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    4 u1.0-b978-1-4160-4224-2..50037-5..docpdf 4 u1.0-b978-1-4160-4224-2..50037-5..docpdf Document Transcript

    • Chapter 34Intrauterine Growth Restriction Robert Resnik, MD, and Robert K. Creasy, MDHuman pregnancy, similar to pregnancy in other polytocous animal tionally have been used in the United States define SGA as a birthspecies, can be affected by conditions that restrict the normal growth weight below the 10th percentile for gestational age. However, it hasof the fetus. The growth-restricted fetus is at higher risk for perinatal been shown4 that mortality for infants with birth weights between themorbidity and mortality, the risk rising with the severity of the restric- 10th and 15th percentile are still increased, with an odds ratio approach-tion. This chapter reviews the various causes of fetal growth restriction ing 2. Conversely, many newborns whose weights are below the 10thand considers the methods of antepartum recognition and diagnosis percentile are perfectly normal and simply constitutionally small. Analong with clinical management. The term intrauterine growth restric- alternative approach, which has sound physiologic and epidemiologiction (IUGR), which we first introduced in the third edition of this text, rationale, is that of using customized rather than population-based fetalis preferred over intrauterine growth retardation, which frequently growth curves.5 This concept uses optimal birth weight as the endconnotes mental retardation to the patient. point of a growth curve; it is based on the ability of a fetus to achieve its growth potential, determined prospectively and independently of maternal pathology. This approach uses the known variables affecting fetal weight, such as maternal height, weight, ethnicity, and parity at the beginning of pregnancy, to calculate fetal weight trajectories andDefinitions optimal fetal weight at delivery. A recent large Spanish study6 showed that customized birth weight percentiles more accurately reflect theAt the beginning of the 20th century all small newborns were thought potential for adverse outcome. Indeed, newborns considered to be ofto be premature, but by the middle of the century the concept of low birth weight by the general standards, but not by the customizedthe undernourished neonate arose, and newborns weighing less than percentiles, did very well. These findings were confirmed by studies2500 g were then classified by the World Health Organization as low- from New Zealand and France.7-9 Customized growth charts can bebirth-weight infants. In the 1960s, Lubchenco, Battaglia and colleagues, downloaded at Gestation Network (http://www.gestation.net [accessedin a series of classic papers, published detailed graphs of birth weight February 5, 2008]).as a function of gestational age and associated adverse outcomes.1,2 It The reliance on only gestational age and birth weight also neglectswas then suggested to classify low-birth-weight neonates into three the issue of body size and length and the clinical observations thatgroups2,3: there are two main clinical types of IUGR newborns: (1) the infant who is of normal length for gestational age but whose birth weight is1. Preterm neonates—newborns delivered before 37 completed weeks below normal (asymmetrically small), and (2) the neonate whose of gestation who are of appropriate size for gestational age (AGA) length and weight are both below normal (symmetrically small). Many2. Preterm and growth-restricted neonates—newborns delivered before SGA newborns are merely constitutionally smaller than others and 37 completed weeks of gestation who are small for gestational age are not at increased risk for either early or remote morbidity and (SGA) mortality.3. Term growth-restricted neonates—newborns delivered after 37 com- One method to evaluate this issue is the ponderal index,10,11 which pleted weeks of gestation who are SGA. (Not all SGA term neonates is calculated from the birth weight (in grams) and the crown-heel are growth restricted; some cases result from the normal distribu- length (in centimeters): tion of neonatal weight among a normal base population.) Ponderal index = (birth weight)/(crown-heel length)3 × 100 The classification of newborns by birth weight percentile is of prog-nostic significance in that those of lower percentiles are at increased Neonates with a ponderal index of less than the 10th percentile forrisk for immediate perinatal morbidity and mortality, as well as sub- gestational age are defined as growth restricted. In term infants, thissequent adult disease. index is not significantly affected by differences in race or sex. The There is continuing debate as to whether the 10th, 5th, or 3rd birth disadvantage of this index is the potential error introduced by cubingweight percentile should be used as a cutoff for designation of SGA. the crown-heel length. It is not clear whether asymmetric IUGR andThe lower the percentile, the higher the risk of poor outcome, but also symmetric IUGR are two distinct entities or are merely reflections ofthe greater the chance that a neonate with IUGR and poor outcome the severity of the growth restriction process (excluding chromosomalwill not be detected. The population-based growth curves that tradi- aberrations and infectious disease).
    • 636 CHAPTER 34 Intrauterine Growth Restriction There is currently no acceptable means, except perhaps by the pon- at 14 to 15 weeks of gestation to 10 g/day at 20 weeks, and to 30 toderal index, to classify a newborn whose weight is more than 2500 g 35 g/day at 32 to 34 weeks. The total substrate needs of the fetus areas having IUGR. The newborn who weighs 2800 g at birth may be thus relatively small in the first half of pregnancy, after which the rategrowth restricted if the mother has had three previous infants weighing of weight gain rises precipitously. The mean weight gain peaks atmore than 3700 g, but the classification systems would place such an approximately 230 to 285 g/wk at 32 to 34 weeks of gestation, afterinfant in the normal growth category.12 which it decreases, possibly even reaching zero weight gain, or even weight loss, at 41 to 42 weeks of gestation (Fig. 34-2).13,17 If growth rate is expressed as the percentage of increase in weight over the previous week, however, the percentage of increase reaches a maximum in theRate of Fetal Growth first trimester and decreases steadily thereafter.Different standards for fetal growth throughout gestation have beenreported. These standards set the normal range, on the basis of statisti-cal considerations, between 2 standard deviations of the mean (2.5th Incidence of Intrauterineto 97.5th percentile) or between the 10th and 90th percentiles for fixedgestational ages. The standards most widely used in the United States Growth Restrictionin the 1960s and 1970s were those developed in Denver, Colorado.1,2 The incidence of IUGR varies according to the population underThe Denver standards, however, do not reflect the increase in median examination, the geographic location, the standard growth curves usedbirth weight that has occurred over the last 4 decades or the birth as reference, and the percentile chosen to indicate abnormal growthweight standards for babies born at sea level. More contemporary (i.e., the 3rd, 5th, 10th, or 15th).standards are available from large geographic regions, such as the state Approximately one fourth to one third of all infants weighing lessof California, based on data from more than 2 million singleton births than 2500 g at birth have sustained IUGR, and approximately 4% tobetween 1970 and 1976.13 Brenner and colleagues14 used data on black 8% of all infants born in developed countries and 6% to 30% ofand white infants from Cleveland and aborted fetuses from North those born in developing countries have been classified as growthCarolina. Ott15 studied newborns from St. Louis. Arbuckle and associ- restricted.18ates16 based their study on more than 1 million singleton births andmore than 10,000 twin gestations in Canada between 1986 and 1988,and Alexander and colleagues17 used information from 3.8 millionbirths in the United States in 1991. A comparison of their 1991 U.S. TABLE 34-1 10TH PERCENTILE OF BIRTHnational data with that of previous reports (Fig. 34-1) reveals that most WEIGHT (g) FOR GESTATIONALof the latter underestimated fetal growth beginning at about 32 weeks. AGE BY GENDER: UNITEDFor example, the use of the Colorado1 or California13 databases would STATES, 1991, SINGLE LIVEhave resulted in only 2.8% and 7.1% of births, respectively, being clas-sified as below the 10th percentile compared with the 1991 data. The BIRTHS TO RESIDENT MOTHERSgender-specific 10th percentile values from 20 to 44 weeks are listed inTable 34-1. Data obtained from study of induced abortions and spontaneousdeliveries indicate that the rate of fetal growth increases from 5 g/day 4000 3500 Lubchenco 3000 Birth weight in grams Brenner Williams 2500 Ott 2000 U.S. Reference 1500 1000 500 0 20 22 24 26 28 30 32 34 36 38 40 42 44 Gestational age in complete weeksFIGURE 34-1 Fetal weight as a function of gestational age byselected references. (From Alexander GR, Himes JH, Kaufman RB,et al: A United States national reference for fetal growth. ObstetGynecol 87:167, 1996. Reprinted with permission from the American From Alexander GR, Himes JH, Kaufman RB, et al: A United StatesCollege of Obstetricians and Gynecologists.) national reference for fetal growth. Obstet Gynecol 87:167, 1996.
    • CHAPTER 34 Intrauterine Growth Restriction 637 300 250 200 Singletons Birth weight gain per week (g) 150 100 Multiples 50 0 50 100 150 200 24 28 32 36 40 44 48 Weeks of gestation completed FIGURE 34-3 Morbidity and mortality in 1560 small-for-FIGURE 34-2 Median growth rate curves for single and multiple gestational-age fetuses. (From Manning FA: Intrauterine growthbirths in California, 1970-1976. (From Williams RL, Creasy RK, retardation. In Manning FA: Fetal Medicine: Principles and Practice.Cunningham GC, et al: Fetal growth and perinatal viability in Norwalk, CT, Appleton & Lange, 1995, p. 312.)California. Obstet Gynecol 59:624, 1982. Reprinted with permissionfrom the American College of Obstetricians and Gynecologists.) the neonatal problems associated with preterm delivery.25 Specific morbidities are discussed later in this chapter and in Chapter 58. Long-term sequelae of IUGR , such as various adult diseases includ- ing chronic hypertension, heart and lung disease, and type 2 diabetes,Perinatal Mortality are discussed in greater detail in Chapter 59. Lower intelligence quo-and Morbidity tients, increased mental retardation, and cerebral palsy have also been reported.26-28IUGR is associated with an increase in fetal and neonatal mortalityand morbidity rates. Perinatal mortality rates for fetuses and neonatesweighing less than the 10th percentile, but between 1500 and 2500 g,were 5 to 30 times greater than those of newborns between the 10th Etiology of Intrauterineand 90th percentiles; for those weighing less than 1500 g, the rates were70 to 100 times greater.13 In addition, for birth weights below the 10th Growth Restrictionpercentile, the fetal and neonatal mortality rates rise as gestation IUGR encompasses many different maternal and fetal entities. Someadvances if birth weights do not increase. can be detected before birth, whereas others can be found only at As depicted in Figure 34-3, Manning showed that perinatal morbid- autopsy. It is important to discern the cause of IUGR, because in manyity and mortality increase if birth weights are below the 10th percentile, cases subsequent pregnancies may also be affected.and markedly so if below the 6th percentile.19 In general, fetal mortality rates for IUGR fetuses are 50% higherthan neonatal mortality rates, and male fetuses with IUGR have a Genetic Factorshigher mortality rate than female fetuses. The 10% to 30% increase in There has been much interest in determining the relative contributionsincidence of minor and major congenital anomalies associated with of factors that produce birth weight variation, namely the maternalIUGR accounts for 30% to 60% of the IUGR perinatal deaths (50% of and fetal genetic factors and the environment of the fetus. Approxi-stillbirths and 20% of neonatal deaths).20 Infants with symmetric mately 40% of total birth weight variation is due to the genetic con-IUGR are more likely to die in association with anomalous develop- tributions from mother and fetus (approximately half from each), andment or infection. If, however, in the absence of congenital abnormali- the other 60% is due to contributions from the fetal environment.29ties, chromosomal defects, and infection, neonates with symmetric Although both parents’ genes affect childhood growth and finalIUGR are probably not at increased risk of neonatal morbidity.21 The adult size, the maternal genes have the main influence on birth weight.incidence of mortality in the preterm newborn is higher if IUGR is The classic horse-pony cross-breeding experiments by Walton andalso present.22 The incidence of intrapartum fetal distress with IUGR Hammond demonstrated the important role of the mother.30 Foals ofapproximates 25% to 50%.23,24 the maternal horse and paternal pony are significantly larger than foals In addition, IUGR may contribute to perinatal morbidity and mor- of the maternal pony and paternal horse, and foals of each cross aretality by leading to both induced and spontaneous preterm births and comparable in size to foals of the pure maternal breed. These results
    • 638 CHAPTER 34 Intrauterine Growth Restrictionclearly demonstrated the widely held thesis of a maternally related and are approximately 1.5 cm shorter at birth. Mosaics of 45,X andconstraint on fetal growth. 46,XX cells are affected to a lesser degree. Although a paucity of reports Similar conclusions of maternal constraint to growth are reached prevents definite conclusions, it appears that the repressive effect onfrom family studies in humans. Low and high birth weights recur in fetal growth is increased with the addition of X chromosomes, each offamilies with seemingly otherwise normal pregnancies. Sisters of which results in a 200- to 300-g reduction in birth weight.43women with IUGR babies tend to have IUGR babies, a trend that is IUGR is associated with numerous other dysmorphic syndromes,not seen in their brothers’ babies.31 There is also a greater similarity in particularly those causing abnormal brain development (see Chaptersbirth weight between maternal half siblings and full siblings than 1 and 17).between paternal half siblings and full siblings. Mothers of IUGR The overall contribution that chromosomal and other genetic dis-infants were frequently growth restricted at birth themselves.32,33 orders make to human IUGR is estimated to be 5% to 20%. Approxi-Although the maternal phenotypic expression—particularly maternal mately 25% of fetuses with early-onset fetal growth restriction couldheight—may affect fetal growth, the evidence for such an influence is have chromosomal abnormalities, and karyotyping via cordocentesisnot convincing. Social deprivation has also been associated with IUGR, can be considered (see Chapter 17). A genetic basis should be consid-a finding not explained by known physiologic or pathologic factors.34 ered strongly if IUGR is encountered in association with neurologic The one definite paternal influence on fetal growth and size at birth impairment or early polyhydramnios.is the contribution of a Y chromosome rather than an X chromosome.The male fetus grows more quickly than the female fetus and weighsapproximately 150 to 200 g more than the female at birth.35 There is Congenital Anomaliesalso a suggestion that paternal size at birth can influence fetal growth, In a study of more than 13,000 anomalous infants, 22% had IUGR.44with birth weights potentially increased by 100 to 175 g.36 Also, the Newborns with cardiac malformations are frequently of low birthgreater the antigenic dissimilarity between the parents, the larger the weight and length for gestation, with the possible exception of thosefetus. with tetralogy of Fallot and transposition of the great vessels. The Whether it is genetically determined or not, women who were SGA subnormal size of many infants with cardiac anomalies (as low as 50%at birth have double the risk of reduced intrauterine growth in their to 80% of normal weight with septal defects) is associated with a sub-fetuses.37 In similar fashion, fetuses destined to deliver preterm have a normal number of parenchymal cells in organs such as the spleen, liver,higher incidence of reduced fetal growth.25,38 The role of the genetic kidneys, adrenals, and pancreas.45 The anencephalic fetus is also usuallyconstitution of mother or fetus in these observations is not clear. growth restricted. Specific maternal genotypic disorders can cause IUGR, one example Approximately 25% of newborns with a single umbilical arterybeing phenylketonuria.39 Infants born to homozygously affected weigh less than 2500 g at birth, and some of these are born preterm.46mothers almost always have IUGR, but whether the reason is an abnor- Abnormal umbilical cord insertions into the placenta are also occa-mal amount of metabolite crossing from mother to fetus or an inher- sionally associated with poor fetal growth.47 The presence of cordent problem in the fetus is unknown. encirclements around the fetal body is also associated with IUGR.48 There is a significant association between IUGR and congenital Structural malformations, single umbilical artery, and monozygoticmalformations (see later discussion) Such abnormalities can be caused twins are relatively rare and probably account for no more than 1% toby established chromosomal disorders or by dysmorphic syndromes, 2% of all human instances of IUGR.such as various forms of dwarfism. Some of these malformations arethe expression of a specific gene abnormality with a known inheritancepattern, whereas others are only presumed to be the result of a gene Infectionmutation or an adverse environmental influence. Infectious disease is known to cause IUGR, but the number of organ- Although in some reports only 2% to 5% of IUGR infants have a isms having this effect is poorly defined, and the extent of the growthchromosomal abnormality, the incidence rises to 20% if IUGR and restriction can be variable There is sufficient evidence for a causalmental retardation are both present.40 Birth weights in infants with relationship between infectious disease and IUGR for two viruses—trisomy 13, 18, and 21 are lower than normal,41,42 with the decrease in rubella and cytomegalovirus,49 and there is evidence for a possiblebirth weight being less pronounced in trisomy 21. The frequency dis- relationship with varicella,50 severe herpes zoster, and human immu-tribution of birth weights in infants with trisomy 21 is shifted to the nodeficiency virus (HIV) infection, although the latter may be com-left of the normal curve after 34 weeks of gestation, resulting in gesta- plicated by other problems associated with HIV (see Chapter 38).tional ages 1 to 1.5 weeks less than normal, and birth weights and With rubella infection, the incidence of IUGR may be as high aslengths are less than in control infants from 34 weeks until term. This 60%, with infected cells remaining viable for many months.51 There iseffect is more marked after 37 weeks of gestation, but birth weights are capillary endothelial damage, hypoplasia, and necrotizing angiopathystill only approximately 1 standard deviation from mean weight. Birth in many fetal organs.52 With cytomegalovirus infection, there is cytoly-weights in translocation trisomy 21 are comparable to those in primary sis, localized necrosis within various fetal organs, and a decrease in celltrisomy 21. Birth weights of newborns who are mosaic for normal and number.5321-trisomic cells are lower than normal but higher than those of 21- Although there are no bacterial infections known to cause IUGR,trisomic infants.29 Newborns with other autosomal abnormalities, such histologic chorioamnionitis is strongly associated with symmetricas deletions (chromosomes 4, 5, 13, and 18) and ring chromosome IUGR between 28 and 36 weeks, and with asymmetric IUGR after 36structure alterations, also have had impaired fetal growth. weeks of gestation.54 Although abnormalities of the female (X) and male (Y) sex chro- Protozoan infections resulting from Toxoplasma gondii, Plasmo-mosomes are frequently lethal (80% to 95% result in first-trimester dium sp., or Trypanosoma cruzi (Chagas disease) reportedly can causespontaneous abortions), they could be a cause of IUGR in a newborn.18,28 IUGR.49Infants with XO sex chromosomes have a lower mean birth weight Although the incidence of maternal infections with various organ-than control infants (approximately 85% of normal for gestational age) isms may be as high as 15%, the incidence of congenital infections is
    • CHAPTER 34 Intrauterine Growth Restriction 639estimated to be no more than 5%. It is believed that infectious disease growth adversely. However, information from experiments usingcan account for no more than 5% to 10% of human IUGR. small animals, in which the fetomaternal mass is much greater than in human pregnancy and the fetal and neonatal growth rate reaches its maximum after birth, must be extrapolated with caution. Nevertheless,Multiple Gestation such animal studies have engendered important concepts.It has long been recognized that multiple pregnancies are associated Winick63 reported that there are three phases of fetal growth: cel-with a high progressive decrease in fetal and placental weight as the lular hyperplasia, followed by both hyperplasia and hypertrophy, andnumber of offspring increases in humans and in various animal species then predominantly hypertrophy. If there is a decrease in available(see Chapter 25).55,56 In both singleton and twin gestations, there is a substrate, the timing of the decrease is reflected in the type of IUGRrelationship between total fetal mass and maternal mass. The increase observed. If the insult occurs early in pregnancy, the fetus is likely toin fetal weight in singleton gestations is linear from approximately 22 be born with a decrease in cell number and cell size (such as might beto 24 weeks until approximately 32 to 36 weeks of gestation.13,17 During observed with severe chronic maternal undernutrition or an inabilitythe last weeks of pregnancy, the increase in fetal weight declines, actu- to increase uteroplacental blood flow during gestation) and to haveally becoming negative after 42 weeks in some pregnancies. symmetric IUGR. If the insult occurs late in gestation, such as with If nutrition is adequate in the neonatal period, the slope of the twin gestation, the fetus is likely to have a normal cell number but aincrease in neonatal weight parallels the increase in fetal weight seen restriction of cell size (which can be returned to normal with adequatebefore 34 to 38 weeks. The decline in fetal weight increase occurs when postnatal nutrition) and to have asymmetric IUGR.the total fetal mass approximates 3000 to 3500 g for either singleton The importance of maternal nutrition in fetal growth and birthor twin gestations. When growth rate is expressed incrementally, the weight was demonstrated by studies in Russia and Holland, whereweekly gain in singletons peaks at approximately 230 to 285 g/wk women suffered inadequate nutrition during World War II. The popu-between 32 and 34 weeks of gestation (see Fig 34-2). In individual twin lation in Leningrad underwent a prolonged period of poor nutrition,fetuses, the incremental weekly gain peaks at 160 to 170 g/wk between during which both preconception nutritional status and gestational28 and 32 weeks of gestation.13 However, recent studies in triplets have nutrition were poor and birth weights were reduced by 400 to 600 g.64indicated that the growth of individual triplets may continue in a linear In Holland, a 6-month famine created conditions that permitted evalu-fashion well beyond a total combined weight of 3500 g.57 Others have ation of the effect of malnutrition during each of the trimesters ofreported that before 35 weeks of gestation, triplets grow at about the pregnancy in a group of women previously well nourished.65 Birth30th percentile for singletons, and by 38 weeks the average weight of weights declined by approximately 10%, and placental weights by 15%,each triplet is at the 10th percentile.58 Significant birth weight discor- only when undernutrition occurred in the third trimester with dailydance also occurs if there is unequal sharing of the placental mass.59 If caloric intake of less than 1500 kcal. The difference in severity of themultifetal reduction is performed, there is an increase in IUGR in the IUGR in these two populations suggests the importance of prepreg-surviving fetuses.60 nancy nutritional status, an idea that has been substantiated.18,66 In The decrease in weight of twin fetuses, frequently with mild IUGR, addition, animal studies indicate that fetal growth, metabolic andis usually due to decreased cell size; the exception is severe IUGR asso- endocrine function, as well as placental status and function in lateciated with monozygosity and vascular anastomoses, wherein cell pregnancy, are significantly altered by the periconception maternalnumber also may be decreased.61 These changes in twins are similar to nutritional status, an effect independent of fetal size.67 More recentthose seen in IUGR secondary to poor uterine perfusion or maternal studies have shown that inadequate weight gain in pregnancy (definedmalnutrition. Twins with mild IUGR have an acceleration of growth as <0.27 kg/wk, or <10 kg at 40 weeks, or based on suggested weightafter birth, so that their weight equals the median weight of singletons gain for body mass indices; see Chapter 10) is associated with anby 1 year of age. This observation supports the thesis that the etiology increased risk of IUGR. Weight gain in the second trimester appearsof poor fetal growth in twin gestations is an inability of the environ- to be particularly important.67 Adequate maternal weight gain by 24 toment to meet fetal needs, rather than an inherent diminished growth 28 weeks in multiple pregnancies correlates positively with good fetalcapacity of the twin fetus. The example of twin fetuses supports the growth.68thesis derived from normal singleton pregnancies that the human fetus It is still unclear whether it is generalized calorie intake reductionis seldom able to express its full potential for growth. or specific substrate limitation (e.g., protein or key mineral restric- Many components of the environment can limit fetal growth (see tion), or both, that is important in producing IUGR (see Chapter 10).later discussions). Twin-to-twin transfusion secondary to vascular Glucose uptake by the fetus is critical, because there is the suggestionanastomoses in monochorionic-monozygotic twins frequently results that little glucogenesis occurs in the normal fetus. In the IUGR fetus,in IUGR of one twin, usually the donor (see Chapter 25). Maternal the maternal-fetal glucose concentration difference is increased ascomplications associated with IUGR occur more frequently with twins, a function of the severity of the IUGR,69 facilitating glucose transferand the incidence of congenital anomalies is almost twice that of sin- across the small placenta. Decreases in zinc content of peripheral bloodgletons, primarily among monozygotic twin gestations. The incidence leukocytes also correlate positively with IUGR,70 and serum zinc con-of IUGR in twins is 15% to 25%16,62; because the incidence of sponta- centrations of less than 60 μg/dL in the third trimester are associatedneous multiple gestations approximates 1%, these pregnancies proba- with a fivefold increase in the incidence of low birth weight.71 Similarly,bly account for less than 3% of all cases of human IUGR. The actual an association between low serum folate levels and IUGR has beenincidence could be closer to 5% because of the increase in multiple reported.72 Although there have been numerous studies on supplemen-gestations secondary to assisted reproductive techniques. tation, there is no convincing evidence that high protein intake or caloric supplementation has a beneficial effect on fetal weight. In addi- tion, if a fetus is receiving decreased oxygen delivery as a result ofInadequate Maternal Nutrition decreased uteroplacental perfusion and has adapted by slowing metab-Numerous animal studies have demonstrated that undernutrition of olism and growth, it may not be advisable to increase substrate deliv-the mother caused by protein or caloric restriction can affect fetal ery. This important issue remains unresolved.
    • 640 CHAPTER 34 Intrauterine Growth Restriction Another maternal nutrient that is important to fetal growth is invade the decidua and myometrium to anchor the placenta, and aoxygen. It is probably a primary determinant of fetal growth. IUGR subpopulation of cytotrophoblasts invades the uterine blood vessels atinfants have a decrease in the partial pressure of oxygen and decreased the implantation site, resulting in extensive remodeling of the vessels.84-87oxygen saturation values in the umbilical vein and artery.73 The median There is a replacement of endothelium and uterine smooth musclebirth weight of infants of women living more than 10,000 feet above cells, which leads to a reduction in uterine arterial resistance and ansea level is approximately 250 g less than that of infants of women increase in uteroplacental perfusion. Apoptosis plays an integral roleliving at sea level.74 Pregnancies complicated by maternal cyanotic in these vascular changes. It has also been suggested that the cytotro-heart disease usually result in IUGR, but it is unclear whether abnor- phoblast initiates lymphangiogenesis in the pregnant uterus; this ismal maternal hemodynamics or the reduction in oxygen saturation (by normally lacking in the nonpregnant state.approximately 40% in the umbilical vein) accounts for the poor fetal A number of reports have revealed that, in many cases of IUGR,growth.75 The association between hemoglobinopathies and IUGR particularly in early IUGR, the depth of invasion by the cytotropho-could be due to decreased blood viscosity or decreased fetal oxygen- blasts is shallow and the endovascular invasion rudimentary; they haveation. Patients with chronic pulmonary disease (e.g., poorly controlled thus confirmed the early classic work of Brosens and colleagues,88 whoasthma, cystic fibrosis, bronchiectasis) and those with severe kypho- described reduced trophoblastic invasion and decreased pregnancy-scoliosis may be at increased risk of IUGR. associated alterations in the placental bed of IUGR pregnancies. The detailed morphologic studies of Aherne and Dunnill89 also demon- strated that the mean surface area and, more importantly, the capillaryEnvironmental Toxins surface area were reduced in the placentas of IUGR newborns. Apop-Maternal cigarette smoking decreases birth weight by approximately tosis at the implantation site is increased with IUGR, and this has been135 to 300 g; the fetus is symmetrically smaller.76,77 If smoking is suggested to be the mechanism limiting endovascular invasion.86,90,91stopped before the third trimester, its adverse effect on birth weight is The placental vascular endothelial growth factor (VEGF) and placentareduced.77 More disturbing is the reported dose-response relationship growth factor (PIGF) were reduced, and antagonists were increased, inbetween maternal smoking and a smaller infant head size, specifically studies of early IUGR confirmed by Doppler imaging.92 In summary,a circumference of less than 32 cm, as well as a head circumference early abnormal implantation plays a key role in IUGR, but the exactmore than 2 standard deviations below that expected for gestational controlling mechanisms behind the impaired placentation remain toage.78 The reason why not all women who smoke have IUGR infants be delineated.could be a function of maternal genetic susceptibility.79 The terminal villi are maldeveloped in IUGR pregnancies when Reduction in birth weight also occurs with maternal alcohol inges- absent end-diastolic flow is demonstrated, indicating that these mor-tion of as little as one to two drinks per day.80 Cocaine use in pregnancy phologic changes are associated with increased vascular impedance.93similarly decreases birth weight, but there is also a reduction of head When end-diastolic flow, is absent, there are more occlusive lesionscircumference that is more pronounced than the reduction in birth of the intraplacental vasculature than when end-diastolic flow isweight.81 Use of other drugs, such as the anticonvulsants phenytoin present.94and trimethadione, warfarin, and heroin, has been implicated in IUGR Information from cordocentesis studies has revealed fetal hypox-(see Chapter 20). emia, hypercapnia, acidosis, and hypoglycemia in severe IUGR.95,96 There is also a decrease in α-aminonitrogen, particularly branched- chain amino acids, in the plasma of the IUGR fetus.97Placental Factors Abnormal insertions of the cord, placental hemangiomas, abruptioAlthough placental size does not necessarily equate with function, our placentae, and placenta previa are also associated with IUGR.98-100inability to clinically properly evaluate human placental function hasresulted in studies of the interrelationships of size, morphometry, andclinical outcome. In general, birth weight increases with increasing Maternal Vascular Diseaseplacental weight in both animals and humans. IUGR without other Substantial evidence from experimental animal studies suggests thatanomalies is usually associated with a small placenta. Chromosomally alterations in uteroplacental perfusion affect the growth and status ofnormal IUGR newborns have a 24% smaller placenta for gestational the placenta as well as the fetus. Ligation of the uterine artery of oneage.82 A small placenta is not always associated with an IUGR newborn, horn of the pregnant rat results in IUGR of those fetuses nearest thebut a large infant from an otherwise normal pregnancy does not have constriction, and fetal and placental weights in guinea pigs, mice, anda small placenta. Placental weight increases throughout normal gesta- rabbits are lowest in the middle of each uterine horn, where arterialtion; with IUGR, the placental weight plateaus after 36 weeks or earlier, perfusion is lowest. Repetitive embolization of the uterine vascular bedand the placenta (after being trimmed of the membranes and cord) during the last quarter of gestation in sheep gives rise to localizedweighs less than 350 g.83 As normal gestation advances, there is a hyalinization and fibrinoid changes in the placenta101 and resultsgreater increase in fetal weight than in placental weight, so there is an in a 40% reduction in placental weight and alterations in organincrease in the fetal-placental weight ratio in large-for-gestational-age growth patterns similar to those observed in IUGR fetuses from preg-(LGA), AGA, and SGA infants in the last half of gestation. In all three nancies complicated by maternal hypertensive disease. In addition,categories, when the fetal-placental weight ratio is greater than 10, umbilical blood flow is reduced and fetal oxidative metabolism isthere is an increased incidence of depressed newborns; this suggests decreased.101,102that it is not only the IUGR fetus that can outgrow the capacity of the It has been strongly suggested in various studies that uteroplacentalplacenta to bring about adequate transfer of necessary nutrients.83 blood flow is decreased in pregnancies complicated by maternal hyper- Adequate trophoblastic invasion of the uterine decidual bed, and tensive disease. Defective trophoblastic invasion of the uterine vascularthe resultant alteration in uterine blood flow, is a vital necessity, not bed results in relatively intact musculoelastic vessels that resist theonly for the initial establishment and adherence of the pregnancy, but normal decrease in uterine vascular resistance.103 Clearance of radioac-for also the adequate supply of nutrients to the fetus. The trophoblasts tive tracers from the intervillous space is reduced in preeclamptic
    • CHAPTER 34 Intrauterine Growth Restriction 641patients.104,105 Because maternal body mass and plasma volume are Although the effects of hypothyroidism or hyperthyroidism on fetalcorrelated, reduced plasma volume or prevention of plasma volume size are not striking, studies in subhuman primates indicate that, whenexpansion could lead to decreased cardiac output and uterine perfu- the mother and fetus are athyroid, there is retarded osseous develop-sion and a resultant decrease in fetal growth.106,107 Alternatively, it may ment and reduced protein synthesis in the fetal brain.125be that abnormal placentation comes first. Maternal diabetes without vascular disease is frequently associated The importance of normal trophoblastic invasion leading to normal with excessive fetal size (see Chapter 46). Although insulin does notmaternal cardiovascular changes has been indicated by central mater- cross the placenta, fetal hyperinsulinemia as well as hyperplasia of thenal cardiovascular studies. IUGR below the 3rd percentile at 25 to 37 pancreatic islet cells is seen frequently with maternal diabetes. Theseweeks of gestation is associated with reduced maternal systolic func- changes are thought to occur as a result of maternal hyperglycemia,tion, increased vascular resistance, and probable lack of volume expan- which leads to fetal hyperglycemia and an increased response of thesion in otherwise normotensive patients.108 fetal pancreas. Fetal hypoinsulinemia produced experimentally in the Uteroplacental flow-velocity waveform studies, using Doppler rhesus monkey results in IUGR; rarely, infants have been born withmethods in pregnancies complicated by hypertension, have shown a severe IUGR and requiring insulin treatment at birth, suggesting hypo-higher incidence of IUGR in pregnancies in which abnormal wave- insulinemia in utero.126,127 If nutrient transfer becomes limited owingforms were recorded. These abnormal waveforms are thought to reflect to placental disease secondary to maternal vascular disease, the fetusabnormally increased resistance to blood flow.109,110 High-resistance of the diabetic mother can sustain IUGR.hypertension is associated with a marked decrease in fetal weight com- Even though human growth hormone is present early in gestation,pared with low-resistance hypertension.111 Increasing uteroplacental there is minimal evidence that it regulates fetal weight, although a defi-resistance, recorded with this methodology, has been positively corre- ciency could retard skeletal growth.128 Convincing evidence is also lackinglated with fetal hypoxemia as determined by cordocentesis in IUGR that adrenal hormones have a role in producing IUGR in humans.fetuses.95 Several small polypeptides with in vitro growth-promoting activity As discussed in Chapter 40, there is conflicting evidence as to have been purified (e.g., insulin-like growth factor 1 [IGF-1], IGF-2),whether the congenital thrombophilias contribute to the clinical devel- but the exact role of these peptides and their binding proteins as fetalopment of IUGR, with most recent studies suggesting the lack of an growth factors and their potential relationship to IUGR are currentlyassociation.112-115 not well understood. There are only fragmentary suggestions relating abnormal ana- Leptin (from Greek leptos, “thin”) is a polypeptide hormone dis-tomic uterine vascular anatomy and IUGR. IUGR may occur at a covered in 1994. It has been shown to moderate feeding behavior andhigher frequency if the pregnancy is in a unicornuate uterus; vascular adipose stores. It is produced predominantly by adipocytes but can alsoabnormalities are likely but unproven in such cases.116 Patients with be produced by the placenta, because neonatal levels fall dramaticallytwo (rather than the usual one) ascending uterine arteries on each side after birth.128 Reported concentrations in IUGR have varied, and theof the uterus also have a higher rate of IUGR.117 However, pregnancy exact role that this hormone plays in fetal growth remains to beafter bilateral ligation of the internal iliac and ovarian arteries, or after clarified.embolization of leiomyomata, is not associated with IUGR.118,119 Because exercise can affect uterine perfusion, this subject has beenstudied extensively. A moderate regimen of weight-bearing exercise inearly pregnancy probably enhances fetal growth.120 However, high Diagnosis of Intrauterinelevels of exercise (>50% of prepregnancy levels) in middle and latepregnancy result mainly in a symmetric reduction in fetal growth and Growth Restrictionneonatal fat mass.121 In assessing levels of aerobic activity, neonatesborn to women in the highest quartile weighed 600 g less than those Determination of Causein the lowest quartile, an effect mainly seen in taller women.122 An attempt should be made to determine the cause of fetal aberrant Clinical maternal vascular disease and the presumed decrease in growth before delivery in order to provide appropriate counseling;uteroplacental perfusion can account for at least 25% to 30% of IUGR perform ultrasonographic evaluation for fetal growth velocity, delin-infants. Undiagnosed decreased perfusion could also be the cause of eate anatomy and function; and obtain neonatal consultation.IUGR in an otherwise normal pregnancy, such as with recurrent idio- The various disorders associated with suboptimal fetal growth werepathic fetal growth restriction. A history of a previous low-birth-weight addressed earlier in this chapter and are summarized in Table 34-2.infant is significantly associated with the subsequent birth of an infant Often, the cause is readily apparent. Among patients with significantwith decreased weight, decreased ponderal index, and decreased head chronic hypertensive disease, those who take prescribed medicationscircumference.123 This finding of symmetric growth restriction is in known to be associated with prenatal growth deficiency, and thosecontrast to the asymmetric IUGR usually seen with maternal vascular whose fetuses have congenital or chromosomal abnormalities, thedisease. diagnosis is easily established and management plans can be made. At Vascular disease becomes more prevalent with advancing age. In times, however, the causal factors can be more elusive. For example,one recent large study, after controlling for confounding variables, the growth restriction associated with preeclampsia may antedate theincidence of SGA births was increased more in nulliparous patients appearance of hypertension or proteinuria by several weeks. In manythan in multiparous patients older than 30 years of age.124 instances, a careful history, maternal examination, and ultrasound evaluation reveal the etiology.Maternal and Fetal HormonesIn general, there is limited transfer of the various circulating History and Physical Examinationmaternal hormones into the fetal compartments (see Chapters 46 Clinical diagnosis of IUGR by physical examination alone is inaccu-through 48). rate; often, the diagnosis is not made until after delivery. Most clinical
    • 642 CHAPTER 34 Intrauterine Growth Restriction TABLE 34-2 DISORDERS AND OTHER FACTORS pattern131 (Fig. 34-4). As discussed previously, intrinsic fetal insults ASSOCIATED WITH INTRAUTERINE occurring early in pregnancy (e.g., infection, exposure to certain drugs or other chemical agents, chromosomal abnormalities, other congeni- GROWTH RESTRICTION* tal malformations) are likely to affect fetal growth at a time of develop- Maternal Factors ment when cell division is the predominant mechanism of growth. Hypertensive disease, chronic or preeclampsia Consequently, musculoskeletal dimensions and organ size may be Renal disease adversely affected, and a symmetric pattern of aberrant growth is Severe nutritional deficiencies (e.g., inflammatory bowel disease, observed. Given this set of circumstances, one might expect to find that markedly inadequate pregnancy weight gain in the underweight the femur length and head circumference are small for a given gesta- woman, malnutrition) tional age, as are the abdominal circumference and overall fetal weight, Pregnancy at high altitude Specific prescribed medications (e.g., antiepileptics) all of which are characterized as symmetric IUGR. Symmetric IUGR Smoking, alcohol use, illicit drug use accounts for approximately 20% to 30% of all growth-restricted fetuses. Fetal Factors At the other end of the spectrum, an extrinsic insult occurring later Multiple gestations in pregnancy, usually characterized by inadequate fetal nutrition due Placental abnormalities to placental insufficiency, is more likely to result in asymmetric growth Infections restriction. In this type, femur length and head circumference are Aneuploidy or structural abnormalities spared, but abdominal circumference is decreased because of subnor- *Growth is also strongly influenced by maternal prepregnancy weight mal hepatic growth, and there is a paucity of subcutaneous fat. The and by ethnicity, which must be considered when evaluating overall most common disorders that limit the availability of fetal substrates growth (by use of customized versus population-based growth for metabolism are the hypertensive complications of pregnancy, curves). which are associated with decreased uteroplacental perfusion, and placental infarcts, which limit the trophoblastic surface area available for substrate transfer. In fact, a falloff in the interval growth of thestudies demonstrate that, with the use of physical examination alone, abdominal circumference is one of the earliest findings in extrinsic orthe diagnosis of IUGR is missed or incorrectly made almost half the asymmetric IUGR132,133; conversely, the finding of an abdominal cir-time. Techniques such as measurement of the symphysis-fundal height cumference in the normal range for gestational age markedly decreasesare helpful in screening for abnormal fetal growth and documenting the likelihood of IUGR. Frequently, these patterns of growth abnor-continued growth if they are performed repeatedly by the same mality merge, particularly after long-standing fetal nutritionalobserver, but they are not sensitive enough for accurate detection of deprivation.most infants with IUGR.129,130 Distinguishing between symmetric and asymmetric IUGR is also Despite the inaccuracy of such indicators, fetal assessment and of considerable clinical significance and may provide useful informa-specific aspects of the patient’s risk factors increase the clinician’s tion for both diagnostic and counseling purposes. For example, a diag-index of suspicion about suboptimal fetal growth, without which nosis of symmetric IUGR in early pregnancy suggests a poor prognosismore definitive laboratory investigation might not be considered. when the diagnostic possibilities are considered (e.g., fetal infection,As discussed earlier, maternal disease entities such as hypertension, aneuploidy); conversely, asymmetric IUGR observed in the third tri-in particular severe preeclampsia and chronic hypertension with mester, particularly if it is associated with maternal hypertension orsuperimposed preeclampsia, carry a high incidence of IUGR. The placental dysfunction, usually imparts a more favorable prognosis withdiagnosis of a multiple gestation suggests the likelihood of diminished careful fetal evaluation, appropriate delivery timing, and skillful neo-fetal growth relative to gestational age, as well as preterm birth. Addi- natal management.tional maternal risk factors include documented rubella or cytomega- Considerable attention has been directed at early ultrasound find-lovirus infection, heavy smoking, heroin or cocaine addiction, ings that may provide for the early prediction of IUGR. In a study ofalcoholism, and poor nutritional status both before conception and 976 women whose pregnancies were the product of assisted reproduc-during pregnancy combined with inadequate weight gain during tive technologies, the risk of delivering an SGA fetus decreased as apregnancy. function of increasing crown-rump length in the first trimester.134 This confirmed previous findings suggesting that suboptimal growth in the first trimester is associated with IUGR.135Ultrasonography Efforts have also been made to correlate Doppler findings in theCurrently, ultrasonographic evaluation of the fetus is the preferred and uterine artery with subsequent pregnancy complications, includingaccepted modality for the diagnosis of inadequate fetal growth. It offers IUGR. Utilizing transvaginal color Doppler at 23 weeks’ gestation,the advantages of reasonably precise estimations of fetal weight, deter- Papageorghiou and colleagues observed that increases in the uterinemination of interval fetal growth velocity, and measurement of several artery pulsatility index and “notching” were associated with subse-fetal dimensions to describe the pattern of growth abnormality. Use of quent development of IUGR, although the predictive value was low.136these ultrasound measurements requires accurate knowledge of gesta- In a more recent study of uterine artery pulsatility index at 11 to 14tional age. Accordingly, if a patient is known to be at risk for a fetal weeks’ gestation, a value greater than the 95th percentile predicted SGAgrowth abnormality, the crown-to-rump length should be determined with accuracy in 23% of the cases, and with increased sensitivity if theduring the first trimester. maternal serum concentration of plasma-associated pregnancy protein Measurements of biparietal diameter, head circumference, abdomi- A (PAPP-A) was low. However, this parameter did not reach statisticalnal circumferences, and femur length allow the clinician to use accepted significance.137 The eventual practical role that uterine artery Dopplerformulas to estimate fetal weight and to determine whether a fetal ultrasound may play in the prediction of IUGR, if any, awaits moregrowth aberration represents an asymmetric, symmetric, or mixed extensive evaluation.
    • CHAPTER 34 Intrauterine Growth Restriction 643 Fetal Head Circumference Fetal Abdominal Circumference vs. vs. Gestational Age (Mean 2 S.D.) Gestational Age (Mean 2 S.D.) 38 36 34 40 32 38 30 36 Fetal circumference (cm) 28 34 Abdominal circumference (cm) 26 32 24 30 22 28 20 26 18 24 16 22 14 20 12 18 10 16 8 14 12 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 10 Gestational age (weeks) 8 6 Fetal Head Circumference/Abdominal 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 Circumference Ratio vs. Gestational age (weeks) Gestational Age (Mean 2 S.D.) 1.6 Fetal Weight 1.4 vs. Gestational Age (Mean 2 S.D.) 4.6 H/A ratio 1.2 4.4 4.2 1.0 4.0 3.8 0.8 3.6 3.4 0.6 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 3.2 Weight (kilograms) Gestational age (weeks) 3.0 2.8 2.6 Femur Length 2.4 vs. 2.2 Gestational Age (Mean 2 S.D.) 2.0 90 1.8 1.6 80 1.4 1.2 70 1.0 Femur length (mm) 0.8 60 0.6 0.4 50 24 26 28 30 32 34 36 38 40 42 Gestational age (weeks) 40 30 20 10 14 16 18 20 22 24 26 28 30 32 34 36 38 40 Gestational age (weeks)FIGURE 34-4 Composite of fetal body measurements used for serial evaluations of fetal growth.
    • 644 CHAPTER 34 Intrauterine Growth Restriction a subsequent analysis of perinatal morbidity and mortality among patients monitored with the BPP, a highly significant inverse correla-Management of Pregnancy tion was observed for IUGR and last test score. If the last test score was 8 or higher, only 3.4% of 6500 high-risk patients had infants withThe cornerstones of management for the pregnancy complicated by IUGR. Conversely, if the last test score was 4 or 2, the incidence ofIUGR are surveillance of fetal growth velocity and function (well- IUGR increased to 29% and 41%, respectively.147being) and determination of appropriate delivery timing. Delivery ator near term is usually indicated if fetal growth has continued to be Doppler Ultrasound Assessment of theadequate and antenatal testing results have been normal. Management Fetal Vasculatureis far more challenging remote from term and requires use of the bio- ARTERIAL CIRCULATIONphysical profile (BPP), measurement of amniotic fluid volume (AFV), There has been great interest in the role of Doppler assessment ofand Doppler assessment of the fetal circulation, combined with good the fetal arterial and venous circulation in predicting and evaluatingclinical judgment. The comments in the following sections pertain fetal growth restriction as well as other fetal complications (see Chapterprimarily to the use of antenatal testing in the preterm fetus with 21). It is now clear that umbilical arterial velocimetry is of considerableIUGR. value in predicting perinatal outcome in the fetus with IUGR, and it is the only modality validated by randomized trials. A substantial pathologic correlation helps to explain the increased vascular resis-Antenatal Fetal Testing tance in IUGR. Specifically, fetuses demonstrating an absence of end-The various diagnostic modalities used for fetal assessment are discussed diastolic flow exhibited maldevelopment of the placental terminalin detail in Chapter 21, but specific points are reemphasized here. villous tree. The correlations among placental pathology, abnormal umbilical artery velocimetry, and IUGR were reviewed by KingdomBiophysical Profile and Amniotic Fluid Volume and coworkers.148The BPP is appealing, inasmuch as it provides a multidimensional Several randomized trials have been reported which, taken together,survey of fetal physiologic parameters. In particular, AFV assessment demonstrated a decrease in perinatal deaths when umbilical arterialis an important aspect of the BPP, because oligohydramnios is a fre- Doppler assessment was used in conjunction with other types of ante-quent finding in the IUGR pregnancy caused by placental insufficiency. natal testing.149-151 A meta-analysis of 12 randomized, controlled trialsThis is presumably a result of diminished fetal blood volume, renal showed that clinical action guided by umbilical Doppler velocimetryblood flow, and urinary output. Human fetal urinary production rates reduced the odds of perinatal death by 38% and decreased the risk ofcan be measured with considerable accuracy,138 and three separate inappropriate intervention in pregnancies thought to be at risk ofstudies have shown decreased rates in the presence of fetal growth IUGR.152 Although the authors hypothesized that this beneficial effectrestriction.139-141 depended on the incidence of absent end-diastolic velocity rather than The significance of AFV with respect to fetal outcome has been well simply decreased flow, the number of studies with sufficient data wasdocumented. Manning and coworkers reported the diagnostic value of inadequate to draw this conclusion. A recent retrospective cohort studyAFV measurement in discriminating normal from aberrant fetal growth. of 151 IUGR fetuses comparing abnormal umbilical artery Doppler, aAmong 91 patients with normal AFV, 86 delivered infants whose birth “nonreactive” nonstress test, and a BPP value of 6 or less confirmedweights were appropriate for gestational age. In contrast, 26 of 29 patients that abnormal Doppler flow was the best predictor of adversewith decreased AFV delivered growth-restricted infants.142 Severe oligo- outcome.153hydramnios is associated with a high risk of fetal compromise.143,144 Therefore, umbilical artery velocimetry plays a significant role in It is likely that the chronic hypoxic state frequently observed in the management of IUGR. A normal velocimetry result in the suspectthe fetus with IUGR is responsible for diverting blood flow from the small fetus is usually indicative of a constitutionally small but other-kidney to other organs that are more critical during fetal life (see wise normal baby,154 although a normal finding is also observed in theChapters 12 and 14). Nicolaides and associates141 observed reduced chromosomally or structurally abnormal fetus.155 Diminished end-fetal urinary flow rates in IUGR, and the degree of reduction was well diastolic flow is rarely associated with significant neonatal morbidity,correlated with the degree of fetal hypoxemia as reflected by fetal blood but the absence or reversal of end-diastolic flow predicts significantlyPO2 measured after cordocentesis. increased perinatal morbidity and mortality and long-term poor neu- The most appropriate technique for assessment of AFV, as well as rologic outcome, compared with continuing diastolic flow.156,157 Fur-the arguments for and against each technique, are addressed in Chap- thermore, markedly diminished end-diastolic flow can be observed atters 21 and 32. It is reasonable to conclude at this time that a single very premature gestational ages, well before the BPP demonstratesvertical pocket smaller than 2 cm, or an amniotic fluid index of less abnormalities. Consequently, abnormal umbilical velocimetry findingsthan 5 cm, or both, suggests that there is a clinically significant decrease should be interpreted in conjunction with other tests of fetal well-in AFV; conversely, a normal AFV is very reassuring with respect to being and in the context of the gestational age.fetal well-being and also suggests the possibility of a normal but con- There also has been interest in the evaluation of middle cerebralstitutionally small fetus. artery flow, inasmuch as the normal adaptive response to hypoxia There is a paucity of evidence from randomized trials to validate within the fetus is to increase cerebral blood flow (“brain-sparing”).the use of the BPP.145 However, its usefulness was suggested by several However, the results from several studies have been contradictory, andlarge observational reports. In a study of 19,221 high-risk pregnancies, the focus of attention has been on umbilical artery flow and the venousManning and colleagues146 observed that the fetal death rate after a circulation.normal BPP score (≥8) was 0.726 in 1000 births; only 14 such fetusesdied. Of the total patient population, approximately 4380 pregnancies VENOUS CIRCULATIONwere complicated by IUGR, and only 4 of those infants died after a In contrast to abnormalities in arterial circulation, abnormalitiesnormal test, yielding a false-negative test rate of less than 1 in 1000. In observed in the venous circulation presumably reflect central cardiac
    • CHAPTER 34 Intrauterine Growth Restriction 645failure, and multiple current studies suggest that specific aberrations The role of low-dose aspirin remains controversial, and mostof flow through the ductus venous and umbilical vein are indicative of studies have examined subsets of women treated for the prevention ofimminent fetal demise, as well as substantial morbidity among survi- preeclampsia. A meticulous analysis of the current data revealed a 10%vors. The temporal sequence of Doppler-measured flow abnormalities reduction in SGA infants, but this strong trend did not achieve statisti-in the arterial and venous circulations of the IUGR fetus has been cal significance.168 This subject was recently reviewed by Berghella.169delineated.158,159 The fetus with severe IUGR first demonstrates changesin the umbilical and middle cerebral arteries. This is followed by altera-tions in the venous circulation, including the ductus venosus (abnor- Timing of Deliverymalities in the atrial portion of the flow) and the umbilical vein The prohibitive perinatal morbidity and mortality rates among IUGR(pulsatile flow). These changes and their pathophysiology have been infants were discussed previously. Controversy continues with regardsummarized in detail by Baschat and Harman.160 What has become to the timing of delivery for such infants to ensure that neurologicclear is that abnormal venous Doppler waveforms in the preterm IUGR damage or fetal intrauterine death does not occur because of chronicfetus are indicative of poor acid-base status and outcome.161,162 There- oxygen deprivation. This problem is underscored by the fact that,fore, the challenge for the clinician is to try to optimize delivery timing if deaths among congenitally infected and anomalous infants arein the very preterm fetus, before significant abnormalities in the venous excluded, the perinatal risk is still higher for growth-restricted infantscirculation occur. than for AGA newborns. Although opinions vary as to the role of preterm versus term delivery of the IUGR fetus, it is usually prudent to deliver the growth-restricted infant close to term, as long as growthAntepartum Therapy continues and antenatal tests are reassuring. Tests of fetal lung matura-Maternal hyperoxia has been shown to increase umbilical PO2 and pH tion may be of value if the course of action is not entirely clear. In thein the hypoxemic, acidotic, growth-restricted fetus.163 Among surviv- case of the preterm fetus, delivery is indicated in the presence of wors-ing fetuses, there was also an improvement in mean velocity of blood ening maternal hypertensive disease, failure of continuing growth, orflow through the thoracic aorta. In support of these findings, Battaglia reversal of umbilical artery flow as assessed by Doppler ultrasound.and coworkers treated 17 of 36 women whose pregnancies were com- The preterm fetus (<34 weeks’ gestation) should receive the benefit ofplicated by IUGR with maternal hyperoxia and confirmed improve- corticosteroids for lung maturation.ment in both blood gases and Doppler flow. They also observed a The Growth Restriction Intervention Trial (GRIT) study under-significant improvement in perinatal mortality in the oxygen-treated scored the difficulty in selecting the most appropriate delivery time topatients.164 However, the evidence is inconclusive regarding whether prevent morbidity.170 In a randomized trial of 548 preterm IUGR preg-chronic maternal oxygen therapy is of value, and any differences nancies (24 to 36 weeks’ gestation) in which fetal compromise wasreported in outcome could be due to more advanced gestational age identified but uncertainty regarding delivery persisted, approximatelyin oxygen-treated groups.165 half of the pregnancies were delivered and the other half continued Nutritional supplements, including antioxidants such as vitamins until the clinical course was clear. There was no difference in mortalityC and E, have not been shown to be effective in reducing the risk of between the two groups. However, among infants with less than 31IUGR.166 There has also been considerable interest in the role of fish weeks’ gestation, severe disabilities were observed in 13% of the imme-oil supplements, but a Cochrane Database Review of six trials revealed diate deliveries, compared with 5% of those that were delayed.no significant difference in the proportion of SGA infants in treated The overall findings and guidelines for evaluation and managementversus untreated groups.167 of the fetus with IUGR are summarized in Table 34-3. TABLE 34-3 EVALUATION AND MANAGEMENT OF THE FETUS WITH INTRAUTERINE GROWTH RESTRICTION From Resnik R: Intrauterine growth restriction. Obstet Gynecol 99:490, 2002.
    • 646 CHAPTER 34 Intrauterine Growth RestrictionIntrapartum Management ReferencesIt has long been recognized that lower Apgar scores and meconium 1. Lubchenco LO, Hansman C, Boyd E: Intrauterine growth as estimatedaspiration, as well as other manifestations of poor oxygenation during from liveborn birth-weight data at 24 to 42 weeks of gestation. Pediatricslabor, occur with greater frequency among IUGR infants. The problem 32:793, 1963. 2. Battaglia FC, Lubchenco LO: A practical classification of newborn infantsof intrapartum asphyxia has been further elucidated by studies dem- by weight and gestational age. J Pediatr 71:159, 1967.onstrating the acid-base status of growth-restricted infants at the 3. Yerushalmy J: Relation of birth weight, gestational age, and the rate oftime of delivery. If moderate-to-severe metabolic acidosis is defined as intrauterine growth to perinatal mortality. Clin Obstet Gynecol 13:107,an umbilical artery buffer base value of less than 37 mEq/L (normal, 1970.>40 mEq/L), almost 50% of IUGR neonates show signs of acidosis at 4. Seeds JW, Peng T: Impaired fetal growth and risk of fetal death: Is the tenththe time of delivery.171 These findings document the problems of oxy- percentile the appropriate standard? Am J Obstet Gynecol 178:658, 1998.genation during labor in such fetuses and emphasize that meticulous 5. Gardosi J: Customized fetal growth standards: Rationale and clinicalfetal surveillance is required during this critical period. application. Semin Perinatol 28:33, 2004. Consequently, the clinician should proceed to cesarean delivery 6. Figueras F, Figueras J, Meler E, et al: Customized birthweight standardsif there is evidence of deteriorating fetal status or an unripe cervix accurately predict perinatal morbidity. Arch Dis Child Fetal Neonatal Educ 92: F277-F280, 2007.or if there is any indication of additional fetal compromise during 7. Groom KM, Poppe KK, North RA, et al: Small-for-gestational age infantslabor. classified by customized or population birthweight centiles: Impact of gestational age at delivery. Am J Obstet Gynecol 197:239.e1-239.e5, 2007. 8. McCowan LM, Harding JE, Stewart AW: Customized birthweight centilesNeonatal Complications and predict SGA pregnancies with perinatal morbidity. BJOG 112:1026-1033,Long-term Sequelae 2005. 9. Ego A, Subtil D, Grange G, et al: Customized versus population-basedThe growth-restricted fetus can experience numerous complications birth weight standards for identifying growth restricted infants: A Frenchin the neonatal period related to the etiology of the growth insult as multicenter study. Am J Obstet Gynecol 194:1042-1049, 2006. 10. Miller HC, Hassanein K: Diagnosis of impaired fetal growth in newbornwell as antepartum and intrapartum factors. These include neonatal infants. Pediatrics 48:511, 1971.asphyxia, meconium aspiration, hypoglycemia and other metabolic 11. Daikoku NH, Johnson JWC, Graf C, et al: Patterns of intrauterine growthabnormalities, and polycythemia (see Chapter 58). After correction for retardation. Obstet Gynecol 54:211, 1979.gestational age, a large population-based outcomes analysis showed 12. Brar HS, Rutherford SP: Classification of intrauterine growth retardation.that the premature IUGR infant is at increased risk of mortality, nec- Semin Perinatol 12:2, 1988.rotizing enterocolitis, and need for respiratory support at 28 days of 13. Williams RL, Creasy RK, Cunningham GC, et al: Fetal growth and peri-age.172 This observation takes on more significance inasmuch as pre- natal viability in California. Obstet Gynecol 59:624, 1982.maturity and IUGR frequently coexist. 14. Brenner WE, Edelman DA, Hendricks CH: A standard of fetal growth for Beyond the neonatal period, data by Low and colleagues173 showed the United States of America. Am J Obstet Gynecol 126:555, 1976.that fetal growth restriction has a deleterious effect on cognitive func- 15. Ott W: Intrauterine growth retardation and preterm delivery. Am J Obstet Gynecol 168:710, 1993.tion, independent of other variables. With the use of numerous stan- 16. Arbuckle TE, Wilkins R, Sherman GJ: Birth weight percentiles by gesta-dardized tests to evaluate learning ability, and excluding those children tional age in Canada. Obstet Gynecol 81:39, 1993.with genetic or major organ system malformations, they found that 17. Alexander GR, Himes JH, Kaufman RB, et al: A United States nationalalmost 50% (37/77) of SGA children had learning deficits at ages 9 to reference for fetal growth. Obstet Gynecol 87:163, 1996.11 years. Blair and Stanley174 also reported a strong association between 18. Kramer MS: Determinants of low birth weight: Methodological assess-IUGR and spastic cerebral palsy in newborns born after 33 weeks of ment and meta-analysis. Bull WHO 65:663, 1987.gestation. This association was highest in IUGR infants who were 19. Manning FA: Intrauterine growth retardation. In Manning FA: Fetal Med-short, thin, and of small head size. Newborns who were at or above the icine: Principles and Practice. Norwalk, CT, Appleton & Lange, 1995,10th percentile for weight but had abnormal ponderal indices were also p 307.at risk for spastic cerebral palsy.175 In a recent Danish autopsy study, 20. Ounsted M, Moar V, Scott WA: Perinatal morbidity and mortality in small-for-dates babies: The relative importance of some maternal factors.investigators observed a significantly lower cell number in the cortex Early Hum Dev 5:367, 1981.of IUGR fetuses and infants compared with normal controls, a finding 21. Dashe JS, McIntire DD, Lucas MJ, et al: Effects of symmetric and asym-that may, in part, explain the clinical observations.176 Other investiga- metric fetal growth on pregnancy outcomes. Obstet Gynecol 96:321,tors have reported more favorable neurologic outcomes in IUGR 2000.infants.177,178 22. Piper JM, Xenakais E-J, McFarland M, et al: Do growth-retarded prema- There is currently substantial research effort to explore the role of ture infants have different rates of perinatal morbidity and mortality thanIUGR and adult disease: the so-called “fetal origins of disease” hypoth- appropriately grown premature infants? Obstet Gynecol 87:169, 1996.esis. This subject is addressed in Chapter 11. The epidemiologic studies 23. Spinello A, Capuzzo E, Egbe TO, et al: Pregnancies complicated by intra-of Barker’s group have indicated that IUGR is a significant risk factor uterine growth retardation. J Reprod Med 40:209, 1995.for the subsequent development of chronic hypertension, ischemic 24. 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