Intrauterine Growth Restriction Versus Small for Gestational Age

Intrauterine growth restriction is not to be confused with small for gestational age (SGA). These two terms are often used interchangeably, but are not synonymous. Fetuses with IUGR fail to reach their in utero growth potential, whereas neonates who are SGA are born less than a prespecified weight percentile (adjusted for gestational age) regardless of the etiology (Figure 16-1). SGA refers to birth weight without consideration to in utero growth. Not all SGA infants are IUGR, and conversely, not all IUGR infants are SGA. The clinician must recognize that a neonate with a birth weight less than the tenth percentile may be SGA, but not IUGR, and a neonate with a birth weight greater than the tenth percentile may be IUGR. In the former case, the “small normal” baby classified as SGA is a reflection of the neonate’s genetics, race, ethnicity, and/or sex. Fifty to 70% of babies born with a birth weight below the tenth percentile on a growth curve are constitutionally small and at low risk for future complications.^2,38 On the other hand, an IUGR infant may have an “AGA” birth weight, but may have suffered from in utero growth deceleration as a consequence of a perinatal insult. Although such patients may escape clinical detection, they represent a high-risk neonatal population that warrants careful attention and follow-up. This decreased fetal growth represents the body’s natural response to a suboptimal in utero environment. While sacrificing the growth of some organs, the IUGR fetus conserves and redirects energy to more vital organs—specifically the brain and heart. This survival mechanism may result in metabolic changes, which set the stage for later neonatal, pediatric, and adult-onset diseases (see Chapter 17). Considering that these two distinct phenotypes, IUGR and SGA, are a culmination of different processes and that IUGR carries short- and long-term consequences, an appreciation and understanding of fetal growth restriction is required.

Asymmetric Versus Symmetric IUGR

The etiology of IUGR can be multifactorial and can be characterized as having maternal, placental, fetal, and environmental origins (see Box 16-1). Babies with IUGR are often characterized as having either asymmetric (type I) or symmetric growth (type 2) (Figure 16-2). Asymmetric growth, representing about 70% to 80% of IUGR cases, is often labeled head sparing and occurs later in gestation.^47,70 Utero-placental insufficiency is one of the most common causes of placental insufficiency and asymmetric IUGR. These fetuses have normal growth until the third trimester of pregnancy, when the fetus’s weight begins to falter. On prenatal ultrasound, the abdominal circumference is decreased and the biparietal diameter, head circumference, and femur length remain within normal ranges. Neonates with asymmetric IUGR will be born with a birth weight less than expected; however, their head and long bones will have followed an appropriate growth trajectory.⁷⁰

On the other hand, all three anthropometric measures, weight, length, and head circumference, are decreased with symmetric IUGR, which makes up about 20% to 30% of IUGR cases (see Figure 16-2).^2,47,70 This growth pattern begins early in pregnancy and is most likely secondary to a decreased number and growth of fetal cells. These fetuses demonstrate a proportional decrease in biparietal diameter, head circumference, abdominal circumference, and femoral length on fetal ultrasound biometry. In comparison, asymmetric IUGR is secondary to a redistribution of fetal blood flow with preferential shunting to the brain. The prognosis for those born with symmetric IUGR is much more guarded when compared with those with asymmetric IUGR with regard to mortality and morbidities such as prematurity, malformations, and aneuploidy.^16,89

Fetal Origins of IUGR

Well-established fetal origins of symmetric IUGR include chromosomal abnormalities, syndromes, and congenital intrauterine infections (see Box 16-1). Classic chromosomal causes include trisomies 13, 18, and 21 and are responsible for 5% to 20% of IUGR cases.^46,64 Fetal infections include rubella, cytomegalovirus, Toxoplasma gondi, and herpes simplex virus and represent about 5% to 10% of IUGR cases.⁶⁵ In addition, multiple gestations, specifically those complicated by twin-to-twin transfusion, inborn errors of metabolism, and dwarf syndromes are other important etiologies that cannot be dismissed. Although maternal diseases tend to result in asymmetric IUGR, advanced and poorly controlled conditions such as severe hypertension and hemoglobinopathies may result in symmetric IUGR.

Maternal and Environmental Origins of IUGR

Maternal and environmental etiologies of IUGR include both chronic and acute diseases that do not necessarily need to be isolated to pregnancy, toxins, pharmacotherapy either illicit or nonillicit, and suboptimal nutrition (see Box 16-1). With advancements in medicine, women who were previously unable to conceive or carry a viable gestation are now able to deliver live newborns. However, many of these maternal diseases represent a challenge to the obstetrician, neonatologist, and pediatrician. Gestational hypertension represents a classic disorder of placental dysfunction (see Chapter 18). Women with diabetes mellitus, specifically when complicated by vasculopathy, are at high risk for delivering IUGR neonates. Considering that female children with cyanotic cardiac disease are now surviving to their reproductive years, their fetuses may encounter prolonged hypoxia, which will adversely affect in utero growth. Other maternal diseases include pulmonary and renal diseases, systemic lupus erythematosus, collagen vascular diseases, antiphospholipid syndrome, severe anemia, and thrombophilia.

Medications and toxins that result in IUGR may either be secondary to deliberate maternal drug therapy or inadvertent drug exposure. Although maternal drug metabolism and the placenta protect the fetus from teratogens, women with liver and renal dysfunction may not adequately clear and/or metabolize specific drugs, thereby increasing the fetus’s exposure and subsequent risk. Classic examples include heavy nicotine use and/or alcohol use, along with medications or therapies to treat maternal epilepsy and cancer.37,52 In these cases, the obstetrician is faced with treating two patients and balancing the risk-benefit ratio for both the mother and fetus.

Nutrition plays a vital role in fetal growth. Either malnutrition or inappropriate nutrition may have far-reaching consequences on the growth of the fetus. Nutrition is not just limited to protein, fat, glucose, and oxygen (macronutrients), but also includes vitamins and minerals (micronutrients). A fetus gestating in the womb of a mother at a higher altitude is less likely to reach his or her growth potential than a fetus at sea level.⁹¹ Moreover, although malnutrition is a common culprit of IUGR, maternal obesity is also associated with IUGR and an increased risk of stillbirth.⁶³ Considering the rising incidence of childhood obesity, the number of overweight and obese pregnant women continues to simultaneously increase and warrants careful attention.

The mother’s country of origin also plays a role in the etiology of IUGR. In well-resourced countries such as the United States, gestational hypertension, tobacco use, poor weight gain, primiparity, and short stature are risk factors for delivering an IUGR neonate. In poorly resourced countries, on the other hand, these factors in addition to malnutrition and malaria are important determinants. Poorly resourced countries are burdened with higher rates of IUGR, with the highest rates occurring in the Indian subcontinent and South Africa.18,39,80,93 These rates may underestimate the number of IUGR infants, considering that the vast majority of neonates are not weighed at birth.⁹³

Multiple Gestations and IUGR

Twin and multiple gestations also deserve careful consideration (see Chapter 22). Multiple gestations continue to increase with the use of artificial reproductive technology.¹⁷ Growth faltering for multiple gestations becomes evident after approximately 28 weeks’ gestation because the uterus and placenta are no longer able to house and adequately nourish the fetuses.⁷⁹ Many believe that growth restriction associated with multiple gestation is a physiologic phenomenon and should not always be considered pathologic. Considering that the average in utero triplet fetal weight exceeds that of a singleton, growth promotion, rather than growth restriction, may be occurring. Twin-to-twin transfusion, wherein the donor is likely to be born IUGR, would be an exception. It remains debatable what fetal and neonatal growth curves should be used to monitor this population.⁶ Regardless, the smaller twin or triplet appears to be at highest risk. In studies of multiple gestations, SGA preterm neonates when compared with their AGA siblings remain smaller and have an increased risk for neurodevelopmental and behavioral issues during the childhood years.⁶⁰ Chorionicity, gestational age, and fetal number appear to be associated with birth weight, with monochorionic twins and increased fetal number resulting in decreased birth weight.⁶⁸

Antenatal Diagnosis

Although early detection of IUGR with antenatal surveillance monitoring, may alter the time of delivery or management, there has been little change in the overall outcome of this high-risk population.³² Studies have failed to provide solid evidence on what type of monitoring should be performed and how often.^32,33 Hypertensive mothers or women carrying twin gestations who were randomized to bed rest did not demonstrate any improvement in fetal growth or overall mortality when compared with those women who were encouraged to continue with their daily activities.^14,15

Ideally, the etiology and severity of fetal growth restriction should direct obstetric and eventually neonatal care. Standard diagnostic tools include a thorough maternal and familial history, maternal physical examination with close attention to nutritional status, fundal height, and fetal palpation, cardiotocography, and ultrasound with Doppler.³⁸ In countries in which ultrasound and Doppler technology and training are not available, the history and physical examination of the mother, family, and fetus may help guide medical care. Accurate gestational dating and fetal weight measurements are essential for tracking fetal growth. Gestational age can be established by the last menstrual period and crown-rump length in the first trimester. Fetal weight can be estimated by multiple formulas using biometric measures (abdominal circumference, head circumference, biparietal diameter, femur length).^34,78 Variations of these formulas are also utilized to estimate gestational age in the second trimester. Various fetal growth curves have been established; however, they are limited by sample size, lack of generalizability to a more heterogeneous or homogenous population, and the inclusion of preterm, IUGR, and IUGR preterm babies (Figure 16-3) (see Appendix B).^31,70 Once maternal risk factors and IUGR are identified, additional testing for aneuploidy or infections can be performed.

In order to accurately demonstrate IUGR on ultrasound, serial examinations are needed. Abdominal circumference has a specificity and negative predictive value close to 90% for diagnosing IUGR.⁴ A decreased abdominal circumference reflects a small liver, and decreased hepatic glycogen stores and subcutaneous fat. Other useful measurements include head circumference, biparietal diameter, and femur length, along with specific ratios of these measurements. For example, an elevated femur length/abdominal circumference and head circumference/abdominal circumference, along with specific combinations of biometric measures, may increase the sensitivity, specificity, and positive and negative predictive value of the test.⁴

The biophysical profile, reflecting fetal acid-base status, is a useful tool to assess risk for IUGR and to monitor those with IUGR (see Chapter 13). In IUGR fetuses, reactivity disappears first, followed by fetal breathing, fetal movement and tone, and last a reduction in amniotic fluid.⁵⁹ Oligohydramnios reflects decreased perfusion of the fetal kidney resulting in decreased urine output and can result in hypoplastic lungs and the need for ventilator support after birth.

The use of Doppler velocities, when available, is helpful as a clinical tool specifically in the case of placental insufficiency (see Chapter 13). Maternal, placental, and fetal circulation can be simultaneously assessed. Uterine arteries reflect maternal circulation, whereas the umbilical and middle cerebral arteries are used to investigate fetal circulation. As gestational age increases, there is a decrease in the resistance of the umbilical artery. However, with placental insufficiency, resistance increases and diastolic flow in the umbilical artery decreases and eventually disappears and even reverses. These findings are noted as absent and reverse end diastolic flow, respectively, and are characterized by the resistance and pulsatile index (Figure 16-4). Progression to absent and reverse diastolic flow occurs when 60% to 70% of the placental villous tree is damaged.⁶¹ Abnormal Doppler velocities, specifically reverse end diastolic flow, have been associated with increased perinatal morbidity and mortality.^32,54,87 At the same time, umbilical venous blood is diverted away from the liver to the heart and the cerebral flow resistance drops, thereby preferentially shunting blood to the brain. With progressive and severe IUGR, decreased middle cerebral flow is considered an ominous sign (see Figure 16-4).

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