UNIVERSITATEA DE STAT DE MADICINA SI FARMACIE “N. TESTEMITANU”

CATEDRA OBSTETRICA SI GINECOLOGIE

Intrauterine Growth Restriction: Identification and Management

Munteanu MarianaIIIrd year resident

2011

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INTRODUCTION

Intrauterine growth restriction (IUGR) is a common diagnosis in obstetrics and carries an increased risk of perinatal mortality and morbidity. Identification of IUGR is crucial because proper evaluation and management can result in a favorable outcome. Certain pregnancies are at high risk for growth restriction, although a substantial percentage of cases occur in the general obstetric population. Accurate dating early in pregnancy is essential for a diagnosis of IUGR. Ultrasound biometry is the gold standard for assessment of fetal size and the amount of amniotic fluid. Growth restriction is classified as symmetric and asymmetric. A lag in fundal height of 4 cm or more suggests IUGR. Serial ultrasonograms are important for monitoring growth restriction, and management must be individualized. General management measures include treatment of maternal disease, good nutrition and institution of bed rest. Preterm delivery is indicated if the fetus shows evidence of abnormal function on biophysical profile testing. The fetus should be monitored continuously during labor to minimize fetal hypoxia.

Approximately 10% of the almost 4 million infants born each year in the United States are classified as low birth weight (LBW). Terminology used to describe the small fetus/newborn can be confusing. The term low birth weight is used clinically by pediatricians postnatally and is defined strictly as a birth weight of <2,500gm. Antenatally, the terms small for gestational age (SGA) and intrauterine growth restriction (IUGR) frequently are used interchangeably. However, the term small for gestational age encompasses a group of fetuses that are small for a variety of reasons that confer varying prognoses. These etiologies include infection, congenital malformations, aneuploidy, multiple gestation, maternal disease, malnutrition, and toxins and the normal or constitutionally small fetus. The term intrauterine growth restriction is a subgroup of SGA and more specifically identifies the fetus that is pathologically small. Placental insufficiency accounts for the majority of IUGR fetuses. It is important to recognize that not all fetuses or newborns classified as SGA are small due to pathologic reasons (i.e., constitutionally small) but simply represent the smaller fetuses/newborns at the lower end of the bell-shaped distribution of the normal population and are small for familial reasons. Conversely, some fetuses or neonates who are average for

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gestational age (AGA) may suffer from relative growth restriction if they are not achieving their individual, genetic growth potential. These babies may have normal weight percentiles for their gestational age but suffer from differential growth delay and show abnormal body proportions or ponderal indices. The prognosis for a given SGA fetus is dependent on the etiology.

The scope of the problem of IUGR is broad, not just because it increases morbidity and mortality of the fetus but also because it does so for the newborn and adult who the fetus is destined to become. IUGR places the fetus at risk for hypoxemia, acidemia, antepartum death, and intrapartum distress. Perinatal mortality rates in growth-restricted neonates are six to ten times greater than in normally grown age-matched controls. In one large series, 52% of unexplained stillbirths were growth restricted. In that series, suboptimal growth carried an odds ratio (OR) of 7.0 for sudden intrauterine unexplained death (95% confidence interval [CI] 3.3 to 15.1). IUGR places the neonate at risk for a number of metabolic disturbances, including polycythemia, pulmonary transition difficulties, intraventricular hemorrhage (IVH), impaired cognitive function, and cerebral palsy. The threshold of viability is both later in gestational age and larger in birth weight among neonates with severe IUGR compared with normally grown infants who are delivered at extremely preterm ages. Several epidemiologic and animal studies in the early 1990s began to report on long-term sequelae of IUGR, including adult hypertension, heart disease, stroke, and diabetes. The theory of fetal programming as the origin of adult disease is commonly referred to as the Barker hypothesis. The challenge in management of the IUGR fetus is to identify the condition and manage it so that adverse sequelae are minimized and balanced against the risks of premature delivery. The use of real-time ultrasound and Doppler velocimetry play pivotal roles in the diagnosis and management of IUGR. This chapter reviews normal placental–fetal growth, etiology of the SGA fetus, screening for growth restriction, and practical uses of ultrasound and Doppler velocimetry in the diagnosis and management of the IUGR fetus.

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Fetal growth is dependent on genetic, placental and maternal factors. The fetus is thought to have an inherent growth potential that, under normal circumstances, yields a healthy newborn of appropriate size. The maternal-placental-fetal units act in harmony to provide the needs of the fetus while supporting the physiologic changes of the mother. Limitation of growth potential in the fetus is analogous to failure to thrive in the infant. The causes of both can be intrinsic or environmental.

Fetal growth restriction is the second leading cause of perinatal morbidity and mortality, followed only by prematurity.1,2 The incidence of intrauterine growth restriction (IUGR) is estimated to be approximately 5 percent in the general obstetric population.3 However, the incidence varies depending on the population under examination (including its geographic location) and the standard growth curves used as reference.4 In assessing perinatal outcome by weight, infants who weigh less than 2,500 g (5 lb, 8 oz) at term have a perinatal mortality rate that is five to 30 times greater than that of infants whose birth weights are at the 50th percentile.5 The mortality rate is 70 to 100 times higher in infants who weigh less than 1,500 g (3 lb, 5 oz).5 Perinatal asphyxia involving multiple organ systems is one of the most significant problems in growth-restricted infants.3

Timely diagnosis and management of IUGR is one of the major achievements in contemporary obstetrics. If the growth-restricted fetus is identified and appropriate management instituted, perinatal mortality can be reduced,6,7

underscoring the need for assessment of fetal growth at each prenatal visit.

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Determinants of Normal and Aberrant Placental Growth

Normal Placental Development

Normal growth of the fetus is dependent on normal placentation and growth of the placenta. The placenta is a dynamic and multifaceted organ that serves as an interface between mother and fetus with the critical role of meeting the metabolic and circulatory demands of the growing fetus. The roles of the placenta include:

Nutritional: Provides oxygen, glucose, amino acid, and volume (fluid) transfer.

Immunologic: Protects the fetus from pathogens and the maternal immune system.

Endocrinologic: Produces numerous hormones, growth factors, cytokines, and other vasoactive mediators.

Metabolic: Serves as the respiratory organ and the kidney for the fetus and is responsible for elimination of carbon dioxide, metabolic acids, and other waste products from the fetus to maintain acidbase balance.

Research has begun to provide an understanding of the complexity of the implantation and placentation processes, which require the production and coordination of numerous angiogenic growth factors (fibroblast growth factor, hepatocyte growth factor, placental growth factor, vascular endothelial growth factor), cell-adhesion molecules, cytokines, nitric oxide, extracellular matrix metalloproteinases, hormones, and transcription factors (hypoxia-inducible factor). This process of coordination begins very early in pregnancy and can dictate whether the pregnancy grows in a normal or abnormal direction. By day 13, the cytotrophoblast layer has differentiated into invasive and noninvasive components. The invasive cytotrophoblast forms cell columns that anchor the trophoblastic tissue to the uterine epithelium and establish blood flow to the placenta and fetus. During this process, the invasive cytotrophoblast cells (extravillous trophoblast):Migrate through the syncytiotrophoblast and into the decidualized endometrium and myometrium.Invade the vessel walls of the maternal spiral arteries in these areas. Induce the remodeling of the spiral arteries from high-resistance to low-resistance vessels.

As the invasive cell columns of the cytotrophoblast penetrate the syncytiotrophoblast, spaces called lacunae are created, which subsequently fuse to form the intervillous space with intervening syncytiotrophoblast columns called trabeculae. The process of intervillous space formation and spiral artery transformation directs an increasing maternal cardiac output into the intervillous

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space. Loss of spiral artery vessel media is the mechanism by which the spiral arteries decrease their resistance to blood flow.

Angiogenesis represents the formation of new blood vessels from endothelial cells and is classified into branching and nonbranching stages. Branching angiogenesis occurs primarily in the first and early second trimesters and leads to the formation of the immature villous tree. Branching angiogenesis continues until the mid second trimester, when there is a transition to nonbranching angiogenesis. During this process, there is a dramatic elongation of the existing placental vascular tree. A dramatic decrease in vascular resistance and an increase in blood flow through the placenta are coincident with this process and occur via progressive loss of the musculoelastic media in the walls of the maternal spiral arterioles. The decrease in resistance is aided on the fetal side by further villous vascular branching, allowing both fetal and maternal circulations to convert to low-resistance, high-capacitance vascular beds. The progressive decline in vascular resistance is reflected in increasing end-diastolic velocities in Doppler flow velocity waveforms (FVW) of both the uterine and the umbilical arteries. In fact, the resistance in the uterine artery has been shown to be lower on the placental side if the placenta is not in the midline, adding further support to the idea of placental-mediated remodeling of the maternal circulation.

Abnormal Placental Development

In pregnancies complicated by preeclampsia and IUGR, trophoblast invasion is limited to the decidualized endometrium, which results in failure of the spiral arteries to become low-resistance vessels. This failure can be detected by Doppler velocimetry of the uterine artery, which supplies blood to the spiral arteries. The blood FVWs in the uterine artery obtained with pulsed-wave Doppler velocimetry are reflective of the waveforms downstream at the spiral arteries. These abnormalities are identified on a Doppler FVW profile by a high-resistance pattern (low velocity of flow at end-diastole relative to that at systole) and by a protodiastolic (early diastolic) notch. Failure of this process to occur on the maternal side of the circulation may lead to adverse effects on both the mother and the fetus. Maternal vascular endothelial dysfunction may lead to production of a variety of vasoactive mediators, which could subsequently lead to the development of preeclampsia. Sibai and colleagues have recently published a hypothesis addressing the observation that preeclampsia and IUGR share similar placental pathology and that women who have had a pregnancy complicated by either are at higher risk of cardiovascular disease later in life. They propose that endothelial dysfunction underlies both conditions by predisposing to shallow placentation but

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that women with metabolic syndrome are prone to preeclampsia. This may be mediated by the action of elevated circulating cytokines. Women with no predisposition to metabolic syndrome, however, may develop IUGR but not preeclampsia. A variety of villous and vascular abnormalities have been described in the placenta of the IUGR fetus. Placentas from IUGR pregnancies have fewer gas-exchanging villi. The villi also are slender, elongated, poorly branched, and poorly capillarized. Vascular abnormalities include reduced branching of stem arteries and disorganized vascular patterns, including less coiling as depicted by placental vascular cast studies. The reduced branching seen in the villous vasculature creates abnormal blood flow and an increase in vascular resistance to flow that can be likened to that of an electric circuit the fewer downstream tributaries that exist from the main supply line, the higher the resistance.

Determinants of Normal and Aberrant Fetal Growth

Normal Fetal Growth

In order for a fetus to grow normally, the placental developmental activities described earlier must proceedundisturbed. Fetal growth velocity increases across gestation until it peaks at 30 to 35 g per day or 230 to 285 g per week between 32 and 34 weeks. After that, the rate of weight gain decreases, reaching a plateau at 40 weeks and even a decline, or weight loss, at 41 to 42 weeks. At 37 weeks gestation, the placenta has reached maximal villous nutrient exchange via a surface area of 11 m2 and weighs approximately 500 g. Coincident with this is maximal amniotic fluid volume and maximal human placental lactogen levels, suggesting peak placental function. Interestingly, although the fetus grows less quickly at term, calorie acquisition by the fetus continues to be quite high. At this time in pregnancy, the fetus is rapidly accumulating fat that provides thermal stability for the immediate postnatal period. Fat has a high caloric content (9 calories/g) compared with carbohydrates and proteins (4 calories/g). The high metabolic demands of the fetus result in a fetal temperature that is 0.5В°C above that of the mother. This difference in temperature is seen in the maternal immediate postpartum shivering, which reflects a compensatory response to the loss of fetal-derived heat.

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For the fetus to achieve maximal growth potential, the uterine placental fetal circulation must be normal in order for the fetus to receive a variety of necessary substrates. A key feature of the uterine vascular bed in pregnancy is the lack of responsiveness to changes in blood gas tensions (PO2, PCO2). Thus, oxygen therapy for either maternal disease or for fetal benefit will not cause vasoconstriction. In contrast, the lack of responsiveness and lack of autoregulation in the uterine vascular bed renders these vessels incapable of compensating for maternal hypotension. Animal studies have shown that the volume blood flows (mL per minute) in the uterine and umbilical circulations are unaffected by maternal hyperoxygenation. This is important clinically since the improvement in fetal PO2 by maternal oxygen therapy does not appear to have an adverse affect on fetal blood flow.

Glucose, oxygen, and amino acids are the major substrates needed for normal fetal growth. Glucose freely crosses the placenta by facilitated diffusion into the fetus. The maternal fetal glucose concentration gradient that exists widens with advancing gestational age in order to accommodate the increasing metabolic demands of the fetus. Under normal circumstances, glucose is metabolized by the fetus to produce energy in the form of adenosine triphosphate (ATP) in the presence of oxygen. Oxygen passes across the placenta to the fetus by simple diffusion and is regulated by concentration gradients and uterine blood flow, as described by the Fick principle. Transplacental transport of all essential and nonessential amino acids occurs by active transport. Animal and human studies have confirmed that amino acid carrier systems are present on both the maternal and fetal sides of the placenta. The placenta is quite active in amino acid metabolism, contributing significantly to net umbilical–fetus uptake of certain amino acids.

Abnormal Fetal Growth

Failure of the placenta to deliver any of these primary substrates to the fetus will result in diminished protein production by the fetus, reduced glucose metabolism, and reduced glycogen deposition in the liver. If oxygen supply is markedly reduced either from an acute or chronic insult, the fetus will convert from an aerobic to an anaerobic metabolic state in order to meet energy (ATP) requirements. Anaerobic metabolism is far less efficient at producing ATP from a given unit of glucose compared with aerobic metabolism. Furthermore, anaerobic activity will produce fixed acids (lactate, urate, etc.), which diffuse slowly across the placenta thus accumulating in the fetal system. If the anaerobic process is not

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reversed, the accumulation of acids will consume available buffers, and the fetal blood pH will fall, leading to an acidemic and acidotic fetus.

The IUGR fetus attempts to compensate for reduced substrate delivery by several mechanisms. From a metabolic standpoint, the fetus changes the maternal–fetal glucose gradient. The normally wide glucose gradient that exists between the mother and fetus, which is needed for movement of glucose to the fetus, widens further. This compensatory mechanism enhances glucose movement across the placenta to the fetus. The smaller AC noted in the IUGR fetus is a result of less hepatic glycogen formation in order to maximize glucose availability. In a similar fashion to the liver, fat stores, which are normally an important depot site for fat-soluble vitamins and fatty acids, are reduced. This change in body composition is reflected in the ponderal index, which neonatologists use as an index of scrawniness. The fetus also adjusts to reduced nutrient delivery by redistributing systemic blood flow to vital organs. The fetus will reduce flow to nonvital organs by reducing vascular resistance and increasing blood flow to the brain, which normally has a relatively high vascular resistance pattern compared with other organ systems. This can be demonstrated with pulsed-wave Doppler velocimetry of the middle cerebral artery (MCA), in which the flow velocity profile shows an increase in end-diastolic velocity. Other organs being spared through vascular redistribution include the heart and adrenal glands.

Intrauterine Growth Restriction Defined

A number of definitions of IUGR have been proposed based on percentile, standard deviation (SD), or growth rate. The most commonly used clinical definition of intrauterine growth restriction is an estimated fetal weight (EFW) less than the tenth percentile as determined by ultrasound. This mirrors the definition of small for gestational age, which originally was described by Battaglia and Lubchenco in 1967 as a birth weight less than the tenth percentile for gestational age. They noted that SGA infants were at increased risk for neonatal death. The problem with the tenth percentile as a cutoff for the diagnosis of IUGR is that a number of fetuses with an EFW below that value will be normally small, otherwise referred to as constitutionally small and not at risk. Studies have demonstrated that if determinants of birth weight such as maternal ethnicity, parity, maternal weight, and height are considered, up to 50% of fetuses at less than the tenth percentile will be constitutionally small. This has been the basis for using other definitions, including less than the third or fifth percentile or less than two SDs from the mean. Some authors have suggested using an abdominal circumference (AC) of less than two SDs for gestational age. The AC measurement represents a single objective

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ultrasound measurement rather than a combination of several fetal biometric ultrasound parameters into a formula where each parameter is weighted differently. This is the measure most closely related to pathologic growth restriction, as it reflects loss of hepatic glycogen stores and subcutaneous fat, which is correlated with fetal nutritional status.

While it seems that an EFW less than the tenth percentile is not a sufficiently strict definition of IUGR, there is also a significant problem associated with the use of more strict criteria. If a definition of less than the third percentile is used, there is a reasonable chance that one could miss some fetuses that do not meet their growth potential and could be at risk for adverse events. No receiver operator curves have been established to assess sensitivity and specificity in order to establish a cutoff for the diagnosis of IUGR. This has been quite difficult to do, in part because of a wide biologic variation between patients and because of a wide variation of parameters used to diagnose IUGR (EFW, AC <2 SD, etc.). Customized growth curves, such as those envisioned and created by Gardosi, which include variables that impact fetal size, may be the answer to establishing a better cutoff value for IUGR. These growth curves are calculated based on maternal ethnicity, parity, height and weight, and fetal gender. When these curves were used in a large retrospective cohort study and compared with the standard population-based growth curve that is based on gestational age alone, a further 4.1% of infants were identified who were SGA. These babies had perinatal outcomes comparable to infants who were SGA by population-based standards, with three- to eightfold increases in perinatal morbidity and mortality above AGA neonates. This study also identified a population of babies who were SGA by population-based standards but not by customized curves and whose perinatal outcomes were similar to AGA babies, with no increased risks based on their size. Software is available (Gestation-related Optimal Weight (GROW) at http://www.gestation.net) in which one may enter specific maternal and fetal variables to generate such a customized growth curve.

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Etiology of Intrauterine Growth Restriction

TABLE 1 Some Causes of Intrauterine Growth Restriction

Placental insufficiency Unexplained elevated maternal alpha- fetoprotein level Idiopathic Preeclampsia

Chronic maternal disease Cardiovascular disease Diabetes Hypertension

Abnormal placentation Abruptio placentae Placenta previa Infarction Circumvallate placenta Placenta accretia Hemangioma

Genetic disorders Family history Trisomy 13, 18 and 21 Triploidy Turner's syndrome (some cases)

Malformations Immunologic

Antiphospholipid syndrome Infections

Cytomegalovirus Rubella Herpes Toxoplasmosis

Metabolic Phenylketonuria Poor maternal nutrition

Substance abuse (smoking, alcohol, drugs) Multiple gestation Low socioeconomic status

The type and timing of insult during fetal development will dictate the subsequent development and morphology of the fetus. Fetal growth in the first trimester is characterized primarily by hyperplasia (growth in the number of cells),

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in the second trimester by a combination of hyperplasia and hypertrophy (growth in the size of existing cells), and in the third trimester primarily by hypertrophy. If an insult occurs in the first half of pregnancy where hyperplasia predominates, all fetal cell numbers can be reduced and lead to a small fetus that is symmetrically proportioned. That is, somatic and cerebral growth will both be similarly reduced. The underlying etiology of symmetric IUGR varies widely and includes karyotypic abnormalities, congenital anomalies, or congenital infections. Maternal medical illness, obstetric conditions, or primary placental pathology place the fetus at risk for uteroplacental insufficiency that may lead to a small fetus that is asymmetrically proportioned. Because there is significant overlap between these two types, body proportion alone cannot be used to determine the etiology. If an insult that typically causes uteroplacental insufficiency occurs sufficiently early in pregnancy, there can be an impact on hyperplasia of cells and a symmetric growth pattern. More commonly, there is an impact on hypertrophy that occurs late in pregnancy and primarily affects fat and hepatic glycogen deposition. The reduction in hepatic glycogen stores reduces liver size and results in an increase in the head circumference to abdominal circumference, which defines asymmetric growth. Asymmetric growth is also characterized by a redistribution of fetal cardiac output to vital organs including the brain, heart, and adrenal glands. The redistribution of blood flow to the head allows the fetal head and brain to be preserved and to maintain a normal growth velocity compared with parameters of somatic growth (abdomen and extremities). This is the basis for the common phrase, “brain sparing.” Thus, the relative proportions of fetal dimensions can provide some insight to the etiology of IUGR based on the symmetric or asymmetric nature of the ultrasound parameters.

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The most widely used definition of IUGR is a fetus whose estimated weight is below the 10th percentile for its gestational age and whose abdominal circumference is below the 2.5th percentile. At term, the cutoff birth weight for IUGR is 2,500 g. Growth percentiles for fetal weight versus gestational age are shown in Figure 1. Approximately 70 percent of fetuses with a birth weight below the 10th percentile for gestational age are constitutionally small8; in the remaining 30 percent, the cause of IUGR is pathologic.

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FIGURE 1 Fetal weight percentiles throughout gestation.

Importance of Accurate Dating

Accurate dating in early pregnancy is essential for making the diagnosis of IUGR. The usual qualifier for reliable dating and establishment of an accurate gestational age is a certain date for the last menstrual period in a woman with regular cycles or assessment of gestational age by an ultrasound examination performed no later than the 20th gestational week, when the margin of error is seven to 10 days. Early ultrasound examination, ideally at eight to 13 weeks of gestation, is more accurate for estimating gestational age than ultrasound assessment later in pregnancy. Although ultrasound assessment is used later in pregnancy to estimate fetal weight, ultrasound dating is only accurate to about three weeks when it is performed at term. An error that is commonly made is to change a patient's due date on the basis of a third-trimester ultrasonogram. Doing so can result in failure to recognize IUGR.

Symmetric and Asymmetric IUGR

IUGR is usually classified as symmetric and asymmetric. Symmetric growth restriction implies a fetus whose entire body is proportionally small. Asymmetric growth restriction implies a fetus who is undernourished and is directing most of its energy to maintaining growth of vital organs, such as the brain and heart, at the expense of the liver, muscle and fat. This type of growth restriction is usually the result of placental insufficiency.

A fetus with asymmetric IUGR has a normal head dimension but a small abdominal circumference (due to decreased liver size), scrawny limbs (because of decreased muscle mass) and thinned skin (because of decreased fat). If the insult causing asymmetric growth restriction is sustained long enough or is severe enough, the fetus may lose the ability to compensate and will become symmetrically growth-restricted. Arrested head growth is of great concern to the developmental potential of the fetus.1

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Diagnosis

The size of the uterus should be assessed at each prenatal visit. Techniques such as serial measurements of the uterine fundus are helpful in documenting continued growth if the measurements are performed by the same person. A tape measure should be used to measure the distance from the top of the pubic symphysis to the dome of the uterine fundus. This measurement, in centimeters, is normally within three weeks of the gestational age between 20 and 38 weeks of gestation. A fundal height that lags by more than 3 cm or is increasing in disparity with the gestational age may signal IUGR. A lag of 4 cm or more certainly suggests growth restriction.1 In addition, IUGR should be suspected if the maternal weight is inadequate or is decreasing.

Increased surveillance should be undertaken in patients who previously had an infant with growth restriction. A history of a previous small-for-gestational-age infant has been reported to be among the most predictive factors for subsequent IUGR. These women have up to a two- to fourfold increased risk of another similarly affected fetus.9,10

Ultrasound Biometry

Ultrasound biometry of the fetus is now the gold standard for assessing fetal growth (Figure 2). The measurements most commonly used are the biparietal diameter, head circumference, abdominal circumference and femur length. Percentiles have been established for each of these parameters, and fetal weight can be calculated. The most sensitive indicator of symmetric and asymmetric IUGR is the abdominal circumference, which has a sensitivity of over 95 percent if the measurement is below the 2.5th percentile.11,12 Accurate dating of the pregnancy is essential in the use of any parameter. In the absence of reliable dating, serial scans at two- or three-week intervals must be performed to identify IUGR. It should always be remembered that each parameter measured has an error potential of about one week up to 20 gestational weeks, about two weeks from 20 to 36 weeks of gestation, and about three weeks thereafter.

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Figure 2. (Top) Ultrasonographic measurement of fetal biparietal diameter (designated by X- - - - - -X) and head circumference. (Center) Ultrasonographic measurement of fetal abdominal circumference. (Bottom) Ultrasonographic measurement of fetal femur length (designated by X- - - - - -X).

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useful is the ratio of the head circumference to the abdominal circumference (HC/AC). Between 20 and 36 weeks of gestation, the HC/AC ratio normally drops almost linearly from 1.2 to 1.0. The ratio is normal in the fetus with symmetric growth restriction and elevated in the infant with asymmetric growth restriction.

Another important use of ultrasound is estimating the amount of amniotic fluid. A decreased volume of amniotic fluid is closely associated with IUGR. Significant morbidity has been found to exist in pregnancies with an amniotic fluid index value of less than 5 cm.13 The amniotic fluid index is obtained by summing the largest cord-free vertical pocket in each of the four quadrants of an equally divided uterus. Percentiles for the amniotic fluid index at each gestational age are shown in Figure 3.14 The combination of oligohydramnios and IUGR portends a

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less favorable outcome, and early delivery should be considered.15,16 Generally, if the pregnancy is at 36 weeks or more, the high risk of intrauterine loss may mandate delivery.

Figure 3. Percentiles for amniotic fluid index based on gestational age.

Management

A patient presents with mild preeclampsia, and her infant demonstrates asymmetric growth restriction. A nonstress test is performed, which reveals normal reactivity. The physician tells the patient to begin bed rest. A 24-hour urine sample for protein demonstrates a level of 0.45 g (slightly elevated). Platelet count and liver function tests reveal normal values. Antenatal steroids are prescribed to promote fetal lung maturity. Daily blood pressure measurements, fetal movement profiles and biweekly nonstress tests remain normal for the next two weeks. At 34 weeks of pregnancy, the patient develops signs and symptoms of severe preeclampsia, and the decision is made to induce labor. The patient delivers a male infant weighing 1,680 g (3 lb, 11 oz), who does well in the intermediate care nursery.

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The management of IUGR must be individualized for each patient. In addition to managing any maternal illness, a detailed sonogram should be performed to search for fetal anomalies, and karyotyping should be considered to rule out aneuploidy.16 Symmetric restriction may be due to a fetal chromosomal disorder or infection. This possibility should be discussed with the patient, who may decide to undergo a diagnostic procedure such as amniocentesis. It should be remembered, however, that many infants with evidence of growth restriction are constitutionally small. Serial ultrasound examinations are important to determine the severity and progression of IUGR.

A controversy involves the timing of delivery to prevent intrauterine demise because of chronic oxygen deprivation. Preterm delivery is indicated if the growth-restricted fetus demonstrates abnormal fetal function tests, and it is often advisable in the absence of demonstrable fetal growth. The risks of prematurity must be weighed against the complications unique to IUGR.4

General management measures include treatment of maternal disease, cessation of substance abuse, good nutrition and institution of bed rest. Although not of proven benefit, bed rest may maximize uterine blood flow. In any case, antenatal testing should be instituted. Options include the nonstress test, the biophysical profile and an oxytocin (Pitocin) challenge test. The biophysical profile involves assessment of fetal well-being with a combination of the nonstress test and four ultrasonographic parameters (amniotic fluid volume, respiratory movements, body movements and muscle tone). The use of Doppler flow velocimetry, usually of the umbilical artery, identifies the growth-restricted fetus at greatest risk for neonatal morbidity and mortality. In controlled trials, Doppler analysis has been associated with improved outcome,1 although it is considered experimental by the American College of Obstetricians and Gynecologists. Each of these tests has a relatively high false-positive rate (i.e., 50 percent) in the low-risk patient.17

Given the high false-positive rate of nonstress tests, the significance of a nonreactive nonstress test should be further evaluated before any management decision is made. A nonreassuring nonstress test followed by assessment of the biophysical profile has been shown to lead to lower rates of intervention when compared with the oxytocin contraction test, with no impact on perinatal outcome.18

Combination testing is thought to more accurately predict the status of the fetus.17 For this reason, close antenatal surveillance is encouraged, with a well-

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timed delivery. A proposed management approach for IUGR is shown in Figure 4. This approach is based on outstanding advances in neonatal care and improved outcome for the low-birth-weight infant.

Figure 4. Proposed management approach in a pregnancy demonstrating fetal growth restriction. Opinions differ on the optimal strategy for management of fetal growth restriction; this algorithm represents one possible approach. (NST=nonstress test; BPP=biophysical profile)

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Labor and Delivery

Because of the increased risk of intrapartum asphyxia, the fetus should be monitored carefully and continuously during labor.19,20 Delivery should be in a hospital capable of dealing with the various neonatal morbidities associated with growth restriction, including asphyxia, meconium aspiration, sepsis, hypoglycemia and malformations. Preterm induction of labor is often required. Amnioinfusion may be of benefit in the presence of a nonreassuring fetal response during labor and a low amniotic fluid index or oligohydramnios. In the face of deteriorating fetal status, a cesarean section should be performed.

In subsequent pregnancies, the use of low-dose aspirin may be of benefit in reducing the incidence of IUGR in selected high-risk women. While the results of a recent meta-analysis showed that early aspirin treatment reduced the risk of IUGR, routine use of aspirin in pregnancy is not advocated.21

Outcome

Most infants who had growth restriction in utero have normal rates of growth in infancy and childhood, although studies have demonstrated that at least one third of them never achieve normal height.22 Many of these infants also are born prematurely, with its similar, albeit independent, morbidities. The lower the birth weight and the earlier the gestational age, the less the child's chance of catching up. Neurologic development is also related to the degree of growth restriction and prematurity.23 Decreased intrauterine growth may possibly have a negative effect on brain growth and mental developmental potential.24 At baseline, children with a history of IUGR have been found to demonstrate attention and performance deficits.25 Minimizing hypoxic episodes during labor and delivery, as well as optimizing neonatal care for these infants, will likely produce the healthiest outcome.

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REFERENCES

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2. Wolfe HM, Gross TL. Increased risk to the growth retarded fetus. In: Gross TL, Sokol RJ, eds. Intrauterine growth retardation: a practical approach. Chicago: Year Book Medical Publishers, 1989:111-24.

3. Neerhof MG. Causes of intrauterine growth restriction. Clin Perinatol 1995;22:375-85.

4. Creasy RK, Resnik R. Intrauterine growth restriction. In: Creasy RK, Resnik R, eds. Maternal-fetal medicine: principles and practice. 3d ed. Philadelphia: Saunders, 1994:558-74.

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6. Manning FA, Hohler C. Intrauterine growth retardation: diagnosis, prognostication, and management based on ultrasound methods. In: Fleischer AC, et al., eds. The principles and practice of ultrasonography in obstetrics and gynecology. 4th ed. Norwalk, Conn.: Appleton & Lange, 1991:331-48.

7. Craigo SD. The role of ultrasound in the diagnosis and management of intrauterine growth retardation. Semin Perinatol 1994;18:292-304.

8. Ott WJ. The diagnosis of altered fetal growth. Obstet Gynecol Clin North Am 1988;15:237-63.

9. Tejani NA. Recurrence of intrauterine growth retardation. Obstet Gynecol 1982;59:329-31.

10.Wolfe HM, Gross TL, Sokol RJ. Recurrent small for gestational age birth: perinatal risks and outcomes. Am J Obstet Gynecol 1987;157:288-93.

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11.Hadlock FP, Deter RL, Harrist RB, Roecker E, Park SK. A date-independent predictor of intrauterine growth retardation: femur length/abdominal circumference ratio. AJR Am J Roentgenol 1983;141:979-84.

12.Brown HL, Miller JM Jr, Gabert HA, Kissling G. Ultrasonic recognition of the small-for-gestational-age fetus. Obstet Gynecol 1987;69:631-5.

13.Rutherford SE, Phelan JP, Smith CV, Jacobs N. The four-quadrant assessment of amniotic fluid volume: an adjunct to antepartum fetal heart rate testing. Obstet Gynecol 1987;70(3 Pt 1):353-6.

14.Moore TR, Cayle JE. The amniotic fluid index in normal human pregnancy. Am J Obstet Gynecol 1990;162:1168-73.

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