Intrauterine Growth Restriction (IUGR)Fetal Growth and Developmenta. Determination of Gestational AgeSeveral terms are used to define the duration of pregnancy, and thus the the fetal age, but these are somewhat confusing. They are shown schematically in figure 1. Gestational age or menstrual age is the time elapsed since the first day of the menstrual period, a time that actually precede conception. This starting time, which is usually about two weeks before ovulation and fertilization and nearly 3 weeks before implantation of the blastocyst, has traditionally been used because most women know their last period. Embryologists describe embryo-fetal development in ovulation age. Or the time in days or weeks from ovulation. Another term is preconceptional age, nearly identical to ovulation age.Clinician customarily calculate gestational age as menstrual age as menstrual age. About 280 days, or 40 weeks, elapse on average between the first day of last menstrual period of the birth of the fetus. This corresponds to 9 and 1/3 calendar months a quick estimate of the due date of a pregnancy based on menstrual data can be made ad follows: add 7 days to the first day of the last period and substract 3 months. For example, if the first day of the last menses was July 5, the due date is 07-05 minus 3 (months) plus 7 (days) = 04-12, or April of the following year. This calculaton has been termed Naegeles rule. Many women undergo first- or early second trimester sonographic examination to confirm gestational age. In these cases, the sonographic estimate is usually a fw days later than that determined by the last period. To rectify this inconsistency and to reduce the number of pregnancies diagnosed as postterm-some have suggested assuming that average pregnancy is actually 283 days long and that 10 days be added to the last menses instead of 7 (Olsen and Clausen, 1998).The period of gestation can also be divided into three units of three calendar months (13 weeks) each. These three trimesters have become important obstetrical milestones.

Normal Fetal GrowthHuman fetal growth is characterized by sequential patterns of tissue and organ, differentiation, and maturation. Development is determined by maternal provision of substrate, placental transfer of these substrates, and fetal-growth potential governed by genome. Steer (1998) has summarized the potential effects of evolutionary pressure on human growth. In humans, there is an increasing conflict between the need to walk---requiring a narrow pelvis---and the need to think---requiring a large brain. Humans may resolving this dilemma by acquiring the ability to restrict growth late in pregnancy. Thus, the ability growth restrict may be adaptive rather than pathological. Lin and Santolaya-Forgas (1998) have divided cell growth into three consecutive phases. The initial phase of hyperplasia occurs in the first 16 weeks and is characterized by rapid increase in cell number. The second phase, which extends up to 32 weeks, includes both cellular hyperplasia and hypertrophy, and it is during this phase that most fetal fat and glycogen deposition take place. The corresponding fetal-growth rates during these three phases are 5 g/day at 15 weeks, 15 to 20 g/day at 24 weeks, and 30 to 35 g/day at 34 weeks (Williams and co0workers, 1982). As shown in figure, there is considerable biological variation in the velocity of fetal growth. Although many factors have been implicated, the precise cellular and molecular mechanisms by which normal fetal growth occurs are not well understood. In early fetal life, the major determinant is the fetal genome, but later in pregnancy, environmental, nutritional, and hormonal influences become increasingly important (Holmes and colleagues, 1998). For example, there is considerable evidence that insulin and insulin-like growth factor-I (IGF-I) and II (IGF-II) have a role in the regulation of fetal growth and weight gain (Chiesa and associates, 2008; Forbes and Westwood, 2008). These growth factors are produced by virtually all fetal organs beginning early in development. They are potent stimulators of cell division and differentiation. Since the discovery of the obesity gene and its protein product, leptin, there has been interest in maternal and fetal serum leptin levels. Fetal concentrations increase during the first two trimesters, and they correlate with birthweight (Catov, 2007;Sivan, 1998; Tamura 1998; and all their colleagues). This relationship however, is controversial in growth- restricted foetuses (Kyriakakou, 2008; Mise, 2007; Mise, 2007; Savvidou, 2006, and all their associates). Angiogenic factors have alse been studied. For example, higher levels of sFlt-1 at 10 to 14 weeks are associated with small-for gestational age infants (Smith and co-workers, 2007).

Figure () Increments in fetal weight gain in grams per day from 24 to weeks gestation. The black line represents the mean and the outer blue lines depict 2 standard deviations. (Data courtesy of Dr. Don McIntire). Fetal growth is also dependent on an adequate supply of nutrients. Glucose transfer has been extensively studied during pregnancy. Both excessive and diminished maternal glucose availability affect fetal growth. Excessive glycemia produces macrosomia, whereas diminished glucose levels have been associated with fetal-growth restriction. The Hyperglycemia and Adverse Pregnancy Outcomes (HAPO) Study Cooperative Research Group (2008) found that elevated cord c-peptide levels, which reflect fetal hyperinsulinemia, have been associated with increased birthweight even in women with maternal glucose levels below the threshold for diabetes. There is less information concerning the physiology of maternal-fetal transfer of other nutrients such as amino acids and lipids. Ronzoni and colleagues (1999) studied maternal-fetal concentrations of amino acids in 26 normal pregnancies. These investigators reported that an increase in maternal amino acid levels led to an increase in fetal levels. In growth-restricted oetuses, amino acid disturbance similar to the biochemical changes seen in postnatal protein-starvation states has also been detected (Economides and colleagues, 1989b). In a study of 38 growth-restricted infants, Jones and colleagues (1999) found impaired used of circulating triglycerides consistent with peripheral adipose depletion.

Fetal-Growth RestrictionLow-birthweight infants who are small-for-gestational age are often designated as having fetal-growth restriction. The term fetal-growth retardation has been discarded because retardation implies abnormal mental function, which is not intent. It is estimated that 3 to 10 percent if infants are growth restricted.DefinitionIn 1963, Lubchenco and co-workers published detailed comparisons of gestational ages with birthweights in an effort to derive norms for expected fetal size at a given gestational week. Battaglia and Lubchenco (1967) then classified small for-gestational-age (SGA) infants as those whose weights were below the 10 percentile for their gestational age. Such infants were shown to be at increased risk for neonatal death. For example, the neonatal mortality rate SGA infants born at 38 weeks was 1 percents compared with 0.2 percent in those with appropriate birthweights.Many infants with birthweight less than 10th percentile, however, are not pathologically growth restricted but are small simply because of normal biological factors. Indeed, Manning and Hohler (1991) and Gardosi and colleagues (1992) concluded that 25 to 60 percent of SGA infants were in fact appropriately grown when maternal ethnic group, parity, weight and height were considered.Because of these disparities, other classifications have been developed. Seed (1984) suggested a definition based on birth-weight below the 5th percentile. Usher and McLean (1969) suggested that fetal-growth standards should be based on men weight-for-age with normal limits defined by 2 standard deviations. This definition would limit SGA infants to 3 percent of birth instead of 10 percent. As demonstrated from their analysis of 122,754 pregnancies, McIntire and colleagues (1999) showed this definition to be clinically meaningful. Also, as shown figure ( ), most adverse outcomes are in infants below the 3rd percentile. Lastly, individual fetal-growth potential has been proposed in place of a population-based cutoff. In this model, a fetus who deviates from its individual optimal size at given gestational age is considered either overgrown or growth restricted (Bukowski and associates, 2008)

Figure () Relationship between birthweight percentile and perinatal mortality and morbidity rates 1560 small-for-gestational age foetuses. A progressive increase in both mortality and morbidity rates is observed as birthweight percentile falls. (Data from Manning, 1995)

Diagnosis and management of intrauterinegrowth restrictionUrsula F. Harkness, MD, MPH*, Giancarlo Mari, MDDivision of Maternal Fetal Medicine, Department of Obstetrics and Gynecology,University of Cincinnati, 231 Albert Sabin Way, PO Box 670526, Cincinnati, OH 45267-0526, USA

Normal growth on a cellular level is not homogeneous but rather follows a pattern that shifts over time from rapid cellular duplication to rapid cellular enlargement [1]. Early growth is characterized by an increase in cell number, and this period has proportional increases in weight, protein, and DNA (phase of hyperplasia). This phase is followed by one in which cell division slows and existing cells enlarge (phase of hyperplasia and hypertrophy). During this time, the increase in DNA is slower than the increase in protein and weight. During the final phase, cell division decreases, and all further growth is due to enlargement of cells (phase of hypertrophy). DNA does not continue to increase, although net protein and weight do. The effects of stimuli that restrict growth may depend in part on when in the sequence of cellular events they occur.Fetal growth is determined by the mother, the fetus, and the placenta. Any factor that affects one of these three environments can result in intrauterine growth restriction (IUGR).

Dating the pregnancyAccurate dating is the most important step in the prenatal management ofthe IUGR fetus. Using the last menstrual period (LMP) to determine gestationalage is often unreliable. In one study, menstrual history could only be obtainedfrom 89.8% of the women enrolled, and 44.7% of these were unreliable becauseof an unsure actual date of LMP, irregular menstrual cycles, recent oralcontraceptive use, or first-trimester bleeding [2]. Ultrasound performed before18 weeks gestation was as good or better for prediction of estimated date ofconfinement than even an optimal menstrual historydepending on thegestational age at which the scan was performed [2].In the first trimester, the crown-rump length (CRL) is used to estimategestational age. This measurement is highly accurate [3,4]. A longitudinal viewof the fetus is found, and the calipers are placed at the outer edge of the cephalic pole and fetal rump with care not to include the yolk sac or fetal limbs. Thepregnancy should be dated by ultrasonography if there is a greater than 7-daydiscrepancy between LMP and CRL [5].In the second trimester, fetal biometry can be used to date a pregnancyaccurately. Chervenak et al [6] studied 152 singletons conceived through in vitrofertilization. These authors used stepwise multiple linear regression to determinethe best equation for gestational age assessment using head circumference (HC),biparietal diameter (BPD), femur length (FL), and abdominal circumference (AC)alone or in combination. The most accurate single parameter was HC, which gavea random error of 3.77 days. Adding AC and FL to HC slightly improved prediction (random error 3.35 days). Based on this study, biometry should beused to date the pregnancy if the discrepancy between LMP and ultrasound dating is greater than 7 days in the absence of congenital anomalies and severe growth delay. The accuracy of a single ultrasonographic measurement for the detection of gestational age decreases as gestational ages increases. The normal distribution of measurements becomes wider as gestational age increases [7]. Serial ultrasound should be performed at 3-week intervals when dating is to be determined using third-trimester sonography. Although precise sonographic assessment of gestational age in the third trimester is not feasible in all cases based on fetal biometry alone, other sonographic markers are currently used to estimate the gestational age. The ossification centers of various long bones are most commonly used in practice. These centers become increasingly echo-dense and larger with advancing gestational age. Although their presence does not give an exact gestational age assessment, it can reassure the clinician that the pregnancy is relatively late into the third trimester. The distal femoral epiphysis is noted at the distal end of the femur in the plane of measurement of this bone. The distal femoral epiphysis is never seen before 28 weeks, and it is observed in 72% of fetuses at 33 weeks, 94% of fetuses at 34 weeks, and 100% of fetuses at 36 weeks[8]. The proximal tibial epiphysis is seen adjacent to the head of the tibia at its proximal end, in the plane of measurement of this bone. The proximal tibial epiphysis is never seen before 34 weeks, and it is found in 35% of fetuses at 35 weeks, 79% of fetuses at 37 weeks, and 100% of fetuses at 39 weeks [8]. Finally, if the proximal humeral epiphysis is greater than or equal to 1 mm, there is at least a probability of 0.69 that the pregnancy is at 40 to 42 weeks [9].

Estimating fetal weightMany different formulae have been used to calculate gestational age. Two thatare commonly used are the Shepard and Hadlock formulae. The Hadlock formula uses head circumference, abdominal circumference, and femur length to estimate fetal weight [10]. The estimate of random error for this method is plus or minus 15% (2 standard deviations). The Shepard formula is based on BPD and AC [11]. The fetal weight estimate, once obtained, is compared with reference ranges. A value between the 10th and 90th percentiles is usually considered normal. These cut-offs are used in an attempt to identify fetuses at risk. Genetic and environmental factors may influence growth, however, and thus different populationshave different growth curves.DefinitionsThe terms small for gestational age (SGA) and IUGR are often used interchangeably,although this is misleading. The growth-restricted fetus is a fetus thatfails to reach its growth potential and is at risk for adverse perinatal morbidity andmortality. The American College of Obstetricians and Gynecologists (ACOG)defines an IUGR fetus as a fetus with an estimated weight below the 10thpercentile [12]. Not all fetuses measuring less than the 10th percentile are at riskfor adverse perinatal outcome; many are just constitutionally small. IUGR refersto the fetus who is SGA and displays other signs of chronic hypoxia ormalnutrition [5]. SGA is defined here as a fetus who measures less than the 10thpercentile for gestational age, whether it be because he is growth-restricted(IUGR) or just constitutionally small. The authors will first discuss the fetus withan estimated weight below the 10th percentile, then suggest ways to differentiatethe small fetus from the at-risk IUGR fetus and to manage the pregnancycomplicated by IUGR.Traditionally, symmetric IUGR has been distinguished from asymmetricIUGR [13]. The former is described as having an early onset. The insult affectsgrowth of skeletal, head, and abdominal measurements, because it occurs at atime when fetal growth is affected primarily by cell division. Asymmetric IUGR,by contrast, has its onset later in gestation, when fetal growth occurs secondary toincreases in cell size. Skeletal and head measurements are spared, but abdominalcircumference is small because of decreased liver size and subcutaneous fat.More recently, the need to distinguish these entities has been questioned, becauseit is unclear whether they can be associated with distinct causes or neonataloutcomes [12]. One study demonstrated, however, that although the etiologies ofU.F. Harkness, G. Mari / Clin Perinatol 31 (2004) 743764 745symmetrically and asymmetrically small fetuses overlap, the latter are at anincreased risk for neonatal and intrapartum complications [14].Consequences of being small for gestational ageShort termEstimated fetal weight below the 10th percentile is a leading risk factor forfetal death [15]. As birth weight decreases from the 10th percentile to the firstpercentile, perinatal morbidity and mortality increase markedly [16]. In term infants, the rates of low 5-minute Apgars, severe acidemia, need for intubation in the delivery room, seizures in the first 24 hours of life, sepsis, and neonatal deathincrease significantly among infants at or below the third percentile for gestational age [17]. In preterm infants, by contrast, there is no specific birth-weight threshold below which neonatal morbidity and mortality are increased; rather,respiratory distress (RDS) and neonatal death increase along a continuum withdecreasing birth weight percentile. In a retrospective review of more than1.4 million deliveries, the risk of RDS, intraventricular hemorrhage (IVH), and necrotizing enterocolitis (NEC) was found to increase significantly in IUGR fetuses as compared with normally grown fetuses beginning at 34 to 35 weeksgestation [18]. (Because the IUGR group was found using an International Classification of Diseases, Ninth Revision [ICD-9] code search of a largestate database, it is difficult to assess whether only IUGR or both IUGR and SGA babies were included.The findings of the aforementioned study contrast with older studies that reported that small neonates had a decreased incidence of RDS [19,20] and IVH [20,21] when compared with appropriate-for-gestational-age preterm neonates, suggesting that in small fetuses there is an adaptive reaction to intrauterine stress. Another study using the Vermont Oxford Network database described a significantincrease in neonatal death, RDS, and NEC among babies whose birth weight was less than the 10th percentile and who weighed between 500 and 1500 g, as compared with appropriate-for-gestational-age (AGA) babies [22]. These authors suggest that the inconsistency between their findings and those of earlier studies may be due to the extent to which confounding variables are addressed and taken into account.Long termThe problems of the small fetus do not end at birth or soon after birth but continue well into childhood and adulthood. Studies have shown that small children have an increased rate of impaired school performance. One study described significantly higher numbers of children with late entry into secondary school and failure to pass or take the baccalaureate examination in the small group as compared with the AGA group, after controlling for maternal age, maternal educational level, parental socioeconomic status, family size, and gender[23]. Another large follow-up study of 14,189 full-term infants from the United Kingdom showed that at 5, 10, and 16 years of age, individuals born with a birth weight less than the fifth percentile had small but significant deficits in academic achievement [24]. At 26 years of age, this same cohort of once SGA babies showed lower levels of professional achievement, despite adjustment for potential confounders. Other studies have described an association between fetuses with weight or height less than the 10th percentile and the development of hypertension, hypercholesterolemia, impaired glucose tolerance, and diabetes in later life [2527]. In the United Kingdom, a follow-up study on 5654 men showed that those with the lowest weight at birth and at 1 year of age had the highest death rate from ischemic heart disease [28]. The bfetal originsQ hypothesis asserts that changes in the intrauterine nutritional or endocrine environment result in permanent alterations in structure, physiology, and metabolism that predispose the affected individual to develop cardiovascular, metabolic, and endocrine disease years later [26]. An endocrine-metabolic reprogramming occurs that enables the small fetus to adapt to its adverse intrauterine environment; after birth, nutrient abundance may lead to a metabolic syndrome and to the development of the above-noted cardiovascular risk factors [25]. This theory is the so-called Barkers hypothesis. Screening for the small fetusFundal height assessmentSeveral studies have estimated that 41% to 86% of SGA babies could bedetected with routine use of symphysis-fundal height measurements [2932].Some of these studies used standard value curves, with the small fundal heightdefined as that below the 10th percentile of standard values for gestational age.The most common method in practice, however, uses the concept that, between20 and 34 weeks, the fundal height in centimeters equals the gestational age inweeks [33]. A measurement in centimeters is taken from the upper edge of thesymphysis pubis to the top of the uterine fundus. A measurement of 3 to 4 cmbelow the expected number suggests inappropriate growth.Ultrasonographic measurementsAccording to one meta-analysis of ultrasonographic measurements, AC andestimated fetal weight (EFW) were the best predictors of fetal weight below the10th percentile [34]. In high-risk populations, the sensitivity using AC of lessthan the 10th percentile was 73% to 95%, whereas using EFW the sensitivity was43% to 89%; in low-risk populations, the corresponding sensitivities were 48% toU.F. Harkness, G. Mari / Clin Perinatol 31 (2004) 743764 74764% for AC and 31% to 73% for EFW. In another study, AC measurements wereshown to predict small fetuses better than BPD, HC, or a combination ofparameters [35]. The sensitivity of a single AC measurement after 25 weeks forthe detection of fetuses with birth weight below the 10th percentile was 48%. Inthe same study, a normal AC was found to exclude fetal growth restriction with afalse-negative rate of about 10%. Another study showed that a single ACmeasurement for the detection of babies with birth weight less than the 10thpercentile was only slightly better than serial fundal height measurements(sensitivity 83% versus 76%); the difference was not statistically significant [36].Thus there is no clear evidence that routine ultrasound is a better screeningmethod for SGA than fundal height measurement in the general population.

Diagnosis of intrauterine growth restriction

The data already reported refer to fetuses with an estimated weight below the 10th percentile. When a fetus has an estimated weight below the 10th percentile in the absence of congenital anomalies and in the presence of a normal amount of amniotic fluid, Doppler velocimetry gives the most important information to differentiate the truly growth-restricted fetus (IUGR) from the fetus that is constitutionally small but otherwise normal.

Umbilical artery

Normal pregnancy is characterized by a low-resistance feto-placental system with continuous forward flow throughout the cardiac cycle. Although several indices to estimate vessel resistance as evaluated by Doppler ultrasonography have been described, the most popular and the simplest of these is the systolic/diastolic (S/D) ratio. This index is a ratio of the maximum systolic flow velocity divided by the minimal end-diastolic flow velocity. Normal reference ranges throughout pregnancy are reported in Fig. 1 [37]. In pregnancies complicated by IUGR, there is a chronological process characterized by increased umbilical artery resistance (increased S/D ratio), absent end-diastolic flow, and finally reverse end-diastolic flow (Fig. 2). Various hypotheses have been proposed to explain the pathophysiology of IUGR and abnormal umbilical artery Doppler velocimetry [38]: (1) reduced placental-stem artery number, (2) primary villus maldevelopment with small, hypovascular, and fibrotic terminal villi, and (3) placental-stem vessel vasoconstriction. Small fetuses with abnormal umbilical artery waveforms are admitted more frequently to the neonatal intensive care unit and stay longer compared with those small fetuses who have normal Doppler velocimetry in the umbilical artery [39,40]. Studies have shown that the perinatal mortality rate in pregnancies complicated by growth restriction or hypertension is higher in fetuses with reversed end diastolic flow (33% to 73%) or absent end-diastolic flow (9% to 41%) in the umbilical artery [4143]. Finally, fetuses with absent and reverse end-diastolic flow in the umbilical artery are at increased risk for impaired mental development, severe motor deficits, and neurodevelopmental delay [44,45]. Eleven randomized studies involving close to 7000 women were included in a meta-analysis that compared the use of Doppler ultrasound of the umbilical artery to no Doppler in high-risk pregnancies, many of which were complicated by IUGR. A trend in reduction of perinatal deaths was seen (odds ratio [OR] 0.71, 95% confidence interval [CI] 0.50 to 1.01), as well as significantly fewer inductions of labor and hospital admissions without untoward effects [46]. These data prompted ACOG to endorse the use of Doppler in high-risk pregnancies. One area of debate and research is whether Doppler can help in timing the delivery of an IUGR fetus. The question arises: In a fetus with an abnormal umbilical artery waveform, is it better to deliver soon after making the diagnosis or to prolong the pregnancy? Each of these managements carries a riskpossible intrauterine hypoxia with continuation of the pregnancy; complications of pre-maturity with early delivery. The Growth Restriction Intervention Trial was a randomized trial that addressed this question in 547 pregnancies between 24 and 36 weeks with singleton or multiple gestations, in circumstances where the provider was uncertain whether to deliver [47]. The median time to delivery was 0.9 days in the deliver-now group (within 48 hours, to allow a steroid course to be given) and 4.9 days in the expectant-management group. Total deaths before discharge were 29 (10%) in the deliver-now group and 27 (9%) in the expectantmanagement group (OR 1.1, 95% CI 0.61 to 1.8). Based on this study, no difference exists between combined antenatal and neonatal mortality rates associated with immediate delivery and rates associated with expectant management until the clinician is no longer uncertain that intervention is necessary. Information on the developmental quotient of the survivors of this study at 2 years of age will be available in the near future. Many authors have suggested that small fetuses with normal umbilical artery flow represent a group not at risk for adverse perinatal outcome. Most of these babies are constitutionally small [4850]. Recently, Baschat and Weiner [51] reported on 308 women with ultrasonographic EFW less than the 10th percentile or AC less than the 2.5th percentile for gestational age. Babies with abnormal umbilical artery Doppler had increased rates of fetal distress associated with chronic hypoxemia, RDS, and admission to a neonatal intensive care unit. The authors suggested that antenatal surveillance may not be necessary in SGA babies if the umbilical artery S/D ratio and amniotic fluid are normal. One study of 167 women with small fetuses with normal umbilical artery Dopplers randomly allocated participants to surveillance that occurred twice weekly or every other week [52]. Although the two groups showed no differences in neonatal morbidity, the more frequently tested group had a higher induction rate. Unfortunately, this study did not have the power to detect clinically important differences in neonatal outcome. These babies could not be assumed to be simply small and healthy, because 32% were admitted to the neonatal special care unit (range of stay 0 to 66 days, mean 4 to 5 days), 20% had hypoglycemia, and 40% had a low ponderal index at birth, despite the fact that the mean gestational age at delivery was 38 weeks. However, 10% of the babies in this study had an abnormal cerebral artery/umbilical artery resistance ratio, a finding that suggests that some of them were growth-restricted babies with blood flow redistribution. Evidence shows that umbilical artery Doppler can be used to distinguish between the high-risk small fetus that is truly growth-restricted and the lower-risk small fetus. A prospective randomized trial is needed to examine the question of whether antenatal surveillance is necessary when fetal growth is less than the 10th percentile, but the umbilical artery S/D and AFI are normal.

Middle cerebral arteryThe fetal response to chronic hypoxia is redistribution of blood flow to the tissues that are most needed, such as the brain, myocardium, and adrenal glands. This phenomenon has been called the bbrain-sparing effect.Q In this scenario, oligohydramnios is thought to occur because of decreased renal perfusion. Mari and Deter [53] described a parabolic pattern of middle cerebral artery (MCA) pulsatility index ([peak systolic velocity ! lowest diastolic velocity]/mean velocity) in normal singletons across gestational age, with higher values from 25 to 30 weeks (Table 1). These authors showed that SGA babies with abnormal pulsatility indices were at a higher risk for perinatal death and neonatal ICU stay of greater than 12 hours [53]. Fig. 3 demonstrates a normal MCA waveform and one that suggests bbrain sparing. The IUGR fetus displays an increased placental resistance, evidenced by an increased S/D ratio of the umbilical artery that is associated with a decreased cerebral vascular resistance quantified by a decreased pulsatility index (PI) of the MCA. Therefore, the cerebral-placental ratio may be a better index to assess the small fetus than the umbilical artery or cerebral vessels [54,55]. The cerebral placental ratio generally refers to the ratio between the MCA PI and the umbilical artery PI. This index, however, has alternatively been defined as the ratio of S/Dor resistance index in the MCA and umbilical artery. In small fetuses, cerebralplacental ratio is a good predictor for longer neonatal ICU stays, low Apgar scores, cord gas pH, cesarean for fetal distress, and other perinatal complications [5659]. The cerebral-placental ratio is a more sensitive predictor than either MCA or umbilical artery velocimetry alone [5659]. Usually the cut-off cerebralplacentalratio below which the fetus is considered to have brain sparing is 1.0 to 1.1 [56,58]. The cerebral-placental ratio does not correlate significantly with perinatal morbidity after 34 weeks [59]. Although an abnormal cerebral Doppler is frequently seen in fetuses with abnormal umbilical artery velocimetry, MCA redistribution may be seen in fetuses with normal umbilical artery waveforms. One study reported an increased rate of emergency cesarean section in small babies with normal umbilical artery velocimetry when the MCA waveform was abnormal [60]. When the uterine artery waveform was also abnormal, the rate of emergency cesarean was reported to be as high as 86%, versus 4% when MCA and uterine artery velocimetry were both normal. The rate of severe morbidity (grades II to IV intraventricular hemorrhage) was significantly increased in the pregnancies delivered by emergency cesarean section. Although abnormal umbilical artery velocimetry is a better predictor of adverse perinatal outcome in the small fetus, MCA PI has a better sensitivity (91.7%) and negative predictive value (98.6%) for major adverse outcome, especially before 32 weeks (when the sensitivity is 95.5% and the negative predictive value is 97.7%) [61]. The cerebral-placental ratio should be used in small fetuses with normal umbilical artery waveforms. When there is absent or reversed flow of theumbilical artery, this index is not needed.

Issues in management of intrauterine growth restriction

Ductus venosusThe ductus venosus (DV) originates from the umbilical vein before it turnsto the right to join the portal vein [62,63]. Blood from the DV then entersthe inferior vena cava. The DV waveform includes two peaks. The first peak(S wave) reflects filling of the right atrium during ventricular systole. The secondpeak (D wave) reflects the passive filling of the ventricles during early diastole.The lowest point of the waveform (A wave) corresponds to atrial contraction(atrial kick) in late diastole [5,62]. In the normal fetus, flow in the DV is forwardmovingtoward the heart during the entire cardiac cycle. When circulatorycompensation of the fetus fails, the DV waveform may become abnormal,showing absent or reversed blood flow (Fig. 4) during atrial contraction. In thesecases, pulsations in the umbilical vein may be seen. These changes may be due toincreasing right ventricular afterload and right-sided heart failure due tomyocardial hypoxia [62].The perinatal mortality in the presence of absent or reversed flow of the DVranges from 63% to 100% [6466]. It appears that the fetus should be deliveredbefore the development of absent or reversed flow of the DV. Therefore, theinclusion of venous Doppler in antepartum surveillance for IUGR fetuses may bebeneficial, although a prospective randomized trial has not yet been done toconfirm this hypothesis [67]. In one study including 224 fetuses with IUGR whounderwent umbilical artery (UA), DV, and umbilical vein assessment, absent orreversed UA waveform was shown to have the highest sensitivity and negativeFig. 4. Ductus venosus velocimetry in a fetus with (A) a normal waveform and (B) reversed bloodflow during atrial contraction (arrow).754 U.F. Harkness, G. Mari / Clin Perinatol 31 (2004) 743764predictive value for acidemia, asphyxia, stillbirth, and neonatal and perinataldeath [67]. Absent or reversed atrial systolic blood-flow velocity in the DV andpulsatile flow in the umbilical vein, however, had the best specificity and positivepredictive values for prediction of the above outcomes. The authors suggestedthat important intrauterine time can be gained for preterm fetuses who haveabsent or reversed UA end-diastolic velocities but normal venous flows.Results of a prospective multicenter longitudinal observational study alsosuggested that Doppler velocimetry of the DV may be useful in timing thedelivery of the IUGR fetus [68]. Of 70 singleton IUGR fetuses delivered between26 and 33 weeks gestation, DV PI was significantly higher, UA PI was significantlyhigher, and short-term heart-rate variation (STV) was significantlylower in the last 24 hours before delivery in babies with adverse outcomes. Pooroutcomes included perinatal death, cerebral hemorrhage of grade II or greater,and bronchopulmonary dysplasia. Two to 7 days before delivery, only DV PI wassignificantly higher. With logistic regression analysis, only DV waveform andgestational agenot UA PI or STVwere predictive of adverse outcomes. Only32% (6/19) of the infants with DV PI of 3 standard deviations or greater and 18%(2/11) of the infants with absent or reversed DV A-wave flow in the 24 hoursbefore delivery had normal outcomes.Although the results of these studies are promising for timing the delivery ofthe IUGR fetus based on DV, data from randomized trials are not yet available tosupport or refute its use. Currently, a multicenter prospective randomized trial isbeing planned in Europe.Other vesselsMany other vessels have been assessed by Doppler ultrasound in the AGA andIUGR fetus [6977]. Those studies have improved our understanding of fetalphysiology and the pathophysiology of the IUGR fetus. However, they do notadd much beyond the information given from assessment of the UA, MCA,and DV.Temporal sequence of Doppler changesRecent longitudinal studies have described a Doppler temporal sequence inthe IUGR fetus before fetal distress. Hecher et al [78] reported findings from aprospective observational multicenter study on 93 singleton pregnancies after24 weeks complicated by IUGR. Amniotic fluid index and UA PI were the firstto become abnormal. These were followed by abnormalities of MCAvelocimetry,aorta Doppler studies, STV of the fetal heart rate, DV waveforms, and inferiorvena cava Doppler studies. This trend appeared both before and after 32 weeks.In the group delivered after 32 weeks, however, the probability of having anygiven abnormality in Doppler velocimetry was lower, and the changes in actualDoppler values and STV were less pronounced.U.F. Harkness, G. Mari / Clin Perinatol 31 (2004) 743764 755Baschat et al [79] longitudinally studied 44 IUGR fetuses with elevatedumbilical artery PI who had a final biophysical profile of less than 6/10 beforedelivery. In 42 fetuses (95.5%), one or more vascular parameters changed. UAand DV indices markedly increased at a median of 4 days before the biophysicalscore deteriorated. Fetal breathing movements declined beginning 2 to 3 daysbefore delivery; the following day, amniotic fluid volume dropped. Loss of fetalmovement and tone occurred on the day of delivery. In 70.5% of these fetuses,Doppler deterioration was complete 24 hours before the biophysical profilechanged. Three patterns of Doppler deterioration were described in this study.The majority of fetuses (72.7%) displayed a sequence of worsening of the UAPI, development of brain sparing, then venous changes. Another group of fetusesshowed venous changes before brain sparing. Finally, some fetuses demonstratedchanges in the DV without ever showing Doppler changes consistent withbrain sparing.Ferrazzi et al [80] evaluated 26 IUGR fetuses with abnormal uterine and UADoppler velocimetry. A temporal sequence of abnormal Doppler changes wasdescribed. Early changes, assumed to reflect increased placental vascular resistanceand hypoxia, included absent end-diastolic flow in the UA and an abnormalMCA PI. Half the fetuses showed these changes 15 to 16 days before delivery.Late changes, thought to indicate circulatory collapse, were reverse flow in theUA and abnormal DV, aortic, and pulmonary outflow tract velocimetry. Half thefetuses were affected by these late changes 4 to 5 days before delivery. These lateDoppler changes correlated significantly with perinatal death.Significantly, not all fetuses appear to follow the same pattern of circulatorydeterioration [79]. In addition, near-term fetuses may not show the sameprogression of circulatory changes [79]. These differences need to be consideredwhen using Doppler velocimetry in the antenatal surveillance of the IUGR fetus.Nonstress testThe heart rate of the fetus that is not affected by acidosis or neurologic depressionwill accelerate in response to fetal movement. This reaction is the basisof the nonstress test (NST). Although abnormal fetal heart-rate patterns arerelated to impaired fetal oxygenation and subsequent neurologic outcome, theseare late changes. Ideally, the fetus should be delivered before evidence ofhypoxemia is noted on fetal heart-rate monitoring to avoid subsequent handicap[81]. However, the NST remains the most common test used in evaluation ofpregnancies complicated by an IUGR fetus.Biophysical profileThe biophysical profile (BPP) is based on the fact that the fetal central nervoussystem initiates and regulates biophysical activity. Neuronal centers deprived ofoxygen have decreased or absent output, which results in alterations in fetalmovement, tone, and breathing. Systemic hypoxia is assumed to be absent as756 U.F. Harkness, G. Mari / Clin Perinatol 31 (2004) 743764long as brain activity is normal, because the brain is one of the most oxygendependenttissues [82].The BPP is a widely used antepartum testing modality. A significant decreasein perinatal mortality is seen in high-risk pregnancies managed with BPP asopposed to those managed with untested historical controls. The perinatal mortalityin one study was 1.86 per 1000 in those tested, compared with 7.69 per1000 in those not tested, for a decrease of 76% [83]. In a large retrospective studyof 26,290 high-risk fetuses who received BPP testing and 58,659 fetuses whodid not receive BPP testing, there was a very significant inverse exponentialrelationship between BPP before delivery and incidence of cerebral palsy [84].The incidence of cerebral palsy when the last BPP score before delivery wasnormal (10/10, 8/10, or 8/8) was 0.7 per 1000, whereas with a score of 0/10 theincidence of cerebral palsy was 333 per 1000. In the same study, these samehigh-risk fetuses were compared with mixed low-risk and high-risk patients notfollowed by BPP; the rate of cerebral palsy was 4.74 per 1000 in the untestedpopulation and 1.33 per 1000 in the tested group, a significant difference.Although the mean birth weight is noted to be smaller in the tested population,the actual number of SGA or IUGR fetuses in this study is unknown.The authors of a review assessing the effects of BPP on perinatal outcomeconclude that there is currently inconclusive evidence from randomizedcontrolled trials to support or argue against the use of BPP as a test of fetalwell-being in high-risk pregnancies, including those with IUGR [85]. Surprisingly,however, the number of patients enrolled in randomized trials using thismethod of antepartum testing is small (2839).CorticosteroidsOne important consideration regarding the use of the BPP in the managementof high-risk pregnancies is the effect of corticosteroids on fetal behavior and thuson the score itself. In a study of 35 women at risk for preterm delivery withoutIUGR and between 28 and 34 weeks, BPPs and Doppler velocimetry of the UAand MCA were performed daily before a first dose of betamethasone and for120 hours afterward [86]. Though none of the BPPs were less than or equal to 6 atbaseline, at 24, 48, and 72 hours poststeroids, 13.3%, 76.7%, and 16.7% wereless than or equal to 6, respectively (P b 0.05). The change in BPP was due todecreased fetal movement, decreased fetal breathing, and more frequentnonreassuring heart-rate tracing. The alteration in BPP in these healthy fetuseswas transient. Doppler indices were not affected by corticosteroid administration.Another prospective study showed findings of decreased fetal breathing anddecreased fetal limb and trunk movements 48 hours from a first dose of betamethasone,with return to baseline at 96 hours; again, Doppler velocimetry ofthe MCA and UA remained unchanged [87]. These effects should be consideredin managing women with IUGR after steroids have been administered.The efficacy of antenatal corticosteroids for the preterm fetus with IUGR hasnot been well studied. One study showed no significant difference in short-termU.F. Harkness, G. Mari / Clin Perinatol 31 (2004) 743764 757morbidity between infants with growth restriction delivered between 26 and31 weeks who received corticosteroids and those who did not, but it did demonstratea significantly higher survival without disability or handicap in the steroidgroup [88]. Another study reported no difference between growth-restrictedfetuses of less than 1750 g given steroids and AGA infants for several neonataloutcomes, including RDS and intraventricular hemorrhage/periventricular leukomalacia[89].However, a very recent study demonstrated that of 19 fetuses with absent orreversed end-diastolic flow (ARED) in the UA, 10 developed transient forwardend-diastolic flow after betamethasone injection, whereas nine fetuses showedpersistent ARED [90]. Although some babies respond to steroids with vasodilationof the fetoplacental circulation and decreased vascular resistance, otherbabies respond with an increase in vascular resistance that may lead to fetaldeterioration. The persistent ARED group had more frequent acute fetal deterioration.The two patients with a fetal demise and the two patients with severeacidosis were in the persistent ARED group. The authors suggest performingDoppler studies the day after steroid administration in IUGR fetuses with ARED.If no forward end-diastolic flow is seen, the fetal venous circulation should beexamined, and delivery should be considered if abnormalities exist. The responseof IUGR fetuses to corticosteroid administration should be studied further.Prediction of intrauterine growth restrictionUterine arteryIUGR and pre-eclampsia have been associated with abnormal velocimetry ofthe uterine arteries. The uterine artery is typically measured using color Dopplerwhere it crosses over the external iliac artery. In the normal pregnancy, the normalwaveform shows high flow throughout diastole. An abnormal waveform ischaracterized by high resistance and an early diastolic notch (Fig. 5). This findingis thought to be related to a failure of trophoblastic invasion of spiral arteries andthe resultant low-resistance circulation.One large study in 5121 unscreened women found that, at the 95th percentilefor mean PI at 23 weeks in the studied population (1.45), the likelihood ratio forsevere adverse outcomes was 5 for nonsmokers and 10 for smokers [91]. Severeoutcome was defined as pre-eclampsia associated with delivery before 34 weeks,birth weight less than the 10th percentile associated with delivery before34 weeks, fetal death, or placental abruption.A multicenter study of 7851 women with singleton pregnancies in anunselected population showed that the sensitivity of transvaginally obtaineduterine Doppler velocimetry with a PI of greater than 1.63 (95th percentile) at23 weeks is 93.3% for predicting pre-eclampsia and fetal growth restriction(FGR) and 56.3% for predicting FGR without pre-eclampsia when deliveryoccurred before 32 weeks [92]. The negative predictive values were 100% and758 U.F. Harkness, G. Mari / Clin Perinatol 31 (2004) 74376499.9%, respectively. When all deliveries were included, the sensitivity decreasedto 69% for prediction of pre-eclampsia and FGR and 13.2% for FGR without preeclampsia.When the screening test was PI greater than 1.63 or the presenceof bilateral notches, the sensitivity for pre-eclampsia and FGR increased to 100%and for FGR without pre-eclampsia to 68.8% in patients delivered before32 weeks, although the screen-positive rate increased from 5.1% to 11.9%.At this time, we are unable to alter the pathophysiology of the progressivedisease process that is first evidenced by abnormal uterine artery Dopplervelocimetry at 23 weeks. These fetuses may, however, benefit from closerantepartum surveillance.SummaryThe first step in the management of the IUGR fetus is diagnosis. Fundal heightis the best screening tool, and ultrasound biometry is the best method fordetecting the small fetus. Doppler velocimetry is the most important meansof diagnosing the IUGR fetus who is at risk for adverse perinatal morbidityand mortality.It is difficult to determine the best time to deliver the IUGR fetus: one mustbalance the risks of prematurity with the risks of further intrauterine decompensation.For the very preterm fetus, there may be some benefit to delayingdelivery until after venous evidence of circulatory decompensation is present,but before the BPP becomes very abnormal. Two complicating factors in themanagement of IUGR are its varied causes and the fact that not all IUGR fetusesdemonstrate the same patterns of decompensation. We need studies that compareFig. 5. Demonstration of (A) normal uterine artery waveform and (B) uterine artery notching (arrow).U.F. Harkness, G. Mari / Clin Perinatol 31 (2004) 743764 759NST, BPP, and Doppler surveillance to one another and to management strategiesthat combine them. 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Ultrasound Obstet Gynecol 2003;21:419 22.[39] Berkowitz GS, Mehalek KE, Chitkara U, Rosenberg J, Cogswell C, Berkowitz RL. Dopplervelocimetry in the prediction of adverse outcome in pregnancies at risk for intrauterinegrowth retardation. Obstet Gynecol 1988;71:7426.[40] Gaziano EP, Knox E, Ferrera B, Brandt DG, Calvin SE, Knox GE. Is it time to reassess therisk for the growth retarded fetus with normal velocimetry of the umbilical artery? Am J ObstetGynecol 1994;170:1734 41.[41] Brar H, Platt LD. Reverse end-diastolic flow velocity on umbilical artery velocimetry in highrisk pregnancies: an ominous finding with adverse pregnancy outcome. Am J Obstet Gynecol1988;159:559 61.U.F. Harkness, G. Mari / Clin Perinatol 31 (2004) 743764 761[42] Karsdorp VHM, van Vugt JMG, van Geijn HP, Kostense PJ, Arduini D, Montenegro N, et al.Clinical significance of absent or reversed end diastolic velocity waveforms in umbilical artery.Lancet 1994;344:1664 8.[43] Zelop CM, Richardson DK, Heffner LJ. 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Br J Obstet Gynaecol 2003;110:27 32.[48] Nienhuis SJ, Vles JSH, Gerver WJM, Hoogland HJ. Doppler ultrasonography in suspectedintrauterine growth retardation: a randomized clinical trial. Ultrasound Obstet Gynecol 1997;9:6 13.[49] Burke G, Stuart B, Crowley P, Scanaill SN, Drumm J. Is intrauterine growth retardationwith normal umbilical artery blood flow a benign condition? BMJ 1990;300:1044 5.[50] Ott WJ. Intrauterine growth restriction and Doppler ultrasonography. J Ultrasound Med2000;19:6615.[51] Baschat AA, Weiner CP. Umbilical artery Doppler screening for detection of the small fetusin need of antepartum surveillance. Am J Obstet Gynecol 2000;182:1548.[52] McCowan LME, Harding JE, Roberts AB, Barker SE, Ford C, Stewart AW. A pilot randomizedcontrolled trial of two regimens of fetal surveillance for small-for-gestational-age fetuses withnormal results of umbilical artery Doppler velocimetry. Am J Obstet Gynecol 2000;182:81 6.[53] Mari G, Deter RL. 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Characteristics of fetal venous blood flow under normal circumstancesand during fetal disease. Ultrasound Obstet Gynecol 1996;7:6883.[63] Kiserud T, Eik-Nes SH. Doppler velocimetry of the ductus venosus. In: Maulik D, editor.Doppler ultrasound in obstetrics and gynecology. New York7 Springer-Verlag; 1997. p. 40322.[64] Goncalves LF, Romero R, Silva M, Ghezzi F, Soto A, Munoz H, et al. Reverse flow in theductus venosus: an ominous sign. Am J Obstet Gynecol 1995;172:266.[65] Ozcan T, Sbracia M, dAncona RL, Copel JA, Mari G. Arterial and venous Doppler velocimetryin the severely growth-restricted fetus and associations with adverse perinatal outcome.Ultrasound Obstet Gynecol 1998;12:39 44.[66] Hecher K, Campbell S, Doyle P, Harrington K, Nicolaides K. Assessment of fetal compromiseby Doppler ultrasound investigation of the fetal circulation. Circulation 1995;91:129 38.[67] Baschat AA, Gembruch U, Weiner CP, Harman CR. Qualitative venous Doppler waveformanalysis improves prediction of critical perinatal outcomes in premature growth-restrictedfetuses. Ultrasound Obstet Gynecol 2003;22:240 5.[68] Bilardo CM, Wolf H, Stigter RH, Ville Y, Baez E, Visser GHA, et al. Relationship betweenmonitoring parameters and perinatal outcome in severe, early intrauterine growth restriction.Ultrasound Obstet Gynecol 2004;23:119 25.[69] Mari G. Arterial blood flow velocity waveforms of the pelvis and lower extremities in normaland growth-retarded fetuses. Am J Obstet Gynecol 1991;165:14351.[70] Abuhamad AZ, Mari G, Bogdan D, Evans III AT. Doppler flow velocimetry of the splenic arteryin the human fetus: is it a marker of chronic hypoxia? Am J Obstet Gynecol 1995;172:820 5.[71] Mari G, Abuhamad AZ, Uerpairojkit B, Martinez E, Copel JA. Blood flow velocity waveformsof the abdominal arteries in appropriate- and small-for-gestational-age fetuses. UltrasoundObstet Gynecol 1995;6:158.[72] Mari G, Deter RL, Uerpairojkit B. 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Early establishment of gestational age, attention to maternal weight gain, and careful measurement of uterine fundal growth throughout pregnancy will identify many cases of abnormal fetal growth in low-risk women. Risk factors, including a previous growth-restricted fetus, increase the possibility of recurrence. Specifically, the rate of recurrence is believed to be nearly 20 percent (Berghella, 2007). In women with risk factors, consideration should be given to serial sonographic evaluation. Although frequency of examinations varies depending on indications, an initial early dating examination followed by a second examination at 32 to 34 weeks, or when otherwise clinically indicated, will identify many cases of growth restriction. Even so, definitive diagnosis frequently cannot be made until delivery. Identification of the inappropriately growing fetus remains a challenge. There are, however, both simple clinical techniques and more complex technologies that may prove useful.Uterine Fundal HeightCarefully performed serial fundal height measurements are a simple, safe, inexpensive, and reasonably accurate screening method to detect SGA fetuses (Gardosi and Francis, 1999). As a screening tool, its principal drawback is imprecision (Jelks and colleagues, 2007). For example, Jensen and Larsen (1991) and Walraven and co-workers (1995) found that this method helped to correctly identify only 40 percent of such infants. Thus, SGA fetuses were both overlooked and overdiagnosed. Despite this,these results do not diminish the importance of carefully performed fundal measurements as a simple screening technique.Technique. The method used by most for fundal height measurement was described by Jimenez and colleagues (1983). Briefly, a tape calibrated in centimeters is applied over the abdominal curvature from the upper edge of the symphysis to the upper edge of the uterine fundus, which is identified by palpation or percussion. The tape is applied with the markings apposed to the maternal abdomen and away from the examiners view to avoid bias. Between 18 and 30 weeks, the uterine fundal height in centimeters coincides within 2 weeks of gestational age. Thus, if the measurement is more than 2 to 3 cm from the expected height, inappropriate fetal growth may be suspected.Sonographic MeasurementsCentral to the debate over whether all pregnancies should routinely undergo sonographic evaluation is the potential for diagnosisof growth restriction (Ewigman and colleagues, 1993). Typically, such routine screening incorporates an initial sonographic examination at 16 to 20 weeks to establish gestational age and identify anomalies. This is repeated at 32 to 34 weeks to evaluate fetal growth (see Chap. 16, p. 352). Ironically, Gardosi and Geirsson (1998) found that accurate gestational dating at the initial examination resulted in a lower diagnosis rate of fetalgrowth restriction. In a study of 8313 pregnancies, Verburg and co-workers (2008) found that sonography prior to 24 weeksoptimally at 10 to 12 weeksprovides a better prediction of gestational age than the last menstrual period. With sonography, the most common method for establishing the diagnosis of fetal-growth restriction is the estimation of fetal weight using multiple fetal biometric measurements. Combining head, abdomen, and femur dimensions has been shown to optimize accuracy with little incremental improvement by addition of other biometric measurements (Platz and Newman, 2008). These are considered separately:1. Femur length (FL) measurement is technically the easiest and the most reproducible2. Biparietal diameter (BPD) and head circumference (HC) measurements are dependent on the plane of section and may also be affected by deformative pressures on the skull3. Abdominal circumference (AC) measurement is more variable, but it is most commonly abnormal in cases of fetal growth restriction because mostly soft tissue is involved Figure ( ).An abdominal circumference within the normal range for gestational age reliably excludes growth restriction, whereas a measurement less than the 5th percentile is highly suggestive of growth restriction (American College of Obstetricians and Gynecologists, 2000b). And as shown in Figure 38-6, such small circumferences are linked to decreased fetal pO2 and pH.Despite its accuracy, sonography used for detection of fetal growth restriction has false-negative findings. Dashe and colleagues (2000) studied 8400 live births at Parkland Hospital in which fetal sonographic evaluation had been performed within 4 weeks of delivery. They reported that 30 percent of growth restricted fetuses were not detected. In a study of 1000 high-risk fetuses, Larsen and associates (1992) performed serial sonographic examinations beginning at 28 weeks and then every 3 weeks. Reporting results to clinicians significantly increased the diagnosis of SGA fetuses. And although elective deliveries in this group were increased, there was no overall improvement in neonatal outcome.

Amnionic Fluid Measurement. An association between pathological fetal-growth restriction and oligohydramnios has long been recognized (see Chap. 21, p. 495). Chauhan and coworkers (2007) found oligohydramnios in less than 10 percent of pregnancies suspected of growth restriction, but this group of women was two times more likely to undergo cesarean delivery for nonreassuring fetal heart rate patterns. As shown in Figure38-7, the smaller the pocket of amnionic fluid, the greater the perinatal mortality rate. One likely explanation for oligohydramniosis diminished fetal urine production caused by hypoxia and diminished renal blood flow (Nicolaides and associates, 1990).Doppler VelocimetryAbnormal umbilical artery Doppler velocimetrycharacterized by absent or reversed end-diastolic flowhas been uniquely associated with fetal-growth restriction The use of Doppler velocimetry in the management of fetal growth restriction has been recommended as a possible adjunct to techniques such as nonstress testing or biophysical profile (American College of Obstetricians and Gynecologists, 2000b). Abnormalities in Doppler flow characterize early versus severe fetal-growth restriction and represent the transition from fetal adaptation to failure. Early changes in placenta-based growth restriction are detected in peripheral vessels such as the umbilical and middle cerebral arteries. Late changes are characterized by abnormal flow in the ductus venosus and aortic and pulmonary outflow tracts, as well as by reversal of umbilical artery flow (Pardi and Cetin, 2006). An example of this is shown in Figure ( )In a series of 604 neonates < 33 weeks who had an abdominal circumference < 5th percentile, Baschat and colleagues (2007) found that the ductus venosus Doppler parameters were the primary cardiovascular factor in predicting neonatal outcome. These late changes are felt to reflect myocardial deterioration and acidemia, which are major contributors to adverse perinatal and neurological outcome. In their longitudinal evaluation of 46 growth-restricted fetuses, Figueras and colleagues (2009) determined that Doppler flow abnormalities at the aortic isthmus preceded those in the ductus venosus by one week. Similarly, Towers and co-workers (2008) prospectively observed 104 fetuses with abdominal circumference 5th percentile. They broadly identified two patterns of progression of Doppler abnormalities: (1) mild placental dysfunction, which remained Gross perinatal mortality per 1000 live births confined to umbilical and middle cerebral arteries, and (2) progressive placental dysfunction, which progressed from peripheral vessels to the ductus venosus at variable intervals depending on gestational age. Both groups of investigators stressed that knowledge of these patterns of progression is critical for planning subsequent fetal surveillance and timing of delivery.

PreventionPrevention of fetal-growth restriction ideally begins preconceptionally with optimization of maternal medical conditions, medications, and nutrition. Smoking cessation is critical. Other risk factors should be tailored to the maternal condition, such as antimalarial prophylaxis for women living in endemic areas and correction of nutritional deficiencies. Studies have shown that treatment of mild to moderate hypertension does not reduce the incidence of SGA infants. During early pregnancy, accurate pregnancy dating is essential. In pregnancies at risk for fetal-growth restriction, for example, those in women with hypertension or prior fetal-growth restriction, prophylaxis with low-dose aspirin beginning early in gestation has been shown to reduce growth restriction by only 10 percent (Berghella, 2007). ManagementOnce fetal-growth restriction is suspected, efforts should be made to confirm the diagnosis, assess fetal condition, and evaluate for anomalies. Growth restriction near term is easier to manage but often missed. As aptly stated by Miller and associates (2008), although growth restriction before 34 weeks is readily recognized, it presents a management challenge. Cordocentesis allows rapid karyotyping for detection of a lethal aneuploidy, which may simplify management. The American College of Obstetricians and Gynecologists (2000b) has concluded that there are not enough data to warrant routine cord blood sampling in this situation. The timing of delivery is crucial, and the risks of fetal death versus the hazards of preterm delivery must be assessed as reported in the Growth Restriction Intervention Trial (GRIT) by Thornton and colleagues (2004). Growth Restriction Near Term Prompt delivery is likely best for the fetus at or near term who is considered growth restricted. In fact, most clinicians recommend delivery at 34 weeks or beyond if there is clinically significant oligohydramnios. With a reassuring fetal heart rate pattern, vaginal delivery may be attempted. Some of these foetuses do not tolerate labor, and cesarean delivery is necessary. Uncertainty about the diagnosis should preclude intervention until fetal lung maturity is assured. Expectant management can be guided using antepartum fetal surveillance techniques.Growth Restriction Remote from TermWhen growth restriction is identified in an anatomically normal fetus prior to 34 weeks, and amnionic fluid volume and fetal surveillance are normal, observation is recommended. Screening for toxoplasmosis, rubella, cytomegalovirus, herpes, and other infections is recommended by some, however, we have not found this to be productive. As long as fetal growth continues and fetal health remains normal, pregnancy is allowed to continue until fetal maturity is reached. In some cases, amniocentesis may be helpful to assess pulmonary maturity. Although the development of oligohydramnios is highly suggestive of fetal-growth failure, it is important to recognize that normal amnionic fluid volume does not preclude growth restriction. Owen and colleagues (2001) reported that 4- and 6-week evaluation intervals were superior to 2-week intervals for predicting growth restriction. Depending on the gestational age when fetal-growth restriction is first suspected, this interval may be impractical clinically, and sonography is usually repeated more frequently. With growth restriction remote from term, no specific treatment ameliorates the condition. For example, there is no evidence that bed rest results in accelerated growth or improved outcome. Despite this, many clinicians intuitively advise a program of modified rest. Nutrient supplementation, attempts at plasma volume expansion, oxygen therapy, antihypertensive drugs, heparin, and aspirin have all been shown to be ineffective (American College of Obstetricians and Gynecologists, 2000b).In most cases diagnosed prior to term, neither a precise etiology nor a specific therapy is apparent. Management decisions hinge on an assessment of the relative risks of fetal death with expectant management versus the risks from preterm delivery. Although reassuring fetal testing may allow observation with continued maturation, there is concern regarding long-term neurological outcome as discussed later (Blair and Stanley, 1992; Thornton and colleagues, 2004). Some authorities believe that various tests of fetal well-being are unnecessary to reduce risks for stillbirth. Weiner and associates (1996) performed nonstress tests, biophysical profiles, and umbilical artery velocimetry within 3 days of delivery in 135 fetuses confirmed at birth to have growth restriction. Other than metabolic acidosis at delivery, which was predicted by absent or reversed end-diastolic umbilical blood flow, morbidity and mortality were determined primarily by gestational age and birthweight and not by abnormal fetal testing. According to the American College of Obstetricians and Gynecologists (2000a), there is no convincing evidence that such testing schemes reducethe risk of long-term neurological deficits. And recently, Baschat and colleagues (2009) provided data that substantiated this opinion. Specifically, they showed that neurodevelopmental outcome at 2 years in growth-restricted fetuses was best predicted by birthweight and gestational age.A review of the status of Doppler velocimetry to aid in delivery timing was provided by Baschat (2004). It is clear that serial changes in Doppler flow represent a new and promising frontier in the management of pregnancies complicated by growth restriction. Nonetheless, the optimal management of the preterm growth-restricted fetus remains problematic. Labor and DeliveryFetal-growth restriction is commonly the result of placental insufficiency due to faulty maternal perfusion, ablation of functional placenta, or both. If present, these conditions are likely aggravated by labor. Equally important, diminished amnionic fluid volume increases the likelihood of cord compression during labor. For these reasons, a woman with a suspected growth-restricted fetus should undergo high-risk intrapartum monitoring. For these and other reasons, the incidence of cesarean delivery is increased. The risk of being born hypoxic or with aspirated meconium is increased. Care for the newborn should be provided immediately by an attendant who can skillfully clear the airway and ventilate the infant as needed. The severely growth-restricted newborn is particularly susceptible to hypothermia and may also develop other metabolic derangementsuch as hypoglycemia, polycythemia, and hyperviscosity. In addition, low-birthweight infants are at increased risk for motor and other neurological disabilities. Risk is highest at the lowest extremes of birthweight (Baschat and colleagues, 2007, 2009; Nelson and Grether, 1997). Long-Term SequelaeIn his book Fetal and Infant Origins of Adult Disease, Barker (1992) hypothesizes that adult mortality and morbidity are related to fetal and infant health. In the context of fetal-growth restriction, there are numerous reports of a relationship between suboptimal fetal nutrition and an increased risk of subsequent adult hypertension and atherosclerosis (Skilton, 2008). Low birthweight has also been implicated in subsequent development of type 2 diabetes, however, some challenge this hypothesis (Hubinette and colleagues, 2001; Huxley and co-workers, 2002). In their systematic review of 30 reports they considered relevant, Whincup and associates (2008) found that in most populations, birthweight was inversely related to type 2 diabetes risk. Smith and colleagues (2001) found that pregnancy complications resulting in low-birthweight infants were associated with increased risk of subsequent ischemic heart disease in the mother. This suggests that common genetic risk factors might explain the link between low birthweight and risk of heart disease in both the developing fetus and the mother. In addition to risk to long-term maternal health, epidemiological studies have found that delivery of a small-for-gestational age infant increases the risk for a subsequent pregnancy complicated by stillbirth (Salihu and associates, 2006; Surkan and co-workers, 2004).