Intrauterine growth restriction (IUGR) is commonly defined as a birth weight less than the 10th percentile at a given gestational age. It has also been defined as a fetus that has not reached its growth potential at a given gestational age.
Small for gestational age (SGA) describes a population of fetuses with a weight below the 10th percentile without reference to the cause.
Prenatal ultrasonography is the imaging method of choice for diagnosing and evaluating possible cases of IUGR. The typical finding is a significant discrepancy in some or all of the fetal biometric parameters as compared with measurements expected based on gestational age alone.
Because sonographic prediction of fetal weight may vary by up to 20% from actual fetal weight, diagnosis and management of IUGR is generally guided by serial sonographic assessments of the fetus.
Pregnancy management depends on the gestational age, the etiology of the IUGR, and the results of fetal surveillance. Fetal testing including Doppler studies and serial growth scans are important for determining whether a pregnancy can be continued expectantly.
Detailed Doppler assessment including umbilical arterial, middle cerebral arterial, ductus venosus, and umbilical venous assessments are used to evaluate fetal status, and may be used to optimize timing of delivery.
Gestational age at delivery is a strong predictor of neonatal outcome in IUGR cases.
Elective delivery is recommended for all cases of IUGR reaching 37 weeks of gestation, while expectant management with close fetal surveillance is recommended for cases less than 34 weeks of gestation. For cases between 34 and 37 weeks of gestation, management is individualized depending on overall fetal status.
A previous pregnancy complicated by IUGR is considered a risk factor for developing IUGR in a subsequent pregnancy. Such cases of recurrent IUGR usually reflect an underlying maternal medical problem, such as chronic hypertension or antiphospholipid antibody syndrome.
Intrauterine growth restriction (IUGR) is commonly defined as a birth weight less than the 10th percentile at a given gestational age (Table 123-1). It has also been defined as a fetus that has not reached its growth potential at a given gestational age, because of one or more causative factors (Lin and Santolaya-Forgas, 1998). The population from which expected fetal growth standards are derived to define the 10th percentile is of major importance. A review of all publications in the English language literature since 1963 that presented values for the 10th percentile of birth weight for gestational age has been published (Goldenberg et al., 1989). It was found that studies differed in how gestational age was determined, types of infants excluded, populations studied, and whether they were controlled for the sex of the infant as well as the race and parity of the mother. The 10th percentile birth weights at each gestational age from these various published standards differed substantially.
Table 123-1Tenth Percentile Birth Weight Cutoffs, in Grams, by Gestational Age and Fetal Gender, from 1991 National United States Population Data ||Download (.pdf) Table 123-1 Tenth Percentile Birth Weight Cutoffs, in Grams, by Gestational Age and Fetal Gender, from 1991 National United States Population Data
|Gestational Age (weeks) ||Male ||Female |
|20 ||270 ||256 |
|21 ||328 ||310 |
|22 ||388 ||368 |
|23 ||446 ||426 |
|24 ||504 ||480 |
|25 ||570 ||535 |
|26 ||644 ||592 |
|27 ||728 ||662 |
|28 ||828 ||760 |
|29 ||956 ||889 |
|30 ||1117 ||1047 |
|31 ||1308 ||1234 |
|32 ||1521 ||1447 |
|33 ||1751 ||1675 |
|34 ||1985 ||1901 |
|35 ||2205 ||2109 |
|36 ||2407 ||2300 |
|37 ||2596 ||2484 |
|38 ||2769 ||2657 |
|39 ||2908 ||2796 |
|40 ||2986 ||2872 |
|41 ||3007 ||2891 |
|42 ||2998 ||2884 |
|43 ||2977 ||2868 |
|44 ||2963 ||2853 |
Different standards for fetal growth throughout gestation have been reported. These standards set the normal range of fetal growth as being between 2 SD of the mean (2.5th to 97.5th percentile) or between the 10th and 90th percentiles for gestational age. Fetal growth curves plotting fetal biometric values against gestational age have been published from a variety of populations. One of the earliest set of growth curves was derived from a population in Denver, Colorado (Lubchenco et al., 1966). These Denver curves soon became the standard fetal growth curves used throughout North America. However, these curves underestimate the incidence of small for gestational age (SGA) infants at sea level, especially during the third trimester, and also do not take into account the increase in birth weight noted during the past 30 years. Although many centers report the continued use of the Denver curves, more contemporary standards are available. These include growth standards from the state of California, based on data from more than 2 million singleton births occurring between 1970 and 1976, and also growth standards from Canada, based on data from more than 1 million singleton births and more than 10,000 twin births occurring between 1986 and 1988, as well as from national US standards, based on data from more than 3 million births in 1991 (Williams et al., 1982; Arbuckle et al., 1993; Alexander et al., 1996). Commonly used cutoffs for defining IUGR in male and female fetuses at various gestational ages are shown in Table 123-1. A further problem with the use of such cutoff values for diagnosing IUGR is that they cannot identify a fetus that has failed to reach its own growth potential, but whose weight is not yet below the usual cutoff value, such as the 10th percentile. Such a fetus may be identified through serial sonography, in which sequential weight estimates are associated with decreasing percentile values for gestational age.
The term intrauterine growth restriction is frequently and erroneously used as a substitute for the original term small for gestational age. SGA describes a population of fetuses with a weight below the 10th percentile without reference to the cause. Most SGA fetuses are normal except the small fetuses that simply reflect the normal weight distribution within a population. The use of a particular cutoff value such as the 10th percentile is clearly arbitrary, and will inevitably include a large number of fetuses that are constitutionally small, without any evidence of pathology. Up to 70% of SGA infants are small because of such constitutional reasons as maternal ethnicity, parity, or body mass index (Lin and Santolaya-Forgas, 1998). IUGR describes a subset of these SGA fetuses whose weight is below the 10th percentile as a result of a pathologic process that is due to a diverse group of disorders. The term intrauterine growth restriction is preferred to intrauterine growth retardation, as the word retardation has a tremendously negative influence on patients.
IUGR has classically been subdivided into two patterns: asymmetric and symmetric IUGR. This provides further information on fetal body size and length, rather than a simple reliance on fetal weight. With symmetric IUGR, both the head and abdomen are decreased proportionately, while asymmetric IUGR refers to a greater decrease in abdominal size, which is also referred to as the head-sparing effect (Lin and Santolaya-Forgas, 1998). Approximately 70% to 80% of cases of IUGR are asymmetric, with the remaining 20% to 30% being symmetric. It was commonly believed that asymmetric IUGR represented placental insufficiency, while symmetric IUGR was more likely to be associated with constitutional problems, such as aneuploidy. However, it is now recognized that the timing of the pathologic insult is of more importance than the actual nature of the underlying pathology in determining the pattern of IUGR, thereby calling into question the clinical utility of subdividing IUGR into such patterns (Lin and Santolaya-Forgas, 1998). Symmetric IUGR can be caused by placental insufficiency occurring early in gestation, so that by the time the fetus is examined it has evolved from an initial asymmetric pattern to a pattern of symmetric IUGR. Overall infant body proportions can be described also by using the ponderal index, which is the birth weight in grams divided by the crown-to-heel length in cubic centimeters.
The list of possible causes of IUGR is extensive and is summarized in Table 123-2. These causes can be conveniently divided into fetal, placental, and maternal factors (Lin and Santolaya-Forgas, 1998). The most common fetal factors associated with IUGR include fetal chromosomal abnormalities, structural fetal malformations, fetal infections, and complications related to multiple gestations (Figure 123-1). Chromosomal abnormalities are a major cause of IUGR (ACOG, 2000). Confined placental mosaicism is three times more common in placentas of IUGR fetuses compared with those from appropriately grown fetuses (Wilkins-Haug et al., 1995). Up to one-fourth of all infants with congenital structural malformations will have IUGR, and the incidence of growth restriction increases significantly as the number of different malformations per infant increases (Khoury et al., 1988). The number of infectious agents proven to cause IUGR is limited; they include rubella and cytomegalovirus, although no known bacterial infections have been linked to IUGR. The importance of defining a subpopulation of fetuses with IUGR lies in its association with adverse pregnancy outcome. The likelihood of perinatal morbidity and perinatal mortality increases significantly as the birth weight percentile decreases, so that once below the third to fifth percentiles, the chances of fetal death increase by as much as 20-fold (Scott and Usher, 1966). For infants weighing less than 1500 grams at term, the perinatal mortality rate is increased at least 70-fold as compared with appropriately grown term infants (Williams et al., 1982). Much of the increased perinatal morbidity and mortality in IUGR fetuses is due to the strong association between aneuploidy and structural fetal malformations with IUGR (Scott and Usher, 1966).
Table 123-2Risk Factors for Intrauterine Growth Restriction ||Download (.pdf) Table 123-2 Risk Factors for Intrauterine Growth Restriction
|Fetal Factors ||Placental Factors ||Maternal Factors |
|Chromosomal abnormalities: |
Single anomalous fetus
|Abnormal trophoblast invasion |
Velamentous cord insertion
|Constitutional factors: |
Poor pregnancy weight gain
Low prepregnancy weight
Inflammatory bowel disease
Severe lung disease
Cyanotic heart disease
Sickle cell anemia
Collagen vascular disease
Chronic renal failure
Past obstetric history:
Previous preterm birth
Monozygotic twins in which the twin on the right is severely growth restricted compared to its co-twin.
The incidence of IUGR varies depending on the population examined and the standard growth curves used to make the diagnosis (Goldenberg et al., 1989). Using the commonly quoted cutoff of the 10th percentile for defining pregnancies at risk for IUGR implies that at least 10% of the entire obstetric population will be labeled as being IUGR. In Europe, the commonly used cutoff for defining IUGR of 2 SD below the mean will include 5% of the total population. Approximately one third of all infants weighing less than 2500 grams at birth are not just small for gestational age, but have sustained IUGR (Lin and Santolaya-Forgas, 1998). Approximately 4% to 7% of all infants born in developed countries and 6% to 30% in developing countries are classified as growth-restricted (Scott and Usher, 1966; Lugo and Cassady, 1971; Galbraith et al., 1979).
Prenatal ultrasonography is the imaging method of choice for diagnosing and evaluating possible cases of IUGR. The typical finding is a significant discrepancy in some or all of the fetal biometric parameters as compared with measurements expected based on gestational age alone. The most common biometric parameters evaluated are the biparietal diameter, head circumference, abdominal circumference, and femur length. These measurements can then be used in a variety of formulas to provide an estimate of fetal weight (Hadlock et al., 1984; Shepard et al., 1982). However, it should be noted that sonographic prediction of fetal weight using such formulas may vary by up to 20% from actual fetal weight, thereby calling into question the accuracy of prenatal sonographic diagnosis of IUGR. For this reason, diagnosis and management of IUGR is generally guided by serial sonographic assessments of the fetus.
In cases of symmetric IUGR, measurements of the fetal head, abdomen, and femur should all be below the expected values for a given gestational age. By contrast, with asymmetric IUGR, measurements of the fetal abdomen will be less than expected, while fetal head and femur measurements will be appropriate for gestational age. While it is generally considered that symmetric IUGR represents an intrinsic insult to the fetus (chromosomal abnormality, fetal infection) and asymmetric IUGR represents an extrinsic insult (placental insufficiency), sonographic differentiation of these patterns may not be clinically relevant. Mixed patterns of fetal growth restriction are also possible, which further limits the clinical utility of subdividing IUGR into symmetric and asymmetric types.
Following the diagnosis of IUGR, a careful sonographic survey should be performed to search for some of the possible causes listed in Table 123-2. In cases of severe IUGR associated with placental problems, oligohydramnios is a frequent finding. In cases of severe IUGR but normal or increased amniotic fluid volume, fetal aneuploidy or structural malformation is likely.
Pulsed Doppler sonographic assessment of the umbilical artery may reveal abnormalities of flow in true cases of IUGR. As placental resistance increases, umbilical arterial flow toward the placenta during diastole will decrease, leading to an increase in the ratio of systolic to diastolic flow (SD ratio). The end-diastolic velocity decreases when approximately one-third of the fetal villous vessels are poorly perfused (Vergani et al., 2005). Eventually, umbilical arterial diastolic flow disappears and may even reverse direction toward the fetus, (absent end-diastolic flow and reversed end-diastolic flow). Absent end-diastolic flow is thought to occur when 60% to 70% of the villous vascular tree is damaged (Vergani et al., 2005). (Figures 123-1A to 123-1D) When these changes occur, the frequency of monitoring and the timing of delivery become important management issues. The risks and benefits of delivery versus expectant management must be balanced.
Umbilical artery Doppler studies demonstrating a normal SD ratio in a fetus at 28 weeks.
Umbilical artery Doppler studies demonstrating decreased diastolic blood flow and an increased SD ratio in a fetus at 28 weeks.
Umbilical artery Doppler study demonstrating absent end-diastolic flow.
Umbilical artery Doppler study demonstrating reversed end-diastolic flow.
Doppler velocimetry has been used to detect signs of fetal compromise before more traditional tests such as the nonstress test and biophysical profile deteriorate. Doppler studies are thought to change in a consistent and temporal pattern; absent end-diastolic flow in the umbilical artery is present before changes in the fetal heart rate tracing. Compensatory increase in cerebral flow also occurs, which is seen as an increase in end-diastolic flow in the middle cerebral arteries. Changes in venous circulation usually occur just prior to development of an abnormal fetal heart rate tracing, although the reliability of this temporal sequence is still unclear. Such venous changes may be demonstrated by absent or reversed flow during the “a” wave in the ductus venosus (Figures 123-2A to 123-2C) or pulsatile umbilical venous flow.
Ductus venosus Doppler demonstrating a normal waveform.
Ductus venosus waveform demonstrating decreased A-wave.
Ductus venosus waveform demonstrating reversal of the A-wave.
The single most likely alternative cause of apparent IUGR following a single prenatal ultrasound examination is incorrect pregnancy dating. Also, because of the inherent inaccuracy of all forms of prenatal estimation of fetal weight, the differential diagnosis of IUGR should always include a normally grown fetus, which is just physiologically small. In addition, at least 70% of all cases of SGA infants are constitutionally small, and do not reflect a pathologic impairment of fetal growth (Lin and Santolaya-Forgas, 1998). Once a diagnosis of pathologic IUGR is considered likely, the differential diagnosis for the underlying cause is extensive and is listed in Table 123-2.
ANTENATAL NATURAL HISTORY
The antenatal natural history of IUGR is difficult to predict in individual cases. The antenatal natural history of fetuses with IUGR secondary to aneuploidy, structural malformation, or infection will be dictated to a large extent by the nature of the particular abnormality.
In cases of IUGR secondary to placental insufficiency, the typical in utero progression involves redistribution of fetal blood flow away from noncritical organs and maintaining cerebral blood flow (Baschat, 2004). This leads to reduced fetal renal blood flow, which often manifests as worsening oligohydramnios. In addition, further growth of the fetal abdominal dimensions is decreased and subcutaneous fat is no longer deposited. Doppler studies demonstrate decreased umbilical arterial diastolic flow, which may become absent or reversed as the IUGR worsens. In contrast, cerebral end-diastolic blood flow increases and, as the condition worsens, central cerebral vasodilation is lost (Arias, 1994).
Because of this apparent sequence in fetal deterioration with IUGR, many investigators have used intensive fetal surveillance in an effort to predict when a fetus with IUGR is sufficiently compromised that in utero death is likely. Unfortunately, the predictive value of such antenatal surveillance is imperfect. It has been suggested that, in fetuses with IUGR, the development of absent or reversed end-diastolic umbilical arterial flow heralds imminent fetal death, and therefore may warrant elective delivery (Reed et al., 1987). However, the time interval between development of such Doppler abnormalities and fetal heart rate tracing abnormalities and fetal death may be days or even weeks, and therefore abnormal Doppler findings alone cannot be relied on to dictate elective premature delivery of a fetus with IUGR (Lin and Santolaya-Forgas, 1999; Cosmi et al., 2005; Vergani et al., 2005).
The Growth Restriction Intervention Trial (GRIT) was carried out to compare immediate delivery of IUGR fetuses versus expectant management to decrease complications of prematurity (The GRIT Study Group, 2003). Patients (547 mothers and 587 babies) were included if IUGR was diagnosed between 24 and 36 weeks’ gestation and the responsible physician was uncertain whether or not to deliver the pregnancy. Umbilical artery Doppler studies were recorded for all patients. Patients were randomized to “immediate delivery” after administration of antenatal steroids or “delay until the physician was no longer uncertain”. The median time to delivery for the immediate delivery group was 0.9 days and was 4.9 days for the delayed delivery group. Total perinatal death rate was 10% in the immediate delivery group versus 9% in the delayed delivery group. Thus, there was no difference in the overall mortality rates between the two groups indicating that there was little evidence for choosing immediate delivery over delayed delivery and vice versa. There were however significantly more stillbirths in the delayed delivery group, although this was balanced by a similar increase in neonatal deaths in the immediate delivery group. This study suggests that obstetricians are currently delivering IUGR pregnancies at the correct time to minimize perinatal mortality. At two-year follow-up, however, the GRIT study group found an increased trend towards disability in the immediate delivery group but no overall difference in the Griffiths developmental quotient (GRIT, 2004). Most of the observed differences were in babies younger than 31 weeks’ gestation at randomization. This study emphasizes the important contribution of gestational age at delivery for patients with IUGR.
When the prenatal diagnosis of IUGR is suspected, the patient should be referred to a maternal–fetal medicine physician for targeted ultrasound examination and counseling regarding further pregnancy management. The ultrasound examination should be repeated, with particular attention paid to all biometric parameters, amniotic fluid status, umbilical artery Doppler indices, and the presence of any structural fetal malformations or stigmata of aneuploidy. Invasive testing for fetal karyotype should be considered (ACOG, 2000). Maternal evaluation should include careful obstetric, medical, family, and genetic histories to evaluate for possible causes of IUGR, as listed in Table 123-2. Maternal serum should be sent for rubella titers, and maternal urine should be evaluated with cytomegalovirus culture. Antiphospholipid antibody testing should be considered in a patient with a history suspicious for this syndrome (ACOG, 2000).
Further pregnancy management will depend on the gestational age and on the presence of additional malformations. If the pregnancy has already reached 37 weeks of gestation, delivery should be considered because of the extremely low risk of pulmonary immaturity. If the pregnancy is at less than 34 weeks of gestation and fetal testing is reassuring, expectant management is generally favored. The frequency of antenatal testing depends on the degree of IUGR, the amniotic fluid status, and umbilical artery Doppler indices (Harman and Baschat, 2003). Periodic fetal assessment using Doppler velocimetry, the fetal nonstress test, and the biophysical profile (traditional or modified) are all considered reasonable monitoring techniques (ACOG, 2000). Expectant management can continue as long as these tests remain reassuring. These tests should be supplemented by daily counting of fetal movements by the mother.
If umbilical artery Doppler indices are abnormal, especially in the presence of absent or reversed end-diastolic flow, more intense surveillance is suggested (Harman and Baschat, 2003). Venous Doppler studies are an independent predictor of adverse perinatal outcomes and should be added if the umbilical artery end-diastolic velocity is absent (Baschat, 2005). The addition of middle cerebral artery Doppler velocimetry also may be a useful predictor for fetuses at risk for neonatal mortality and morbidity (Vergani et al., 2005). Nonetheless, pregnancies may continue for days or weeks with reassuring fetal testing despite the presence of absent or reversed end-diastolic umbilical arterial flow (Lin and Santolaya-Forgas, 1999). Likewise, it is uncertain if delivery because of an abnormal venous Doppler improves outcomes (Hofstaetter et al., 2002; Bilardo et al., 2004). It is important to note that even in cases of IUGR neonatal outcomes are predominantly determined by gestational age at delivery (Cosmi et al., 2005). Thus, managing IUGR in a preterm infant can be a state of clinical equipoise requiring a delicate balance between continuing the pregnancy in a potentially hostile uterine environment versus delivering a neonate who will be confronted with the challenges of prematurity. Both expectant management and preterm delivery have the potential for long-term adverse consequences. Further studies are needed to determine the optimal management protocols for pregnancies complicated by IUGR.
For pregnancies between 34 and 37 weeks of gestation, further pregnancy management should be individualized and may be guided by fetal lung maturity indices. It is not unreasonable to manage all pregnancies with IUGR and reassuring fetal testing expectantly until 37 weeks of gestation, at which time elective delivery is arranged (Craigo et al., 1996). Using this management scheme, delivery before 37 weeks occurs only with nonreassuring fetal testing. If amniocentesis has documented fetal lung maturity during this 34- to 37-week gestational age range, delivery should be arranged promptly.
The mode of delivery for fetuses with IUGR should be based entirely on standard obstetric practices. There is no evidence to support a policy of routine cesarean delivery for all fetuses with IUGR (ACOG, 2000). That being said, it is quite common for IUGR pregnancies to demonstrate significant fetal heart rate changes during labor, most likely due to either oligohydramnios or diminished placental reserve. For this reason, decision on mode of delivery should be individualized depending on obstetric factors such as parity and cervical favorability. If an induction of labor is pursued for an individual fetus with IUGR, continuous electronic monitoring of the fetal heart rate should be conducted. The hospital location of delivery will depend on the gestational age and the presence of additional fetal abnormalities. In general, the optimal site for delivery of a fetus with severe IUGR will be a tertiary care facility with the immediate availability of a perinatologist and neonatologist to guide management.
Many fetal interventions have been evaluated in cases of IUGR to maximize neonatal outcome. These include treating any underlying problems, such as maternal hypertension. Behavior modification for the mother may include smoking cessation and modified bed rest (Lin and Santolaya-Forgas, 1999). More specific therapies for the fetus have included maternal low-dose aspirin therapy. In initial studies, there was a suggestion of increased fetal and placental weight associated with aspirin use (Trudinger et al., 1988). However, this potential benefit was subsequently refuted in a large randomized trial in which the administration of low-dose aspirin to the mother was shown to have no effect on the rate of IUGR or any other perinatal outcome measure (CarIt is et al., 1998). Another possible fetal intervention is the antenatal administration to the mother of high-dose oxygen therapy, which in small studies has been shown to, at least transiently, improve umbilical arterial pH and oxygen content (Nicolaides et al., 1987). However, before this intervention can be recommended, larger, well-designed studies need to be completed.
Because of their lack of placental reserve, infants with IUGR are more likely to require immediate resuscitation in the delivery room than appropriately grown infants. Problems that may be encountered include neonatal asphyxia, mec-onium aspiration, hypothermia, polycythemia, hypoglycemia, and other metabolic abnormalities. The infant should be examined carefully for any signs of structural malformation that may have been missed with prenatal ultrasonography, for dysmorphic features suggestive of chromosomal abnormality, and for signs of perinatal infection with rubella, cytomegalovirus, varicella, syphilis, and toxoplasmosis (Alkalay et al., 1998). If any stigmata of perinatal infection or aneuploidy are present, appropriate serologic titers or karyotype should be obtained. A consultation with a clinical geneticist should also be obtained, if dysmorphic features are noted on examination.
No surgical treatments have been described.
The long-term outcome of infants with IUGR will depend on the underlying cause and on the presence of additional malformations. Considerable data have now accumulated linking IUGR with poor cognitive function and adverse neurologic outcome in later childhood. In one study of 171 children with spastic cerebral palsy, it was found that up to 22% of cases could be attributed to IUGR, although a causal relationship could not be established (Blair and Stanley, 1990). In another study of 218 newborns at high risk, including 77 with IUGR, evaluation of cognitive skills at ages 9 to 11 revealed a significant learning deficit for infants with IUGR (Low et al., 1992). Data also suggest that IUGR infants can be expected to have higher rates of impaired gross motor development, lower intelligence quotient, and speech or reading disabilities (Gembruch and Gortner, 1998).
In a review of the many studies of long-term outcome of infants with IUGR, however, it was shown that after correcting for the effects of prematurity, most of the adverse cognitive outcomes could be diluted by socioenvironmental conditions (Hack, 1998). Therefore, it was suggested that fetal IUGR per se may not have a significant impact on final cognitive outcome in adulthood. Nonetheless, long-term follow-up has suggested that a history of IUGR may place these patients at risk for adult-onset hypertension and cardiovascular complications (Barker et al., 1989).
GENETICS AND RECURRENCE RISK
As described in Table 123-2, there are many genetic influences that can be associated with IUGR, ranging from genetic abnormalities such as aneuploidy to constitutional factors such as maternal height and weight. A previous pregnancy complicated by IUGR is considered a risk factor for developing IUGR in a subsequent pregnancy. Such cases of recurrent IUGR usually reflect an underlying maternal medical problem, such as chronic hypertension or antiphospholipid antibody syndrome. In the future, routine assessment of first trimester uterine artery Doppler studies might be useful to predict pregnancies at risk for IUGR and perhaps to modify pregnancy management (Dugoff et al., 2005).
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