated with IUGR.
Estimation of IUGR may vary based on the neonatal or fetal growth charts used to define IUGR, with some evidence that individualized centiles may be even more predictive.
Perinatal mortality rates are four to eight times higher for IUGR babies and ∼20% to 80% of stillborn infants are IUGR. The latter are due to the individual causes of growth restriction in an IUGR pregnancy and a failure of the fetal adaptive responses of redistribution of fetal blood flow to key organs leading to a decrease in fetal growth rate (Figure 26-1) leading to an increased risk of fetal mortality.
Pathophysiology
In utero mechanisms
IUGR in the human fetus can be caused by factors that are of maternal, placental, or fetal origin (Figure 26-1) including living at high altitude, maternal undernutrition, hyperthermia, drug and alcohol abuse, placentation abnormalities, intrauterine infection, and fetal chromosomal abnormalities.
Fetal adaptations in IUGR
A reduction in substrate supply from the mother to the fetus, the endpoint of most of the above associations, results in fetal adaptations in a range of organ systems (Figure 26-2). An understanding of these adaptations provides an appropriate framework for determining the organ systems that are most vulnerable in the IUGR neonate and provides the underlying mechanisms that explain not only the increased risk of perinatal mortality and morbidity, but also the increased risk of specific diseases in adult life in this patient population.
Fetal blood gas
Analysis of cord blood samples at birth shows that IUGR fetuses are relatively hypoxemic, hypoglycemic, and acidotic when compared to appropriate for gestational age (AGA) fetuses (Table 26-1).
Endocrine adaptations to reduced substrate supply
The neuroendocrine adaptations to reduced substrate supply have an important role in the redistribution of cardiac output, regulation of fetal blood pressure, and regulation of fetal growth. Analysis of cord blood samples at birth shows that IUGR fetuses have higher circulating plasma cortisol and noradrenaline concentrations compared to appropriately grown fetuses (Table 26-2).
Cardiovascular adaptations to reduced substrate supply
In order to survive exposure to hypoxemia, the fetus adapts by redistributing fetal cardiac output (Table 26-3) and slows body growth (Figure 26-3).
Ultrasound studies in human fetuses also suggest that redistribution of blood flow toward the brain occurs with chronic hypoxemia, with evidence of increased blood flow velocity in the cerebral arteries, thus increasing oxygen and nutrient supply to the brain. Similarly, fetal adrenal and heart growth are relatively spared but at the cost of a decrease in fetal gut and then somatic growth.
Respiratory adaptations to reduced substrate supply
Endogenous glucocorticoids are increased in IUGR fetuses. These might be expected to improve respiratory maturation in these fetuses if born preterm, but the impact of IUGR on surfactant maturation is not clear.
Some studies suggest that lung growth and surfactant production were accelerated in IUGR fetuses.
Impact of exogenous glucocorticoids on fetal adaptation in the IUGR fetus
Exogenous glucocorticoids are administered to pregnant women at risk of preterm labor occurring after 24 weeks’ gestation. This promotes surfactant production and fetal lung maturation and thus reduces the incidence of neonatal RDS, as well as preterm mortality and illness severity.
There are conflicting data on whether antenatal glucocorticoids are or are not associated with a reduction in the complications associated with preterm delivery in IUGR fetuses.
Risk factors
Worldwide the most common cause of IUGR is maternal undernutrition that may only have to occur at specific times of the pregnancy to affect the growth of the fetus.
In the developed world, the most common cause of IUGR is placental insufficiency. A reduction in placental size or transport capacity leads to impaired substrate transfer from the mother to the fetus.
About 10% of cases are secondary to congenital infection.
Chromosomal and other genetic disorders are reported in 5% to 15% of IUGR infants.
Clinical presentation and diagnosis
Signs and symptoms
Small size for gestational age, as plotted on standardized neonatal growth charts.
Loss of normal fat distribution, demonstrated by loose skin around the thighs and upper arms and a scaphoid abdomen.
The skin generally is accelerated in maturation with thickening, wrinkling, and may be dry and flaky.
The presence of obvious body disproportion with a relatively large head and small thin body complete the typical IUGR infant appearance.
In addition to a complete neonatal assessment and the above general features of reduced substrate supply or hypoxia-related IUGR, specific examination for the signs and symptoms of genetic conditions and those of the congenital infections should be undertaken, with appropriate testing if indicated.
Management
If the presence of IUGR is identified, a number of modifications to the normal management at any particular gestational age may need to be undertaken. It should be remembered that care must be taken using maturity-based assessments of gestational age, such as Ballard scoring, in the IUGR infant, if accurate menstrual history or ultrasound scan data are unavailable, as these scores may over estimate gestational age due to the increased skin and other maturities induced in growth restriction.
Obstetric monitoring and timing of delivery
Screening for IUGR
Fetal weight estimates can be derived using ultrasound measures of biparietal diameter, head circumference, femoral length, and abdominal circumference.
Serial fundal measurements are useful but Doppler velocimetry and fetal biometry are necessary.
Gestational age must be known for these measures to be useful in determining optimal weight at each gestational age.
Use of the appropriate growth charts assist in distinguishing between physiological and pathological smallness. Customized growth charts are better for predicting intrauterine fetal death in IUGR fetuses than population-based growth charts.
In combination, maternal BMI, symphysial-fundal height measurement and sonography can be used to decrease stillbirth in IUGR pregnancies by 20%.
Antenatal detection of IUGR allows skilled neonatologists to be present at the birth for assessment and resuscitation and possible decisions about elective delivery.
Sonography in the IUGR fetus
An estimated fetal weight of <3rd percentile and abnormal umbilical artery Doppler is strongly associated with poor perinatal outcomes.
SGA fetuses are more likely to have an increase myocardial performance index, possibly due to myocardial damage (troponin I is increased). They are also more likely to have cardiac remodeling and abnormal echocardiograms despite normal uterine artery Doppler. However, SGA fetuses are just as likely as controls to have abnormal ductus venosus pulsatility index in the week prior to term delivery.
Timing of delivery
In singleton pregnancies at term, there is no difference in adverse perinatal outcome with labor induction or expectant pregnancy monitoring.
Although neonatal admissions are lower after 38 weeks’ gestation, there are no differences in development or behavior at 2 years of age between these management approaches.
Care of the IUGR infant in the NICU
Thermoregulation: The IUGR infant is at risk of hypothermia because of increased heat loss and decreased heat supply. The increased heat loss is due to a larger surface area to weight ratio compared to AGA infants and reduced adipose insulation. The decrease in heat supply is due to decreased brown fat, reduced glucose supply (decreased glycogen stores, decreased secondary sources of gluconeogenesis, eg, white fat) and increased competition for glucose (relatively large brain and growth requirements). Management requires support to prevent and treat thermoregulatory issues.
Respiratory intervention: The requirement for respiratory intervention may be due to all of the causes described elsewhere at each gestational age. While RDS may be no different in incidence (see above), respiratory management may be complicated by the short- and long-term effects of undernutrition, with decreased energy stores and increased oxidative stress, and reduced respiratory muscle mass. In addition, a number of other neonatal respiratory conditions are more common in the IUGR infant.
Hypoxic ischemic effects such as respiratory depression, meconium aspiration, persistent pulmonary hypertension of the newborn (PPHN; see below), pulmonary hemorrhage, patent ductus arteriosus (see PDA below).
This will comprise observation, monitoring, supplemental oxygen, pressure support (CPAP), and ventilation as is appropriate for the gestational age and presentation.
Cardiovascular problems
PPHN is more common in the IUGR infant and while it may complicate the problems of prematurity it is primarily a clinical entity of the term or late preterm infant. The pathophysiology of PPHN in the IUGR infant is related to a number of processes including both anatomical and functional changes in the pulmonary vasculature. Presentations may range from effortless tachypnea and mild hypoxemia to catastrophic collapse with respiratory and cardiovascular failure. There is no evidence to suggest any different approach is required in the IUGR infant.
Patent ductus arteriosus (PDA) is more common in the IUGR infant (possibly as high as 60% in the less than 32-week-gestation infants) and this, therefore, increases the risk of pulmonary hemorrhage. The “steal effect” on somatic blood flow may also add to the in utero gut ischemia and thus contribute to the pathogenesis of NEC. There is no evidence to suggest any different approach to treatment is required in the IUGR infant.
Myocardial effects of IUGR: The clinical scenario of a severely IUGR baby who is sick in intensive care and then develops increasing myocardial failure, ventricular dilation, and poor output is well recognized. The underlying reasons for this are not clear. There is evidence of higher coronary blood flow, suggestive of increased metabolic demand, leading to a decrease in flow reserve. Histological studies confirm the depletion of glycogen stores, but also suggest an immaturity of cardiomyocyte development. In combination, these would lead to the clinical scenario of a heart with no reserve and one that rapidly slips into energy failure and dilated myopathy in the very sick infant.
Microvascular effects of IUGR: There is little information on the microvascular and regional effects of regional blood flow redirection. The microvascular mechanisms of the in utero brain sparing vascular flows are not fully understood and there is very little postnatal data available in this area. There is some evidence that in LBW infants microvascular changes may be visible in the retina at birth, and this may have implications for future cardiovascular health (see below).
Hypotension is more common in the growth-restricted infant, primarily due to the increased level of illness in both premature and term infants compared to their age-matched controls. It has been suggested that in view of the potential for myocardial pump failure, care be taken with both the use of fluid loading and the use of inotropes in the IUGR infant. Some recommend treatment to maintain some vasodilation, to avoid excessive afterload if inotropic support is required, ie, dobutamine rather than dopamine, but the evidence for this specific population is not clear.
Hematological problems
Red blood cells: The primary red cell response to growth restriction is polycythemia, secondary to in utero hypoxia. This can be symptomatic and also drives an increased risk of postnatal jaundice, requiring treatment. It should be remembered, particularly if partial exchanges are required, that because of the asymmetric nature of most growth restriction, the circulating volume is relatively higher in growth-restricted infants (in term infants 106 mL/kg vs 86 mL/kg). Growth restriction in twin pregnancies may have either increased or decreased red cell mass dependent of fetal connections. IUGR infants are at risk of anemia in the later months of infancy.
White blood cells and immune function: The incidence of neutropenia is increased with IUGR, independent of the presence of congenital or perinatally acquired infection (both of which occur more frequently in the growth-restricted fetus). The cause of this is not known, but it is usually self-limiting and treatment does not change outcome. While some differences in specific immune measures have been documented in growth-restricted newborns, the overall belief that immunity is functionally different has only limited clinical evidence.
Platelets and clotting: Growth restriction is associated with abnormalities in platelet numbers. These are both decreased in number across the population and the incidence of absolute thrombocytopenia is increased. Despite this, symptoms are rare and treatment is not usually required. The causes are multifactorial including increased consumption (placental microclots, polycythemia, and decreased production). The platelets produced are more immature and many platelet indices may be abnormal.
Feeding and weight gain
The nutrition, feeding, and growth targets of the IUGR infant have been, perhaps, the subject of most practice variation among neonatologists over the past 20 years. A number of issues need consideration: the risks of hypoglycemia; the risks of NEC; and the prevention of postnatal growth failure.
Hypoglycemia
The IUGR infant at any gestation is at increased risk of hypoglycemia. It is often present in utero and, with loss of any placental substrate, is exacerbated postnatally.
The normal glucogenic response is poor due to depletion of glycogen reserves and the presence of increased counterregulatory hormones, such as insulin. Further, lipid supplies, for alternate fuel production, are limited and protein is required to maintain an anabolic state and essential cell turnover. When this is coupled with the increased glucose consumption for thermoregulation and the upregulation of glucose transport into the brain, the main metabolic organ in the newborn, the glucose capacity may be rapidly exceeded.
In practical terms, this means that early feeding should be instituted, appropriate for gestational age, and that glucose blood levels should be monitored closely. The normal levels defining hypoglycemia apply and the glucose delivery target remains 6 to 8 mg/kg/min initially, but most would aim for the higher end of the range. This should be increased as required to keep the plasma glucose in a normal range. With the exception of those requiring minimal enteral feeding initially, most would start with breast milk but add IV dextrose solutions as required increasing volume initially if required and then concentration. Central line access is sometimes required for high dextrose/parenteral nutrition concentrations, but attempts to maintain some minimal enteral feeding are currently recommended, as this improves gut hormone production. Finally, high glucose requirement or persistent hypoglycemia will require provision of other nutritional components, eg, lipid and protein in appropriate amounts, and consideration of investigation for other contributors, eg, hyperinsulinemia, hypocortisolemia, and low growth hormone production. Ideally these hormonal levels should be screened for at the time of an episode of hypoglycemia. It is thought that the presence of severe episodic or chronic low-grade hypoglycemia both may contribute to the adverse neurological/developmental outcomes of the IUGR infant.
Risk of NEC
It is generally accepted that the incidence of NEC is increased in infants with growth restriction. It is thought that the redistribution of in utero blood flow away from the gut leads to both structural and functional immaturity and thus increases the propensity to the pathophysiology involved. In general, the rates of NEC vary so widely between centers and countries that the actual number attributed to growth restriction cannot be defined. A feeding protocol that includes early feeding with minimal enteral feeds (trophic feeding), cautious feeding increases and the use of breast milk wherever possible, is indicated in the IUGR infant.
Prevention of postnatal growth failure
It is generally thought that the postnatal growth pattern in premature infants should be to aim for their expected ideal in utero trajectory. This is rarely achieved. Despite the fact that growth-restricted infants may not show the normal postnatal weight loss, regaining in utero expected weight is rarely possible in the short term. A weight increase parallel or increasing toward the normal centiles is, therefore, the aim and can be achieved by a number of routes.
In the early period, in addition to minimal enteral feeds, parenteral nutrition may be required. There is increasing evidence that early and high use of protein may be beneficial and lipid should be introduced early, as for other parenterally fed infants. Slow increases in enteral feeds, followed by addition of supplementation to breast milk to improve growth, may be required. Early supplementation of calcium may prevent hypocalcemia. Prolonged use of parenteral nutrition in this group, as with premature infants, is associated with an increased risk of hyperglycemia, infection, and cholestatic liver failure, but there is no evidence that these are more common in the growth-restricted infant.
Prognosis
Neonatal outcomes in IUGR babies
The IUGR infant is at increased risk of perinatal mortality and morbidities.
RDS, hypoxic-ischemic encephalopathy, IVH, necrotizing enterocolitis (NEC), disrupted thermoregulation, hypoglycemia, and hematological disturbances are all more common in infants with fetal growth restriction.
These babies have longer hospital stays and higher health care costs compared to infants who have appropriate growth for their gestational age. In a 2005 US study, it was estimated that the additional financial burden resulting from IUGR, including health care and educational resource costs, was around $51,600 per individual.
The incidence of IUGR increases with increasing prematurity and thus contributes significantly to neonatal deaths.
For the term or late preterm infant, despite the above-mentioned specific illnesses, the overall mortality of those surviving neonatal care, compared to AGA infants, is not increased. For the premature infant, IUGR outcomes are comparable to a similar infant by weight rather than gestation. Thus, compared to gestationally matched infants a number of the typical outcomes of prematurity may be increased including chronic lung disease, retinopathy of prematurity, NEC, IVH, and mortality.
Discharge
Discharge criteria for the IUGR infant remain as for the premature infant; the infant needs to be physiologically and medically stable and feeding enough to continue at home with the available levels of support.
Discharge planning for the IUGR infant should be tailored to the individual needs of the infant and family, based on the associated medical and developmental issues still present at discharge.
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