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Physical Growth: Physical Examination of the Newborn Infant and the Physical Environment
There are tiny, puny infants with great vitality. Their movements are untiring and their crying lusty, for their organs are quite capable of performing their allotted functions. These infants will live, for although their weight is inferior … their sojourn in the womb was longer. Pierre Budin, The Nursling
An infant’s problems and prognosis are in large part determined by birth weight and gestational age. The designations low birth weight (LBW), very low birth weight (VLBW), and extremely low birth weight (ELBW) have been applied to all infants weighing less than 2500 g, 1500 g, and 1000 g at birth, respectively, regardless of the duration of gestation. Infants are further classified by gestational age into the designations of preterm, early term, term, and postterm, if they have completed less than 37, 37–38, 39–41, and more than 41 weeks of pregnancy, respectively. Formerly referred to as near-term infants, late preterm infants, who have completed more than 34 and less than 37 weeks’ gestation, account for almost three-quarters of preterm births. Therefore prevention of late preterm delivery would make the biggest impact in reducing the overall rate of premature birth. Late preterm infants have significant in-hospital morbidity and a threefold higher mortality rate when compared with term infants. Late preterm infants are also at higher risk of neurodevelopmental impairment when compared with age-matched infants born at term.
An infant’s size at birth is dependent on two factors: gestational age and intrauterine growth velocity. The proportion of LBW infants who are preterm as opposed to those with abnormal intrauterine growth varies among countries. In developed countries, the majority of LBW infants are premature, whereas in developing countries, intrauterine growth restriction (IUGR) is the major contributing factor. However, as the standard of living improves in developing countries, the proportion of LBW infants who are premature rises in comparison to those who have been growth restricted, suggesting a relationship between socioeconomic status and appropriate intrauterine growth.
Infants are classified as appropriate for gestational age (AGA) if their birth weight falls between the 10th and 90th percentiles, small for gestational age (SGA) if their birth weight is below the 10th percentile, and large for gestational age (LGA) if their birth weight is above the 90th percentile ( Fig. 4.1 )
Birth weights of liveborn singleton Caucasian infants at gestational ages from 24 to 42 weeks.
From Battaglia F, Lubchenco L. A practical classification of newborn infants by weight and gestational age. J Pediatr. 1967;7:159.
Determinants of Fetal Growth
Normal fetal growth requires contributions from the mother, the placenta, and the fetus. Numerous maternal metabolic adjustments are made during pregnancy to provide an uninterrupted supply of nutrients to the developing fetus. Foremost among these are adjustments in carbohydrate metabolism. During a normal pregnancy, a mother will experience mild fasting hypoglycemia and postprandial hyperglycemia, associated with an increased basal insulin level and relative insulin resistance. Maternal glucose use is attenuated, whereas ketones and free fatty acids increasingly serve as substrate for maternal tissues. These alterations in maternal metabolism allow for a continuous supply of glucose to the developing fetus from the mother, which is the primary substrate used for fetal oxidative metabolism, even during periods of maternal fasting. However, during relatively extended periods of maternal fasting, the fetus is also able to use ketones to serve its energy and synthetic needs. Maternal serum levels of lipids increase during gestation. In midpregnancy, fat is stored for fetal use during late pregnancy, when demands increase. Maternal metabolic adaptions to pregnancy are so effective in supplying the fetus with required nutrients that only severe maternal malnutrition (e.g., wartime famine) during the third trimester may cause a reduction in birth weight. Starvation during the first trimester results in placental growth to compensate for the reduced energy supply to the fetus. If nutrition is then restored in the second and third trimester, birth weight is actually increased above what it would have been in the absence of early malnutrition.
The human placenta is a highly active endocrine organ, and produces hormones with direct effect on growth, including growth factors and human placental lactogen (HPL), also known as chorionic somatomammotropin. HPL is produced by the syncytiotrophoblast cells. Its growth-promoting effects are mediated by the stimulation of fetal insulin-like growth factors (IGF) production and increasing nutrient availability. Elevation of maternal serum lipids plays a role here as well. The expression of the HPL gene is regulated, in part, by apoprotein A1, the major protein component of high-density lipoprotein. The fetus plays a role in its own growth by producing a variety of polypeptide IGF molecules and modulating binding proteins. These substances are produced by a variety of fetal tissues, with site, timing, and control of expression varying with each IGF.
Intrauterine Growth Restriction
The growth trajectory of a fetus results from the combined effects of genetic programming and the growth support it receives from its mother. A fetus’ genetic growth potential is determined by contributions from the mother and the father, but these contributions are not necessarily of equal influence. For example, genomic imprinting causes approximately 30 genes to be active or inactive, depending on the individual parent from whom they are inherited. Paternal imprinting tends to encourage fetal growth, whereas maternal imprinting tends to restrict fetal growth. Although maternal and paternal genes have an approximately equal contribution to adult height and weight, the height and weight of the mother contribute more than 90% of the influence on birth weight.
IUGR is often defined as failure of the fetus to reach its genetic growth potential, but this definition is not comprehensive, as genetic potential can be modified according to nutrient supply. In addition, some babies’ genetic growth potential is inherently abnormal because of genetic diseases such as aneuploidy. For example, a high proportion of babies with trisomy 21 fail to reach their expected “genetic growth potential” based solely on parental size.
Ideally, the classification of fetuses as growth restricted should rely on functional measures, the most obvious of which is the risk of intrauterine or neonatal demise. Other typical indicators of inadequate growth status include an inability to cope with the hypoxia of labor resulting in fetal acidosis and neonatal depression, the passage of meconium during labor, and neonatal dysfunction such as hypoglycemia and hypothermia. In the longer term, catch-up growth may be either incomplete (resulting in reduced adult size) or excessive (leading to adult obesity, hypertension, and insulin resistance with an increased risk of diabetes). The concept of IUGR leading to long-term sequelae has led to the “fetal origins of adult disease or metabolic syndrome” hypothesis proposed by Barker and his colleagues.
IUGR does not relate directly to percentile birth weight. Although babies who are SGA are at increased risk of the dysfunction typical of IUGR, many will be small but healthy babies. There is no clear threshold of percentile birth weight below which the risk of dysfunction increases; rather, the risk rises steadily as the percentile birth weight falls. One approach that could improve the correlation between percentile birth weight and neonatal health is that of using “customized birth weight percentiles” in which the percentile birth weight of a particular baby is adjusted to take into account the mother’s height, weight, racial origin, and other relevant factors. However, some factors known to influence birth weight are pathologic. For example, severely underweight or overweight mothers are more likely to have babies who are born preterm or become macrosomic, and it would be inappropriate to correct percentiles to this extent. Mothers from some racial groups are twice as likely to deliver stillborn infants if the pregnancy is complicated by fetal growth restriction, and again, correction for this would clearly be inappropriate. It has been argued that using percentile charts based on estimated fetal weights of fetuses growing normally, instead of percentiles based on actual birth weights, may give a better indication of the incidence and role of fetal growth restriction on neonatal disease; however, this approach is limited by the inherent difficulty of obtaining accurate fetal measurements.
Perhaps the most appropriate way of defining IUGR is using serial ultrasound measurements of fetal size. Measurements from 22 weeks’ gestation onward can be used to establish the “normal” growth velocity for an individual fetus, and a subsequent decline in this growth trajectory fulfills the requirements for the definition of growth restriction. Prospective studies have shown that such measurements are at least as good a predictor of intrapartum dysfunction as percentile birth weight. It is possible for a fetus who was initially growing on the 90th percentile to experience slowing of growth typical of IUGR and sustain associated perinatal problems despite having a birth weight within the “normal” range. This phenomenon demonstrates that it is possible to have IUGR without being born SGA.
Pattern of Fetal Growth
With the use of anthropometric measurements, including fetal weight, length, and head circumference, fetal growth standards have been determined for different reference populations from various locations. From these data, it is apparent that there are variations in “normal” weight at any given gestational age from one environment to another. This variation is related to a number of factors including sex, race, socioeconomic status, and even altitude. But this brings into question what is meant by “normal”. For example, babies born at high altitude are, on average, smaller than those born at sea level. Thus, when growth charts for babies born at altitude are constructed, the 10th percentile, commonly used as the boundary between AGA and SGA, will be at a lower birth weight than that for babies born at sea level. (For example, babies that are on the 11th percentile for altitude might be on the 8th percentile for sea level and would be categorized as AGA for altitude but as SGA for sea level.) However, infants born at altitude are at higher risk for intrauterine or intrapartum demise. This begs the question: Should it be regarded as “normal” if more babies are stillborn? The purpose of customized percentiles is to correct for variations in birth weight because of physiologic variations in the mother and her environment, not to correct for conditions that may be pathologic or that are associated with a worse outcome.
The Colorado data, presented by Lubchenco et al in the 1960s, summarized standards of intrauterine growth for Caucasian (55%), African American (15%), and Hispanic (30%) newborns born between 1948 and 1961 in Denver. The graphic display of this relationship provides a useful and simple method for determining the birth weight percentiles with respect to gestational age and the local population. What such standards cannot do, however, is indicate whether the population as a whole (e.g., Hispanics compared with Caucasians) is disadvantaged. Equivalent designations of weight for gestational age between two different populations should be based on equivalent risk of poor outcome, rather than simply on the population distribution of birth weight.
Ten years after the Colorado data were published, Brenner et al published fetal weight curves based on more than 30,000 pregnancies (including live born, electively terminated, or spontaneous intrauterine demise). These curves, which were adjusted for parity, race, and sex, demonstrated nearly linear growth between 20 and 38 weeks of gestation, with slowing thereafter. Using such nomograms, fetal growth may be longitudinally plotted throughout pregnancy, and a decline in growth velocity may be detected, which would indicate IUGR. A decline in fetal growth velocity is indicative of risk of poor fetal or neonatal outcome, regardless of the absolute weight percentile at the time of delivery. For example, a fetus that had been growing along the 80th percentile but experiences a decline in growth velocity and is born with a weight at the 40th percentile for gestational age (IUGR but AGA) can be as clinically significant as a fetus that is growing along the 10th percentile and declines in growth velocity to eventually be born at the fifth percentile for gestational age (IUGR and SGA). Thus, many clinicians consider that the best descriptor of IUGR is “a decline in fetal growth velocity,” rather than being on, or falling below, a particular percentile.
Antenatal Assessment of Intrauterine Growth
Clinical Assessment of Gestational Age
Optimal management of the pregnant woman and her fetus is highly dependent on an accurate knowledge of the gestational age of the fetus. Gestational age is important for interpretation of common tests (e.g., nuchal translucency screening for trisomy 21), scheduling invasive procedures (e.g., amniocentesis), planning the delivery of high-risk fetuses (e.g., assessing the risk of respiratory distress syndrome [RDS]), and assessing fetal growth and size. Determination of the expected date of delivery (due date) can be made with varying degrees of certainty by history of menstrual cycles, physical examination of the pregnant woman, and a variety of clinical obstetrical milestones. Serial ultrasound examination of the developing fetus is the most accurate predictor of gestational age, except in cases where the date of conception is precisely known (as with pregnancies conceived by in vitro fertilization).
In Caucasian women, the average duration of pregnancy is 280 days, counting from the first day of the last menstrual period. However, because conception occurs, on average, on day 14 of the menstrual cycle, the true duration of gestation is 266 days. There is now good evidence that gestational age varies among racial groups, being 5 to 7 days shorter, for example, in South Asians and black Africans. Between 22 and 34 weeks’ gestation, in an appropriately growing singleton fetus, there is a reasonable correlation between the age of the fetus in weeks and the height of the uterine fundus in centimeters when measured as the distance over the abdominal wall from the superior border of the symphysis pubis to the top of the fundus. This measurement is frequently used for screening, but it is very unreliable in obese individuals, who account for 30% or more of Western populations. Obesity also makes ultrasound measurements more difficult and less reliable. For these reasons, the efficiency of screening for growth restriction is particularly poor in obese women. The size of the uterus changes more slowly in late pregnancy because as the fetus grows, the relative proportion of amniotic fluid decreases. Although physical examination estimates of gestational age have a standard deviation of plus or minus 2 weeks in the first trimester, this extends to 4 weeks in the second trimester and 6 weeks in the third trimester.
Assessment of Gestational Age
Forty percent of pregnant women have an uncertain last menstrual period, making accurate estimation of gestational age by history alone challenging. Since the 1970s, antenatal determination of gestational age using serial ultrasound studies of the fetus has become universal in developed countries. The type of ultrasound, the parameters measured, and the accuracy of the study vary with the progression of pregnancy.
It is possible to visualize the gestational sac by ultrasound as early as 5 weeks’ gestation. The optimal time to determine gestational age by ultrasound is between 7 and 9 weeks’ gestation using a high-resolution transvaginal ultrasound probe to measure crown-rump length. Routine ultrasound screens for dating, however, are usually performed between 11 and 14 weeks’ gestation, the optimal time to evaluate the nuchal translucency thickness, which is used as a marker for risk of Down syndrome. Another scan at 20 to 22 weeks’ gestational age is usually done for comprehensive fetal anomaly screening. Measurements at this stage of pregnancy are less reliable for assessing gestational age because to estimate gestational age from the size of the fetus, one must assume that the fetus is growing appropriately. By definition, 10% of babies will be SGA, and another 10% will be LGA. When the fetus is growing rapidly during the first trimester, the change in size from week to week is substantial; therefore the standard deviation of likely gestational age is small. Typically, 2 standard deviations are only 3 to 4 days different from the mean. Thus, it can be assumed that the fetus is likely to be of the average gestational age for a particular size, plus or minus 3 to 4 days. During the first trimester, fetuses smaller than 2 standard deviations below the mean for gestational age are at high risk for demise. However, the normal range of size increases as gestation advances, and accuracy of dating in the second trimester is generally no better than plus or minus 7 days. Ultrasound measures size and not gestational age. The most commonly used ultrasound measurements for determining estimated gestational age during the second trimester are head circumference, biparietal diameter, abdominal circumference, and femur length. Each of these measurements decreases in accuracy with increasing gestational age, particularly after 20 weeks, because of increasing normal variation with advancing gestation. A composite fetal size based on the average of these four measurements is used to enhance the accuracy of the assessment. Fetal abdominal circumference provides the most accurate estimate of fetal weight and growth velocity.
Intrauterine Growth Restriction
IUGR can result from a multitude of pathologic and nonpathologic processes (see later discussion). The terms IUGR and SGA are often used interchangeably but actually describe two different phenomena that may occur concurrently, but each may also exist without the other. IUGR describes a decrease in fetal growth velocity independent of absolute weight, whereas SGA describes an infant with a birth weight less than the 10th percentile for gestational age, independent of fetal growth velocity. Approximately 70% of babies who have IUGR will also be SGA. However, most babies who are born SGA were not growth restricted as fetuses and thus will not have the risk of physiologic dysfunction associated with IUGR. If the 3rd percentile were used as the cutoff (approximately 2 standard deviations below the mean), a much higher proportion of babies would actually show dysfunction secondary to growth restriction.
Epidemiology and Etiology of Fetal Growth Restriction
Normal fetal growth is dependent on contributions of the mother, the placenta, and the fetus, and aberrant growth may result from disturbances in any of these contributors.
Race
Almost without exception, studies in the United States have demonstrated a significantly higher rate of IUGR, preterm birth, and LBW in African Americans when compared with their Caucasian contemporaries. European studies have shown that black African mothers have an average gestational length that is about 5 days shorter than that of Caucasian mothers. This is compensated for by accelerated maturity in black Africans. A study conducted in South Carolina over a 20-year period showed that between 1975 and 1979, African American babies born at less than 37 weeks of gestation consistently had a lower perinatal mortality for gestational age than did Caucasian babies. However, this relationship reversed at term, with African American babies born at greater than 37 weeks’ gestation having a higher rate of perinatal mortality as compared with Caucasian babies, and they were more likely to suffer from obstructed labor and meconium aspiration syndrome.
Analysis of data between 1990 and 1994 showed that although gestation-specific perinatal mortality had reduced in both groups, the same pattern of lower mortality before 37 weeks and higher mortality after 37 weeks in black infants persisted. More recently, 22 million infants born between 1989 and 1991 in the United States were studied, and the results were similar.
European studies have shown that babies of South Asian origin have increased perinatal mortality at all gestational ages when compared with Caucasian babies. This is likely because of the fact that South Asian babies have a lower birth weight across the gestational age range when compared with Caucasian infants. Babies born in India are, on average, approximately 600 g lighter than those born in Europe. Studies of South Asian babies born in developed countries show that the deficit persists but on average is reduced to 300 g. It may be conjectured that infants of South Asian descent have a lower average birth weight when compared to gestational age–matched Caucasian infants as an adaptation to smaller average maternal size of South Asian women, thus minimizing perinatal death as a result of obstructed labor. However, South Asian individuals born in Europe have a very high incidence of diabetes and cardiovascular disease. This highlights one of the pitfalls of customized fetal growth nomograms. Although South Asian infants born in Europe may, on average, be larger than babies born in India, correcting for this difference may actually be correcting for a pathologic process with serious long-term sequela.
Prior Obstetric and Family History
Women who are younger than 15 years of age, older than 45 years of age, have a history of miscarriages or unexplained stillbirths after 20 weeks’ gestation, or have prior preterm deliveries are at increased risk for delivering a growth-restricted baby. Familial factors also appear to play a role in the birth weight of babies. Mothers of one LBW infant were frequently LBW infants themselves and are more likely to deliver subsequent LBW babies than other age-matched mothers, and their siblings are more likely to parent LBW infants than other age-matched parents.
Altitude
Infants born at altitude are, on average, smaller than infants born at sea level. When comparing growth curves, most authors note that Lubchenco’s data were generated in Denver, the “mile-high city,” and that the 10th percentile on these nomograms is lower than the 10th percentile of data collected from centers closer to sea level. Yip was able to demonstrate a “dose-dependent” effect of altitude on the LBW rate , with a two- to threefold greater rate of LBW seen at altitudes greater than 2000 meters than at sea level.
Maternal Factors Contributing to Intrauterine Growth Restriction
In developed countries, factors that are known to contribute to IUGR include race, prior obstetric history, maternal nutritional status (prepregnancy weight and weight gain during pregnancy), maternal short stature, smoking, preeclampsia, chronic hypertension, multiple gestation, and female sex of the fetus. In developing nations, malaria is also a significant factor.
Maternal Nutritional Status
Although prepregnancy weight and weight gain during pregnancy are both indicators of maternal nutritional status, they affect fetal growth and birth weight independently of one another. It remains controversial as to whether preconception nutritional intervention in women who are poorly nourished may be beneficial to future pregnancy outcomes. However, it does not confer additional benefit to pregnancy outcomes to provide preconception nutritional supplementation to women who are already well nourished. An obese mother, without other comorbid risk factors such as hypertension, is unlikely to deliver a growth-restricted baby, even if she gains relatively little weight during the pregnancy.
Smoking
Cigarette smoking has consistently been identified as a dose-dependent contributor to abruptio placentae, late intrauterine fetal demise, LBW, and IUGR. Women who smoke during pregnancy are 3 to 4.5 times more likely to have a fetus affected by IUGR, with average birth weights decreasing by 70 g to 400 g, and these effects are particularly pronounced in babies born to mothers of advanced maternal age. Multiple mechanisms may contribute to the detrimental effect of smoking on fetal growth and overall pregnancy outcomes. Nicotine and subsequent catecholamine release, along with reduced synthesis of prostacycline, result in placental vasoconstriction and elevated vascular resistance. This causes decreased delivery of nutrients and oxygen from mother to fetus across the placenta. Fetal carboxyhemoglobin levels also increase, which further interferes with delivery of oxygen to the developing fetal tissues. It has also been suggested that smoking causes indirect effects on fetal growth by causing suboptimal nutritional status both before and during pregnancy. The mechanism for this is thought to be an increased metabolic rate in woman who smoke, rather than decreased maternal caloric intake. In contrast, smoking mothers actually may consume more calories than their nonsmoking counterparts, and supplementing the diet of smoking mothers is ineffective in offsetting the detrimental effects on the fetus. However, if a pregnant woman successfully ceases to smoke before the third trimester, her infant’s birth weight will be indistinguishable from those babies whose mothers did not smoke during pregnancy at all.
A variety of other drug exposures, including alcohol, marijuana, cocaine, and amphetamines, have been associated with adverse fetal effects. With the exception of alcohol, the effects of these agents are not as well established or as pervasive as is tobacco. Certain prescription drugs, particularly antiepileptic drugs, can result in fetal growth restriction and specific malformation syndromes.
Preeclampsia/Hypertension
Maternal chronic hypertension is an independent risk factor for IUGR and subsequent SGA infants. Advanced maternal age further increases the risk of SGA in infants born to mothers with chronic hypertension ( Table 4.1 ). Superimposed preeclampsia on chronic hypertension poses the greatest risk of severe IUGR and subsequent adverse perinatal outcomes to infants of hypertensive mothers. Chronic hypertension and preeclampsia are both vascular problems in nature and are likely to have a common pathophysiologic effect on the placenta. Potential medical therapies aimed at preventing fetal growth restriction by improving placentation and placental blood flow is an area of active research.
TABLE 4.1
Effect of Chronic Hypertension on the Risk of Small for Gestational Age by Maternal Age
| Small for Gestational Age Births (%) | ||
|---|---|---|
| Maternal Age | Normotensive | Chronic Hypertension |
| <26 years | 10 | 6 |
| 26–30 years | 7 | 14 |
| >30 years | 5 | 18 |
Multiple Gestations
The presence of more than one fetus in the uterus often results in SGA offspring. The presence and time of onset of fetal growth restriction is determined by the number of fetuses: the more fetuses, the more likely there is to be growth restriction, and the earlier it is likely to be observed.
Other
Finally, a variety of chronic maternal medical conditions are likely to have a negative effect on fetal growth. Gastrointestinal conditions that jeopardize maternal overall nutrition, or the mother’s ability to absorb certain nutrients, such as inflammatory bowel disease or short gut syndrome, may have a negative effect on fetal growth or availability of certain nutrients to the developing fetus. Diseases that affect the oxygen content of the mother’s blood, such as hemoglobinopathies, severe maternal anemia, or cyanotic heart disease, may all affect availability of oxygen to the fetus, thus having a negative effect on fetal growth. Maternal vasculopathies, such as can be seen with advanced diabetes mellitus, can result in IUGR. The potential role of psychosocial stressors in IUGR is unclear. A summary of the relative contributions of the various factors with direct causal impact is provided in Fig. 4.2 .
Placental Contributions
The placenta is comprised of fetal tissue. It follows that circumstances that ultimately result in abnormal fetal growth often similarly affect placental growth. There is a known significant correlation between infant birth weight and both placental weight and villus surface area. Likewise, there are placental pathologic correlates of known causes of IUGR (intrauterine infections, chromosomal anomalies, hypertensive disorders, multiple gestations) and gross placental and cord abnormalities (chronic abruptio placentae, choriohemangioma, extensive infarction, and abnormal cord insertions), which are likely to result in restricted fetal growth. However, the majority of cases of IUGR are idiopathic, with the epidemiologic risk factors discussed earlier (e.g., previous fetal losses, extremes of maternal age, previous preterm or SGA infant, substance abuse) as the only clue. The cause of growth failure in these infants is presumed to be the result of the ill-defined uteroplacental insufficiency. Human and animal in vivo studies, Doppler ultrasound investigations, and pathologic evaluations have identified an array of placental abnormalities that may well shed a unifying light on these apparently disparate groups of mother–infant dyads ( Box 4.1 ). As a result of these investigations, the central role of the placenta in the development of the growth-restricted baby is coming to the forefront.
BOX 4.1
Findings in the Placenta in Fetal Growth Restriction
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Uteroplacental Blood Flow
-
Diminished blood flow
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Increased vascular resistance
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Absent spiral artery remodeling
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Atherosis of vessels of parietal decidua
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Fetoplacental Blood Flow
-
Increased irregularity of luminal size
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Abnormal umbilical Doppler flow studies
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Decreased number of placental arterial vessels
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Decreased size of placental vessels
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Decreased artery to villus ratio
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Interface of Maternal and Fetal Circulations
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Cytotrophoblastic hyperplasia
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Thickened basement membrane
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Chronic villitis
Diminished Potential: Fetal Contributions
Genetic potential for fetal growth is inherited from both parents. Although this is the major determinant of early fetal growth, fetal growth is subsequently modulated by a multitude of environmental factors. IUGR can result from a variety of conditions (e.g., congenital infections) in which a genetically normal fetus is prohibited from growing appropriately, or as a result of a genetic aberration that precludes the fetus from growing appropriately.
Congenital Infections
During the rubella pandemic of 1962 to 1964, IUGR was found to be the most consistent characteristic of congenitally infected infants, with 60% of affected infants weighing less than the 10th percentile at birth and 90% weighing less than the 50th percentile. Cytomegalovirus (CMV) is the infectious organism most commonly associated with IUGR today, although 90% of infants congenitally infected with CMV are asymptomatic. Symptomatic congenial CMV is most commonly characterized by hepatosplenomegaly and microcephaly with paraventricular calcifications. Diagnosis can be made reliably with viral polymerase chain reaction (PCR) from the urine obtained within 14 days of birth. Salivary CMV PCR may also be used for diagnosis, but must be collected immediately following birth before first breast feeding, and if positive should be confirmed with urine, as false positives have been derived from saliva. Human immunodeficiency virus has also been associated with IUGR, even when adjusted for confounding variables, which can be difficult to separate. Zika virus infection during pregnancy has been associated with an array of adverse clinical outcomes in the developing fetus, including intrauterine demise, IUGR, and central nervous system abnormalities with marked microcephaly. Although numerous other bacterial, protozoal, and viral pathogens are known to invade the developing fetus, most of these infants develop appropriately.
Genetic Factors
About 8% of all SGA infants have a major congenital anomaly. Conversely, the incidence of growth restriction in infants with significant congenital anomalies is 22%, nearly three times that of the general population, and a correlation exists between the number of malformations and frequency of IUGR. A wide array of chromosomal aberrations (aneuploidy, deletions, translocations) are associated with IUGR. The likelihood of finding a chromosomal disorder in an SGA infant with a congenital anomaly is approximately 6%. Uniparental disomy, a chromosomal disorder wherein a pair of homologous chromosomes are inherited from the same parent, has been associated with IUGR. Single-gene disorders and inborn errors of metabolism (such as maternal and fetal phenylketonuria) are likewise represented in this population. In addition, there are well over 100 syndromes without identified chromosomal abnormalities that are associated with IUGR.
Identification and Management of Growth Restriction
A major problem is knowing which babies are at risk of growth restriction and should therefore have their growth monitored. Using classic risk factors and uterine fundal height measurements, at best, two-thirds of babies with growth restriction can be detected antenatally. In routine clinical practice, the proportion is actually often much lower, with typically about 30% detected in antenatal screening. Attempts have been made to detect intrauterine growth restriction in low-risk populations using a single assessment at 32 to 34 weeks’ gestation. However, a single measurement cannot indicate growth trajectory as opposed to size; therefore it could be used to determine that a fetus is SGA but not whether this is the result of IUGR. Conversely, a fetus that is AGA at 32 to 34 weeks’ gestational age has not necessarily followed an appropriate growth trajectory. Indeed, a Cochrane review showed that the harm from false-positive ultrasound diagnoses exceeds the benefit when screening is done in this way. Regular growth velocity profiling for every baby would be prohibitively expensive.
Currently, usual obstetric practice is to monitor the fetuses with risk factors for growth restriction from maternal (e.g., hypertension) and epidemiologic factors (e.g., a previous growth-restricted baby) by ultrasound measurement every 2 weeks. Measurements at more frequent intervals are not reliable indicators of poor growth because the change in fetal size is within the error of the measurement. If growth slows, the next step is to measure umbilical artery blood flow velocity waveforms. A raised pulsatility index (ratio of systolic velocity to diastolic velocity), or even worse, absent or reversed end-diastolic flow, indicates increased resistance to perfusion of the placenta, putting the fetus at risk for hypoxia. If these factors are identified, fetal medicine specialists can move on to assessing fetal vascular redistribution as a response to early hypoxia. This redistribution can be detected by Doppler studies of key fetal organs, including the brain (by study of the middle cerebral artery), to detect the maintenance of the oxygen supply to them, thereby protecting their vital functions. At the same time, flow to less vital organs is reduced. Impaired cardiac function in the fetus can be demonstrated using venous Doppler examination of the precordial veins (ductus venosus, inferior vena cava, or superior vena cava), hepatic veins, and head and neck veins. Combining the umbilical artery, middle cerebral artery, and venous Doppler examinations provides information about the degree of placental insufficiency, the level of blood flow redistribution, and the degree of cardiac compromise, respectively.
There is no currently known effective treatment to improve the growth pattern of a fetus. If it is likely that delivery will be indicated because of IUGR at less than 35 weeks’ gestation, antenatal steroids should be given to improve lung maturity before delivery. Recent data suggests that there may be benefit to the infant if antenatal steroids are administered before delivery at less than 37 weeks’ gestational age, as long as there are no comorbidities affecting the pregnancy that are potential contraindications to antenatal steroids (such as gestational diabetes or chorioamnionitis). Antenatal steroids will help abate RDS, one of the most common and potentially severe morbidities related to prematurity.
Prenatal management of IUGR fetus is aimed at determining the best time and mode of delivery. Gestational age is a critical factor in this decision. Deciding on the appropriate time of delivery is particularly difficult before 30 weeks’ gestation, when the risks of prematurity to the neonate are substantial. Early delivery of growth-restricted fetuses with an abnormal umbilical artery waveform results in a high live born rate but at the cost of rates of high neonatal mortality and morbidity. Alternatively, delaying delivery until the fetal heart rate pattern is abnormal has been reported to result in a nearly fivefold increase in fetal demise. However, neonatal deaths before discharge fall by more than one-third when delayed until there is a nonreassuring fetal heart rate tracing, and overall the total mortality is unchanged. Further, there is some evidence that long-term outcome may be improved by delaying delivery until there is a nonreassuring fetal heart rate tracing.
Small-for-Gestational-age Infants
Lubchenco et al defined SGA as having a birth weight less than the 10th percentile. By definition then, 10% of all newborns in a given population are too small. Others have proposed other cutoff percentiles (e.g., the 25th, 15th, 5th, or 3rd), or 2 standard deviations from the mean, which would correspond to approximately 2.5% of the population. However, as previously noted, being SGA does not necessarily mean an infant was growth restricted. This distinction is made between the growth trajectory throughout fetal development (IUGR) and the absolute weight of a fetus or infant at a given time (percentile weight for gestational age).
Excluding SGA infants who have significant congenital anomalies and infections, there is a group of SGA infants with a relatively characteristic physical appearance: head disproportionately large as compared to the trunk, thin extremities, long nails, large anterior fontanelle, wide or overlapping cranial sutures, thin umbilical cord with little Wharton jelly, scaphoid abdomen, diminished subcutaneous fat, and loose skin on the arms, legs, back, abdomen, and buttocks, which may be dry and flaky with little vernix caseosa. The facial appearance has been likened to that of a “wizened old man.”
Measuring the weight, length, and head circumference allows for further classification of the SGA infant as either symmetrically SGA (those infants with decreased length and head circumference) or asymmetrically SGA (relatively normal length with relative “head sparing”). The distinction between symmetric and asymmetric SGA is often used as both a diagnostic tool and a prognostic indicator. The symmetrically SGA newborn, historically representing approximately 20% of all SGA infants, is thought to result from an injury or process (congenital infection, genetic disorders) that occurred or began in the early stages of the pregnancy, during the phase of growth primarily characterized by cellular hyperplasia. The prognosis for eventual growth and development of these infants is somewhat guarded, in large part because of the underlying etiology. The asymmetrical (“wasted”) SGA baby, on the other hand, has been proposed to result from a third-trimester insult interfering with delivery of oxygen and nutrients (the effect of maternal hypertensive disorders, maternal starvation, advanced diabetes) during the cellular hypertrophy phase of fetal growth. This latter group has a much better prognosis than the symmetric SGA.
Body proportionality is often measured as weight/length, with the three most common being weight for length (weight/length), body mass index (weight/length), and ponderal index (weight/length), and all of these indices have been used to attempt to further differentiate between the subgroups of symmetric and asymmetric SGA. Similarly, a normal frequency distribution of head-to-abdominal circumference ratio is seen in antenatal ultrasound assessments of growth-restricted fetuses, with increased severity of growth restriction being associated with increased asymmetry.
However, the clinical significance of symmetry of SGA has come into question. In some populations, symmetrical SGA infants are found more frequently than asymmetrical infants. Salafia found that IUGR preterm infants born to mothers suffering from preeclampsia were far more likely to be symmetrical than asymmetrical, and David found an equal distribution of a small number of chromosomal abnormalities between the symmetrical and asymmetrical populations. These data suggest that although body proportionality helps characterize an SGA infant, they are certainly not the only factors guiding diagnosis and prognosis.
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