CR-6 Chapter 34

Chapter 34 – Intrauterine Growth Restriction

Robert Resnik, MD, Robert K. Creasy, MD

Human pregnancy, similar to pregnancy in other polytocous animal species, can be affected by conditions that restrict the normal growth of the fetus. The growth-restricted fetus is at higher risk for perinatal morbidity and mortality, the risk rising with the severity of the restriction. This chapter reviews the various causes of fetal growth restriction and considers the methods of antepartum recognition and diagnosis along with clinical management. The term intrauterine growth restriction (IUGR), which we first introduced in the third edition of this text, is preferred over intrauterine growth retardation, which frequently connotes mental retardation to the patient.

Definitions

At the beginning of the 20th century all small newborns were thought to be premature, but by the middle of the century the concept of the undernourished neonate arose, and newborns weighing less than 2500 g were then classified by the World Health Organization as low-birth-weight infants. In the 1960s, Lubchenco, Battaglia and colleagues, in a series of classic papers, published detailed graphs of birth weight as a function of gestational age and associated adverse outcomes.[1,2] It was then suggested to classify low-birth-weight neonates into three groups[2,3]:

The classification of newborns by birth weight percentile is of prognostic significance in that those of lower percentiles are at increased risk for immediate perinatal morbidity and mortality, as well as subsequent adult disease.

There is continuing debate as to whether the 10th, 5th, or 3rd birth weight percentile should be used as a cutoff for designation of SGA. The lower the percentile, the higher the risk of poor outcome, but also the greater the chance that a neonate with IUGR and poor outcome will not be detected. The population- based growth curves that traditionally have been used in the United States define SGA as a birth weight below the 10th percentile for gestational age. However, it has been shown[4] that mortality for infants with birth weights between the 10th and 15th percentile are still increased, with an odds ratio approaching 2. Conversely, many newborns whose weights are below the 10th percentile are perfectly normal and simply constitutionally small. An alternative approach, which has sound physiologic and epidemiologic rationale, is that of using customized rather than population-based fetal growth curves.[5] This concept uses optimal birth weight as the end 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 and optimal fetal weight at delivery. A recent large Spanish study[6] showed that customized birth weight percentiles more accurately reflect the potential for adverse outcome. Indeed, newborns considered to be of low birth weight by the general standards, but not by the customized percentiles, did very well. These findings were confirmed by studies from New Zealand and France.[7–9] Customized growth charts can be downloaded at Gestation Network (http://www.gestation.net [accessed February 5,

2008]).

The reliance on only gestational age and birth weight also neglects the issue of body size and length and the clinical observations that there are two main clinical types of IUGR newborns: (1) the infant who is of normal length for gestational age but whose birth weight is below normal (asymmetrically small), and (2) the neonate whose length and weight are both below normal (symmetrically small). Many SGA newborns are merely constitutionally smaller than others and are not at increased risk for either early or remote morbidity and mortality.

One method to evaluate this issue is the ponderal index,[10,11] which is calculated from the birth weight (in grams) and the crown-heel length (in centimeters):

Ponderal index = (birth weight)/(crown-heel length)[3] × 100

1. Preterm neonates—newborns delivered before 37 completed weeks of gestation who are of appropriate size for

gestational age (AGA)

2. Preterm and growth-restricted neonates—newborns delivered before 37 completed weeks of gestation who are small

for gestational age (SGA)

3. Term growth-restricted neonates—newborns delivered after 37 completed weeks of gestation who are SGA. (Not all

SGA term neonates are growth restricted; some cases result from the normal distribution of neonatal weight among a normal base population.)

Page 1 of 2/Intrauterine Growth Restriction/Definitions

Neonates with a ponderal index of less than the 10th percentile for gestational age are defined as growth restricted. In term infants, this index is not significantly affected by differences in race or sex. The disadvantage of this index is the potential error introduced by cubing the crown-heel length. It is not clear whether asymmetric IUGR and symmetric IUGR are two distinct entities or are merely reflections of the severity of the growth restriction process (excluding chromosomal aberrations and infectious disease).

There is currently no acceptable means, except perhaps by the ponderal index, to classify a newborn whose weight is more than 2500 g as having IUGR. The newborn who weighs 2800 g at birth may be growth restricted if the mother has had three previous infants weighing more than 3700 g, but the classification systems would place such an infant in the normal growth category.[12]

Copyright © 2010 Elsevier Inc. All rights reserved. Read our Terms and Conditions of Use and our Privacy Policy. For problems or suggestions concerning this service, please contact: [email protected]

Page 2 of 2/Intrauterine Growth Restriction/Definitions

Rate of Fetal Growth

Different standards for fetal growth throughout gestation have been reported. These standards set the normal range, on the basis of statistical considerations, between 2 standard deviations of the mean (2.5th to 97.5th percentile) or between the 10th and 90th percentiles for fixed gestational ages. The standards most widely used in the United States in the 1960s and 1970s were those developed in Denver, Colorado.[1,2] The Denver standards, however, do not reflect the increase in median birth weight that has occurred over the last 4 decades or the birth weight standards for babies born at sea level. More contemporary standards are available from large geographic regions, such as the state of California, based on data from more than 2 million singleton births between 1970 and 1976.[13] Brenner and colleagues[14] used data on black and white infants from Cleveland and aborted fetuses from North Carolina. Ott[15] studied newborns from St. Louis. Arbuckle and associates[16] based their study on more than 1 million singleton births and more than 10,000 twin gestations in Canada between 1986 and 1988, and Alexander and colleagues[17] used information from 3.8 million births in the United States in 1991. A comparison of their 1991 U.S. national data with that of previous reports (Fig. 34-1) reveals that most of the latter underestimated fetal growth beginning at about 32 weeks. For example, the use of the Colorado[1] or California[13] databases would have resulted in only 2.8% and 7.1% of births, respectively, being classified as below the 10th percentile compared with the 1991 data. The gender-specific 10th percentile values from 20 to 44 weeks are listed in Table 34-1.

FIGURE 34-1 Fetal weight as a function of gestational age by selected references. (From Alexander GR, Himes JH, Kaufman RB, et al: A United States national reference for fetal growth. Obstet Gynecol 87:167, 1996. Reprinted with permission from the American College of Obstetricians and Gynecologists.)

Page 1 of 3//Rate of Fetal Growth

Data obtained from study of induced abortions and spontaneous deliveries indicate that the rate of fetal growth increases from 5 g/day at 14 to 15 weeks of gestation to 10 g/day at 20 weeks, and to 30 to 35 g/day at 32 to 34 weeks. The total substrate needs of the fetus are thus relatively small in the first half of pregnancy, after which the rate of weight gain rises precipitously. The mean weight gain peaks at approximately 230 to 285 g/wk at 32 to 34 weeks of gestation, after 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 the first trimester and decreases steadily thereafter.

TABLE 34-1 10TH PERCENTILE OF BIRTH WEIGHT (g) FOR GESTATIONAL AGE BY GENDER: UNITED STATES, 1991, SINGLE LIVE BIRTHS TO RESIDENTMOTHERS Rights were not granted to include this table in electronic media. Please refer to the printed book. From Alexander GR, Himes JH, Kaufman RB, et al: A United States national reference for fetal growth. Obstet Gynecol 87:167, 1996



FIGURE 34-2 Median growth rate curves for single and multiple births in California, 1970-1976. (From Williams RL, Creasy RK, Cunningham GC, et al: Fetal growth and perinatal viability in California. Obstet Gynecol 59:624, 1982Reprinted with permission from the American College of Obstetricians and Gynecologists.)


Incidence of Intrauterine Growth Restriction

The incidence of IUGR varies according to the population under examination, the geographic location, the standard growth curves used as reference, and the percentile chosen to indicate abnormal growth (i.e., the 3rd, 5th, 10th, or 15th).

Approximately one fourth to one third of all infants weighing less than 2500 g at birth have sustained IUGR, and approximately 4% to 8% of all infants born in developed countries and 6% to 30% of those born in developing countries have been classified as growth restricted.[18]


Page 1 of 1//Incidence of Intrauterine Growth Restriction

Perinatal Mortality and Morbidity

IUGR is associated with an increase in fetal and neonatal mortality and morbidity rates. Perinatal mortality rates for fetuses and neonates weighing less than the 10th percentile, but between 1500 and 2500 g, were 5 to 30 times greater than those of newborns between the 10th and 90th percentiles; for those weighing less than 1500 g, the rates were 70 to 100 times greater.[13] In addition, for birth weights below the 10th percentile, the fetal and neonatal mortality rates rise as gestation advances if birth weights do not increase.

As depicted in Figure 34-3, Manning showed that perinatal morbidity and mortality increase if birth weights are below the 10th percentile, and markedly so if below the 6th percentile.[19]

In general, fetal mortality rates for IUGR fetuses are 50% higher than neonatal mortality rates, and male fetuses with IUGR have a higher mortality rate than female fetuses. The 10% to 30% increase in incidence of minor and major congenital anomalies associated with IUGR accounts for 30% to 60% of the IUGR perinatal deaths (50% of stillbirths and 20% of neonatal deaths).[20] Infants with symmetric IUGR are more likely to die in association with anomalous development or infection. If, however, in the

FIGURE 34-3 Morbidity and mortality in 1560 small-for-gestational-age fetuses. Rights were not granted to include this figure in electronic media. Please refer to theprinted book. (From Manning FA: Intrauterine growth retardation. In Manning FA: Fetal Medicine: Principles and Practice. Norwalk, CT, Appleton & Lange, 1995, p. 312.)

Page 1 of 2//Perinatal Mortality and Morbidity

absence of congenital abnormalities, chromosomal defects, and infection, neonates with symmetric IUGR are probably not at increased risk of neonatal morbidity.[21] The incidence of mortality in the preterm newborn is higher if IUGR is also present.[22] The incidence of intrapartum fetal distress with IUGR approximates 25% to 50%.[23,24]

In addition, IUGR may contribute to perinatal morbidity and mortality by leading to both induced and spontaneous preterm births and 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 including chronic hypertension, heart and lung disease, and type 2 diabetes, are discussed in greater detail in Chapter 59. Lower intelligence quotients, increased mental retardation, and cerebral palsy have also been reported.[26–28]


Page 2 of 2//Perinatal Mortality and Morbidity

Etiology of Intrauterine Growth Restriction

IUGR encompasses many different maternal and fetal entities. Some can be detected before birth, whereas others can be found only at autopsy. It is important to discern the cause of IUGR, because in many cases subsequent pregnancies may also be affected.

Genetic Factors

There has been much interest in determining the relative contributions of factors that produce birth weight variation, namely the maternal and fetal genetic factors and the environment of the fetus. Approximately 40% of total birth weight variation is due to the genetic contributions from mother and fetus (approximately half from each), and the other 60% is due to contributions from the fetal environment.[29]

Although both parents' genes affect childhood growth and final adult size, the maternal genes have the main influence on birth weight. The classic horse-pony cross-breeding experiments by Walton and Hammond demonstrated the important role of the mother.[30] Foals of the maternal horse and paternal pony are significantly larger than foals of the maternal pony and paternal horse, and foals of each cross are comparable in size to foals of the pure maternal breed. These results clearly demonstrated the widely held thesis of a maternally related constraint on fetal growth.

Similar conclusions of maternal constraint to growth are reached from family studies in humans. Low and high birth weights recur in families with seemingly otherwise normal pregnancies. Sisters of women with IUGR babies tend to have IUGR babies, a trend that is not seen in their brothers' babies.[31] There is also a greater similarity in birth weight between maternal half siblings and full siblings than between paternal half siblings and full siblings. Mothers of IUGR infants were frequently growth restricted at birth themselves.[32,33] Although the maternal phenotypic expression—particularly maternal height—may affect fetal growth, the evidence for such an influence is not convincing. Social deprivation has also been associated with IUGR, a finding not explained by known physiologic or pathologic factors.[34]

The one definite paternal influence on fetal growth and size at birth is the contribution of a Y chromosome rather than an X chromosome. The male fetus grows more quickly than the female fetus and weighs approximately 150 to 200 g more than the female at birth.[35] There is also a suggestion that paternal size at birth can influence fetal growth, with birth weights potentially increased by 100 to 175 g.[36] Also, the greater the antigenic dissimilarity between the parents, the larger the fetus.

Whether it is genetically determined or not, women who were SGA at birth have double the risk of reduced intrauterine growth in their fetuses.[37] In similar fashion, fetuses destined to deliver preterm have a higher incidence of reduced fetal growth.[25,38] The role of the genetic constitution of mother or fetus in these observations is not clear.

Specific maternal genotypic disorders can cause IUGR, one example being phenylketonuria.[39] Infants born to homozygously affected mothers almost always have IUGR, but whether the reason is an abnormal amount of metabolite crossing from mother to fetus or an inherent problem in the fetus is unknown.

There is a significant association between IUGR and congenital malformations (see later discussion) Such abnormalities can be caused by established chromosomal disorders or by dysmorphic syndromes, such as various forms of dwarfism. Some of these malformations are the expression of a specific gene abnormality with a known inheritance pattern, whereas others are only presumed to be the result of a gene mutation or an adverse environmental influence.

Although in some reports only 2% to 5% of IUGR infants have a chromosomal abnormality, the incidence rises to 20% if IUGR and mental retardation are both present.[40] Birth weights in infants with trisomy 13, 18, and 21 are lower than normal,[41,42] with the decrease in birth weight being less pronounced in trisomy 21. The frequency distribution of birth weights in infants with trisomy 21 is shifted to the left of the normal curve after 34 weeks of gestation, resulting in gestational ages 1 to 1.5 weeks less than normal, and birth weights and lengths are less than in control infants from 34 weeks until term. This effect is more marked after 37 weeks of gestation, but birth weights are still only approximately 1 standard deviation from mean weight. Birth weights in translocation trisomy 21 are comparable to those in primary trisomy 21. Birth weights of newborns who are mosaic for normal and 21-trisomic cells are lower than normal but higher than those of 21-trisomic infants.[29] Newborns with other autosomal abnormalities, such as deletions (chromosomes 4, 5, 13, and 18) and ring chromosome structure alterations, also have had impaired fetal growth.

Although abnormalities of the female (X) and male (Y) sex chromosomes are frequently lethal (80% to 95% result in first-trimester spontaneous abortions), they could be a cause of IUGR in a newborn.[18,28] Infants with XO sex chromosomes have

Page 1 of 2//Etiology of Intrauterine Growth Restriction

a lower mean birth weight than control infants (approximately 85% of normal for gestational age) and are approximately 1.5 cm shorter at birth. Mosaics of 45,X and 46,XX cells are affected to a lesser degree. Although a paucity of reports prevents definite conclusions, it appears that the repressive effect on fetal growth is increased with the addition of X chromosomes, each of which results in a 200- to 300-g reduction in birth weight.[43]

IUGR is associated with numerous other dysmorphic syndromes, particularly those causing abnormal brain development (see Chapters 1 and 17).

The overall contribution that chromosomal and other genetic disorders make to human IUGR is estimated to be 5% to 20%. Approximately 25% of fetuses with early-onset fetal growth restriction could have chromosomal abnormalities, and karyotyping via cordocentesis can be considered (see Chapter 17). A genetic basis should be considered strongly if IUGR is encountered in association with neurologic impairment or early polyhydramnios.


Page 2 of 2//Etiology of Intrauterine Growth Restriction

Congenital Anomalies

In a study of more than 13,000 anomalous infants, 22% had IUGR.[44] Newborns with cardiac malformations are frequently of low birth weight and length for gestation, with the possible exception of those with tetralogy of Fallot and transposition of the great vessels. The subnormal size of many infants with cardiac anomalies (as low as 50% to 80% of normal weight with septal defects) is associated with a subnormal number of parenchymal cells in organs such as the spleen, liver, kidneys, adrenals, and pancreas.[45] The anencephalic fetus is also usually growth restricted.

Approximately 25% of newborns with a single umbilical artery weigh less than 2500 g at birth, and some of these are born preterm.[46] Abnormal umbilical cord insertions into the placenta are also occasionally associated with poor fetal growth.[47] The presence of cord encirclements around the fetal body is also associated with IUGR.[48]

Structural malformations, single umbilical artery, and monozygotic twins are relatively rare and probably account for no more than 1% to 2% of all human instances of IUGR.


Page 1 of 1//Congenital Anomalies

Infection

Infectious disease is known to cause IUGR, but the number of organisms having this effect is poorly defined, and the extent of the growth restriction can be variable There is sufficient evidence for a causal relationship between infectious disease and IUGR for two viruses—rubella and cytomegalovirus,[49] and there is evidence for a possible relationship with varicella,[50] severe herpes zoster, and human immunodeficiency virus (HIV) infection, although the latter may be complicated by other problems associated with HIV (see Chapter 38).

With rubella infection, the incidence of IUGR may be as high as 60%, with infected cells remaining viable for many months.[51] There is capillary endothelial damage, hypoplasia, and necrotizing angiopathy in many fetal organs.[52] With cytomegalovirus infection, there is cytolysis, localized necrosis within various fetal organs, and a decrease in cell number.[53]

Although there are no bacterial infections known to cause IUGR, histologic chorioamnionitis is strongly associated with symmetric IUGR between 28 and 36 weeks, and with asymmetric IUGR after 36 weeks of gestation.[54]

Protozoan infections resulting from Toxoplasma gondii, Plasmodium sp., or Trypanosoma cruzi (Chagas disease) reportedly can cause IUGR.[49]

Although the incidence of maternal infections with various organisms may be as high as 15%, the incidence of congenital infections is estimated to be no more than 5%. It is believed that infectious disease can account for no more than 5% to 10% of human IUGR.


Page 1 of 1//Infection

Multiple Gestation

It has long been recognized that multiple pregnancies are associated with a high progressive decrease in fetal and placental weight as the number of offspring increases in humans and in various animal species (see Chapter 25).[55,56] In both singleton and twin gestations, there is a relationship between total fetal mass and maternal mass. The increase in fetal weight in singleton gestations is linear from approximately 22 to 24 weeks until approximately 32 to 36 weeks of gestation.[13,17] During the last weeks of pregnancy, the increase in fetal weight declines, actually becoming negative after 42 weeks in some pregnancies.

If nutrition is adequate in the neonatal period, the slope of the increase in neonatal weight parallels the increase in fetal weight seen before 34 to 38 weeks. The decline in fetal weight increase occurs when the total fetal mass approximates 3000 to 3500 g for either singleton or twin gestations. When growth rate is expressed incrementally, the weekly gain in singletons peaks at approximately 230 to 285 g/wk between 32 and 34 weeks of gestation (see Fig 34-2). In individual twin fetuses, the incremental weekly gain peaks at 160 to 170 g/wk between 28 and 32 weeks of gestation.[13] However, recent studies in triplets have indicated that the growth of individual triplets may continue in a linear fashion well beyond a total combined weight of 3500 g.[57] Others have reported that before 35 weeks of gestation, triplets grow at about the 30th percentile for singletons, and by 38 weeks the average weight of each triplet is at the 10th percentile.[58] Significant birth weight discordance also occurs if there is unequal sharing of the placental mass.[59] If multifetal reduction is performed, there is an increase in IUGR in the surviving fetuses.[60]

The decrease in weight of twin fetuses, frequently with mild IUGR, is usually due to decreased cell size; the exception is severe IUGR associated with monozygosity and vascular anastomoses, wherein cell number also may be decreased.[61] These changes in twins are similar to those seen in IUGR secondary to poor uterine perfusion or maternal malnutrition. Twins with mild IUGR have an acceleration of growth after birth, so that their weight equals the median weight of singletons by 1 year of age. This observation supports the thesis that the etiology of poor fetal growth in twin gestations is an inability of the environment to meet fetal needs, rather than an inherent diminished growth capacity of the twin fetus. The example of twin fetuses supports the thesis derived from normal singleton pregnancies that the human fetus is seldom able to express its full potential for growth.

Many components of the environment can limit fetal growth (see later discussions). Twin-to-twin transfusion secondary to vascular anastomoses in monochorionic-monozygotic twins frequently results in IUGR of one twin, usually the donor (see Chapter 25). Maternal complications associated with IUGR occur more frequently with twins, and the incidence of congenital anomalies is almost twice that of singletons, primarily among monozygotic twin gestations. The incidence of IUGR in twins is 15% to 25%[16,62]; because the incidence of spontaneous multiple gestations approximates 1%, these pregnancies probably account for less than 3% of all cases of human IUGR. The actual incidence could be closer to 5% because of the increase in multiple gestations secondary to assisted reproductive techniques.


Page 1 of 1//Multiple Gestation

Inadequate Maternal Nutrition

Numerous animal studies have demonstrated that undernutrition of the mother caused by protein or caloric restriction can affect fetal growth adversely. However, information from experiments using 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, such animal studies have engendered important concepts.

Winick[63] reported that there are three phases of fetal growth: cellular hyperplasia, followed by both hyperplasia and hypertrophy, and then predominantly hypertrophy. If there is a decrease in available substrate, the timing of the decrease is reflected in the type of IUGR observed. If the insult occurs early in pregnancy, the fetus is likely to be born with a decrease in cell number and cell size (such as might be observed with severe chronic maternal undernutrition or an inability to increase uteroplacental blood flow during gestation) and to have symmetric IUGR. If the insult occurs late in gestation, such as with twin gestation, the fetus is likely to have a normal cell number but a restriction of cell size (which can be returned to normal with adequate postnatal nutrition) and to have asymmetric IUGR.

The importance of maternal nutrition in fetal growth and birth weight was demonstrated by studies in Russia and Holland, where women suffered inadequate nutrition during World War II. The population in Leningrad underwent a prolonged period of poor nutrition, during which both preconception nutritional status and gestational nutrition were poor and birth weights were reduced by 400 to 600 g.[64] In Holland, a 6-month famine created conditions that permitted evaluation of the effect of malnutrition during each of the trimesters of pregnancy in a group of women previously well nourished.[65] Birth weights declined by approximately 10%, and placental weights by 15%, only when undernutrition occurred in the third trimester with daily caloric intake of less than 1500 kcal. The difference in severity of the IUGR in these two populations suggests the importance of prepregnancy nutritional status, an idea that has been substantiated.[18,66] In addition, animal studies indicate that fetal growth, metabolic and endocrine function, as well as placental status and function in late pregnancy, are significantly altered by the periconception maternal nutritional status, an effect independent of fetal size.[67] More recent studies have shown that inadequate weight gain in pregnancy (defined as <0.27 kg/wk, or <10 kg at 40 weeks, or based on suggested weight gain for body mass indices; see Chapter 10) is associated with an increased risk of IUGR. Weight gain in the second trimester appears to be particularly important.[67] Adequate maternal weight gain by 24 to 28 weeks in multiple pregnancies correlates positively with good fetal growth.[68]

It is still unclear whether it is generalized calorie intake reduction or specific substrate limitation (e.g., protein or key mineral restriction), or both, that is important in producing IUGR (see Chapter 10). Glucose uptake by the fetus is critical, because there is the suggestion that little glucogenesis occurs in the normal fetus. In the IUGR fetus, the maternal-fetal glucose concentration difference is increased as a function of the severity of the IUGR,[69] facilitating glucose transfer across the small placenta. Decreases in zinc content of peripheral blood leukocytes also correlate positively with IUGR,[70] and serum zinc concentrations of less than 60 μg/dL in the third trimester are associated with a fivefold increase in the incidence of low birth weight.[71] Similarly, an association between low serum folate levels and IUGR has been reported.[72] Although there have been numerous studies on supplementation, there is no convincing evidence that high protein intake or caloric supplementation has a beneficial effect on fetal weight. In addition, if a fetus is receiving decreased oxygen delivery as a result of decreased uteroplacental perfusion and has adapted by slowing metabolism and growth, it may not be advisable to increase substrate delivery. This important issue remains unresolved.

Another maternal nutrient that is important to fetal growth is oxygen. It is probably a primary determinant of fetal growth. IUGR infants have a decrease in the partial pressure of oxygen and decreased oxygen saturation values in the umbilical vein and artery.[73] The median birth weight of infants of women living more than 10,000 feet above sea level is approximately 250 g less than that of infants of women living at sea level.[74] Pregnancies complicated by maternal cyanotic heart disease usually result in IUGR, but it is unclear whether abnormal maternal hemodynamics or the reduction in oxygen saturation (by approximately 40% in the umbilical vein) accounts for the poor fetal growth.[75] The association between hemoglobinopathies and IUGR could be due to decreased blood viscosity or decreased fetal oxygenation. Patients with chronic pulmonary disease (e.g., poorly controlled asthma, cystic fibrosis, bronchiectasis) and those with severe kyphoscoliosis may be at increased risk of IUGR.


Page 1 of 1//Inadequate Maternal Nutrition

Environmental Toxins

Maternal cigarette smoking decreases birth weight by approximately 135 to 300 g; the fetus is symmetrically smaller.[76,77] If smoking is stopped before the third trimester, its adverse effect on birth weight is reduced.[77] More disturbing is the reported dose-response relationship between maternal smoking and a smaller infant head size, specifically a circumference of less than 32 cm, as well as a head circumference more than 2 standard deviations below that expected for gestational age.[78] The reason why not all women who smoke have IUGR infants could be a function of maternal genetic susceptibility.[79]

Reduction in birth weight also occurs with maternal alcohol ingestion of as little as one to two drinks per day.[80] Cocaine use in pregnancy similarly decreases birth weight, but there is also a reduction of head circumference that is more pronounced than the reduction in birth weight.[81] Use of other drugs, such as the anticonvulsants phenytoin and trimethadione, warfarin, and heroin, has been implicated in IUGR (see Chapter 20).


Page 1 of 1//Environmental Toxins

Placental Factors

Although placental size does not necessarily equate with function, our inability to clinically properly evaluate human placental function has resulted in studies of the interrelationships of size, morphometry, and clinical outcome. In general, birth weight increases with increasing placental weight in both animals and humans. IUGR without other anomalies is usually associated with a small placenta. Chromosomally normal IUGR newborns have a 24% smaller placenta for gestational age.[82] A small placenta is not always associated with an IUGR newborn, but a large infant from an otherwise normal pregnancy does not have a small placenta. Placental weight increases throughout normal gestation; with IUGR, the placental weight plateaus after 36 weeks or earlier, and the placenta (after being trimmed of the membranes and cord) weighs less than 350 g.[83] As normal gestation advances, there is a greater increase in fetal weight than in placental weight, so there is an increase in the fetal-placental weight ratio in large-for-gestational-age (LGA), AGA, and SGA infants in the last half of gestation. In all three categories, when the fetal-placental weight ratio is greater than 10, there is an increased incidence of depressed newborns; this suggests that it is not only the IUGR fetus that can outgrow the capacity of the placenta to bring about adequate transfer of necessary nutrients.[83]

Adequate trophoblastic invasion of the uterine decidual bed, and the resultant alteration in uterine blood flow, is a vital necessity, not only for the initial establishment and adherence of the pregnancy, but for also the adequate supply of nutrients to the fetus. The trophoblasts invade the decidua and myometrium to anchor the placenta, and a subpopulation of cytotrophoblasts invades the uterine blood vessels at the implantation site, resulting in extensive remodeling of the vessels.[84–87] There is a replacement of endothelium and uterine smooth muscle cells, which leads to a reduction in uterine arterial resistance and an increase in uteroplacental perfusion. Apoptosis plays an integral role in these vascular changes. It has also been suggested that the cytotrophoblast initiates lymphangiogenesis in the pregnant uterus; this is normally lacking in the nonpregnant state.

A number of reports have revealed that, in many cases of IUGR, particularly in early IUGR, the depth of invasion by the cytotrophoblasts is shallow and the endovascular invasion rudimentary; they have thus confirmed the early classic work of Brosens and colleagues,[88] who described reduced trophoblastic invasion and decreased pregnancy-associated alterations in the placental bed of IUGR pregnancies. The detailed morphologic studies of Aherne and Dunnill[89] also demonstrated that the mean surface area and, more importantly, the capillary surface area were reduced in the placentas of IUGR newborns. Apoptosis at the implantation site is increased with IUGR, and this has been suggested to be the mechanism limiting endovascular invasion.[86,90,91] The placental vascular endothelial growth factor (VEGF) and placenta growth factor (PIGF) were reduced, and antagonists were increased, in studies of early IUGR confirmed by Doppler imaging.[92] In summary, early abnormal implantation plays a key role in IUGR, but the exact controlling mechanisms behind the impaired placentation remain to be delineated.

The terminal villi are maldeveloped in IUGR pregnancies when absent end-diastolic flow is demonstrated, indicating that these morphologic changes are associated with increased vascular impedance.[93] When end-diastolic flow, is absent, there are more occlusive lesions of the intraplacental vasculature than when end-diastolic flow is present.[94]

Information from cordocentesis studies has revealed fetal hypoxemia, 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.[97]

Abnormal insertions of the cord, placental hemangiomas, abruptio placentae, and placenta previa are also associated with IUGR.[98–100]


Page 1 of 1//Placental Factors

Maternal Vascular Disease

Substantial evidence from experimental animal studies suggests that alterations in uteroplacental perfusion affect the growth and status of the placenta as well as the fetus. Ligation of the uterine artery of one horn of the pregnant rat results in IUGR of those fetuses nearest the constriction, and fetal and placental weights in guinea pigs, mice, and rabbits are lowest in the middle of each uterine horn, where arterial perfusion is lowest. Repetitive embolization of the uterine vascular bed during the last quarter of gestation in sheep gives rise to localized hyalinization and fibrinoid changes in the placenta[101] and results in a 40% reduction in placental weight and alterations in organ growth patterns similar to those observed in IUGR fetuses from pregnancies complicated by maternal hypertensive disease. In addition, umbilical blood flow is reduced and fetal oxidative metabolism is decreased.[101,102]

It has been strongly suggested in various studies that uteroplacental blood flow is decreased in pregnancies complicated by maternal hypertensive disease. Defective trophoblastic invasion of the uterine vascular bed results in relatively intact musculoelastic vessels that resist the normal decrease in uterine vascular resistance.[103] Clearance of radioactive tracers from the intervillous space is reduced in preeclamptic patients.[104,105] Because maternal body mass and plasma volume are correlated, reduced plasma volume or prevention of plasma volume expansion could lead to decreased cardiac output and uterine perfusion and a resultant decrease in fetal growth.[106,107] Alternatively, it may be that abnormal placentation comes first.

The importance of normal trophoblastic invasion leading to normal maternal cardiovascular changes has been indicated by central maternal cardiovascular studies. IUGR below the 3rd percentile at 25 to 37 weeks of gestation is associated with reduced maternal systolic function, increased vascular resistance, and probable lack of volume expansion in otherwise normotensive patients.[108]

Uteroplacental flow-velocity waveform studies, using Doppler methods in pregnancies complicated by hypertension, have shown a higher incidence of IUGR in pregnancies in which abnormal waveforms were recorded. These abnormal waveforms are thought to reflect abnormally increased resistance to blood flow.[109,110] High-resistance hypertension is associated with a marked decrease in fetal weight compared with low-resistance hypertension.[111] Increasing uteroplacental resistance, recorded with this methodology, has been positively correlated with fetal hypoxemia as determined by cordocentesis in IUGR fetuses.[95]

As discussed in Chapter 40, there is conflicting evidence as to whether the congenital thrombophilias contribute to the clinical development of IUGR, with most recent studies suggesting the lack of an association.[112–115]

There are only fragmentary suggestions relating abnormal anatomic uterine vascular anatomy and IUGR. IUGR may occur at a higher frequency if the pregnancy is in a unicornuate uterus; vascular abnormalities are likely but unproven in such cases.[116] Patients with two (rather than the usual one) ascending uterine arteries on each side of the uterus also have a higher rate of IUGR.[117] However, pregnancy after bilateral ligation of the internal iliac and ovarian arteries, or after embolization of leiomyomata, is not associated with IUGR.[118,119]

Because exercise can affect uterine perfusion, this subject has been studied extensively. A moderate regimen of weight-bearing exercise in early pregnancy probably enhances fetal growth.[120] However, high levels of exercise (>50% of prepregnancy levels) in middle and late pregnancy result mainly in a symmetric reduction in fetal growth and neonatal fat mass.[121] In assessing levels of aerobic activity, neonates born to women in the highest quartile weighed 600 g less than those in the lowest quartile, an effect mainly seen in taller women.[122]

Clinical maternal vascular disease and the presumed decrease in uteroplacental perfusion can account for at least 25% to 30% of IUGR infants. Undiagnosed decreased perfusion could also be the cause of IUGR in an otherwise normal pregnancy, such as with recurrent idiopathic fetal growth restriction. A history of a previous low-birth-weight infant is significantly associated with the subsequent birth of an infant with decreased weight, decreased ponderal index, and decreased head circumference.[123] This finding of symmetric growth restriction is in contrast to the asymmetric IUGR usually seen with maternal vascular disease.

Vascular disease becomes more prevalent with advancing age. In one recent large study, after controlling for confounding variables, the incidence of SGA births was increased more in nulliparous patients than in multiparous patients older than 30 years of age.[124]


Page 1 of 1//Maternal Vascular Disease

Maternal and Fetal Hormones

In general, there is limited transfer of the various circulating maternal hormones into the fetal compartments (see Chapters 46 through 48).

Although the effects of hypothyroidism or hyperthyroidism on fetal size are not striking, studies in subhuman primates indicate that, when the mother and fetus are athyroid, there is retarded osseous development and reduced protein synthesis in the fetal brain.[125]

Maternal diabetes without vascular disease is frequently associated with excessive fetal size (see Chapter 46). Although insulin does not cross the placenta, fetal hyperinsulinemia as well as hyperplasia of the pancreatic islet cells is seen frequently with maternal diabetes. These changes are thought to occur as a result of maternal hyperglycemia, which leads to fetal hyperglycemia and an increased response of the fetal pancreas. Fetal hypoinsulinemia produced experimentally in the rhesus monkey results in IUGR; rarely, infants have been born with severe IUGR and requiring insulin treatment at birth, suggesting hypoinsulinemia in utero.[126,127] If nutrient transfer becomes limited owing to placental disease secondary to maternal vascular disease, the fetus of the diabetic mother can sustain IUGR.

Even though human growth hormone is present early in gestation, there is minimal evidence that it regulates fetal weight, although a deficiency could retard skeletal growth.[128] Convincing evidence is also lacking that adrenal hormones have a role in producing IUGR in humans.

Several small polypeptides with in vitro growth-promoting activity have been purified (e.g., insulin-like growth factor 1 [IGF-1], IGF-2), but the exact role of these peptides and their binding proteins as fetal growth factors and their potential relationship to IUGR are currently not well understood.

Leptin (from Greek leptos, “thin”) is a polypeptide hormone discovered in 1994. It has been shown to moderate feeding behavior and adipose stores. It is produced predominantly by adipocytes but can also be produced by the placenta, because neonatal levels fall dramatically after birth.[128] Reported concentrations in IUGR have varied, and the exact role that this hormone plays in fetal growth remains to be clarified.


Page 1 of 1//Maternal and Fetal Hormones

Diagnosis of Intrauterine Growth Restriction

Determination of Cause

An attempt should be made to determine the cause of fetal aberrant growth before delivery in order to provide appropriate counseling; perform ultrasonographic evaluation for fetal growth velocity, delineate anatomy and function; and obtain neonatal consultation.

The various disorders associated with suboptimal fetal growth were addressed earlier in this chapter and are summarized in Table 34-2. Often, the cause is readily apparent. Among patients with significant chronic hypertensive disease, those who take prescribed medications known to be associated with prenatal growth deficiency, and those whose fetuses have congenital or chromosomal abnormalities, the diagnosis is easily established and management plans can be made. At times, however, the causal factors can be more elusive. For example, growth restriction associated with preeclampsia may antedate the appearance of hypertension or proteinuria by several weeks. In many instances, a careful history, maternal examination, and ultrasound evaluation reveal the etiology.

TABLE 34-2 -- DISORDERS AND OTHER FACTORS ASSOCIATED WITH INTRAUTERINE GROWTH RESTRICTION[*]


Maternal Factors Hypertensive disease, chronic or preeclampsia Renal disease

Severe nutritional deficiencies (e.g., inflammatory bowel disease, markedly inadequate pregnancy weight gain in the underweight woman, malnutrition)

Pregnancy at high altitude Specific prescribed medications (e.g., antiepileptics) Smoking, alcohol use, illicit drug use

Fetal Factors Multiple gestations Placental abnormalities Infections Aneuploidy or structural abnormalities* Growth is also strongly influenced by maternal prepregnancy weight and by ethnicity, which must be considered when evaluating overall

growth (by use of customized versus population-based growth curves).

Page 1 of 1//Diagnosis of Intrauterine Growth Restriction

History and Physical Examination

Clinical diagnosis of IUGR by physical examination alone is inaccurate; often, the diagnosis is not made until after delivery. Most clinical studies demonstrate that, with the use of physical examination alone, the diagnosis of IUGR is missed or incorrectly made almost half the time. Techniques such as measurement of the symphysis-fundal height are helpful in screening for abnormal fetal growth and documenting continued growth if they are performed repeatedly by the same observer, but they are not sensitive enough for accurate detection of most infants with IUGR.[129,130]

Despite the inaccuracy of such indicators, fetal assessment and specific aspects of the patient's risk factors increase the clinician's index of suspicion about suboptimal fetal growth, without which more definitive laboratory investigation might not be considered. As discussed earlier, maternal disease entities such as hypertension, in particular severe preeclampsia and chronic hypertension with superimposed preeclampsia, carry a high incidence of IUGR. The diagnosis of a multiple gestation suggests the likelihood of diminished fetal growth relative to gestational age, as well as preterm birth. Additional maternal risk factors include documented rubella or cytomegalovirus infection, heavy smoking, heroin or cocaine addiction, alcoholism, and poor nutritional status both before conception and during pregnancy combined with inadequate weight gain during pregnancy.


Page 1 of 1//History and Physical Examination

Ultrasonography

Currently, ultrasonographic evaluation of the fetus is the preferred and accepted modality for the diagnosis of inadequate fetal growth. It offers the advantages of reasonably precise estimations of fetal weight, determination of interval fetal growth velocity, and measurement of several fetal dimensions to describe the pattern of growth abnormality. Use of these ultrasound measurements requires accurate knowledge of gestational age. Accordingly, if a patient is known to be at risk for a fetal growth abnormality, the crown-to-rump length should be determined during the first trimester.

Measurements of biparietal diameter, head circumference, abdominal circumferences, and femur length allow the clinician to use accepted formulas to estimate fetal weight and to determine whether a fetal growth aberration represents an asymmetric, symmetric, or mixed pattern[131] (Fig. 34-4). As discussed previously, intrinsic fetal insults occurring early in pregnancy (e.g., infection, exposure to certain drugs or other chemical agents, chromosomal abnormalities, other congenital malformations) are likely to affect fetal growth at a time of development when cell division is the predominant mechanism of growth. Consequently, musculoskeletal dimensions and organ size may be adversely affected, and a symmetric pattern of aberrant growth is observed. Given this set of circumstances, one might expect to find that the femur length and head circumference are small for a given gestational age, as are the abdominal circumference and overall fetal weight, all of which are characterized as symmetric IUGR. Symmetric IUGR accounts for approximately 20% to 30% of all growth-restricted fetuses.

Page 1 of 2//Ultrasonography

At the other end of the spectrum, an extrinsic insult occurring later in pregnancy, usually characterized by inadequate fetal nutrition due to placental insufficiency, is more likely to result in asymmetric growth restriction. In this type, femur length and head circumference are spared, but abdominal circumference is decreased because of subnormal hepatic growth, and there is a paucity of subcutaneous fat. The most common disorders that limit the availability of fetal substrates for metabolism are the hypertensive complications of pregnancy, 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 the abdominal circumference is one of the earliest findings in extrinsic or asymmetric IUGR[132,133]; conversely, the finding of an abdominal circumference in the normal range for gestational age markedly decreases the likelihood of IUGR. Frequently, these patterns of growth abnormality merge, particularly after long-standing fetal nutritional deprivation.

Distinguishing between symmetric and asymmetric IUGR is also of considerable clinical significance and may provide useful information for both diagnostic and counseling purposes. For example, a diagnosis of symmetric IUGR in early pregnancy suggests a poor prognosis when the diagnostic possibilities are considered (e.g., fetal infection, aneuploidy); conversely, asymmetric IUGR observed in the third trimester, particularly if it is associated with maternal hypertension or placental dysfunction, usually imparts a more favorable prognosis with careful fetal evaluation, appropriate delivery timing, and skillful neonatal management.

Considerable attention has been directed at early ultrasound findings that may provide for the early prediction of IUGR. In a study of 976 women whose pregnancies were the product of assisted reproductive technologies, the risk of delivering an SGA fetus decreased as a 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.[135]

Efforts have also been made to correlate Doppler findings in the uterine artery with subsequent pregnancy complications, including IUGR. Utilizing transvaginal color Doppler at 23 weeks' gestation, Papageorghiou and colleagues observed that increases in the uterine artery pulsatility index and “notching” were associated with subsequent development of IUGR, although the predictive value was low.[136] In a more recent study of uterine artery pulsatility index at 11 to 14 weeks' gestation, a value greater than the 95th percentile predicted SGA with accuracy in 23% of the cases, and with increased sensitivity if the maternal serum concentration of plasma-associated pregnancy protein A (PAPP-A) was low. However, this parameter did not reach statistical significance.[137] The eventual practical role that uterine artery Doppler ultrasound may play in the prediction of IUGR, if any, awaits more extensive evaluation.


FIGURE 34-4 Composite of fetal body measurements used for serial evaluations of fetal growth.

Page 2 of 2//Ultrasonography

Management of Pregnancy

The cornerstones of management for the pregnancy complicated by IUGR are surveillance of fetal growth velocity and function (well-being) and determination of appropriate delivery timing. Delivery at or near term is usually indicated if fetal growth has continued to be adequate and antenatal testing results have been normal. Management is far more challenging remote from term and requires use of the biophysical profile (BPP), measurement of amniotic fluid volume (AFV), and Doppler assessment of the fetal circulation, combined with good clinical judgment. The comments in the following sections pertain primarily to the use of antenatal testing in the preterm fetus with IUGR.

Antenatal Fetal Testing

The various diagnostic modalities used for fetal assessment are discussed in detail in Chapter 21, but specific points are reemphasized here.

Biophysical Profile and Amniotic Fluid Volume

The BPP is appealing, inasmuch as it provides a multidimensional survey of fetal physiologic parameters. In particular, AFV assessment is an important aspect of the BPP, because oligohydramnios is a frequent finding in the IUGR pregnancy caused by placental insufficiency. This is presumably a result of diminished fetal blood volume, renal blood flow, and urinary output. Human fetal urinary production rates can be measured with considerable accuracy,[138] and three separate studies have shown decreased rates in the presence of fetal growth restriction.[139–141]

The significance of AFV with respect to fetal outcome has been well documented. Manning and coworkers reported the diagnostic value of AFV measurement in discriminating normal from aberrant fetal growth. Among 91 patients with normal AFV, 86 delivered infants whose birth weights were appropriate for gestational age. In contrast, 26 of 29 patients with decreased AFV delivered growth-restricted infants.[142] Severe oligohydramnios is associated with a high risk of fetal compromise.[143,144]

It is likely that the chronic hypoxic state frequently observed in the fetus with IUGR is responsible for diverting blood flow from the kidney to other organs that are more critical during fetal life (see Chapters 12 and 14). Nicolaides and associates[141] observed reduced fetal urinary flow rates in IUGR, and the degree of reduction was well correlated with the degree of fetal hypoxemia as reflected by fetal blood PO2 measured after cordocentesis.

The most appropriate technique for assessment of AFV, as well as the arguments for and against each technique, are addressed in Chapters 21 and 32. It is reasonable to conclude at this time that a single vertical pocket smaller than 2 cm, or an amniotic fluid index of less than 5 cm, or both, suggests that there is a clinically significant decrease in AFV; conversely, a normal AFV is very reassuring with respect to fetal well-being and also suggests the possibility of a normal but constitutionally small fetus.

There is a paucity of evidence from randomized trials to validate the use of the BPP.[145] However, its usefulness was suggested by several large observational reports. In a study of 19,221 high-risk pregnancies, Manning and colleagues[146] observed that the fetal death rate after a normal BPP score (≥8) was 0.726 in 1000 births; only 14 such fetuses died. Of the total patient population, approximately 4380 pregnancies were complicated by IUGR, and only 4 of those infants died after a normal test, yielding a false-negative test rate of less than 1 in 1000. In a subsequent analysis of perinatal morbidity and mortality among patients monitored with the BPP, a highly significant inverse correlation 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 with IUGR. Conversely, if the last test score was 4 or 2, the incidence of IUGR increased to 29% and 41%, respectively.[147]

Doppler Ultrasound Assessment of the Fetal Vasculature

ARTERIAL CIRCULATION

There has been great interest in the role of Doppler assessment of the fetal arterial and venous circulation in predicting and evaluating fetal growth restriction as well as other fetal complications (see Chapter 21). It is now clear that umbilical arterial velocimetry is of considerable 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 resistance in IUGR. Specifically, fetuses demonstrating an absence of end-diastolic flow exhibited maldevelopment of the placental terminal villous tree. The correlations among placental pathology, abnormal umbilical artery velocimetry, and IUGR were

Page 1 of 2//Management of Pregnancy

reviewed by Kingdom and coworkers.[148]

Several randomized trials have been reported which, taken together, demonstrated a decrease in perinatal deaths when umbilical arterial Doppler assessment was used in conjunction with other types of antenatal testing.[149–151] A meta-analysis of 12 randomized, controlled trials showed that clinical action guided by umbilical Doppler velocimetry reduced the odds of perinatal death by 38% and decreased the risk of inappropriate intervention in pregnancies thought to be at risk of IUGR.[152] Although the authors hypothesized that this beneficial effect depended on the incidence of absent end-diastolic velocity rather than simply decreased flow, the number of studies with sufficient data was inadequate to draw this conclusion. A recent retrospective cohort study of 151 IUGR fetuses comparing abnormal umbilical artery Doppler, a “nonreactive” nonstress test, and a BPP value of 6 or less confirmed that abnormal Doppler flow was the best predictor of adverse outcome.[153]

Therefore, umbilical artery velocimetry plays a significant role in the management of IUGR. A normal velocimetry result in the suspect small fetus is usually indicative of a constitutionally small but otherwise normal baby,[154] although a normal finding is also observed in the chromosomally or structurally abnormal fetus.[155] Diminished end-diastolic flow is rarely associated with significant neonatal morbidity, but the absence or reversal of end-diastolic flow predicts significantly increased perinatal morbidity and mortality and long-term poor neurologic outcome, compared with continuing diastolic flow.[156,157] Furthermore, markedly diminished end-diastolic flow can be observed at very premature gestational ages, well before the BPP demonstrates abnormalities. Consequently, abnormal umbilical velocimetry findings should be interpreted in conjunction with other tests of fetal well-being and in the context of the gestational age.

There also has been interest in the evaluation of middle cerebral artery flow, inasmuch as the normal adaptive response to hypoxia within the fetus is to increase cerebral blood flow (“brain-sparing”). However, the results from several studies have been contradictory, and the focus of attention has been on umbilical artery flow and the venous circulation.

VENOUS CIRCULATION

In contrast to abnormalities in arterial circulation, abnormalities observed in the venous circulation presumably reflect central cardiac failure, and multiple current studies suggest that specific aberrations of flow through the ductus venous and umbilical vein are indicative of imminent fetal demise, as well as substantial morbidity among survivors. The temporal sequence of Doppler-measured flow abnormalities in the arterial and venous circulations of the IUGR fetus has been delineated.[158,159] The fetus with severe IUGR first demonstrates changes in the umbilical and middle cerebral arteries. This is followed by alterations in the venous circulation, including the ductus venosus (abnormalities in the atrial portion of the flow) and the umbilical vein (pulsatile flow). These changes and their pathophysiology have been summarized in detail by Baschat and Harman.[160] What has become clear is that abnormal venous Doppler waveforms in the preterm IUGR fetus are indicative of poor acid-base status and outcome.[161,162] Therefore, the challenge for the clinician is to try to optimize delivery timing in the very preterm fetus, before significant abnormalities in the venous circulation occur.


Page 2 of 2//Management of Pregnancy

Antepartum Therapy

Maternal hyperoxia has been shown to increase umbilical PO2 and pH in the hypoxemic, acidotic, growth-restricted fetus.[163] Among surviving fetuses, there was also an improvement in mean velocity of blood flow through the thoracic aorta. In support of these findings, Battaglia and coworkers treated 17 of 36 women whose pregnancies were complicated by IUGR with maternal hyperoxia and confirmed improvement in both blood gases and Doppler flow. They also observed a significant improvement in perinatal mortality in the oxygen-treated patients.[164] However, the evidence is inconclusive regarding whether chronic maternal oxygen therapy is of value, and any differences reported in outcome could be due to more advanced gestational age in oxygen-treated groups.[165]

Nutritional supplements, including antioxidants such as vitamins C and E, have not been shown to be effective in reducing the risk of IUGR.[166] There has also been considerable interest in the role of fish oil supplements, but a Cochrane Database Review of six trials revealed no significant difference in the proportion of SGA infants in treated versus untreated groups.[167]

The role of low-dose aspirin remains controversial, and most studies have examined subsets of women treated for the prevention of preeclampsia. A meticulous analysis of the current data revealed a 10% reduction in SGA infants, but this strong trend did not achieve statistical significance.[168] This subject was recently reviewed by Berghella.[169]


Page 1 of 1//Antepartum Therapy

Timing of Delivery

The prohibitive perinatal morbidity and mortality rates among IUGR infants were discussed previously. Controversy continues with regard to the timing of delivery for such infants to ensure that neurologic damage or fetal intrauterine death does not occur because of chronic oxygen deprivation. This problem is underscored by the fact that, if deaths among congenitally infected and anomalous infants are excluded, the perinatal risk is still higher for growth-restricted infants 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 growth continues and antenatal tests are reassuring. Tests of fetal lung maturation may be of value if the course of action is not entirely clear. In the case of the preterm fetus, delivery is indicated in the presence of worsening maternal hypertensive disease, failure of continuing growth, or reversal of umbilical artery flow as assessed by Doppler ultrasound. The preterm fetus (<34 weeks' gestation) should receive the benefit of corticosteroids for lung maturation.

The Growth Restriction Intervention Trial (GRIT) study underscored the difficulty in selecting the most appropriate delivery time to prevent morbidity.[170] In a randomized trial of 548 preterm IUGR pregnancies (24 to 36 weeks' gestation) in which fetal compromise was identified but uncertainty regarding delivery persisted, approximately half of the pregnancies were delivered and the other half continued until the clinical course was clear. There was no difference in mortality between the two groups. However, among infants with less than 31 weeks' gestation, severe disabilities were observed in 13% of the immediate deliveries, compared with 5% of those that were delayed.

The overall findings and guidelines for evaluation and management of the fetus with IUGR are summarized in Table 34-3.


TABLE 34-3 EVALUATION AND MANAGEMENT OF THE FETUS WITH INTRAUTERINE GROWTH RESTRICTION Rights were not granted to include this table inelectronic media. Please refer to the printed book.

Page 1 of 1//Timing of Delivery

Intrapartum Management

It has long been recognized that lower Apgar scores and meconium aspiration, as well as other manifestations of poor oxygenation during labor, occur with greater frequency among IUGR infants. The problem of intrapartum asphyxia has been further elucidated by studies demonstrating the acid-base status of growth-restricted infants at the time of delivery. If moderate-to-severe metabolic acidosis is defined as an umbilical artery buffer base value of less than 37 mEq/L (normal, >40 mEq/L), almost 50% of IUGR neonates show signs of acidosis at the time of delivery.[171] These findings document the problems of oxygenation during labor in such fetuses and emphasize that meticulous fetal surveillance is required during this critical period.

Consequently, the clinician should proceed to cesarean delivery if there is evidence of deteriorating fetal status or an unripe cervix or if there is any indication of additional fetal compromise during labor.


Page 1 of 1//Intrapartum Management

Neonatal Complications and Long-term Sequelae

The growth-restricted fetus can experience numerous complications in the neonatal period related to the etiology of the growth insult as well as antepartum and intrapartum factors. These include neonatal asphyxia, meconium aspiration, hypoglycemia and other metabolic abnormalities, and polycythemia (see Chapter 58). After correction for gestational age, a large population-based outcomes analysis showed that the premature IUGR infant is at increased risk of mortality, necrotizing enterocolitis, and need for respiratory support at 28 days of age.[172] This observation takes on more significance inasmuch as prematurity and IUGR frequently coexist.

Beyond the neonatal period, data by Low and colleagues[173] showed that fetal growth restriction has a deleterious effect on cognitive function, independent of other variables. With the use of numerous standardized tests to evaluate learning ability, and excluding those children with genetic or major organ system malformations, they found that almost 50% (37/77) of SGA children had learning deficits at ages 9 to 11 years. Blair and Stanley[174] also reported a strong association between IUGR and spastic cerebral palsy in newborns born after 33 weeks of gestation. This association was highest in IUGR infants who were short, thin, and of small head size. Newborns who were at or above the 10th percentile for weight but had abnormal ponderal indices were also at risk for spastic cerebral palsy.[175] In a recent Danish autopsy study, investigators observed a significantly lower cell number in the cortex of IUGR fetuses and infants compared with normal controls, a finding that may, in part, explain the clinical observations.[176] Other investigators have reported more favorable neurologic outcomes in IUGR infants.[177,178]

There is currently substantial research effort to explore the role of IUGR and adult disease: the so-called “fetal origins of disease” hypothesis. This subject is addressed in Chapter 11. The epidemiologic studies of Barker's group have indicated that IUGR is a significant risk factor for the subsequent development of chronic hypertension, ischemic heart disease, type 2 diabetes, and obstructive lung disease.[179] Maternal and fetal malnutrition seem to have both short- and long-term effects. The concept of programming during intrauterine life, however, needs to include a host of other factors, such as the genotype of both mother and fetus, maternal size and obstetric history, and postnatal and lifestyle factors.


Page 1 of 1//Neonatal Complications and Long-term Sequelae

References

1. Lubchenco LO, Hansman C, Boyd E: Intrauterine growth as estimated from liveborn birth-weight data at 24 to 42 weeks of gestation. Pediatrics 1963; 32:793.

2. Battaglia FC, Lubchenco LO: A practical classification of newborn infants by weight and gestational age. J Pediatr 1967; 71:159.

3. Yerushalmy J: Relation of birth weight, gestational age, and the rate of intrauterine growth to perinatal mortality. Clin Obstet Gynecol 1970; 13:107.

4. Seeds JW, Peng T: Impaired fetal growth and risk of fetal death: Is the tenth percentile the appropriate standard?. Am J Obstet Gynecol 1998; 178:658.

5. Gardosi J: Customized fetal growth standards: Rationale and clinical application. Semin Perinatol 2004; 28:33.

6. Figueras F, Figueras J, Meler E, et al: Customized birthweight standards accurately predict perinatal morbidity. Arch Dis Child Fetal Neonatal Educ 2007; 92:F277-F280.

7. Groom KM, Poppe KK, North RA, et al: Small-for-gestational age infants classified by customized or population birthweight centiles: Impact of gestational age at delivery. Am J Obstet Gynecol 2007; 197:239.e1-239.e5.

8. McCowan LM, Harding JE, Stewart AW: Customized birthweight centiles predict SGA pregnancies with perinatal morbidity. BJOG 2005; 112:1026-1033.

9. Ego A, Subtil D, Grange G, et al: Customized versus population-based birth weight standards for identifying growth restricted infants: A French multicenter study. Am J Obstet Gynecol 2006; 194:1042-1049.

10. Miller HC, Hassanein K: Diagnosis of impaired fetal growth in newborn infants. Pediatrics 1971; 48:511.

11. Daikoku NH, Johnson JWC, Graf C, et al: Patterns of intrauterine growth retardation. Obstet Gynecol 1979; 54:211.

12. Brar HS, Rutherford SP: Classification of intrauterine growth retardation. Semin Perinatol 1988; 12:2.

13. Williams RL, Creasy RK, Cunningham GC, et al: Fetal growth and perinatal viability in California. Obstet Gynecol 1982; 59:624.

14. Brenner WE, Edelman DA, Hendricks CH: A standard of fetal growth for the United States of America. Am J Obstet Gynecol 1976; 126:555.

15. Ott W: Intrauterine growth retardation and preterm delivery. Am J Obstet Gynecol 1993; 168:710.

16. Arbuckle TE, Wilkins R, Sherman GJ: Birth weight percentiles by gestational age in Canada. Obstet Gynecol 1993; 81:39.

17. Alexander GR, Himes JH, Kaufman RB, et al: A United States national reference for fetal growth. Obstet Gynecol 1996; 87:163.

18. Kramer MS: Determinants of low birth weight: Methodological assessment and meta-analysis. Bull WHO 1987; 65:663.

19. Manning FA: Intrauterine growth retardation. In: Manning FA, ed. Fetal Medicine: Principles and Practice, Norwalk, CT: Appleton & Lange; 1995:307.

20. Ounsted M, Moar V, Scott WA: Perinatal morbidity and mortality in small-for-dates babies: The relative importance of some maternal factors. Early Hum Dev 1981; 5:367.

21. Dashe JS, McIntire DD, Lucas MJ, et al: Effects of symmetric and asymmetric fetal growth on pregnancy outcomes. Obstet Gynecol 2000; 96:321.

22. Piper JM, Xenakais E-J, McFarland M, et al: Do growth-retarded premature infants have different rates of perinatal morbidity and mortality than appropriately grown premature infants?. Obstet Gynecol 1996; 87:169.

Page 1 of 8//References

23. Spinello A, Capuzzo E, Egbe TO, et al: Pregnancies complicated by intrauterine growth retardation. J Reprod Med 1995; 40:209.

24. Minior VK, Divon MY: Fetal growth restriction at term: Myth or realty. Obstet Gynecol 1998; 92:57.

25. Morken N-H, Kallen K, Jacobsson B: Fetal growth and onset of delivery: A nationwide population-based study of preterm infants. Am J Obstet Gynecol 2006; 195:154.

26. Blair E, Stanley F: Intrauterine growth and spastic cerebral palsy: I. Association with birth weight for gestational age. Am J Obstet Gynecol 1990; 162:229.

27. Goldenberg RL, DuBard MB, Cliver SP, et al: Pregnancy outcomes and intelligence at age 5 years. Am J Obstet Gynecol 1996; 175:1511.

28. Wienerroither H, Steiner H, Tomaselli J, et al: Intrauterine blood flow and long term intellectual, neurologic and social development. Obstet Gynecol 2001; 97:449.

29. Polani PE: Chromosomal and other genetic influences on birth weight variation. In: Elliot K, Knight J, ed. Size at Birth, Amsterdam: Associated Scientific Publishers; 1974.

30. Walton A, Hammond J: The maternal effects on growth and conformation in the Shire horse-Shetland pony crosses. Proc R Soc Biol 1938; 125:311.

31. Johnstone F, Inglis L: Familial trends in low birth weight. BMJ 1974; 3:659.

32. Ounsted M, Ounsted C: Maternal regulations of intrauterine growth. Nature 1966; 187:777.

33. Simpson JW, Lawless RW, Mitchell AC: Responsibility of the obstetrician to the fetus: 2. Influence of prepregnancy weight and pregnancy weight gain on birth weight. Obstet Gynecol 1975; 45:481.

34. Wilcox MA, Smith SJ, Johnson IR, et al: The effect of social deprivation on birthweight, excluding physiologic and pathologic effects. BJOG 1995; 102:918.

35. Thomson AM, Billewicz WZ, Hytten FE: The assessment of fetal growth. J Obstet Gynaecol Br Commonw 1968; 75:906.

36. Klebanoff MA, Mednick BR, Schulsinger C, et al: Father's effect on infant birth weight. Am J Obstet Gynecol 1998; 178:1022.

37. Klebanoff MA, Schulsinger C, Mednick BR, et al: Preterm and small-for-gestational-age birth across generations. Am J Obstet Gynecol 1997; 176:521.

38. Bukowski R, Gahn D, Denning J, et al: Impairment of growth in fetuses destined to deliver preterm. Am J Obstet Gynecol 2001; 185:463.

39. Saugstad LF: Birth weights in children with phenylketonuria and in their siblings. Lancet 1972; 1:809.

40. Snijders RJM, Sherrod C, Gosden CM, et al: Fetal growth retardation: Associated malformations and chromosomal abnormalities. Am J Obstet Gynecol 1993; 168:547.

41. Chen ATL, Chan Y-K, Falek A: The effects of chromosome abnormalities on birth weight in man: II. Autosomal defects. Hum Hered 1972; 22:209.

42. Peuschel SM, Rothman KJ, Ogilvy JD: Birth weight of children with Down's syndrome. Am J Ment Defic 1976; 80:442.

43. Barlow P: The influence of inactive chromosomes on human development: Anomalous sex chromosome complements and the phenotype. Hum Genet 1973; 17:105.

44. Khoury MJ, Erickson D, Cordero JE, et al: Congenital malformation and intrauterine growth retardation: A population study. Pediatrics 1988; 82:83.

45. Naeye RL: Unsuspected organ abnormalities associated with congenital heart disease. Am J Pathol 1965; 47:905.

46. Froehlich LA, Fujikura R: Significance of a single umbilical artery. Am J Obstet Gynecol 1966; 94:174.

47. Feldman DM, Borgida AF, Trymbulak WP, et al: Clinical implications of velamentous cord insertion in triplet gestations. Am J Obstet Gynecol 2002; 186:809.


48. Sornes T: Umbilical cord encirclements and fetal growth restriction. Obstet Gynecol 1995; 86:725.

49. Klein JO, Remington JS: Current concepts of infections of the fetus and newborn infant. In: Remington JS, Klein JO, ed. Infectious Diseases of the Fetus and Newborn Infant, 4th ed.. Philadelphia: WB Saunders; 1995.

50. Alkalay AL, Pomerance JJ, Rimoin DL: Fetal varicella syndrome. J Pediatr 1987; 111:320.

51. Peckham CS: Clinical laboratory study of children exposed in utero to maternal rubella. Arch Dis Child 1972; 47:571.

52. Preblud SR, Alford Jr CA: Rubella. In: Remington JS, Klein JO, ed. Infectious Diseases of the Fetus and Newborn Infant, 3rd ed.. Philadelphia: WB Saunders; 1990.

53. Naeye RL: Cytomegalovirus disease: The fetal disorder. Am J Clin Pathol 1967; 47:738.

54. Williams MC, O'Brien WF, Nelson RN, et al: Histologic chorioamnionitis is associated with fetal growth restriction in term and preterm infants. Am J Obstet Gynecol 2000; 183:1094.

55. Barcroft J, Kennedy JA: The distribution of blood between the fetus and placenta in sheep. J Physiol 1939; 95:173.

56. McKeown T, Record RG: Observations on foetal growth in multiple pregnancy in man. J Endocrinol 1952; 8:386.

57. Jones JS, Newman RB, Miller MC: Cross-sectional analysis of triplet birth weight. Am J Obstet Gynecol 1991; 164:135.

58. Elster AD, Bleyl JL, Craven TE: Birth weight standards for triplets under modern obstetric care in the United States, 1984-1989. Obstet Gynecol 1991; 77:387.

59. Fick AL, Feldstein VA, Norton ME, et al: Unequal placental sharing aand birth weight discordance in monochorionic diamniotic twins. Am J Obstet Gynecol 2006; 195:178.

60. Silver RK, Helford BT, Russell TL, et al: Multifetal reduction increases the risk of preterm delivery and fetal growth restriction: A case control study. Fertil Steril 1997; 67:30.

61. Naeye RL, Benirschke K, Hagstrom JWC, et al: Intrauterine growth of twins as estimated from liveborn birth weight data. Pediatrics 1966; 37:409.

62. Secher NJ, Kaern J, Hansen PK: Intrauterine growth in twin pregnancies: Prediction of fetal growth retardation. Obstet Gynecol 1985; 66:63.

63. Winick M: Cellular changes during placental and fetal growth. Am J Obstet Gynecol 1971; 109:166.

64. Antonov AN: Children born during siege of Leningrad in 1942. J Pediatr 1947; 30:250.

65. Stein Z, Susser M: The Dutch famine, 1944–1945, and the reproductive process: I. Effects on six indices at birth. Pediatr Res 1975; 9:70.

66. Abrams B, Newman V: Small-for-gestational-age birth: Maternal predictors and comparison with risk factors of spontaneous preterm delivery in the same cohort. Am J Obstet Gynecol 1991; 164:785.

67. Oliver MH, Hawkes P, Harding JE: Periconceptual undernutrition alters growth trajectory and metabolic and endocrine responses to fasting in late-gestation fetal sheep. Pediatr. Res 2005; 57:591.

68. Luke B, Nugent C, van de Ven C, et al: The association between maternal factors and perinatal outcome in triplet pregnancies. Am J Obstet Gynecol 2002; 187:752.

69. Marconi AM, Paolin C, Buscaglia M, et al: The impact of gestational age and fetal growth on the maternal-fetal glucose concentration differences. Obstet Gynecol 1996; 87:937.

70. Wells JL, James DK, Luxton R, et al: Maternal leukocyte zinc deficiency at start of third trimester as a predictor of fetal growth retardation. BMJ 1987; 294:1054.

71. Neggers YH, Cutter GR, Alvarez JO, et al: The relationship between maternal serum zinc levels during pregnancy and birthweight. Early Hum Dev 1991; 25:75.

72. Goldenberg RL, Tamura T, Cliver SP, et al: Serum folate and fetal growth retardation: A matter of compliance?. Obstet Gynecol 1992; 79:71.


73. Lackman F, Capewell V, Gagnon R, et al: Fetal umbilical cord oxygen values and birth to placental weight ratio in relation to size at birth. Am J Obstet Gynecol 2001; 185:674.

74. Lichty JA, Ting RY, Bruns PD, et al: Studies of babies born at high altitude. Am J Dis Child 1957; 93:666.

75. Novy MJ, Peterson EN, Metcalfe J: Respiratory characteristics of maternal and fetal blood in cyanotic congenital heart disease. Am J Obstet Gynecol 1968; 100:821.

76. Wen SW, Goldenberg RL, Cutter GR, et al: Smoking, maternal age, fetal growth and gestational age at delivery. Am J Obstet Gynecol 1990; 162:53.

77. Cliver SP, Goldenberg RL, Cutter GR, et al: The effect of cigarette smoking on neonatal anthropometric measurements. Obstet Gynecol 1995; 85:625.

78. Kallen K: Maternal smoking during pregnancy and infant head circumference at birth. Early Hum Dev 2000; 58:197.

79. Wang X, Zuckerman B, Pearson C, et al: Maternal cigarette smoking, metabolic gene polymorphism and infant birth weight. JAMA 2002; 287:195.

80. Mills JL, Graubard BI, Harley EE, et al: Maternal alcohol consumption and birthweight: How much drinking during pregnancy is safe?. JAMA 1984; 252:1875.

81. Little BB, Snell LM: Brain growth among fetuses exposed to cocaine in utero: Asymmetrical growth retardation. Obstet Gynecol 1991; 77:361.

82. Heinonen S, Taipale P, Saarikoski S: Weights of placenta from small-for-gestational-age infants revisited. Placenta 2001; 86:428.

83. Molteni RA, Stys SJ, Battaglia FC: Relationship of fetal and placental weight in human beings: Fetal/placental weight ratios at various gestational ages and birth weight distributions. J Reprod Med 1978; 21:327.

84. Fisher SJ: The placental problem: Linking abnormal cytotrophoblast differentiation to the maternal symptoms of preeclampsia. Reprod Biol Endocrinol 2004; 2:53.

85. Kaufman P, Black S, Huppertz B: Endovascular trophoblast invasion: Implications for the pathogenesis of intrauterine growth retardation and peeeclampsia. Biol Reprod 2003; 69:1.

86. Red-Horse K, Rivera J, Schanz A, et al: Cytotrophoblast induction of arterial apoptosis and lymphangiogenesis in an in vivo model of human placentation. J Clin Invest 2006; 116:2643.

87. Huppertz B, Kadyrov M, Kingdom JCP: Apoptosis and its role in the trophoblast. Am J Obstet Gynecol 2006; 195:29.

88. Brosens I, Dixon HG, Robertson WB: Fetal growth retardation and the arteries of the placental bed. BJOG 1977; 84:656.

89. Aherne W, Dunnill MS: Quantitative aspects of placental structure. J Pathol Bacteriol 1966; 91:123.

90. Ishihara N, Matsuo H, Murakoshi H, et al: Increased apoptosis in syncytiotrophoblast in human term placentas complicated by either preeclampsia or intrauterine growth retardation. Am J Obstet Gynecol 2002; 186:158.

91. Levy R, Smith SD, Yusuf K, et al: Trophoblast apoptosis from pregnancies complicated by fetal growth restriction is associated with enhanced p53 expression. Am J Obstet Gynecol 2002; 186:1056.

92. Crispi F, Dominguez C, Llurba E, et al: Placental growth factors and uterine artery Doppler findings for characterization of different subsets in preeclampsia and in intrauterine growth restriction. Am J Obstet Gynecol 2006; 195:201.

93. Krebs C, Marca LM, Leiser RL, et al: Intrauterine growth restriction with absent end-diastolic flow velocity in the umbilical artery is associated with maldevelopment of the placental terminal villous tree. Am J Obstet Gynecol 1996; 175:1534.

94. Salafia CM, Pezzullo JC, Minior VK, et al: Placental pathology of absent and reversed end-diastolic flow in growth restricted fetuses. Obstet Gynecol 1997; 90:830.

95. Soothill PW, Nicolaides KH, Bilardo K, et al: Uteroplacental blood velocity index and umbilical venous PO2, PCO2, pH, lactate and erythroblast count in growth retarded fetuses. Fetal Ther 1986; 1:174.

96. Soothill PW, Nicolaides KH, Campbell S: Prenatal asphyxia, hyperlactiacidemia, hypoglycemia and erythroblastosis in growth retarded fetuses. BMJ 1987; 294:1046.


97. Cetin I, Corbetta C, Sereni LP, et al: Umbilical amino acid concentrations in normal and growth-retarded fetuses sampled in utero by cordocentesis. Am J Obstet Gynecol 1990; 162:253.

98. Shanklin DR: The influence of placental lesions and the newborn infant. Pediatr Clin North Am 1970; 17:25.

99. Ananth CV, Wilcox AJ: Placental abruption and perinatal mortality in the United States. Am J Epidemiol 2001; 153:332.

100. Ananth CV, Demissie K, Smulian JC, et al: Relationship among placenta previa, fetal growth restriction and preterm delivery: A population based study. Obstet Gynecol 2001; 98:299.

101. Creasy RK, Barrett CT, de Swiet M, et al: Experimental intrauterine growth retardation in the sheep. Am J Obstet Gynecol 1972; 112:566.

102. Clapp III JF, Szeto HH, Larrow R, et al: Fetal metabolic response to experimental placental vascular damage. Am J Obstet Gynecol 1981; 140:446.

103. Kong TY, DeWolf F, Robertson WB, et al: Inadequate maternal vascular response to placentation in pregnancies complicated by preeclampsia and small-for-gestational age infants. BJOG 1986; 93:1049.

104. Dixon HG, Browne JCM, Davey DA: Choriodecidual and myometrial blood flow. Lancet 1963; 2:369.

105. Kaar K, Joupilla P, Kuikka J, et al: Intervillous blood flow in normal and complicated late pregnancy measured by means of an intravenous Xe133 method. Acta Obstet Gynecol Scand 1980; 59:7.

106. Rosso P, Donoso E, Braun S, et al: Hemodynamic changes in underweight pregnant women. Obstet Gynecol 1992; 79:908.

107. Duvekot JJ, Cheriex EC, Pieters FAA, et al: Maternal volume homeostasis in early pregnancy in relation to fetal growth restriction. Obstet Gynecol 1995; 85:361.

108. Bamfo JE, Kametas NA, Turan O, et al: Maternal cardiac function in fetal growth. BJOG 2006; 113:784.

109. Fleischer A, Schulman H, Farmakides G, et al: Uterine artery Doppler velocimetry in pregnant women with hypertension. Am J Obstet Gynecol 1986; 154:806.

110. Campbell S, Bewley S, Cohen-Overbeek T: Investigation of the uteroplacental circulation by Doppler ultrasound. Semin Perinatol 1987; 11:362.

111. Easterling TR, Benedetti TJ, Carlson KC, et al: The effect of maternal hemodynamics on fetal growth in hypertensive pregnancies. Am J Obstet Gynecol 1991; 165:902.

112. Infante-Rivard C, Rivard GE, Yotov WV, et al: Absence of association of thrombophilia polymorphisms with intrauterine growth restriction. N Engl J Med 2002; 347:19-25.

113. Dizon-Townson D, Miller C, Sibai B, et al: The relationship of the factor V Leiden mutation and pregnancy outcomes for the mother and fetus. Obstet Gynecol 2005; 106:517-524.

114. Franchi F, Cetin I, Todros T, et al: Intrauterine growth restriction and genetic predisposition to thrombophilia. Haematologica 2004; 89:444-449.

115. Salomon O, Seligsohn U, Steinberg DM, et al: The common prothrombotic factors in nulliparous do not compromise blood flow in the feto-maternal circulation and are not associated with preeclampsia or intrauterine growth restriction. Am J Obstet Gynecol 2004; 191:2002-2009.

116. Andrews MC, Jones Jr HW: Impaired reproductive performance of the unicornuate uterus: Intrauterine growth retardation, infertility, and recurrent abortion in five cases. Am J Obstet Gynecol 1982; 144:173.

117. Burchell RC, Creed F, Rasoulpour M, et al: Vascular anatomy of the human uterus and pregnancy wastage. BJOG 1978; 85:698.

118. Shinagawa S, Nomura Y, Kudoh S: Full-term deliveries after ligation of bilateral internal iliac arteries and infundibulopelvic ligaments. Acta Obstet Gynecol Scand 1981; 60:439.

119. Pron G, Mocarski E, Bennett J, et al: Pregnancy after uterine artery embolization for leiomyomata: The Ontario Multicenter Trial. Obstet Gynecol 2005; 105:67.

120. Clapp JF, Kim H, Burciu B, et al: Beginning regular exercise in early pregnancy: Effect upon fetoplacental growth. Am J


Obstet Gynecol 2000; 183:1484.

121. Clapp JF, Kim H, Burciu B, et al: Continuing regular exercise during pregnancy: Effect of exercise volume on fetoplacental growth. Am J Obstet Gynecol 2002; 186:142.

122. Perkins CCD, Pivarnik JM, Paneth N, et al: Physical activity and fetal growth during pregnancy. Obstet Gynecol 2007; 109:81.

123. Goldenberg RL, Hoffman HJ, Cliver SP, et al: The influence of previous low birth weight or birth weight, gestational age, and anthropometric measurement in the current pregnancy. Obstet Gynecol 1992; 79:276.

124. Cnattingius S, Forman MR, Poerendes HW, et al: Effect of age, parity and smoking on pregnancy outcome: A population based study. Am J Obstet Gynecol 1993; 168:16.

125. Thorburn GD: The role of the thyroid gland and kidneys in fetal growth. In: Elliot K, Knight J, ed. Size at Birth, Amsterdam: Associated Scientific Publishers; 1974.

126. Liggins GC: The influence of the fetal hypothalamus and pituitary on growth. In: Elliot K, Knight J, ed. Size at Birth, Amsterdam: Associated Scientific Publishers; 1974.

127. Sherwood WG, Chance GW, Hill DE: A new syndrome of pancreatic agenesis. Pediatr Res 1974; 8:360.

128. Henson MC, Castracane VD: Leptin in pregnancy. Biol Reprod 2006; 74:218.

129. Neilson JP: Symphysis-fundal height measurement in pregnancy. Cochrane Database Syst Rev 2000.CD000944

130. Mongelli M, Gardosi J: Symphysis-fundus height and pregnancy characteristics in ultrasound-dated pregnancies. Obstet Gynecol 1999; 94:591-594.

131. Hadlock FP, Harrist RB, Carpenter RD, et al: Sonographic estimation of fetal weight. Radiology 1984; 150:535.

132. Snijders RJ, Nicolaides KH: Fetal biometry at 14-40 weeks gestation. Ultrasound Obstet Gynecol 1994; 4:34.

133. Chang TC, Robson SC, Boys RJ, et al: Prediction of the small-for-gestational age infant: Which ultrasonic measurement is best?. Obstet Gynecol 1992; 80:1030.

134. Bukowski R, Smith GC, Malone FD, et al: Fetal growth in early pregnancy and risk of delivering low birth weight infant: Prospective cohort study. BMJ 2007; 334:836.

135. Smith GC, Smith MF, McNay MB, et al: First-trimester growth and the risk of low birth weight. N Engl J Med 1998; 339:1817.

136. Papageorghiou AT, Yu CK, Bindra R, et al: The Fetal Medicine Foundation Second Trimester Screening Group: Multicenter screening for pre-eclampsia and fetal growth restriction by transvaginal uterine artery Doppler at 23 weeks of gestation. Ultrasound Obstet Gynecol 2001; 18:441.

137. Pilalis A, Souka AP, Antsaklis P, et al: Screening for preeclampsia and fetal growth restriction by uterine artery Doppler and PAPP-A at 11-14 weeks gestation. Ultrasound Obstet Gynecol 2007; 29:135.

138. Rabinowitz R, Peters MT, Sanjay V, et al: Measurement of fetal urine production in normal pregnancy by real time ultrasonography. Am J Obstet Gynecol 1989; 161:1264.

139. Wladimiroff JW, Campbell S: Fetal urine production rates in normal and complicated pregnancies. Lancet 1974; 2:151.

140. Kurjak A, Kirkinen P, Latin V, et al: Ultrasonic assessment of fetal kidney function in normal and complicated pregnancies. Am J Obstet Gynecol 1981; 141:266.

141. Nicolaides KH, Peters MT, Vyas S: Relation of rate of urine production to oxygen tension in small-for-gestational age fetuses. Am J Obstet Gynecol 1990; 162:387.

142. Manning FA, Hill LM, Platt LD: Qualitative amniotic fluid volume determination by ultrasound: Antepartum detection of intrauterine growth retardation. Am J Obstet Gynecol 1981; 139:254.

143. Chamberlain PF, Manning FA, Morrison I, et al: Ultrasound evaluation of amniotic fluid: I. The relationship of marginal and decreased amniotic fluid volume to perinatal outcome. Am J Obstet Gynecol 1984; 150:245.

144. Bastide A, Manning FA, Harman C, et al: Ultrasound evaluation of amniotic fluid: Outcome of pregnancies with severe oligohydramnios. Am J Obstet Gynecol 1986; 154:895.


145. Alfirevic Z, Neilson JP: Biophysical profile for fetal assessment in high risk pregnancies. Cochrane Database Syst Rev 2000.CD000038

146. Manning FA, Morrison I, Harman CR, et al: Fetal assessment based on fetal biophysical profile scoring: Experience in 19,221 high-risk pregnancies. Am J Obstet Gynecol 1987; 157:880.

147. Manning FA, Harman CR, Morrison I, et al: Fetal assessment based on fetal biophysical profile scoring. Am J Obstet Gynecol 1990; 162:703.

148. Kingdom JCP, Burrell SJ, Kaufmann P: Pathology and clinical implications of abnormal umbilical artery Doppler waveforms. Ultrasound Obstet Gynecol 1997; 9:271.

149. Almstrom H, Axelsson O, Cnattingius S, et al: Comparison of umbilical artery velocimetry and cardiotacography for surveillance of small-for-gestational-age fetuses: A multicenter randomized controlled trial. Lancet 1992; 340:936.

150. Omtzigt AM, Reuwer PJ, Bruinse HW: A randomized controlled trial on the clinical value of umbilical Doppler velocimetry in antenatal care. Am J Obstet Gynecol 1994; 170:625.

151. Pattison RC, Norman K, Odendal HJ: The role of Doppler velocimetry in the management of high-risk pregnancies. BJOG 1994; 101:114.

152. Alfirevic Z, Neilson JP: Doppler ultrasonography in high-risk pregnancies: Systematic review with meta-analysis. Am J Obstet Gynecol 1995; 172:1379.

153. Gonzalez JM, Stamillo DM, Ural S, et al: Relationship between abnormal fetal testing and adverse perinatal outcomes in intrauterine growth restriction. Am J Obstet Gynecol 2007; 196:e48.

154. Ott WJ: Intrauterine growth restriction and Doppler ultrasonography. J Ultrasound Med 2000; 19:661.

155. Wladimiroff JW, vd Wijngaard JA, Degani S, et al: Cerebral and umbilical arterial waveforms in normal and growth-retarded pregnancies. Obstet Gynecol 1987; 69:705.

156. Karsdorp VH, van Vugt JM, van Geijn HP, et al: Clinical significance of absent or reversed end-diastolic velocity waveforms in the umbilical artery. Lancet 1994; 334:1664.

157. Valcamonico A, Danti L, Frusca T, et al: Absent end-diastolic velocity in umbilical artery: Risk of neonatal morbidity and brain damage. Am J Obstet Gynecol 1994; 170:796.

158. Ferrazzi E, Bozzo M, Rigano S, et al: Temporal sequence of abnormal Doppler changes in the peripheral and central circulatory systems of the severely growth-restricted fetus. Ultrasound Obstet Gynecol 2002; 19:140.

159. Baschat AA, Gembruch U, Harman CR: The sequence of changes in Doppler and biophysical parameters as severe fetal growth restriction worsens. Ultrasound Obstet Gynecol 2001; 18:571.

160. Baschat AA, Harman CR: Antenatal assessment of the growth restricted fetus. Curr Opin Obstet Gynecol 2001; 13:161.

161. Schwarze A, Gembruch U, Krapp M, et al: Qualitative venous Doppler flow waveform analysis in preterm intrauterine growth-restricted fetuses with ARED flow in the umbilical artery-correlation with short term outcome. Ultrasound Obstet Gynecol 2005; 25:573.

162. Turan S, Turan OM, Berg C, et al: Computerized fetal heart rate analysis, Doppler ultrasound and biophysical profile score in the prediction of acid-base status of growth-restricted fetuses. Ultrasound Obstet Gynecol 2007; 30:750.

163. Nicolaides KH, Bradley RJ, Soothill PW, et al: Maternal oxygen therapy for intrauterine growth retardation. Lancet 1987; 1:942.

164. Battaglia C, Artini PG, d'Ambrogio G, et al: Maternal hyperoxygenation in the treatment of intrauterine growth retardation. Am J Obstet Gynecol 1992; 167:430.

165. Gulmezoglu AM, Hofmeyer GJ: Maternal oxygen administration for suspected and impaired fetal growth. Cochran Database Syst Rev 2000.CD000137

166. Rumbold AR, Crowther CA, Haslam RR, et al: ACTS Study Group. Vitamins C and E and the risks of reeclampsia and perinatal complications. N Engl J Med 2006; 354:1796.

167. Makrides M, Duley L, Olsen SAF: Marine oil, and other prostaglandin precursor, supplementation for pregnancy uncomplicated by preeclampsia or intrauterine growth restriction. Cochrane Database Syst Rev 2006.CD003402


168. Duley L, Henderson-Smart DJ, Meher S, et al: Antiplatelet agents for preventing pre-eclampsia and its complications. Cochrane Database Syst Rev 2007.CD004659

169. Berghella V: Prevention of recurrent fetal growth restriction. Obstet Gynecol 2007; 110:904.

170. Thornton JG, Hornbuckle J, Vail A, et al: Infant wellbeing at 2 years of age in the Growth Restriction Intervention Trial (GRIT): Multicentered randomised controlled trial. Lancet 2004; 364:513.

171. Low JA, Boston RW, Pancham SR: Fetal asphyxia during the intrapartum period in growth-retarded infants. Am J Obstet Gynecol 1972; 113:351.

172. Garite TJ, Clark R, Thorp JA: Intrauterine growth restriction increases morbidity and mortality among premature neonates. Am J Obstet Gynecol 2004; 191:481.

173. Low JA, Handley-Derry MH, Burke SO, et al: Association of intrauterine fetal growth retardation and learning deficits at age 9 to 11 years. Am J Obstet Gynecol 1992; 167:1499.

174. Blair E, Stanley F: Intrauterine growth and spastic cerebral palsy: I. Association with birth weight and gestational age. Am J Obstet Gynecol 1990; 162:229.

175. Blair E, Stanley F: Intrauterine growth and spastic cerebral palsy: II. The association with morphology at birth. Early Hum Dev 1992; 28:91.

176. Samuelsen GB, Pakkenberg B, Bogdanovic N, et al: Severe cell reduction in the future brain cortex in human growth-restricted fetuses and infants. Am J Obstet Gynecol 2007; 197:56.e1-56.e7.

177. Paz I, Laor A, Gale R, et al: Term infants with fetal growth restriction are not all at increased risk for low intelligence scores at 17 years. J Pediatr 2001; 138:87.

178. McCowan LME, Pryor J, Harding JE: Perinatal predictors of neurodevelopmental outcome in small-for-gestational-age children at 18 months of age. Am J Obstet Gynecol 2002; 186:1069.

179. In: Barker DJP, Robinson RJ, ed. Fetal and Infant Origins of Adult Disease, London: British Medical Journal; 1992.



Documents

CR-6 Chapter 34